USC 12.1 by Radcliffe Cardiology

US Cardiology Review

Volume 12 • Issue 1 • Spring 2018

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Volume 12 • Issue 1 • Spring 2018

Recognition, Diagnosis, and Management of Heart Failure with Preserved Ejection Fraction Meshal Soni, MD and Edo Y Birati, MD

Fulminant Myocarditis: A Review of the Current Literature Emily Seif, MD, Leway Chen, MD, MPH, and Bruce Goldman, MD

Interventional Echocardiography: Field of Advanced Imaging to Support Structural Heart Interventions Roy Arjoon, MD, Ashley Brogan, MD, and Lissa Sugeng, MD, MPH

Catheter Ablation for Ventricular Tachycardia in Patients with Structural Heart Disease Timothy M Markman, MD Daniel A McBride, MD and Jackson J Liang, DO

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Heart valve surgery for removing expandable transcatheter aortic valve implantation

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X-ray showing the correct placement of catheter ablation for atrial fibrillation

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Volume 12 • Issue 1 • Spring 2018

www.USCjournal.com

Editor in Chief Professor Donald E Cutlip, MD Harvard Medical School, Boston, MA

Section Editor (Interventional/Structural)

Section Editor (Imaging)

Section Editor (Heart Failure)

Carey Kimmelstiel, MD

Warren Manning, MD

Leway Chen, MD, MPH

Tufts Medical Center, Boston, MA

Harvard Medical School, Boston, MA

University of Rochester, Rochester, NY

Deputy Editors Kashish Goel, MBBS

Chad A Kliger, MD, MS, FACC, FSCAID

Rajalakshmi Santhanakrishnan, MBBS

Mayo Clinic, Rochester, MN

Lenox Hill Heart and Vascular Institute, New York, NY

Wright State University, Dayton, OH

Ankur Kalra, MD, FACP, FACC, FSCAI Case Western Reserve University School of Medicine, Cleveland, OH

Ronnie Ramadan, MD Harvard Medical School, Boston, MA

Bruce Stambler, MD Piedmont Healthcare, Atlanta, GA

Editorial Board Uma Mahesh R Avula, MD

C Michael Gibson, MS, MD

Columbia University, New York, NY

Beth Israel Deaconess Medical Center, Boston, MA

Ralph G. Brindis, MD

Bill Gogas, MD, PhD

University of California, San Francisco, CA

Emory University School of Medicine, Atlanta, GA

Michael R Gold, MD

Todd Brown, MD, MSPH

University of Alabama, Birmingham, AL

Medical University of South Carolina, Charleston, SC

Leo Buckley, PharmD

Barry H Greenberg, MD

Virginia Commonwealth University, Richmond, VA

Robert Chait, MD, FACC, FACP JFK Medical Center, Atlantis, FL

University of California San Diego School of Medicine, La Jolla, CA

Thomas A Haffey, MD, DO

Western University of Health Sciences, Pomona, CA

Gregory J Dehmer, MD, MACC, FACP, FAHA, MSCAI Texas A&M University College of Medicine, Bryan, TX, USA

Elizabeth Kaufman, MD

Case Western Reserve University, Cleveland, OH

Morton J Kern, MD

University of California at Irvine, Orange, CA

NA Mark Estes III, MD

Tufts University School of Medicine, Boston, MA

Bernard J Gersh, MB, ChB, DPhil Mayo Clinic, Rochester, MN

Richard Kones, MD, FAHA, FESC, FCCP, FRSM, FAGS Cardiometabolic Research Institute, Houston, TX

Roberto M Lang, MD

University of Chicago, Chicago, IL

Jackson J Liang, MD, DO

Hospital of the University of Pennsylvania, Philadelphia, PA

Sylvia Mamby, MD, FACC, FASE Emeritus Staff, Mayo Clinic

Patrick T O’Gara, MD

Brigham and Women's Hospital, Boston, MA

Duane Pinto, MD, MSc

Harvard Medical School, Boston MA

Krishna Pothineni, MD

University of Arkansas for Medical Sciences, Little Rock, AR

Elizabeth Ross, MD, FACC

Emeritus Member, American College of Cardiology

W Douglas Weaver, MD

Wayne State University, Detroit, MA

Managing Editor Rosie Scott • Production Helena Clements • Design Tatiana Losinska Sales & Marketing Executive William Cadden • New Business & Partnership Director Rob Barclay Business Development Manager, USA Mark Watson • Publishing Director Leiah Norcott • Commercial Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O'Neill •••••••••••••••••••••••••

Editorial Contact Rosie Scott rosie.scott@radcliffecardiology.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffecardiology.com •

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Published by Radcliffe Cardiology. All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use there of. Where opinion is expressed, it is that of the authors and does not necessarily coincide with the editorial views of Radcliffe Cardiology. Statistical and financial data in this publication have been compiled on the basis of factual information and do not constitute any investment advertisement or investment advice. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS © 2018 All rights reserved ISSN: 1758-3896 • eISSN: 1758-390X

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Established: March 2016 Frequency: Bi-annual Current issue: Spring 2018

Aims and Scope • US Cardiology Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in cardiac failure practice. • US Cardiology Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • US Cardiology Review provides comprehensive update on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • US Cardiology Review is a bi-annual journal comprising review articles and editorials. • The structure and degree of coverage of the journal is determined by the Editor-in-Chief, with the support of the Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of US Cardiology Review is replicated in full online at www.USCjournal.com

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is returned to the reviewers to ensure the revised version meets their quality expectations. Once approved, the manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • Contributors are identified and invited by the Managing Editor with guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor formalise the working title and scope of the article. • Subsequently, the Managing Editor provides an ‘Instructions to Authors’ document and additional submission details. • The journal is always keen to hear from leading authorities wishing to discuss potential submissions, and will give due consideration to any proposals. Please contact the Managing Editor for further details. The ‘Instructions to Authors’ information is available for download at www.USCjournal.com.

Reprints Editorial Expertise US Cardiology Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors are recognised authorities from their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Peer Review • On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief, and/or a member of the Editorial Board, sends the manuscript to members of the Peer Review Board, who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are either accepted without modification, accepted pending modification, in which case the manuscripts are returned to the author(s) to incorporate required changes, or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

All articles included in US Cardiology Review are available as reprints. Please contact Liam O’Neill at liam.oneill@radcliffecardiology.com

Distribution and Readership US Cardiology Review is distributed bi-annually through controlled circulation to senior professionals in the field.

Copyright and Permission Radcliffe Cardiology is the sole owner of all articles and other materials that appear in US Cardiology Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor, Rosie Scott at rosie.scott@radcliffecardiology.com.

Online All manuscripts published in US Cardiology Review are available free-to-view at www.USCjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Cardiac Failure Review, Interventional Cardiology Review and European Cardiology Review. n

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Contents

Foreword Donald E Cutlip, MD

Heart Failure

Recognition, Diagnosis, and Management of Heart Failure with Preserved Ejection Fraction Meshal Soni, MD, and Edo Y Birati, MD

Fulminant Myocarditis: A Review of the Current Literature

Influence of Race in the Association of Diabetes and Heart Failure

Emily Seif, MD, Leway Chen, MD, MPH, and Bruce Goldman, MD

Hou Tee Lu, MD, FRCP, Rusli Bin Nordin, MBBS, MPH, PhD, and Aizai Azan Bin Abdul Rahim, MD, FESC, FACC

Interventional Cardiology

Interventional Echocardiography: Field of Advanced Imaging to Support Structural Heart Interventions

A Decade Later, Continued Transformation of Transcatheter Aortic Valve Replacement

Transcatheter Heart Valve Thrombosis: Incidence, Predictors, and Clinical Outcomes

Appropriate Use Criteria and the Imaging Mandate

Roy Arjoon, MD, Ashley Brogan, MD, and Lissa Sugeng, MD, MPH

Michael N Young, MD, and Sammy Elmariah, MD, MPH

Ahmad Younes, MD, Guilherme F Attizzani, MD, and Ankur Kalra, MD

Gregory J Dehmer, MD, Leah White, MPH, and John U Doherty, MD

Risk Prevention

Microvascular Coronary Artery Disease: Review Articles

Diabetes Drugs and Cardiovascular Event Reduction: A Paradigm Shift

Abdulah Alrifai, MD, Mohamad Kabach, MD, Jonathan Nieves, MD, Jesus Pino, MD, and Robert Chait, MD, FACC

Erik M Kelly, MD and Donald E Cutlip, MD

Electrophysiology

Catheter Ablation for Ventricular Tachycardia in Patients with Structural Heart Disease

His Bundle Pacing: State of the Art

The Subcutaneous Implantable Cardioverter-Defibrillator: New Insights and Expanding Populations

Timothy M Markman, MD Daniel A McBride, MD, and Jackson J Liang, DO

Matthew F Yuyun, MD, MPhil, PhD, and Ghulam Muqtada Chaudhry, MD, FACC, FHRS

Thomas A Turnage, MD, John A Kpaeyeh Jr, MD, and Michael R Gold, MD, PhD

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Supporting life-long learning for interventional cardiovascular professionals Led by Editor-in-Chief Donald E Cutlip and underpinned by an editorial board of renowned physicians, US Cardiology is a peer-reviewed journal that publishes reviews. Available in print and online, US Cardiology articles are free-to-access, and aim to support continuous learning for physicians within the field.

Call for Submissions US Cardiology Review publishes invited contributions from prominent experts, but also welcomes speculative submissions of a superior quality. For further information on submitting an article, or for free access to the journal, please visit:

www.USCjournal.com

Radcliffe Cardiology US Cardiology Review is part of the Radcliffe Cardiology family. For further information, including access to thousands of educational reviews from across the speciality, visit:

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Radcliffe Cardiology

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Foreword

Donald E Cutlip MD is the Editor in Chief of US Cardiology Review journal, the Director of the Cardiac Catheterization Laboratory at The Cardiovascular Institute, Beth Israel Deaconess Medical Center, and Professor of Medicine at Harvard Medical School, Boston, MA.

he Editorial Board and staff are pleased to present the latest issue of US Cardiology Review. There are 12 very relevant review papers covering four cardiovascular subspecialties.

The issue leads with an update on heart failure with preserved ejection by Drs Birati and Soni, and is followed by a review of fulminant myocarditis by Dr Seif and colleagues. The early recognition and guided therapy in these conditions is critical to improved survival. Next, Dr Lu discusses how the interaction between diabetes and race carries significant implications for the management and prevention of heart failure. In the subsequent section, there are three papers addressing current issues in structural interventional cardiology. The increasing role of interventional echocardiography in guiding transcatheter structural procedures is reviewed by Dr Arjoon and colleagues. Drs Young and Elmariah next provide an interesting historical perspective on the rapid evolution of transcatheter aortic valve replacement, and Dr Younes and colleagues offer a timely, focused update on the issue of leaflet thrombosis following these procedures. This section concludes with an important statement by Dr Dehmer and colleagues on the implications of the appropriate use criteria mandate for ordering certain cardiac imaging procedures that is scheduled for implementation in 2020. Following are two papers in the Risk Prevention section. Dr Alrifai and colleagues provide a thorough discussion of the diagnosis and implications of microvascular dysfunction in adverse cardiovascular outcomes, and Drs Kelly and Cutlip review the recent data for improved cardiovascular outcomes with newer glucose-lowering medications, and discuss the implications of these findings for the treatment of type 2 diabetes. This issue concludes with three papers in the Electrophysiology section. Drs Liang and McBride provide a contemporary review of the role and outcomes of ablation for the treatment of ventricular tachycardia. These procedures are increasing in frequency, and it is helpful to have a current discussion of the evidence. This is followed by two papers on contemporary device therapy alternatives. Drs Yuyun and Chaudhry review His bundle pacing as an alternative to RV or bi-ventricular pacing, and Dr Turnage and colleagues review the role of subcutaneous ICD as an alternative to transvenous lead placement. We think this compilation of papers is applicable to a number of contemporary practice situations. As usual, we thank the authors and our reviewers for their efforts, and we hope the reviews will be useful in the care of your patients. n

DOI: 10.15420/usc.2018.12.1.FO1

ÂŠ RADCLIFFE CARDIOLOGY 2018

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Heart Failure

Recognition, Diagnosis, and Management of Heart Failure with Preserved Ejection Fraction Meshal Soni, MD and Edo Y Birati, MD 1

1,2

1. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 2. Cardiovascular Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Abstract The clinical syndrome of heart failure with preserved ejection fraction (HFpEF) is unique in terms of etiologies, diagnostic criteria, costs, and treatment modalities when compared to heart failure with reduced ejection fraction. There is an emerging paradigm shift that recognizes the clinical syndrome of HFpEF and its various phenotypes. Understanding these HFpEF phenotypes is crucial to understanding the pathophysiology of HFpEF, which in turn can further guide our management strategies. This review outlines the diagnostic criteria, introduces the common clinical phenotypes, and discusses treatments currently utilized in practice for the management of HFpEF.

Keywords Heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, left ventricular hypertrophy, phenotypic characteristics, pulmonary hypertension, obesity, renal dysfunction Disclosure: The authors have no conflicts of interest to declare. Received: 4 September 2017 Accepted: 10 November 2017 Citation: US Cardiology Review 2018;12(1):8–12. DOI: 10.15420/usc.2017:21:1 Correspondence: Edo Y Birati, Heart Failure and Transplant Program, Department of Medicine, Cardiovascular Division, University of Pennsylvania, Perelman Center for Advanced Medicine, South Tower, 11th floor, 3400 Civic Center Boulevard, Philadelphia, PA 19104. E: Edo.birati@uphs.upenn.edu

The history of documented heart failure in medical literature dates back as early as the late 1700s, when William Withering recognized the therapeutic use of foxglove in patients with “dropsy”. The extract from the foxglove plant contained the cardiac glycoside digitalis, and edema – known as “dropsy” – was described in patients we now presume had the clinical syndrome of heart failure.1 Over the centuries, growing medical knowledge along with the expanding body of literature has led to an increasing understanding of heart failure, and notably awareness of the distinct clinical syndromes of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection failure (HFpEF). Data from the National Health and Nutrition Examination Survey estimated an incidence of 5.7 million people >20 years of age had heart failure between 2009 and 2012 in the US alone.2 Currently, the prevalence of HFrEF and HFpEF is fairly even, at about 50 %.3 Data from the Framingham Heart Study noted the 5- and 10-year mortality rates for HFpEF and HFrEF to be similar.4 In comparison to HFrEF, an increased proportion of HFpEF patients die from extra-cardiac etiologies due to the role that multiple chronic comorbidities play in the development of HFpEF.5 A study comparing clinical workload and costs in HFrEF and HFpEF found that the costs are greatest within 3 months to 1 year after heart failure hospitalizations in HFpEF patients due to the frequency of non-cardiac-related hospitalizations.6 Utilizing US Census Bureau data, the American Heart Association predicts that over 8 million people will have heart failure by 2030.7 It also predicts

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that the total cost of heart failure will more than double, from $31 billion in 2012 to an estimated $70 billion by 2030.7 A brief survey of the heart failure literature to date reveals essential differences in epidemiology, pathophysiology, diagnosis, therapeutic modalities, and outcomes for HFpEF when compared to HFrEF. In the current review, we focus on the unique characteristics of HFpEF.

Diagnosis The diagnosis of HFpEF may be challenging. The diagnostic criteria for HFpEF include clinical signs and symptoms of heart failure and preserved left ventricular ejection fraction (LVEF) with echocardiographic evidence of left ventricular (LV) diastolic dysfunction or relevant structural heart disease (left atrial enlargement, LV hypertrophy) (see Table 1).8 The typical signs and symptoms of heart failure entail the presence of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, lowerextremity edema, jugular venous distention, positive hepatojugular reflux, displacement of the point of maximal apical impulse, S3 heart sound, and reduced exercise capacity.8 The LVEF cutoff for diagnosing HFpEF varies between studies, ranging from >40 % to >50 %. According to the current European Society of Cardiology guidelines, the LVEF cutoff required for diagnosis of HFpEF is ≥50 %,8,9 whereas HFrEF is defined as a LVEF of ≤40 %, leading to a phenotypic middle zone of patients with a LVEF of between 41 % and 49 % defined in the current guidelines as heart failure with mid-range ejection fracture.8,10

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Recognition, Diagnosis, and Management Assessment of brain natriuretic peptide (BNP) is part of the diagnostic criteria for HFpEF, although patients may have normal levels of this peptide.5,8,11 Anjan et al. studied BNP levels in HFpEF patients diagnosed clinically and echocardiographically. Using registry data from the Northwestern HFpEF Program, they found that one-third of patients exhibited normal BNP levels, and that obesity was an independent risk factor in this subset of HFpEF patients.5 It is postulated that there is a deficit in BNP generation, release or clearance that might be related to receptor signaling within the visceral adipose tissue, which would account for the normal or lower levels of BNP in obese/overweight HFpEF patients.5

Biochemical Pathophysiology It is increasingly being recognized that inflammation at the systemic level, at the coronary endothelial level and within the myocardial extracellular milieu has a role in the development of HFpEF. Comorbidities such as diabetes mellitus, chronic kidney disease, anemia, and obesity contribute to systemic inflammation through an increase in the production and release of inflammatory cytokines such as interleukin 6 and tumor necrosis factor.12 The European Metabolic Road to Diastolic Heart Failure (MEDIA) HFpEF registry noted the prevalence of metabolic syndrome in their HFpEF population to be as high as 85 %.13 These comorbidities create an oxidative cellular environment, with reactive oxygen species diverting nitric oxide away from its crucial role in cardiomyocyte functioning. This inflammatory activation leads to alterations in paracrine signaling between the coronary endothelial cells and the cardiac myocytes. This then leads to decreased levels of nitric oxide, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG), which are central components of a cascade pathway essential for cardiomyocyte functioning. PKG is a crucial protein due to its role in the phosphorylation of titin within the cardiac myocyte cytoskeleton, which decreases cardiac myocyte stiffening.3,11,14 Down-regulation of PKG leads to cardiac myocyte hypertrophy, which at the ventricular level contributes to LV chamber stiffening, causing impaired lusitropy and diastolic dysfunction which are the hallmarks of HFpEF. Inflammation within the coronary endothelial cells also leads to increased expression and release of adhesion molecules, such as vascular cell adhesion molecule and E-selectin. These adhesion molecules induce monocytes to release transforming growth factor-beta, which leads to collagen deposition within the interstitium, further contributing to the stiffness leading to concentric LV hypertrophy (LVH).3,12,14 This highlights a fundamental difference in mechanism to the scattered foci of fibrosis leading to eccentric LVH seen with HFrEF, which is more so due to cardiac myocyte loss from ischemia with deposition of collagen to compensate for that loss.

Clinical Phenotypes The fact that clinical trials for pharmacologic therapies have failed to improve outcomes in HFpEF patients has led to a new paradigm shift to viewing HFpEF as a heterogeneous syndrome with different phenotypic characteristics with dissimilar outcomes.15 The emergence of this concept may improve our understanding of this syndrome and may result in specific therapies for each phenotype. The main phenotypes are summarized below.

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Table 1: Diagnostic Criteria for Heart Failure with Preserved Ejection Fraction* 7 1. Symptoms of heart failure: - Dyspnea - Orthopnea - Paroxysmal nocturnal dyspnea - Fatigue - Reduced exercise capacity 2. Signs of heart failure on physical examination: - Jugular venous distention - Positive hepatojugular reflux - Lower extremity edema - Displaced point of maximal apical impulse - S3 heart sound 3. Echocardiography – left ventricular ejection fraction ≥50 % and at least one echocardiographic finding: - Diastolic dysfunction - Left atrial enlargement or left ventricular hypertrophy - Left atrial volume Index >34 mL/m2 - Left ventricular mass index greater than or equal to: 115 g/m2 in male patients 95 g/m2 in female patients - E/e’ greater than or equal to 13 4. Elevation of natriuretic peptides - B-type natriuretic peptide >35 pg/ml - N-terminal pro-B type natriuretic peptide >125 pg/ml *According to this suggested criteria, all the above criteria must meet for the diagnosis of heart failure with preserved ejection fraction. Of note, patients at early stages of heart failure or on diuretic therapy may not have signs of heart failure.

Pulmonary HTN A common clinical phenotype is HFpEF with pulmonary hypertension (pHTN). Database comparisons have found a higher prevalence of pHTN among HFpEF patients than HFrEF, with pHTN affecting 70–80 % of the HFpEF population.3,5,16 Molecular changes leading to LVH and stiffness lead to impaired filling of the left ventricle, increasing reliance on left atrial contraction for both LV filling and left atrium (LA) emptying. As this process progresses over time, the elevated LV filling pressures are transmitted back to the LA, and compensatory augmentation in LA activity is no longer sufficient. This leads to backflow into the pulmonary circulation, which over time affects the right ventricular (RV) afterload. This pathologic cascade infers HFpEF leading to pHTN, as per the World Health Organization Group 2 pHTN classification system. However, it is now being better recognized that the reciprocity between pHTN and RV dysfunction lead to further clinical deterioration of HFpEF, causing unfavorable morbidity and mortality outcomes. Elevated LA pressures causing backflow into the pulmonary circulation lead to damage at the alveolar–capillary interface, leading to increased permeability and impairments in gas exchange. Acutely this leads to decompensation in heart failure, but chronically the elevated pressures within the pulmonary capillary networks lead to remodeling. This remodeling extends to the pulmonary arterioles and arteries, and can be irreversible. This accounts for the natural progression of pHTN and, in turn, worsening of HFpEF. Understanding the pathologic molecular and cellular changes that occur with pulmonary microvasculature remodeling can aid the application of treatment to slow the progression of these deleterious changes. Different ways of stratifying the severity of the HFpEF–pHTN phenotype have been proposed, including the concept of “coupling” of the right

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Heart Failure ventricle and pulmonary circulation.17 Guazzi et al. describe the use of the tricuspid annular plane systolic excursion to pulmonary artery systolic pressure ratio as an indicator of RV contractile function. His group studied pulmonary artery systolic pressure measurements for the ratio both via invasive hemodynamic and Doppler echocardiographic monitoring, with noted correlation between both kinds of measurements (r = 0.69, p<0.0001).17 This study highlights the importance of not assessing pHTN–HFpEF in a vacuum and calls for concurrent evaluation of the right ventricle, which is beneficial for categorization of disease severity, prognosis and future therapy-related targets.16,17 Recognition of pHTN as one of the clinical phenotypes of HFpEF is of paramount significance when studying therapies targeting this particular pathophysiologic cascade, with controlled randomized trials determining the efficacy, safety and outcomes of these therapies.

Obesity It is estimated that >80 % of HFpEF patients have a BMI >25 kg/m2.3 In a study comparing obese to non-obese HFpEF patients, type 2 diabetes mellitus and obstructive sleep apnea were found to be more prevalent in obese HFpEF patients. Obese HFpEF patients were found to have increased LV cavity measurements, suggesting remodeling, and increased RV chamber size, despite adjusting for obstructive sleep apnea and higher biatrial resting pressures when compared to both non-obese HFpEF and control individuals.18 The authors also noted that compared to non-obese HFpEF and control patients, HFpEF patients who were obese demonstrated elevated pulmonary capillary wedge pressures and impairments with pulmonary artery compliance during exercise. Based on Fick’s principle, oxygen consumption (VO2) = cardiac output (CO) × arteriovenous oxygen difference (Ca – Cv).13 In this study, no differences in exercise arteriovenous oxygen concentration were noted between the HFpEF and control patients. However, exercise peak VO2 was found to be inversely correlated with weight. Obese HFpEF patients also demonstrated greater degrees of chronotropic incompetence when compared to control patients.18 It is postulated that much of the inflammation at the endothelial cellular and systemic level that leads to HFpEF also causes chronotropic incompetence.3

Renal Dysfunction HFpEF can lead to renal dysfunction via increased right heart pressures secondary to RV dysfunction and pHTN. It can also lead to decreased effective arterial volume, and therefore decreased renal perfusion though decreased cardiac output from both reduced stroke volume and chronotropic incompetence. Reciprocally, renal dysfunction can lead to the pathogenesis of HFpEF by contributing to systemic inflammation through the release of inflammatory growth factors, through the accumulation of uremic products and decreased erythropoietin levels. Increased central venous pressures leading to congestion in the renal venous system highlight the importance of diuresis in HFpEF patients with a renal dysfunction phenotype.3

Treatment Numerous trials have aimed to evaluate various therapeutic strategies in HFpEF patients. The vast majority of these therapies have not proven to be effective, and most current pharmacologic treatments for HFpEF are used to alleviate symptoms. In this section, we review the current evidence. The recommended regimens for this patient population are given in Table 2.

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Mineralocorticoid Receptor Antagonists The renin–angiotensin system (RAS) contains many therapeutic targets for heart failure treatment. Aldosterone, a hormone implicated in the pathogenesis of myocardial and extracellular fibrosis, contributes to LV remodeling in both HFrEF and HFpEF. In the notable landmark Treatment of Preserved Cardiac Function Heart Failure with an Aldesterone Agonist (TOPCAT) trial, while spironolactone did not reduce the primary endpoints of hospitalization for heart failure, aborted cardiac arrest, or death from cardiovascular-related causes within the entire study population, there was a reduction in heart failure-related hospitalizations in HFpEF patients enrolled due to elevated BNP/NT pro-BNP levels in the Americas. The study authors considered whether regional discordances in enrollment, diagnosis, and hospitalization practices in Russia and Georgia compared to the US might have accounted for the observed outcomes rather than actual spironolactone inadequacy. 19 Patients from the Americas were enrolled pretty evenly on the basis of either prior heart failure hospitalizations in the preceding year or elevated BNP levels in the preceding 60 days, while the majority of patients from Russia and Georgia were enrolled on the basis of heart failure hospitalizations. According to the current guidelines, HFpEF patients with heart failure admission within the past year or elevated BNP, and with glomerular filtration rate >30 ml/min and potassium level <5 mEq/l, should be considered for treatment with an aldosterone antagonist (class IIb recommendation).20

Phosphodiesterase Inhibitors The nitric oxide–cyclic guanosine monophosphate (cGMP)–PKG pathway for the prevention of cardiomyocyte hypertrophy can be perturbed in many ways, including decreased bioavailability of nitric oxide or the degradation of cGMP by phosphodiesterase-5A.3,11,14 The use of phosphodiesterase-5 inhibitors, including sildenafil, prevents cGMP destruction, thus increasing the bioavailability of nitric oxide to promote vasodilatation of the pulmonary microvasculature and prevent cardiomyocyte stiffening by facilitating phosphorylation of titin through the effects of PKG.3,11,12 Phosphodiesterase-5 inhibitors selectively target the pulmonary circulation, and have fewer effects on systemic vasodilatation than endothelin receptor antagonists or prostacyclin agonists.16 Although impairments in right ventricular and pulmonary circulation coupling noted in obese HFpEF patients suggested a theoretical benefit with the use of pulmonary vasodilators in obese and pHTN HFpEF phenotypes,17 these drugs did not improve activity or quality of life and are not recommended for routine therapy according to the current practice guidelines (see Table 2).20

Angiotensin-converting Enzyme Inhibitors/Angiotensin-II Receptor Blockers Therapeutic targets within the RAS can reduce LV remodeling and slow the up-regulation of sodium and water reabsorption at the nephron level, which can have symptomatic and long-term diseasemodifying effects in heart failure patients. Additionally, angiotensinconverting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) have been shown to increase nitric oxide availability, thus preventing the pathophysiologic cascade toward myocyte hypertrophy.11 While ACE inhibitors and ARBs have demonstrated improvements in morbidity and mortality outcomes in HFrEF patients, clinical trials have failed to demonstrate significant improvements in outcomes in HFpEF

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Recognition, Diagnosis, and Management Table 2: Treatment Recommendations for Stage C Heart Failure with Preserved Ejection Fraction (HFpEF) based on the American College of Cardiology, American Heart Association, and Heart Failure Society of America Recommendation Treatment of hypertension is recommended in all HFpEF patients

Class of Recommendation I

Consider treatment with beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers for hypertension in HFpEF patients

IIa

Treatment with diuretics is recommended for symptom relief in HFpEF patients with volume overload

In patients with HFpEF and symptomatic atrial fibrillation, consider management of atrial fibrillation according to current guidelines

IIa

In patients with HFpEF and coronary disease that is symptomatic or contributing to the heart failure symptoms, or with evidence of ischemia, consider revascularization

IIa

In HFpEF patients with heart failure admission within the past year or elevated brain natriuretic peptide and creatinine <2.5 mg/dl, glomerular filtration rate >30 ml/min and potassium level <5 mEq/l, consider treatment with an aldosterone antagonist

IIb

Routine use of phosphodiesterase type 5 inhibitors or nitrates is ineffective

III

Routine use of nutritional supplements is not recommended

III

Modified from Yancy et al., 201720 with permission from Elsevier.

patients. This highlights the need to stratify HFpEF patients into clinical phenotypic cohorts in randomized control trials to extract potentially significant outcomes. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) trial randomized elderly HFpEF patients (average age 76 years) to the ACE inhibitor perindopril or to placebo. Both a clinical diagnosis of heart failure and echocardiographic evidence of a LVEF >40 % with noted diastolic dysfunction were the diagnostic criteria for HFpEF in the trial.21 The PEP-CHF study was not able to demonstrate a statistically significant difference in all-cause mortality and hospitalizations related to heart failure between the two groups. However, there was a possible reduction in heart failure-related hospitalizations in the first year within the perindopril-treated arm of the study.21 The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved) trial served to assess candesartan therapy in HFpEF patients with New York Heart Association functional classes II–IV. This study found a modest decrease in the frequency of heart failure-related hospitalizations in the candesartan-treated patients compared to placebo.22 The Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) evaluated the impact of this ARB on mortality and cardiovascular-related hospitalizations in patients >60 years of age, with an LVEF >45 %, and whom were classified as New York Heart Association functional class II–IV. They found that irbesartan therapy did not affect the study endpoints. However, it is worth noting that in the irbesartan-treated arm 39 % of patients were also taking ACE inhibitors, 28 % were taking spironolactone, and 73 % were on beta-blockers. The trial investigators proposed that patients already on multiple drugs targeting the RAS system were unlikely to demonstrate further gain with the addition of an ARB to their regimen.23 Since most HFpEF patients suffer from hypertension, ACE inhibitors or ARBs are recommended in these patients. In addition, current guidelines recommend the use of ARBs in HFpEF patients to reduce hospitalizations (class IIa recommendation) (see Table 2).20

RAS in HFpEF, beta-blockers can curtail RAS activation by reducing the release of renin. Beta-blockers can also be utilized in HFpEF patients with atrial fibrillation or coronary artery disease.24 The Effects of Long-term Administration of Nebivolol on the Clinical Symptoms, Exercise Capacity, and Left ventricular Function of Patients with Diastolic Dysfunction (ELANDD) trial studied the use of nebivolol therapy for 6 months in patients with diastolic dysfunction and a LVEF >45 %. The trial found no statistically significant improvements in peak VO2 and walking distance during 6-min walk testing.25 The trial investigators outlined the negative chronotropic effects of nebivolol as the etiology for the reduced exercise tolerance noted in their study superimposed onto the wellknown concept of chronotropic incompetence seen in HFpEF patients during exercise.18,25 Utilizing the Swedish heart failure registry, Lund et al. studied the effects of beta-blocker therapy in matched cohorts of HFpEF patients, performing a consistency analysis using control HFrEF patients on beta-blocker therapy. They found a reduction in all-cause mortality but not heart failure hospitalizations for HFpEF patients on beta-blocker therapy.26 A metaanalysis performed by Bavishi et al. utilizing 17 studies (15 observational studies and two randomized-controlled trials) found a 19 % decrease in all-cause mortality in HFpEF patients on beta-blocker therapy.27 It should be noted that meta-analyses have limitations, especially with regards to confounding variables and adjustment for covariates within the individual studies included. Current practice guidelines recommend the use of beta-blockers to control hypertension in HFpEF patients as a class IIa recommendation (see Table 2).20

Statins In addition to the lipid-lowering properties of statins, this class of drugs has an independent mechanism that modulates redox reactions at the endothelial level. This mechanism is favorable in HFpEF patients as it helps to improve the availability of nitric oxide as part of the nitric oxide–cGMP–PKG cascade, reducing cardiomyocyte hypertrophy. This benefit has been confirmed by studies measuring levels of PKG and nitric oxide derivatives in endomyocardial biopsy tissue samples from HFpEF patients treated with statins.3,12,28

Beta-blockers Beta blockade has many potential mechanisms of action in the pathophysiologic processes of HFpEF. Due to up-regulation of the

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A study by Fukuta et al. that evaluated HFpEF patients on statin therapy noted a reduced mortality, even after propensity score matching

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Heart Failure their sample population.29 The study investigators attributed the improvement in survival not only to the beneficial effects of statin therapy on coronary artery disease, but also to the antioxidant and antiinflammatory properties of statins in HFpEF. In a meta-analysis of 11 studies, Liu et al. found a 40 % decrease in all-cause mortality with statin use in HFpEF patients.30 They also noted a decrease in mortality rates at both short- (<5 years) and long-term intervals (>5 years) with statin use within the HFpEF population.30

Future Therapeutic Options: Mechanical Circulatory Support Devices For patients with severe refractory HFpEF in whom the above therapies have provided no benefit in terms of mitigating disease progression and symptoms, durable mechanical circulatory support (MCS) devices may reduce LV filling pressures and allow decongestion and increased cardiac output. The greatest logistical challenge when implanting MCS devices in HFpEF compared to HFrEF patients is the reduced LV chamber dimensions. In a theoretical paper, Burkhoff et al. studied the role of a partial MCS device called the Synergy® system, which entailed cannulation of the LA with forward flow directed into the subclavian artery. This micropump system was theoretically found to reduce pulmonary and left atrial pressures while increasing cardiac output in HFpEF patients. Furthermore, implantation of this device consists of a minimally invasive approach, with the device

Silverman ME. William Withering and an account of the foxglove. Clin Cardiol 1989;12:415–8. DOI: 10.1002/clc.4960120714. 2. Mozaffarian D, Benjamin EJ, Go AS, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015;131:e29–e322. DOI: 10.1161/CIR.0000000000000152; PMID: 25520374 3. Shah SJ, Kitzman DW, Borlaug BA, et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap. Circulation 2016;134:73–90. DOI: 10.1161/ CIRCULATIONAHA.116.021884; PMID: 27358439. 4. Lee DS, Gona P, Vasan RS, et al. Relation of disease pathogenesis and risk factors to heart failure with preserved or reduced ejection fraction: insights from the Framingham Heart Study of the National Heart, Lung, and Blood Institute. Circulation 2009;119:3070–7. DOI: 10.1161/CIRCULATIONAHA.108.815944; PMID: 19506115. 5. Anjan VY, Loftus TM, Burke MA, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart failure with preserved ejection fraction. Am J Cardiol 2012;110:870–6. DOI: 10.1016/ j.amjcard.2012.05.014; PMID: 22681864. 6. Murphy TM, Waterhouse DF, James S, et al. A comparison of HFrEF vs HFpEF’s clinical workload and cost in the first year following hospitalization and enrollment in a disease management program. Int J Cardiol 2017;232:330–5. DOI: 10.1016/j.ijcard.2016.12.057; PMID: 28087180. 7. Heidenreich PA, Albert NM, Allen LA, et al. on behalf of the American Heart Association Advocacy Coordinating Committee, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Radiology and Intervention, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Stroke Council. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail 2013;6:606–19. DOI: 10.1161/ HHF.0b013e318291329a; PMID: 23616602. 8. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37: 2129– 200. DOI: 10.1093/eurheartj/ehw128; PMID: 27206819. 9. Lekavich CL, Barksdale DJ, Neelon V, Wu JR. Heart failure preserved ejection fraction (HFpEF): an integrated and strategic review. Heart Fail Rev 2015;20:643–53. DOI: 10.1007/s10741-0159506-7; PMID: 26404098. 10. Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nature Rev Cardiol 2017;14:591–

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placed within the subcutaneous tissue, similar to pacemaker placement.31 Further studies are needed to evaluate whether this invasive therapy will improve survival. Another potential therapeutic option is the placement of a transcatheter interatrial shunt device in HFpEF patients with refractory symptoms on medical therapy. In the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP–HF) study, HFpEF patients demonstrated reduced pulmonary capillary wedge pressures during exercise at 6 months following implantation of the interatrial shunt device. These patients also demonstrated beneficial progress in their 6-min walk times and quality of life metrics.32

Conclusion With the HFpEF population projected to exceed that of the HFrEF population, the study of the clinically variegated syndrome of HFpEF remains crucial. While the therapeutic modalities discussed in this review pose a theoretical and practical benefit in the management of HFpEF patients, it is essential that future randomizedcontrolled clinical trials utilize the many different clinical phenotypes of HFpEF in their study design. Better understanding of the role of chronic comorbidities in the pathogenesis and clinical phenotypes of HFpEF will allow for treatment at patient and population-wide levels. n

602. DOI: 10.1038/nrcardio.2017.65; PMID: 28492288. 11. N anayakkara S, Kaye DM. Targets for heart failure with preserved ejection fraction. Clin Pharmacol Ther 2017;102:228–37. DOI: 10.1002/cpt.723. 12. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263–71. DOI: 10.1016/j.jacc.2013.02.092; PMID: 23684677. 13. Dobre, D, et al. Comparison of the echocardiographic definition of left ventricular diastolic dysfunction using the 2007 ESC and the 2009 EAE/ASE recommendations in metabolic syndrome patients. Eur Heart J 35:1037. 14. Franssen C, Chen S, Unger A, et al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail 2016;4:312–24. DOI: 10.1016/j.jchf.2015.10.007; PMID: 26682792. 15. Shah SJ, Katz DH, Selvaraj S, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation 2015;131:269–79. DOI: 10.1161/ CIRCULATIONAHA.114.010637; PMID: 25398313. 16. Guazzi M, Gomberg-Maitland M, Arena R. Pulmonary hypertension in heart failure with preserved ejection fraction. J Heart Lung Transplant 2015;34:273–81. DOI: 10.1016/ j.healun.2014.11.003; PMID: 25577563. 17. Guazzi M, Dixon D, Labate V, et al. RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes. JACC Cardiovasc Imag 2017;10:1211–21. DOI: 10.1016/j.jcmg.2016.12.024; PMID: 28412423. 18. Obukata M, Reddy YNV, Pislaru SV, et al. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 2017;136:6–19. DOI: 10.1161/CIRCULATIONAHA.116.026807; PMID: 28381470. 19. Pfeiffer MP, Pitt B, McKinlay SM. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–92. DOI: 10.1056/NEJMoa1313731; PMID: 25006726. 20. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137–e161. DOI: 10.1161/ CIR.0000000000000509; PMID: 28455343. 21. Cleland JGF, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338–45. DOI: 10.1093/eurheartj/ehl249; PMID: 16963472. 22. Yusuf S, Pfeffer MP, Swedberg K, et al. CHARM Investigators and Committees. Effects of candesartan in patients

23.

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31.

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with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM- Preserved Trial. Lancet 2003;362:777–81. DOI: 10.1016/S0140-6736(03)14285-7; PMID: 13678871. Massie BM, Carson PE, McMurray JJ, et al. I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359;2456–67. DOI: 10.1056/NEJMoa0805450; PMID: 19001508. Polsinelli V, Shah SJ. Advances in the pharmacotherapy of chronic heart failure with preserved ejection fraction: an ideal opportunity for precision medicine. Expert Opin Pharmacol 2017;18:399–409. DOI: 10.1080/14656566.2017.1288717; PMID: 28129699. Conraads VM, Metra M, Kamp O, et al. Effects of the longterm administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: Results of the ELANDD study. Eur J Heart Fail 2011;14:219–25. DOI: 10.1093/eurjhf/hfr161; PMID: 22147202. Lund LH, Benson L, Dahlström U, et al. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 2014;312:2008–18. DOI: 10.1001/jama.2014.15241; PMID: 25399276 Bavishi C, Chatterjee S, Ather S, et al. Beta-blockers in heart failure with preserved ejection fraction: a meta-analysis. Heart Fail Rev 2015;20:193–201. DOI: 10.1007/s10741-014-9453-8; PMID: 25034701. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004;109:III39–43. DOI: 10.1161/01. CIR.0000131517.20177.5a; PMID: 15198965. Fukuta H, Sane DC, Brucks S, Little WC. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation 2005;112:357–63. DOI: 10.1161/CIRCULATIONAHA.104. 519876; PMID: 16009792. Liu G, Zheng XX, Xu YL, et al. Meta-analysis of the effect of statins on mortality in patients with preserved ejection fraction. Am J Cardiol 2014;113:1198–204. DOI: 10.1016/ j.amjcard.2013.12.023; PMID: 24513478. Burkhoff D, Maurer MS, Joseph SM, et al. Left atrial decompression pump for severe heart failure with preserved ejection fraction theoretical and clinical considerations. JACC Heart Fail 2015;3:275–82. DOI: 10.1016/j.jchf.2014.10.011; PMID: 25770409. Hasenfuß G, Hayward C, Burkhoff D, et al. REDUCE LAP-HF Study Investigators. A Transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAPHF): a multicentre, open-label, single-arm, phase 1 trial. Lancet 2016;387:1298–304. DOI: 10.1016/S0140-6736(16)00704-2; PMID: 27025436.

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Heart Failure

Fulminant Myocarditis: A Review of the Current Literature Emily Seif, MD, Leway Chen, MD, MPH, and Bruce Goldman, MD University of Rochester Medical Center, Rochester, NY

Abstract Myocarditis is an inflammatory disease of the myocardium with a wide spectrum of symptoms and severity. Fulminant myocarditis is a small cohort of this disease that tends to present with sudden onset acute heart failure, cardiogenic shock, or life-threatening arrhythmias. The most common type, and the one with the best likelihood for recovery, is lymphocytic myocarditis. More rare, and often more fatal, forms are eosinophilic myocarditis and giant cell myocarditis. Delayed recognition and lack of standardized therapy guidelines continue to challenge clinicians treating these critically ill patients. This article will review the most up-to-date literature regarding recognition and recommended treatment for fulminant myocarditis as it pertains to clinical practice.

Keywords Fulminant myocarditis, lymphocytic, giant cell, eosinophilic Disclosure: The authors have no conflict of interest to declare. Received: 19 November 2017 Accepted: 23 January 2018 Citation: US Cardiology Review 2018;12(1):13–6. DOI: 10.14520/usc.2017:31:1 Correspondence: Emily Seif, University of Rochester Medical Center, 601 Elmwood Ave, Box 679A, Rochester, NY 14642, USA. E: Emily_Seif@URMC.Rochester.edu

Myocarditis is an inflammatory disease of the myocardium. It has a wide spectrum of severity, with symptoms ranging from mild fevers, shortness of breath, and palpitations to severe hemodynamic collapse. Fulminant myocarditis is a rare form of severe myocarditis that presents with sudden-onset acute heart failure, cardiogenic shock, or life-threatening arrhythmias.1 Prognosis and management of this type of myocarditis varies based on endomyocardial biopsy histopathology, and is classified according to diagnostic criteria initially developed in 1986.2 The microscopic appearance of the myocardial inflammation forms the basis for this classification system.3 The most common microscopic type, and the one with the greatest likelihood of recovery, is lymphocytic myocarditis. More rare, and often more fatal, forms are giant cell myocarditis and eosinophilic myocarditis. In this article, case examples of these three forms of adult fulminant myocarditis will be presented, as well as a review of the current literature on their causes and therapy recommendations.

Lymphocyte Myocarditis A 61-year-old woman with a history of Crohn’s disease presented with several days of palpitations and shortness of breath. ECG was noted for sinus tachycardia, low voltage, and frequent non-sustained ventricular tachycardia. Troponin T was elevated to 0.09 ng/ml. An echocardiogram showed severe biventricular failure and a left ventricular ejection fraction (LVEF) of 23 %. Angiography was noted for a 70 % mid-left anterior descending artery lesion. Right heart catheterization revealed cardiogenic shock and elevated filling pressures out of proportion for ischemic heart disease. The patient was initiated on inotropes for supportive care but continued to clinically deteriorate, with subsequent cardiac arrest from ventricular

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tachycardia. An endomyocardial biopsy was then obtained, which revealed fulminant lymphocytic myocarditis, and she was placed on extracorporeal membrane oxygenation (ECMO) support in the veno-arterial configuration. Further investigation did not identify any precipitant. She was treated with a slow steroid taper and several doses of intravenous gamma-globulin (IVIG) and plasmapheresis. Mechanical support was discontinued on day 30 after she experienced partial recovery. Unfortunately, she eventually expired from complications of her disease. Lymphocytic myocarditis is the most common form of fulminant myocarditis. It is often triggered by a viral infection, either as a primary or secondary immune response.4 Of the viruses, coxsackie B virus and the cytomegaloviruses are the most frequently reported.5 Other infectious causes include bacterial, fungal, and parasitic infections. Medications, toxins, and autoimmune diseases (Takayasu’s disease and granulomatosis with polyangiitis) have also been described. Endomyocardial biopsy can be considered if there is a failure to respond to supportive care or if there is concern over an alternative diagnosis.6 Characteristic histopathology reveals an exclusively or predominately lymphocytic infiltrate with inconspicuous numbers of plasma cells, macrophages, and/or neutrophils (Figure 1).1 As in the case above, the most widely employed therapy for lymphocytic myocarditis is glucocorticoid therapy. However, while a systematic Cochrane review found that steroid therapy may improve LVEF, the use of glucocorticoids in lymphocytic myocarditis has not been shown to reduce mortality.7 Similarly, the use of antiviral therapy, plasmapheresis or IVIG is not routinely recommended due to insufficient human data in the adult population.8,9 This recommendation differs from the pediatric

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Heart Failure Figure 1: Lymphocytic Myocarditis

There is a diffuse inflammatory infiltrate composed almost entirely of lymphocytes and associated with multiple foci of lymphocyte-mediated myocyte injury or necrosis, evident as intracytoplasmic inflammation and/or myocyte dropout (arrows). Hematoxylin and eosin; 20Ă— original magnification.

Figure 2: Endomyocardial Biopsy Showing Giant Cell Myocarditis

There are large areas of necrosis with an inflammatory infiltrate that includes multinucleated giant cells (arrows), as well as eosinophils and macrophages (circles). Hematoxylin and eosin; 20Ă— original magnification.

Figure 3: ECG of Eosinophilic Myocarditis

population, in which there is some evidence for the use of IVIG in the treatment of lymphocytic myocarditis.10 This difference may reflect the wider variety of inflammatory etiologies seen in the pediatric population. Small adult studies do suggest some clinical benefit from combination immunosuppression therapy, such as azathioprine in combination with steroids. Unfortunately, these studies were underpowered and predominately from the era before mycophenolate mofetil, which has

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generally supplanted the use of azathioprine since its introduction in 1995. The true effectiveness of any of these treatments, though, is difficult to ascertain because of the high rate of spontaneous recovery with supportive care in these patients.11

Giant Cell Myocarditis A 70-year-old man without prior cardiac history presented with 3 days of progressive dyspnea, orthopnea, and fatigue. ECG showed a

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Fulminant Myocarditis new trifascicular block and a Troponin I elevation of 23.78 ng/ml. An echocardiogram revealed a new global cardiomyopathy with an LVEF of 35–40 %. Shortly after admission, he experienced complete heart block, ventricular tachycardia, and sinus arrest. Urgent angiography showed non-obstructive coronary artery disease and right heart catheterization was consistent with biventricular heart failure and cardiogenic shock. Endomyocardial biopsy demonstrated giant cell myocarditis. The patient was initiated on immunosuppressive therapy with steroids and thymoglobulin, and maintained on cyclosporine and mycophenolate. Once stabilized, he underwent implantable cardiac defibrillator (ICD) for secondary prevention. As an outpatient, he continued on standard heart failure medications, steroid taper, cyclosporine, and mycophenolate therapy. Giant cell myocarditis is a rare, often fatal disease that tends to affect middle-aged adults. It is classically characterized by fulminant heart failure, ventricular arrhythmias and atrioventricular block. The myocardial disease is mediated by T lymphocyte inflammation and it has an association with systemic autoimmune diseases such as thymomas and inflammatory bowel disease. Endomyocardial biopsy is recommended if there is clinical suspicion for giant cell myocarditis.12,13 The characteristic histopathology reveals a mixed inflammatory infiltrate containing lymphocytes, plasma cells, macrophages, and eosinophils, along with numerous multinucleated giant cells without granulomas. This is typically associated with widespread myocyte necrosis, often of the coagulative type (Figure 2).1,13 Treatment of giant cell myocarditis is aimed at attenuating T-cell function. Combination therapies with prednisone, thymoglobulin, cyclosporine, and azathioprine have been used. Alternatives such as mycophenolate mofetil, methotrexate, or the T-cell antibody muromonab-CD3 have also been utilized.1 Discontinuation of prednisone therapy at 6–12 months can be considered if the patient has been medically stable.14 Unfortunately, giant cell myocarditis continues to have a high mortality rate, either from fulminant heart failure or ventricular arrhythmias. In the patients enrolled in the Multicenter Giant Cell Myocarditis Study who were treated with immunosuppressive therapy, the average survival time was 12.3 months.15 Of those who underwent cardiac transplantation, 26 % experienced recurrent giant cell infiltrate of their transplanted heart. Based on the 2017 American Heart Association/American College of Cardiology/ Heart Rhythm Society criteria for appropriate use, in patients with giant cell myocarditis and malignant ventricular arrhythmias, an ICD may be considered (class IIb recommendation) if life expectancy is greater than 1 year.16

Eosinophilic Myocarditis A 30-year-old healthy woman presented with several days of chest pain and fevers. An admission ECG was notable for pronounced anterior ST elevations (Figure 3). Troponin I was elevated to 10.77 ng/ml and her echocardiogram revealed a globally reduced LVEF of 25 %. She experienced sustained ventricular tachycardia with hemodynamic instability. Angiography revealed normal coronary arteries, and a right heart catheterization was consistent with biventricular failure and cardiogenic shock. She underwent emergent placement of ECMO in the veno-arterial configuration. Peripheral

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Figure 4: Necrotizing Eosinophilic Myocarditis

There is a mixed inflammatory infiltrate including numerous eosinophils (arrows) as well as foci of coagulative necrosis (oval). Hematoxylin and eosin; 20× original magnification.

eosinophil count was 0 but endomyocardial biopsy demonstrated diffuse eosinophilic invasion of the myocardium, and a diagnosis of acute eosinophilic myocarditis was made. Further investigation did not identify any precipitant of her myocarditis. She was treated with a slow steroid taper. Mechanical support was able to be discontinued after 6 days, when an echocardiogram showed recovered biventricular function. As an outpatient, she continued on standard heart failure medications and steroid taper without recurrence of her heart failure. Fulminant eosinophilic myocarditis is a very rare myocarditis mostly reported in adolescents and young adults. It can present as cardiogenic shock, conduction disease, or acute myocardial infarction.17 It can be associated with drug reactions, parasitic infections, hematologic cancers, hypereosinophilic syndrome, or eosinophilic granulomatosis with polyangiitis. Still other cases remain idiopathic or undefined.18 The presence of peripheral eosinophilia should heighten the suspicion for eosinophilic myocarditis, but in one review only 75 % of biopsy-confirmed eosinophilic myocarditis demonstrated any peripheral eosinophilia.18,19 Endomyocardial biopsy can be considered if the clinical diagnosis is in question. The characteristic histopathology of eosinophilic myocarditis is of a mixed inflammatory cell infiltrate containing prominent numbers of eosinophils without giant cells (Figure 4).20 Treatment is focused on timely identification of the disease, treatment of underlying etiologies or withdrawal of any causative agents, and supportive care.19 However, as in the case presented, the etiology is not always apparent.20 Given the underlying inflammatory nature of the disease, treatment with high-dose corticosteroids has had documented success, although no randomized controlled trials have been conducted.21,22 Additional immunosuppressive therapy has been used but remains controversial. While recognition of eosinophilic myocarditis is improving, data regarding its recurrence, risk of future ventricular arrhythmias, and development of post-inflammatory dilated cardiomyopathy are still lacking.18 Therefore, prophylactic ICD placement is not recommended at this time.16

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Heart Failure Table 1: Comparison of Fulminant Myocarditis Types Myocarditis Type

Lymphocytic

Giant Cell

Eosinophilic

Prevalence

Common

Rare

Very rare

Biopsy

Only if failure to improve or development of conduction disease/arrhythmias

Yes

May be appropriate* if etiology is not apparent

Histopathology

Primarily lymphocytic infiltrate

Mixed infiltrate with giant cells

Mixed infiltrate with prominent numbers of eosinophils

Treatment

Supportive care

Immunosuppression

Withdrawal/treatment of causative agent; immunosuppression may be appropriate

Implantable Cardiac Defibrillator Recommended

May be appropriate

Prognosis

Good

Poor

*May be appropriate if there is a lack of a clear trigger and/or lack of peripheral eosinophilia and the diagnosis is in question.

Summary The differences between the three types of fulminant myocarditis are summarized in Table 1. Survival in fulminant myocarditis depends on timely identification and implementation of advanced circulatory support. Biventricular dysfunction remains the main predictor of death or need for transplantation.21,22 Endomyocardial biopsy is recommended for all patients (class I recommendation) presenting with fulminant heart failure of less than 2 weeks’ duration with hemodynamic compromise, new-onset heart failure

aisch B, Ruppert V, Pankuweit S. Management of fulminant M myocarditis: a diagnosis in search of its etiology but with therapeutic options. Curr Heart Fail Rep 2014;11:166–77. DOI: 10.1007/s11897-014-0196-6; PMID: 24723087 Aretz HT, Billingham ME, Edwards WD, et al. Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol 1987;1:3–14. PMID: 3455232 Biesbroek PS, Beek AM, Germans T, et al. Diagnosis of myocarditis: Current state and future perspectives. Int J Cardiol 2015;191:211–9. DOI: 10.1016/j.ijcard.2015.05.008; PMID: 25974197 Hare JM, Baughman KL. Fulminant and acute lymphocytic myocarditis: the prognostic value of clinicopathological classification. Eur Heart J 2001;22:269–70. DOI: 10.1053/ euhj.2000.2272; PMID: 11161940 Friman G, Wesslén L, Fohlman J, et al. The epidemiology of infectious myocarditis, lymphocytic myocarditis and dilated cardiomyopathy. Eur Heart J 1995;16(Suppl O):36–41. DOI: 10.1093/eurheartj/16.suppl_O.36; PMID: 8682098 Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–52. DOI: 10.1161/ CIR.0b013e31829e8807; PMID: 23741057 Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis. Cochrane Database Syst Rev 2013;10:CD004471. 10.1002/14651858.CD004471.pub3; PMID: 24136037 Robinson JL, Hartling L, Crumley E, et al. A systematic review of intravenous gamma globulin for therapy of acute myocarditis. BMC Cardiovasc Disord 2005;5:12. DOI: 10.1186/1471-2261-5-12; PMID: 15932639 PMCid:PMC1173096 Schultz JC, Hilliard AA, Cooper LT Jr, Rihal CS. Diagnosis and treatment of viral myocarditis. Mayo Clin Proc

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11.

12.

13.

14.

15.

16.

of 2 weeks’ to 3 months’ duration with dilated cardiomyopathy, new ventricular arrhythmias, second- or third-degree heart block, or failure to respond to usual support care within 1–2 weeks.6,23. Endomyocardial biopsy can be considered for those with eosinophilia and recent-onset heart failure with potential allergic reaction (class IIa recommendation). Immunosuppression has a potential therapeutic role but requires further investigation before a standardized approach can be recommended. Clinicians should be suspicious for fulminant myocarditis in any patient presenting with new-onset malignant arrhythmias, conduction disease, or sudden cardiovascular collapse. n

2009;84:1001–9. DOI: 10.1016/S0025-6196(11)60670-8; PMID: 19880690 Robinson J, Hartling L, Vandermeer B, Klassen TP. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev 2015;5:CD004370. DOI: 10.1002/14651858.CD004370.pub3; PMID: 25992494 Jones SR, Herskowitz A, Hutchins GM, Baughman KL. Effects of immunosuppressive therapy in biopsy-proved myocarditis and borderline myocarditis on left ventricular function. Am J Cardiol 1991;68:370–6. DOI: 10.1016/0002-9149(91)90834-8; PMID: 1858678 Khan T, Selvakumar D2, Trivedi S, et al. The value of endomyocardial biopsy in diagnosis and guiding therapy. Pathology 2017;49:750–6. DOI: 10.1016/j.pathol.2017.08.004; PMID: 29021100 Kalra A, Kneeland R, Samara MA, Cooper LT Jr. The changing role for endomyocardial biopsy in the diagnosis of giant-cell myocarditis. Cardiol Ther 2014;3:53–9. DOI: 10.1007/s40119-0140028-5; PMID: 25135591 Kandolin R, Lehtonen J, Salmenkivi K, et al. Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail 2013;6:15–22. DOI: 10.1161/ CIRCHEARTFAILURE.112.969261; PMID: 23149495 Cooper LT Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis – natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators. N Engl J Med 1997;336:1860–6. DOI: 10.1056/NEJM199706263362603; PMID: 9197214 Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2017;

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DOI: 10.1016/j.jacc.2017.10.054; PMID: 2909729; epub ahead of press. Enriquez A, Castro P, Gabrielli L, et al. Acute necrotizing eosinophilic myocarditis presenting as ST-elevation myocardial infarction: a case report. Can J Cardiol 2011;27:870.e1–3. DOI: 10.1016/j.cjca.2011.07.618; PMID: 22001778 Brambatti M, Matassini MV, Adler ED, et al. Eosinophilic myocarditis: characteristics, treatment, and outcomes. J Am Coll Cardiol 2017;70:2363–75. DOI: 10.1016/j.jacc.2017.09.023; PMID: 29096807 Rizkallah J, Desautels A, Malik A, et al. Eosinophilic myocarditis: two case reports and review of the literature. BMC Res Notes 2013;6:538. DOI: 10.1186/1756-0500-6-538; PMID: 24344829 Al Ali AM, Straatman LP, Allard MF, Ignaszewski AP. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 2006;22:1233–7. DOI: 10.1016/S0828-282X(06)70965-5; PMID: 17151774 Caforio AL, Calabrese F, Angelini A, et al. A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis. Eur Heart J 2007;28:1326– 33. DOI: 10.1093/eurheartj/ehm076; PMID: 17493945 Ammirati E, Cipriani M, Lilliu M, et al. Survival and left ventricular function changes in fulminant versus nonfulminant acute myocarditis. Circulation 2017;136:529–45. DOI: 10.1161/ CIRCULATIONAHA.117.026386; PMID: 28576783 Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914–31. DOI: 10.1016/j.jacc.2007.09.008; PMID: 17980265

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Heart Failure

Influence of Race in the Association of Diabetes and Heart Failure Hou Tee Lu, MD, FRCP, 1,2 Rusli Bin Nordin, MBBS, MPH, PhD 2, and Aizai Azan Bin Abdul Rahim, MD, FESC, FACC 3 1. Division of Cardiology, Sultanah Aminah Hospital, Johor, Malaysia; 2. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Johor, Malaysia; 3. National Heart Institute, Kuala Lumpur, Malaysia

Abstract Heart failure is a global public health problem with high mortality and readmission rates. Race and ethnicity are useful concepts when attempting to understand differential health risks and health disparities. With cardiovascular diseases accounting for most deaths globally, eliminating racial disparities in cardiac care has become a new challenge in cardiology. Significant racial differences exist in patients with heart failure. African American patients in the US have a significantly higher incidence of heart failure, lower ejection fraction and are younger at presentation compared to White, Hispanic and Chinese American patients. These findings are explained by a higher burden of risk factors such as diabetes mellitus, hypertension, obesity and lower household incomes among African Americans. The authors believe that these findings are applicable to other racial groups across the globe. The prevalence of predisposing risk factors probably has a stronger influence on the incidence of heart failure than the racial factor alone. The interaction between race and diabetes mellitus has important public health implications for the management and prevention of heart failure.

Keywords Race, ethnicity, diabetes mellitus, heart failure Disclosure: The authors have no conflicts of interest to declare. Received: 9 September 2017 Accepted: 30 November 2017 Citation: US Cardiology Review 2018;12(1):17–21. DOI: 10.15420/usc.2017:24:2 Correspondence: Hou Tee Lu, Sultanah Aminah Hospital, Jalan Masjid Abu Bakar, 80100 Johor Bahru, Johor, Malaysia; E: luhoutee@gmail.com

Heart failure (HF) is a global public health problem, affecting an estimated 26 million people worldwide and resulting in more than 1 million hospitalizations annually in the US and Europe.1 This HF pandemic is also evident in Asia and other parts of the world.2–4 Although the outcomes for HF patients have improved with the discovery of multiple evidencebased drug and device therapies, hospitalized HF patients continue to experience unacceptably high mortality and readmission rates that have not changed in the past two decades. In parallel with increasing life expectancies worldwide, the proportion of patients with HF is increasing, and an increased percentage of patients are being hospitalized for HF.

Race and Ethnicity in Heart Failure Race and ethnicity are interrelated concepts that have a long history in the fields of human biology and public health.5 The terms “race” and “ethnicity” are often used interchangeably, and there are no widelyaccepted definitions. Race is typically used to refer to groups that share biological similarities; whereas ethnicity refers to shared identity-based ancestry, language and cultural similarities. In many cases, racial and ethnic groups may overlap considerably. Race and ethnicity are useful concepts when attempting to understand differential health risks and health disparities.6 With cardiovascular disease (CVD) accounting for most deaths globally, eliminating racial disparities in cardiac care has become a new challenge in cardiology.7 Furthermore, understanding racial influence in cardiovascular care is important in designing effective measures to eliminate disparities. Traditional risk factors, such as hypertension and ischemic heart disease (IHD), are common in HF patients but vary

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substantially among the world’s regions.8 It is important to consider these racial differences in the evaluation and management of patients with HF.9 In the US, there are striking differences in the risk factors, incidence, response to treatment and outcomes of HF within each ethnic group. Conventional risk factors, such as hypertension, diabetes mellitus (DM) and IHD, will still predict those at high risk. It is often thought that White Americans tend to develop congestive HF from IHD. For African Americans, hypertension and DM tend to be the primary cause.10 HF affects different racial groups differently, and there are discrepancies in its outcomes as well. Interestingly, the differences in risk factor profiles do not explain the differences in mortality between racial groups. Furthermore, significant racial differences are found in neurohormonal stimulation and pharmacological response in HF. Although most HF treatments are similar, research has demonstrated racial differences in response to therapy. For example, one study suggests that angiotensinconverting enzyme inhibitors are particularly effective in Whites and that hydralazine plus isosorbide dinitrate can be equally effective in Blacks.11

Search Strategy We conducted a systematic search of published literature in the following online databases: PubMed, Google Scholar, Ovid MEDLINE, Scopus, and Web of Science. Search terms included “race”, “ethnic”, “heart failure”, and “diabetes mellitus.” A large number of trials that have investigated racial differences in HF have been based on studies in the US on African Americans, Hispanic, Chinese American and White participants. The Multiethnic Study of Atherosclerosis (MESA), which started in 2001, was

Access at: www.USCjournal.com

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Heart Failure Table 1: Influence of Race/Ethnicity in the Association of Diabetes and Heart Failure (HF) in the US Paper

Title

Study design

Races

Results and Conclusion

Eaton, et al., 201226 Racial and ethnic differences Prospective Blacks, Whites, Asians, Pacific Islanders, in incident hospitalized HF in and Hispanic women postmenopausal women

Black women have higher rates of HF compared with White, Asian/Pacific Islander and Hispanic women. The higher risk of incident HF in Black women is explained largely by adjustment for lower household incomes and diabetes.

Aronow, et al., 199928

Comparison of incidences of Prospective African Americans, Hispanics, and congestive heart failure in Whites older African-Americans, Hispanics, and Whites

Significant independent risk factors for congestive HF were male gender, hypertension, coronary artery disease, diabetes, and age.

Bahrami, et al., 200810

Differences in the incidence Population- Whites, African Americans, Hispanics, of congestive HF by ethnicity: based and Chinese Americans the Multi-Ethnic Study of Atherosclerosis

The higher risk of incident congestive HF among African Americans was related to differences in the prevalence of hypertension, diabetes, and lower socioeconomic status.

Association of race/ethnicity Retrospective Whites, Blacks, and Hispanics Thomas, et al., 201124 with clinical risk factors, quality of care, and acute outcomes in patients hospitalized with HF

Hispanic and Black patients hospitalized with HF were younger, had lower left ventricular ejection fractions, and had more diabetes and hypertension than White patients. However, they had similar or better in-hospital mortality rates.

Characteristics and outcomes Retrospective African Americans, and Whites Kamath, et al., 200825 in African American patients with decompensated HF

African American patients with acute decompensated HF were younger, had a higher prevalence of hypertension, diabetes, and obesity than White patients. However, African Americans had lower in-hospital mortality.

Shan, et al., 201638

The impact of race on the Retrospective Whites, Blacks, and Hispanics prognosis of preclinical diastolic dysfunction: a large multiracial urban population study

the first large-scale study exploring the role of racial or ethnic differences in heart diseases. Using data from MESA, this review discusses current understanding of the influence of race in the association between DM and HF, the possible mechanisms for these observed differences, and how these may impact on patient management.

Diabetes Mellitus and Heart Failure The mechanism of HF in patients with DM can be explained by a higher prevalence of risk factors – such as IHD, hypertension, and obesity – and a direct metabolic effect – such as insulin resistance, and increased levels of circulating fatty acids. Both HF and DM are believed to share pathophysiologic processes, including neurohormonal activation, endothelial dysfunction, and increased oxidative stress.12–15

Diabetes Mellitus Predisposes Patients to Heart Failure DM is an independent risk factor for the development of HF. The Framingham Study revealed a 2.4-fold increase in symptomatic HF in men and a 5.0-fold increase in women with DM, independent of coexisting hypertension or IHD.15 Traditional risk factors for HF – including hypertension, hyperlipidemia, premature atherosclerosis, and left ventricular hypertrophy – occur with increased frequency in the diabetic population and may directly contribute to the development of HF.13,16 DM accelerates the development of atherosclerosis and increases the risk of myocardial infarction and ischemic HF. DM may act synergistically with other risk factors such as hypertension to increase

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Blacks and Hispanics had more hypertension, diabetes, renal disease, and cerebrovascular disease. However, Whites experienced worse survival compared with Blacks and Hispanics, despite their higher burden of risk factors.

the risk of HF.12 Diabetic cardiomyopathy is a cardiac entity defined as ventricular dysfunction in the absence of coronary artery disease (CAD) and hypertension.14 A US health maintenance study demonstrated that every 1 % increase in baseline glycosylated hemoglobin level correlated with a 15 % increased risk of developing HF.17 DM substantially increases the risk of death, ischemic events and HF,18 particularly in females.19 In the UK Prospective Diabetes Study, poor glycemic control was associated with an increased risk of HF in patients with DM.20

Heart Failure Predisposes Patients to Diabetes Mellitus In a community-based study, among patients with HF the prevalence of DM increased markedly over time.21 HF itself has been shown to be associated with the development of insulin resistance and new-onset DM. Poorer functional class of HF is associated with the development of DM. Among patients with CAD, advanced heart failure (New York Heart Association class III) is associated with a significantly increased risk (1.7-fold) of developing DM during 6- to 9-year follow-up.22 The higher incidence of hyperglycemia in HF patients with poorer functional class could theoretically be due to either insulin resistance or a greater reduction in the capacity of pancreatic beta-cells to secrete insulin. Patients with severe HF are more likely to be sedentary. Lack of physical activity in patients with severe HF leads to decreased muscle mass. Muscle is the major site of glucose utilization, and thus a loss of muscle mass increases insulin resistance.

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Influence of Race on Diabetes and Heart Failure Interactive Effect of Race/Ethnicity and Diabetes in Relation to Heart Failure Trials that have examined racial differences in risk factors, the incidence and outcomes of HF in US are shown in Table 1. The main sources of evidence come from observational, retrospective and non-randomized trials.

Risk Factors for Heart Failure Previous studies have shown a higher prevalence of HF among African Americans, but the reasons for this finding have not been fully understood. A higher burden of risk factors, such as hypertension, DM, a genetic predisposition to cardiomyopathy, and exposure to toxins (including drugs and alcohol), have all been postulated to play a role.23 Subsequently, most work related to racial differences in HF has suggested that differences may be attributable to the relative importance of different risk factors or the issue of access to care.24 Relative to White patients, Hispanic and African American patients were significantly younger, had lower left ventricular ejection fractions, and had more DM, hypertension and obesity.1,24,25

Incidence of Heart Failure According to a prospective, large, population-based study in the US, African American patients have a significantly higher risk for incident HF compared to White, Hispanic and Chinese American patients.10 In another study of younger patients (<50 years), incident HF was more common among Blacks than Whites.23 A hospital-based study of post-menopausal women involving a multiracial cohort found that Black women had a higher age-adjusted incidence of HF compared to White, Hispanic and Asian/Pacific Islander women.26 This excess risk was explained largely by adjustment for lower household incomes and DM for Black women.26 African Americans and Mexican Americans have approximately double the prevalence of DM compared to White Americans.27 Higher rates of hypertension and DM associated with poverty and other environmental factors, such as high calorie intake among African Americans, largely explain racial differences in the risk of developing HF.10 However, in a multiracial prospective study of 2,893 older people (mean age 81 years) in the US, no significant difference was found in the incident of congestive HF among African Americans, Hispanics, and Whites. The Cox regression model showed that the significant independent risk factors for HF were male gender, hypertension, CAD, DM and age.28 HF with preserved ejection fraction (HFpEF) is an increasingly prevalent condition associated with morbidity and mortality. Clinical manifestations of HFpEF are similar to those observed in HF with reduced ejection fraction. Researchers found that the incidence rates of HFpEF were similar across all races (Whites, Blacks, Hispanics and Chinese). Risk factors such as age, hypertension, DM and BMI were significant predictors of incident HFpEF.29 Outside the US, a UK study involving 1 million patients that focused on racial differences in the lifetime presentation of CVD found no differences in initial presentation with HF between White, South Asian and Black patients.30 Unlike the US studies, Black patients in this study had rates of hypertension comparable to White patients. A population-based study in the US examining diabetic cardiomyopathy using cardiac magnetic resonance imaging of individuals from four ethnic groups (White, African American, Hispanic and Chinese) found that end diastolic volume and stroke volume were reduced, and left ventricular mass was increased in Blacks with DM. This study

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concluded that ethnicity-specific differences in left ventricular mass, end diastolic volume, and stroke volume were associated with abnormal glucose metabolism and were independent of subclinical CVD.31 Another interesting study from the MESA group showed that NT-proB natriuretic peptide concentrations differed significantly by race. Natriuretic peptides are cardiac-derived hormones with favorable cardiometabolic actions. Low natriuretic peptide levels are associated with increased risks of hypertension and DM. In multivariable models, NT-proB natriuretic peptide levels were lower in Black and Chinese people compared with Whites. Hispanics had intermediate hormone concentrations.32

Progression of Heart Failure Racial differences play an important role in the progression from asymptomatic left ventricular dysfunction to congestive HF. In the Studies of Left Ventricular Dysfunction (SOLVD), African Americans with mild to moderate left ventricular systolic dysfunction were at higher risk for progression to HF than Whites.33 The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) recently identified this group as a population at high risk for the development of clinical HF.34 Hispanics/ Latinos are particularly vulnerable to cardiac dysfunction because they have an increased prevalence of risk factors for HF, with higher rates of DM, obesity and hypertension.35â€“37 Half of the participants in HCHS/SOL were obese or hypertensive, and two-thirds had DM or were pre-diabetic. Cardiac dysfunction was present in almost half of the cohort and was due predominantly to diastolic dysfunction. Furthermore, of all cardiac dysfunction, upwards of 95Â % was unrecognized or subclinical. A study was performed to assess the impact of race in patients with preclinical diastolic dysfunction. Despite Blacks and Hispanics having more hypertension, DM, renal disease, and cerebrovascular disease than Whites, time to HF was similar among the three racial groups.38

Outcomes of Heart Failure African Americans are more likely to be readmitted to hospital, to spend longer in hospital and to have higher hospital costs (reflecting more complex and difficult-to-treat conditions), as well as being less likely to be treated by cardiologists, suggesting worse access to and quality of care than other racial groups.39 These differences are likely related to socioeconomic and behavioral characteristics, including disparities in access to and quality of health care, as documented by congestive HF morbidity and mortality studies.40 The difference in the risk factor profile was unable to explain the differences in mortality between racial groups. Despite the higher burden of risk factors (DM, hypertension and obesity) and lower ejection fraction among African American and Hispanic HF patients, Whites experienced similar or worse survival after adjustment for known predictors.24,25,38,41,42 Future studies are required to improve our understanding of the impact of mechanisms of race on HF outcomes. There are numerous published data on HF and ethnicity outside the US focusing on different racial groups. The simplified review below provides a glimpse of the epidemiological differences in HF in different geographic regions of the world. A retrospective cohort study that was conducted on 4.7 million people in Scotland to determine the incidence of first HF hospitalization or death by racial group found that South Asians (Pakistani men and women) had

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Heart Failure a higher risk ratio than White British and Chinese.43 In the Middle East, a study involving seven Arabian Gulf states (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, the United Arab Emirates, and Yemen) reported that acute HF patients from this region were a decade younger than their Western counterparts, with a high prevalence of IHD and DM, and a higher risk of acute HF with reduced ejection fraction.44 In Africa, acute HF has a predominantly non-ischemic cause, most commonly hypertension. The condition occurs in middle-aged adults, affects men and women equally, and is associated with high mortality. The outcomes are similar to those observed in non-African acute HF registries, suggesting that acute HF has a dire prognosis globally, regardless of the cause.45 In Asia, recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. HF hospitalizations are on the rise and, compared with Western counterparts, HF occurs at a younger age. It is characterized by more severe clinical features and worse outcomes in south-east Asian patients.3 The at-risk population is increasing at a faster rate in Asia than in other parts of the world, and reflects increases in the prevalence of CAD, hypertension, DM, obesity, and tobacco use. Prospective multi-national data highlight the significant heterogeneity among Asian patients with stable HF, and the important influence of both race and regional income level on patient characteristics. The prevalence of DM is highest in south-eastern Asians and lowest in north-eastern Asians, with notable geographic and racial variations.2 South-east Asian countries, such as Malaysia and Singapore, consist of multiracial Asians (Malay, Chinese, Indian and other ethnic minorities); an ideal population to use when exploring racial variations in CVDs. Compared to other regions of Asia, south-east Asia has the greatest burden of risk factors (hypertension and DM).2 The adjusted odds ratio of DM was 4.9 higher in Indians compared to Malays and Chinese, particularly in high-income regions.2 In Malaysia, a prospective survey of congestive HF in a single center showed variations in associated etiological factors between racial groups. CAD was the main etiology of HF, followed by

mbrosy AP, Fonarow GC, Butler J, et al. The global health and A economic burden of hospitalizations for heart failure. Lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63:1123–33. DOI: 10.1016/j.jacc.2013.11.053; PMID: 24491689. Lam CS, Teng TH, Tay WT, et al. Regional and ethnic differences among patients with heart failure in Asia: the Asian Sudden Cardiac Death in Heart Failure Registry. Eur Heart J 2016;37: 3141–53. DOI: 10.1093/eurheartj/ehw331; PMID: 27502121. Mentz RJ, Roessig L, Greenberg BH, et al. Heart failure clinical trials in East and Southeast Asia. Understanding the importance and defining the next steps. JACC Heart Fail 2016;4:419–27. DOI: 10.1016/j.jchf.2016.01.013; PMID: 27256745. Shimokawa H, Miura M, Nochioka K, Sakata Y. Heart failure s a general pandemic in Asia. Eur J Heart Fail 2015;17:884–92. DOI: 10.1002/ejhf.319; PMID: 26222508. Damon A. Race, ethnic group, and disease. Social Biology 1969;16:69–80. DOI: 10.1080/19485565.1969.9987804; PMID: 5810364. Winker MA. Measuring race and ethnicity: why and how? JAMA 2004;292:1612–14. DOI: 10.1001/jama.292.13.1612; PMID: 15467065. Peterson E, Yancy CW. Eliminating racial and ethnic disparities in cardiac care. N Engl J Med 2009;360:1172–74. DOI: 10.1056/ NEJMp0810121; PMID: 19297569. Khatibzadeh S, Farzadfar F, Oliver J, et al. Worldwide risk factors for heart failure: a systematic review and pooled analysis. Int J Cardiology 2013;168:1186–94. DOI: 10.1016/j.ijcard.2012.11.065; PMID: 23201083. Afzal A, Ananthasubramaniam K, Sharma N, et al. Racial differences in patients with heart failure. Clin Cardiol 1999;22: 791–94. PMID: 10626081.

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hypertension. DM was the risk factor affecting the majority of Indians as compared to Malays and Chinese.46 A higher rate of DM in Indians compared to other races has been confirmed by studies and multi-center registries worldwide.47–50 A prospective observational study consisting of the multiracial population in Singapore showed that Indian and Malay patients had worse HF outcomes than Chinese patients. These differences were attributed to a greater prevalence of DM among Indians. However, the cause of the poorer prognosis in Malays is unclear in this study.51 There are more data on racial differences in HF in different parts of the globe, however these data are beyond the scope of current review. In the authors’ opinion, patients with DM have higher rates of HF due to its adverse effects on endothelial dysfunction, altered metabolism and increased oxidative stress, clustering with other predisposing risk factors (DM and hypertension) that accelerate the development of atherosclerosis and increase the risk of IHD.12–14,16 If the predisposing risk factors are more prevalent in any racial group, they will increase the incidence of HF.2,10 We also think that the outcomes of HF may be influenced by the control of DM, regardless of racial differences. If diabetes control is poor due to low educational status, access-to-care or socioeconomic issues, we believe this will have direct impact on mortality rate regardless of racial background. The current review reinforces the need for optimal control of DM to effectively reduce the increasing social burden of HF.

Conclusions The interaction between race and DM carry important public health implications for the management and prevention of HF. African American patients in the US have a significantly higher incidence of HF, lower ejection fraction, and are younger at presentation compared to White, Hispanic and Chinese American patients. These findings are largely explained by the higher burden of risk factors such as DM, hypertension, obesity, and lower household incomes among African Americans. The authors believe that these findings are applicable to other racial groups. The prevalence of predisposing risk factors probably has a stronger influence on the incidence of HF than the racial factor alone. n

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Influence of Race on Diabetes and Heart Failure

heart failure. Arch Intern Med 2008;168:1152–8. DOI: 10.1001/ archinte.168.11.1152; PMID: 18541822. 26. E aton CB, Abdulbaki AM, Margolis KL, et al. Racial and ethnic differences in incident hospitalized heart failure in postmenopausal women: the Women’s Health Initiative. Circulation 2012;126:688–96. DOI: 10.1161/ CIRCULATIONAHA.111.066688; PMID: 22753306. 27. Katzmarzk PT, Staiano AE. New race and ethnicity standards: elucidating health disparities in diabetes. BMC Med 2012;10:42. DOI: 10.1186/1741-7015-10-42; PMID: 22546706. 28. Aronow WS, Ahn C, Kronzon I. Comparison of incidences of congestive heart failure in older African-Americans, Hispanics, and whites. Am J Cardiol 1999;84:611–2, A9. DOI: 10.1016/S00029149(99)00392-6. 29. Silverman MG, Patel B, Blanksteine R, et al. Impact of race, ethnicity, and multimodality biomarkers on the incidence of new onset heart failure with preserved ejection fraction (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol 2016;117:1474–81. DOI: 10.1016/j.amjcard.2016.02.017; PMID: 27001449. 30. George J, Mathur R, Shah AD, et al. Ethnicity and the first diagnosis of a wide range of cardiovascular diseases: associations in a linked electronic health record cohort of 1 million patients. PLoS One 2017;12:e0178945. DOI: 10.1371/ journal.pone.0178945; PMID: 28598987. 31. Bertoni AG, Goff DC, D’Agostino RB, et al. Diabetic cardiomyopathy and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 2006;29:588–94. DOI: 10.2337/diacare.29.03.06.dc05-1501; PMID: 16505511. 32. Gupta DK, Daniels LB, Cheng S, et al. Differences in natriuretic peptide levels by race/ethnicity (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol 2017;120:1008–15. DOI: 10.1016/ j.amjcard.2017.06.030; PMID: 28750825. 33. Dries DL, Exner D, Gersh B, et al. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 1999;340:609–16. DOI: 10.1056/NEJM199907223410414; PMID: 10419390. 34. Mehta H, Armstrong A, Swett K, et al. Burden of systolic and diastolic left ventricular dysfunction among Hispanics in the

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United States: Insights from the Echocardiographic Study of Latinos (ECHO-SOL). Circ Heart Fail 2016;9:e003733. DOI: 10.1161/ CIRCHEARTFAILURE.115.002733; PMID: 27048764. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults: The third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 1998;21:518–24. PMID: 9571335. Sorlie PD, Allison MA, Avilés-Santa ML, et al. Prevalence of hypertension, awareness, treatment, and control in the Hispanic Community Health Study/Study of Latinos. Am J Hypertens 2014;27:793–800. DOI: 10.1093/ajh/hpu003; PMID: 24627442. Rodriguez CJ, Allison M, Daviglus ML, et al. American Heart Association Council on Epidemiology and Prevention; American Heart Association on Clinical Cardiology; American Heart Association Council on Cardiovascular and Stroke Nursing. Status of cardiovascular disease and stroke in Hispanics/Latinos in the United States: a science advisory from the American Heart Association. Circulation 2014;130:593–625 DOI: 10.1161/ CIR.0000000000000071; PMID: 25098323. Shan J, Zhang L, Holmes AA, Taub CC. The impact of race on the prognosis of preclinical diastolic dysfunction: a large multiracial urban population study. Am J Med 2016;129:222.e1–10. DOI: 10.1016/j.amjmed.2015.08.036; PMID: 26475254. Philbin EF, DiSalvo TG. Influence of race and gender on care process, resource use, and hospital-based outcomes in congestive heart failure. Am J Cardiol 1998;82:76–81. DOI: 10.1016/S0002-9149(98)00233-1; PMID: 9671013. Alexander M, Grumbach K, Selby J, et al. Hospitalization for congestive heart failure: explaining racial differences. JAMA 1995;274:1037–42. PMID: 7563454. Qian F, Parzynski CS, Chaudhry SI, et al. Racial differences in heart failure outcomes evidence from the Tele-HF Trial (Telemonitoring to Improve Heart Failure Outcomes). JACC Heart Fail 2015;3:531–8. DOI: 10.1016/j.jchf.2015.03.005; PMID: 26160368. Ziaeian B, Heidenreich PA, Xu H, et al. Race/ethnic differences in outcomes among hospitalized Medicare patients with heart failure and preserved ejection fraction. JACC Heart Fail 2017;5:483–93. DOI: 10.1016/j.jchf.2017.02.012; PMID: 28501527.

43. B hopal RS, Bansal N, Fischbacher CM, et al. Ethnic variations in heart failure: Scottish Health and Ethnicity Linkage Study (SHELS). Heart 2012;98:468–73. DOI: 10.1136/heartjnl-2011301191; PMID: 22285972. 44. Panduranga P, Al-Zakwani I, Sulaiman K, et al. Comparison of Indian subcontinent and Middle East acute heart failure patients: results from the Gulf Acute Heart Failure Registry. Indian Heart J 2016;68:36–44. DOI: 10.1016/j.ihj.2015.11.019; PMID: 27056651. 45. Damasceno A, Mayosi BM, Sani M, et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries. Arch Intern Med 2012;172:1386–94. DOI: 10.1001/ archinternmed.2012.3310; PMID: 22945249. 46. Chong AY, Rajaratnam R, Hussein NR, Lip GY. Heart failure in a multiethnic population in Kuala Lumpur, Malaysia. Eur J Heart Fail 2003;5:569–74. DOI: 10.1016/S1388-9842(03)000138; PMID: 12921820. 47. Hughes K, Yeo PP, Lun KC, et al. Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. II. Differences in risk factor levels. J Epidemiol Community Health 1990;44:29–35 DOI: 10.1136/jech.44.1.29; PMID: 2348145. 48. Lu HT, Nordin RB. Ethnic differences in the occurrence of acute coronary syndrome: results of the Malaysian National Cardiovascular Disease (NCVD) Database Registry (March 2006 – February 2010). BMC Cardiovasc Disord 2013;13:97. DOI: 10.1186/1471-2261-13-97; PMID: 24195639. 49. Meadows TA, Bhatt DL, Cannon CP, et al. Ethnic differences in cardiovascular risks and mortality in atherothrombotic disease: Insights from the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Mayo Clin Proc 2011;86:960–7. DOI: 10.4065/mcp.2011.0010; PMID: 21964173. 50. Cappuccio FP, Cook DG, Atkinson RW, Strazzullo P. Prevalence, detection and management of cardiovascular risk factors in different ethnic groups in South London. Heart 1997;78:555–63. PMID: 9470870. 51. Raymond Lee, Chan SP, Chan YH, et al. Impact of race on morbidity and mortality in patients with congestive heart failure: a study of the multiracial population in Singapore. Int J Cardiol 2009;134:422–5. DOI: 10.1016/j.ijcard.2007.12.107; PMID: 18372060.

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Interventional Cardiology

Interventional Echocardiography: Field of Advanced Imaging to Support Structural Heart Interventions Roy Arjoon, MD, Ashley Brogan, MD, and Lissa Sugeng, MD, MPH Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT

Abstract Multimodality imaging, particularly echocardiography, is paramount in planning and guiding structural heart disease interventions. Transesophageal echocardiography remains unique in its ability to provide real-time 2D and 3D imaging of valvular heart disease and anatomic cardiac defects, which directly impacts the strategy and outcome of these procedures. This review summarizes the role of transesophageal echocardiography in patients undergoing the most common structural heart disease interventions.

Keywords Interventional echocardiography, atrial septal defect closure, patent foramen ovale closure, MitraClip, transcatheter aortic valve replacement, left atrial appendage occlusion, WATCHMAN Disclosure: Roy Arjoon and Ashley Brogan have no conflicts of interest to declare. Lissa Sugeng has worked on the Siemens Healthineers Speaker’s Bureau and Advisory Board and on the Philips Healthcare Advisory Board. Received: 4 August 2017 Accepted: 19 October 2017 Citation: US Cardiology Review 2018;12(1):22–7. DOI: 10.15420/usc.2017:16:1 Correspondence: Lissa Sugeng, Yale School of Medicine, Section of Cardiovascular Medicine, P.O. Box 208017, New Haven, CT 06520-8017. E: lissa.sugeng@yale.edu

Cardiovascular medicine has undergone a momentous change over the past 2 decades with the development of percutaneous transcatheter interventions for structural heart disease. This field has the greatest growth in interventional cardiology for the foreseeable future.1–3 The number of patients with acquired valvular heart disease and adult congenital heart disease will only rise in the future as the population expands and ages. Multimodality imaging using cardiac CT, echocardiography, fluoroscopy, and fusion imaging are necessary in structural heart disease interventions. Transesophageal echocardiography (TEE), in particular, provides unique real-time 3D echocardiography of valvular heart disease and anatomic cardiac defects before, during, and after transcatheter therapies. This review will summarize the role of TEE in patients undergoing percutaneous mitral valve (MV) repair (MitraClip), left atrial appendage (LAA) closure, transcatheter aortic valve replacement (TAVR), and atrial septal defect (ASD)/patent foramen ovale (PFO) closure.

Left Atrial Appendage Occlusion Approximately 2.7–6.1 million people in the US have atrial fibrillation (AF).4 As the population ages, this number is expected to increase. AF increases the risk of ischemic stroke by five-fold and the strokes are typically more severe compared to non-AF-related strokes.5 Although oral anticoagulation (OAC) is the mainstay treatment for stroke prevention, up to 40 % of patients do not receive OAC, typically due to contraindications or bleeding risk.6 LAA occlusion devices are an alternative for patients with contraindications or prohibitive bleeding risk on OAC. The most common percutaneous occlusion devices include the WATCHMAN device (Boston Scientific), the AMPLATZER™ Cardiac Plug (St. Jude Medical), and the LARIAT® system (SentreHEART). The LARIAT system may be used off-label

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for a similar indication, although the US Food and Drug Administration (FDA) has raised safety concerns in this setting.7 This review will focus on the role of TEE with the WATCHMAN device, since it is the only FDAapproved device for stroke prevention in non-valvular AF. TEE assessment prior to WATCHMAN device placement includes: evaluation for LAA thrombus; LAA size, morphology, and the number and depth of the lobes; and assessment of other structural abnormalities. While meticulous evaluation for thrombus in the LAA from 0° to 180° is performed, the LAA ostium width and depth are measured at 0°, 45°, 90°, and 135° (see Figure 1). The ostium width is measured from the level of the left main artery or mitral annulus to a point 2 cm below the tip of the pulmonary vein ridge. The depth is measured from the ostium to the LAA apex. The maximum LAA ostium width must be ≥17 mm or ≤31 mm to accommodate a device and the depth must be at least as long as the maximum LAA ostium width.8–10 Real-time 3D TEE has emerged as a potentially faster and more accurate way to assess the size and morphology of the LAA. Small studies suggest the real-time 3D TEE assessment of LAA morphology is equivalent to MRI or CT, and superior to assessment using 2D TEE imaging.11–13 Three-dimensional assessment may also obviate the need to assess the LAA at multiple angles to obtain the maximum LAA ostium width and LAA depth.12,13 More widespread use of 3D TEE could potentially reduce cost and patients’ exposure to radiation/contrast; nonetheless, it is limited to centers with access to such technology. Intraprocedurally, TEE is used to initially guide transseptal puncture and to confirm optimal positioning of the delivery system. Optimal device

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Interventional Echocardiography placement is when the axis of the device aligns with the long axis of the LAA. Color flow evaluation over the device is needed prior to final deployment to assess for adequate LAA occlusion, defined as mild leak or less into the LAA with a jet diameter <3 mm (see Figure 2). Finally, at the end of the procedure, TEE is used to assess for changes in transmitral and pulmonary vein flow, along with potential complications including pericardial effusion, tamponade or device migration.8–10 Patients remain on aspirin and OAC for at least 30 days after device implantation, and a TEE is done to assess for thrombus and residual peri-device leak, with the same protocol at baseline. If residual flow into the LAA is >5 mm in diameter, then the patient should continue or restart anticoagulation.

Figure 1: Transesophageal Echocardiography Measurement of Left Atrial Appendage Prior to Watchman Procedure

Transcatheter Aortic Valve Replacement Calcific aortic stenosis (AS) remains the most common form of valvular disease in developed countries, affecting approximately 2 % of people >65 years.14 Surgical aortic valve replacement is typically considered the treatment of choice for patients with symptomatic severe AS. However, many of these patients are considered inoperable due to significant surgical risk. The development of transcatheter aortic valve replacement (TAVR) gave high and intermediate risk patients an equally efficacious, but less invasive, option for valve replacement.15 TAVR requires multimodality imaging support. Specifically, echocardiography plays an essential role in the identification of patients with severe AS, sizing of the prosthesis, intraprocedural guidance, and the follow-up of prosthetic valve function. Two-dimensional and Doppler echocardiography remain the workhorses for the diagnosis of severe AS. TEE with Doppler is often less accurate due to difficulties with ultrasound beam alignment. However, TEE planimetry provides an alternative method for patients with suboptimal transthoracic echocardiography (TTE) evaluation. It correlates quite well with a continuity equation-derived valve area on TTE and with valve area derived from the Gorlin formula in the catheterization lab.16 Three-dimensional TEE, which obviates geometric assumptions of the elliptical aortic apparatus, may provide an even more accurate assessment of the left ventricular outflow tract/aortic annulus, aortic root, and aortic valve. Several studies have looked at annular sizing between 3D TEE and multidetector CT (MDCT) for TAVR size selection prior to implant (see Figure 3A and B). This question is important, since undersizing can result in device embolization or significant paravalvular leak, an independent predictor of mortality after TAVR.17 Similarly, oversizing can result in conduction abnormalities and aortic root rupture.17 Unfortunately, no clear answer exists. The majority of studies suggest that 3D TEE results in undersizing of the aortic annulus compared to MDCT, though with small absolute differences.18–22 In contrast, some small studies showed good correlation between 3D TEE and MDCT for annular sizing and for predicting paravalvular leak.23–26 At least some of this difference may be related to the lower spatial resolution of 3D TEE at the time, image dropout secondary to significant calcification at the annulus or aortic valve, and center experience.27 Notably, heavy aortic calcification limits 3D TEE evaluation of planimetry and annulus measurements due to image dropout. TEE with 3D and automated software (see Figure 3C), may ultimately provide pre-TAVR patients with ‘one-stop shopping’ for the evaluation of the entire aortic apparatus with excellent temporal and good spatial resolution, while avoiding contrast and radiation. Concomitant TEE during the TAVR procedure aids in the placement of the valve, allows visualization of balloon aortic valvuloplasty, helps with

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The left atrial appendage width and depth are measured at 0°, 45°, 90°, and 135°. The maximum left atrial appendage ostium width must be ≥17 mm or ≤31 mm to accommodate a device and the depth must be at least as long as the maximum left atrial appendage ostium width.

Figure 2: Transesophageal Echocardiography Evaluation of the WATCHMAN Device Post-procedure

After implantation, the Watchman device is evaluated at 0°, 45°, 90°, and 135°. Successful implantation is defined as <3 mm of leak into the left atrial appendage. This patient has no evidence of leak into the left atrial appendage with color Doppler assessment.

sizing, identifies heavily calcified aortic annuli, identifies shallow coronary ostia origin, and provides rapid feedback to the interventionalist on complications. However, the routine use of intraprocedural TEE versus TTE proves controversial. The general trend is to use TEE-guided TAVR placement during cases necessitating general anesthesia, and those with transapical, transaortic or subclavian approaches for image quality reasons. A number of studies have shown that conscious sedation is becoming more prevalent with a transfemoral approach, and outcomes have been similar despite greater use of TTE over TEE.28–32 Regardless of the specific modality chosen, echocardiography plays an essential role in TAVR. The interventionalist and echocardiographer should localize the prosthesis below the aortic annulus and monitor its relationship to the MV and left ventricular outflow tract. The team must also look for the prosthesis to assume its predicted circular shape in the short axis

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Interventional Cardiology Figure 3: Transesophageal Echocardiography and Computed Tomography Evaluation of the Aortic Annulus

(A) Multiplanar reconstructions of a 3D aortic valve with short axis measurement of the annulus performed manually, (B) Corresponding computed tomography annular measurement and (C) Automated eSie Valve tracking of the annulus in the same patient.

view.9,33 Once implanted, TEE or TTE is used to confirm optimal anatomical position, aortic valve area >1.2 cm2, mean gradient <20 mmHg, peak velocity <3 m/sec, and absence of moderate or severe regurgitation.34 TTE is performed at 24 hours, 30 days, and then at least annually after the procedure. Evaluation must include TAVR function (aortic valve area, mean gradient, peak gradient and peak velocity), the presence of intravalvular/ paravalvuar regurgitation, right ventricular systolic pressure, and potential for other complications. These complications include left ventricular dysfunction related to coronary ostium occlusion, prosthesis migration/ embolization, MV damage, tamponade, and aortic root damage.35

Percutaneous Mitral Valve Repair Degenerative MV disease is the most common cause of mitral regurgitation (MR).36 Surgical (MV) repair is the standard treatment to improve symptoms and prevent heart failure, with low mortality and high success rates at “mitral referral centers.” However, for patients who are high risk for surgery, palliative treatment with medications was the only choice until 2013, when MitraClip was FDA-approved for patients with symptomatic severe degenerative MR. The Efficacy of Vasopressin Antagonism in hEart failuRE: Outcome Study With Tolvaptan (EVEREST) trial in 2008 was the first randomized controlled trial comparing surgery versus percutaneous repair in high-risk patients. Most recently, a 5-year follow-up for durability was evaluated. While there were high rates of initial 3+ or 4+ MRs, this did not significantly increase over time. Additionally, there were no differences in long-term survival, left ventricular function, or dimensions. Although surgery has superior outcomes, there is evidence that a percutaneous alternative is safe, improves heart failure symptoms, and left ventricular dimensions.37 Identifying patients who meet the criteria for MitraClip starts with transthoracic echo imaging. Based on quantitative and qualitative parameters, patients must have moderate to severe or severe MR due to degenerative MV disease, left ventricular dimensions <6 cm, and left ventricular ejection fraction >20 %. TEE imaging is needed to confirm the severity of regurgitation, the jet origin (which ideally should be from the A2–P2 scallops), and the MV area (which should be >3 cm2). The

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prolapse or flail gap should be <10 mm and the width <15 mm. Patients with these echo criteria included in the EVEREST cohort were more likely to have a successful intervention without the need for a recurrent procedure. Patients with functional MR have recently been included in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) trial. On TEE imaging, a coaptation length of ≥2 mm and a depth of <11 mm were needed for inclusion in the study.38–40 Relative echocardiographic contraindications include pathology at the body of the leaflet, severe calcifications at the site of grasping zone, small (<3.5 cm2) valve area and high gradients (>4 mmHg), small grasping zone <7 mm, Barlow’s disease with significant regurgitation of A1–P1 or A3–P3 scallops, and rheumatic disease.40 Though most of the assessment is 2D, 3D echocardiography should be used in the initial evaluation for MitraClip, since it may provide a better assessment of the etiology of regurgitation, dimensions of the MV, and an alternative to estimating severity.38–40 Three-dimensional TEE is an essential tool for the interventionalist in MitraClip procedures. Close collaboration between the primary operator and the echocardiographer is necessary to achieve successful placement. A complete 2D/3D TEE study prior to the procedure is paramount. Evaluation of the all pulmonary veins, in addition to all MR parameters, is invaluable to judge the success of the MitraClip procedure. TEE guidance begins with the transseptal puncture. Localization of the optimum position is posterior and superior in the septum with a height 3.5–4.0 cm from the MV annular plane depending on the MV pathology. 41–43 Functional MR is due to tethering of the MV causing the mitral leaflets to be lower in the ventricle versus degenerative mitral leaflets, which are higher and are in the left atrium. Imaging planes for obtaining this optimal site include short axis with an angle of 30° at the base for anterior–posterior orientation, the bicaval at 90–120° for superior and inferior orientation, and a fourchamber at 0° to assist with height the annulus (see Figure 4A). 42 The steerable catheter is introduced through the guide catheter, as seen on the 3D echocardiography in Figure 4B, and can be under continuous 2D echocardiography with biplane imaging as needed. The echocardiographer provides feedback on the proximity of the tip of this catheter and the wall of the left atrium. The MitraClip is directed to the left atrial appendage and then flexed downwards to the MV while using 3D imaging. A surgical view of the MV from a left atrial orientation allows positioning of the MitraClip perpendicular to the coaptation line and directly over the origin of MR (see Figure 4D). 42 Occasionally, to confirm the position of the clip, a surgical view of the MV with decreased 3D enables the opened clip orientation to be viewed. The device is advanced into the left ventricle using biplane imaging, preferably using a bicommissural view and long-axis view on the opposite plane (see Figure 4C). The clip is positioned in the long-axis view to grab the anterior and posterior leaflets using 2D echocardiography. Successful placement of the clip is seen if the severity of MR decreases to <2+. 42 Evaluation of MR should include regurgitant volume by continuity equation, vena contracta when possible, and pulmonary vein evaluation. The flow convergence method is challenging, since it may overestimate MR when assessing multiple jets and underestimate MR in eccentric jets. 42 Equally important is the assessment of MV stenosis,

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Interventional Echocardiography Figure 4: Transesophageal Echocardiography of MitraClip Transcatheter Mitral Valve Repair

(A) Biplane of the interatrial septum (IAS) demonstrates a 4-chamber (left) and bicaval (right) view simultaneously, the transeptal puncture guide (green circle) indicates 4 cm above the mitral annulus which is optimal for degenerative mitral regurgitation; (B) 3D transesophageal echocardiography view of the IAS from the left atrium shows the guide catheter (red arrow) crossing the IAS; (C) Biplane view of the mitral valve: bicommissural (left) and long axis (right) as the MitraClip is advanced into the left ventricle to grasp the anterior and posterior leaflets; (D) Surgeon’s view of the mitral valve after MitraClip is implanted creating a double orifice.

particularly with multiple MitraClips prior to device release. A complete post-device evaluation should determine the presence of pericardial effusion, ventricular or leaflet perforation, and residual iatrogenic ASDs. 42 Patients with shunts post procedure do worse clinically. The shunt assessment should be done with 3D TEE, since it has proven to be more accurate in predicting size compared to 2D TEE, which underestimates diameter and area. 44,45 The EVEREST cohort had strict and specific echocardiographic variables that did not reflect the real-life situations of patients. A 12-month followup study compared patients who met strict EVEREST criteria to patients representing a real-life cohort.46 Acute and 30-day outcomes were similar. At 1 year, reduction in MR and improvement in left ventricular dimensions were also comparable. This study argues that the MitraClip should be expanded to those patients with less ideal echocardiographic features.46 More recently, a long-term outcomes study compared the patients that fulfilled the strict inclusion criteria to those who did not. Regardless of EVEREST criteria, the authors found a 95 % primary success rate and a significant reduction in MR severity. However, those who did not meet the strict criteria were more likely to require an additional intervention due to recurrent MR.47

Atrial Septal Defect/Patent Foramen Ovale Closure Catheter intervention with the assistance of echocardiography has created a suitable alternative for the closure of uncomplicated secundum ASD and PFO. The indications for ASD closure include right ventricular and atrial enlargement, evidence of paradoxical embolism, or documented orthodeoxia-platypnea, and may be considered when a significant shunt is present.48 Currently, there are no approved indications for PFO closure other than documented orthodeoxia-platypnea, although catheter intervention can be used off-label for paradoxical embolization.49

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Figure 5: Three-dimensional Transesophageal Echocardiography During Atrial Septal Defect Closure

(A) 3D transesophageal echocardiography imaging of an “oblique” view of the atrial septum. The guide catheter is clearly visible across the atrial septum (arrows); (B) expansion of the left disk (arrow); (C) the disk is pulled back toward the atrial septum; (D) a further slight rotation of the volume dataset enables the visualization of the expansion of the right disk; (E) the right disk is pushed against the atrial septum (arrow); (F) this perspective enables one to see septal tissue (pink arrow) entrapped between the disks (white arrows). Faletra et al., 2014.53 Reproduced with permission from Elsevier.

TTE with agitated saline is usually the initial step in the detection of atrial shunts and in assessing the hemodynamic consequences.50 A TEE should be considered when the TTE is negative but high clinical suspicion remains, or to confirm an ASD or PFO, evaluate for pulmonary shunt, and define anatomy.50 There are defined imaging planes on TEE that are used to assess the size and rims of an ASD. TEE should begin with an entire sweep of the atrial septum at 0° (four-chamber) followed by 90° (bicaval view) with and without color Doppler. At 0°, an investigation of the interatrial septum (IAS) starts from superior vena cava down to the inferior vena cava, and at 90° an entire sweep from right-to-left should be viewed. At 30° the anterior portion of the IAS adjacent to the aorta and the posterior rim is assessed.50,51 There are a number of anatomical features that are required to confirm catheter closure suitability and device choice. Defects >38 mm and those with a deficient rim <5 mm may require surgery, though deficient rims anterior adjacent to the aorta are less problematic.52 Transcatheter repair of ASDs that are in proximity to the mitral and tricuspid valve and deficient with rims adjacent to the superior vena cava and inferior vena cava are typically avoided. There are several types of device available, and the presence of certain anatomical features will sway the use of one device over another. For example, the GORE® HELEX® device (W. L. Gore & Associates) can be considered in place of the widely used AMPLATZER™ Septal Occluder (St. Jude Medical) when there is a deficient rim, since its softer disks may lead to less erosion.52 Real-time 3D TEE helps to define the shape, size and rim of the ASD, since it provides an enface view. This image can then be rotated to view the septum from the right and left atrium, enabling us to appreciate the dynamic geometry in diastole and systole. The pre-assessment for a PFO should include size of the left and right atrial opening, total length of the PFO tunnel, the presence of aneurysm, and the location and extent of the Eustachian ridge and valve. The pre-assessment for ASD closure includes thickness of the secondary septum, rim size, and defect size.9,50,51

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Interventional Cardiology Once appropriate patients and devices are selected, 3D TEE can assist in the septal puncture from the oblique and lateral views, and in the case of ASDs it has been shown to provide better definition of septal anatomy and visualization of catheters. From the oblique and lateral views, the guide catheter can be seen clearly crossing the IAS. While in this view, rotating from right to left creates a view of the catheter in the left atrium, allowing for disk expansion. A lateral perspective allows visualization of the right disk expansion, resulting in the IAS being sandwiched by two expanded disks (see Figure 5).53 In addition to 3D visualization, biplane imaging aids in the placement of the device, ensuring alignment with the IAS. A successful closure is defined by complete closure with residual shunt <1–2 mm.52 With regard to long-term follow up, TTE is sufficient to

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anari Z, Weintraub WS. Cost-effectiveness of transcatheter F versus surgical management of structural heart disease. Cardiovasc Revasc Med 2016;17:44–7. DOI: 10.1016/j. carrev.2015.08.011; PMID: 26440768. Faxon D, Williams DO. The changing face of interventional cardiology. Circ Cardiovasc Interv 2012;5:325–7. DOI: 10.1161/ CIRCINTERVENTIONS.112.971671; PMID: 22715447 Yadav K, Halim SA, Vavalle J. Training in structural heart interventions. J Am Coll Cardiol 2014;64:2296–8; discussion 2298. DOI: 10.1016/j.jacc.2014.10.002; PMID: 25456763. January CT, Wann S, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1–76. DOI: 10.1016/j. jacc.2014.03.022; PMID: 24685669. Albertsen IE, Rasmussen LH, Overvad TF, et al. Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis. Stroke 2013;44:1329–36. DOI: 10.1161/STROKEAHA.113.000883; PMID: 23482597. Marzec LN, Want J, Shah ND, et al. Influence of direct oral anticoagulants on rates of oral anticoagulation for atrial fibrillation. J Am Coll Cardiol 2017;69:2475–84. DOI: 10.1016/j. jacc.2017.03.540; PMID: 28521884. Chatterjee S, Herrmann HC, Wilensky RL, et al. Safety and procedural success of left atrial appendage exclusion with the Lariat device: a systematic review of published reports and analytic review of the FDA MAUDE database. JAMA Intern Med 2015;175:1104–9. DOI: 10.1001/jamainternmed.2015.1513; PMID: 25938303. Masoudi FA, Calkins H, Kavinsky CJ, et al. American College of Cardiology; Heart Rhythm Society; Society for Cardiovascular Angiography and Interventions. 2015 ACC/HRS/SCAI left atrial appendage occlusion device societal overview. Heart Rhythm 2015;12:e122–36. DOI: 10.1016/j.hrthm.2015.06.034; PMID: 26134035. Patrianakos AP, Zacharaki AA, Skalidis EI, et al. The growing role of echocardiography in interventional cardiology: The present and the future. Hellenic J Cardiol 2017;58:17–31. DOI: 10.1016/j. hjc.2017.01.008; PMID: 28163148. Saw J, Lempereur M. Percutaneous left atrial appendage closure: procedural techniques and outcomes. JACC Cardiovasc Interv 2014;7:1205–20. DOI: 10.1016/j.jcin.2014.05.026; PMID: 25459035. Sommer M, Roehrich A, Boener F, et al. Value of 3D TEE for LAA morphology. JACC Cardiovasc Imaging 2015;8:1107–10. DOI: 10.1016/j.jcmg.2014.07.030; PMID: 26381771. Yosefy C, Azhibekov Y, Brodkin B, et al. Rotational method simplifies 3-dimensional measurement of left atrial appendage dimensions during transesophageal echocardiography. Cardiovasc Ultrasound 2016;14:36. DOI: 10.1186/s12947–016–0079–y; PMID: 27553013. Yosefy C, Laish-Farkash A, Azhibekov Y, et al. A new method for direct three-dimensional measurement of left atrial appendage dimensions during transesophageal echocardiography. Echocardiography 2016;33:69–76. DOI: 10.1111/echo.12983; PMID: 26053456. Lindman BR, Clavel MA, Mathieu P, et al. Calcific aortic stenosis. Nat Rev Dis Primers 2016;2:16006. DOI: 10.1038/nrd2016.6; PMID: 27188578. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252–89. DOI: 10.1016/j.jacc.2017.03.011; PMID: 28315732. Stoddard MF, Arce J, Liddell NE, et al. Two-dimensional transesophageal echocardiographic determination of

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assess for migration, residuals shunts, right atrial and right ventricular size, and pulmonary artery pressure, if available.9

Conclusion The trend towards developing less invasive procedures for structural heart disease has led to an increased need for echocardiography support in the diagnosis of disease, sizing of devices, procedural guidance, and monitoring to determine the success or failure of procedures. There is a high demand for improved spatial and temporal resolution via 2D and 3D imaging to meet these expectations. Evolving technology is expanding the role and improving the accuracy of 2D and 3D TEE and TTE in the rapidly-growing fields of structural cardiology and interventional echocardiography. n

aortic valve area in adults with aortic stenosis. Am Heart J 1991;122:1415–22. DOI: 10.1016/0002–8703(91)90585–6; PMID: 1951006. Kasel AM, Cassese S, Belizifer S, et al. Standardized imaging for aortic annular sizing: implications for transcatheter valve selection. JACC Cardiovasc Imaging 2013;6:249–62. DOI: 10.1016/j. jcmg.2012.12.005; PMID: 23489539. Husser O, Holzamer A, Resch M, et al. Prosthesis sizing for transcatheter aortic valve implantation – comparison of three dimensional transesophageal echocardiography with multislice computed tomography. Int J Cardiol 2013;168:3431–8. DOI: 10.1016/j.ijcard.2013.04.182; PMID: 23688431. Ng AC, Delgado V, van der Kley F, et al. Comparison of aortic root dimensions and geometries before and after transcatheter aortic valve implantation by 2- and 3-dimensional transesophageal echocardiography and multislice computed tomography. Circ Cardiovasc Imaging 2010;3:94–102. DOI: 10.1161/ CIRCIMAGING.109.885152; PMID: 19920027. Tsang W, Bateman MG, Weinert L, et al. Accuracy of aortic annular measurements obtained from three-dimensional echocardiography, CT and MRI: human in vitro and in vivo studies. Heart 2012;98:1146–52. DOI: 10.1136/ heartjnl–2012–302074; PMID: 22773684. Tsuneyoshi H, Komiya T, Shimamoto T. Accuracy of aortic annulus diameter measurement: comparison of multi-detector CT, two- and three-dimensional echocardiography. J Card Surg 2016;31:18–22. DOI: 10.1111/jocs.12664; PMID: 26560800. Wiley BM, Kovacic JC, Basnet S, et al. Intraprocedural TAVR annulus sizing using 3D TEE and the “turnaround rule”. JACC Cardiovasc Imaging 2016;9:213–5. DOI: 10.1016/j.jcmg.2015.02.018; PMID: 26093927. Buzzatti N, Maisano F, Latib A, et al. Computed tomographybased evaluation of aortic annulus, prosthesis size and impact on early residual aortic regurgitation after transcatheter aortic valve implantation. Eur J Cardiothorac Surg 2013;43:43–50; discussion 50–1. DOI: 10.1093/ejcts/ezs155; PMID: 22551969. Faletti R, Gatti M, Salizzoni S, et al. Cardiovascular magnetic resonance as a reliable alternative to cardiovascular computed tomography and transesophageal echocardiography for aortic annulus valve sizing. Int J Cardiovasc Imaging 2016;32:1255–63. DOI: 10.1007/s10554–016–0899–8; PMID: 27117264. Rendon A, Hamid T, Kanaganayagam G, et al. Annular sizing using real-time three-dimensional intracardiac echocardiography-guided trans-catheter aortic valve replacement. Open Heart 2016;3:e000316. DOI: 10.1136/ openhrt–2015–000316; PMID: 27158522 PMCid:PMC4854149. Stortecky S, Heg D, Gloekler S, et al. Accuracy and reproducibility of aortic annulus sizing using a dedicated threedimensional computed tomography reconstruction tool in patients evaluated for transcatheter aortic valve replacement. EuroIntervention 2014;10:339–46. DOI: 10.4244/EIJV10I3A59; PMID: 24273249. Bleakley C, Eskandari M, Monaghan M. 3D transoesophageal echocardiography in the TAVI sizing arena: should we do it and how do we do it? Echo Res Pract 2017;4:R21–R32. DOI: 10.1530/ ERP–16–0041; PMID: 28302656. Attizzani GF, Ohno Y, Latib A, et al. Transcatheter aortic valve implantation under angiographic guidance with and without adjunctive transesophageal echocardiography. Am J Cardiol 2015;116:604–11. DOI: 10.1016/j.amjcard.2015.05.024; PMID: 26081069. Dall’Ara G, Eltchaninoff H, Moat N, et al. Transcatheter Valve Treatment Sential Registry (TCT) Investigators of the EuroObservational Research Programme (EORP) of the European Society of Cardiology. Local and general anaesthesia do not influence outcome of transfemoral aortic valve implantation. Int J Cardiol 2014;177:448–54. DOI: 10.1016/j. ijcard.2014.09.025; PMID: 25443245. Jensen HA, Condado JF, Deireddy C, et al. Minimalist transcatheter aortic valve replacement: The new standard for

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surgeons and cardiologists using transfemoral access? J Thorac Cardiovasc Surg 2015;150:833–9. DOI: 10.1016/j.jtcvs.2015.07.078; PMID: 26318351. Oguri A, Yamamoto M, Mouillet G, et al. FRANCE 2 Registry Investigators. Clinical outcomes and safety of transfemoral aortic valve implantation under general versus local anesthesia: subanalysis of the French Aortic National CoreValve and Edwards 2 registry. Circ Cardiovasc Interv 2014;7:602–10. DOI: 10.1161/CIRCINTERVENTIONS.113.000403; PMID: 25006175. Villablanca A, Mohananey D, Nikolic K, et al. Comparison of local versus general anesthesia in patients undergoing transcatheter aortic valve replacement: A meta–analysis. Catheter Cardiovasc Interv 2017. DOI: 10.1002/ccd.27207; PMID: 28738447; epub ahead of press. Kronzon I, Jelnin V, Ruiz CE, et al. Optimal imaging for guiding TAVR: transesophageal or transthoracic echocardiography, or just fluoroscopy? JACC Cardiovasc Imaging 2015;8:361–70. DOI: 10.1016/j.jcmg.2015.01.003; PMID: 25772839. Martín M1, Luyando LH, de la Hera JM, et al. The importance of echocardiography in transcatheter aortic valve implantation: TAVI: a multimodality approach. Echocardiography 2014;31:911. DOI: 10.1111/echo.12633; PMID: 25080842. Otto CM, Kumbhani JD, Alexander KP, et al. 2017 ACC Expert Consensus Decision Pathway for Transcatheter Aortic Valve Replacement in the Management of Adults With Aortic Stenosis: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2017;69:1313–46. DOI: 10.1016/j.jacc.2016.12.006; PMID: 28063810. Enriquez–Sarano M, Akins CW, Vahanian A. Mitral regurgitation. Lancet 2009;373:1382–94. DOI: 10.1016/S0140–6736(09)60692–9. Feldman T, Kar S, Elmariah S, et al. EVEREST II Investigators. Randomized comparison of percutaneous repair and surgery for mitral regurgitation: 5-year results of EVEREST II. J Am Coll Cardiol 2015;66:2844–54. DOI: 10.1016/j.jacc.2015.10.018; PMID: 26718672. Silvestry FE, Rodriguez LL, Herrmann HC, et al. Echocardiographic guidance and assessment of percutaneous repair for mitral regurgitation with the Evalve MitraClip: lessons learned from EVEREST I. J Am Soc Echocardiogr 2007;20:1131–40. DOI: 10.1016/j. echo.2007.02.003; PMID: 17570634. Feldman T, Kar S, Rinaldi M, et al. EVEREST Investigators. Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol 2009;54:686–94. DOI: 10.1016/j.jacc.2009.03.077; PMID: 19679246. Hahn RT. Transcathether valve replacement and valve repair: review of procedures and intraprocedural echocardiographic imaging. Circ Res 2016;119:341–56. DOI: 10.1161/ CIRCRESAHA.116.307972; PMID: 27390336. Altiok E, Becker M, Hamada S, et al. Optimized guidance of percutaneous edge-to-edge repair of the mitral valve using real-time 3-D transesophageal echocardiography. Clin Res Cardiol 2011;100:675–81. DOI: 10.1007/s00392–011–0296–1; PMID: 21369924. Wunderlich NC, Siegel RJ. Peri-interventional echo assessment for the MitraClip procedure. Eur Heart J Cardiovasc Imaging 2013;14:935–49. DOI: 10.1093/ehjci/jet060; PMID: 24062377. Biner S, Perk G, Kar S, et al. Utility of combined two-dimensional and three-dimensional transesophageal imaging for catheterbased mitral valve clip repair of mitral regurgitation. J Am Soc Echocardiogr 2011;24:611–7. DOI: 10.1016/j.echo.2011.02.005; PMID: 21435839. Saitoh T, Izumo M, Furugen A, et al. Echocardiographic evaluation of iatrogenic atrial septal defect after catheter-based mitral valve clip insertion. Am J Cardiol 2012;109:1787–91. DOI: 10.1016/j.amjcard.2012.02.023; PMID: 22475361. Schueler R, Öztürk C, Wedekind JA, et al. Persistence of iatrogenic atrial septal defect after interventional mitral valve

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Interventional Echocardiography repair with the MitraClip system: a note of caution. JACC Cardiovasc Interv 2015;8:450–9. DOI: 10.1016/j.jcin.2014.10.024; PMID: 25703879. 46. Attizzani GF, Ohno Y, Capodanno D, et al. Extended use of percutaneous edge-to-edge mitral valve repair beyond EVEREST (Endovascular Valve Edge-to-Edge Repair) criteria: 30-day and 12-month clinical and echocardiographic outcomes from the GRASP (Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation) registry. JACC Cardiovasc Interv 2015;8(1 Pt A):74–82. DOI: 10.1016/j.jcin.2014.07.024; PMID: 25499300. 47. Lesevic H, Karl M, Braun D, et al. Long-term outcomes after MitraClip implantation according to the presence or absence of EVEREST inclusion criteria. Am J Cardiol 2017;119:1255–61. DOI: 10.1016/j.amjcard.2016.12.027; PMID: 28237285.

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48. W arnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease). Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;52:e143–263. DOI: 10.1016/j.jacc.2008.10.001; PMID: 19038677. 49. Sommer RJ, Hijazi ZM, Rhodes Jr JF. Pathophysiology of congenital heart disease in the adult: part I: Shunt lesions. Circulation 2008;117:1090–9. DOI: 10.1161/ CIRCULATIONAHA.107.714402; PMID: 18299514

50. R ana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure. JACC Cardiovasc Imaging 2010;3:749–60. DOI: 10.1016/j. jcmg.2010.01.007; PMID: 20633854. 51. Rana BS, Shapiro LM, CmCarthy KP, Ho SY. Three-dimensional imaging of the atrial septum and patent foramen ovale anatomy: defining the morphological phenotypes of patent foramen ovale. Eur J Echocardiogr 2010;11:i19–25. DOI: 10.1093/ ejechocard/jeq122; .PMID: 21078835 52. Bissessor N. Current perspectives in percutaneous atrial septal defect closure devices. Med Devices (Auckl) 2015;8:297–303. DOI: 10.2147/MDER.S49368. 53. Faletra FF, Pedrazzini G, Pasotti E, et al. 3D TEE during catheterbased interventions. JACC Cardiovasc Imaging 2014;7:292–308. DOI: 10.1016/j.jcmg.2013.10.012; PMID: 24651102.

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Interventional Cardiology

A Decade Later, Continued Transformation of Transcatheter Aortic Valve Replacement Michael N Young, MD and Sammy Elmariah, MD, MPH Cardiology Division, Massachusetts General Hospital, Boston, MA

Abstract The emergence of transcatheter aortic valve replacement as an effective treatment option in appropriately selected patients with severe aortic valve stenosis has proven to be revolutionary to the fields of interventional cardiology and cardiac surgery. As percutaneous technologies continue to mature and indications for transcatheter valve therapy concurrently expand, the contemporary management of valvular heart disease necessitates a multidisciplinary heart team approach that considers the indication, multimodality imaging, anesthetic and procedural strategy, and selection of the appropriate valve prosthesis for each patient. We provide an overview of the historical development of transcatheter aortic valve replacement, commercially available and investigative devices, landmark clinical trial data, and developments on the horizon that aim to further advance the care of patients with aortic valve disease.

Keywords Transcatheter heart valves, transcatheter aortic valve replacement, aortic stenosis, surgical risk, clinical trials Disclosure: The authors have no relevant conflicts of interest to declare. Received: 12 October 2017 Accepted: 6 December 2017 Citation: US Cardiology Review 2018;12(1):28–32. DOI: 10.15420/usc.2017:25:2 Correspondence: Sammy Elmariah, MD MPH, Massachusetts General Hospital, 55 Fruit Street, GRB 815, Boston, MA 02114, USA. E: selmariah@mgh.harvard.edu

Severe aortic valve stenosis (AS) is a chronic, progressive illness that confers significant morbidity and mortality. Once symptomatic, patients with severe AS will ultimately succumb to the disease if it is not promptly corrected.1 Historically, surgical aortic valve replacement (SAVR) served as the exclusive therapeutic option to correct this mechanical problem.2 However, in 2002, Alain Cribier performed the first-in-man percutaneous implantation of a bioprosthetic aortic valve.3 Since this pivotal moment in the field of structural heart disease, transcatheter aortic valve replacement (TAVR) has developed into a contemporary, effective treatment option for severe AS. Multiple large, randomized clinical trials have demonstrated the superiority of TAVR versus medical therapy in the extreme surgical risk patient population, as well as the comparability of TAVR versus SAVR in all but the lowest surgical risk population to date.4–9 Since 2002, the equipment, techniques, and performance of TAVR continue to transform at a rapid pace.10 Yet, considerable work remains to fully eliminate the known complications of percutaneous valve replacement, including paravalvular leak and complete heart block requiring permanent pacemaker implantation, and to clearly determine the durability of transcatheter heart valves (THV).11 Furthermore, clinicians continue to seek innovative methods to minimize peri-procedural sedation, reduce hospital length of stay, and optimize cost effectiveness.12,13 In this focused review, we summarize the evolution of balloon-expandable and selfexpanding THVs and highlight innovative valve platforms presently under investigation. We provide a timeline and summary of the landmark clinical trials showing favorable clinical outcomes following TAVR, as well as the evidence supporting its use in extreme, high, and intermediate surgical risk subgroups. We also emphasize exciting developments in peri-procedural

Access at: www.USCjournal.com

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TAVR management and adjunctive technological advancements that continue to revolutionize the field.

Commercial and Investigational Transcatheter Heart Valves Two valve platforms are currently commercially available within the US – the Edwards SAPIEN balloon-expandable bioprosthesis and the Medtronic self-expanding bioprosthesis. The Edwards SAPIEN 3 THV is a trileaflet, bovine bioprosthesis based on a cobalt chromium frame, available in four sizes (20, 23, 26, and 29 mm) and deployed through a 14–16 French Commander Delivery System (transfemoral) or 18–21 French Certitude Sheath (transapical). With improvement in delivery sheath designs, the third-generation SAPIEN 3 THV can be advanced through 14–16 French expandable sheaths, whereas first-generation and second-generation THVs required much larger delivery profiles (up to 24 French and 20 French, respectively). In addition, as opposed to the older generation valves, the SAPIEN 3 THV comes with a polyethylene terephthalate skirt designed to reduce paravalvular regurgitation (PVR). Of historical note, the Edwards SAPIEN THV platform directly evolved from Dr. Alain Cribier’s initial design. The Medtronic self-expanding, supra-annular valve consists of porcine pericardial tissue mounted on a nitinol stent frame. While the firstgeneration CoreValve® offered sizes between 26 and 31 mm delivered through an 18 French sheath, there is a wider breadth of sizing options with the newer generation Evolut™ PRO (23, 26, and 29 mm) and Evolut R (34 mm) bioprostheses. The Evolut PRO line, also a third-generation device,

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Continued Transformation of Transcatheter Aortic Valve Replacement is delivered through a 16 French in-line sheath, thus allowing for a minimal luminal diameter of 5.5 mm for transarterial access. Routes for valve delivery include transfemoral, transaxillary, and transaortic access. A primary advantage of the new-generation Medtronic self-expanding valves includes the opportunity for recapturing and repositioning prior to permanent valve deployment. Furthermore, the Evolut PRO possesses an outer porcine pericardial tissue wrap to enhance prosthesis-to-annular contact and thus minimize paravalvular leak. In complement to the evolving designs of the Edwards SAPIEN and Medtronic CoreValve THVs, there has been considerable effort devoted to the development and study of alternative percutaneous valve designs. Table 1 depicts design specifications of the newest generation, commercially available THVs approved for TAVR, while Figure 1 provides an illustration of investigational THVs. Each investigational THV is engineered with features designed specifically to address known challenges of valve deployment or complications following TAVR. For example, the Lotus™ Valve System (Boston Scientific) is a mechanically expanded THV that consists of bovine pericardial tissue mounted on a woven nitinol stent frame. An outer adaptive seal is included on the valve specifically to minimize paravalvular leak, while the delivery system also permits retrievability and repositioning as needed. In addition, larger stent cell design purportedly may reduce the risk of coronary obstruction.14 Similarly, the Portico™ Valve (St. Jude Medical) is a self-expanding valve with a porcine pericardial sealing cuff. This valve is entirely resheathable prior to deployment (as opposed to Medtronic Evolut THV, which is partially recapturable). The valve leaflets and cuff are also treated with anticalcification technology.15 The CENTERA Valve (Edwards Lifesciences) is a self-expanding bovine valve that sits at the annular level on a nitinol stent frame. One unique feature of this valve’s delivery system includes a motorized, detachable handle.16 The JenaValve™ is yet another bioprosthesis composed of porcine pericardial tissue on a self-expanding nitinol stent, with CE-mark approval for transapical deployment.17 This THV possesses an active anchoring mechanism that resists valve migration during deployment.

TAVR Outcome Data for Extreme, High, and Intermediate Surgical Risk Groups PARTNER-1 and PARTNER-2 Clinical Trials The 2- and 5-year data from the Placement Of Aortic Transcatheter Valves (PARTNER)-1 inoperable and high surgical risk cohorts were published in 2012 and 2015 (Figure 2).7,8,18,19 For inoperable patients (cohort B), mortality rates in the TAVR group using the first-generation, balloon-expandable, Edwards SAPIEN valve were 43.3 % compared with 68.0 % with standard therapy (p<0.001) at 2 years and 71.8 % versus 93.6 % (p<0.0001) at 5 years. Patients undergoing transcatheter valve therapy also exhibited substantially improved New York Heart Association (NYHA) Class symptoms. At 2 years, stroke rates were higher in the TAVR population (13.8 % versus 5.5 %; p<0.01), a difference driven predominately by early peri-procedural embolic events. However, at 5 years, stroke rates were comparable between groups (16 % versus 18.2 %; p=0.56). Finally, echocardiographic results adjudicated at an independent imaging core laboratory revealed durable prosthetic valve hemodynamics out to 5 years post-TAVR, and there was no evidence of structural deterioration of implanted THVs.

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Table 1: Design Specifications of Commercially-Available Transcatheter Heart Valves Characteristics

Edwards SAPIEN 3

Deployment

Balloon-expandable Self-expanding

Frame composition

Cobalt-chromium

Nitinol

Leaflet tissue

Bovine

Porcine

Prosthesis sizes (mm) 20, 23, 26, 29 Delivery sheath (sizes)

eSheath (14–16 F)

Advantages Outer sealing skirt

Medtronic Evolut R/PRO

23, 26, 29 (34 mm option for Evolut R) InLine sheath (14–16 F) Supra-annular position; recapturable; outer sealing wrap for Evolut Pro

Figure 1: Investigational Transcatheter Heart Valve Platforms

Portico

Centera INVESTIGATIONAL PLATFORMS

Lotus

Acurate

JenaValve

The ACURATE™ (Boston Scientific), CENTERA (Edwards Lifesciences), JenaValve™ (JenaValve Technology), Lotus™ (Boston Scientific), Portico™ (St. Jude Medical) valve prostheses are shown.

Meanwhile, in the high-risk PARTNER A cohort, all-cause mortality rates were not statistically different between the transcatheter and surgical valve replacement groups at 1 year (24.3 % versus 26.8 %; p=0.45), 2 years (33.9 % versus 35 %; p=0.78), and 5 years (67.8 % versus 62.4 %; p=0.76). Rates of hospital readmission, functional status, stroke or transient ischemic attack, and valve performance by echocardiography were all comparable between TAVR and SAVR. Of note, moderate or severe PVR occurred more frequently in the transcatheter group compared with surgery (6.9 % versus 0.9 %; p<0.001). Higher severity of PVR was also associated with increased late mortality post-TAVR (72.4 % versus 56.6 %; p=0.003 for severe versus mild/ no aortic regurgitation). Overall, these longer-term data from PARTNER-1 supported the comparability of TAVR using a balloon-expandable THV versus SAVR in the high surgical risk patient population. Furthermore, for both the inoperable and high-risk PARTNER cohorts, THV hemodynamics remained stable out to 5 years without evidence of structural deterioration (inoperable: mean aortic valve area 1.52 cm2, mean gradient 10.9 mmHg; high-risk: mean aortic valve area 1.6 cm2, mean gradient 10.7 mmHg).7,8 In 2016, Leon and colleagues published results from the PARTNER2A clinical trial, a study that randomized 2,032 intermediate surgical risk patients with severe AS to SAVR or TAVR (second-generation SAPIEN XT THV).9 At 2 years, all-cause death or stroke was similar between groups (19.3 % versus 21.1 %; p=0.25 for TAVR versus SAVR, respectively). While major vascular complications occurred more

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Interventional Cardiology frequently in the transcatheter group than surgery (7.9 % versus 5.0 %; p=0.008, respectively) at 30 days, TAVR patients suffered lower rates of life-threatening bleeding (10.4 % versus 43.4 %; p<0.001), acute kidney injury (1.3 % versus 3.1 %; p=0.06), and new-onset AF (9.1 % versus 26.4 %; p<0.001). TAVR also compared favorably to SAVR in terms of intensive care unit (median 2 versus 4 days, p<0.001) and hospital length of stay (median 6 versus 9 days; p<0.001). Pacemaker implantation rates within 30 days (8.5 % versus 6.9 % for TAVR versus SAVR; p=0.17) and readmission rates at 2 years (19.6 % versus 17.3 %; p=0.22) were similar between groups. Notably, the frequency and severity of PVR were higher in the transcatheter group compared with surgery. TAVR patients with moderate or severe PVR suffered higher all-cause mortality than trace or no PVR (hazard ratio 2.85; 95 % CI [1.57–5.21]; p<0.001).

United States CoreValve Pivotal Trial and SURTAVI In close succession to the PARTNER trials, the US Pivotal Trials studied the efficacy of the self-expanding Medtronic CoreValve for severe AS for the extreme and high surgical risk populations (Figure 2).4,5 The CoreValve Extreme Risk Pivotal Trial enrolled 489 patients in a non-randomized, single-arm study design. The primary endpoint of 12-month all-cause mortality or major stroke occurred in 127 patients (26 %). Individually, all-cause mortality occurred in 119 patients (24.3 %) and major stroke in 19 patients (4.3 %). There was a significant improvement in NYHA class symptomatology at 12 months post-valve implantation compared with baseline. In 2015, Yakubov et al published 2-year outcomes for this extreme risk cohort, showing an increase in the primary endpoint to 38.0 % (all-cause mortality 36.6 %, major stroke 5.1 %). Impressively, 94 % patients in the cohort reported NYHA class I or II symptoms. Valve hemodynamics remained durable at 2 years.20 The US Pivotal Trial for high surgical risk patients randomized 795 patients 1:1 to self-expanding CoreValve versus conventional surgical valve replacement. TAVR was superior to SAVR with respect to all-cause mortality at 1 year (intention-to-treat, absolute risk reduction 4.8 %; p=0.04 for superiority).4 At 3 years, the combined endpoint of all-cause mortality or stroke for TAVR versus SAVR was 37.3 % versus 46.7 %; p=0.006, respectively. There was an overall higher frequency of permanent pacemaker implantation following TAVR compared with SAVR present at 1, 2, and 3 years of follow-up (22.3 % versus 11.3 %, p<0.001; 25.8 % versus 12.8 %, p<0.001; and 28 % versus 14.5 %, p<0.001, respectively). However, TAVR performed favorably compared with SAVR with respect to major adverse cardiovascular or cerebrovascular events, all stroke, major or life-threatening bleeding, and acute kidney injury. Functional class by NYHA symptomatology was comparable between groups. Notably, TAVR patients treated through the ileofemoral access route experienced more rapid improvements in functional status and heart failure symptomatology compared with SAVR. The incidence of moderate or severe PVR was overall quite low in the study (6.8 %). Finally, mean aortic valve gradients at 3 years post-TAVR compared favorably to surgery, with no evidence of clinical valve thrombosis or structural deterioration in either group.6 Most recently, in 2017, Reardon and colleagues published results from the Safety And Efficacy Study Of The Medtronic Corevalve System In The Treatment Of Severe, Symptomatic Aortic Stenosis In Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) study.21 This intermediate surgical risk trial randomized 1,746 patients in 87 centers to

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TAVR using a self-expanding THV (CoreValve bioprosthesis 84 %, Evolut R 16 %) versus SAVR. At 24 months, TAVR was non-inferior to SAVR with respect to the composite primary endpoint of all-cause death or disabling stroke (12.6 % versus 14.0 %, respectively; 95 % credible interval [Bayesian analysis] for difference −5.2 to 2.3 %; posterior probability of non-inferiority >0.999). As seen in the high risk US pivotal trial, a higher proportion of patients undergoing transcatheter valve replacement suffered a major vascular complication (6.0 % versus 1.1 %) or required permanent pacemaker implantation (25.9 % versus 6.6 %). However, SAVR patients had higher rates of blood transfusions, acute kidney injury, and AF compared with TAVR. While the TAVR cohort demonstrated more favorable hemodynamic profiles on echocardiography compared with SAVR, moderate or severe PVR also occurred more frequently at 1 year with TAVR (5.3 % versus 0.6 %). The investigators concluded that TAVR was a non-inferior alternative to SAVR for patients with severe AS at intermediate surgical risk.

Minimalist TAVR Traditionally, TAVR was performed under general anesthesia, deep sedation, endotracheal intubation with mechanical ventilation, and transesophageal echocardiographic guidance (TEE).12 However, in recent years there has been considerable interest in minimizing the amount of ancillary invasive procedures. Thus, experienced centers have successfully performed TAVR using local anesthesia and conscious sedation alone. In these cases, operators may elect to use transthoracic echocardiography or fluoroscopy alone for guiding valve deployment. This ‘minimalist’ philosophy is based on the theory that procedural time is reduced, recovery is expedited, and hospital length of stay can be shortened. Furthermore, the associated risks, albeit low, of general anesthesia, intubation, and TEE may be avoided completely. Opponents of minimalist TAVR cite the lack of randomized trial data to support the use of conscious sedation over general anesthesia or transesophageal echocardiographic versus transthoracic or fluoroscopic guidance during TAVR deployment. Furthermore, TEE is considered to be a very safe procedure with low event rates, even with conscious sedation. Babaliaros and colleagues published results of minimalist versus standard approach TAVR based on data from their institutional experience.13 In this observational study, procedure room time, intensive care unit time, and hospital length of stay were all shorter for the minimalist approach. Meanwhile, 30-day clinical outcomes and survival beyond a median of 1 year were comparable between groups. The ensuing cost analysis performed also favored the minimalist approach versus standard care ($45,485 ± 14,397 versus $55,377 ± 22,587; p<0.001). Regardless, the minimalist approach should be determined on a case-by-case basis and vetted by the multidisciplinary heart team during the pre-procedural planning period.

Cerebral Embolic Protection While stroke rates post-TAVR have improved over time, there is enthusiasm around the development of devices to further minimize this risk.22–24 For example, the Sentinel™ Cerebral Protection System (Claret Medical Inc.) recently received US Food and Drug Administration (FDA) clearance for use during TAVR. This device consists of a dualfilter system with a 6F articulating sheath delivered via the right radial artery. The proximal nitinol filter (15 mm) is situated in the right brachiocephalic artery while the distal filter (10 mm) is positioning in the left common carotid artery.

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Continued Transformation of Transcatheter Aortic Valve Replacement Figure 2: Timeline of the Landmark TAVR Clinical Trials and Commercial Approval by the FDA Publication of the PARTNER-2 (Cohort A) Trial 2016

Publication of the PARTNER-1 (Cohort A) Trial 2010

FDA expands indication for Sapien XT/3 THV for intermediate risk patients 8/2016 FDA expands indication for Sapien 3 in aortic and mitral VIV 6/2017

Publication of the PARTNER-1 (Cohort B) Trial 2011

Publication of the SURTAVI Trial 2017 First-in-man TAVI performed by Dr. Alain Cribier 2002

FDA expands indication for CoreValve, Evolut R/Pro for intermediate risk patients 7/2017

FDA approves Sapien THV for inoperable patients 11/2011 and high risk patients 6/2012

Publication of the US Pivotal Trial (Extreme and High Surgical Risk Cohorts) 2014

FDA approves CoreValve THV for extreme risk patients 1/2014 and high risk patients 6/2014

FDA = Food and Drug Administration; PARTNER = Placement Of Aortic Transcatheter Valves trial; TAVI = transcatheter aortic valve implantation; TAVR = transcatheter aortic valve replacement; THV = transcatheter heart valve.

In the Sentinel clinical trial,25 although there were no statistically significant differences in terms of major adverse cardiac and cerebrovascular events or new lesion volume by MRI, investigators reported 99 % debris captured by the device post-TAVR. In a recent propensity-matched analysis published by Seeger and colleagues, use of cerebral protection with the Sentinel device was associated with a reduced rate of disabling and nondisabling stroke (OR 0.29; 95 % CI [0.10–0.93]; p=0.03) as well as reduced composite primary endpoint of all-cause mortality or allstroke (OR 0.30; 95 % CI [0.12–0.77]; p=0.01). While this study was not randomized, it does suggest a potential neurological benefit of cerebral protection during TAVR.26 Another device – the TriGUARD™ 3 HDH Embolic Deflection Device (Keystone Heart) – uses a polymeric mesh that fully covers the supraaortic trunk takeoffs, delivered through an 8F system from the groin. This device is currently under investigation and not commercially available for use in the US (the Cerebral Protection to Reduce Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation [REFLECT] trial is ongoing [ClinicalTrials.gov NCT 02536196]). Further study is merited to understand the specific immediate and long-term advantages that may be conferred by these innovative technologies.

Expanding Indications Given the game-changing success of TAVR in the treatment of calcific aortic valve stenosis, tremendous efforts have ensued to apply this technology to other forms of valvular heart disease including: congenital bicuspid aortic valve stenosis; prosthetic valve degeneration; mixed or pure aortic regurgitation; mitral, tricuspid, or pulmonic valve diseases; and alternative AS patient populations (e.g. asymptomatic severe AS, moderate AS with left ventricular dysfunction).27 For instance, several institutions have published observational studies that proclaim the feasibility and safety of performing TAVR for bicuspid AS.28–30 However, there have been no large-scale, randomized control trials designed specifically for this congenital patient

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population. Lingering concerns regarding the percutaneous treatment of congenital bicuspid aortic valve disease include concomitant ascending aortic disease and dilatation, unusual valve geometries, and unknown long-term durability of THVs, particularly with respect to this inherently younger patient cohort. Several of these critiques are also echoed for transcatheter therapy in non-calcified valvular lesions such as mixed or pure aortic regurgitation, in which there may be higher risk for valve malapposition and embolization. Therefore, additional investigation – ideally in the context of randomized comparative data – is warranted prior to widespread expansion of TAVR to such populations. In addition, transcatheter valve-in-valve (ViV) therapy has received growing attention as a means to avoid redo sternotomy for patients with failed surgical bioprostheses. The Valve-in-Valve International Data Registry introduced in 2010 represents the largest global experience of aortic ViV to date, and 30-day mortality was 7.6 % in this cohort.31,32 While aortic ViV is associated with lower frequencies of PVR and pacemaker implantation, there are higher reported rates of malpositioning, coronary obstruction, and residual prosthetic valve gradients. ViV procedures have most commonly employed the use of the Medtronic CoreValve and Edwards SAPIEN XT THV, although there have been published reports using alternative prostheses such as the Portico and SAPIEN 3 valves. Notably, in June 2017, the US FDA expanded the approval indication for the SAPIEN 3 THV in failed bioprosthetic valves in the aortic or mitral positions for high-risk patients. Finally, one of the remaining patient populations of immense interest is the low surgical risk cohort. While the PARTNER-1, PARTNER-2A, US Pivotal, and SURTAVI clinical trials have substantiated the effectiveness of TAVR for extreme, high, and intermediate risk subgroups, current trials are underway to randomize low-risk patients to either surgical or percutaneous valve replacement. These include PARTNER-3 (The Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in

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Interventional Cardiology Low Risk Patients with Aortic Stenosis; ClinicalTrials.gov NCT02675114), and the Medtronic Transcatheter Aortic Valve Replacement in Low Risk Patients (ClinicalTrials.gov NCT02701283). In 2016 and 2017, respectively, the US FDA granted an expanded indication approval for the balloonexpandable, Edwards SAPIEN 3 and SAPIEN XT THVs and the selfexpanding, CoreValve and Evolut R/Pro THVs in intermediate-risk patients with severe AS. As the indications for TAVR have expanded over time (Figure 2), vigorous debate continues with respect to the lowest surgical risk patient population. For instance, the long-term durability of transcatheter bioprosthetic valves beyond 5 years is as yet unclear. In addition, implanting THVs in younger, low-risk patients may confer an increased downstream probability of requiring more ViV procedures over their collective lifetimes. With each additional ViV TAVR, a patient is subject to the risks of procedural complications, obstructed coronary access over time, increased residual THV gradients, and reduced aortic valve areas for body size (i.e. patient–prosthesis mismatch). Furthermore, the lifetime impact of residual paravalvular leak or permanent pacemaker in this patient group is of concern and should be prospectively studied. Data from the low-risk Edwards and Medtronic clinical trials will hopefully clarify the clinical impact of the above concerns, including THV durability several years post-implantation (i.e. 10 years or more), and of course, inform us of the comparability of TAVR and SAVR in this lowest-risk subgroup.

tto CM, Prendergast B. Aortic-valve stenosis--from patients at O risk to severe valve obstruction. N Engl J Med 2014;371:744–56. DOI: 10.1056/NEJMra1313875; PMID: 25140960 2. Schwarz F, Baumann P, Manthey J, et al. The effect of aortic valve replacement on survival. Circulation 1982;66:1105–10. DOI: 10.1161/01.CIR.66.5.1105; PMID: 7127696 3. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002;106:3006–8. DOI: 10.1161/01.CIR.0000047200.36165.B8; PMID: 12473543 4. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aorticvalve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790–8. DOI: 10.1056/NEJMoa1400590;PMID: 24678937 5. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63:1972–81. DOI: 10.1016/j.jacc.2014.02.556; PMID: 24657695 6. Deeb GM, Reardon MJ, Chetcuti S, et al. 3-Year Outcomes in High-Risk Patients Who Underwent Surgical or Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2016;67:2565–74. DOI: 10.1016/j.jacc.2016.03.506; PMID: 27050187 7. Kapadia SR, Leon MB, Makkar RR, et al. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): A randomised controlled trial. Lancet 2015;385:2485–91. DOI: 10.1016/S0140-6736(15)60290-2; PMID: 25788231 8. Mack MJ, Leon MB, Smith CR, et al. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): A randomised controlled trial. Lancet 2015;385:2477–84. DOI: 10.1016/S0140-6736(15)60308-7; PMID: 25788234 9. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. DOI: 10.1056/NEJMoa1514616; PMID: 27040324 10. Figulla HR, Webb JG, Lauten A, Feldman T. The transcatheter valve technology pipeline for treatment of adult valvular heart disease. Eur Heart J 2016;37:2226–39. DOI: 10.1093/eurheartj/ ehw153; PMID: 27161617 11. Khatri PJ, Webb JG, Rode´s-Cabau J, et al. Adverse effects associated with transcatheter aortic valve implantation: a metaanalysis of contemporary studies. Ann Intern Med 2013;158:35-46. DOI: 10.7326/0003-4819-158-1-201301010-00007; PMID: 23277899 12. Jensen HA, Condado JF, Devireddy C, et al. Minimalist transcatheter aortic valve replacement: The new standard for surgeons and cardiologists using transfemoral access? J Thorac

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Conclusions Since Alain Cribier performed the first-in-human TAVR in 2002, we have witnessed an unparalleled revolution in the field of structural heart disease and intervention. Data from the PARTNER-1 and US Pivotal Trials support the efficacy of TAVR out to 5 and 3 years, respectively, although the longer-term durability of THVs beyond this time frame remains to be seen. Recently, the PARTNER-2A and SURTAVI clinical trials have consistently demonstrated the non-inferiority of TAVR to SAVR in intermediate-risk patient populations, while we anticipate results from the low-risk clinical trials (e.g. PARTNER-3), presently in enrolment. In the past decade, the designs of the traditional balloon-expandable and self-expanding THVs have steadily evolved in attempts to attenuate known risks of TAVR, such as paravalvular leak and pacemaker implantation. Examples of design modifications incorporated into newer device iterations include sealing skirts and re-sheathable platforms. Furthermore, there has been a movement to make TAVR as minimally invasive as possible, with some operators performing this procedure under local anesthesia, conscious sedation, and fluoroscopic guidance alone. At the heart of the TAVR movement, the consistent foundation for success throughout this era is the multidisciplinary heart team approach to patient care. By leveraging the skills and expertise of interventional cardiologists, cardiac surgeons, anesthesiologists, nursing, and other allied health professionals, the opportunity to provide patientcentered, holistic care is achieved for any patient being considered for surgical or percutaneous aortic valve replacement. n

Cardiovasc Surg 2015:150;833–9. DOI: 10.1016/j.jtcvs.2015.07.078; PMID: 26318351 Babaliaros V, Devireddy C, Lerakis S, et al. Comparison of transfemoral transcatheter aortic valve replacement performed in the catheterization laboratory (minimalist approach) versus hybrid operating room (standard approach): outcomes and cost analysis. JACC Cardiovasc Interv 2014;7:898-904. DOI: 10.1016/j. jcin.2014.04.005; PMID: 25086843 Meredith IT, Walters DL, Dumonteil N, et al. 1-year outcomes with the fully repositionable and retrievable lotus transcatheter aortic replacement valve in 120 high-risk surgical patients with severe aortic stenosis: Results of the REPRISE II study. JACC Cardiovasc Interv 2016;9:376–84. DOI: 10.1016/j.jcin.2015.10.024; PMID: 26892084 Willson AB, Rodès-Cabau J, Wood DA, et al. Transcatheter aortic valve replacement with the St. Jude medical portico valve: First-in-human experience. J Am Coll Cardiol 2012;60:581–6. DOI: 10.1016/j.jacc.2012.02.045; PMID: 22657270 Binder RK, Schäfer U, Kuck KH, et al. Transcatheter aortic valve replacement with a new self-expanding transcatheter heart valve and motorized delivery system. JACC Cardiovasc Interv 2013;6:301–7. DOI: 10.1016/j.jcin.2013.01.129; PMID: 23517843 Treede H, Mohr F-W, Baldus S, et al. Transapical transcatheter aortic valve implantation using the JenaValveTM system: acute and 30-day results of the multicentre CE-mark study. Eur J Cardiothorac Surg 2012;41:e131–8. DOI: 10.1093/ejcts/ezs129; PMID: 22508111 Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter AorticValve Replacement for Inoperable Severe Aortic Stenosis. N Engl J Med 2012;366:1696–704. DOI: 10.1056/NEJMoa1202277; PMID: 22443478 Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686–95. DOI: 10.1056/NEJMoa1200384; PMID: 22443479 Yakubov SJ, Adams DH, Watson DR, et al. 2-year outcomes after iliofemoral self-expanding transcatheter aortic valve replacement in patients with severe aortic stenosis deemed extreme risk for surgery. J Am Coll Cardiol 2015;66:1327–34. DOI: 10.1016/j.jacc.2015.07.042; PMID: 26383718 Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediaterisk patients. N Engl J Med 2017;376:1321–31. DOI: 10.1056/ NEJMoa1700456; PMID: 28304219 Rodés-Cabau J, Kahlert P, Neumann FJ, et al. Feasibility and exploratory efficacy evaluation of the embrella embolic deflector system for the prevention of cerebral emboli in

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patients undergoing transcatheter aortic valve replacement: The PROTAVI-C pilot study. JACC Cardiovasc Interv 2014;7:1146–55. DOI: 10.1016/j.jcin.2014.04.019; PMID: 25341709 Lansky AJ, Schofer J, Tchetche D, et al. A prospective randomized evaluation of the TriGuardTM HDH embolic DEFLECTion device during transcatheter aortic valve implantation: Results from the DEFLECT III trial. Eur Heart J 2015;36:2070–8. DOI: 10.1093/eurheartj/ehv191; PMID: 25990342 Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis. JAMA 2016;316:592. DOI: 10.1001/jama.2016.10302; PMID: 27532914 Kapadia SR, Kodali S, Makkar R, et al. Protection against cerebral embolism during transcatheter aortic valve replacement. J Am Coll Cardiol 2017;69:367-377. PMID: doi: 10.1016/j.jacc.2016.10.023; PMID: 27815101 Seeger J, Gonska B, Otto M, Rottbauer W, Wöhrle J. Cerebral embolic protection during transfemoral aortic valve replacement significantly reduces death and stroke compared with unprotected procedures. JACC Cardiovasc Interv 2017;10:2297– 303. DOI: 10.1016/j.jcin.2017.06.037; PMID: 28917515 Praz F, Windecker S, Huber C, Carrel T, Wenaweser P. Expanding indications of transcatheter heart valve interventions. JACC Cardiovasc Interv 2015;8:1777–96. DOI: 10.1016/j.jcin.2015.08.015; PMID: 26718509 Kochman J, Rymuza B, Huczek Z. Transcatheter aortic valve replacement in bicuspid aortic valve disease. Curr Opin Cardiol 2015;30:594–602. DOI: 10.1097/HCO.0000000000000219; PMID: 26398414 Perlman GY, Blanke P, Dvir D, et al. Bicuspid Aortic Valve Stenosis: Favorable Early Outcomes with a Next-Generation Transcatheter Heart Valve in a Multicenter Study. JACC Cardiovasc Interv 2016;9:817–24. DOI: 10.1016/j.jcin.2016.01.002; PMID: 27101906 Yoon S-H, Lefèvre T, Ahn J-M, et al. Transcatheter aortic valve replacement with early- and new-generation devices in bicuspid aortic valve stenosis. J Am Coll Cardiol 2016;68:1195–205. DOI: 10.1016/j.jacc.2016.06.041; PMID: 27609682 Dvir D, Webb J, Brecker S, et al. Transcatheter aortic valve replacement for degenerative bioprosthetic surgical valves: Results from the global valve-in-valve registry. Circulation 2012;126:2335–44. DOI: 10.1161/CIRCULATIONAHA.112.104505; PMID: 23052028 Dvir D, Barbanti M, Tan J, Webb JG. Transcatheter aortic valvein-valve implantation for patients with degenerative surgical bioprosthetic valves. Curr Probl Cardiol 2014;39:7–27. DOI: 10.1016/j.cpcardiol.2013.10.001; PMID: 24331437

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Interventional Cardiology

Transcatheter Heart Valve Thrombosis: Incidence, Predictors, and Clinical Outcomes Ahmad Younes, MD, Guilherme F Attizzani, MD, and Ankur Kalra, MD Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Division of Cardiovascular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH

Abstract Since its initial approval, the number of transcatheter aortic valve replacement procedures performed has increased exponentially with evolving indications that now include patients at intermediate risk for perioperative mortality following surgery. Multiple studies and reports have observed the phenomenon of leaflet dysfunction and thrombosis on follow-up imaging that may be associated with serious adverse outcomes. This review provides an insight into the incidence, predictors, management, and follow-up of transcatheter heart valve thrombosis.

Keywords Transcatheter aortic valve replacement, transcatheter heart valve, leaflet thrombosis, hypoattenuated leaflet thickening, leaflet motion Disclosure: The authors have no conflicts of interest to declare. Received: 16 November 2017 Accepted: 21 December 2017 Citation: US Cardiology Review 2018;12(1):33–5. DOI: 10.15420/usc.2017:32:2 Correspondence: Ankur Kalra, MD, FACP, FACC, FSCAI, Division of Cardiovascular Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Mailstop LKS 5038, Cleveland, OH 44106, USA. E: kalramd.ankur@gmail.com

Transcatheter aortic valve replacement (TAVR) is a recent innovation that has transformed the care of patients with symptomatic severe aortic stenosis. It has emerged as an alternative for surgical aortic valve replacement (SAVR) in prohibitive-, high-risk, and more recently, intermediate-risk surgical patients. More than 200,000 TAVRs have been performed in 65 countries around the world.1 As for surgical valves, transcatheter heart valve (THV) thrombosis is a rare, but serious, clinical adverse event with reported mortality rates reaching 30 %.2 Multiple reports and studies have shed light on the incidence of THV leaflet thrombosis. This article summarizes the current and evolving literature on the incidence, predictors, and clinical outcomes of THV thrombosis.

Transcatheter Heart Valve Thrombosis: Emerging Concerns THV-reduced leaflet mobility was first described by Makkar et al. in patients enrolled in the Portico Re-sheathable Transcatheter Aortic Valve System US Investigational Device Exemption (PORTICO IDE) trial, and the Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and Its Treatment with Anticoagulation (RESOLVE) and Subclinical Aortic Valve Bioprosthesis Thrombosis Assessed with Four-Dimensional Computed Tomography (SAVORY) registries.3 Patients underwent a dedicated 4D, volume-rendered computed tomography (CT) scan at different time intervals post TAVR with reduced leaflet motility

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ranging from 13 to 40 %. Although the study was underpowered for clinical outcomes, several important findings were described: (i) the incidence of stroke or transient ischemic attack (TIA) was higher in patients with reduced leaflet mobility (18 % versus 1 %; p=0.007); (ii) patients on therapeutic anticoagulation with warfarin had a lower incidence of reduced leaflet mobility compared with patients on dual antiplatelet therapy (0 % versus 51 %; p=0.007); and (iii) therapeutic anticoagulation completely resolved the CT finding of reduced leaflet mobility. In a retrospective analysis of 4,266 consecutive patients who underwent TAVR with Edwards Sapien/Sapien XT (Edwards Lifesciences) and Medtronic CoreValve (Medtronic, Inc.) in 12 centers, Latib et al. reported 26 patients with valve thrombosis, defined as valve dysfunction in addition to either histopathology or an imaging modality demonstrating evidence for thrombosis, or an appropriate hemodynamic response to anticoagulation, restoring normal prosthetic valve function within 2 months of therapy.4 The incidence of clinically significant leaflet thrombosis was reported as 0.61 % in this large multicenter registry, with the majority of patients presenting with worsening dyspnea (65 %) and having increased transvalvular gradients (92 %).4 A recent report from The Manufacturer and User Facility Device Experience (MAUDE) database revealed 30 cases of structural valve dysfunction due to leaflet thrombosis (Edwards Sapien = 20; CoreValve = 10) out of the 5,691 TAVR-related adverse events.

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Interventional Cardiology Clinical Versus Subclinical Transcatheter Heart Valve Thrombosis Clinically significant THV thrombosis manifests as either heart failure or stroke or TIA, and has been associated with adverse clinical events, including cardiogenic shock in 6.7 % of cases and death in 10.7–30.0 % of cases.2,4,5 Subclinical THV thrombosis is diagnosed if there is either an increase in transaortic mean gradient on follow-up studies by 10 mmHg or direct visualization of thrombus on the leaflets; or a CT scan identifying reduced leaflet motility along with hypoattenuated leaflet thickening are documented on cardiovascular imaging in the absence of the aforementioned clinical manifestations, followed by resolution of imaging findings following a course of anticoagulation. Interpretable CT scans (from 890 patients) in RESOLVE and SAVORY registries identified subclinical THV thrombosis in 106 patients; normal leaflet motion was restored in 31 patients after initiation of anticoagulation.6

Hypoattenuated Leaflet Thickening Versus Hypoattenuation Affecting Motion As Predictors of Thrombosis An important distinction in the natural history of progression of THV leaflet thrombosis is the imaging characteristic of the valve, and its implication on prognosis and clinical outcomes. As noted in earlier studies, hypoattenuated leaflet thickening (HALT) observed on CT scans performed post implantation was not a rare finding, and was dependent on post-procedural antithrombotic therapy. In a study evaluating Edwards Sapien 3 transcatheter aortic valves on post-TAVR CT scans (median 5 days), HALT was noted in 10.3 % of asymptomatic patients, with near resolution after anticoagulation.7 In another study with longerterm follow-up of Edwards Sapien XT valves, multi-detector CT scans identified HALT in 1.4 % of patients at discharge, 10 % at 6 months, and 14.3 % at 1 year.8 In their analysis from the SAVORY registry that included patients undergoing both TAVR (n=75) and SAVR (n=30), Søndergaard et al. identified HALT in 38.1 % and hypoattenuation affecting motion (HAM) in 20.2 %.9 Of these, progression was identified in 15.5 % of patients, and regression in 10.7 %. Progression was less likely in patients on vitamin-K antagonists (VKA) and other forms of oral anticoagulants (OR 0.014; P=0.036). The investigators postulated that subclinical leaflet thrombosis is a common finding after both TAVR and SAVR, and may progress from normal leaflet motion to HALT, to the more severe HAM, at variable intervals after valve implantation. Evaluating populationspecific risk factors, Midha et al. analyzed data from patients in the RESOLVE registry, excluding patients on anticoagulation.10 The analysis concluded that: (i) Edwards Sapien 3 valves that were 10 % overexpanded (per diameter) had a higher propensity toward developing a thrombus; and (ii) CoreValve Evolut R valve implantation depth correlated with increased thrombus volume. In another analysis of a multicenter registry that included 1,521 patients, valve hemodynamic deterioration (VHD) was present in 4.5 % of the cohort during followup where multiple risk factors were identified to be independent

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predictors of VHD.11 These risk factors included: the absence of anticoagulant therapy at hospital discharge, a valve-in-valve (TAVR in a surgical valve) procedure, the use of a 23-mm valve, and a higher body mass index.

Management of Clinical and Subclinical Transcatheter Heart Valve Thrombosis In the study by Latib et al., the vast majority of patients with subclinical THV thrombosis were treated conservatively with anticoagulation with improved transvalvular gradients on follow-up echocardiography.4 There was a reduction in transaortic mean gradient from 41.9 to 16.9 mmHg after a median of 39 days of therapeutic anticoagulation. Similarly, for HALT and HAM that were identified on follow-up CT scans, there was regression of HAM and improved leaflet motion after anticoagulation in the study by Søndergaard et al.9 The initiation of anticoagulation (either warfarin or direct oral anticoagulants) was effective in restoration of normal leaflet function in 100 % in patients with HALT and HAM, where dual antiplatelet therapy failed to do so with progression or persistence of leaflet motion abnormality in the absence of anticoagulation. The current European Society of Cardiology (ESC)/European Association of Cardio-Thoracic Surgery (EACTS) guidelines for the management of bioprosthetic valve thrombosis recommend treatment with a VKA and/or unfractionated heparin before reintervention.12

Valve Imaging Post Transcatheter Aortic Valve Replacement There is no consensus with regard to imaging modality of choice and frequency for valve imaging post TAVR. The current ESC guidelines recommend imaging after TAVR or SAVR with a transthoracic echocardiogram to be routinely performed within 30 days to establish baseline valve function, another echocardiogram 1 year after implantation, and annually thereafter.12 HALT and HAM identified on CT imaging as primordial forms of leaflet thrombosis were associated with only mild increase in transvalvular gradients.7,13 Relying completely on echocardiography alone may therefore be a challenge. In cases reported from the MAUDE database, the occurrence of leaflet thrombosis was highest in the first year post implant, suggesting that a closer follow-up with advanced imaging at least in the first year post procedure may be of high clinical value.2

Conclusion With expanding indications, TAVR will increasingly continue to require a practical, safe, and cost-effective follow-up strategy to ensure valve structure and function integrity. HAM and HALT incidences noted on follow-up imaging are not trivial, and are thought to be primordial to valve thrombosis as they can either progress or regress in accordance with medical therapy. With the inclusion of a broader patient population, early and timely diagnosis of leaflet dysfunction will be critical for delivering appropriate therapy and improving patient outcomes. n

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Transcatheter Heart Valve Thrombosis 1.

ahl TP, Kodali SK, Leon MB. Transcatheter Aortic Valve V Replacement 2016: a modern-day ‘through the looking-glass’ adventure. J Am Coll Cardiol 2016;67:1472–87. DOI: 10.1016/j. jacc.2015.12.059; PMID: 27012409. Hafiz AM, Kalra A, Ramadan R, et al. Clinical or symptomatic leaflet thrombosis following transcatheter aortic valve replacement: insights from the U.S. FDA MAUDE Database. Structural Heart 2017;1:256–64. DOI: 10.1080/24748706.2017.1366086. Makkar RR, Fontana G, Sondergaard L. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2016;374:1591–2. DOI: 10.1056/NEJMc1600179; PMID: 27096589. Latib A, Naganuma T, Abdel-Wahab M, et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015;8:pii: e001779. DOI: 10.1161/ CIRCINTERVENTIONS.114.001779; PMID: 25873727. Hansson NC, Grove EL, Andersen HR, et al. Transcatheter aortic valve thrombosis: incidence, predisposing factors,

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and clinical implications. J Am Coll Cardiol 2016;68:2059–69. DOI: 10.1016/j.jacc.2016.08.010; PMID: 27580689. Chakravarty T, Sondergaard L, Friedman J, et al. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389:2383–92. DOI: 10.1016/S0140-6736(17)30757-2; PMID: 28330690. Pache G, Schoechlin S, Blanke P, et al. Early hypo-attenuated leaflet thickening in balloon-expandable transcatheter aortic heart valves. Eur Heart J 2016;37:2263–71. DOI: 10.1093/eurheartj/ ehv526; PMID: 26446193. Yanagisawa R, Hayashida K, Yamada Y, et al. Incidence, predictors, and mid-term outcomes of possible leaflet thrombosis after TAVR. JACC Cardiovasc Imaging 2016;pii: S1936-878X(16)30897-X. DOI: 10.1016/j.jcmg.2016.11.005; PMID: 28017712. Sondergaard L, De Backer O, Kofoed KF, et al. Natural history of subclinical leaflet thrombosis affecting motion in bioprosthetic aortic valves. Eur Heart J 2017;38:2201–7. DOI: 10.1093/eurheartj/ ehx369; PMID: 28838044.

10. M idha PA, Raghav V, Sharma R, et al. The fluid mechanics of transcatheter heart valve leaflet thrombosis in the neo-sinus. Circulation 2017;136:1598–609. DOI: 10.1161/ CIRCULATIONAHA.117.029479; PMID: 28724752. 11. Del Trigo M, Munoz-Garcia AJ, Wijeysundera HC, et al. Incidence, timing, and predictors of valve hemodynamic deterioration after transcatheter aortic valve replacement: multicenter registry. J Am Coll Cardiol 2016;67:644–55. DOI: 10.1016/j.jacc.2015.10.09; PMID: 26868689. 12. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739–91. DOI: 10.1093/eurheartj/ehx391; PMID: 28886619. 13. Vollema EM, Kong WKF, Katsanos S, et al. Transcatheter aortic valve thrombosis: the relation between hypo-attenuated leaflet thickening, abnormal valve haemodynamics, and stroke. Eur Heart J 2017;38:1207–17. DOI: 10.1093/eurheartj/ehx031; PMID: 28369242.

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Interventional Cardiology

Appropriate Use Criteria and the Imaging Mandate Gregory J Dehmer, MD, 1 Leah White, MPH, 2 and John U Doherty, MD 3 1. Baylor Scott & White Health and Texas A&M College of Medicine, Temple TX; 2. Appropriate Use Criteria Task Force, American College of Cardiology, Washington, DC; 3. Sidney Kimmel Medical College, Thomas Jefferson University and Division of Cardiology, Jefferson Heart Institute, Philadelphia, PA

Abstract Appropriate use criteria (AUC) have existed for over 30 years and are being deployed with increasing frequency to study the delivery of healthcare. The goal of AUC is to advise all stakeholders about the reasonable use of testing procedures or therapies to improve symptoms, quality of life, and health outcomes. Numerous studies have shown the favorable effects of AUC to limit the overuse of unnecessary procedures while also promoting high-quality clinical care and cost savings. AUC evaluating only a single imaging modality have been replaced by multimodality documents, making it easier for the clinician to evaluate the appropriateness of multiple imaging methods in various clinical scenarios. The Protecting Access to Medicare Act of 2014 contained language mandating the use of AUC when ordering certain advanced cardiac imaging tests, and this requirement is currently scheduled for implementation in January 2020. Clinicians need to be aware of the increasing use of AUC and the financial implications of the AUC mandate legislation.

Keywords Appropriate use criteria, quality, healthcare reform Disclosure: Drs Dehmer and Doherty are co-chairs of the Appropriate Use Criteria Task Force of the American College of Cardiology, a voluntary, unpaid position. Ms White is team leader for the Appropriate Use Criteria Task Force and is an employee of the American College of Cardiology. Received: 11 November 2017 Accepted: 6 December 2017 Citation: US Cardiology Review 2018;12(1):36–40. DOI: 10.15420/usc.2017:29:1 Correspondence: Gregory J Dehmer, Cardiology Division (MS-33-ST156), Scott & White Medical Center, 2401 South 31st Street, Temple, Texas 76508. E: Gregory.Dehmer@BSWHealth.org

Since the first report of a methodology to assess the appropriateness of medical technologies, the number and application of appropriate use criteria (AUC) has expanded.1 Interest in AUC occurred because of a desire to control the rising costs of medical care, especially in the area of cardiac imaging. For example, ambulatory visits in which a cardiac stress test with imaging was ordered or performed in adults without known coronary artery disease increased from 59 % in 1993–1995 to 87 % in 2008–2010.2 About 35 % of these tests were in low-risk patients, many without a complaint of angina or even chest pain, thus possibly resulting in unnecessary testing at an estimated annual cost of $501 million. Many believe that the sole use of AUC is to curb treatment overuse, but several of the initial publications using this methodology addressed the underuse of coronary angiography and coronary revascularization.3,4 In addition to the American College of Cardiology, other organizations have developed AUC related to cardiac imaging and to a wide range of topics, from orthopedic procedures to the use of urinary catheters.5–7 The goal of AUC is to advise clinicians, patients, and policy makers about the reasonable use of testing procedures or therapies to improve symptoms, quality of life, and health outcomes. As such, the AUC comprise one of the three main components used to translate evidence from randomized clinical trials and registries into the delivery of high-value clinical care (see Figure 1).8 The unique format of the AUC incorporates symptoms, risk factors, clinical history, and diagnostic data

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into brief clinical scenarios (also called indications) to identify patients for whom a test or therapy is appropriate based on the best available evidence or expert consensus.

Effect of AUC on Clinical Care As AUC have developed, several studies have assessed the effect of AUC on the use of testing modalities and clinical care. For example, Doukky et al. evaluated the use of single-photon emission computed tomography (SPECT)–myocardial perfusion imaging (MPI) in a prospective cohort study of 1,511 consecutive patients undergoing outpatient testing.9 Subjects were stratified according to test appropriateness using the 2009 AUC for SPECT–MPI and were followed for 27±10 months. Among subjects whose MPIs were classified as appropriate or uncertain, an abnormal scan predicted an increase in the occurrence of adverse cardiac events; whereas among those with MPIs classified as inappropriate, an abnormal study failed to predict such events. Moreover, the authors concluded that appropriate MPIs provided incremental prognostic value beyond myocardial perfusion and ejection fraction data. Other studies have shown a reduction in MPI usage related to the AUC, with a favorable financial impact.10 The effect of AUC on the use of echocardiography has also been studied, with variable findings. Some studies show a high rate of appropriate test ordering; whereas others show appropriate testing rates of about 50 % with little improvement over time.11,12

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Appropriate Use Criteria and the Imaging Mandate Figure 1: The Three Documents that Shape Clinical Care Evidence from randomized trials and other sources

Performance Measures

Appropriate Use Criteria

Performance measures are derivatives of clinical practice guidelines that focus on critical recommendations and are constructed to be measurable with a numerator and denominator.

Appropriate use criteria are a derivative of clinical practice guidelines in which information is presented in clinical scenarios and used for benchmarking performance.

Common goals to: 1) increase use of effective diagnostic testing and therapeutic treatments, 2) decrease use of unnecessary or potentially harmful testing and therapy, 3) improve patient outcomes and 4) reduce costs There are three central documents that help guide clinical care. Clinical practice guidelines evaluate and summarize the existing medical literature, with a heavy emphasis on randomized controlled trials, and use of other data sources (non-randomized trials, meta-analyses, and registry data). When necessary, expert opinion also helps to inform the clinical practice guidelines. Both performance measures and appropriate use criteria are derivatives of clinical practice guidelines. All three documents aim to improve effective and appropriate patient care and outcomes. From Antman and Peterson, 2009.8 Adapted with permission from Wolters Kluwer.

Figure 2: Effect of the Coronary Revascularization Appropriate Use Criteria on Clinical Care 40

New Terminology The American College of Cardiology’s efforts to develop AUC has evolved, with the publication of new AUC documents on different topics and updates to the original documents. Although some minor modifications have been made over time, the fundamental methods adhere to the established and validated RAND/UCLA appropriateness method (see Figure 3).1,22 One of the most notable changes has been in the nomenclature used for appropriateness categorization.23 The original classification term for an “appropriate” diagnostic or therapeutic procedure remains and is defined as: “one in which the expected clinical benefit exceeds the risks of the procedure by a sufficiently wide margin such that the procedure is generally considered acceptable or reasonable care.”23 It is important to emphasize that use of the term “appropriate” should not be interpreted as a mandate that all tests or therapies with

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38.4

35.1

33.2

30 25

26.2 22.3

20 15

22.3 16.5

15.8

13.3

10.7

5 0

Changes in AUC Over Time

Expert consensus

Clinical Practice Guidelines

Percentage change

Coronary artery revascularization by coronary artery bypass surgery or percutaneous coronary intervention (PCI) has been the topic of several AUC documents and updates, most recently in 2017.13–15 Desai and colleagues examined nearly 2.7 million PCI procedures from 766 hospitals entered into the National Cardiovascular Data Registry (NCDR) and showed the effect of AUC on coronary revascularization in clinical care.16 They evaluated trends in PCI utilization and procedural appropriateness, as determined by the first AUC for coronary revascularization published in 2009.13 Among the study cohort, the number of PCIs for acute indications remained similar over the 5 years of observation, whereas the number of PCIs for non-acute indications decreased. Importantly, the number of non-acute PCIs classified as inappropriate decreased from 26.2 % to 13.3 % during the study period (see Figure 2). Over the same period of observation, patients undergoing non-acute PCI had increases in angina severity, the use of antianginal medications and high-risk noninvasive findings. This suggested the AUC caused a favorable change in the use of PCI to focus on patients with important symptoms and stress test abnormalities who were well treated with medications. Similar trends were shown using data from the New York State database.17 In that study, the percentage of inappropriate PCIs for all patients decreased from 18.2 % in 2010 to 10.6 % in 2014, and was even more marked among Medicaid patients (15.3 % to 6.8 %). These changes occurred after the New York Department of Health shared appropriateness ratings with hospitals and announced the intention to withhold reimbursement for stable Medicaid patients undergoing inappropriate PCIs. Delays in obtaining and cleaning data, declining PCI rates over time, and the objections of professional societies all resulted in the denial process not being implemented.18 Likewise, in Washington State, the use of PCI for elective indications decreased over time with simultaneous improvements in PCI appropriateness.19 However, improvements in PCI appropriateness were limited to a minority of hospitals, with the largest decline in PCIs classified as inappropriate. Finally, one of the intended uses of the AUC is to help study variations in care. This was demonstrated in a study examining the relationship between high PCI utilization in certain geographic areas and the number of PCIs classified as inappropriate.20 Data from the Medicare limited data set and the NCDR were used and showed that geographic regions with lower PCI rates had a higher proportion of PCIs performed for appropriate indications. A similar decrease in the utilization of diagnostic angiography alone was shown related to use of the AUC.21

Class III/IV angina

2 or more antianginals

Low-risk stress test 2010

High-risk stress test

Inappropriate non-acute PCIs

2014

Changes in the variables reflecting clinical care and non-acute PCI appropriateness after the release of the 2009 appropriate use criteria for coronary artery revascularization. PCI = percutaneous coronary intervention.

this rating be performed in all clinical scenarios. Rather, services rated as “appropriate” should be considered reasonable, but not automatically required. Clinical judgment and patient preference are factors that should also be considered. The prior term “uncertain” has been replaced by “may be appropriate,” now defined as: “At times an appropriate option for management of patients in this population due to variable evidence or agreement regarding the benefits/risks ratio, potential benefit based on practice experience in the

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Interventional Cardiology Figure 3: Stages in the Development of Appropriate Use Criteria AUC Task Force identifies a topic for new AUC and defines scope of work Nominations for writing group and rating panel members solicited and received Writing group members identified and they develop scenarios, assumptions and definitions aided by literature review and guideline mapping External review of developed scenarios with subsequent revision as needed First round of ratings performed without interaction among the raters Ratings tabulated and analyzed for variation Second round of ratings developed during face-to-face meeting of rating panel Ratings finalized with additional limited round of ratings if needed Text of manuscript completed and subject to external and internal review

AUC manuscript published This entire process can take up to 2–3 years to complete. AUC = appropriate use criteria.

absence of evidence, and/or variability in the population; effectiveness for individual care must be determined by a patient’s physician in consultation with the patient based on additional clinical variables and judgment along with patient preferences (i.e. procedure may be acceptable and may be reasonable for the indication).”23 Confusion about the previous term “uncertain” resulted in some stakeholders incorrectly considering this rating as either appropriate or inappropriate, depending on their viewpoint. A rating of “may be appropriate” can be assigned to a therapy or procedure because high-quality evidence about its use in specific patients is deficient. Therapies or services in this category should be utilized based on clinical judgment, patient and provider preferences and include shared decision-making. As emphasized in all of the newer AUC documents, individual coverage determinations should not be made based on a service being rated as “may be appropriate.” Finally, the prior term “inappropriate” has been replaced by “rarely appropriate,” now defined as: “Rarely an appropriate option for management of patients in this population due to the lack of a clear benefit/risk advantage; rarely an effective option for individual care plans; exceptions should have documentation of the clinical reasons for proceeding with this care option (i.e., procedure is not generally acceptable and is not generally reasonable for the indication).”23 The term “rarely appropriate” was substituted in the revised AUC methodology because of substantial misunderstanding about the term “inappropriate” in earlier documents. Physicians were concerned about the implications of their care being labeled as inappropriate when in uncommon situations it may be the best option for a particular patient. Scenarios constructed for the AUC typically contain three to five clinical characteristics and test results to categorize a group of patients commonly encountered in clinical practice. Unfortunately, this may exclude some subtle and unique findings that might affect decision

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making for an individual patient. “Rarely appropriate” is not equivalent to “inappropriate,” and thus in some clinical scenarios indicates that a therapy or procedure could still be used. The newer term of “rarely appropriate” better reflects the complexity of patient care and decision making, although physicians should be aware that procedures in this category should be justified by unique patient circumstances, and that these circumstances should be adequately documented to justify the use of rarely appropriate services.

Single Modality to Multimodality Documents Many of the initial AUC documents focused on the use of a single imaging modality, such as SPECT MPI or echocardiography in clinical scenarios.24,25 In the current environment, there are multiple techniques available for cardiac imaging, each having different characteristics, advantages and disadvantages in certain clinical situations. The AUC Task Force felt it would be easier for the clinician to use one document that provided a side-by-side rating of multiple imaging modalities rather than refer to multiple documents for individual imaging techniques. Using a side-by-side rating format also eliminated concerns about differences in the characteristics of clinical scenarios resulting from the use of individual documents for each test. It is important to emphasize that in this multimodality format, ratings are not intended to be competitive, thereby ranking one test the best among the others. Rather, the intent was to identify and rate all of the imaging tests that would or would not be reasonable for a given clinical scenario and allow the clinician to determine which would be the best for a particular patient in the setting described. Figure 4 shows an example of the multimodality format from the 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease document.26

The AUC Mandate The Protecting Access to Medicare Act of 2014 contained directives for the use of AUC which were then were amended into the Social Security Act directing the Centers for Medicare and Medicaid Services (CMS) to establish a program to promote the use of AUC for advanced diagnostic imaging services.27 This incorporated eight priority clinical areas, which in addition to suspected or diagnosed coronary artery disease included suspected pulmonary embolism, traumatic or non-traumatic headache, hip pain, low back pain, shoulder pain (to include suspected rotator cuff injury), cancer of the lung (primary or metastatic, suspected or diagnosed), and cervical or neck pain. In July 2017, the CMS released the proposed 2018 Medicare Physician Fee Schedule, which included a proposal to delay the implementation of the AUC requirement until January 1, 2019, but this has now been further delayed until 2020. Currently, advanced imaging services include MRI, CT, nuclear imaging and PET, but not echocardiography. The CMS define AUC as criteria that are evidence based (to the extent feasible) and assist professionals who order and furnish applicable imaging services to make the most appropriate treatment decisions for a specific clinical condition. The directive mandates that, to have claims processed, providers must submit proof that an AUC was consulted through a clinical decision support mechanism. Only AUC developed by entities meeting “providerled entity” (PLE) standards can be used. Generally, PLEs are national professional medical specialty societies or other organizations that are composed primarily of providers or practitioners who, either within or outside the organization, predominantly provide direct patient care. PLEs

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Appropriate Use Criteria and the Imaging Mandate Figure 4: Example of the Format used in a Multimodality Appropriate Use Criteria Document

Indication Text 1.

• Low pre-test probability of CAD • ECG interpretable AND able to exercise

• Low pre-test probability of CAD • ECG uninterpretable OR unable to exercise

• Intermediate pre-test probability of CAD • ECG interpretable AND able to exercise

• Intermediate pre-test probability of CAD • ECG uninterpretable OR unable to exercise

• High pre-test probability of CAD • ECG interpretable AND able to exercise

• High pre-test probability of CAD • ECG uninterpretable OR unable to exercise

Exercise ECG

Stress RNI

Stress Echo

Stress CMR

Calcium Scoring

CCTA

Invasive Coronary Angiography

Each row identifies an indication (scenario) allowing the display of appropriateness scores for several testing modalities. This format allows the clinician to access the appropriateness ratings for several imaging tests in one document rather than referring to multiple documents. A = appropriate; M = may be appropriate; R = rarely appropriate; CAD = coronary artery disease; CMR = cardiac magnetic resonance; CCTA = coronary computed tomographic angiography; Echo = echocardiogram; RNI = radionuclide imaging. From Wolk et al., 2014.26 Reproduced with permission from Elsevier.

must apply and then reapply every 5 years to the CMS and to be qualified must adhere to evidence-based processes and other requirements when developing or modifying the AUC. A list of the current qualified PLEs is given in Table 1. The second part of the AUC mandate requires the use of a Clinical Decision Support Mechanism (CDSM). CDSMs are the electronic portals through which a clinician accesses AUC during the patient encounter and by which specific patient information and testing results from the electronic health record are incorporated to determine the appropriateness rating. With a fully-embedded CDSM platform, practitioners interact directly with their primary user interface, minimizing interruption to the clinical workflow. For each interaction, the CDSM must record a unique Decision Support Number that connects the provider’s National Provider Identifier number, the selected indication and service, and the applicability of AUC to that order. Without this information associated with the bill to Medicare, payment is not made. Similar to qualified PLEs, CDSMs must be qualified as meeting the requirements of the CMS. Those meeting the requirements are posted on the CMS website.28 The value of using a point-of-care CDSM was demonstrated in a prospective trial that showed a reduction in the inappropriate use of all cardiac imaging modalities from 22 % to 6 %.29

The AUC Summit In part stimulated by the AUC mandate, and because of the increasing number of organizations becoming qualified as PLEs, a 1-day cardiovascular AUC summit meeting was organized by the American College of Cardiology and held in Washington, DC, on August 9, 2017. The meeting was led by an independent moderator and attended by representatives from the CMS, key leaders from the qualified PLEs, stakeholders from several primary care professional organizations and leaders from companies developing CDSMs. The goals of the summit were to develop recommendations for: forming effective partnerships and collaborations among those who will develop AUC; and implementation strategies, communication to clinicians, and tools for clinicians to utilize to meet the AUC mandate. Workgroups consisting of attendees are being formed to address key areas in preparation for the AUC mandate. One of these areas will focus on the importance

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Table 1: Qualified Provider-led Entities as of June 2017 American College of Cardiology Foundation American College of Radiology Banner University Medical Group – Tucson University of Arizona* Center for Diagnostic Imaging Quality Institute Cedars-Sinai Health System* Intermountain Healthcare Massachusetts General Hospital, Department of Radiology Medical Guidelines Institute* Memorial Sloan Kettering Cancer Center* National Comprehensive Cancer Network Sage Evidence-based Medicine & Practice Institute* Society for Nuclear Medicine and Molecular Imaging University of California Medical Campuses University of Utah Health* University of Washington School of Medicine Virginia Mason Medical Center* Weill Cornell Medicine Physicians Organization *Newly-qualified provider-led entities as of June 30, 2017.

of achieving some level of harmonization among the appropriateness ratings from the different PLEs. Data comparing AUC from different professional organizations are limited, but a study comparing the ratings of two professional organizations for myocardial perfusion imaging found substantial discordance.30 When comparing ratings within a cohort of 592 patients, 18.8 % could not be matched to a rating from the other organization, 59.0 % had the same appropriateness rating, and 22.3 % were discordant. Overall, the agreement of appropriateness between the two methods was poor. Discordant AUC recommendations will lead to confusion for all stakeholders in this process. Hopefully, by working together a structure can be developed that will preserve the ability of independent qualified PLEs to develop AUC yet result in harmonization of the recommendations.

Conclusions As the entire healthcare system moves away from a fee-for-service structure to one based on the quality and value of services, the use of AUC will likely expand. As this occurs, it is important to emphasize

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Interventional Cardiology that the AUC were never intended to be an arbitrator of payment for an individual patient. Rather the AUC were developed as a method to characterize, study and refine care and the use of medical resources

10.

11.

12.

13.

Brook RH, Chassin MR, Fink A, et al. A method for the detailed assessment of the appropriateness of medical technologies. Int J Technol Assess Health Care 1986;2:53–63. PMID: 10300718. Ladapo JA, Blecker S, Douglas PS. Physician decision making and trends in the use of cardiac stress testing in the United States. Ann Intern Med 2014;161:482–90. DOI: 10.7326/M14-0296; PMID: 25285541. Kravitz RL, Laouri M, Kahan JP, et al. Validity of criteria used for detecting underuse of coronary revascularization. JAMA 1995;274:632–8. PMID: 7637144. Laouri M, Kravitz RL, French WJ, et al. Underuse of coronary revascularization procedures: application of a clinical method. J Am Coll Cardiol 1997;29:891–7. PMID: 9120171. Sheng AY, Castro A, Lewiss RE. Awareness, utilization, and education of the ACR appropriateness criteria: A review and future directions. J Am Coll Radiol 2016;13:131–6. DOI: 10.1016/ j.jacr.2015.08.026; PMID: 26499160. American Academy of Orthopedic Surgeons. Appropriate Use Criteria. 2015. Available at: www.orthoguidelines.org/go/auc/ (accessed December 11, 2017) Meddings J, Saint S, Fowler KE, et al. The Ann Arbor criteria for appropriate urinary catheter use in hospitalized medical patients: Results obtained by using the RAND/UCLA appropriateness method. Ann Intern Med 2015;162:S1–34. DOI: 10.7326/M14-1304; PMID: 25938928. Antman EM, Peterson ED. Tools for guiding clinical practice from the American Heart Association and the American College of Cardiology: What are they and how should clinicians use them? Circulation 2009;119:1180–5. DOI: 10.1161/ CIRCULATIONAHA.109.856757; PMID: 19273729. Doukky R, Hayes K, Frogge N, et al. Impact of appropriate use on the prognostic value of single-photon emission computed tomography myocardial perfusion imaging. Circulation 2013;128:1634–43. DOI: 10.1161/CIRCULATIONAHA.113.002744; PMID: 24021779. Roifman I, Austin PC, Qui F, et al. Impact of the publication of appropriate use criteria on utilization rates of myocardial perfusion imaging studies in Ontario, Canada: A populationbased study. J Am Heart Assoc 2017;6:e005961. DOI: 10.1161/ JAHA.117.005961; PMID: 28584072. Patil HR, Coggins TR, Kusnetzky LL, et al. Evaluation of appropriate use of transthoracic echocardiography in 1,820 consecutive patients using the 2011 revised appropriate use criteria for echocardiography. Am J Cardiol 2012;109:1814–7. DOI: 10.1016/j.amjcard.2012.02.025; PMID: 22449633. Ladapo JA, Blecker S, O’Donnell M, et al. Appropriate use of cardiac stress testing with imaging: A systematic review and meta-analysis. PLoS ONE 2016:11: e0161153. DOI: 10.1371/journal. pone.0161153. Patel MR, Dehmer GJ, Hirshfeld JW, et al. American College of Cardiology Foundation Appropriateness Criteria Task Force; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association for Thoracic Surgery; American Heart Association, and the American Society of Nuclear Cardiology Endorsed by the American Society of Echocardiography; Heart Failure Society of America; Society of Cardiovascular Computed Tomography. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 appropriateness criteria

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among patient populations. Used for this intent, the AUC have potential to be one of several tools available to help reform the delivery of healthcare in the future. n

for coronary revascularization. J Am Coll Cardiol 2009;53:530–3. DOI: 10.1016/j.jacc.2008.10.005; PMID: 19195618. 14. P atel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/ ASNC/SCAI/SCCT/STS 2016 appropriate use criteria for coronary revascularization in patients with acute coronary syndromes: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society of Thoracic Surgeons. J Am Coll Cardiol 2017;69:570–91. DOI: 10.1007/s12350-017-0780-8; PMID: 28265967. 15. Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ ASE/ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease: a report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons. J Am Coll Cardiol 2017;69:2212–41. DOI: 10.1007/s12350-017-0917-9; PMID: 28608183. 16. Desai NR, Bradley SM, Parzynski CS, et al. Appropriate use criteria for coronary revascularization and trends in utilization, patient selection, and appropriateness of percutaneous coronary intervention. JAMA 2015;314:2045–53. DOI: 10.1001/ jama.2015.13764; PMID: 26551163. 17. Hannan EL, Samadashvili Z, Cozzens K, et al. Changes in percutaneous coronary interventions deemed “inappropriate” by appropriate use criteria. J Am Coll Cardiol 2017;69:1234–42. DOI: 10.1016/j.jacc.2016.12.025; PMID: 28279289. 18. Society for Cardiovascular Angiography and Interventions. Changing New York’s State of Mind. SCAI Newsletter. 2014. Available at: www.scai.org/Press/detail.aspx?cid=e8531bb565c4-4153-a1d5-2b387274a54f#.Wb5tMNOGNGM (accessed September 18, 2017). 19. Bradley SM, Bohn CM, Malenka DJ, et al. Temporal trends in percutaneous coronary intervention appropriateness: Insights from the clinical outcomes assessment program. Circulation 2015;132:20–6. DOI: 10.1161/CIRCULATIONAHA.114.015156; PMID: 26022910. 20. Thomas MP, Parzynski CS, Curtis JP, et al. Percutaneous coronary intervention utilization and appropriateness across the United States. PLoS ONE 2015;10:e0138251. DOI: 10.1371/ journal.pone.0138251; PMID: 26379053. 21. Arbel Y, Qiu F, Bennell MC, et al. Association between publication of appropriate use criteria and the temporal trends in diagnostic angiography in stable coronary artery disease: A population-based study. Am Heart J 2016;175:153–9. DOI: 10.1016/j.ahj.2016.02.014; PMID: 27179734. 22. Fitch K. The RAND/UCLA Appropriateness Method User’s Manual. Santa Monica, CA: RAND, 2001. 23. Hendel RC, Patel MR, Allen JM, et al. Appropriate use of cardiovascular technology: 2013 ACCF Appropriate use criteria methodology update. J Am Coll Cardiol 2013;61:1305–17. DOI: 10.1016/j.jacc.2013.01.025; PMID: 23433633.

24. B rindis RG, Douglas PS, Hendel RC, et al. American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group; American Society of Nuclear Cardiology; American Heart Association. ACCF/ ASNC appropriateness criteria for single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI): a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group and the American Society of Nuclear Cardiology. J Am Coll Cardiol 2005;46:1587–605. DOI: 10.1016/ j.jacc.2005.08.029; PMID: 16226194. 25. Douglas PS, Khandheria B, Stainback RF, et al. ACCF/ASE/ ACEP/ASNC/SCAI/SCCT/SCMR 2007 appropriateness criteria for transthoracic and transesophageal echocardiography: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American Society of Echocardiography, American College of Emergency Physicians, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society for Cardiovascular Magnetic Resonance endorsed by the American College of Chest Physicians and the Society of Critical Care Medicine. J Am Coll Cardiol 2007;50:187–204. DOI: 10.1016/j.jacc.2007.05.003; PMID: 17616306. 26. Wolk MJ, Bailey SR, Doherty JU, et al. ACCF/AHA/ASE/ ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;63:380–406. DOI: 10.1016/ j.jacc.2013.11.009; PMID: 24355759. 27. Centers for Medicare and Medicaid Services. Appropriate Use Criteria Program. 2017. Available at: www.cms.gov/Medicare/ Quality-Initiatives-Patient-Assessment-Instruments/AppropriateUse-Criteria-Program/index.html (accessed December 11, 2017). 28. Centers for Medicare and Medicaid Services. Clinical Decision Support Mechanisms. 2017. Available at: www.cms.gov/ Medicare/Quality-Initiatives-Patient-Assessment-Instruments/ Appropriate-Use-Criteria-Program/CDSM.html (accessed December 11, 2017). 29. Lin FY, Dunning AM, Narula J, et al. Impact of an automated multimodality point-of-order decision support tool on rates of appropriate testing and clinical decision making for individuals with suspected coronary artery disease: A prospective multicenter study. J Am Coll Cardiol 2013;62:308–16. DOI: 10.1016/j.jacc.2013.04.059; PMID: 23707319. 30. Winchester DE, Wolinsky D, Beyth RJ, Shaw LJ. Discordance between appropriate use criteria for nuclear myocardial perfusion imaging from different specialty societies: A potential concern for health policy. JAMA Cardiol 2016;1:207–10. DOI: 10.1001/jamacardio.2016.0030.

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Risk Prevention

Microvascular Coronary Artery Disease Abdulah Alrifai, MD, Mohamad Kabach, MD, Jonathan Nieves, MD, Jesus Pino, MD, and Robert Chait, MD, FACC Cardiology Department, University of Miami/JFK Medical Center, Atlantis, FL

Abstract Recently it has become more apparent that microvascular dysfunction is responsible for morbidity and mortality in many different cardiovascular diseases. It is no longer felt to be benign, and besides accounting for angina symptoms, it likely plays a role in heart failure with preserved ejection fraction, as well as in Takotsubo syndrome and various inflammatory diseases associated with ischemia and atherosclerosis. Coronary microvascular disease can be diagnosed by means of invasive coronary reactivity testing and noninvasively by echocardiography, computerized tomography, magnetic resonance, and positron emission tomography. Unfortunately, treatment has been more empiric, and not as well evaluated by randomized trials as in other disease states. Beta blockers, nitrates, and calcium channel blockers have all been used with varying degrees of success. Given its prevalence, particularly among women, its increased recognition and importance mandates further research into prompt diagnosis and more robust studies of its treatment.

Keywords Microvascular angina, microvascular coronary artery disease, microvascular endothelial dysfunction, myocardial hypersensitivity, coronary reactivity testing Disclosure: The authors have no conflicts of interest to declare. Received: 8 November 2017 Accepted: 5 December 2017 Citation: US Cardiology Review 2018;12(1):41–5. DOI: 10.15420/usc.2017:27:1 Correspondence: Robert Chait, MD, FACC, University of Miami/JFK Medical Center, 5301 Congress Avenue, Atlantis, FL 33462, USA. E: bobchait@gmail.com

More than 10 million Americans suffer annually from angina.1 For decades, most of the attention has been focused on epicardial coronary artery disease (CAD). In a European registry of 11,000 stable angina patients, 65 % of women and 32 % of men had no obstructive CAD (<50 % stenosis); however, multiple other studies have demonstrated only 30 % of patients have significant obstructive epicardial CAD.2 In 1973 Harvey Kemp was one of the first to describe ‘cardiac syndrome X’ in patients with typical angina pectoris with ischemic electrocardiographic changes but in the absence of epicardial obstructive CAD.3 The terms ‘cardiac syndrome X’, ‘microvascular angina,’ or ‘chest pain with normal coronary arteries’ have been used interchangeably in the literature referring to the chest pain associated with coronary microvascular dysfunction (CMVD). There is some impetus to abandon the term syndrome X given the lack of a standard definition. Patients with CMVD have higher endothelium-dependent and endothelium-independent impairment of microvascular function.4 Coronary flow reserve (CFR), which is the ratio of coronary blood flow (CBF) at maximal dilatation to CBF at rest, is abnormal in patients with microvascular dysfunction. Hypertension, insulin resistance, and hyperlipidemia are well-known risk factors.5 While women have been consistently found to have less obstructive CAD than men, many reports have demonstrated a higher prevalence of CMVD in women, including one study in which 55 % were women.6 In the Women’s Ischemia Syndrome Evaluation (WISE) trial, angina was linked to increased mortality at 5 years.7 In fact, in patients with angiographically documented non-obstructive disease, the risks are the same as patients with significant single-vessel disease.7 During the last decade CMVD has been validated as a significant cause of myocardial ischemia and has also

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been associated with a wide range of diseases. Approximately 20–30 % of patients with successful coronary bypass surgery will continue to suffer from angina, which may result from microvascular disease.8 CMVD may be responsible for ‘false positive’ stress tests in which ischemia is detected but without significant or even ‘normal’ coronaries visualized by coronary angiography. More recently CMVD has been linked to the development of heart failure with preserved ejection fraction (HFpEF)9 and Takotsubo syndrome.10,11 Patients with various chronic inflammatory diseases, such as rheumatoid arthritis and systemic lupus erythematosus, also have an increased risk of premature CAD. Risk factors inducing oxidative stress and inflammation may trigger endothelial dysfunction, and thus altered vasomotion of the microcirculation.12 Given the increasingly recognized importance of microvascular disease, we present this review focusing on the mechanisms leading to CMVD, its diagnostic evaluation, as well as possible treatment options, and propose a practical diagnostic algorithm for CMVD.

Microvascular Dysfunction Pathophysiology Several theories are suggested to explain the pathophysiology of CMVD. This involves both pre-arterioles (vessels of 100–500 µm in diameter) and arterioles (<100 um), which are the resistance vessels responsible for the abnormal coronary artery blood flow. Structural alterations, including smooth muscle hypertrophy around the vascular wall, results in increased vessel resistance and is seen in hypertrophy from left

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Risk Prevention Figure 1: Proposed Algorithm for the Diagnosis of Microvascular Angina Angina + signs of myocardial ischemia Coronary angiography Coronary stenosis

Absent

Mild DS<50 %

Moderate DS 50-70 %

≥0.80 no or <75 % diameter reduction +angina +ischemic ECG changes

Microvascular Angina Endothelial dysfunction

Severe DS>70 %

FFR

Acetylcholine Test

no or <75 % diameter reduction no angina no ischemic ECG changes

Anomalous coronary origin Myocardial bridge Coronary aneurysm

<0.80

≥75 % diameter reduction +angina +ischemic ECG changes

Vasospastic Angina

Significant atherosclerotic CAD

Non-atherosclerotic CAD

Adenosine Test

CFR ≥ 2.5

“True” Syndrome X False positive entry criteria: Non-cardiac chest pain False negative tests = non-anginal microvascular angina

CFR < 2.5

Microvascular Angina Endothelium-independent dysfunction

CAD = coronary artery disease; CFR = coronary flow reserve; DS = diameter stenosis; FFR = fractional flow reserve. Reprinted with permission from Elsevier. Source: Radico, et al., 2014.34

ventricular hypertrophy secondary to hypertension or hypertrophic cardiomyopathy, and have been described as part of CMVD mechanism;13 however, other studies have failed to establish any mechanism.14 Patients with CMVD have similar risk factors as those with epicardial CAD. CMVD can occur in patients with and without obstructive CAD. Functional abnormalities are likely the most widely accepted and recognized mechanism of CMVD. Dysfunction of microcirculation resistance has been reported in a large number of studies. An impairment of endothelium-dependent vasodilation due to reduced nitric oxide (NO) release is among the most commonly proposed mechanisms of CMVD in stable microvascular angina (MVA) patients. In addition to NO, acetylcholine (ACh) governs the endothelialindependent mechanism, which has been proven by reduced CBF to ACh. Both, endothelium-dependent and endothelium-independent need to be tested by means of coronary reactivity response to adenosine and ACh. ACh has dual antithetical effects on the coronary arteries by binding to muscarinic (M3) receptor on the surface of vascular smooth

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muscle cells and elicits an intracellular release of calcium ions leading to vasoconstriction, whereas endothelial M3 receptor-mediated calcium release activates the endothelial NO synthase (eNOS or NOS3) through a calmodulin-dependent pathway. NO is then released and, in vascular smooth muscle cells, activates soluble guanylate-cyclase, which converts guanosine triphosphate into cyclic guanosine monophosphate. The subsequent activation of guanosine monophosphate-dependent protein kinase induces a cascade of intracellular events with the final effect of decreasing intracellular calcium concentrations, leading to vasodilation. Adenosine binds to its receptors (A2a) on the surface of vascular smooth muscle cells, activating adenylate cyclase and leading to an increase in cyclic adenosine monophosphate (cAMP) concentration and cAMPdependent protein kinase activation. The latter results in potassium channel opening, resulting in a hyperpolarization of vascular smooth muscle cells, inhibits the entry of calcium and also activates inducible NOS (iNOS or NOS2), thus producing vasodilation.15–17 While there is a reduction in the endothelium-dependent vasodilation due to changes in CBF, this does not seem sufficient to fully account for

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Microvascular Coronary Artery Disease CMVD in these patients. The potential direct vasoconstrictor effects of ACh are not highly specific for the assessment of endothelial function, and in some studies, the metabolic pathway of NO did not seem to be affected.18 Other studies have shown enhanced vasoconstrictor activity in coronary microcirculation in several patients with stable MVA. Ergonovine injection, mental stress, and hyperventilation can all result in an impairment of CBF. In some patients, ACh-induced angina was associated with a reduction of CBF in the absence of epicardial vasoconstriction, and even exercise was suggested to induce vasoconstriction rather than vasodilation. Of note, endothelin-1 serum levels were found to increase in the coronary sinus during atrial pacing. Finally, in some typical patients with cardiac syndrome X, basal microvascular constriction was suggested by the evidence of slow coronary flow.

Figure 2: Acetylcholine and Adenosine Coronary Vascular Effects

ACH

Ca2+

Endothelial cell

+ Ca2+

+ Calmodulin eNOS

Testing in Microvascular Angina Multiple diagnostic modalities have been proposed to diagnose patients with microvascular dysfunction. Both invasive (thrombolysis in myocardial infarction [TIMI] frame rate, intracoronary Doppler flow wire [IDFW] recording with coronary reactivity testing) and noninvasive (PET, CT, cardiac magnetic resonance imaging) tests can be used.19,20 Evidence for ischemia with non-obstructive CAD by ECG, decreased tissue perfusion detected by an increased TIMI frame count that measures myocardial blush grade, or transient perfusion defects on adenosine stress imaging may warrant further evaluation for microvascular disease.

ADE Ca2+

K+

PKG A2a

sGC

Thus, several structural and functional alterations have been described in patients with stable MVA. The reduced CBF response to direct arteriolar vasodilators (dipyridamole, adenosine) with induction of ischemic ST-segment changes and angina, however, suggests a major role for a primary increased vasoconstriction of small coronary resistive vessels. Indeed, the poor response to vasodilators of these areas can allow a blood steal phenomenon by normal microvessels, resulting in microvascular ischemia. Accordingly, microvascular constriction may limit the vasodilator response to exercise (thus favoring effort angina) and in some cases may also facilitate the impairment of myocardial blood flow, and thus angina at rest. It has been difficult to obtain clear evidence of myocardial ischemia in patients with stable MVA. In addition, the patchy distribution of CMVD, which in turn may not lead to wall motion abnormalities or poor evidence for abnormal perfusion, can be due to several other reasons, including: the inappropriateness (type and/or dose) of the stress stimulus; the limitations of current technical methods to detect minor degrees of myocardial ischemia; and the intermittent nature of CMVD.

tery ry ar ona Cor

cGMP GTP

+ iNOS

+ – + ATP + PKA + cAMP

M3 ACH

Vascular smooth muscle cell Ca2+

AC = adenylate cyclase ; ACh = acetylcholine; ADE = adenosine; ATP = adenosine triphosphate; CAD = coronary artery disease; CFR = coronary flow reserve; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; CMR = cardiovascular magnetic resonance; DS = diameter stenosis; eNOS = endothelial nitric oxide synthase; FFR = fractional flow reserve; GTP = guanosine triphosphate; iNOS = inducible nitric oxide synthase; M3 = muscarinic; NO = nitric oxide; PKA = protein kinase activation; PKG = guanosine monophosphate-dependent protein kinase; sGC = soluble guanylate-cyclase. Reprinted with permission from Elsevier. Source: Radico, et al., 2014.34

estimate CBF by calculating the ratio between the diastolic peak flow velocity during the maximal vasodilation (e.g. adenosine) and the coronary flow velocity at rest. A ratio less than 2.0 (normal 2.5–5.0) is used as a marker of microvascular dysfunction, and it correlates with invasive testing in the 85–97 % range. Finally, TEDE is inexpensive, reliable, and widely available.20–22

Cardiac Magnetic Resonance Imaging CMR is one of the most reliable tests for evaluation of microvascular dysfunction. CMR can also assess the cardiac anatomy and general cardiovascular function. A vasodilator agent such as adenosine is used to increase the CBF, and gadolinium is used to enhance visualization of the sub-endocardium region. Changes in gadolinium enhancement are correlated with an abnormal coronary flow and microvascular dysfunction. Unfortunately, CMR is expensive, can be limited by motion artifact, and challenging in patients with claustrophobia and implanted devices.19–21,23

Positron Emission Tomography

The microvascular function can be evaluated indirectly by determining the CFR, which is measured by using vasoactive agents such as adenosine, dipyridamole (endothelium-independent vasodilator), or ACh (endothelium-dependent).19,20

PET is considered one of the most reliable methods to evaluate microvascular dysfunction. PET uses a flow tracer that allows the determination of total regional myocardial blood flow at rest and after a vasodilator challenge. Unfortunately, PET is expensive, not broadly available, and its use in the daily clinical practice is very limited to specialized centers.21

Noninvasive Testing in Microvascular Angina

Computerized Tomography

Transthoracic Echocardiographic Doppler Echocardiogram

CT is one of the newest noninvasive methods to diagnose microvascular dysfunction. After injection of contrast, computational fluid dynamics are obtained in a specific anatomical segment. Coronary flow and pressures are calculated using mathematical models, and thus allow evaluation of the microvascular function.

With varying degrees of difficulty, transthoracic echocardiographic Doppler echocardiogram (TEDE) can be an initial diagnostic test to evaluate the microvascular function. TEDE can sometimes visualize the left anterior descending, and by using color Doppler flow mapping

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Risk Prevention New multidetector CTs have an excellent spatial resolution, costeffectiveness, and allow the evaluation of the entire heart, albeit at the expense of radiation exposure.21,22,24

definition for CMVD. The diagnosis was defined as CFR <2.5 using PET, CMR, invasive coronary Doppler, or invasive intracoronary thermodilution. Patients with evidence of epicardial CAD (>50 %) were excluded.25

Invasive Methods

The studies that evaluated sildenafil, quinapril, enalapril, atenolol, estrogens, and TENS application demonstrated benefits in their respective endpoints.28 It should be noted that studies of long-acting nitrates have shown no positive effect on microvessels as they do in the epicardial vessels, and thus are not recommended.29

Several invasive techniques have been used to evaluate microvascular function, including thermodilution, gas washout method, and intracoronary Doppler flow wire. By far, flow wire assessment is the most common technique used.21

Intracoronary Doppler Flow Wire IDFW is considered the gold standard in the evaluation of coronary microcirculation. IDFW directly measures the CBF velocity, direction, and pressure in an epicardial artery. Additionally, IDFW can evaluate the response to intracoronary injection of vasodilators and vasoconstrictors medications. A ratio of resting versus maximal hyperemia post adenosine infusion will allow for a cutoff between abnormal and normal microvascular function.21,24

Treatment in Microvascular Angina Currently, the evidence for effective therapy in the treatment of CMVD is limited as there are no large randomized trials available. Therefore, most clinicians will treat CMVD with traditional antianginal therapies that have not necessarily been shown to improve patient outcomes. Studies usually lack specificity and involve patients with cardiac chest pain that may be attributed to other etiologies. Furthermore, the studies have limited contributions because of their small sample sizes, short-term follow-up periods and a lack of a universally agreed upon definition for CMVD. CMVD has been classified as occurring with normal coronary arteries, obstructive CAD, and with underlying structural myocardial disease. Therefore, treatment may also be variable depending on the type of CMVD. Most importantly, no studies have assessed whether treating CMVD will result in any long-term prognostic benefits.25 Given that the prognosis of patients with non-obstructive CAD is the same as single vessel disease, it is important that these patients be monitored routinely, managed aggressively, and not ignored and labeled with a diagnosis of non-cardiac chest pain.26 Lifestyle modifications remain of utmost importance. Patients should specifically be encouraged to exercise, participate in weight loss programs, and stop smoking.26,27 In addition to these modifiable risk factors, diabetes and hypertension should be strictly controlled and focus on similar parameters to those used in CAD.27 Most of the data collected for the medical management of CMVD have been extrapolated from several meta-analyses all utilizing a similar

helps CE, Buysman EK, Gomez Rey G. Costs and clinical P outcomes associated with use of ranolazine for treatment of angina. Clin Ther 2012;34:1395–407.e4. DOI: 10.1016/j. clinthera.2012.04.025; PMID: 22608105. Melikian N, De Bruyne B, Fearon WF, MacCarthy PA. The pathophysiology and clinical course of the normal coronary angina syndrome (cardiac syndrome X). Prog Cardiovasc Dis 2008;50:294–310. DOI: 10.1016/j.pcad.2007.01.003; PMID: 18156008. Kemp HG Jr. Left ventricular function in patients with the anginal syndrome and normal coronary arteriograms. Am J Cardiol 1973;32:375–6. DOI: 10.1016/S0002-9149(73)80150-X; PMID: 4725584.

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In a study, sildenafil showed improvement in CFR but was not assessed for symptomatic relief. The WISE control trial demonstrated improvement in angina and CFR with the use of quinapril.30 Atenolol was shown to reduce the number of angina symptoms.30 Other medications such as ranolazine, ivabradine, fasudil, and nicorandil continue to be considered and studied in the treatment of CMVD.27 Preliminary data suggests endothelin-1 antagonists or rho-kinase inhibitors may be useful in the prevention of endothelial cell dysfunction, vascular smooth muscle cell spasm, as well as the accumulation of inflammatory cells in the adventitia of vessels. Hence, by enhancing vaso-relaxation and reducing vascular inflammation both CFR and angina symptoms would likely show improvement. Finally, with the recent findings of the Cardiovascular Risk Reduction Study (Reduction in Recurrent Major CV Disease Events [CANTOS trial]) it would be reasonable to consider anti-inflammatory medications for future studies in the treatment of CMVD.31 However, it should be noted that some of the medications that showed benefit did not demonstrate this as a class effect. For example, fluvastatin alone showed improvement in CFR, exercise tolerance, and symptoms but pravastatin did not.32 In a similar fashion, verapamil and nifedipine have been shown to improve symptoms, require less nitrate usage, and improved exercise tolerance but were associated with fatal arrhythmias. Unlike verapamil, diltiazem did not show any benefit at all.33 Until further studies are completed truly satisfactory treatment options for this problem remains elusive.

Conclusion While greater awareness of microvascular disease has occurred, all too often patients are dismissed as non-cardiac given the lack of epicardial disease. While women predominate it is a problem that occurs in men as well. Moreover, evidence now shows that the prognosis is not benign. Either noninvasive or invasive coronary reactivity testing should be undertaken. Risk factor modification and perhaps eventually anti-inflammatory treatment as well as anti-ischemic agents should then be initiated. n

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Circulation 1999;99:1795–801. DOI: 10.1161/01.CIR.99.14.1795; PMID: 10199874. 18. D esideri G, Gaspardone A, Gentile M, et al. Endothelial activation in patients with cardiac syndrome X. Circulation 2000;102:2359– 64. DOI: 10.1161/01.CIR.102.19.2359; PMID: 11067789. 19. Frans S. Non-invasive assessment of coronary microvascular dysfunction. Heart and Metabolism 2008;40:15–9. 20. Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation 2010;121:2317–25. DOI: 10.1161/ CIRCULATIONAHA.109.900191; PMID: 20516386. 21. Lanza GA, Camici PG, Galiuto L, et al. Methods to investigate coronary microvascular function in clinical practice. J Cardiovasc Med (Hagerstown) 2013;14:1–18. DOI: 10.2459/ JCM.0b013e328351680f; PMID: 23222188. 22. Feher A, Sinusas AJ. Quantitative assessment of coronary microvascular function. Circ Cardiovasc Imaging 2017;10:e006427. DOI: 10.1161/CIRCIMAGING.117.006427; PMID: 28794138. 23. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med 2002;346:1948–53. DOI: 10.1056/NEJMoa012369; PMID: 12075055. 24. Nakazato R, Heo R, Leipsic J, Min JK. CFR and FFR assessment with PET and CTA: strengths and limitations. Curr Cardiol Rep 2014;16:484. DOI: 10.1007/s11886-014-0484-5; PMID: 24652346. 25. Löffler AI, Bourque JM. Coronary microvascular dysfunction, microvascular angina, and management. Curr Cardiol Rep 2016;18:1. DOI: 10.1007/s11886-015-0682-9; PMID: 26694723. 26. Pepine CJ, Ferdinand KC, Shaw LJ, et al. Emergence of nonobstructive coronary artery disease: a woman’s problem and need for change in definition on angiography. J Am Coll Cardiol 2015;66:1918–33. DOI: 10.1016/j.jacc.2015.08.876; PMID: 26493665. 27. Chen C, Wei J, AlBadri A, et al. Coronary microvascular dysfunction - epidemiology, pathogenesis, prognosis, diagnosis,

risk factors and therapy. Circ J 2016;81:3–11. DOI: 10.1253/circj. CJ-16-1002; PMID: 27904032. 28. M arinescu MA, Löffler AI, Ouellette M, et al. Coronary microvascular dysfunction, microvascular angina, and treatment strategies. JACC Cardiovasc Imaging 2015;8:210–20. DOI: 10.1016/j. jcmg.2014.12.008; PMID: 25677893. 29. Russo G, Di Franco A, Lamendola P, et al. Lack of effect of nitrates on exercise stress test results in patients with microvascular angina. Cardiovasc Drugs Ther 2013;27:229–34. DOI: 10.1007/s10557-013-6439-z; PMID: 23338814. 30. Denardo SJ, Wen X, Handberg EM, et al. Effect of phosphodiesterase type 5 inhibition on microvascular coronary dysfunction in women: a Women’s Ischemia Syndrome Evaluation (WISE) ancillary study. Clin Cardiol 2011;34:483–7. DOI: 10.1002/clc.20935; PMID: 21780138. 31. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–31. DOI: 10.1056/NEJMoa1707914; PMID: 28845751. 32. Kaski JC, Rosano G, Gavrielides S, Chen L. Effects of angiotensinconverting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina. J Am Coll Cardiol 1994;23:652–7. DOI: 10.1016/0735-1097(94)907501; PMID: 8113548. 33. Cannon RO 3rd, Watson RM, Rosing DR, Epstein SE. Efficacy of calcium channel blocker therapy for angina pectoris resulting from small-vessel coronary artery disease and abnormal vasodilator reserve. Am J Cardiol 1985;56:242–6. DOI: 10.1016/0002-9149(85)90842-2; PMID: 4025160. 34. Radico F, Cicchitti V, Zimarino M, et al. Angina pectoris and myocardial ischemia in the absence of obstructive coronary artery disease: practical considerations for diagnostic tests, JACC: Cardiovasc Intervent 2014;7: 453-63, DOI: 10.1016/ j.jcin.2014.01.157; PMID: 24746648.

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Diabetes Drugs and Cardiovascular Event Reduction: A Paradigm Shift Erik M Kelly, MD 1 and Donald E Cutlip, MD 1,2 1. Division of Cardiology and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA; 2. Baim Institute for Clinical Research, Boston, MA

Abstract This review article summarizes the recent cardiovascular outcome data for sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues, which have been found to reduce cardiovascular events. We also detail the implications these new medications will have on clinical practice through a review of recent diabetes guidelines and cost-effectiveness data.

Keywords Cardiovascular outcomes, cost-effectiveness, glucagon-like peptide-1 analogues, guidelines, sodium–glucose cotransporter-2 inhibitors, diabetes Disclosure: The authors have no conflicts of interest to declare. Received: 26 November 2017 Accepted: 15 January 2018 Citation: US Cardiology Review 2018;12(1):46–50. DOI: 10.15420/usc.2017:35:1 Correspondence: Erik M Kelly, Division of Cardiology and Department of Medicine, Beth Israel Deaconess Medical Center, West Campus, Baker 4, 185 Pilgrim Road, Boston, MA 02215. E: emkelly@bidmc.harvard.edu

Diabetes mellitus is one of the most common chronic diseases, affecting >30 million people in the US and 422 million worldwide.1,2 Alarmingly, both the incidence and prevalence of type 2 diabetes have doubled in the US since 1990.3 This is driven by an aging population, obesity, physical inactivity, and prolonged survival in those with diabetes, among other factors. It is estimated that diabetes will affect >54 million people in the US by 2030.4 Cardiologists routinely care for patients with diabetes, as those with the condition have a two- to four-fold increased risk of developing coronary heart disease.5 Indeed, coronary heart disease is the leading cause of morbidity and mortality in those with diabetes, with over one-third having a myocardial infarction in their lifetimes.6 Furthermore, diabetes patients with an acute coronary syndrome have worse clinical outcomes compared with people without diabetes.7 Patients with diabetes also have a two- to five-fold increased risk of developing heart failure.8

cardiovascular safety of these drugs arose following the University Group Diabetes Program study in 1975, which demonstrated excess cardiac deaths in patients treated with tolbutamide compared with placebo or insulin.13 Subsequent studies with other agents in this drug class demonstrated similar results.14–16 For example, a recent review and meta-analysis of 82 randomized controlled trials and 26 observational studies showed an increased risk of all-cause mortality, cardiovascularrelated mortality, myocardial infarction, and stroke with sulfonylureas compared with other glucose-lowering drugs.17 As a result of the totality of evidence, all drugs in the sulfonylurea class carry a ‘black box’ warning for increased risk of cardiovascular mortality.

The UK Prospective Diabetes Study, among others, found that intensive glycemic control significantly reduces microvascular complications but fails to modify macrovascular risk in patients with diabetes.9 While contemporary meta-analyses suggest that intensive glycemic control does reduce the risk of cardiovascular events, these benefits appear modest compared with the cardiovascular risk reductions associated with the modification of other traditional risk factors.10,11 Importantly, several classes of diabetes medications have been associated with adverse cardiovascular events. Specifically, sulfonylureas are associated with increased cardiovascular mortality while thiazolidinediones and dipeptidyl peptidase-4 (DPP-4) inhibitors are associated with higher rates of heart failure.

Thiazolidinediones are synthetic ligands for peroxisome proliferativeactivated receptor gamma, which improves insulin sensitivity in peripheral tissues.18 First approved by the US Food and Drug Administration (FDA) in 1999, the safety of these agents was called into question following a 2007 meta-analysis showing that rosiglitazone was associated with an increased risk of myocardial infarction and death from cardiovascular causes.19 These drugs have also been associated with an increased risk of heart failure.20,21 More recent studies dispute the increased risk of myocardial infarction with rosiglitazone and there are data supporting the cardioprotective effects of pioglitazone.22,23 However, the increased risk of heart failure, weight gain and bone fractures, along with a potential association with bladder cancer, has led to significant reductions in the use of these drugs.24 The concerns about peripheral edema and heart failure have also resulted in product labels cautioning against the use of thiazolidinediones in patients with heart failure, with a contraindication for initiation in patients with New York Heart Association Class III or IV.25

Sulfonylureas have been used for the treatment of type 2 diabetes for >50 years. Their main effect is through raising serum insulin concentrations via stimulation of the pancreatic beta cells.12 Concerns over the

DPP-4 inhibitors are a class of oral hypoglycemic agents that block the action of endogenous DPP-4 – a protease that degrades incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory

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Diabetes Drugs and Cardiovascular Outcomes Table 1: Summary of New Diabetes Drug Cardiovascular Outcome Trials Drug Name CV Outcome Trial

Empagliflozin

Canagliflozin

Liraglutide

Semaglutide

EMPA-REG OUTCOME

CANVAS

LEADER

SUSTAIN-6

−14 % (0.74–0.99)

−14 % (0.75–0.97)

−13 % (0.78–0.97)

−26 % (0.58–0.95)

CV mortalityb

−38 % (0.49–0.77)

−22 % (0.66–0.93)

All-cause mortalityb

−32 % (0.57–0.82)

−15 % (0.74–0.97)

MIb

Strokeb

−39 % (0.38–0.99)

HF hospitalizationb

−35 % (0.50–0.85)

−33 % (0.52–0.87)

Primary

Endpointa,b

aIn

all studies, the primary composite endpoint was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. bRelative risk. CV = cardiovascular; HF = heart failure; MI = myocardial infraction; NS = not statistically significant.

polypeptide, thereby increasing their serum concentrations. GLP-1 and gastric inhibitory polypeptide are released in the postprandial state and act by reducing gastric motility, stimulating insulin secretion, and decreasing postprandial glucagon release.26 The initial cardiovascular safety and efficacy trial for saxagliptin showed no effect on ischemic events but an increased rate of heart failure hospitalizations.27 Another agent in the class, alogliptin, was associated with a higher, but not statistically significant, risk of heart failure hospitalizations. 28 Two subsequent meta-analyses found that DDP-4 inhibitors were associated with an increased risk of heart failure.29,30 Despite the above data, the association with heart failure does not appear to be a class effect, as a double-blind, placebo-controlled trial of sitagliptin versus placebo among patients with type 2 diabetes and atherosclerotic vascular disease found no affect on the risk of heart failure hospitalizations.31 Due to safety concerns with some glycemic agents, in 2008 the FDA along with the European Medicines Agency mandated that new type 2 diabetes drugs demonstrate cardiovascular safety through large-scale randomized controlled trials.32 In the years since their inception, not only have these paradigm-shifting regulations led to diabetes drug trials that demonstrate cardiovascular safety, but several have recently shown improved cardiovascular outcomes, including reduced cardiovascular and all-cause mortality. Currently, there are two classes of diabetes medications with demonstrated reductions in cardiovascular and allcause mortality: sodium–glucose cotransporter-2 (SGLT-2) inhibitors and GLP-1 analogues (see Table 1).

Review of Clinical Trial Evidence

significant reduction in cardiovascular events. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) randomized 7,020 patients with type 2 diabetes and established cardiovascular disease to 10 mg or 25 mg of empagliflozin or placebo once daily.37 Patients in both groups received additional offstudy treatments for glycemic control at the discretion of their providers. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The outcome measures were analyzed using the pooled empagliflozin group. At a median follow up of 3.1 years, patients receiving empagliflozin had a 14 % relative risk reduction in the primary outcome (hazard ratio [HR] 0.86, 95.02 % confidence interval [CI] 0.74–0.99, p=0.04 for superiority). This result was primarily driven by a 38 % relative risk reduction in cardiovascular death (HR 0.62, CI 0.49–0.77, p<0.001). There was no between-group difference in the risk of myocardial infarction or stroke. Patients randomized to empagliflozin also had a 32 % relative reduction in the risk of death from any cause (HR 0.68, CI 0.57–0.82, p<0.001) and a 35 % reduction in heart failure hospitalizations (HR 0.65, CI 0.50–0.85, p=0.002). Those treated with empagliflozin had a mean reduction in weight of approximately 2 kg and a mean reduction in systolic blood pressure of approximately 4 mmHg. Kidney disease outcomes were also investigated as a secondary endpoint in the EMPA-REG OUTCOME trial. There was a significant reduction in incident or worsening nephropathy and lower rates of clinically relevant renal events in patients randomized to empagliflozin.38 There was a similar benefit with each dose of empagliflozin studied in the trial. While the drug was well tolerated overall, there was an increased rate of genitourinary infections among patients receiving empagliflozin compared with placebo.

SGLT-2 Inhibitors SGLT-2 is a glucose transporter in the proximal tubule of nephrons that is responsible for 90 % of glucose reabsorption.33 Individuals with loss-of-function mutations in the gene for SGLT-2 rarely develop type 2 diabetes or obesity, an observation that led to the development of pharmaceuticals to target this protein pathway.34 Inhibitors of SGLT-2 block glucose reabsorption in the nephron, but also cause decreased sodium reabsorption. While the primary effect of these agents is on serum glucose reduction, they also promote a modest diuretic effect, weight loss, and lower blood pressure.35,36 The cardiovascular outcomes trial for the SGLT-2 inhibitor empagliflozin was the first study of a new diabetes drug to demonstrate a statistically

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The safety and efficacy of canagliflozin was studied in the CANaglifozin cardioVascular Assessment Study (CANVAS) Program, which integrated data from two trials of 10,142 patients with type 2 diabetes and high cardiovascular risk who were randomized to receive this SGLT-2 inhibitor or placebo.39 High cardiovascular risk was defined as either symptomatic atherosclerotic cardiovascular disease (65.5 % of participants) or being ≥50 years of age with two or more cardiovascular risk factors. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. At a mean follow-up of 188 weeks, treatment with canagliflozin led to a 14 % relative risk reduction in the primary endpoint compared with placebo (HR 0.86, 95 % CI 0.75– 0.97, p<0.001 for noninferiority, p=0.02 for superiority). Superiority was

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Risk Prevention not demonstrated for the first secondary endpoint (all-cause mortality, p=0.24), so according to the statistical plan further hypothesis testing was discontinued and other results were reported as exploratory and not considered statistically significant. These secondary outcomes included a 33 % relative risk reduction in heart failure hospitalizations in those treated with canagliflozin (HR 0.67, CI 0.52–0.87). Unlike empagliflozin, canagliflozin was not shown to reduce cardiovascular or all-cause mortality. Those treated with canagliflozin had a mean body weight reduction of 1.6 kg and a mean systolic blood pressure reduction of 3.93 mmHg. While it did not reach statistical significance, there was a trend toward benefit with respect to the progression of albuminuria and adverse renal outcomes. Notably, there was a significantly increased risk of amputations in the canagliflozin group (HR 1.97, CI 1.41–2.75) with 71 % of amputations occurring at the level of the toe or metatarsal. Similar to empagliflozin, there was an increased risk of genitourinary infections among patients treated with canagliflozin. Interestingly, empagliflozin and canagliflozin produced only modest hemoglobin HbA1c reductions (0.54 % and 0.58 %, respectively) with convergence of levels toward the end of the trials. Moreover, the cardiovascular benefits of both drugs were noted early. These observations suggest that their benefits may result from direct cardiovascular effects rather than improved glycemic control. While there were modest improvements in body weight and blood pressure in both studies, these are unlikely to fully account for the cardiovascular benefits demonstrated. There is a general belief that the rapid natriuresis and glycosuria induced by these agents may explain the early cardiovascular benefits through reductions in circulating volume and resultant decreases in filling pressures.40,41 Other postulated mechanisms by which SGLT-2 inhibitors exert their cardiovascular benefits include reduction in glomerular hypertension, red blood cell expansion, and ketone-body elevation.36,37,40,42 As a result of the EMPA-REG OUTCOME trial, in 2016 the FDA approved empagliflozin to reduce the risk of cardiovascular death in patients with type 2 diabetes. 43 Canagliflozin does not yet have this FDAapproved indication.

GLP-1 Analogues GLP-1 is a peptide hormone that increases insulin secretion and decreases glucagon release in a glucose-dependent manner. 44 GLP-1 analogues were developed to exploit these effects. They have been found to reduce serum glucose levels and weight through increasing glucose-dependent insulin secretion, decreasing glucagon secretion, delaying gastric emptying, and increasing satiety. 44,45 Two drugs from this class, liraglutide and semaglutide, have been shown to improve cardiovascular outcomes. Liraglutide is an injectable, long-acting GLP-1 receptor analogue that has been shown to lower serum glucose levels, reduce blood pressure, and promote weight loss.44,46 The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial randomized 9,340 patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo.47 High cardiovascular risk was defined as established cardiovascular disease or age >60 years with one or more cardiovascular risk factors. With a median followup of 3.8 years, patients treated with liraglutide had a 13 % relative

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risk reduction in the primary composite outcome of cardiovascular mortality, nonfatal myocardial infarction, or nonfatal stroke (HR 0.87, 95 % CI 0.78–0.97, p<0.001 for noninferiority, p<0.01 for superiority). This effect was largely driven by a 22 % reduction in cardiovascular death. The rate of all-cause mortality was also significantly reduced in the liraglutide group compared with placebo (HR 0.85, CI 0.74–0.97, p=0.02). Patients treated with liraglutide had a mean weight loss of 2.3 kg and there was no significant difference in blood pressure compared with placebo. A pre-specified secondary analysis showed that liraglutide use resulted in lower rates of the development and progression of diabetic kidney disease.48 This effect was driven primarily by a reduction in new-onset persistent macroalbuminuria. The rates of renal adverse events were similar between the two groups. Finally, there was no significant reduction in heart failure hospitalizations among patients treated with liraglutide compared with placebo (4.7 % versus 5.3 %, p=0.14). As a class, GLP-1 analogues carry a warning for increased incidence of pancreatitis; however, rates were similar with liraglutide compared to placebo in this trial. More patients in the liraglutide group discontinued therapy due to adverse events, which were largely driven by gastrointestinal disorders. Subsequently, the once-weekly injectable GLP-1 analogue semaglutide was assessed for cardiovascular safety in the Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6) trial.49 A total of 3,297 patients with type 2 diabetes and high cardiovascular risk, defined in the same way as the LEADER trial, were randomized to semaglutide or placebo. The composite primary endpoint was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. After a median followup of 2.1 years, patients treated with semaglutide had a 26 % relative risk reduction in the primary endpoint (HR 0.74, 95 % CI 0.58–0.95, p<0.001 for noninferiority). This reduction was due to fewer nonfatal strokes (1.6 % versus 2.7 %, p=0.04) and myocardial infarctions (2.9 % versus 3.9 %, p=0.12). Unlike liraglutide, semaglutide was not found to reduce cardiovascular mortality. There was also no significant reduction in heart failure hospitalizations among patients treated with semaglutide. Patients in the treatment group had mean body weight reductions of between 3.6 kg and 4.9 kg based on drug dose. Mean systolic blood pressure was 1.3 mmHg lower in the treatment group than placebo. Like liraglutide, more patients treated with semaglutide discontinued therapy due to adverse events, which were mainly gastrointestinal. However, semaglutide was also associated with a significant increase in rates of retinopathy complications. Two other GLP-1 receptor agonists, exenatide and lixisenatide, have been assessed for cardiovascular safety. The cardiovascular outcome trials for these drugs showed no increase or decrease in cardiovascular events or adverse events compared with placebo.50,51 A cardiovascular outcome trial was stopped early for the candidate GLP-1 receptor agonist taspoglutide due to reported anaphylactoid and anaphylactic reactions.52 The cardiovascular benefits seen with liraglutide and semaglutide occurred later than in the SGLT-2 inhibitor trials. This suggests that their mechanism of action involves the modification of atherothrombotic pathways, rather than hemodynamic alterations. Other postulated mechanisms include blood pressure reduction, renal protective effects, and weight loss.53

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Diabetes Drugs and Cardiovascular Outcomes In 2017, based on the results of the LEADER trial, the FDA approved a new indication for liraglutide to reduce the risk of major cardiovascular events in patients with type 2 diabetes and established cardiovascular disease.54 Semaglutide is currently being reviewed by the FDA.

Implications for Clinical Practice Until recently, most US-based guidelines for type 2 diabetes pharmacotherapy management focused primarily on HbA1c and weight effects as well as risk of hypoglycemia. The results of recent cardiovascular outcome trials have prompted a change in diabetes management guidelines. 55 For example, the 2017 American Diabetes Association standards of care recommend considering empagliflozin or liraglutide in patients with suboptimally controlled diabetes and atherosclerotic cardiovascular disease, recognizing the cardiovascular benefits of these agents. 56 The Canadian Diabetes Association was the first body to prioritize cardiovascular disease status in choosing add-on therapy in its 2016 interim update, stating “the presence of clinical cardiovascular disease and the effect of antihyperglycemic agents on cardiovascular outcomes should be considered the top priority in choosing add-on treatment regimens.”57 Governing bodies have also started recognizing the cardiovascular effects of these new agents. The 2016 Joint European Society of Cardiology guidelines give a Class IIa, Level B recommendation to consider SGLT-2 inhibitors early in the course of type 2 diabetes in patients with comorbid cardiovascular disease to reduce cardiovascular and total mortality. 58 It is likely that more societies and guideline committees will recognize the cardiovascular benefits of these agents and prioritize their use in treatment in the coming years. Excitement over the cardiovascular outcomes associated with these new agents must be tempered by an objective analysis of their costeffectiveness compared with alternative treatments. Indeed, the average

athers C, Loncar D. Projections of global mortality and burden M of disease from 2002 to 2030. PLOS Med 2006;3:e422. DOI: 10.137/journal.pmed.0030442; PMID: 17132052. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Departments of Health and Human Services, 2017. Available at: http://bit.ly/2tnbN35 (accessed February 13, 2018). Geiss L, Wang J, Cheng Y, et al. Prevalence and incidence trends for diagnosed diabetes among adults aged 20 to 79 years, United States, 1980–2012. JAMA 2014;213:1218–26. DOI: 10.1001/ jama.2014.11494; PMID: 25247518. Rowley W, Bezold C, Arikan Y, et al. Diabetes 2030: Insights from yesterday, today, and future trends. Popul Health Manag 2017;20:6– 12. DOI: 10.1089/pop.20150181; PMID: 5278808. Diabetes Drafting Group. Prevalence of small vessel and large vessel disease in diabetic patients from 14 centres. The World Health Organization Multinational Study of Vascular Disease in Diabetics. Diabetologia 1985;28:S615–S40. PMID: 4065455. Fang J, Alderman M. Impact of the increasing burden of diabetes on acute myocardial infarction in New York City: 1990– 2000. Diabetes 2006;55:768–73. DOI: 10.2337/diabetes.55.03.06. db05-1196; PMID: 16505241. Wiviott S, Braunwald E, Angiolillo D, et al. TRITON-TIMI 38 Investigators. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel – Thrombolysis in Myocardial Infarction 38. Circulation 2008;118:1626–36. DOI: 10.1161/CIRCULATIONAHA.108.791061; PMID: 18757948. Aguilar D. Management of type 2 diabetes in patients with heart failure. Curr Treat Options Cardiovasc Med 2008;10:465–75. DOI: 10.1007/s11936-008-0039-4; PMID: 19026177. UK Prospective Diabetes Study Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet

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10.

11.

12.

13.

14.

15.

16.

17.

monthly cost for empagliflozin is $410, as compared with <$10 per month for other agents such as metformin and glipizide.59–61 In the UK, Huseyin Naci and colleagues found that prevention of one cardiovascular event with empagliflozin would cost approximately £73,431 if used in a high-risk population.62 This cost would increase to £322,361 if offered to lower-risk patients.62 Canagliflozin was found to be cost-effective compared with sitagliptin in patients with poorly controlled type 2 diabetes in a Mexican study.63 In a US analysis of liraglutide compared with sitagliptin, the incremental cost-effectiveness ratio was between $25,742 and $37,234 per quality-adjusted life year gained, based on liraglutide dose.64 In all sensitivity analyses, the incremental cost-effectiveness ratios remained below the commonly accepted threshold of $50,000 per quality-adjusted life year.64 Similar cost-effectiveness for liraglutide was found in a Greek analysis, where liraglutide was associated with higher direct medical costs but an overall cost saving due to reductions in the treatment of diabetes-related complications.65 Taken together, these studies suggest that the use of novel diabetes agents may be cost-effective, but further study is needed to assess their role as primary treatment specifically for cardiovascular event reduction.

Conclusion In the years since the paradigm-shift in diabetes drug approval, we have seen SGLT-2 inhibitor and GLP-1 receptor agonist trials demonstrate reduced cardiovascular events and mortality. It remains to be seen whether a similar paradigm-shift will follow in the way practitioners approach the management of patients with type 2 diabetes and comorbid cardiovascular disease. Moreover, questions remain regarding the cost-effectiveness of these medications. If the recent changes to society guidelines are any indication, we are likely to see cardiovascular disease risk become an important factor in diabetes drug selection going forward. As such, cardiologists should become familiar with these agents and the populations that stand to benefit from their use. n

1998;352:837–53. DOI: 10.1016/S0140-6736(98)07019-6; PMID: 9742976. Ray K, Seshasai S, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomized controlled trials. Lancet 2009;373:1765–72. DOI: 10.1016/S01406736(09)60697-8; PMID: 19465231. Control Group, Turnbull F, Abraira C, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288–98. DOI: 10.1007/s00125-009-1479-0; PMID: 19655124. Ashcroft F. Mechanisms of the glycaemic effects of sulfonylureas. Horm Metab Res 1996;28:456–63. DOI: 10.1055/s2007-979837; PMID: 8911983. The University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of pheniformin therapy. Diabetes 1975;24:S65–S184. PMID: 1090475. Pantalone K, Kattan M, Yu C, et al. Increase in overall morality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab 2012;14:803–9. DOI: 10.1111/j.1463-1326.2012.01604.x; PMID: 22486923. Schramm T, Gislason G, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without previous myocardial infarction: a nationwide study. Eur Heart J 2001;32:1900-8. DOI: 10.1093/eurheartj/ehr077; PMID: 21471135. Hemmingsen B, Schroll J, Lund S, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 2013;4:CD009008. DOI: 10.1002/14651858. CD009008.pub2; PMID: 23633364. Bain S, Druyts E, Balijepalli C, et al. Cardiovascular events and all-cause mortality associated with sulphonylureas compared with other antihyperglycemic drugs: a Bayesian metaanalysis of survival data. Diabetes Obes Metab 2017;19:329–35.

DOI: 10.1111/dom.12821; PMID: 27862902. 18. C ampbell I. The clinical significance of PPAR gamma agonism. Curr Mol Med 2005;5:349–63. DOI: 10.2174/1566524053766068; PMID: 15892654. 19. Nissen S, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. DOI: 10.1056/NEJMoa072761; PMID: 17517853. 20. Home P, Pocock S, Beck-Nielsen H, et al. RECORD Study Team. Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD): a multicenter, randomised, open-label trial. Lancet 2009;373:2125– 35. DOI: 10.1016/S0140-6736(09)60953-3; PMID: 19501900. 21. Hernandez A, Usmani A, Rajamanickam A, Moheet A. Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials. Am J Cardiovasc Drugs 2011;11:115–28. DOI: 10.2165/11587580-000000000-00000; PMID: 21294599. 22. Stone J, Furuya-Kanamori L, Barendregt J, Doi SA. Was there really any evidence that rosiglitazone increased the risk of myocardial infarction or death from cardiovascular causes? Phamacoepidemiol Drug Saf 2015;24:233–7. DOI: 10.1002/pds.3736; PMID: 25515780. 23. Dormandy J, Charbonnel B, Eckland D, et al. PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. DOI: 10.1016/S0140-6736(05)67528-9; PMID: 16214598. 24. Cariou B, Charbonnel B, Staels B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol Metab 2012;23:205–15. DOI:10.1016/j.tem.2012.03.001; PMID: 22513163. 25. Nathan D, Buse J, Davidson M, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding

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33.

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mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. DOI: 10.1056/NEJMoa1504720; PMID: 26378978. 38. W anner C, Inzucchi S, Lachin J, et al. EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34. DOI: 10.1056/ NEJMoa1515920; PMID: 27299675. 39. Neal B, Perkovic V, Mahaffey K, et al. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. DOI: 10.1056/NEJMoa1611925; PMID: 28605608. 40. Heerspink H, Perkins B, Fitchett D, et al. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 2016;134:752–72. DOI: 10.1161/ CIRCULATIONAHA.116.021887; PMID: 27470878. 41. Marx N, McGurie D. Sodium–glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J 2016;37:3192–200. DOI: 10.1093/eurheartj/ehw110; PMID: 27153861. 42. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care 2016;39:1108–14. DOI: 10.2337/dc16-0330; PMID: 27289126. 43. US Food and Drug Administration. 2016. FDA News Release. FDA approves Jardiance to reduce cardiovascular death in adults with type 2 diabetes. Available at: http://bit.ly/2zpO57Z (accessed February 13, 2018). 44. Nauk M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2016;18:203–16. DOI: 10.111/dom.12591; PMID: 26489970. 45. Robinson L, Holt T, Rees K, et al. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open 2013;3:e001986. DOI: 10.1136/bmjopen-2012-001986; PMID: 23355666. 46. Du Q, Wang Y, Yang S, et al. Liraglutide for the treatment of type 2 diabetes mellitus: a meta-analysis of randomized placebocontrolled trials. Adv Ther 2014;31:1182–95. DOI: 10.1007/s12325014-0164-2; PMID: 25388240. 47. Marso S, Daniels G, Brown-Frandsen K, et al. LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–22. DOI: 10.1056/NEJMoa1603827; PMID: 27295427. 48. Mann J, Ørsted D, Brown-Frandsen K, et al. LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017;377:839–48. DOI: 10.1056/NEJMoa1616011; PMID: 28854085. 49. Marso S, Bain S, Consoli A, et al. SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–44. DOI: 10.1056/ NEJMoa1607141; PMID: 27633186. 50. Holman R, Bethel M, Mentz R, et al. EXSCEL Study Group. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2017;377:1228–39. DOI: 10.1056/ NEJMoa1612917; PMID: 28910237. 51. Pfeffer M, Claggett B, Diaz R, et al. ELIXA Investigators.

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Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247–57. DOI: 10.1056/ NEJMoa1509225; PMID: 26630143. Rosenstock J, Balas B, Charbonnel B, et al. T-emerge 2 Study Group. The fate of taspoglutide, a weekly GLP-1 receptor agonist, versus twice-daily exenatide for type 2 diabetes: the T-emerge 2 trial. Diabetes Care 2013;36:498–504. DOI: 10.2337/ dc12-0709; PMID: 23139373. Drucker D. The cardiovascular biology of glucagonlike peptide-1. Cell Metab 2016;24:15–30. DOI: 10.1016/j. cmet.2016.06.009; PMID: 27345422. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc. August 2017. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care 2017;40(Suppl 1):S64–S74. DOI: 10.2337/dc17-S011; PMID: 27979895. American Diabetes Association. Standards of medical care in diabetes – 2017: summary of revisions. Diabetes Care 2017;40(Suppl 1):S4–S5. DOI: 10.2337/dc17-S003; PMID: 27979887. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Pharmacologic management of type 2 diabetes: 2016 interim update. Can J Diabetes 2016;40:484–6. DOI: 10.1016/j.jcjd.2016.09.003; PMID: 27912867. Piepoli M, Hoes A, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice, developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;252:207–74. DOI: 10.1016/atherosclerosis.2016.05.037; PMID: 27664503. Zimmermann J. Empagliflozin (Jardiance) for type 2 diabetes mellitus. Am Fam Physician 2916;94:1014–15. PMID: 28075091. GoodRx. Metformin: Generic Glucophage. Available at: www. goodrx.com/metformin (accessed November 5, 2017). GoodRx. Glipizide: Generic Glucotrol. Available at: www.goodrx. com/glipizide (accessed November 5, 2017). Naci H, Basu S, Yudkin J. Preventing cardiovascular events with empagliflozin: at what cost? Lancet Diabetes Endocrinol 2015;3:931. DOI: 10.1016/S2213-8587(15)00439-8; PMID: 26590682. Neslusan C, Teschemaker A, Johansen P, et al. Costeffectiveness of canagliflozin versus sitagliptin as add-on to metformin in patients with type 2 diabetes mellitus in Mexico. Value Health Reg Issues 2015;8:8–19. DOI: 10.1016/j. vhri.2015.01.002. Lee W, Samyshkin Y, Langer J, Palmer JL. Long-term clinical and economic outcomes associated with liraglutide versus sitagliptin therapy when added to metformin in the treatment of type 2 diabetes: a CORE Diabetes Model analysis. J Med Econ 2012;15(Suppl 2):S28–S37. DOI: 10.3111/13696998.2012.716111; PMID: 22834986. Tzanetakos C, Melidonis A, Verras C, et al. Cost-effectiveness analysis of liraglutide versus sitagliptin or exenatide in patients with inadequately controlled type 2 diabetes on oral antidiabetic drugs in Greece. BMC Health Serv Res 2014;14:419. DOI: 10.1186/1472-6963-14-419; PMID: 25245666.

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Electrophysiology

Catheter Ablation for Ventricular Tachycardia in Patients with Structural Heart Disease Timothy M Markman, MD 1,2, Daniel A McBride, MD 1, and Jackson J Liang, DO 1,2 1. Department of Medicine; 2. Cardiovascular Division, Electrophysiology Section, Hospital of the University of Pennsylvania, University of Pennsylvania, Philadelphia, PA

Abstract Ventricular tachycardia is a potentially fatal arrhythmia that occurs most frequently in patients with structural heart disease. Acute and longterm management can be complex, requiring an integrated approach with multiple therapeutic modalities including antiarrhythmic drugs, implantable cardioverter defibrillators, and catheter ablation. Each of these options has a role in management of ventricular tachycardia and are generally used in combination. It is essential to be aware that each approach has potential deleterious consequences that must be balanced while establishing a treatment strategy. Catheter ablation for ventricular tachycardia is performed with increasing frequency with rapidly evolving techniques. In this review, we discuss the acute and long-term management of ventricular tachycardia with a focus on techniques and evidence for catheter ablation.

Keywords Ventricular tachycardia, arrhythmias, structural heart disease, catheter ablation, radiofrequency ablation, antiarrhythmic drugs Disclosure: The authors have no conflicts of interest to declare. Received: 9 November 17 Accepted: 20 December 17 Citation: US Cardiology Review, 2018;12(1):51–6. DOI: 10.15420/usc.2017:28:3 Correspondence: Jackson J Liang, DO, Electrophysiology Section, Division of Cardiology Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19103. E: Jackson.liang@uphs.upenn.edu

Ventricular tachycardia (VT) occurs most frequently in patients with structural heart disease. Management of VT in these patients can be complex, requiring an integrated approach with multiple therapeutic modalities. Antiarrhythmic drugs (AADs) can be effective in the management of VT and implantable cardioverter defibrillators (ICDs) have been shown to effectively prevent sudden cardiac death due to ventricular arrhythmias.1–3 Unfortunately, ICDs do not prevent the recurrence of episodes of VT and appropriate ICD shocks are associated with significant morbidity and increased rates of mortality.4,5 AADs can be used to minimize the frequency of ICD shocks, but long-term use may be required to achieve continued VT suppression and these medications can have substantial side effects. Radiofrequency catheter ablation of VT is an effective treatment method for patients with VT in the setting of structural heart disease.6,7 Although there is limited evidence that catheter ablation improves overall mortality,8 catheter ablation is clearly effective in reducing VT burden and decreasing the number of appropriate ICD therapies. As technology and procedural techniques have improved over time, catheter ablation for VT has become an increasingly utilized treatment strategy. While optimal timing of VT ablation remains debated, it is often considered only late in the course of progressive structural heart disease, especially at institutions with less experience in the procedure.9,10 In this review, we discuss the management of VT with a focus on patients with underlying structural heart disease, including the use of AADs and ICDs. We also

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review the basics of VT ablation, the evidence behind the procedure, and future directions in the field.

Initial Management of Ventricular Tachycardia Once a diagnosis of VT is made, acute management is initially focused on achieving hemodynamic stability. If the VT causes hemodynamic instability – a function of both characteristics of the arrhythmia (especially rate) and the patient’s underlying cardiac function – electrical cardioversion can successfully restore sinus rhythm, at least temporarily. Patients who are hemodynamically unstable during VT or those with major comorbidities should be admitted to an intensive care unit where metabolic, respiratory, or other circulatory derangements should be immediately identified and corrected. Further acute management generally focuses on AADs, reprogramming of ICDs to decrease the frequency of recurrent shocks, and termination of clinically significant arrhythmias with anti-tachycardia pacing, and occasionally catheter ablation (Table 1 and Figure 1).11,12 The use of ICDs has been shown to substantially improve mortality and decrease the risk of sudden cardiac death in patients with VT both for primary and secondary prevention.1,2,5 Even with ICDs in place, AADs are also generally required both in the acute and long-term management of VT to decrease the rate of recurrent arrhythmias. AADs can reduce the incidence of both appropriate and inappropriate ICD shocks. However, all AADs may cause side effects and proarrhythmic effects have been reported in nearly 10 % of patients treated with AADs for ventricular arrhythmias.13,14

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Electrophysiology Table 1: Therapeutic Options for the Treatment of VT Indications

Advantages

Disadvantages

Anti-arrhythmic drugs (AADs)

First-line management of VT or VT storm

Inexpensive, rapid effect, decrease in frequency of ICD shocks

Contraindications and side effects of each AAD, lifelong drug therapy

Implantable cardioverter defibrillators (ICDs)

Secondary prevention from VT or VT, primary prevention with ischemic and non-ischemic cardiomyopathy

Mortality benefit

Does not prevent VT, increased mortality risk with shocks, infections, procedural complications

Catheter ablation

VT storm, recurrent or idiopathic VT

Reduced VT burden and frequency of ICD shocks, decrease need for AADs

Invasive, procedural complications, potential need for repeat procedures

Sympathetic denervation

Refractory VT

Reduced VT burden and frequency of ICD shocks

Limited evidence, invasive, procedural complications

VT = ventricular tachycardia.

Figure 1: Ventricular Tachycardia Management Algorithm Ventricular tachycardia of unknown etiology

Acute ischemia History of angina, coronary artery disease risk factors, ECG changes consistent with ischemia

Other reversible causes Drugs use, electrolyte or metabolic abnormalities, trauma, central venous catherter in right ventricle

Urgent angiogram and revascularization

Address reversible causes Echocardiogram, clinical history, family history

Secondary prevention ACE inhibitor, betablockers, statin, antiplatelet agents

Re-evaluate left ventricular ejection fraction

Structural heart disease Dilated or infiltrative cardiomyopathy, aortic valve disease, coronary artery disease Address underlying cause Valve repair, guideline directed medical therapy, steroids, etc.

Secondary prevention ICD

Inherited arrhythmogenic disease Long QT syndrome, Brugada Syndrome, arrhythmogenic right ventricular dysplasia, etc

Antiarrhythmic drugs (see Table 2)

No detectable heart disease

Catheter ablation

ACE = angiotensin-converting enzyme; ICD = implantable cardioverter defibrillator.

Beta-blockers effectively suppress adrenergic tone, which can be markedly increased acutely in the setting of VT. Beta-blockers also have long-term benefits, especially in patients with underlying structural heart disease and reduced left ventricular systolic function.15,16 Amiodarone is perhaps the most widely used AAD for VT and can be safely used in the acute setting with impressive efficacy.17,18 Several issues arise with amiodarone use. Acute use of amiodarone can cause hypotension and hemodynamic instability, and, in some patients,

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can also increase defibrillation thresholds. Serious long-term adverse effects of the medication include liver dysfunction, thyroid disease, pulmonary fibrosis, and ophthalmologic complications. 19,20 Lidocaine is an intravenously delivered class 1B AAD that can be effective especially for the treatment of ischemic VT. Importantly, central nervous system side effects of hallucinations, tremors, or seizures can occur with high doses.21,22 For this reason, monitoring lidocaine levels in the blood is recommended. Mexiletine is a similar class IB agent

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Catheter Ablation for Ventricular Tachycardia Table 2: Antiarrythmic Drugs for the Treatment of Ventricular Tachycardia Route

Common dosing

Contraindications or warnings

Important Adverse Effects

Beta-blocker

PO or IV

Varies by individual agent

Severe bradycardia or heart block without a pacemaker, decompensated heart failure, Prinzmetal’s variant angina

Hypotension, sinus bradycardia, AV block, bronchospasm, fatigue, depression, sexual dysfunction

Amiodarone

PO or IV

PO: 400–1200 mg daily in divided doses

Severe bradycardia or heart block without a pacemaker, decompensated heart failure, prolonged QT interval

Hypo- and hyper-thyroidism, pulmonary fibrosis, hepatotoxicity, bradycardia, QT interval prolongation, photosensitivity and skin discoloration, corneal deposits, neuropathy

IV: 150 mg bolus; 0.5–1.0 mg/min infusion Lidocaine

1.0–1.5 mg/kg bolus, repeat 0.5–0.75 mg/kg every 5–10 min as needed up to 3 mg/kg; 1–4 mg/min infusion

Severe bradycardia or heart block without a pacemaker, Wolf–Parkinson–White syndrome

Gastrointestinal disturbances, bradycardia, hypotension, agitation, seizures, dizziness, altered sensorium, dysarthria, psychosis

Mexiletine

450–900 mg daily

Severe bradycardia or heart block without a pacemaker, reduced left ventricular ejection fraction or heart failure, inherited long QT syndrome (except long QT syndrome 3)

Gastrointestinal disturbances, bradycardia, hypotension, tremor, dizziness, dysarthria

Procainamide

PO or IV

PO: 1000–4000 mg daily in divided doses

Severe bradycardia, heart block, or intraventricular conduction delay without a pacemaker, coronary artery disease, reduced left ventricular ejection fraction or heart failure, hypotension, Brugada syndrome

Drug-induced lupus, rash, myalgia, bone marrow suppression, vasculitis, bradycardia, hypotension, QT interval prolongation

Severe bradycardia or heart block without a pacemaker, decompensated heart failure, Prinzmetal’s variant angina, prolonged QT interval

Hypotension, sinus bradycardia, AV block, bronchospasm, fatigue, depression, sexual dysfunction, QT interval prolongation

IV: 100–1000 mg load; 2–6 mg/min infusion Sotalol

PO or IV

PO: 160–320 mg in divided doses IV: 75–300 mg twice daily

AV = atrioventricular; IV = intravenous; PO = orally.

that can be administered orally. While the efficacy of mexiletine when given as monotherapy is limited, it can result in improved VT suppression when used in conjunction with amiodarone. Procainamide, a class IC agent that has also been shown to be effective for the acute management of VT, although acute use can be limited by hypotension and chronic use by a number of side effects including drug-induced lupus, gastrointestinal disturbances, and hematologic abnormalities (Table 2).23,24

Catheter Ablation for Ventricular Tachycardia Although some form of AAD combined with ICD therapy is currently the standard of care for the management of VT, it is important to remember that both of these treatments are not true cures for the disorder. Continued AAD use may be necessary to achieve long-term VT suppression, but long-term side effects must be considered, especially as many patients with VT also have significant pulmonary, renal, or hepatic dysfunction. Catheter ablation is an invasive strategy that offers the potential of cure by destroying or isolating arrhythmogenic tissue. Successful elimination of VT with catheter ablation can allow for reduction or discontinuation of AADs, thus removing the risks of developing side effects with long-term AAD use.25 In recent years there has been a growing role for catheterbased ablation both in the acute and long-term management of VT.9 This growth is due in part to marked improvement in the knowledge of the pathological basis of arrhythmias, as well as the continued evolution in our ability to identify the origin of an arrhythmia and destroy or isolate tissue necessary for arrhythmia generation or propagation.26

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Catheter ablation can be especially useful in the management of VT storm in patients with ischemic and non-ischemic cardiomyopathy.27,28 VT storm is defined as at least three distinct episodes of sustained VT or ventricular fibrillation within the last 24 hours or the occurrence of incessant VT for at least 12 hours.29 Initial management focuses on achieving hemodynamic stability, which may include intra-aortic balloon pumps (IABPs), percutaneous left ventricular assist devices (pLVADs), or extracorporeal membrane oxygenation (ECMO).12 AADs and ICD reprograming are also essential, although catheter ablation has a growing role given the superiority over medical therapy in reducing arrhythmic burden.6,8 In order to maximize the likelihood of successful catheter ablation, precise location of the suspected arrhythmogenic foci or circuits is necessary. This is achieved through a variety of mapping techniques including activation mapping, pace mapping, entrainment mapping, and substrate mapping. In activation mapping, VT is induced with ongoing electrogram analysis to determine the VT circuit or site of earliest activation representing the VT exit site. Pace mapping involves pacing at different sites in the ventricles to identify the site with the best match, representing the site of origin of a focal arrhythmia or the exit site of a reentrant arrhythmia.30,31 Entrainment mapping involves identifying critical sites of reentrant VT circuits by examining responses to ventricular overdrive pacing during sustained VT.32,33 Finally, substrate mapping is commonly used when VT cannot be induced or sustained VT cannot be hemodynamically tolerated. In these cases,

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Electrophysiology arrhythmogenic substrate is indirectly identified by the presence of abnormal electrograms (e.g. fractionated, low-voltage potentials, or late signals after the QRS), or evidence of scar on imaging.34–36 Importantly, VT must be inducible, sustained, and hemodynamically stable in order for activation and entrainment mapping to be performed. In cases in which VT is not tolerated due to hemodynamic compromise, hemodynamic-support devices such as ECMO, IABP, or pLVAD (i.e. Impella or Tandemheart) can be helpful. Pre-procedural magnetic resonance imaging can also be used to guide ablation. Late-gadolinium enhancement in both ischemic and non-ischemic cardiomyopathy can accurately localize potentially arrhythmogenic substrate, and its use has been associated with improved ablation outcomes.37–39

To date, there have been four major prospective randomized controlled trials evaluating catheter ablation for VT in patients with ischemic cardiomyopathy. In the first, the Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia (SMASH-VT) study, relatively lowrisk patients with prior MI who had a history of a single episode of a ventricular arrhythmia or appropriate ICD therapy, but had not received therapy with AADs (class I or III) were randomized to either substratebased endocardial ablation or standard medical therapy.48 Although there was a significant decrease in the likelihood of recurrent VT requiring ICD therapy (67 versus 88 %; p=0.007), the trial was not powered for mortality, and the exclusion of patients receiving AADs severely limits the clinical relevance of this trial.

The most commonly used energy for catheter ablation at the current time is radiofrequency energy, which utilizes alternating current to deliver energy at the catheter tip with subsequent thermal injury and coagulation necrosis. Importantly, this method is critically dependent on contact with the target myocardium and stability during ablation.40,41 Other forms of ablation including DC ablation (electrical energy) or cryoablation (freezing to achieve necrosis) have also been used in certain settings.40,42,43 Other strategies including electroporation and noninvasive external radiotherapy ablation have also been shown to be effective in preliminary studies and may be options to consider in the near future.

The Ventricular Tachycardia Ablation in Coronary Heart Disease (VTACH) study prospectively evaluated patients with a prior MI, reduced left ventricular ejection fraction (<50 %), and stable VT who would otherwise qualify for a secondary prevention ICD.49 All patients were eligible to receive AADs and the ablation technique was at the discretion of the operator. Of the 107 patients included in the analysis with approximately 2 years of follow-up, the 52 in the ablation group had improved freedom from recurrent ventricular arrhythmias (47 versus 29 %; p=0.04), but there was no significant difference in mortality rates. Although the VTACH study demonstrated the ability for catheter ablation to substantially reduce the risk of recurrent VT, it is equally important to note the ≥50 % risk of VT recurrence within 2 years and associated need for ICDs in these patients regardless of whether ablation was performed.

Catheter ablation procedures are associated with several notable complications that must be considered, although the rates of these complications are low. Vascular injury at the access site is the most common complication, due to the fact that multiple largediameter femoral venous and arterial sheaths may be necessary and intraprocedural anticoagulation is often required. The Multicenter European Radiofrequency Survey (MERFS) examined complication rates for all types of radiofrequency catheter ablations and found that death occurred in 0.13 %, embolic stroke in 0.5 %, cardiac tamponade requiring pericardial drainage in 0.8 %, complete heart block in 0.6 %, and arterial or venous thrombosis in 0.4 %.44 Importantly, rates of complication are heavily influenced by patient and arrhythmia characteristics as well as degree of operator and center experience. While older patients are likely to have more comorbidities, our experience has shown that VT ablation can be safely and effectively performed, thus older age alone should not exclude patients from being offered VT ablation.45

Evidence for Catheter Ablation Catheter ablation for VT has been performed with increasing frequency over the past few years. Most evidence to date demonstrates the benefit of ablation with reduction in recurrent VT and thus appropriate ICD shocks; however, improvement in overall survival, quality of life, or healthcare costs has not been definitively shown (Table 3). Substantial heterogeneity of patient and arrhythmia characteristics as well as ablation techniques utilized limit the interpretability of many of the observational studies that have been published; however, available data suggest improved freedom from VT and transplant-free survival.6,46 Standards have been proposed for trials to report specific clinical characteristics (e.g. type and severity of VT), procedural techniques (e.g. mapping criteria and definition of procedural success), and efficacy endpoints (e.g. mortality and specifics of VT recurrence).47

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The Catheter Ablation for Ventricular Tachycardia in Patients with Implantable Cardioverter Defibrillator (CALYPSO) trial was designed to determine the feasibility of conducting a prospective trial comparing early ablation versus AADs in patients with ischemic cardiomyopathy, no contraindication to AADs, and ICDs that had delivered appropriate therapy.10 The study was terminated prematurely after having experienced challenges with enrollment – over nearly 2 years, 243 patients were screened, 27 enrolled, and only 17 completed 6 months of followup. Although underpowered to detect any differences in outcomes, CALYPSO highlighted an important clinical limitation for enrollment in trials evaluating early VT ablation – this procedure is rarely considered in patients who have not already failed AAD therapy. The Ventricular Tachycardia Ablation Versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease (VANISH) trial asked a clinically relevant question about patients with a history of ischemic cardiomyopathy and recurrent VT despite use of AADs.50 Patients were randomized to catheter ablation versus escalation of AAD therapy, which included the initiation of amiodarone in patients not already taking amiodarone, or the addition of mexiletine in patients already taking amiodarone. Among 259 patients over approximately 28 months of follow-up, the primary outcome, a composite endpoint of all-cause mortality, VT storm, or appropriate ICD shock after 30-day treatment period, occurred in fewer patients who were randomized to ablation versus AAD therapy escalation (59.1 versus 68.5 %; p=0.04). Importantly, while ablation-related procedural complications (e.g. bleeding, vascular injury, or cardiac perforation) did occur, treatment-related adverse events were more common in patients randomized to AAD therapy escalation. Importantly, the VANISH trial demonstrated that among high-risk patients with recurrent VT despite

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Catheter Ablation for Ventricular Tachycardia Table 3: Four Major Prospective Randomized Controlled Trials Evaluating Catheter Ablation for VT Study

Year

Patient population

Study arms

Findings

Comments

Substrate Mapping and Ablation in Sinus Rhythm to Halt Ventricular Tachycardia –SMASH-VT

2007

Prior MI with history of single ventricular arrhythmia or appropriate ICD therapy, but no prior AAD use

Substrate-based endocardial ablation versus standard medical therapy

• Ablation decreased the likelihood of recurrent VT requiring ICD therapy (67 versus 88 %; p=0.007) • No significant difference in mortality rates

Exclusion of patients receiving AADs limits the clinical relevance

Ventricular Tachycardia Ablation in Coronary Heart Disease – VTACH

2010

Prior MI, reduced left ventricular ejection fraction (<50 %), and stable VT, qualifying for a secondary prevention ICD

Catheter ablation and ICD versus ICD alone. Both groups were eligible to receive AADs

• Ablation group had improved freedom from recurrent ventricular arrhythmias (47 versus 29 %; p=0.044) • No significant difference in mortality rates

Ablation reduced the frequency of recurrent VT; however, there was a >50 % recurrence rate within 2 years

Catheter Ablation for Ventricular Tachycardia in Patients with Implantable Cardioverter Defibrillator –CALYPSO

2015

Ischemic heart disease, no contraindication to AADs, and received ≥1 ICD shock or ≥3 antitachycardia pacing therapies for VT

Catheter ablation versus AAD (first line: amiodarone, Sotalol; second line: mexiletine, ranolazine, dofetilide)

• Lower risk of recurrent VT in the AAD arm: 6 (43 %) versus 8 (62 %) • Median time to recurrent VT was longer in the ablation arm: 75 versus 57 days

Significant difficulty enrolling patients. Underpowered to detect any differences in outcomes

Ventricular Tachycardia Ablation versus Escalated Antiarrhythmic Drug Therapy in Ischemic Heart Disease – VANISH

2016

Prior MI, ICD, and recurrent VT despite use of AADs

Catheter ablation versus escalation of AAD therapy (amiodarone, mexiletine)

• Composite endpoint (allcause mortality, VT storm, or appropriate ICD shock after 30 days) occurred less in ablation versus AAD escalation (59.1 versus 68.5 %; p=0.04) • Adverse events more common in patients randomized to AAD escalation

For patients with recurrent VT despite AAD therapy, catheter ablation is a valuable strategy that avoids AAD related adverse events

AAD = anti-arrhythmic drug; ICD = implantable cardioverter defibrillator; VT = ventricular tachycardia.

AAD therapy catheter ablation is a valuable strategy that avoids some of the adverse events associated with AAD therapy. There are many obstacles to completion of randomized controlled trials for VT ablation. In fact, a recent systematic review of clinical trials for VT ablation identified 15 randomized controlled trials comparing ablation in the National Institutes of Health or International Standard Randomised Controlled Trial Number registry.6 Only the four studies discussed above have been completed, three are ongoing, and the remaining eight have either been terminated or have an unknown status. To increase the number of VT ablation studies and improve the evidence for catheter ablation, changes are necessary in enrollment strategies, provider education, and standardized reporting outcomes, as mentioned earlier.

Future Directions Many unanswered questions remain regarding the efficacy and safety of VT ablation due to inadequate evidence randomized controlled trials to guide management. The majority of studies to date, including all the major randomized controlled trials, have only enrolled patients with ischemic cardiomyopathy. Randomized controlled trials are needed in patients with non-ischemic cardiomyopathies as management varies significantly in current clinical practice; although, our group has shown substantial reduction in VT burden following catheter ablation in these patients.51 The ideal timing of ablation in the natural history of VT and patient characteristic, including age, and comorbidities need to be examined in greater detail. Patients are often referred for VT ablation late in their clinical course, and some studies have suggested improved

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outcomes with earlier referral after onset of VT.52,53 Additionally, longterm outcomes for patients should be explored with extended follow-up included in trials evaluating not only mortality and recurrent VT, but also the need for repeat ablation and quality of life after ablation. The role of alternative treatment strategies for refractory VT such as sympathetic denervation also warrants additional investigation. Sympathetic activity is critically involved in both the initiation and maintenance of VT and decreased sympathetic tone, through epidural anesthesia or cardiac sympathetic denervation, has been shown to reduce VT burden and frequency of ICD shocks.54–57 Sympathetic denervation involves removal of the lower third of the stellate ganglion and T2–T4 thoracic ganglion most often through a video-assisted thorascopic approach. Further investigation is needed to determine the ideal approach, laterality of denervation, and patient population that would benefit most from this procedure.57,58

Conclusion Catheter ablation for VT is a valuable technique that has been clearly shown to decrease the frequency of VT recurrence and ICD shocks. Its use will continue to expand as techniques and operator experience improve over time. It is important for cardiologists to be aware of catheter ablation as a therapeutic option for VT and to refer early in the course of the disease to centers that have experience with the procedure so that all management options can be considered. Further research is essential to address the ideal timing, technique, efficacy, and safety of this procedure. n

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Electrophysiology 1.

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Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 2004;110:2591–6. Liang JJ, Muser D, Santangeli P. Ventricular tachycardia ablation clinical trials. Card Electrophysiol Clin 2017;9:153–65. DOI: 10.1016/j. ccep.2016.10.012; PMID: 28167083. Liang JJ, Santangeli P, Callans DJ. Long-term outcomes of ventricular tachycardia ablation in different types of structural heart disease. Arrhythm Electrophysiol Rev 2015;4:177–83. DOI: .10.15420/aer.2015.4.3.177; PMID: 26835122. Santangeli P, Muser D, Maeda S, et al. Comparative effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: A systematic review and meta-analysis of randomized controlled trials. Heart Rhythm 2016;13:1552–9. DOI: 10.1016/j.hrthm.2016.03.004; PMID: 26961297. Palaniswamy C, Kolte D, Harikrishnan P, et al. Catheter ablation of postinfarction ventricular tachycardia: ten-year trends in utilization, in-hospital complications, and in-hospital mortality in the United States. Heart Rhythm 2014;11:2056–63. DOI: 10.1016/j. hrthm.2014.07.012; PMID: 25016150. Al-Khatib SM, Daubert JP, Anstrom KJ, et al. Catheter ablation for ventricular tachycardia in patients with an implantable cardioverter defibrillator (CALYPSO) pilot trial. J Cardiovasc Electrophysiol 2015;26:151–7. DOI: 10.1111/jce.12567; PMID: 25332150. Della Bella P, Baratto F, Tsiachris D, et al. Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex ventricular arrhythmias: long-term outcome after ablation. Circulation 2013;127:1359–68. DOI: 10.1161/CIRCULATIONAHA.112.000872; PMID: 23439513. Muser D, Santangeli P, Liang JJ. Management of ventricular tachycardia storm in patients with structural heart disease. World J Cardiol 2017;9:521–30. DOI: 10.4330/wjc.v9.i6.521; PMID: 28706587. Stanton MS, Prystowsky EN, Fineberg NS, et al. Arrhythmogenic effects of antiarrhythmic drugs: a study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol 1989;14:209–15; discussion 216–7. PMID: 2738263. Epstein AE, Hallstrom AP, Rogers WJ, et al. Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA 1993;270:2451–5. PMID: 8230622. Nademanee K, Taylor R, Bailey WE, et al. Treating electrical storm: sympathetic blockade versus advanced cardiac life support-guided therapy. Circulation 2000;102:742–7. PMID: 10942741. Brodine WN, Tung RT, Lee JK, et al. Effects of beta-blockers on implantable cardioverter defibrillator therapy and survival in the patients with ischemic cardiomyopathy (from the Multicenter Automatic Defibrillator Implantation Trial-II). Am J Cardiol 2005;96:691–5. DOI: 10.1016/j.amjcard.2005.04.046; PMID: 16125497. Josephson ME, Nisam S. The AVID trial: evidence based or randomized control trials--is the AVID study too late? Antiarrhythmics Versus Implantable Defibrillators. Am J Cardiol 1997;80:194–7. PMID: 9230158. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006;295:165–71. DOI: 10.1001/jama.295.2.165; PMID: 16403928. Jung W, Manz M, Pfeiffer D, et al. Effects of antiarrhythmic drugs on epicardial defibrillation energy requirements and the rate of defibrillator discharges. Pacing Clin Electrophysiol 1993;16:198–201. PMID: 7681571. SCT Working Group on Data Monitoring, Dixon DO, Freedman RS, et al. Guidelines for data and safety monitoring for clinical trials not requiring traditional data monitoring committees. Clin Trials 2006;3:314–9. DOI: 10.1191/1740774506cn149oa; PMID: 16895048. MacMahon S, Collins R, Peto R, et al. Effects of prophylactic lidocaine in suspected acute myocardial infarction. An

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Gorgels AP, van den Dool A, Hofs A, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol 1996;78:43–6. PMID: 8712116. Liang JJ, Yang W, Santangeli P, et al. Amiodarone discontinuation or dose reduction following catheter ablation for ventricular tachycardia in structural heart disease. JACC: Clinical Electrophysiology 2017;309. DOI: 10.1016/j. jacep.2016.11.005. Josephson ME. Clinical cardiac electrophysiology. 5th Edition ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2016. Muser D, Lian JJ, Pathak RK, et al. Dilated cardiomyopathy compared with ischemic cardiomyopathy. JACC: Clinical Electrophysiology 2017;371. DOI: 10.1016/j.jacep.2017.01.020. Vergara P, Tung R, Vaseghi M, et al. Successful ventricular tachycardia ablation in patients with electrical storm reduces recurrences and improves survival. Heart Rhythm 2018;15:48–55. DOI: 10.1016/j.hrthm.2017.08.022; PMID: 28843418. Pedersen CT, Kay GN, Kalman J, et al. EHRA/HRS/APHRS expert consensus on ventricular arrhythmias. Europace 2014;16:1257–83. DOI: 10.1093/europace/euu194; PMID: 25172618. Gerstenfeld EP, Dixit S, Callans DJ, et al. Quantitative comparison of spontaneous and paced 12-lead electrocardiogram during right ventricular outflow tract ventricular tachycardia. J Am Coll Cardiol 2003;41:2046–53. PMID: 12798580. Azegami K, Wilber DJ, Arruda M, et al. Spatial resolution of pacemapping and activation mapping in patients with idiopathic right ventricular outflow tract tachycardia. J Cardiovasc Electrophysiol 2005;16:823–9. DOI: 10.1111/j. 1540-8167.2005.50041.x; PMID: 16101622. Downar E, Saito J, Doig JC, et al. Endocardial mapping of ventricular tachycardia in the intact human ventricle. III. Evidence of multiuse reentry with spontaneous and induced block in portions of reentrant path complex. J Am Coll Cardiol 1995;25:1591–600. PMID: 7759710. Stevenson WG, Khan H, Sager P, et al. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation 1993;88:1647–70. PMID: 8403311. Cassidy DM, Vassallo JA, Miller JM, et al. Endocardial catheter mapping in patients in sinus rhythm: relationship to underlying heart disease and ventricular arrhythmias. Circulation 1986;73:645–52. PMID: 3948367. Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation 2000;101:1288–96. PMID: 10725289. Nazarian S, Bluemke DA, Halperin HR. Applications of cardiac magnetic resonance in electrophysiology. Circ Arrhythm Electrophysiol 2009;2:63–71. DOI: 10.1161/CIRCEP.108.811562; PMID: 19808444. Perez-David E, Arenal A, Rubio-Guivernau JL, et al. Noninvasive identification of ventricular tachycardia-related conducting channels using contrast-enhanced magnetic resonance imaging in patients with chronic myocardial infarction: comparison of signal intensity scar mapping and endocardial voltage mapping. J Am Coll Cardiol 2011;57:184–94. DOI: 10.1016/j.jacc.2010.07.043; PMID: 21211689. Siontis KC, Kim HM, Sharaf Dabbagh G, et al. Association of preprocedural cardiac magnetic resonance imaging with outcomes of ventricular tachycardia ablation in patients with idiopathic dilated cardiomyopathy. Heart Rhythm 2017;14:1487–93. DOI: 10.1016/j.hrthm.2017.06.003; PMID: 28603002. Sasaki T, Miller CF, Hansford R, et al, Myocardial structural associations with local electrograms: a study of postinfarct ventricular tachycardia pathophysiology and magnetic resonance-based noninvasive mapping. Circ Arrhythm Electrophysiol 2012;5:1081–90. DOI: 10.1161/CIRCEP.112.970699; PMID: 23149263. Huang SK, Graham AR, Lee MA, et al. Comparison of catheter ablation using radiofrequency versus direct current energy: biophysical, electrophysiologic and pathologic observations. J Am Coll Cardiol 1991;18:1091–7. PMID: 1894854. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency

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Electrophysiology

His Bundle Pacing: State of the Art Matthew F Yuyun, MD, MPhil, PhD 1,2, and Ghulam Muqtada Chaudhry, MD, FACC, FHRS 1,2 1. Lahey Hospital & Medical Center, The Landsman Heart and Vascular Center, Burlington, MA; 2. Tufts University School of Medicine, Boston

Abstract Traditional right ventricular pacing can be associated with adverse remodeling, leading to left ventricular dysfunction, functional mitral regurgitation, left atrial dilatation, as well as atrial and ventricular arrhythmias. His bundle pacing (HBP) has emerged as a viable and reliable alternative to right ventricular pacing. HBP has been around since the 1970s, but remained dormant even after the index clinical study in humans in 2000. However, with recently rejuvenated interest, it appears to be a promising strategy for achieving synchronous ventricular pacing. Multiple studies have now shown that HBP is feasible, safe, and offers better outcomes when compared with right ventricular pacing. It has also emerged as an alternative to biventricular pacing for the provision of cardiac resynchronization therapy. This review gives a systematic appraisal of the history, feasibility, safety, techniques, efficacy, benefits, complications, and challenges, and offers a future perspective, of HBP.

Keywords His bundle pacing, pacing, pacemaker, cardiac resynchronization therapy Disclosure: The authors have no conflicts of interest to declare. Received: 5 December 2017 Accepted: 30 January 2018 Citation: US Cardiology Review 2018;12(1):57–65. DOI: 10.15420/usc:2017:36:2 Correspondence: Ghulam M Chaudhry, MD, FACC, FHRS, Associate Professor of Medicine Tufts University School of Medicine, Director Cardiac Electrophysiology Laboratories, Director Cardiology Fellowship Program, Lahey Hospital & Medical Center, 41 Burlington Mall Road, Burlington, MA 01805, USA. E: ghulam.m.chaudhry@lahey.org

Cardiac pacing has evolved considerably over the years from its initial introduction as a lifesaving measure by asynchronous ventricular pacing. Pitfalls of ventricular-only pacing were recognized relatively early, which led to the introduction of atrioventricular (AV) synchronous pacing that was subjected to rigorous clinical studies.1 A meta-analysis of major pacing mode trials revealed that AV synchronous pacing, either through atrial pacing (AAI) or dual-chamber pacing (DDD), compared with ventricular pacing (VVI) reduces the incidence of AF and stroke, but not heart failure hospitalization or mortality, even though some individual studies have shown a significant benefit of physiological pacing with respect to overall mortality and heart failure.1 However, persistent right ventricular apical (RVA) pacing can be associated with ventricular dyssynchrony and left ventricular adverse remodeling.2,3 Results of the Mode Selection Trial (MOST) showed that >40 % of DDD and >80 % of VVI were associated with increased risk of heart failure hospitalizations, and that risk of AF increased linearly with cumulative percentage ventricular pacing.2 Results of the Dual-Chamber and VVI Implantable Defibrillator (DAVID) trial showed that >40 % of VVI is independently predictive of heart failure hospitalization and death.3 In an effort to reduce the percentage of RV pacing, pacemaker programming algorithms such as Managed Ventricular Pacing (MVP) and Search AV+ (SAV+) (Medtronic), Reverse Mode Switch (RYTHMIQ, Boston Scientific), SafeR mode (LivaNova), Ventricular Intrinsic Preference (VIP, St. Jude Medical), and AV hysteresis and VP suppression (Biotronik) have been successful to some extent.4 However, these programming algorithms are of limited value in patients who are dependent on ventricular pacing. Although implanting an AAI pacemaker in patients

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with preserved AV, interventricular, and intraventricular conduction might seem appropriate, there remains a potential risk of developing AV block in the future.5,6 Pacing from RV sites other than RV apex have been evaluated in many studies. Systematic reviews and meta-analyses of trials comparing non-RVA sites to RVA pacing site have shown that non-RVA pacing may offer modest, but significant, hemodynamic benefit over RVA pacing.7,8 However, data regarding any advantage in exercise capacity, functional class, quality of life, or survival were limited and inconclusive.8 In patients with ventricular pacing indication and/or anticipated highpercentage ventricular pacing, and left ventricular ejection fraction (LVEF) >35–50 %9 or any LVEF,10 two major studies assessed usefulness of addition of an LV pacing lead to provide cardiac resynchronization therapy (CRT; or biventricular pacing ) compared with pacing without CRT (standard RV pacing). The Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK-HF) trial showed that implanting a biventricular pacemaker compared with RV pacing significantly improved the primary endpoint, which was a composite of death, urgent care visit for heart failure, or a 15 % increase in LV end systolic volume index (LVESVI), but this was driven mainly by increases in LVESVI.9 The Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization (BIOPACE) study revealed no superiority of biventricular pacing compared with RV pacing.10 Recently, His bundle pacing (HBP) has emerged as a novel physiologic strategy for achieving ventricular pacing, and has brought renewed hope and excitement into the pacing arena. Although HBP was first reported by Scherlag et al. in 1967,11 the first significant clinical series in humans was not published until 2000 by

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Electrophysiology Deshmukh et al.12 Despite that, HBP did not receive much attention until more recently and is now emerging as a promising modality to preserve synchronous ventricular pacing. Many studies have shown that HBP is feasible and safe, and offers better outcomes with respect to left ventricular end diastolic and end systolic diameters and systolic function, shorter interventricular electromechanical delay, improvement in quality of life, reduction in New York Heart Association (NYHA) class, and improvement in 6-min walk, when compared with RV pacing,12–24 and is effective for CRT.25–30 The objective of this review is to give a systematic appraisal of the history, feasibility, safety, techniques, efficacy, benefits, complications, and challenges, and to offer a future perspective, of HBP, as the search for the optimal pacing site continues.

History of His Bundle Pacing The history of HBP has recently been reviewed in detail.31 The study of cardiac conduction system has accomplished several anatomical, physiological, pathophysiological, and therapeutic clinical milestones. The Czech anatomist and physiologist Jan Evangelista Purkinje was the first to describe, in 1839, the fibrous tissue (Purkinje fibers) that conducts stimuli along the ventricular endocardium to all parts of the heart. In 1893, Wilhelm His Jr, a Swiss cardiologist and anatomist, discovered the auriculoventricular bundle (His bundle) linking the atria to the ventricular septum, leading to the concept of His-Purkinje system. He pioneered studies in cardiac conduction and coined the term ‘heart block.’32 In 1899, Wenckebach described the phenomenon that later bore his name.33 In 1906, Dr Tawara, a Japanese pathologist, discovered the AV node and in his publication described a treelike structure of the AV node, the His bundle, bundle branches, and Purkinje fibers, which served as a pathway of AV conduction and excitation of mammalian heart.34 In 1907, in England Arthur Keith and Martin Flack discovered the sinoatrial node as the origin of cardiac pulsations.35 In 1924, Woldemar Mobitz, a Russianborn German physician classified second-degree AV block.36 In 1958, Alanis et al. demonstrated the first His bundle recordings using isolated perfused hearts of dog and cats.37 In 1967, Scherlag et al. were the first to describe His bundle recording and stimulation using the epimyocardial approach in dogs undergoing open chest surgery, and a year later were able to demonstrate direct HBP using an endocardial approach in dogs, followed by publication in 1969 of their technique for recording His bundle electrograms in humans.38 In 1970, Narula et al. demonstrated HBP in patients who underwent right heart catheterization, during which the pacing impulse to ventricular activation time was the same as the HV interval during normal sinus rhythm and remained constant at different pacing rates.39 In 1976 Williams et al. published results of their experiments in anesthetized open-chest dogs and defined non-selective HBP (capture His bundle and ventricle or atrium) versus selective HBP (capture of His bundle alone).40 In 1992, Karpawich et al. described a new endocardial electrode implant approach to permanent HBP in dogs during thoracotomy using a customdesigned active-fixation lead with an exposed helix.41 In 2000, Deshmukh et al. demonstrated that permanent direct HBP was feasible in 12 out of 18 patients with permanent AF and dilated cardiomyopathy undergoing AV node ablation, and at follow-up HBP resulted in a reduction of left ventricular dimensions and improved cardiac function.12 This landmark report ignited heightened interest in

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this area and further clinical studies have now successfully demonstrated the feasibility and safety of HBP and its impact on improved positive ventricular remodeling.13,15,17,23 These studies have shown the superiority of HBP compared with RV pacing with respect to ventricular synchrony and positive remodeling.14,16,19–22 More recently, safety in patients with infranodal AV block has been demonstrated (see Table 1).24 There is now accruing evidence that selective HBP provides cardiac resynchronization in CRT non-responders, in those who experienced failure of LV lead placement via the coronary sinus,25,30 and in all-comers with CRT indication (see Table 2).26–30

Feasibilty and Safety of His Bundle Pacing After pioneering the publication of the first therapeutic clinical series of HBP in humans in 2000, Deshmukh et al. published results in 2004 showing that selective HBP led to significant improvements in NYHA class and left ventricular systolic function in 54 patients with severe cardiomyopathy, permanent AF, and narrow QRS after an average of 42 months of follow-up.13 In 2006, Zanon et al. conducted a feasibility study showing that direct HBP could be accomplished with a new system consisting of a steerable catheter and an active-fixation lead in 92 % of the patients in whom it was attempted.42 Since then, several publications across the world have corroborated these findings, as shown in Table 1. Most recently, data from high-volume HBP centers at Indiana University School of Medicine, Indianapolis, Indiana, and Geisinger Wyoming Valley Hospital, Wilkes-Barre, Pennsylvania, have demonstrated the feasibility, safety, as well as the reliability of the procedural technique using custommade delivery sheaths and active-fixation leads.22–24,30,43,44 As shown in Table 1, the implant success rates in attempted HBP from studies that published the denominator number from which successful HBP was achieved varies from 56–95 %, with most recent studies showing improvement in implant success rates of as high as 70–90 % with enhanced implanter experience. The indications of pacing varied from sick sinus syndrome, permanent AF patients undergoing AV node ablation, AV nodal level of atrioventricular block with narrow QRS, and even infranodal block. HBP was performed with and without back-up RVP across studies. Some studies have demonstrated safety of HBP with long-term follow-up data in patients with infranodal block without back-up RV lead.24 It has been observed that pacing thresholds, sensing, and impedance parameters after HBP are reliably stable at follow-up.13,15,19,44 Although thresholds have been noted to be modestly higher during generator change than during implant, they remained relatively stable and reliable. Sensing and impedance parameters have also remained stable at followup. One study demonstrated that in 20 patients undergoing generator change at mean duration of 70 ± 24 months after initial implant, His bundle capture threshold at implant was 1.95 ± 1.1 V @ 0.5 ms. At the time of generator change, the HBP threshold was higher at 2.5 ± 1.2 V @ 0.5 ms (p=0.02). There were no significant differences in the sensing amplitude or pacing impedance at the time of generator change.44 Most importantly, the QRS duration in patients with narrow QRS at implant tended to remain unchanged with HBP at follow-up.15

Procedural Technique Most published series have used the Medtronic implanting equipment systems for direct HBP,42,43 which includes delivery sheath and

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His Bundle Pacing: State of the Art

Sample Pacing size indication

SHPB/ NSHB

RVP

Outcomes

FUD

HBP

Failed lead at FU

13/23 (56.5 %)

225 ± 87 days

42 months

HBP Implant thresholds

- LVEF ↑20 ± 9 % to 31 ± 11 %; P<0.01 - LVEDD ↓ 59 ± 8 to 52 ± 6 mm; P<0.01 - LVESD ↓ 51 ± 10 to 43 ± 8 mm; P<0.01

- IVD 41.2 ± 12.6 ms; P<0.5 -S PD 124.9 ± 62.6 ms; P<0.05

10.2 ± 4.1 mins

3 months

21 months

1.61 ± 0.55 V @0.5 ms

15 ± 8.8 mins

12 months

26/91 (31.9 %)

0.6 ± 0.3 V @0.5 ms

18.9 ± 9 min

Back-up RV lead 2/12

- LVEF ↑23±11 % to 33 ±15 % - NYHA ↓3.5 to 2.2; P<0.05

Successful HBP 23.4 ± 8.3 months

2/54

- IVD 4.7 ± 16.8 ms - SPD 49.2 ± 39.8 ms

3/23

QRS 123.1 ± 13.9 ms IVD 34 ± 14 ms NYHA 1.75 ± 0.4 LVEF 53.4 ± 7.9 6MWT 431 ± 73 m QOL, MR, and TR improved compared with RVP (P<0.05)

0.92 ± 0.7 V @0.5 ms

12/54

0/16

- NYHA from 2.2 ± 0.8 to 1.7 ± 0.7; P<0.05 - QOL score from 32.5 ± 15 to 16.2 ± 8.7; P<0.05 - MR improved; P<0.05

2.4 ± 1.0 V @ 0.5 ms

- SHBP 39/54 (72.2 %) - NSHBP 15/54 (27.8 %)

2/65

- Threshold 1.3 ± 0.9 @0.5 ms

0/12 (0 %)

- SHBP 23/23 (100 %) - NSHBP 0/23

3/59

Table 1: Studies Showing HBP Feasibility, Safety, and Comparison with RVP Author & Year Published 18

Cardiomyopathy LVEF 23 % ±11, Persistent AF, QRS <120 ms 23/24 (95.8 %)

<20 ins

12/18 (66 %) - SHBP 12/12 (100 %) - NSHBP 0/12

SSS, slow VR AF, supra-hisian AVB

1.5 ± 0.8 V @1 m

12/307

QRS 164.5 ± 18 ms IVD 47 ± 19 ms; P<0.05 NYHA 2.5 ± 0.4; P<0.05 LVEF 50.0 ± 7.9 6 MWT 360 ± 71 m; P<0.05

SHBP 20 ± 10 15 ± 9 mins months NHSBP 18 ± 13 mins

16/16 (100 %)

126 (41 %)

17/65 (26.2 %)

59/91 (65 %)

- SHBP 22/59 (37.3 %) - NSHBP 37/59 (62.7 %)

- SHBP 4/65 (6.2 %) -N SHBP 61/65 (93.8 %)

- SHBP 4/16 (25 %) -N NSHBP 12/16 (75 %)

Chronic AF, AVNA

AVB or CRT indication with failed CS lead NA

- SHBP 87/307(28 %) -N SHBP 220/307 (72 %)

65/68 (95.6 %)

91/182

307

Chronic AS, AVNA (52) Sinus + AVB (16) - Narrow QRS

16/18 (88.9 %)

Chronic AF, LVEF <40 %, QRS < 120 ms, AVNA

Deshmukh et al. 200012

Deshmukh et al. 200413

Catanzariti et al. 200616 Occhetta et al. 200614

Occhetta et al. 200715

BarbaPichardo et al. 201017 Zanon et al. 201118

SSS, AVB, ORS 108 ± 21 ms, LVEF 51 ± 11 %

SHBP vs NSHBP NA resulted in higher threshold, lower R amplitude (P<0.001), and higher impedance (p =0.008). 12 (3.9 %) events at follow-up (high thresholds or displacement)

(Continued)

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94 HBP, 98 RVP

100

Cantanzariti et al. 201319

Pastore et al. 201420

Kronborg et al. 201421

Sharma et al. 201522

Vijayaraman et al. 201523

Vijayaraman et al. 201524

Successful HBP

84/100 (84 %)

-S HBP 22/84 (26.2 %) - NSHBP 62/84 (73.8 %)

60/67 (90 %) - S HBP 27/60 (45 %) - NSHBP 33/60 (55 %)

75/94 (80 %) - S HBP 34/75 (45 %) - NSHBP 41/75 (55 %)

-S HBP 4/32 (12.5 %) - NSHBP 28/32 (87.5 %)

- SHBP 17 (45.9 %) - NSHBP 20 (54.1 %)

-S HBP 20/26 (76.9 %) -N SHBP 6/26 (23.1 %)

SHPB/ NSHB

19/94 (20.2 %)

32/32 (100 %)

37/37 (100 %)

26/26 (100 %)

Back-up RV lead

1.3 ± 0.9 V @0.5 ms

1.45 ± 0.5 V @0.5 ms

1.35 ± 0.9 V

HBP Implant thresholds

11 ± 6 mins

9.2 ± 3.7 mins

12.7 ± 8 mins

19 ± 12 months

1 year

Yearly

24 months

6 months

34.6 ± 11 months

FUD

5/84

1/60

3/75

Failed lead at FU

- FT 10 ± 14 mins; p=0.14 - PT 64 ± 25 mins; p=0.01 - Threshold 0.6 ± 0.5 V @0.5 ms; p<0.001 - R-wave 13.7 ± 5.7 mv; p=0.035 - HF 15 %; p=0.02 - Mortality 18 %; p=0.45

- LVEF 50 ± 9 %; p<0.005 - LVESV 49 ± 26 ml; p<0.03

- L VEF 65.2 ± 10.1 %; P=0.49 - PASP 34.1 ± 9.7 mmHg; p<0.001 - LAVmin index 40.7 ± 26.1 ml/m2; p=0.003 - LV dyssynchrony ↑ during RVP; p<0.001

- LVEF 50.1 ± 8.8; P<0.001 - IVD 33.4 ± 19.5 ms; p=0.003 - MR worsened during RVAP; P=0.018

RVP

-F /U threshold 1.7 ± 1.0 V NA @0.5 ms - Normalization His-Purkinje conduction in 76 % of infranodal patients

- Implant thresholds HBIC present vs absent 1.16 ± 0.4 V vs 1.75 ± 0.7 V @0.5 ms; p<0.05 - 1 year F/U thresholds HBIC present vs absent 1.31 ± 0.6 V vs 1.98 ± 0.9 V @0.5 ms; p<0.05

- FT 12.7 ± 8 mins - PT 79 ± 25 mins - Threshold 1.35 ± 0.9 V @0.5 ms - R-wave 6.8 ± 5.3 mv - HF 2 % - Mortality 13 %

- LVEF 55 ± 10 % - LVESV 42 ± 21 ml

- LVEF 66.3 ± 8 % - PASP 29.4 ± 7.9 mmHg - LAVmin index 35.1 ± 20.3 ml/m2

- LVEF 57.3 ± 8.5 % - IVD 7.1 ± 4.7 ms

HBP

Outcomes

AVB = atrioventricular block; AVNA = atrioventricular node ablation; CS = coronary sinus; FT = fluoroscopy time; FUD = follow-up duration in months; HBIC = His bundle injury current; HBP = His bundle pacing; IVD = interventricular delay = interventricular dyssynchrony; LAVmin index = minimal volume of left atrium; LVEF = left ventricular ejection fraction; NA = not available; NSHBP = non-selective His bundle pacing; PASP = pulmonary artery systolic pressure; PT = procedure time; RVP = right ventricular pacing; SHBP = selective His bundle pacing; SPD = septal to left posterior wall motion delay; SSS = sick sinus syndrome.

Unselected AVB - AV nodal 46 % - Infranodal 54 %

SSS 40 % AVB 60 %

Consecutive SSS 38 %, AVB 62 %

Higher-degree AVB, 32/38 LVEF <40 %, ORS (84.2 %) <120 ms

AVB, QRS < 120 ms NA

AF with SVR, SSS, NA 2nd and, 3rd degree AVB, QRS 102 ± 14.4 ms

Sample Pacing size indication

Author & Year Published

Table 1: (Cont.)

Electrophysiology

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His Bundle Pacing: State of the Art

Sample

Study

Pacing HBP

Successful placements

Leads nodal

Infra-

Table 2: CRT Through His Bundle Pacing Author indication

16/16

8/21

21/21

9/9

21/21

RV lead, HBP lead, no mention of RA lead

21/29 (72 %) demonstrated narrowing of QRS at implant

29/38 (13 in ICD patients; 16 in CRTD patients)

Dual chamber ICD: HBP lead to RA port, ICD to RV port; CRTD HBP lead to LV port, RA, and ICD leads

HBP lead

16/21 (76.2 %)

95/106 (90 %) Group I = 30/95 Group II = 65/95

RA lead, RV lead, HBP lead to LV port

RA lead, RV ICD lead, LV and HBP lead. HBP and LV leads connected to LV port via Y-adapter

9/16 (56 %)

design

Prospective

Longstanding CHB, chronic RVP and RVP-induced cardiomyopathy

RA lead, RV ICD lead, HBP lead

size Prospective

Prospective

ICD indication 13/38: Permanent AF, AVNA, LEFF <35 %; CRTD indication 25/38

CRT indication, LBBB, QRS >130 ms

Prospective

Indication for CRT (BBB, QRS >120 ms, NYHA II–IV, LVEF <35 %)

Randomized crossover

Heart failure, LBBB, NYHA III, indication for CRT & ICD, failed CS lead placement

and Year Published

106

Barba16 Pichardo et al. 201325

Lustgarten et al. 201526

Vijayaraman et al. 201627

Su et al. 201628

Ajijola et al. 201729

Sharma et al. 201730

Group I = Failed LV lead or CRT nonresponders; Group II = primary strategy (AVB, BBB, high pacing burden) and CRT indication

FUD

31.33 ± 21.45 months

6 and 12 months

Failed lead at FU 0/9

Implant

Follow-up

Outcomes

- Capture threshold 3.09 ± 0.44 V Impedance 311 ± 52.8 LA size 56.3 ± 4.4 mm LVEDD 65.9 ± 4.0 mm LVESD 55.4 ± 4.6 mm LVEF 29 %

-C apture threshold 3.7 ± 0.54 V; p<0.05 Impedance 301 ± 50.2; p=0.67 LA size 52.9 ± 4.2 mm; p=NS L VEDD 59.5 ± 4.25 mm; p<0.01 LVESD 51.2 ± 3.6 mm; p<0.05 LVEF 36 %, p<0.05 -

- QRS 117 ± 20 m; p<0.001 -C apture threshold 1.75 ± 0.9 V @0.5 ms - LVEF 49 %; p=0.01

- NYHA 1.9; P<0.001 -6 -min walk test 383 feet; p=0.009 - LVEF 32 %; p=0.043 - QOL score 38; p=0.006

- QRS 181 ± 17 ms - Capture threshold 1.8 ± 1.2 V @0.5 ms - LVEF 32 %

RWA and CT with HBP tip-RV coil configuration remained stable and better than those with HBP unipolar or bipolar, p<0.05; and less pulse energy delivered, p=0.017

1/21, 12 patients completed the cross over -

Integrated HBP to RV coil configuration had higher RWA and lower CT than HBP unipolar or bipolar, p<0.05

-C apture threshold 1.4 ± 0.8 @0.6 ms - LVEDD 4.5 ± 0.3 cm; p<0.001 - LVEF 41 ± 13 %; p<0.001 - NYHA II; p<0.001

NYHA 2.9 6-min walk test 269 feet LVEF 26 % QOL score 54 No significant difference in clinical outcomes between HBP and BiVP

- QRS ↓ from 180 ± 23 to 129 ± 13 ms; P<0.001 - Capture threshold 1.9 ± 1.2 V @0.6 ms - LVEDD 5.4 ± 0.4 cm - LVEF 27 ± 10 % - NYHA III

- QRS 117 ± 18 ms; p<0.0001 - LVEF 43 ± 13 %; p=0.0001 - NYHA 1.8 ± 0.6; p=0.0001

1.6 ± 1 year NA

3 months

12 months

14 months

7/91 leadrelated complications

- Capture threshold 1.4 ± 0.9 V in Group I and 2.0 ± 1.2 V @ 1 ms in Group II - QRS 157 ± 33 ms - LVEF 30 ± 10 % - NYHA 2.8 ± 0.5

BBB = bundle branch block; BiVP = biventricular pacing; CHB = complete heart block; CRT = cardiac resynchronization therapy; CS = coronary sinus; CT = capture threshold; HBP = His bundle pacing; ICD = implantable cardioverter defibrillator; LA = left atrium; LBBB = left bundle branch block; LVEDD = left ventricular end diastolic diameter; LVEF = left ventricular ejection fraction; LVESD = left ventricular end systolic diameter; NS = not significant; NYHA = New York Heart Association; QOL = quality of life; RA = right atrium; RV = right ventricle; RVP = right ventricular pacing; RWA = R wave amplitude.

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Electrophysiology active-fixation lead utilizing a fixed non-extendable screw. There are isolated reports of successful deployment of traditional pacemaker leads with a retractable screw (Tendril 1488 or 1788, St. Jude Medical).17,25 The commonly used equipment necessary for HBP include an appropriately sized peel-away sheath inserted through the cephalic or axillary or subclavian vein, through which a steerable or deflectable (SelectSite, model C304 Medtronic Inc.) or non-deflectable (model C315) His bundle delivery catheter sheath is inserted. Through the chosen delivery sheath, a bipolar, non-stylet-driven, fixed-screw pacing lead (SelectSecure model 3830, Medtronic Inc.) is maneuvered to the His area. Some studies report the use of diagnostic multipolar catheters (such as CRD-2, St. Jude Medical) placed from the femoral or axillary veins to map a discrete local Hisbundle electrogram with fluoroscopic guidance, before placing the His permanent pacing lead.29 However, most reported series have used the His bundle lead itself to directly map the His electrogram without need for a mapping catheter, during which unipolar His electrograms and Hisventricular and paced-ventricular intervals are measured by means of a multi-channel electrophysiology analysis systems (e.g. Cardiolab, Pruka GE) or directly on a Medtronic pacing system analyzer (model 2290) at sweep speeds of 50–100 mm/s. The lead is advanced in an antero-posterior (AP) fluoroscopic projection and placed with help of right anterior oblique (RAO) and left anterior oblique (LAO) projections. After identifying a His bundle electrogram by mapping the His bundle region, pacing is performed to confirm His bundle capture. The lead is then fixed into position by means of four to five clockwise rotations of the entire lead to anchor the nonextendable screw.42,43 The His bundle injury current is usually elusive at implant, with an experienced HBP center succeeding to register only 37 % success, while in the remaining 63 %, only the His bundle electrogram was recorded.23 When obtained, His bundle injury current is similar to myocardial injury current seen during RV pacing, and indicates direct contact of the fixation screw to the junctional tissue and is associated with significantly lower pacing thresholds compared with patients in whom the injury current was not recorded. Acute His bundle trauma can occur during manipulation and fixation attempts causing bundle branch block; however, complete resolution of conduction block usually occurs in majority of patients. Vijarayaman et al. observed trauma to the His bundle in 7.8 % of patients undergoing permanent HBP, with complete resolution of conduction block occurring in 68 % and persistence of right bundle branch block in 32 %.45

Selective Versus Non-selective His Bundle Pacing Successful selective HBP (also referred to as direct or pure HBP) occurs when ventricular activation is occurring solely over the His–Purkinje system and is defined using the following criteria: (1) His–Purkinjemediated cardiac activation and repolarization, as evidenced by ECG concordance of QRS and T-wave complexes; (2) the pacing spike-QRS interval being almost identical to the His–ventricular interval (this can be further confirmed by presence of late ventricular electrogram on the pacing lead, precluding the possibility of local capture); and (3) His bundle capture in an all-or-none fashion, as demonstrated by the absence of QRS widening at a lower pacing output.12,40,46 Non-selective HBP occurs when there is simultaneous capture of the His bundle and the basal ventricle and can be recognized from the surface ECG leads by changes in onset and amplitude of the QRS with appreciable T-wave alterations,40 and is defined by the following criteria: (1) no isoelectric interval between pacing stimulus and QRS; (2) recording

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His bundle electrogram on the pacing lead; (3) electrical axis of the paced QRS concordant with the electrical axis of the spontaneous QRS (if known); and (4) narrowing of QRS at higher output due to fusion between RV and His bundle capture and widening of QRS at lower output due to loss of His bundle capture, or vice versa.46,47 This was sometimes referred to as ‘para-Hisian pacing,’ but this term is no longer used in the context of permanent HBP to avoid confusion with para-Hisian pacing performed during electrophysiology studies to distinguish retrograde activation over AV node from that over the accessory pathway during intermittent His bundle capture. As consistent and reliable capture of His bundle requires higher output than RV capture, selective HBP results in a higher pacing threshold than non-selective HBP.18 However, the lower pacing threshold in non-selective HBP likely reflects capture of the ventricular tissue. Although it would be appropriate to strive to achieve selective HBP, which is more physiologic than non-selective HBP, the latter could also be an acceptable endpoint.

His Bundle Pacing Versus Right Ventricular Pacing There is now ample evidence in the literature that right ventricular apical pacing can be associated with electrical and mechanical ventricular dyssynchrony and adverse remodeling, potentially leading to left ventricular dysfunction, functional mitral regurgitation, left atrial dilatation, atrial and ventricular arrhythmias.15,48,49 There have been suggestions that nonapical site of ventricular pacing might portend better clinical outcomes. Although randomized control trials and meta-analyses of these trials have depicted higher left ventricular ejection fractions in patients with non-apical RV pacing compared with apical RV pacing, findings on survival have been rather limited and inconclusive as most studies were not powered to assess survival.7,8 In a large meta-analysis of 14 randomized controlled trials, Shimony et al observed that non-apical RV pacing compared to apical RV pacing, led to improved LVEF at the end of followup with a weighted mean difference of 4.27 % (95 % CI 1.15–7.40 %). This improvement in LVEF was more pronounced in patients with ≥ 12 months of follow-up and those with baseline LVEF of ≤ 40–45 %. However, they found that data regarding exercise capacity, functional class, quality of life, and survival were limited and inconclusive, highlighting the need for additional RCTs examining this issue.8 The advent of HBP has provided an alternative to RV pacing. HBP leads to preservation of narrow QRS in patients with baseline ventricular synchrony, and normalization of baseline bundle branch block in a significant number of patients. Many studies have compared RV pacing with His bundle and found encouraging results in favor of HBP.14,16,19–22 As shown in Table 1, HBP was associated at follow-up with significantly reduced left ventricular end diastolic and left ventricular end systolic dimensions, improved LVEF, reduced left atrial dimensions, reduction in NHYA class, improved quality of life, and reduction in hospitalization for heart failure. There was, however, no significant difference in mortality. It has been depicted that HBP when compared with RV apical pacing, results in reduced left atrial anatomical dimensions and better atrial function as a result of a more physiological left ventricular electromechanical activation and relaxation.20

His Bundle Pacing and QRS Normalization in Prior His Purkinje System Block In 1919 Kaufman and Rothberger were first to describe the longitudinal fascicular dissociation in the His bundle whereby conduction in the

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His Bundle Pacing: State of the Art His bundle was through tissue pathways originating from the AV node that were pre-destined to become separate bundle branches. In 1971, James et al. examined the fine structure of the His bundle on light and electron microscopy and described the longitudinal partitioning of strands of Purkinje cells collagen spanning into the bundle branches, and formed the anatomic basis for suspecting longitudinal separation of conduction within the normal His bundle.50 In the late 1960– 1970s, studies by Narula, Scherlag, and El-Sherif et al. demonstrated normalization of bundle branch disease with HBP in animal models and humans, supporting the concept of diseased tissue manifesting with longitudinal dissociation within the His bundle.38,39,51 This concept has been confirmed by recent clinical reports of permanent HBP resulting in narrow paced QRS in patients with previous bundle branch block. By pacing and reengaging previously latent fascicular tissue causing narrowing of the QRS complexes in such patients suggests intra-Hisian location of majority of infra nodal heart blocks.24 This sets the stage for an exciting option of restoration of electrical cardiac synchrony utilizing pacing lead in the His bundle instead of implantation of a left ventricular lead via coronary sinus.25–30

His Bundle Pacing and Cardiac Resynchronization Therapy The overall burden of heart failure in terms of incidence, prevalence, mortality, and management cost is significant, and increases with increasing age. In the USA, economic burden of heart failure is the excess of $30 billion annually, and the prevalence of heart failure now exceeds 5.8 million and each year more than 550,000 new cases are diagnosed.52,53 Despite recent advances in diagnosis and treatment of heart failure, 5- and 10-year survival after diagnosis still remains only approximately 50 % and 10 %, respectively, and following hospitalization with heart failure, 30-day re-admission rates are approximately 25 %. In addition, there is proven association of left ventricular dysfunction with an increased risk of sudden cardiac death.53 CRT with left ventricular lead placement via the coronary sinus in patients with heart failure and evidence of cardiac dyssynchrony is now an established adjunctive therapy in these patients. It is associated with independently significant reduction in mortality and heart failure re-hospitalizations, improvement in quality of life, increase in LVEF, reduction in NYHA class, etc. Unfortunately, approximately 30 % of heart failure patients with cardiac dyssynchrony are non-responders to CRT.54 This can be secondary to patient characteristics, progression of intrinsic disease or inability to implant lead in appropriate location because of technical and anatomical challenges. It is worthwhile noting that nonresponse is a relative phenomenon, as some response can be lackluster with LVEF improvement, but no clinical improvement. Furthermore, difficulty of coronary sinus cannulation, lack of suitable venous anatomy, and phrenic nerve stimulation are some of the additional obstacles that hamper successful CRT. Although direct LV lead placement via epicardial approach is possible, it is a major undertaking, limited by access to appropriate surgical teams,25 and associated with high risk of lead failure over time. The observation of HBP leading to restoration of narrow QRS in patients with bundle branch block (electrical resynchronization), which is a manifestation of the phenomenon referred to as longitudinal dissociation,

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generated interest as to whether this could induce mechanical resynchronization and supplant traditional CRT.26 The feasibility of HBP in CRT-indicated patients was first reported by Lustgarten et al. in 2010, whereby 7 of 10 consecutively studied patients normalized their QRS in response to direct HBP.55 Three years later, Barba-Pichardo et al. conducted a similar study, but with clinical outcomes report in 9 out 16 patients with heart failure, LBBB, NYHA III, indication for CRT and implantable cardioverter defibrillator, who failed LV lead placement via the coronary sinus. After an average follow-up of 31 months, LV end-diastolic and end systolic volumes were significantly reduced and LVEF increased from 29 % at baseline to 36 %.25 As shown in Table 2, other studies have reported similar findings and improvements in NYHA class,26–30 as well as some case reports.56–59 In the most recent study by Sharma et al., successful HBP in 95/106 (90 %) of patients divided into Group I (failed LV lead or CRT non-responders) and Group II (primary strategy in patients with complete heart block, bundle branch block, highpacing burden, and CRT indication) led to improvement in LVEF from 30 % at baseline to 43 % at follow-up (P<0.001), and reduction in NYHA class from a mean of 2.8 to 1.8 (P<0.001). The authors concluded that HBP may be considered as a rescue strategy for failed biventricular pacing and may be a reasonable primary alternative to biventricular for CRT.30 Unfortunately, there is not sufficient data from these studies to determine whether there is a survival benefit.

Challenges of His Bundle Pacing and the Future Directions HBP is technically a challenging procedure. However, results from highvolume implanting centers suggest that success rates steadily improve with progressive operator experience. This has been helped by the custom-made HBP leads and delivery sheaths, although the need for even better implanting kits remains. Other challenges at implant include failure to map the His bundle, failure to capture the His bundle, as well as lower R-wave amplitudes and high-pacing thresholds when compared with RV pacing. Low R-wave amplitude might raise safety concerns about ability to sense ventricular arrhythmias, while high-pacing thresholds may adversely affect device longevity.28 Long-term performance of the commercially available specialized HBP lead is unknown. There is also no reported experience with extraction of HBP leads. Extraction of smallcaliber, fixed-screw leads can by itself be challenging, but with peculiar location of non-stylet-driven HBP leads, the outcomes of extraction remain unknown for now. However, one will anticipate that with the available contemporary extraction equipment, such a challenge should be feasibly overcome. Publication of any extraction case reports or series in the area of HBP should be encouraged. Although short- to mediumterm studies have been re-assuring, concerns remain about proximal conduction disease progressing to infra-Hisian block in His bundle-paced patients. Most studies in the field of HBP have been case series with rare exceptions, even if some of these had comparative groups. Therefore, there is a need for randomized controlled trails in this field before any firm recommendations can be made with a certain degree of comfort in future pacing guidelines. The current HBP Versus Coronary Sinus Pacing for Cardiac Resynchronization Therapy (HIS-SYNC) study, which is comparing the effectiveness of physiologic pacing from a His bundle lead position versus the standard LV pacing with lead in the coronary sinus branches in subjects with heart failure undergoing CRT, will hopefully help to provide more clarity. Recently, recommendations from ‘A Multi-Center

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Electrophysiology HBP Collaborative Working Group For Standardization Of Definitions, Implant Measurements And Follow-Up’ has been published.46 This was a collaboration between several implanters with significant experience in HBP to establish a uniform set of definitions encompassing the different forms of HBP as well as define a standardized approach to gathering data endpoints to ensure consistency in reported outcomes.

Conclusion HBP is feasible, safe, and efficacious. It offers a superior ventricular synchronous pacing strategy and better outcomes with respect to LV end diastolic and end systolic diameters and systolic function, shorter

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28.

29.

30.

31.

32.

33.

interventricular electromechanical delay, improvement in quality of life, reduction in NYHA class, and improvement in 6-min walk when compared with RV pacing. HBP can potentially provide more definitive electrical resynchronization and can be considered in heart failure patients with wide QRS who are non-responders to bi-ventricular pacing or those with failed transvenous-coronary sinus LV leads, or may even be employed as a primary CRT pacing strategy pending the results of an ongoing trial. However, implantation can be technically challenging, and this modality has not yet been subjected to the rigor of randomized trials to determine its long-term efficacy and safety compared with traditional pacing strategies. n

Electrophysiol 2006;16:81–92. DOI: 10.1007/s10840-006-9033-5; PMID: 17115267. Barba-Pichardo R, Morina-Vazquez P, Fernandez-Gomez JM, et al. Permanent His-bundle pacing: seeking physiological ventricular pacing. Europace 2010;12:527–33. DOI: 10.1093/ europace/euq038; PMID: 20338988. Zanon F, Svetlich C, Occhetta E, et al. Safety and performance of a system specifically designed for selective site pacing. Pacing Clin Electrophysiol 2011;34:339–47. DOI: 10.1111/j.15408159.2010.02951.x; PMID: 21070258. Catanzariti D, Maines M, Manica A, et al. Permanent His-bundle pacing maintains long-term ventricular synchrony and left ventricular performance, unlike conventional right ventricular apical pacing. Europace 2013;15:546–53. DOI: 10.1093/europace/ eus313; PMID: 22997222. Pastore G, Aggio S, Baracca E, et al. Hisian area and right ventricular apical pacing differently affect left atrial function: an intra-patients evaluation. Europace 2014;16:1033–9. DOI: 10.1093/ europace/eut436; PMID: 24473501. Kronborg MB, Mortensen PT, Poulsen SH, et al. His or para-His pacing preserves left ventricular function in atrioventricular block: a double-blind, randomized, crossover study. Europace 2014;16:1189–96. DOI: 10.1093/europace/euu011; PMID: 24509688. Sharma PS, Dandamudi G, Naperkowski A, et al. Permanent Hisbundle pacing is feasible, safe, and superior to right ventricular pacing in routine clinical practice. Heart Rhythm 2015;12:305–12. DOI: 10.1016/j.hrthm.2014.10.021; PMID: 25446158. Vijayaraman P, Dandamudi G, Worsnick S, Ellenbogen KA. Acute His-bundle injury current during permanent His-bundle pacing predicts excellent pacing outcomes. Pacing Clin Electrophysiol 2015;38:540–6. DOI: 10.1111/pace.12571; PMID: 25588497. Vijayaraman P, Naperkowski A, Ellenbogen KA, Dandamudi G. Electrophysiologic insights into site of atrioventricular block. Lessons from permanent His bundle pacing. J Am Coll Cardiol EP 2015;1:571–81. Barba-Pichardo R, Manovel Sanchez A, Fernandez-Gomez JM, et al. Ventricular resynchronization therapy by direct His-bundle pacing using an internal cardioverter defibrillator. Europace 2013;15:83–8. DOI: 10.1093/europace/eus228; PMID: 22933662. Lustgarten DL, Crespo EM, Arkhipova-Jenkins I, et al. His-bundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: A crossover design comparison. Heart Rhythm 2015;12:1548–57. DOI: 10.1016/j.hrthm.2015.03.048; PMID: 25828601. Vijayaraman P, Dandamudi G, Mascarenhas V. His bundle pacing can reverse adverse electrical and structural remodelling induced by right ventricular pacing in patients with longstanding complete heart block. Heart Rhythm 2016;13:S40, AB17-06. Su L, Xu L, Wu SJ, Huang WJ. Pacing and sensing optimization of permanent His-bundle pacing in cardiac resynchronization therapy/implantable cardioverter defibrillators patients: value of integrated bipolar configuration. Europace 2016;18:1399–405. DOI: 10.1093/europace/euv306; PMID: 26581403. Ajijola OA, Upadhyay GA, Macias C, et al. Permanent His-bundle pacing for cardiac resynchronization therapy: Initial feasibility study in lieu of left ventricular lead. Heart Rhythm 2017;14:1353– 61. DOI: 10.1016/j.hrthm.2017.04.003; PMID: 28400315. Sharma PS, Dandamudi G, Herweg B, et al. Permanent Hisbundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: a multicenter experience. Heart Rhythm 2017; pii: S1547-5271(17)31207-9. DOI: 10.1016/j. hrthm.2017.10.014; PMID: 29031929. Dandamudi G, Vijayaraman P. History of His bundle pacing. J Electrocardiol 2017;50:156–60. DOI: 10.1016/j. jelectrocard.2016.09.011; PMID: 27720211. Roguin A. Wilhelm His Jr. (1863-1934)--the man behind the bundle. Heart Rhythm 2006;3:480–3. DOI: 10.1016/j. hrthm.2005.11.020; PMID: 16567300. Upshaw CB Jr, Silverman ME. The Wenckebach phenomenon: a salute and comment on the centennial of its original description. Ann Intern Med 1999;130:58–63. PMID: 9890852.

34. S uma K. Sunao Tawara: a father of modern cardiology. Pacing Clin Electrophysiol 2001;24:88–96. PMID: 11227976. 35. Silverman ME, Hollman A. Discovery of the sinus node by Keith and Flack: on the centennial of their 1907 publication. Heart 2007;93:1184–7. DOI: 10.1136/hrt.2006.105049; PMID: 17890694. 36. Silverman ME, Upshaw CB, Jr., Lange HW. Woldemar Mobitz and His 1924 classification of second-degree atrioventricular block. Circulation 2004;110:1162–7. DOI: 10.1161/01. CIR.0000140669.35049.34; PMID: 15339865. 37. Alanis J, Gonzalez H, Lopez E. The electrical activity of the bundle of His. J Physiol 1958;142:127–40. PMID: 13564423. 38. Scherlag BJ, Lau SH, Helfant RH, et al. Catheter technique for recording His bundle activity in man. Circulation 1969;39:13–8. PMID: 5782803. 39. Narula OS, Scherlag BJ, Samet P. Pervenous pacing of the specialized conducting system in man. His bundle and A-V nodal stimulation. Circulation 1970;41:77–87. PMID: 5420636. 40. Williams DO, Scherlag BJ, Hope RR, et al. Selective versus nonselective His bundle pacing. Cardiovasc Res 1976;10:91–100. PMID: 1253199. 41. Karpawich PP, Gates J, Stokes KB. Septal His-Purkinje ventricular pacing in canines: a new endocardial electrode approach. Pacing Clin Electrophysiol 1992;15:2011–5. PMID: 1279590. 42. Zanon F, Baracca E, Aggio S, et al. A feasible approach for direct his-bundle pacing using a new steerable catheter to facilitate precise lead placement. J Cardiovasc Electrophysiol 2006;17:29–33. DOI: 10.1111/j.1540-8167.2005.00285.x; PMID: 16426396. 43. Vijayaraman P, Dandamudi G. How to perform permanent His bundle pacing: tips and tricks. Pacing Clin Electrophysiol 2016;39:1298–304. DOI: 10.1111/pace.12904; PMID: 27273200. 44. Vijayaraman P, Dandamudi G, Lustgarten D, Ellenbogen KA. Permanent His bundle pacing: Electrophysiological and echocardiographic observations from long-term follow-up. Pacing Clin Electrophysiol 2017;40:883–91. DOI: 10.1111/pace.13130; PMID: 28569391. 45. Vijayaraman P, Dandamudi G, Ellenbogen KA. Electrophysiological observations of acute His bundle injury during permanent His bundle pacing. J Electrocardiol 2016;49:664–9. 9 DOI: 10.1016/j. jelectrocard.2016.07.006; PMID: 2745772. 46. Vijayaraman P, Dandamudi G, Zanon F, et al. Permanent His bundle pacing (hbp): recommendations from a multi-center hbp collaborative working group for standardization of definitions, implant measurements and follow-up. Heart Rhythm 2017. 47. Hirao K, Otomo K, Wang X, et al. Para-Hisian pacing. A new method for differentiating retrograde conduction over an accessory AV pathway from conduction over the AV node. Circulation 1996;94:1027–35. PMID: 8790042. 48. Manolis AS. The deleterious consequences of right ventricular apical pacing: time to seek alternate site pacing. Pacing Clin Electrophysiol 2006;29:298–315. DOI: 10.1111/j.15408159.2006.00338.x; PMID: 16606399. 49. Prinzen FW, Peschar M. Relation between the pacing induced sequence of activation and left ventricular pump function in animals. Pacing Clin Electrophysiol 2002;25:484–98. PMID: 11991375. 50. James TN, Sherf L. Fine structure of the His bundle. Circulation 1971;44:9–28. PMID: 5561420. 51. El-Sherif N, Amay YLF, Schonfield C, et al. Normalization of bundle branch block patterns by distal His bundle pacing. Clinical and experimental evidence of longitudinal dissociation in the pathologic his bundle. Circulation 1978;57:473–83. PMID: 624157. 52. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:e240–327. DOI: 10.1161/CIR.0b013e31829e8776; PMID: 23741058. 53. Roger VL. Epidemiology of heart failure. Circ Res 2013;113:646–59. DOI: 10.1161/CIRCRESAHA.113.300268; PMID: 23989710. 54. Daubert C, Behar N, Martins RP, et al. Avoiding non-responders to cardiac resynchronization therapy: a practical guide. Eur Heart J 2017;38:1463–72. DOI: 10.1093/eurheartj/ehw270; PMID: 27371720.

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His Bundle Pacing: State of the Art 55. L ustgarten DL, Calame S, Crespo EM, et al. Electrical resynchronization induced by direct His-bundle pacing. Heart Rhythm 2010;7:15–21. DOI: 10.1016/j.hrthm.2009.09.066; PMID: 19914142. 56. Slawuta A, Bialy D, Moszczynska-Stulin J, et al. Dual chamber cardioverter-defibrillator used for His bundle pacing in patient with chronic atrial fibrillation. Int J Cardiol 2015;182:395–8. DOI: 10.1016/j.ijcard.2014.12.129; PMID: 25617606.

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57. S han P, Su L, Chen X, et al. Direct His-bundle pacing improved left ventricular function and remodelling in a biventricular pacing nonresponder. Can J Cardiol 2016;32:1577.e1–e4. DOI: 10.1016/j.cjca.2015.10.024; PMID: 26899255. 58. Dabrowski P, Kleinrok A, Kozluk E, Opolski G. Physiologic resynchronization therapy: a case of his bundle pacing reversing physiologic conduction in a patient with CHF and

LBBB during 2 years of observation. J Cardiovasc Electrophysiol 2011;22:813–7. DOI: 10.1111/j.1540-8167.2010.01949.x; PMID: 21087328. 59. Manovel A, Barba-Pichardo R, Tobaruela A. Electrical and mechanical cardiac resynchronisation by novel direct his-bundle pacing in a heart failure patient. Heart Lung Circ 2011;20:769–72. DOI: 10.1016/j.hlc.2011.05.617; PMID: 21700496.

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Electrophysiology

The Subcutaneous Implantable Cardioverter-Defibrillator: New Insights and Expanding Populations Thomas A Turnage, MD, John A Kpaeyeh Jr, MD, and Michael R Gold, MD, PhD Division of Cardiology, Medical University of South Carolina, Charleston, SC

Abstract Implantable cardioverter defibrillators (ICDs) have become a mainstay of treatment in patients at risk for sudden cardiac death. The majority of contemporary ICDs are implanted transvenously; however, this approach carries acute procedural and long-term risks. The subcutaneous ICD (S-ICD) was developed, in part, to circumvent some of these adverse events or as an alternative option in patients unable to undergo transvenous implantation. Early promising trials evaluating the S-ICD were small and focused on niche populations. More recently, larger trials included broader populations with worse heart failure and co-morbidities that may be more representative of typical ICD recipients. These studies have consistently demonstrated positive results. This review describes the S-ICD system, implantation, and the safety and efficacy of the device.

Keywords Subcutaneous ICD, implantation, safety, efficacy, sudden cardiac death Disclosure: MRG has received consulting fees and performed clinical trials with Boston Scientific, Medtronic and St Jude. TAT and JAK have no conflicts of interest to declare. Received: 3 December 2017 Accepted: 16 December 2017 Citation: US Cardiology Review 2018;12(1):66–70. DOI: 10.15420/usc.2017:37:1 Correspondence: Michael R Gold MD, PhD, FHRS – Michael E Assey Professor of Medicine, Division of Cardiology, Medical University of South Carolina, 114 Doughty Street – MSC 592, Charleston, SC 29425-5920, USA. E: goldmr@musc.edu

Introduction Implantable cardioverter-defibrillators (ICD) demonstrate a mortality reduction in patients at risk for sudden cardiac death.1–4 Transvenous lead placement with a subcutaneous, pectoral pulse generator has been the standard approach for ICD implantation for the past two decades,5 and have a high rate of successful implantation and a very low risk of in-hospital mortality.6 Despite increased operator experience, improvements in technology and surgical technique, there are risks inherent in the surgical procedure and transvenous ICDs. Recent data from the US National Cardiovascular Data Registry (NCDR) demonstrate an adverse event rate of 2.2 % and a 1.56 % major adverse event rate (defined as death, cardiac arrest, lead dislodgment, hemothorax, pneumothorax, tamponade, urgent cardiac surgery, myocardial infarction, cerebral vascular accident, and set screw problem).7 Although there is a low overall risk of periprocedural complications, additional long-term risks are associated with transvenous ICDs. Rates of infection are reported near 1.5 %,7,8 and may include cardiac and non-cardiac sites. Lead complication rates approach 10 % in randomized controlled trials8 and the annual failure rate increases proportionally with time after implantation.9 Reasons for failure include dislodgment, insulation defects, fracture, loss of capture, inability to sense appropriately, or abnormal impendence. In an effort to address these concerns, an entirely subcutaneous ICD (Cameron Health/Boston Scientific) was developed gaining Conformité Européene (CE) approval in Europe in 2008 and Food and Drug Administration (FDA) approval in 2012.5

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Subcutaneous Implantable Cardioverterdefibrillator System, Screening, and Implantation The subcutaneous ICD system consists of a pulse generator that is connected to a lead containing a single high-voltage, low-impedance shock coil and two sensing electrodes. The device senses from one of three different vectors: proximal ring to generator (primary); distal tip electrode to generator (secondary); and distal tip to proximal ring electrode (alternate). The volume of the first generation of the device is 69 ml, with a mass of 145 g.10 The second generation is slightly smaller, with a volume of 59.5 mL and mass of 130 g.11 Preliminary short-term trials beginning in 2001 sought to identify the most effective electrode position for the subcutaneous ICD (S-ICD) on the basis of anatomical landmarks. Four different electrode positions were tested and the most effective location was a left lateral pulse generator with an 8-cm coil electrode positioned to the left of the sternum.12 Patients under consideration for S-ICD implantation should undergo a preimplant ECG to assess for QRS-T wave morphology to reduce double counting of T-waves resulting in inappropriate defibrillations.13 ECG screening is necessary to ensure patient compatibility with one of the three vectors utilized with the S-ICD device. In the largest registry to date, patients were required to pass the screening in at least one vector in the supine and standing position. Of the 1637 patients evaluated, full data on all three vectors were available for review in 1622 patients. ECG vector screening was acceptable in two and all three vectors in 93.8 % and 51.4 % of patients, respectively. Lower BMI or higher left ventricular

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The S-ICD: New Insights ejection fraction (LVEF) were predictive characteristics of patients only passing one vector.14 The generator is implanted between the mid-axillary and anterior axillary lines connected to the electrode, which is tunneled typically 1 to 2 cm to the left of and parallel to the sternum.15 Figure 1 illustrates the anatomic location as well as the sensing vectors of the S-ICD system. In early implantations, the lead was tunneled via an inferior and superior parasternal incision (three-incision technique). In a recent trial, however, the majority of implantations were via the two-incision technique, requiring only an inferior sternal incision.14 A study of 69 patients implanted with an S-ICD at three German centers demonstrated a mean implantation time of 70.8 ± 27.9 min, which did not differ significantly from conventional ICD implantation times.16 Sedation strategies have varied widely across trials, with the rates of general anesthesia use ranging from 47 %17 to 100 %.18 In the recently published US S-ICD post-market approval study (S-ICD PAS), general anesthesia was utilized in 64.1 % of implantations.14 Arrhythmia termination is typically tested using 65 J shocks at the conclusion of the procedure. Once implanted, the device output is a non-programmable 80 J shock. The device automatically reverses the polarity of the shock if the initial attempt is unsuccessful. Maximum therapy consists of five defibrillations.18 Aside from 30 sec of post-shock asystole demand pacing, the device has no anti-bradycardic or anti-tachycardia (ATP) functions.15 The 2017 American Heart Association/American College of Cardiology/ Heart Rhythm Society guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death recommend S-ICD implantation in patients meeting criteria for ICD whom: • h ave inadequate vascular access or an unacceptable risk of infection (Class I, level of evidence [LOE] B- non-randomized [NR]); or • pacing for bradycardia, termination of ventricular tachycardia, or CRT is neither needed nor anticipated (Class IIa, LOE B-NR). S-ICD implantation is not recommended in patients in whom pacing for bradycardia, ATP, or CRT is necessary or envisioned (Class III, LOE B-NR).13

Populations Studied Evaluation of the clinical trials investigating the S-ICD system requires knowledge of the population analyzed. Early studies commonly included a high proportion of niche populations who were younger with little or no structural heart disease and fewer co-morbidities than most series of patients receiving transvenous ICDs. Mean age ranged from 42 to 53 years.16–22 Two publications reported median ages of 20 and 33 years.23,24 The majority of early cohorts consisted of fewer than 120 patients.16–19,23,24 Subsequently, the results from the EFFORTLESS (Evaluation oF FactORs ImpacTing Clinical Outcome and Cost EffectiveneSS of the S-ICD) registry were reported on a population of 985 S-ICD recipients.25 Within these studies, the prevalence of primary electrical heart disease ranged from 20 %16 to 75 %.23 When reported, mean LVEF was greater than 35 % in all cases16–22,25 and greater than 40 % in five studies.16–18,21,25 Primary prevention was the initial indication for implantation in 42 %18 to 79 %20 of cases. Men represented at least 70 % of each cohort16–22,25 in all but one trial, where men accounted for 9 out of 16 patients.23 Although these studies provided valuable information regarding the S-ICD system, as

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Figure 1: S-ICD System

Anatomic location and sensing vectors of the subcutaneous implantable cardioverter-defibrillator system.

noted above the cohorts studied are not entirely representative of typical ICD patients. Accordingly, these differences should be considered when extrapolating the results to broader populations. Two recent publications have analyzed S-ICD implantation in larger populations with higher prevalence of concomitant co-morbidities. Friedman et al retrospectively analyzed NCDR ICD data from 2012 to 2015 and performed a propensity matched analysis of 5760 patients in a 1:1:1 fashion to compare outcomes among patients implanted with S-ICD, single-chamber, and dual chamber ICD. Patients implanted with S-ICD were found to be more often younger, female, African American, and dialysis dependent, and were more likely to have experienced prior cardiac arrest when compared with more traditional ICD counterparts. Mean LVEF was 32 % and the prevalence of dialysis dependence was 20 % in the S-ICD cohort.26 A second study, mandated following FDA approval (PAS study), prospectively enrolled and followed patients who received an S-ICD. This population consisted of 1637 S-ICD recipients, 13.4 % of whom were on dialysis. Mean LVEF (32 %) was also lower than other prior S-ICD studies and patients within this study had more co-morbidities than prior publications. The majority of patients had both heart failure and hypertension and over one-third had diabetes. Patients with an LVEF < 35 % and heart disease constituted approximately 75 % of all patients. Additionally, a lower number of patients with inherited channelopathies were enrolled.14 The PAS study demonstrated that in contemporary clinical practice, the S-ICD population has shifted more from selected niche population to typical ICD cohorts. Table 1 compares the populations studied from the S-ICD Clinical Investigation (IDE), EFFORTLESS, and S-ICD PAS trials.

Safety As with any medical procedure, there are risks inherent in the implantation of ICDs. However, these risks differ among the types of ICDs implanted. Complications associated with the implantation of transvenous ICDs include pneumothorax, hemothorax, nerve or vascular damage, hematoma, infection, lead dislodgment or malfunction, cardiac perforation, and tamponade. A meta-analysis of traditional ICD

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Electrophysiology Table 1: Baseline Patient Characteristics: S-ICD IDE, EFFORTLESS, and S-ICD PAS S-ICD IDE

EFFORTLESS

S-ICD PAS

Patients

314

985

1637

Age (years)

51.9 ± 15.5

48.0 ± 17.0

52.0 ± 15.0

Male

74.1 %

72.0 %

68.6 %

Mean LVEF

36.1 ± 15.9 %

43.0 ± 18.0 %

32.0 ± 14.6 %

LVEF ≤ 35 %

57.7 %

75.4 %

Primary prevention

79.0 %

64.9 %

76.7 %

CHF

61.4 %

26.5 %

74.0 %

HTN

15.3 %

28.3 %

61.6 %

Diabetes

11.3 %

33.6 %

Kidney disease

8.2 %

25.6 %

Baseline patient characteristics in three large trials. CHF = congestive heart failure; HTN = hypertension; LVEF = left ventricular ejection fraction; NR = not reported.

randomized controlled trials demonstrated a complication rate of 9.1 %, though a few studies included devices implanted via a thoracotomy. This was compared with a ‘real-world’ complication rate of 3.08 % for ICD implantation derived from NCDR between 2006 to 2010.8 Discrepancy between the two rates may be, at least somewhat, accounted for by the intrinsic nature of a comparison between randomized controlled trials and registry data. It is likely that the NCDR registry underestimates longterm complications given the nature of the data collection post implant. A second publication also corroborated the reported complication rate from the NCDR data during that same time period.27 The rates of the most common adverse events were as follows: lead dislodgement 1.02 %, hematoma 0.86 %, pneumothorax 0.44 %, and cardiac arrest 0.29 %.27 Other studies quote slightly higher rates of pneumothorax and hematoma.6,8 NCDR data from 2010 to 2011 demonstrate an even lower adverse event rate.7 Although ICD periprocedure adverse event rates are acceptably low, the complications associated with a chronic indwelling transvenous ICD, if present, often lead to significant comorbidity and reoperation. Infection has been reported in 1.5 % of transvenous devices.7,8 The infection may range from localized pocket or wound infection to fulminant endocarditis. Most patients ultimately require explantation in order to treat the infection successfully. Lead malfunction or defects typically require reoperation with implantation of additional transvenous leads and abandonment of the problematic lead. Annual failure rates of transvenous leads increase with time after implantation. The estimated lead survival rate at 5 and 8 years is 85 % and 60 %, respectively. Annual failure rate of leads at least 10 years old is 20 %.9 The S-ICD system was designed, in part, as a way to circumvent many of the complications associated with transvenous ICD implantation. Safety analyses of the S-ICD and comparison with that of conventional ICDs are crucial to its development and clinical acceptance. Earlier S-ICD trials demonstrated a higher rate of complications than later ones, reflective of increased operator experience and improved technology. In the initial trial describing the S-ICD system, thirteen of 55 patients had device related adverse events.12 In a Dutch cohort of 118 patients, sixteen experienced complications and adverse events

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were more frequent in the initial 15 implantations.17 In the S-ICD IDE study, which had rigorous FDA oversight, Weiss et al reported a 180day complication-free rate of 92.1 % for all complications and, more specifically, 99 % for complications caused by the S-ICD system.20 Early results from EFFORTLESS reported similarly low complications with complication-free rates of 97 % and 94 % at 30 and 260 days, respectively.21 Recently, a large registry corroborated high complicationfree rates of the S-ICD.14 A propensity-matched analysis found that the in-hospital complication rates associated with S-ICD (0.9 %) were not significantly different than that of single chamber or dual chamber ICDs.26 A second analysis found that complication rates between S-ICD and transvenous ICDs were similar, but that the nature of the complications was different. S-ICDs reduced lead complication rates but it was at the cost of non-lead related complications.28 Reported rates of infection and hematoma formation in S-ICDs14,22 are similar to rates previously reported in conventional ICDs.7,8,27 However, importantly, S-ICD infections are localized and have not been associated with bacteremia or systemic involvement. Improvement in the complication rate suggests a learning curve associated with the implantation of S-ICDs. A pooled cohort from the IDE study and EFFORTLESS registry demonstrates a significantly decreased complication rate with more experienced operators.29 Technology advances have also contributed to decreased S-ICD adverse events. Parasternal lead migration was encountered frequently in early clinical trials; however, in at least two trials, no further lead migration was observed following the introduction of a xiphoid suture sleeve to the operative protocol.17,19 Inappropriate shocks are associated with worsened quality of life, increased healthcare costs,30,31 so minimizing such events has been an area of intense study for ICDs. The cause of inappropriate shocks with S-ICD have been inappropriate sensing of myopotentials, T-wave oversensing, changes in QRS morphology, or failure to discriminate supraventricular tachycardia (SVT). In one study, no further inappropriate shocks were observed following a software update specifically addressing myopotential oversensing.19 Other software updates addressing T-wave oversensing, changes in sensing vectors during exercise, or the addition of new templates have led to reductions in inappropriate therapy.17 For transvenous ICDs, conservative programming of tachycardia treatment zones by prolonging detection duration or increasing threshold rates for therapy has been shown to not only reduce inappropriate shocks, but also improve mortality.32 The Subcutaneous versus Transvenous Arrhythmia Recognition Testing (START) study demonstrated that the S-ICD discriminated SVT more effectively than transvenous ICD systems.33 Thus, the use of dual zone programming employing a conditional zone (rate plus discriminators) markedly reduces inappropriate shocks.34 Continued reductions in inappropriate shocks as well as improvements in device implantation and technique with new generations of the S-ICD device will likely lead to an even more acceptable safety profile. These differences in the types of lead complications and inappropriate shocks between transvenous and subcutaneous ICDs has been further supported by a recent meta-analysis.35 The safety profiles of a device are also affected by longevity. A device with a shorter battery life or time to the elective replacement interval (ERI) exposes the patient to more procedures with their intrinsic risks.

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The S-ICD: New Insights Conventional ICDs implanted after 2002 were found to have a mean battery life of 5.6 years.36 Although device longevity varies somewhat with manufacturer and programmed mode, overall longevity of devices continues to improve with more recently implanted devices.37 The manufacturer of the S-ICD initially projected device longevity of 5 years.10 A nearly 6-year follow-up of 55 patients enrolled in the European Regulatory Trial demonstrated a device replacement rate of 47 %. The majority of devices were replaced on ERI (81 %) and the median time for device replacement was 5 years. Premature battery depletion occurred in 9 % of the initial S-ICD cohort leading to a field safety notification regarding a battery manufacturing issue. Following correction, premature battery depletion was observed in 0.6 % in the IDE trial and 0.2 % in the EFFORTLESS registry.38 Published rates of premature battery depletion in transvenous ICDs are 8–9 %.39,40 The second generation S-ICD system has manufacturer projected longevity of over 7 years,11 though this will need to be validated with subsequent analyses.

Efficacy S-ICD devices are effective in appropriately sensing and terminating VT/VF. Conversion testing is typically performed immediately following implantation with induction of VT/VF and a 65 J shock providing an adequate (15 J) safety margin.12,16,18,19 An early trial comparing temporary S-ICD systems with transvenous ICDs found that conversion efficacy was similar, though S-ICD systems had higher defibrillation thresholds.12 Moreover, the START study demonstrated no significant differences in ventricular arrhythmia detection for S-ICDs and transvenous devices.33 A larger study of 899 episodes of induced VT/VF established a 99.8 % rate of successful VT/VF detection and defibrillation. In those instances where VT/VF was successfully detected, successful defibrillation was obtained in 100 % of patients.20 An early study of 40 consecutive S-ICD patients did demonstrate a low conversion efficacy with the initial shock; however, 96.4 % had successful conversion within the five allotted shocks.18 Recent large trials further corroborate the ability of the S-ICD system to successfully defibrillate induced VT/VF.14,26 Failure of conversion with the first shock is predicted by patient height and BMI.14 Conversion testing has also been performed ≥ 150 days after implantation. Of the 75 patients with evaluable results, 72 (96 %) were successfully converted at 65 J. The three other patients were successfully converted at 80 J.20 Mean time to therapy has been reported at 14.6 and 19.2 sec20,22 and is in line with the current paradigm for programming of defibrillation therapy for transvenous systems.30

T he Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from nearfatal ventricular arrhythmias. N Engl J Med 1997;337:1576–83. DOI: 10.1056/NEJM199711273372202; PMID: 9411221. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933–40. DOI: 10.1056/NEJM199612263352601; PMID: 8960472. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–83. DOI: 10.1056/ NEJMoa013474; PMID: 11907286. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–37. DOI: 10.1056/NEJMoa043399; PMID: 15659722. Lewis GF, Gold MR. Safety and efficacy of the subcutaneous implantable defibrillator. J Am Coll Cardiol 2016;67:445–54. DOI: 10.1016/j.jacc.2015.11.026; PMID: 26821634. van Rees JB, de Bie MK, Thijssen J, et al. Implantation-related complications of implantable cardioverter-defibrillators and

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Induction of VT/VF and conversion testing indicates proper device functioning in a controlled setting. However, demonstration of termination of spontaneous episodes is obligatory to show the true benefit of ICDs. Weiss et al reported 119 spontaneous VT/VF episodes in 21 patients. There were 38 discrete VT/VF episodes and 81 that occurred during VT/ VF storms. The first shock conversion rate for the discrete episodes was 92.1 % and all but one was terminated with ≥ 1 shocks. The exception was an episode of monomorphic VT, which terminated spontaneously while the device was charging for a second shock.20 In the EFFORTLESS registry, the overall successful conversion rate for spontaneous episodes was 97.4 %.25 Other investigations have found similarly high rates of successful first shock17 and overall shock efficacy.22

Limitations Despite evidence establishing the safety and efficacy of the S-ICD, the device does have limitations. The system does not have the ability to provide chronic anti-bradycardic, anti-tachycardic pacing, or CRT. It is able to provide up to 30 sec of post-shock asystole pacing at a rate of 50 bpm.15 The inability to provide pacing chronically emphasizes the importance of appropriate patient screening to exclude those patients with, or who may develop, bradycardic indications. In the 3-year follow-up of the EFFORTLESS registry, the S-ICD was explanted for the indication of bradycardia in 0.1 %, ATP in 0.5 %, and CRT in 0.4 % of patients.25 Low rates of S-ICD explantation and transition to transvenous devices for bradycardia, CRT, or ATP likely reflect the importance of proper patient selection.

Conclusion The S-ICD device is a safe and effective alternative to contemporary transvenous ICDs in selected patients. Additionally, new studies have demonstrated both safety and efficacy in broader, sicker populations.14,26 This is being studied in even more detail in the UNTOUCHED trial of primary prevention patients with a reduced ejection fraction. 41 Though direct randomized comparisons between the two systems are currently unavailable, the Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter-Defibrillator Therapy (PRAETORIAN) trial is ongoing. 42 In selected patients, and arguably most, who qualify for ICD therapy without an indication for pacing, CRT, or ATP, the subcutaneous ICD system should be considered. n

cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cardiol 2011;58:995–1000. DOI: 10.1016/j.jacc.2011.06.007; PMID: 21867832. 7. Kremers MS, Hammill SC, Berul CI, et al. The National ICD Registry Report: version 2.1 including leads and pediatrics for years 2010 and 2011. Heart Rhythm 2013;10:e59–65. DOI: 10.1016/j.hrthm.2013.01.035; PMID: 23403056. 8. Ezzat VA, Lee V, Ahsan S, et al. A systematic review of ICD complications in randomised controlled trials versus registries: is our ‘real-world’ data an underestimation? Open Heart 2015;2:e000198. DOI: 10.1136/openhrt-2014-000198; PMID: 25745566. 9. Kleemann T, Becker T, Doenges K, et al. Annual rate of transvenous defibrillation lead defects in implantable cardioverter-defibrillators over a period of >10 years. Circulation 2007;115:2474–80. DOI: 10.1161/CIRCULATIONAHA.106.663807; PMID: 17470696. 10. Lupo PP, Pelissero G, Ali H, et al. Development of an entirely subcutaneous implantable cardioverter-defibrillator. Progress in cardiovascular diseases. 2012;54:493–7. DOI; 10.1016/j. pcad.2012.03.006; PMID: 22687590. 11. Emblem MRI S-ICD System Product Details. Boston Scientific. Available from: http://www.bostonscientific.com/en-US/

products/defibrillators/emblem-s-icd-system.html 12. B ardy GH, Smith WM, Hood MA, et al. An entirely subcutaneous implantable cardioverter-defibrillator. N Engl J Med 2010;363:36– 44. DOI: 10.1056/NEJMoa0909545; PMID: 20463331. 13. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2017. DOI: 10.1016/j. hrthm.2017.10.036. 14. Gold MR, Aasbo JD, El-Chami MF, et al. Subcutaneous implantable cardioverter-defibrillator post-approval study: clinical characteristics and perioperative results. Heart Rhythm 2017;14:1456–63. DOI: 10.1016/j.hrthm.2017.05.016; PMID: 28502872. 15. Rowley CP, Gold MR. Subcutaneous implantable cardioverter defibrillator. Circ Arrhythm Electrophysiol 2012;5:587–93. DOI: 10.1161/CIRCEP.111.964676; PMID: 22715237. 16. Kobe J, Reinke F, Meyer C, et al. Implantation and follow-up of totally subcutaneous versus conventional implantable cardioverter-defibrillators: a multicenter case-control study.

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Electrophysiology Heart Rhythm 2013;10:29–36. DOI; 10.1016/j.hrthm.2012.09.126; PMID: 23032867. 17. O lde Nordkamp LR, Dabiri Abkenari L, Boersma LV, et al. The entirely subcutaneous implantable cardioverter-defibrillator: initial clinical experience in a large Dutch cohort. J Am Coll Cardiol 2012;60:1933–9. DOI; 10.1016/j.jacc.2012.06.053; PMID:23062537. 18. Aydin A, Hartel F, Schluter M, et al. Shock efficacy of subcutaneous implantable cardioverter-defibrillator for prevention of sudden cardiac death: initial multicenter experience. Circ Arrhythm Electrophysiol 2012;5:913–9. DOI; 10.1161/CIRCEP.112.973339; PMID: 22923274. 19. Dabiri Abkenari L, Theuns DA, Valk SD, et al. Clinical experience with a novel subcutaneous implantable defibrillator system in a single center. Clin Res Cardiol 2011;100:737–44. DOI: 10.1007/ s00392-011-0303-6; PMID: 21416191. 20. Weiss R, Knight BP, Gold MR, et al. Safety and efficacy of a totally subcutaneous implantable-cardioverter defibrillator. Circulation 2013;128:944–53. DOI; 10.1161/ CIRCULATIONAHA.113.003042; PMID: 23979626. 21. Lambiase PD, Barr C, Theuns DA, et al. Worldwide experience with a totally subcutaneous implantable defibrillator: early results from the EFFORTLESS S-ICD Registry. Eur Heart J 2014;35:1657–65. DOI: 10.1093/eurheartj/ehu112; PMID: 24670710. 22. Burke MC, Gold MR, Knight BP, et al. Safety and efficacy of the totally subcutaneous implantable defibrillator: 2-year results from a pooled analysis of the IDE Study and EFFORTLESS Registry. J Am Coll Cardiol 2015;65:1605–15. DOI: 10.1016/j. jacc.2015.02.047; PMID: 25908064. 23. Jarman JW, Lascelles K, Wong T, et al. Clinical experience of entirely subcutaneous implantable cardioverter-defibrillators in children and adults: cause for caution. Eur Heart J 2012;33:1351– 9. DOI: 10.1093/eurheartj/ehs017; PMID: 22408031. 24. Jarman JW, Todd DM. United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn. Europace 2013; 15:1158–65. DOI: 10.1093/europace/eut016; PMID: 23449924. 25. Boersma L, Barr C, Knops R, et al. Implant and midterm outcomes of the Subcutaneous Implantable Cardioverter-

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Defibrillator Registry: the EFFORTLESS Study. J Am Coll Cardiol 2017;70:830–41. DOI: 10.1016/j.jacc.2017.06.040; PMID: 28797351. Friedman DJ, Parzynski CS, Varosy PD, et al. Trends and in-hospital outcomes associated with adoption of the subcutaneous implantable cardioverter defibrillator in the United States. JAMA Cardiol 2016;1:900–11. DOI: 10.1001/ jamacardio.2016.2782; PMID: 27603935. Freeman JV, Wang Y, Curtis JP, et al. Physician procedure volume and complications of cardioverter-defibrillator implantation. Circulation 2012;125:57–64. DOI: 10.1161/ CIRCULATIONAHA.111.046995; PMID: 22095828. Brouwer TF, Yilmaz D, Lindeboom R, et al. Long-term clinical outcomes of subcutaneous versus transvenous implantable defibrillator therapy. J Am Coll Cardiol 2016;68:2047–55. DOI: 10.1016/j.jacc.2016.08.044; PMID: 27810043. Knops RE, Brouwer TF, Barr CS, et al. The learning curve associated with the introduction of the subcutaneous implantable defibrillator. Europace 2016;18:1010–5. DOI: 10.1093/ europace/euv299; PMID: 26324840. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Coll Cardiol 2008;51:1357–65. DOI: 10.1016/j.jacc.2007.09.073; PMID: 18387436. van Rees JB, Borleffs CJ, de Bie MK, et al. Inappropriate implantable cardioverter-defibrillator shocks: incidence, predictors, and impact on mortality. J Am Coll Cardiol 2011;57:556– 62. DOI: 10.1016/j.jacc.2010.06.059; PMID: 21272746. Moss AJ, Schuger C, Beck CA, et al. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012;367:2275–83. DOI: 10.1056/NEJMoa1211107; PMID: 23131066. Gold MR, Theuns DA, Knight BP, et al. Head-to-head comparison of arrhythmia discrimination performance of subcutaneous and transvenous ICD arrhythmia detection algorithms: the START study. J Cardiovasc Electrophysiol 2012;23:359–66. DOI: 10.1111/j.1540-8167.2011.02199.x; PMID: 22035049.

34. G old MR, Weiss R, Theuns DA, et al. Use of a discrimination algorithm to reduce inappropriate shocks with a subcutaneous implantable cardioverter-defibrillator. Heart Rhythm 2014;11:1352–8. DOI: 10.1016/j.hrthm.2014.04.012; PMID: 24732366. 35. Basu-Ray I, Liu J, Jia X, et al. Subcutaneous versus transvenous implantable defibrillator therapy: a meta-analysis of casecontrol studies. JACC Clin Electrophysiol 2017;3:1484–6. DOI: 10.1016/j.jacep.2017.07.017 36. Thijssen J, Borleffs CJ, van Rees JB, et al. Implantable cardioverter-defibrillator longevity under clinical circumstances: an analysis according to device type, generation, and manufacturer. Heart Rhythm 2012;9:513–9. DOI: 10.1016/j. hrthm.2011.11.022; PMID: 22094073. 37. von Gunten S, Schaer BA, Yap SC, et al. Longevity of implantable cardioverter defibrillators: a comparison among manufacturers and over time. Europace 2016;18:710–7. DOI: 10.1093/europace/ euv296; PMID: 26609076. 38. Theuns DA, Crozier IG, Barr CS, et al. Longevity of the subcutaneous implantable defibrillator: long-term follow-up of the European regulatory trial cohort. Circ Arrhythm Electrophysiol 2015;8:1159–63. DOi: 10.1161/CIRCEP.115.002953; PMID: 26148819. 39. Manolis AS, Maounis T, Koulouris S, et al. “Real life” longevity of implantable cardioverter-defibrillator devices. Clin Cardiol 2017;40:759–64. DOI: 10.1002/clc.22729; PMID: 28543134. 40. Hauser RG, Hayes DL, Epstein AE, et al. Multicenter experience with failed and recalled implantable cardioverter-defibrillator pulse generators. Heart Rhythm 2006;3:640–4. DOI: 10.1016/j. hrthm.2006.02.011; PMID: 16731462. 41. Gold MR, Knops R, Burke MC, et al. The design of the understanding outcomes with the S-ICD in Primary Prevention Patients with Low EF Study (UNTOUCHED). Pacing Clin Electrophysiol 2017;40:1–8. DOI: 10.1111/pace.12994; PMID: 27943348. 42. Olde Nordkamp LR, Knops RE, Bardy GH, et al. Rationale and design of the PRAETORIAN trial: a Prospective, RAndomizEd comparison of subcuTaneOus and tRansvenous ImplANtable cardioverter-defibrillator therapy. Am Heart J 2012;163:753–60. DOI: 10.1016/j.ahj.2012.02.012; PMID: 22607851.

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