USC 13.1 by Radcliffe Cardiology

US Cardiology Review

Volume 13 • Issue 1 • Spring 2019

www.USCjournal.com

Volume 13 • Issue 1 • Spring 2019

Role of High-sensitivity Cardiac Troponin in Acute Coronary Syndrome Mahesh Anantha Narayanan, MD, and Santiago Garcia, MD

Percutaneous Coronary Intervention: Developments in the Last 12 Months Rhian E Davies, DO, and J Dawn Abbott, MD

Conduction Abnormalities After Transcatheter Aortic Valve Replacement Somsupha Kanjanauthai, MD, Kabir Bhasin, MD, Luigi Pirelli, MD, and Chad A Kliger, MD

Can Early Management of Hypertension by General Practitioners Improve Outcome? Deborah L Nadler, MD, and Athena Poppas, MD FACC

ISSN: 1758-3896 • eISSN: 1758-390X

Cardiac Sarcoidosis Following a 6-month Course of Prednisone

3D Image of Coronary Artery Plaque

MitraClip Device and Angiograph Display

Radcliffe Cardiology

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Volume 13 • Issue 1 • Spring 2019

www.USCjournal.com

Editor in Chief Dr Ankur Kalra Case Western Reserve University School of Medicine, Cleveland, OH

Section Editor (Interventional/Structural)

Section Editor (Imaging)

Section Editor (Preventive Cardiology)

Section Editor (Electrophysiology)

Rishi Puri, MD, PhD, FRACP

Akhil Narang, MD, FACC Northwestern University, Chicago, IL

John W McEvoy, MB, BCh, BAO, MEd, MHS, FRCPI

Sourbha S Dani, MD, FACC

Cleveland Clinic, Cleveland, OH

National University of Ireland, Galway, Ireland

Eastern Maine Medical Center, Bangor, ME

Deputy Editors Leway Chen, MD, MPH

Chad A Kliger, MD, MS, FACC, FSCAID

Bruce Stambler, MD

University of Rochester, Rochester, NY

Lenox Hill Heart and Vascular Institute, New York, NY

Piedmont Healthcare, Atlanta, GA

Sahil Khera MD, MPH

Yogesh Reddy, MD, MSc

Columbia University, New York City, NY

Mayo Clinic, Rochester, MN

Aditya Khetan, MD

Rajalakshmi Santhanakrishnan, MBBS

Case Western Reserve University, Cleveland, OH

Wright State University, Dayton, OH

Editorial Board Ralph G Brindis, MD

Medical University of South Carolina, Charleston, SC

Leo Buckley, PharmD

Thomas A Haffey, MD, DO

Virginia Commonwealth University, Richmond, VA

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

Western University of Health Sciences, Pomona, CA

Dinesh K Kalra, MD, FACC, FSCCT, FSCMR Rush University Medical Center, Chicago, IL

Morton J Kern, MD

Donald E Cutlip, MD

University of California at Irvine, Orange, CA

Harvard Medical School, Boston, MA

Jackson J Liang, MD, DO

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

NA Mark Estes III, MD

Hospital of the University of Pennsylvania, Philadelphia, PA

Duane Pinto, MD, MSc

Harvard Medical School, Boston, MA

Tufts University School of Medicine, Boston, MA

Krishna Pothineni, MD

Bernard J Gersh, MB, ChB, DPhil

Rahul Sharma, MD, FACP, FACC, FSCAI

Mayo Clinic, Rochester, MN

Cover image © AdobeStock and Shutterstock

Michael R Gold, MD

University of California, San Francisco, CA

University of Arkansas for Medical Sciences, Little Rock, AR Virginia Tech Carilion School of Medicine, Roanoke, VA

Bill Gogas, MD, PhD

W Douglas Weaver, MD

Emory University School of Medicine, Atlanta, GA

Wayne State University, Detroit, MI

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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 thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Cardiology. Radcliffe Cardiology, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire SL8 5AS, UK © 2019 All rights reserved ISSN: 1758-3896 • eISSN: 1758-390X

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Established: March 2016 | Frequency: Bi-annual | Current issue: Spring 2019

Aims and Scope

Submissions and Instructions to Authors

• 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.

• Contributors are identified by the Editor-in-Chief with the support of the Editorial Board and Managing Editor. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.USCjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Rosie Scott rosie.scott@radcliffe-group.com

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

Reprints All articles included in US Cardiology Review are available as reprints. Please contact Rob Barclay at rob.barclay@radcliffe-group.com

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

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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.

Articles published within this journal are open access, which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly. The author retains all non-commercial rights for articles published herein under the CC-BY-NC 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/legalcode). Radcliffe Cardiology retain all commercial rights for articles published herein unless otherwise stated. Permission to reproduce an article for commercial purposes, either in full or in part, should be sought from the publication’s Managing Editor.

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. • 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.

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.

Cardiology

Lifelong Learning for Cardiovascular Professionals

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Contents

Foreword Ankur Kalra, MD, FACP, FACC, FSCAI

DOI: https://doi.org/10.15420/usc.2019.8.1

Interventional Cardiology: Coronary Role of High-sensitivity Cardiac Troponin in Acute Coronary Syndrome

Mahesh Anantha Narayanan, MD, and Santiago Garcia, MD DOI: https://doi.org/10.15420/usc.2018.16.1

Percutaneous Coronary Intervention: Developments in the Last 12 Months

Rhian E Davies, DO, and J Dawn Abbott, MD DOI: https://doi.org/10.15420/usc.2019.1.1

Role of Drug-coated Balloons in Small-vessel Coronary Artery Disease

Michael Megaly, MD, MS, Marwan Saad, MD, PhD, and Emmanouil S Brilakis, MD, PhD DOI: https://doi.org/10.14520/usc.2019.4.1

Interventional Cardiology: Structural Heart Conduction Abnormalities After Transcatheter Aortic Valve Replacement

Somsupha Kanjanauthai, MD, Kabir Bhasin, MD, Luigi Pirelli, MD, and Chad A Kliger, MD DOI: https://doi.org/10.14520/usc.2018.7.2

Value of MitraClip in Reducing Functional Mitral Regurgitation

Mehmet Ali Elbey, MD, Luis Augusto Palma Dalan, MD, and Guilherme Ferragut Attizzani, MD DOI: https://doi.org/10.14520/usc.2018.19.1

Transcatheter Edge-to-edge Repair of Severe Tricuspid Regurgitation

Shu-I Lin, MD, Mizuki Miura MD, PhD, Francesco Maisano, MD, Michel Zuber, MD, Mara Gavazzoni, MD, Edwin C Ho, MD, Alberto Pozzoli, MD, and Maurizio Taramasso, MD, PhD DOI: https://doi.org/10.14520/usc.2018.20.1

Heart Failure and Cardiomyopathies Diagnosis and Therapy of Cardiac Sarcoidosis: A Clinical Perspective

Steven R Sigman, MD, FASNC DOI: https://doi.org/10.15420/usc.2018.3.1

Cardiometabolic Disorders Diabetic Cardiomyopathy: Five Major Questions with Simple Answers

Miguel Alejandro Rodriguez-Ramos, MD DOI: https://doi.org/10.15420/usc.2018.18.2

Everything in Moderation: Investigating the U-Shaped Link Between HDL Cholesterol and Adverse Outcomes

Marc P Allard-Ratick, MD, Pratik B Sandesara, MD, Arshed A Quyyumi, MD, FACC, FRCP, and Laurence S Sperling, MD, FACC, FAHA, FACP, FASPC DOI: https://doi.org/10.14520/usc.2019.3.2

Electrophysiology The Next 10 Years in Atrial Fibrillation

Jeffrey L Turner, DO, and Nassir Marrouche, MD DOI: https://doi.org/10.15420/usc.2018.21.2

Editor’s Pick Can Early Management of Hypertension by General Practitioners Improve Outcome?

Deborah L Nadler, MD, and Athena Poppas, MD FACC DOI: https://doi.org/10.15420/usc.2019.5.1

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Foreword

Ankur Kalra, MD, FACP, FACC, FSCAI is the Editor-in-Chief of US Cardiology Review, Member of the Staff, Department of Cardiovascular Medicine, Cleveland Clinic; Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

am excited to bring you the Spring 2019 issue of US Cardiology Review. This is my second issue as the incumbent Editor-in-Chief, and my first as Member of the Staff, Department of Cardiovascular Medicine at the Cleveland Clinic. I have made a concerted effort in reaching out to colleagues who I have trained and worked with at different stages in my career to contribute to this issue. They are all experts in their respective fields, and I am immensely grateful for their effort in contributing to US Cardiology Review. We all share a common goal: to deliver contemporary science to the practicing clinician in a concise, ready-for-action, succinct format. Structural heart disease takes center stage in this issue. Somsupha Kanjanauthai et al. discuss what the future holds for transcatheter aortic valve replacement. Mehmet Ali Elbey et al. take an in-depth look at the data from the MITRA-FR and COAPT trials and implications for the contemporary management of patients with secondary mitral regurgitation. Shu-I Lin et al. discuss transcatheter edge-to-edge repair of severe tricuspid regurgitation. In the interventional cardiology section, Rhian Davies and J Dawn Abbott write about recent advances in percutaneous coronary intervention, Mahesh Anantha Narayanan and Santiago Garcia educate us on the utility of high-sensitivity troponin in the evaluation of patients with acute coronary syndrome, and Michael Megaly et al. discuss the role of drug-coated balloons (versus stents) in small-vessel interventions. We have an exciting cardiometabolic disorders section in this issue of the journal. Marc P Allard-Ratick et al. discuss the role of high-density lipoprotein cholesterol in cardiovascular outcomes, and Miguel Rodriguez-Ramos writes about diabetic cardiomyopathy. The cardiomyopathy and electrophysiology sections have an article each on cardiac sarcoidosis by Steven R Sigman and advances in AF by Jeffrey L Turner and Nassir Marrouche, respectively. The Editor’s Pick for this issue is a stellar piece by Deborah L Nadler and Athena Poppas on the early management of essential hypertension. I am also excited to announce Radcliffe Cardiology’s foray into a podcast series with the Spring 2019 issue. “Parallax with Ankur Kalra”, US Cardiology Review’s podcast, will bring the journal’s content to life in a conversational, digestible format. We aspire to be the go-to podcast for accessing latest cardiovascular medicine content that will help take care of patients in the most contemporary fashion feasible. I hope you enjoy reading the latest issue of US Cardiology Review.

DOI: https://doi.org/10.15420/usc.2019.8.1

Access at: www.USCjournal.com

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Interventional Cardiology: Coronary

Role of High-sensitivity Cardiac Troponin in Acute Coronary Syndrome Mahesh Anantha Narayanan, MD, 1 and Santiago Garcia, MD 2 1. Division of Cardiovascular Disease, Department of Medicine, University of Minnesota, Minneapolis, MN; 2. Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, MN

Abstract Chest pain is one of the most common reasons for an emergency room (ER) visit in the US, with almost 6 million ER visits annually. High-sensitivity cardiac troponin (hscTn) assays have the ability to rapidly rule in or rule out acute coronary syndrome with improved sensitivity, and they are increasingly being used. Though hscTn assays have been approved for use in European, Australian, and Canadian guidelines since 2010, the FDA only approved their use in 2017. There is no consensus on how to compare the results from various hscTn assays. A literature review was performed to analyze the advantages and limitations of using hscTn as a standard biomarker to evaluate patients with suspected ACS in the emergency setting.

Keywords Acute coronary syndrome, myocardial infarction, troponin, cardiac biomarkers Disclosure: The authors have no conflicts of interests to declare. Received: November 4, 2018 Accepted: February 4, 2019 Citation: US Cardiology Review 2019;13(1):5–10. DOI: https://doi.org/10.15420/usc.2018.16.1 Correspondence: Santiago Garcia, Minneapolis Heart Institute, 920 East 28th Street, Suite 300-MR 33300, Minneapolis, MN 55417. E: garci205@umn.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Chest pain is one of the most common reasons for an emergency room (ER) visit in the US with almost 6 million ER visits annually.1 According to the fourth universal definition of MI, acute MI (AMI) requires a rise and/or fall in cardiac troponin (cTn) with at least one value above the 99th percentile upper reference limit.2,3 Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are the preferred biomarkers in acute coronary syndrome (ACS).2–5 Although contemporary cTn assays are used routinely in the US for risk stratification and the diagnosis of patients presenting with suspected ACS, they have important limitations compared to high-sensitivity cardiac troponin (hscTn) assays: • They are highly imprecise: most contemporary assays have a total imprecision (coefficient of variation) of 10–20% at the 99th percentile for the diagnosis of AMI. • They have limited analytical sensitivity: contemporary assays can only quantify cTn in <35% of healthy individuals below the 99th percentile.4 These limitations have led to prolonged serial sampling protocols being used to achieve optimal diagnostic accuracy, which mean increases in hospitalizations, length of stay, and costs.4,6–10 In conventional troponin assays, troponin elevation is considered to be an all or nothing phenomenon. The presence of troponin elevation above the 99th percentile reference range suggests myocardial injury

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but no troponin elevation above the 99th percentile is considered normal, even though this does not necessarily mean the absence of an ACS, as conventional assays are unable to detect small ischemic events. Particularly where there is atypical chest pain and no troponin elevation, patients who are experiencing an ACS are at risk of being discharged early because the decision-making process is subjective.9 To overcome this difficulty, hscTn assays were introduced and have slowly gained importance. These can be used to classify patients more appropriately as ‘true’ or ‘no’ ACS, and do not require repeat assays at 6 and 12 hours, unlike conventional cTn assays. HscTn assays are able to detect troponins at a concentration about 1/10 of the lower reference range of conventional troponin assays.2 While hscTn assays have been in clinical use since 2015 in Europe, the FDA only approved their use in the US in 2017.7 There is a lack of clarity on interpreting the results of hscTn assays, despite a decade of published studies, as they differ significantly from conventional troponin assays.10 This review discusses the basics of hscTn assays and their interpretation in patients presenting with symptoms suggestive of ACS.

Basics of Troponin Analysis in Acute Coronary Syndrome CTnI and cTnT are contractile components present in the myocardium and are exclusive to cardiac muscles.2,3,11 They work in coordination with calcium ions to promote binding of actin and myosin, thus promoting

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Interventional Cardiology: Coronary cardiac muscle contraction. CTn consists of troponin T (protein molecule attaching troponin complex to actin), troponin C (calcium binding site) and troponin I (inhibits myosin head interaction in the absence of calcium). While troponin C can be found in both skeletal and cardiac muscles, troponin T and I are specific and sensitive, so are called cardiacspecific troponins. It is important to understand the concept of the ‘early releasable troponin pool’ (ERTP). Almost 95% of troponin is bound to actin filaments while about 5% of it is free in the cytoplasm, which constitutes the ERTP.12 The troponin in the ERTP is the first to be released following any myocardial injury but, with normal renal function, gets cleared immediately from the blood pool. The structurally bound troponin, on the other hand, is released over a period of several days, causing a gradual rise in troponin. The half-life of cTn is around 2 hours.

What do the Guidelines Say? The IFCC guidelines recommend hscTn assays because of their ability to measure cTn values above the assay’s LoD in more than 50% of individuals.6,13 The 2015 European Society of Cardiology (ESC) guidelines give a class I indication for use of both the rapid 0/1-hour rule-out and rule-in protocols and the 0/3-hour protocol.7 The European algorithm allows triage in about 75% of patients. It is important to remember that all troponin assays are associated with some false positive and false negative results, but this is minimal with hscTn.

Approved High-sensitivity Troponin Assays There are at least four hscTn assays that are approved and in clinical use. One of them measures troponin T (Elecsys®, Roche Diagnostics) and the other three assays measure troponin I (ARCHITECT STAT troponin I, Abbott; Access hs-cTnI, Beckman Coulter; hs-cTnI ADVIA Centaur, Siemens). The reference ranges for each of the individual tests is shown in Table 1.

Common Definitions of Clinical Importance While using hscTn assays, interpreting the values requires an in-depth understanding of a few definitions. The precision of the hscTn assay is defined by the coefficient of variation (CoV). This is the ratio of standard deviation to the mean value of a series of troponin samples. Generally, hscTn assays are approved for use per guidelines if their CoV is <10% at the 99th percentile. If the CoV is 10–20%, the test can still be used but tests that have CoV >20% are not acceptable for clinical use. Limit of blank (LoB) is the highest concentration of troponin reported by a hscTn assay when there is no troponin in the sample. Limit of detection (LoD) refers to the lowest possible concentration of troponin that can reliably be differentiated from LoB. Limit of quantification (LoQ) refers to the lowest troponin concentration reported by a particular laboratory, and this may or may not correlate with LoD. Delta refers to a clinically significant change in troponin levels measured over fixed intervals which is used to identify myocardial injury, even if troponins are in the <99th percentile. The hscTn assays analyze troponin as a continuous variable, rather than a fixed value.

What is High Sensitivity? An hscTn assay should be able to detect low concentrations of troponins and should have high sensitivity and precision. The Internal Federation of Clinical Chemistry (IFCC) Task Force on Cardiac Bio-Markers defines hscTn assays as: having a total imprecision (CoV) ≤10% at the 99 th percentile; and being able to measure cTn above the LoD in ≥50% of healthy subjects. 4,13 The hscTn assays have increased analytical sensitivity and reduced variability, which facilitates integration into clinical pathways.7 Therefore, hscTn assays should be able to measure troponins consistently and accurately in a majority of healthy individuals (who have very low concentrations) with negligible variability. Multiple factors affect hscTn assay results, including age, sex, standardization of methods and specimen type, and these should be considered while reporting absolute values. As an example, men usually have a slightly higher value than women.6,13 Also, patients aged over 60 years have relatively higher troponin at baseline.14 The IFCC recommends establishing the 99th percentile for any particular assay using appropriate statistical power, which requires a minimum of 300 male and 300 female patients.

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Algorithms Using High-sensitivity Troponin Assays At least four protocols are worth discussing: • rule-out strategies using hscTn; • accelerated protocol with serial repeat hscTn assays for rule-out/ rule-in; • hscTn combined with risk scores; and • single hscTn measurement.

Rule-out Strategies Using hscTn: Absent Troponin at Presentation As hscTn assays measure very low troponin values, it makes sense that a one-time troponin assay should be able to exclude ACS with a very high clinical diagnostic accuracy (negative predictive value). A number of studies have shown that a low concentration of troponin levels using hscTn assays, below the LoD or LoB, has a very high negative predictive value (Table 2).15–20 Troponin levels lower than LoD values can exclude ACS with >99% confidence according to published meta-analyses.21,22 However, unstable angina cannot be ruled out with this approach.23 The FDA does not allow reporting troponin levels below 6 ng/dl, which is greater than both the LoD and the LoB for the Roche hscTn assay. This technically prevents patients being discharged from ED on the basis of on a single low concentration hscTn and opinions on this issue have been mixed.24 Of note, low troponin values below the LoD may have a lower sensitivity, so the ESC guidelines recommend re-testing >3-hour symptom onset before presentation when troponin values are less than the LoD.25 There are a few unanswered questions with this approach including: should the test be done on all patients or only those with nonischemic EKGs? Should LoB or LoD be used? Will the test maintain CoV <10% at such low level troponins?

Accelerated Protocol with Serial Repeat hscTn Assays for Rule-in/Rule-out Most centers in the US use longer troponin rule-out algorithms.26,27 However, the 2015 ESC guidelines give a class I recommendation for 0/1-hour hscTn protocol.7 A few 1- and 2-hour algorithms use hscTn.28–31 The presence of serial, dynamic hscTn promotes an early rule-in ACS with higher specificity whereas the absence of serial hscTn elevation promotes early rule-out ACS with high sensitivity.4,32,33 It is important

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High-sensitivity Troponins in ACS Table 1: Relevant Approved High-sensitivity Troponin Assays Name

Assay type

Limit of blank

Limit of detection

99th percentile

10% CoV

ARCHITECT STAT Troponin I® (Abbott)

Troponin I

1.3 ng/l

1.9 ng/l

26 ng/l

4.7 ng/l

Access hs-cTnI® (Beckman Coulter)

Troponin I

1.7 ng/l

2.3 ng/l

17 ng/l

5.6 ng/l

Elecsys® (Roche Diagnostics)

Troponin T

3 ng/l

5 ng/l

14 ng/l

13 ng/l

HscTnI ADVIA® Centaur (Siemens)

Troponin I

0.9 ng/l

2.2 ng/l

47 ng/l

9 ng/l

CoV = coefficient of variation; hscTn = high-sensitivity troponin. Source: Andruchow et al. 2018. Reproduced with permission from Elsevier.

to remember that dynamic troponin elevation does not confirm ACS as it could indicate MI. In addition, an absolute increase in troponin concentration has been shown to have a higher diagnostic accuracy than relative changes in troponins.34

High-sensitivity Cardiac Troponin with Risk Scores A few studies have examined the use of EKG, hscTn, and clinical risk prediction scores at some centers.35–40 Most of these covered accelerated diagnostic protocols combining some risk scores, most commonly Thrombolysis in Myocardial Infarction (TIMI). Data on what would be the most appropriate risk score and the ideal troponin assay to use are still limited. Future studies testing combinations of various test scores with different hscTn assays are essential.

similar sensitivities of >96% and a negative predictive value of >99%, while the 3-hour algorithm appears to have a mildly lower sensitivity but similar negative predictive value.18,51–54 As 1-hour algorithms depend on a small rise in troponin concentration, this may carry a risk of missing an ACS. Therefore, the 2-hour repeat strategy seems to be the most reasonable approach, even though guidelines do not support one over the other. As mentioned above, using risk scores, including the Global Registry of Acute Coronary Events (GRACE) or History, ECG, Age, Risk factors and Troponin (HEART) score, along with the hscTn assay could help to improve the sensitivity of analysis. The HEART score seems to be preferred above other risk scores.55 Nevertheless, to avoid unsafe early discharges in patients with evolving ACS, it is essential to consider the overall picture including serial EKGs and risk assessment tools.

Single High-sensitivity Cardiac Troponin at Presentation The concept of selecting a threshold for hscTn based on clinical need rather than the analytical ability of the test has been emerging recently, as shown in the High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome (High-STEACS) study.41 The investigators did not use the LoD or LoB cut-offs, but rather they used a fixed cut-off of 5 ng/l to safely discharge patients with possible ACS. The study showed a negative predictive value of 99.6% for the primary outcome of index MI, subsequent MI, or early cardiac mortality.

Interpreting Elevated Troponin at Presentation Any degree of troponin elevation, irrespective of etiology, is associated with a poor prognosis.42–45 That said, troponin values five times the normal have been shown to be associated with poor outcomes in ACS with an estimated positive predictive value of 90% and a specificity of >95%. Serial troponin rise is important to define MI, so stable elevated values over a period of time should be investigated for the presence of possible macrocomplexes, even while using hscTn assays.46

To summarize, there are at least six algorithms. The 0/3-hour algorithm from the European guidelines and the 2–hour advanced diagnostic pathway use risk score prediction tools whereas the 0/2-hour, 0/1hour ESC, modified 0/1-hour ESC and the current US state-of-the-art algorithms (6- and 12-hour troponins) do not include risk prediction tools. While implementing the early rule-in/rule-out algorithms, it is essential to make sure that the patient has had chest pains for at least 3 hours before presentation, or an evolving ACS may be missed, and an erroneous early discharge made. While using these algorithms, patients should be involved in shared decision making, especially where there is a low likelihood of ACS and the patient cannot stay longer because of other reasons. In such cases, it is essential to advise the patient regarding the risks and to establish an outpatient follow-up within a reasonable amount of time.

Type I Versus Other Types of Myocardial Injury What is the Ideal Time to Repeat Troponin Assays? In patients with symptoms suggestive of ACS, it is recommended that an initial troponin should be taken at presentation, followed by a second sample obtained at a fixed time interval between 1 and 3 hours. The idea behind obtaining a second troponin with the hscTn assay is to identify clinically significant changes in troponin levels, both relative and absolute. Since small relative changes in troponin elevations could be related to the analytical errors of the test itself, it is recommended that absolute rather than relative changes in troponin levels are used.47–49 A number of studies have compared the efficacy of 1-, 2-, and 3-hour repeat troponins. Studies have shown that 1- and 2-hour algorithms carry

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An ideal troponin assay should not only identify a possible myocardial injury but also help practitioners to understand the pathophysiology of MI. Differentiating whether an MI is a true type I MI secondary to a plaque rupture causing a type I MI, or various other mimics of plaque rupture including but not limited to cardiomyopathy, myocarditis, pulmonary embolism with right heart strain, hypertensive emergency, coronary vasospasm, stress cardiomyopathy, or demand ischemia.56 Knowing this is important when deciding the next step in patient care and to avoid unnecessary investigations and anxiety. Unfortunately, most troponin assays, including hscTn, cannot be used to differentiate between different types of MI using one absolute value. This could be related to the various cut-off values for the different algorithms

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Interventional Cardiology: Coronary Table 2: Rapid Rule-in/Rule-out Algorithm with Undetectable Troponin at Presentation Study

Troponin

Assay

Cut-off Value

ECG exclusions

Number (%)

Study Endpoint

NPV (%)

Meeting Inclusion Criteria Bandstein et al. 201417

Roche hscTnT

Elecsys (Roche Diagnostics)

<5 ng/l (LoD)

Patients with initial electrocardiographic changes indicating MI were excluded

8,907/14,636 (61%) Acute MI (30 days)

99.8

Acute MI (1 year)

99.4

Death (30 days)

100

Death (1 year)

99.6

Roche hscTnT

Elecsys (Roche Diagnostics)

<3 ng/l (LoB)

None specified

195/703 (28%)

Index hospitalization acute MI

100

Body et al. 201566

Roche hscTnT

Elecsys (Roche Diagnostics)

3 ng/l (LoB)

None

24/463 (5.2%)

Acute MI

100

Major adverse cardiac events

100

Acute MI

100

Major adverse cardiac events

100

Acute MI

Major adverse cardiac events – 30 days

Acute MI

100

Major adverse cardiac events

100

Fatal or nonfatal acute MI within 30 days (including index visit)

100

Major adverse cardiac events – 30 days (including index visit)

98.6

Fatal or nonfatal acute MI within 30 days (including index visit)

100

Major adverse cardiac events – 30 days (including index visit)

98.9

Body et al. 2011

3 ng/l (LoB)

5 ng/l (LoD)

Carlton et al. 201567

Roche hscTnT

Elecsys (Roche Diagnostics)

3 ng/l (LoB)

Nonischemic electrocardiogram

22/463 (4.8%)

None

96/463 (20.7%)

Nonischemic electrocardiogram

80/463 (17.3%)

Excluded if present: ST-segment elevation MI or left bundle branch block not known to be old, electrocardiographic changes diagnostic of ischemia and arrhythmias

73/922 (7.9%)

5 ng/l (LoD)

270/922 (29.3%)

Chenevier-Gobeaux et al. 201619

Roche hscTnT

Elecsys (Roche Diagnostics)

3 ng/l (LoB)

Excluded ST-segment elevation MI

45/413 (11%)

Non-ST elevation MI

99.3

Reichlin et al. 20098

Roche hscTnT

Elecsys (Roche Diagnostics)

2 ng/l (LoD)

None specified

718 consecutive patients

Acute MI

100

Rubini Gimenez et al. 201368

Roche hscTnT

Elecsys (Roche Diagnostics)

5 ng/l (LoD)

None specified

550/2,072 (26.5%)

Acute MI

98.4

Siemens hscTnI

HscTnI ADVIA® Centaur (Siemens)

0.5 ng/l (LoD)

None specified

164/1,180 (13.9%)

Acute MI

98.8

Beckman Coulter hscTnI

Access hs-c TnI® (Beckman Coulter)

2 ng/l (LoD)

None specified

132/1,151 (11.5%)

Acute MI

99.2

Abbott hscTnI

ARCHITECT STAT Troponin I® (Abbott)

1.9 ng/l (LoD)

None specified

198/1,567 (12.6%)

Acute MI

100

Abbott hscTnI

ARCHITECT STAT Troponin I (Abbott)

1.9 ng/l (LoD)

ST-segment elevation MI excluded.

444/1,631 (27%)

Acute MI

99.6

Abbott hscTnl

ARCHITECT STAT Troponin I (Abbott)

<5 ng/l (HighSTEACS)

ST-segment elevation MI excluded.

812/1,631 (50%)

Acute MI

98.9

Roche hscTnT

Elecsys (Roche Diagnostics)

<5 ng/l (LoD)

ST-segment elevation MI excluded

160/478 (33%)

Acute coronary syndrome

Non-ST-elevation MI

100

Unstable angina

Sandoval et al. 201769

Thelin et al. 201523

LoB = limit of blank; LoD = limit of detection; NPV = negative predictive value.

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High-sensitivity Troponins in ACS and so practitioners are left with to depend on serial troponin (whether a 1-hour or 6-hour repeat) and serial EKG changes. Even in the current era of hscTn, differentiating between various types of MIs continues to be a challenge. However, hscTn has be shown to diagnose fewer MIs than conventional troponins, so is less likely to give false-positive results for other types of MI.57

The Indeterminate Grey Zone A limitation of using hscTn is there is a subgroup of patients who clearly do not fit into the rule-in or the rule-out algorithms. About 15–40% of patients fall into an indeterminate grey zone.30,50,58,59 These patients have an intermediate to a high risk of having a cardiac event, including death, with an ACS incidence of 5–20%.30,50,52,58,59 The ESC guidance document recommends using clinical judgement while dealing with patients in this grey zone.60 This focuses on patients: • w ho experience typical symptoms but have hscTn less than the 99th percentile; • who experience typical symptoms with hscTn less than the 99th percentile but at least above LoD; • who experience typical symptoms with hscTn greater than the 99th percentile but without any dynamic change in levels during repetition; and • who experience typical symptoms with hscTn greater than the 99th percentile and with dynamic change in the levels during repetition but without any acute coronary pathology including rupture, erosion or dissection. This involves reviewing previous medical records for chronic hscTn elevations, performing serial EKGs, repeating hscTn at a fixed time interval, and using a risk prediction tool (preferably the HEART score). This helps to classify patients who fall into this grey zone as low, intermediate and high risk.

wens PL, Barrett ML, Gibson TB, et al. Emergency department O care in the United States: a profile of national data sources. Ann Emerg Med 2010;56:150–65. https://doi.org/10.1016/j. annemergmed.2009.11.022; PMID: 20074834. Thygesen K, Mair J, Giannitsis E, et al. How to use highsensitivity cardiac troponins in acute cardiac care. Eur Heart J 2012;33:2252–7. https://doi.org/10.1093/eurheartj/ehs154; PMID: 22723599. Thygesen K, Mair J, Katus H, Plebani M, Venge P, Collinson P, et al. Recommendations for the use of cardiac troponin measurement in acute cardiac care. Eur Heart J 2010;31:2197– 204. https://doi.org/10.1093/eurheartj/ehq251; PMID: 20685679. Apple FS, Jaffe AS, Collinson P, et al. IFCC educational materials on selected analytical and clinical applications of high sensitivity cardiac troponin assays. Clin Biochem 2015;48:201–3. https://doi.org/10.1016/j.clinbiochem.2014.08.021; PMID: 25204966. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; ESC Scientific Document Group. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019; 40:237–269. https://doi.org/10.1093/eurheartj/ehy462; PMID: 30165617. Apple FS, Ler R, Murakami MM. Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin Chem 2012;58:1574–81. https://doi.org/10.1373/clinchem.2012.192716; PMID: 22983113. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J

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10.

11.

12.

13.

14.

Age- and Sex-specific Algorithms At least four clinical variables correlate with outcomes in patients with ACS including age, sex, time of chest pain onset and renal dysfunction. Three algorithms have been proposed. The first incorporates all four parameters, but is not commonly used. The second algorithm uses sex-specific cut-offs but does not account for renal dysfunction and age; this is because previous studies have shown that women presenting with ACS are older than men by almost 5–8 years on average.61–63 Female sex is usually associated with relatively lower troponin, but the age factor compensates well for the troponin difference without the need for using age-adjusted cut-off values (the higher age in women increases their troponin levels and corrects the age difference). However, using only sex-specific cut-off values reclassifies only a few patients into a different risk category compared to uniform cutoff criteria.61,64 The third model, recommended by the ESC guidelines, uses uniform cut-off values for all patients without accounting for age, sex, or renal function.7 Further research on the effect of these confounder variables on hscTn assays is essential.

Conclusion HscTn is clearly a significant advance in the early and accurate diagnosis of ACS and has the potential to improve patient outcomes through early, appropriate evidence-based interventions. In patients who do not have ACS, it helps to rule out MI and helps to discharge patients early, thus reducing patient anxiety, unnecessary admissions and costs. It is important to understand how to interpret hscTn results because they differ from conventional troponin assays. In addition, there is an intermediate zone where it is difficult to rule in or rule out MI. Until further evidence becomes available, clinicians should combine hscTn with appropriate risk prediction tools. The importance of shared decision making and clinical judgement should never be underestimated.

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https://doi.org/10.1136/heartjnl-2015-308505; PMID: 26955848. 54. C hapman AR, Anand A, Boeddinghaus J, et al. Comparison of The efficacy and safety of early rule-out pathways for acute myocardial infarction. Circulation 2017;135:1586–96. https://doi. org/10.1161/CIRCULATIONAHA.116.025021; PMID: 28034899. 55. Six AJ, Cullen L, Backus BE, Greenslade J, et al. The HEART score for the assessment of patients with chest pain in the emergency department: a multinational validation study. Crit Pathw Cardiol 2013;12:121–6. https://doi.org/10.1097/ HPC.0b013e31828b327e; PMID: 23892941. 56. Body R, Carlton E. Understanding cardiac troponin part 1: avoiding troponinitis. Emerg Med J 2018;35:120–5. https://doi. org/10.1136/emermed-2017-206812; PMID: 28784609. 57. Sandoval Y, Smith SW, Schulz KM, Murakami MM, Love SA, Nicholson J, et al. Diagnosis of type 1 and type 2 myocardial infarction using a high-sensitivity cardiac troponin I assay with sex-specific 99th percentiles based on the third universal definition of myocardial infarction classification system. Clin Chem 2015;61:657–63. https://doi.org/10.1373/ clinchem.2014.236638; PMID: 25672334. 58. Mueller C, Giannitsis E, Christ M, et al. Multicenter evaluation of a 0–hour/1–hour algorithm in the diagnosis of myocardial infarction with high-sensitivity cardiac troponin T. Ann Emerg Med 2016;68:76–87.e4. https://doi.org/10.1016/j. annemergmed.2015.11.013; PMID: 26794254. 59. Pickering JW, Greenslade JH, Cullen L, et al. Assessment of the European Society of Cardiology 0–hour/1–hour algorithm to rule-out and rule-in acute myocardial infarction. Circulation 2016;134:1532–41. https://doi.org/10.1161/ CIRCULATIONAHA.116.022677; PMID: 27754881. 60. Katus H, Ziegler A, Ekinci O, et al. Early diagnosis of acute coronary syndrome. Eur Heart J 2017;38:3049–55. https://doi. org/10.1093/eurheartj/ehx492; PMID: 29029109. 61. Rubini Gimenez M, Twerenbold R, Boeddinghaus J, et al. Clinical effect of sex-specific cutoff values of high-sensitivity cardiac troponin T in suspected myocardial infarction. JAMA Cardiol 2016;1:912–20. https://doi.org/10.1001/jamacardio.2016.2882; PMID: 27653005. 62. Cullen L, Greenslade JH, Carlton EW, et al. Sex-specific versus overall cut points for a high sensitivity troponin I assay in predicting 1–year outcomes in emergency patients presenting with chest pain. Heart. 2016;102:120–6. https://doi.org/10.1136/ heartjnl-2015-308506; PMID: 26729608. 63. Shah AS, Griffiths M, Lee KK, et al. High sensitivity cardiac troponin and the under-diagnosis of myocardial infarction in women: prospective cohort study. BMJ 2015;350:g7873. https:// doi.org/10.1136/bmj.g7873; PMID: 25609052. 64. Mueller-Hennessen M, Lindahl B, Giannitsis E, et al. Diagnostic and prognostic implications using age- and gender-specific cutoffs for high-sensitivity cardiac troponin T – sub-analysis from the TRAPID-AMI study. Int J Cardiol 2016;209:26–33. https://doi. org/10.1016/j.ijcard.2016.01.213; PMID: 26878470. 65. Andruchow JE, Kavsak PA, McRae AD. Contemporary emergency department management of patients with chest pain: a concise review and guide for the high-sensitivity troponin era. Can J Cardiol 2018;34:98–108. https://doi.org/10.1016/j. cjca.2017.11.012; PMID: 29407013. 66. Body R, Burrows G, Carley S, et al. High-sensitivity cardiac troponin t concentrations below the limit of detection to exclude acute myocardial infarction: a prospective evaluation. Clin Chem 2015;61:983–9. https://doi.org/10.1373/ clinchem.2014.231530; PMID: 25979953. 67. Carlton EW, Cullen L, Than M, Gamble J, Khattab A, Greaves K. A novel diagnostic protocol to identify patients suitable for discharge after a single high-sensitivity troponin. Heart 2015;101(13):1041-6. https://doi.org/10.1136/ heartjnl-2014-307288; PMID: 25691511. 68. Rubini Giménez M, Hoeller R, Reichlin T, et al. Rapid rule out of acute myocardial infarction using undetectable levels of highsensitivity cardiac troponin. Int J Cardiol. 2013;168(4):3896-901. https://doi.org/10.1016/j.ijcard.2013.06.049; PMID: 23876467. 69. Sandoval Y, Smith SW, Thordsen SE, et al. Diagnostic performance of high sensitivity compared with contemporary cardiac troponin i for the diagnosis of acute myocardial infarction. Clin Chem 2017;63:1594–604. https://doi.org/10.1373/ clinchem.2017.272930; PMID: 28701316.

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Interventional Cardiology: Coronary

Percutaneous Coronary Intervention: Developments in the Last 12 Months Rhian E Davies, DO, and J Dawn Abbott, MD Division of Cardiology, Rhode Island Hospital, Brown Medical School, Providence, RI

Abstract In 2018, there were several studies that significantly added to the field of interventional cardiology. Research was focused on understanding the role of percutaneous coronary intervention (PCI) in various clinical syndromes, optimizing outcomes for high-risk lesion subsets, and building an evidence base for greater adoption of PCI guided by physiology and intracoronary imaging. In the area of innovation, novel and iterative developments in drug-eluting stents (DES) and scaffold platforms were compared with current generation DES. This article summarizes the research from last year which has had the most impact on PCI techniques and clinical care.

Keywords Angina, cardiogenic shock, drug-eluting stent, bifurcation, restenosis, intracoronary imaging, coronary physiology Disclosure: J Dawn Abbott has research grants with no direct compensation from SINOMED, Biosensors USA, Abbott Vascular, AstraZeneca and Bristol-Myers Squibb. RD has no conflicts of interest to declare. Received: January 16, 2019 Accepted: February 4, 2019 Citation: US Cardiology Review 2019;13(1):11–5. DOI: https://doi.org/10.15420/usc.2019.1.1 Correspondence: J Dawn Abbott, Department of Medicine, Division of Cardiology, Warren Alpert Medical School of Brown University, 593 Eddy Street, RIH APC814, Providence, RI 02903. E: JAbbott@Lifespan.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Percutaneous Coronary Intervention for Clinical Syndromes Stable Angina The primary benefit of percutaneous coronary intervention (PCI) over medical therapy in patients with stable angina is the improved quality of life. The PCI in stable angina (ORBITA) trial was the first sham-controlled trial of PCI where 200 medically optimized patients with single vessel disease were randomized to PCI or placebo procedure.1 The trial failed to show a benefit of PCI at 6 weeks in the primary endpoint of exercise treadmill time or secondary endpoints of patient-centered outcomes. Limitations of the trial included high exercise time and low ischemic burden at baseline and a short follow-up period.1 The effect of medications and the uncertainty of stent treatment may have also influenced exercise time. The landmark trial, however, showed similar short-term outcomes in both study groups, and its findings support shared decision making and a conservative approach in patients with stable angina and similar risk profiles to those in the trial.

Cardiogenic Shock Holger et al. reported the 1-year outcomes of the randomized Culprit lesion only PCI versus multi-vessel PCI in Cardiogenic Shock (CULPRITSHOCK) trial.2 The primary endpoint at 30 days favored the culprit-only approach, with significantly lower rates of the composite of death or renal-replacement therapy (45.9% versus 55.4%, p=0.01).2 At 1 year follow-up, there was a trend towards lower risk of the composite of death and recurrent infarction in the culprit-only group (relative risk 0.87; 95% CI: 0.76–1.00) that did not reach statistical significance. In addition,

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rates of repeat revascularization (32.3% versus 9.4%; relative risk 3.44; 95% CI [2.39–4.95]), and rehospitalization for heart failure occurred more frequently in the culprit-only group.2 The 1-year results support a culprit-only approach in the acute setting for MI with cardiogenic shock, however, when patients stabilize and their risk of acute kidney injury is lower, ischemia-guided or complete revascularization to prevent subsequent unplanned revascularization or admissions may improve long-term outcomes in this high-risk patient cohort. Unloading the left ventricle (LV) with mechanical support before revascularization in acute ST segment elevation MI (STEMI) has also been under investigation. The theory is that unloading will limit infarct size and translate into lower mortality. The recent multi-center, prospective, randomized trial by Kapur et al. demonstrated feasibility of implantation of the Impella CP device (Abiomed) in STEMI with a mean longer door to balloon time of 25 minutes, with no difference in clinical outcomes or infarct size.3 A larger pivotal trial to compare pre-reperfusion unloading to the standard of care is needed before implementing a change in clinical practice.

Out-of-hospital Cardiac Arrest The optimal timing of cardiac catheterization in patients with outof-hospital cardiac arrest (OHCA) of presumed cardiac cause but without STEMI is unknown. The French Registry for OHCA evaluated the association between an immediate invasive strategy and survival in a cohort of 1,410 patients, according to their cardiac arrest hospital prognosis score.4 This score is calculated from: age, setting

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Interventional Cardiology: Coronary or arrest, initial rhythm, duration from collapse to basic life support and from basic life support to return of spontaneous circulation, pH and epinephrine dose.4 They observed higher rates of early coronary angiography in patients with better predicted prognosis (a low-risk score) and an overall survival rate at hospital discharge of 32%.4 An immediate invasive strategy was independently associated with better survival in low-risk patients (OR: 2.3, 95% CI [1.4–3.9]; p=0.001), but not in medium-risk (p=0.55) and high-risk (p=0.43) patients.4 This suggests that, until randomized data are available, immediate coronary angiography in OHCA upon arrival to the hospital should focus on patients with preserved neurological status.4

Coronary Lesion Subsets Chronic Total Occlusions New techniques and equipment has accelerated interest in chronic total occlusions (CTO). The CrossBoss First trial was a multicenter, randomized-controlled trial that compared upfront use of the CrossBoss microcatheter (Boston Scientific) versus standard wire escalation for antegrade CTO crossing.5 This study included 246 patients and showed no difference in procedural success, procedure time or equipment cost suggesting that either approach is reasonable. Werner et al. performed a randomized trial in 396 patients to assess symptomatic improvement with CTO PCI. Patients were randomized 2:1 to CTO PCI or optimal medical therapy.6 At 1 year there was a greater improvement in the patients’ Seattle Angina Questionnaire scores and they were free from angina with PCI (p=0.003).6 Additionally, those who underwent PCI were found to have an improved overall quality of life (p=0.007).6 This study suggests that an objective assessment of angina burden and quality of life in CTO patients may identify those with the greatest potential to benefit from revascularization.

Bifurcations At the end of 2017, the Double Kissing Crush (DK Crush) V trial was published. This randomized trial of unprotected distal left main coronary artery (UPLM) bifurcation lesions compared a planned two-stent strategy (PS) with a double kissing crush technique versus provisional stenting in 482 patients.7 In order to participate, operators needed to demonstrate competence in the performance of a minimum of 3–5 DK crush cases and perform 300 PCIs per year for 5 years, including at least 20 LM PCIs per year.7 Target lesion failure at 1 year was significantly lower in the DK crush group (5.0% versus 10.7%; HR 0.42; 95% CI [0.21–0.85]; p=0.02).7 In the 13-month angiographic follow up, the rates of in-stent restenosis (ISR) in the main vessel was similar between the PS and DK Crush subgroups.7 However, the rate of ISR at the ostium of the side branch was 12% with PS versus 5.0% in the DK crush (p=0.09) group, further supporting the use of DK Crush for UPLM bifurcation lesions.7

protection devices.8 Patients were randomized 1:1 to BMS or DES for de novo SVG stenosis of 50–99% in grafts 2.25–4.5 mm in diameter.8 Randomization was stratified by presence of diabetes and number of lesions.8 At 12 months, the incidence of target vessel failure was 17% in the DES group versus 19% in the BMS group (adjusted HR 0.92, 95% CI [0.63–1.34], p=0.70).8 The 5-year results of the Efficacy Study of Drug-Eluting and Bare Metal Stents in Bypass Graft Lesions (ISAR-CABG) study, which randomized 610 patients to first generation DES versus BMS for SVG stenosis, showed no difference in the primary endpoint of death, MI, or target lesion revascularization (HR 0.98, 95% CI [0.79–1.23]; p=0.89).9 Although the 1-year outcomes favored DES with significantly lower target lesion revascularization, there was a twofold higher risk during years one to five that negated the initial benefit.9 The mechanism of late DES failure is unclear but it is maybe due to inadequate suppression of neointimal hyperplasia or early neoatherosclerosis. Further investigation is needed to determine the optimal approach to PCI in patients with SVG disease. At present, PCI with either BMS or DES is an acceptable choice for SVG PCI, however, the studies were not powered to assess SVG subgroups in which DES may confer a benefit or harm. An additional consideration is to perform native vessel PCI for SVG failure when it is a feasible option.

Thrombus-containing Lesions Primary PCI in STEMI is high risk due to thrombus and potential for no reflow. While earlier studies showed a benefit of manual thrombus aspiration on procedural outcomes, large randomized trials demonstrated that routine use of aspiration thrombectomy had no benefit on mortality. A meta-analysis by Jolly et al. evaluated the use of thrombus aspiration during primary PCI.10 Randomized controlled trials, including at least 1,000 patients comparing manual thrombectomy and PCI alone in patients with STEMI were included. Routine thrombus aspiration did not improve clinical outcomes. However, in the subset with high thrombus burden, the trend towards a reduction in cardiovascular death were balanced by an increased risk of stroke or transient ischemic attack.10 The meta-analysis supports the current guideline recommendation against routine use of aspiration in STEMI.11

Calcified Lesions Calcified coronary lesions increase PCI complexity and complications. Intravascular lithotripsy (IVL) has recently been approved in Europe for severely calcified lesions. It uses sonic pressure waves locally to effectively fracture both intimal and medial calcium in the artery wall without damage to surrounding soft vascular tissue.12 The Shockwave Coronary Lithoplasty® (DISRUPT CAD II; NCT03328949) post-market study is currently recruiting in Europe, to study IVL technology in calcified coronary lesions.

Saphenous Vein Graft Interventions Acute procedural complications and risk of target vessel failure of PCI for saphenous vein graft interventions (SVG) lesions has led interventionalists to consider native vessel over SVG PCI when feasible. In 2018, two studies were published that questioned the efficacy of drug-eluting stents (DES) compared with bare metal stents (BMS) for saphenous vein graft (SVG) interventions. The Drug-Eluting Stents vs. Bare Metal Stents In Saphenous Vein Graft Angioplasty (DIVA) trial, a double-blind, randomized trial at Veterans Affairs centers, focused on SVG PCI with planned embolic

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In-stent Restenosis The optimal management of DES in-stent restenosis (ISR) is controversial. The Restenosis Intra-stent of Drug-eluting Stents: Paclitaxel-eluting Balloon versus Everolimus-eluting Stent (RIBS IV) trial randomized patients with DES ISR to either a paclitaxel-eluting balloon (DEB) or everolimus-eluting stent (EES). At 3 years, cardiac death, MI and target lesion revascularization was significantly lower in the EES arm (12.3% versus 20.1%; p=0.04).13 However, the Drug-eluting bAlloon for in-stent

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Percutaneous Coronary Intervention in 2018 Restenosis (DARE) trial, a non-inferiority study comparing DEB and DES for ISR (56% with DES-ISR) showed similar rates of target lesion revascularization at 12 months with DES (7.1% versus DEB 8.8%; p=0.65).14 Therefore, it is reasonable to consider use of DEB instead of DES in ISR, when available, reserving additional layers of DES in case of DEB failure.

Physiology and Image Guidance Physiology-guided Percutaneous Coronary Intervention The DEFINE REAL study added to available data on management of multivessel disease. This study included 484 patients with multivessel coronary artery disease of at least 40% stenosis by visual assessment on coronary angiography.15 Operators were asked to define their initial management plan based on diagnostic angiography.14 Subsequent invasive physiology was performed with either instant wave-free ratio (iFR) or fractional flow reserve (FFR) and a final management plan was developed. There was two- and three-vessel disease present in 73.3% and 26.7% of patients, respectively. Lesions investigated were intermediate with median percentage stenosis (60%), median FFR (0.84), and median iFR (0.92).15 Reclassification of overall management increased with the number of vessels investigated (one vessel: 37.3%; two vessels: 45.0%; three vessels: 66.7%; p=0.002) and incorporating iFR in the decision process was associated with investigation of more vessels (p=0.04) and higher reclassification (p=0.0001).15 This study demonstrates that coronary artery disease management changes dramatically when decisions are based on physiologic data added to anatomic data. The 5-year outcomes of the Fractional flow reserve versus Angiography for Multivessel Evaluation (FAME-2) trial was published in 2018, demonstrating continued benefit of PCI compared with medical therapy in patients with FFR <0.8.16 The rate of the primary endpoint of death, MI or urgent revascularization was lower in the PCI group than in the medical therapy group (13.9% versus 27.0%; p<0.001).17 There were no significant differences between the PCI group and the medical therapy group in the rates of death or MI.16 Relief from angina was more pronounced after PCI compared with medical therapy.17 This trial supports the role of PCI for improving symptoms of angina and the need for urgent revascularization over medical therapy alone. There are several physiologic measures that can be used to guide PCI. A meta-analysis of 23 studies involving 6,381 cases of stenosis comparing iFR to FFR was published in 2018 by De Rosa et al.18 They found the two indices were highly correlated (0.798 [0.78–0.82]; p<0.001). In a pooled per protocol population (n=4,486) of the Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularization (DEFINE-FLAIR) trial and Instantaneous Wave-Free Ratio Versus FFR in Patients With Stable Angina Pectoris or ACS (iFR-SWEDEHEART) trial, Escaned et al. evaluated the safety of deferral of coronary revascularization in FFR compared to iFR.19 Coronary revascularization was deferred in 2,130 patients and deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group.19 Despite the higher rate of deferral in the iFR group, at 1 year the composite of all-cause death, non-fatal MI or unplanned revascularization in the deferred population was low (4%) and similar between the iFR and FFR groups.19 Additionally, if patients who presented with acute coronary syndrome were deferred, they had a significantly increased event rate when compared with those with stable

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angina at 1 year.19 These studies support the use of either measure for routine use in PCI.

Image-guided Percutaneous Coronary Intervention The use of intracoronary imaging modalities was investigated in a large observational study involving 87,166 PCI patients from 2005 to 2015. Use of optical coherence tomography (OCT) compared with PCI with angiography alone, was associated with longer stent length. After propensity matching, mortality was lower in procedures with OCT (HR 0.39 [0.021–0.77]) but not different in OCT versus intravascular ultrasound (IVUS)-guided PCI (HR 0.88 [0.061–1.38]). 16 Overall, this observational study supports the use of imaging, including IVUS or OCT, to guide PCI.

Devices Drug-eluting Stents In 2018, there were several reports of long-term outcomes of randomized clinical trials investigating the current generation of durable polymer DES. In the DUrable polymer-based sTent CHallenge of Promus ElemEnt versus ReSolute integrity (DUTCH PEERS TWENTE II) trial, which enrolled 1,811 all-comers to zotirolimus versus everolimuseluting stents, 5-year incidence of target vessel failure (13.2% versus 14.2%) and definite or probable stent thrombosis were similar (1.5% versus 1.3%).20 The 5-year outcomes for the Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions (PLATINUM), was also reported.21 This trial randomized 1,530 patients to the platinum-chromium everolimus-eluting stent (PtCr-EES) versus the cobalt-chromium everolimus-eluting stent (CoCrEES) and demonstrated comparable safety and effectiveness with target lesion failure rates of 9.1% versus 9.3%, respectively (HR: 0.97; p=0.87). There were low rates of stent thrombosis and other adverse events.21 The 5-year outcomes were also acceptable in subgroup analysis for vessels that were <2.50 mm and lesions longer than 24 mm in length when treated with PtCr-EES.21 In this trial, the metal alloy did not influence PCI outcome.21 These results show excellent efficacy and safety of the current generation DES used in clinical practice and serve as a comparator for newer DES that are being developed. There have been several randomized clinical trials which showed promising results regarding bioresorbable polymer DES (Table 1). Among these was MiStent SES Versus the XIENCE EES Stent (DESSOLVE III), where the sirolimus-eluting bioabsorbable polymer stent (MiStent, Stentys) was compared with an everolimus-eluting durable polymer stent (EES) and found to be non-inferior at 12 months.22 A Study to Evaluate the Efficacy and Safety of BuMA Supreme Drug Eluting Stent (DES) (RCT) (PIONEER-II) was a non-inferiority trial that compared the BuMA Supreme bioresorbable polymer SES versus a contemporary durable polymer zotarolimus-eluting stent (ZES) in terms of angiographic in-stent late lumen loss at 9-month follow-up as the primary endpoint. At the 9-month follow-up, this primary endpoint was not met.23 PIONEER III, which is powered for clinical endpoints, is currently enrolling. The Harmonized Assessment by Randomized Multicentre Study of OrbusNEich’s Combo StEnt (HARMONEE) study incorporated the use of OCT. This was a randomized trial comparing EES versus OrbusNeich’s

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Interventional Cardiology: Coronary Table 1: Bioresorbable Polymer Drug Eluting Stent Trials of 2018 Study

Devices

Endpoints

Event rates

MiStent (sirolimus BRP) (Stentys) versus Xience EES (Abbot Vascular)

DOCE 12 months

5.8% versus 6.5% (−0.8% 95% CI [−3.3–1.8], p non-inferiority=0.0001)

PIONEER II23

BuMA (sirolimus BRP) (Sino Medical) versus ZES

LLL 9 month

0.29 ± 0.33 mm versus 0.14 ± 0.37 mm (p non-inferiority=0.45)

BIOFLOW II25

Orsiro (sirolimus BRP) (Biotronik) versus Xience EES (Abbot Vascular)

TLF and ST 5 years

10.4% versus 12.7%, p=0.5; 0.7% versus 2.8% p=0.1

Japan USA HARMONEE24

OrbusNEich’s Combo Stent (Sirolimus BRP w anti-CD34+ coating) versus EES

TVF and OCT strut coverage 1 year

7% versus 4.2% (2.8% [95% CI −1.0%, 6.5%] p noninferiority=0.02; 91.3% versus 74.8% p<0.001)

DESSOLVE III

BRP = bioresorbable polymer; DOCE = device oriented composite endpoint; EES = everolimus eluting stent; LLL = late lumen loss; OCT = optical coherence tomography; ST = stent thrombosis; TLF = target lesion failure; TVF = target vessel failure; ZES = zotarolimus eluting stent.

Combo stent, which combined sirolimus and an abluminal BP with a novel endoluminal anti-CD34+ antibody coating designed to capture endothelial progenitor cells and promote healing. The combo stent did demonstrate non-inferiority for 1 year TVF in comparison with EES, with superior strut-based tissue coverage by OCT as a surrogate of EPC capture technology activity.24 Long-term, 5-year outcomes for the Study of the Orsiro Drug Eluting Stent System (BIOFLOW II) study demonstrated similar rates of target lesion failure and stent thrombosis in the Orsiro sirolimus BP stent compared with EES.25

Bioresorbable Vascular Scaffolds The only bioresorbable coronary scaffold (BRS) approved in the US, the ABSORB everolimus-eluting scaffold (Abbot Vascular), was removed from the market in September 2017 for occurrence of very late scaffold thrombosis. Bioresorbable scaffolds continue to be under investigation because of their many promising features. Included among these trials is the randomized comparison of the NeoVas sirolimus-eluting BRS to a metallic EES in 560 patients. Eligible patients had a single de novo native coronary artery lesion with a reference vessel diameter of 2.5 to 3.75 mm and a lesion length ≤20 mm.26 Angiographic follow-up was performed in all patients at 1 year. The primary endpoint was angiographic in-segment 1.

l-Lamee R, Thompson D, Dehbi HM, Sen S, et al. Percutaneous A coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 2018;391:31–40. https://doi. org/10.1016/S0140-6736(17)32714-9; PMID: 29103656. Thiele H, Akin I, Sandri M, et al. One-year outcomes after PCI strategies in cardiogenic shock. N Engl J Med 2018;379:1699–1710. https://doi.org/10.1056/NEJMoa1808788. PMID: 30145971. Kapur NK, Alkhouli MA, DeMartini TJ, et al. Unloading the left ventricle before reperfusion in patients with anterior ST-segment– elevation myocardial infarction. Circulation 2019;139:337–46. https://doi.org/10.1161/CIRCULATIONAHA.118.038269; PMID: 30586728. Bougouin W, Dumas F, Karam N, et al. Should we perform an immediate coronary angiogram in all patients after cardiac arrest? Insights from a large French registry. JACC Cardiovasc Interv 2018;11:249–56. https://doi.org/10.1016/j.jcin.2017.09.011; PMID: 29413238. Karacsonyi J, Tajti P, Rangan BV, et al. Randomized comparison of a CrossBoss first versus standard wire escalation strategy for crossing coronary chronic total occlusions. JACC Cardiovasc Interv 2018;11:225–33. https://doi.org/10.1016/j.jcin.2017.10.023 PMID: 29413236. Werner GS, Martin-Yuste V, Hildick-Smith D, et al. A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. Eur Heart J 2018;39:2484–93. https://doi.org/10.1093/ eurheartj/ehy220; PMID: 29722796. Chen SL, Zhang JJ, Han Y, et al. Double kissing crush versus provisional stenting for left main distal bifurcation lesions: DKCRUSH-V randomized trial. J Am Coll Cardiol 2017;70:2605–17. https://doi.org/10.1016/j.jacc.2017.09.1066; PMID: 29096915. Brilakis ES, Edson R, Bhatt DL, et al. Drug-eluting stents versus

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10.

11.

12.

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late loss (LL), and the major secondary endpoint was the rate of angina. Baseline and follow-up OCT and FFR were performed in a pre-specified subgroup of patients. 1-year in-segment late loss with NeoVas and EES were 0.14 ± 0.36 mm versus 0.11 ± 0.34 mm.26 Additionally at 1 year, the two groups were similar in regards to the rates of recurrent angina.26 OCT at 1 year demonstrated a higher proportion of covered struts, less strut malapposition and a smaller minimal lumen area with NeoVas.26 Non-significant differences were found by FFR among the two groups.26 Longer-term outcomes are needed to determine the incidence of potential late scaffold issues. Future BRS platforms will have thinner struts and potentially more rapid absorption.

Conclusion In 2018, there were advances across the spectrum of interventional cardiology, including the role of PCI in various clinical syndromes, techniques, and outcomes in a high-risk lesion subset, the design of stents, and use of functional and image-guided PCI. The future of PCI will continue to expand through research and bring advancements, including the increasing use of robotics, hemodynamic support, tele-stenting, and artificial intelligence, with the goal of improving and extending the lives of patients who have coronary artery disease.

bare-metal stents in saphenous vein grafts: a double-blind, randomised trial. Lancet 2018;391:1997–2007. https://doi. org/10.1016/S0140-6736(18)30801-8; PMID: 29759512. Colleran R, Kufner S, Mehilli J, et al. Efficacy over time with drugeluting stents in saphenous vein graft lesions. J Am Coll Cardiol 2018;71:1973–82. https://doi.org/10.1016/j.jacc.2018.03.456; PMID: 29724350. Jolly SS, James S, Džavík V, et al. Thrombus aspiration in ST-segment-elevation myocardial infarction: an individual patient meta-analysis: thrombectomy trialists collaboration. Circulation 2017;135:143–52. https://doi.org/10.1161/ CIRCULATIONAHA.116.025371; PMID: 27941066. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/ SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/ AHA Guideline for the Management of ST-Elevation Myocardial Infarction. J Am Coll Cardiol 2016;67:1235–1250. https://doi.org/10.1016/j.jacc.2015.10.005; PMID: 26498666. Intravascular Lithotripsy for coronary artery disease launched in Europe. 2018. Available at: https://cardiovascularnews.com/ intravascular-lithotripsy-for-coronary-artery-disease-launchedin-europe/ (accessed 29 December 2018). Alfonso F, Pérez-Vizcayno MJ, Cuesta J, et al. 3-year clinical follow-up of the RIBS IV clinical trial: a prospective randomized study of drug-eluting balloons versus everolimus-eluting stents in patients with in-stent restenosis in coronary arteries previously treated with drug-eluting stents. JACC Cardiovasc Interv 2018;11:981–91. https://doi.org/10.1016/j.jcin.2018.02.037; PMID: 29798776. Baan J, Claessen BE, Dijk KB, et al. A randomized comparison

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of paclitaxel-eluting balloon versus everolimus-eluting stent for the treatment of any in-stent restenosis: the DARE trial. JACC Cardiovasc Interv 2018;11:275–83. https://doi.org/10.1016/j. jcin.2017.10.024; PMID: 29413242. Van Belle E, Gil R, Klauss V, et al. Impact of routine invasive physiology at time of angiography in patients with multivessel coronary artery disease on reclassification of revascularization strategy: results from the DEFINE REAL study. JACC Cardiovasc Interv 2018; 11:354–65. https://doi.org/10.1016/j.jcin.2017.11.030. PMID: 29471949. Jones DA, Rathod KS, Koganti S, et al. Angiography alone versus angiography plus optical coherence tomography to guide percutaneous coronary intervention. JACC Cardiovasc Interv 2018;11:1313–21. https://doi.org/10.1016/j.jcin.2018.01.274; PMID: 30025725. Xaplanteris P, Fournier S, Pijls NHJ, et al. Five-year outcomes with PCI guided by fractional flow reserve. N Engl J Med 2018;379:250–9. https://doi.org/10.1056/NEJMoa1803538; PMID: 29785878. De Rosa S, Polimeni A, Petraco R, et al. Diagnostic performance of the instantaneous wave-free ratio. Circ Cardiovasc Interv 2018;11:e004613. https://doi.org/10.1161/ CIRCINTERVENTIONS.116.004613; PMID: 29326150. Escaned J, Ryan N, Mejía-Rentería H, et al. Safety of the deferral of coronary revascularization on the basis of instantaneous wave-free ratio and fractional flow reserve measurements in stable coronary artery disease and acute coronary syndromes. JACC Cardiovasc Interv 2018;11:1437–49. https://doi.org/10.1016/j. jcin.2018.05.029; PMID: 30093050. Zocca P, Kok MM, Tandjung K, et al. 5-year outcome following randomized treatment of all-comers with zotarolimus-eluting resolute integrity and everolimus-eluting PROMUS element

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Percutaneous Coronary Intervention in 2018

coronary stents. JACC Cardiovasc Interv 2018;11:462–9. https://doi. org/10.1016/j.jcin.2017.11.031; PMID: 29519378. 21. K elly CR, Teirstein PS, Meredith IT, Farah B, et al. Long-term safety and efficacy of platinum chromium everolimus-eluting stents in coronary artery disease. JACC Cardiovasc Interv 2017;10:2392–400. https://doi.org/10.1016/j.jcin.2017.06.070; PMID: 29217001. 22. de Winter RJ, Katagiri Y, Asano T, et al. A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial. Lancet 2018;391:431–40. https://doi.org/10.1016/S0140-

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6736(17)33103-3; PMID: 29203070. 23. v on Birgelen C, Asano T, Amoroso G, et al. First-in-man randomised comparison of the BuMA Supreme biodegradable polymer sirolimus-eluting stent versus a durable polymer zotarolimus-eluting coronary stent: the PIONEER trial. EuroIntervention 2018;13:2026–35. https://doi.org/10.4244/EIJ-D17-00462; PMID: 28923787. 24. Saito S, Krucoff MW, Nakamura S, et al. Japan-United States of America Harmonized Assessment by Randomized Multicentre Study of OrbusNEich’s Combo StEnt (Japan-USA HARMONEE) study: primary results of the pivotal registration study of combined endothelial progenitor cell capture and drug-eluting.

Eur Heart J 2018;39:2460–8. https://doi.org/10.1093/eurheartj/ ehy275; PMID: 29931092. 25. L efèvre T, Haude M, Neumann FJ, et al. Comparison of a novel biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent: 5-year outcomes of the randomized BIOFLOW-II Trial. JACC Cardiovasc Interv 2018;11:995–1002. https://doi.org/10.1016/j.jcin.2018.04.014; PMID: 29798778. 26. Han Y, Xu B, Fu G, et al. A randomized trial comparing the NeoVas sirolimus-eluting bioresorbable scaffold and metallic everolimus-eluting stents. JACC Cardiovasc Interv 2018;11:260–72. https://doi.org/10.1016/j.jcin.2017.09.037; PMID: 29413240.

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Interventional Cardiology: Coronary

Role of Drug-coated Balloons in Small-vessel Coronary Artery Disease Michael Megaly, MD, MS, 1,2 Marwan Saad, MD, PhD, 3,4 and Emmanouil S Brilakis, MD, PhD 1 1. Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, MN; 2. Division of Cardiovascular Medicine, Hennepin Healthcare, Minneapolis, MN; 3. Division of Cardiovascular Medicine, Department of Medicine, University of Arkansas, Little Rock, AR; 4. Department of Cardiovascular Medicine, Ain Shams University, Cairo, Egypt

Abstract Percutaneous coronary intervention of small-vessel coronary artery disease (SVD) remains challenging due to difficulties with device delivery and high restenosis rate, even with the use of newer-generation drug-eluting stents. Drug-coated balloons represent an attractive emerging percutaneous coronary intervention option in patients with SVD. Potential advantages of drug-coated balloons in SVD include enhanced deliverability because of their small profile, avoidance of foreign-body implantation, and shorter duration of dual antiplatelet therapy.

Keywords Drug-coated balloons, drug-eluting stents, small-vessel disease, coronary artery disease Disclosure: EB: consulting/speaker honoraria from Abbott Vascular, American Heart Association (associate editor, Circulation), Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), CSI, Elsevier, GE Healthcare, InfraRedx, and Medtronic; research support from Siemens, Regeneron, and Osprey; shareholder MHI Ventures; board of trustees, Society of Cardiovascular Angiography and Interventions. The other authors have have no conflicts of interest to declare. Received: January 27, 2019 Accepted: January 31, 2019 Citation: US Cardiology Review 2019;13(1):16–20. DOI: https://doi.org/10.14520/usc.2019.4.1 Correspondence: Emmanouil S Brilakis, Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, 920 E 28th Street #300, Minneapolis, MN 55407. E: esbrilakis@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Percutaneous coronary intervention (PCI) of small-vessel coronary artery disease (SVD) is challenging because of difficulties with equipment delivery and high restenosis rates. Drug-coated balloons (DCBs) are an attractive emerging PCI option for patients with SVD.

incidence of repeat revascularization with BMS over BA – 14.9% versus 18.7%, OR 0.76 (95% CI [0.61–0.95]) p=0.02 – with no difference in MI (1.3% versus 1.7%, p=0.18) or mortality (3.1% versus 4.2%, p=0.42).13 However, BMS remained associated with unacceptable rates of repeat revascularization and MACE at 14.9% and 17.6% respectively.13

Small-vessel coronary artery disease SVD was defined in the Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries (ISAR-SMART) trial as coronary lesions in a vessel with a reference diameter (RVD) of <2.8 mm.1 In current practice, the term “very small-vessel coronary artery disease“ (CAD) is often used when the RVD is 2.0–2.25 mm.2,3 Approximately 40–50% of coronary lesions occur in small vessels,4 and 30–50% of coronary interventions are performed for SVD lesions.5 SVD is commonly associated with female sex, old age, diabetes, peripheral arterial disease (PAD), and long lesion length.6,7

First-generation Drug-eluting Stents

Balloon Angioplasty and Bare Metal Stents

Drug-eluting stents (DES) were developed aiming to reduce the risk of in-stent restenosis (ISR) compared with BMS.14,15 DES were superior to BMS in SVD in multiple studies.16–18 The risk of ISR with first-generation DES (paclitaxel-eluting stents [PES] and sirolimus-eluting stents [SES]) in SVD, however, remained high.19,20 This higher rate of restenosis with first-generation DES was attributed to sustained drug release and the inflammatory effect of the polymer, causing delayed healing, and paradoxical vasoconstriction with exercise in the stented segments.21–26 Moreover, the use of DES in SVD was associated with a higher risk of stent thrombosis.25,27–29

PCI in patients with SVD can be challenging because of higher risk for procedural complications, such as dissection and perforation, as well as long-term major adverse cardiac events (MACE).4,8,9,10,11 Historically, the use of balloon angioplasty (BA) in SVD has been associated with high restenosis rates due to elastic recoil and negative remodeling.12 In the ISAR-SMART trial, bare metal stents (BMS) were not superior to BA in 404 patients with SVD.1 A large meta-analysis published in 2005, however, which included 4,383 patients with SVD, demonstrated lower

In the prospective Taxus in Real-life Usage Evaluation (TRUE) registry, the incidence of stent thrombosis was 2.1% at 1 year among 675 patients (926 lesions) with SVD (RVD <2.75 mm) who received PES. Angiographic follow-up, completed in 465 patients (618 lesions) at 4–8 months, demonstrated 15.5% incidence of in-stent restenosis and a 25.2% incidence of in-segment restenosis.25 In 2007, Lee et al. reported 0.4% incidence of stent thrombosis in 1,068 patients (1,269 lesions)

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DCB in Small-vessel CAD with SVD (RVD <2.8 mm) treated with SES after a mean follow-up of 23.2±7.9 months. At 6-month angiographic follow-up (completed in 751 patients with 889 lesions), the incidence of in-stent restenosis and in-segment restenosis was 6.5% and 8.7%, respectively.27 In a study by Briguori et al., the incidence of restenosis in patients who received thick-strut, first-generation DES compared with those who received thin-strut DES were 36% versus 28.5%, respectively (p=0.009).19

Second-generation Drug-eluting Stents Second-generation DES (zotarolimus-eluting stents [ZES], everolimuseluting stents [EES] and biolimus-eluting stents [BES]), and smallerdiameter DES specifically designed for SVD (such as the Resolute Onyx®, Medtronic, available in 2.0 mm diameter) were associated with good outcomes and low risk of ISR.30–35 Despite the progress achieved, the small vessel diameter has a limited ability to accommodate neointimal tissue growth, hence ISR and target lesion revascularization (TLR) continue to occur.36 In the prospective, single arm SPIRIT Small Vessel (SPIRIT SV) registry, the 12-month incidence of TLR with XIENCE V nano EES in 150 patients with SVD (RVD <2.5 mm) was 5.1%.37 In the single-arm XIENCE V Everolimus Eluting Coronary Stent System USA Post-Approval (XIENCE V USA) study, the 12-month incidence of TLR in 838 patients with SVD (RVD <2.5 mm) who received XIENCE V EES was 3.1%.38 The BAsel Stent Kosten Effektivitäts Trial (BASKET-SMALL) pilot study randomized 191 patients with SVD to first-generation PES (Taxus Liberté®, Boston Scientific; 91 patients) or a second-generation ZES (Endeavor Sprint®, Medtronic; 100 patients). The incidence of target vessel revascularization (TVR) at 1 year was 6.6% versus 2% for PES and ZES, respectively.39 In a retrospective study of 1,132 patients with SVD (RVD <2.5 mm) who received either a BES (NOBORI®, Terumo; 612 patients) or a cobalt chromium EES (XIENCE V; 520 patients), the incidence of TLR at 2 years was 8.3% versus 8.4% for BES and EES, respectively (p=1.0).40

paclitaxel; some newer DCBs use sirolimus.52,53 The drug is delivered to the vessel wall with mechanical balloon expansion, usually for 30–60 seconds, after proper preparation of the vessel.50 The half-life of the drug in the tissue is approximately 2 months, depending on balloon type, coating technique, excipient used, and drug concentration.54,55 Because of these differences, a class effect of DCBs cannot be assumed.56 First-generation DCBs (e.g. DIOR-I®, Eurocor) were used in the early feasibility studies, but outcomes improved with newer-generation DCBs.57 The difference in efficacy has been attributed mainly to the absence of a matrix containing an elution excipient. The newer-generation DCBs (e.g. SeQuent Please®, B Braun) have a matrix consisting of an excipient to enhance lipophilicity, increase local tissue–drug transfer, and facilitate rapid absorption of the drug by the vascular wall. The balloon elution excipient is an important factor affecting the safety and efficacy of DCBs, as it determines the durability of drug dose, the downstream drug dose, the relative uptake by the vessel wall, and the drug retention.58 Different excipients are used in newer-generation DCBs; for example, the contrast agent iopromide is used in the SeQuent Please DCB (B Braun), and urea is used in the IN.PACT Falcon DCB (Medtronic).

Drug-coated Balloons in Small-vessel Disease The first trial to study the use of DCB in SVD was the single-arm PaclitaxelEluting PTCA-Balloon Catheter to Treat Small Vessel (PEPCAD-I) trial in 118 patients with SVD (mean diameter of 2.36 mm) using the SeQuent Please balloon.63 Approximately 30% of the patients required bailout BMS stenting and 18% had ISR at follow-up. Many single-arm registries have since reported favorable outcomes with DCBs in SVD.47,48,64–66

The first trial in humans to study the use of DCBs in peripheral arterial disease lesions was the Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries (THUNDER) trial, published in 2008. THUNDER randomized 154 patients with femoropopliteal lesions to angioplasty with paclitaxel versus no paclitaxel and demonstrated that DCB was associated with significantly lower late lumen loss and lower risk of TLR.41 Multiple subsequent studies have shown that DCBs are associated with superior outcomes compared with uncoated BA in femoropopliteal lesions.42

The first randomized trial to compare DCBs to stenting was the Paclitaxelcoated balloon versus drug-eluting stent during PCI of small coronary vessels (PICCOLETO) trial that included vessels with RVD <2.75 mm. It was stopped prematurely due to the superiority of the DES arm.67 However, this trial had many limitations: the DCB used was the firstgeneration DIOR-I DCB, hence tissue delivery of the drug was low; lesion preparation before use of DCBs was performed in <90% of cases; the rate of bailout BMS stenting was high (34%); and many bifurcation lesions were included (22.5%). Moreover, the DES used in the control arm was the first-generation paclitaxel-coated Taxus Liberté. In 2012, the Balloon Elution and Late Loss Optimization (BELLO) trial randomized 182 patients with SVD (mean diameter of 2.15 mm) to the IN.PACT Falcon DCB (90 patients) versus Taxus DES (92 patients). The study demonstrated comparable clinical outcomes at 6 months and up to 3 years.68,69

For the treatment of obstructive CAD, DCBs were first considered in 2003 as a potential treatment for ISR after BMS and DES in the Treatment of in-Stent Restenosis by Paclitaxel Coated PTCA Balloons (PACCOCATH–ISR I) trial, which enrolled 52 patients. The study showed significantly lower 6-month late lumen loss compared with uncoated BA.43 Multiple subsequent studies confirmed the effectiveness of DCBs in reducing angiographic late lumen loss in ISR lesions.44–46 Drug-coated balloons were further studied in de novo coronary lesions including bifurcation lesions.47–51

In 2016, Siontis et al. performed a large network meta-analysis of various PCI treatments for SVD.70 A total of 19 randomized clinical trials involving 5,072 patients were included, and the sirolimus-eluting stents were found to be the most effective treatment for reducing subsequent percentage diameter stenosis, followed by paclitaxel-eluting stents, then DCBs. However, both the PICCOLETO and BELLO studies were included, despite their many limitations, as discussed above. Also, none of the trials used second-generation DESs.

DCBs are semicompliant balloons coated with a highly lipophilic, antiproliferative drug. The most commonly used drug currently is

Observational studies were subsequently conducted, showing that DCBs were comparable to second-generation DESs in SVD, even in

Drug-coated Balloons

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Interventional Cardiology: Coronary Table 1: Randomized Controlled Trials Studying the Use of Drug-coated Balloons in Small-vessel Coronary Artery Disease Study

Drug-coated

Comparison arm

balloon type

Number of

Follow-up Main outcomes

patients (DCB/

time

comparison arm) PICCOLETO 201067

DIOR-I (Eurocor)

Paclitaxel-eluting stent (Taxus Liberté)

28/29

9 months

TLR numerically higher with DCB (32.1% versus 10.3%, p=0.15) MACE higher with DCB (35.7% versus 13.8%, p= 0.054) Trial stopped early

BELLO 201268

IN.PACT FALCON (Medtronic)

Paclitaxel-eluting stent (Taxus Liberté)

90/92

6 months

Similar binary restenosis (8.9% versus 14.1%, p=0.25) Similar TLR (4.4% versus 7.6%, p=0.37) Similar MACE (7.8% versus 13.2%, p=0.77)

Funatsu et al. 201776

SeQuent Please (B Braun)

Uncoated balloon angioplasty

92/41

6 months

Lower binary restenosis with DCB (13.3% versus 42.5%, p<0.01) Similar TLR (3.4% versus 10.3%, p=0.2)

BASKET-SMALL 2 201873

SeQuent Please (B Braun)

Everolimus-eluting XIENCE 382/376 stent (Abbott Vascular) or the paclitaxel-eluting Taxus Element Stent (Boston Scientific)

12 months Similar TVR (3.5% versus 4.5%, p=0.44) Similar MACE (7.5% versus 7.3%, p=0.92)

RESTORE-SVD China 201874

Restore (Cardionovum)

Zotarolimus-eluting stent (RESOLUTE, Medtronic)

9 months

116/114

Similar TLF (4.4% versus 2.6%, p=0.72)

BASKET-SMALL = Basel Kosten Effektivitäts Trial-Drug-Coated Balloons versus Drug-eluting Stents in Small Vessel Interventions; BELLO = Balloon Elution and Late Loss Optimization trial; BMS = bare metal stent; DCB = drug-coated balloon; DES = drug-eluting stent; MACE = major adverse cardiovascular events; PICCOLETO = paclitaxel-coated balloon versus drug-eluting stent during PCI of small coronary vessels; RESTORE-SVD China = Assess the Efficacy and Safety of RESTORE Paclitaxel Eluting Balloon Versus RESOLUTE Zotarolimus Eluting Stent for the Treatment of Small Coronary Vessel Disease; TLF = target lesion failure; TLR = target lesion revascularization; TVR = target vessel revascularization.

Figure 1: Percutaneous Treatment of Small-vessel Coronary Artery Disease

Small vessel disease 1. Uncoated balloon angioplasty

2. Bare metal stents

High risk for restenosis and repeat revascularization

3. Drug-eluting stents Risk factors

Peripheral artery disease

Long lesions

Diabetes

Old age

Women

Prolonged Lower risk of use of dual restenosis and target lesion antiplatelet therapy revascularization

Vessel diameter 2–3 mm 4. Drug-coated balloons (DCB) Excipient: dimethyl sulfate Drug: paclitaxel

Dior-I DCB (Eurocor)

Small profile

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Excipient: iopromide Drug: paclitaxel

SeQuent Please DCB (B Braun)

Promotes plaque reduction and stabilization

Excipient: SAFEPAX® Drug: paclitaxel

Excipient: urea Drug: paclitaxel

IN.PACT Falcon DCB (Medtronic)

Promotes vascular healing

Low risk for restenosis

Restore DCB (Cardionovum)

Short duration of dual antiplatelet therapy (4 weeks)

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DCB in Small-vessel CAD vessels with a diameter of 2 mm.71,72 The randomized non-inferiority Basel Kosten Effektivitäts Trial–Drug-Coated Balloons versus DrugEluting Stents in Small Vessel Interventions 2 (BASKET-SMALL 2) trial was the first and largest trial to compare the use of DCBs and secondgeneration DES.73 The study randomized 758 patients with SVD (RVD <3 mm) to PCI using the the SeQuent Please DCB or a DES (XIENCE V or Taxus Element). The first-generation Taxus was used in 24% of patients in the DES arm. During 12 months of follow-up, the incidence of MACE was 7.3% versus 7.5% in the DES and DCB arms, respectively (HR 0.97; 95% CI [0.58–1.64], p=0.9180).

The recently published Assess the Efficacy and Safety of RESTORE Paclitaxel Eluting Balloon Versus RESOLUTE Zotarolimus-Eluting Stent for the Treatment of Small Coronary Vessel Disease (RESTORE SVD China) randomized, non-inferiority study compared the Restore® DCB (Cardionovum), a paclitaxel-coated balloon that uses the SAFEPAX matrix, based on an ammonium salt compound, and the RESOLUTE DES in SVD (RVD 2.25–2.75 mm).74 At 9 months, the Restore DCB was noninferior to the RESOLUTE DES for in-segment percent diameter stenosis in 230 patients. At 1 year, the Restore DCB and RESOLUTE DES had comparable incidence of TLF (4.4% versus 2.6%, p=0.72). A recently published meta-analysis of 1,824 patients demonstrated that DCBs had better outcomes than uncoated BA, and comparable

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angiographic and clinical outcomes with DES in SVD during a mean follow-up of 15 months.75 Most evidence on DCBs was derived from studies of paclitaxel-coated balloons. More recently, the use of sirolimus-coated balloons was reported to have favorable outcomes in 156 patients with SVD enrolled in the single-arm prospective NANOLUTÈ registry.52 At 12 months, the incidence of target lesion revascularization/target vessel revascularization was 2.8%, and the incidence of MACE was 3.8%. The randomized controlled trials studying the outcomes of DCB in SVD are summarized in Table 1. In clinical practice, the treatment options for patients with SVD include medical therapy alone, BA, or stenting with a DES. Drug-coated balloons provide an alternative option for these difficult-to-treat lesions with outcomes that are comparable to DES in most studies. However, the 2018 European Society of Cardiology/European Association for CardioThoracic Surgery guidelines on myocardial revascularization do not support the use of DCB angioplasty for de novo lesions because the published evidence is limited.56

Conclusion Drug-coated balloons offer an attractive treatment option for patients with SVD due to good deliverability, avoidance of foreign-body implantation, and possibly shorter DAPT duration.

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Interventional Cardiology: Structural Heart

Conduction Abnormalities After Transcatheter Aortic Valve Replacement Somsupha Kanjanauthai, MD, Kabir Bhasin, MD, Luigi Pirelli, MD, and Chad A Kliger, MD Valve and Structural Heart Center, Lenox Hill Heart and Lung, New York, NY

Abstract Transcatheter aortic valve replacement (TAVR) has been established as a therapeutic option for patients with severe symptomatic aortic stenosis who are of intermediate or higher surgical risk. Several periprocedural complications are reduced with newer transcatheter heart valve generations; however, conduction abnormalities and the need for permanent pacemaker implantation have remained unchanged and are the most frequent TAVR complications. The close relationship of the atrioventricular node and left bundle branch to the subaortic region explains these potential conduction abnormalities. This article highlights conduction abnormalities after TAVR with a focus on basic conduction system anatomy in relation to the aortic valve, the mechanism, incidence, predisposing factors for occurrence, impact on mortality and finally, proposed treatment algorithms for management.

Keywords Conduction abnormalities, left bundle branch block, pacemaker implantation, right bundle branch block, sudden cardiac death, transcatheter aortic valve replacement Disclosure: CK receives speaking honorarium from Medtronic and Siemens Healthineers. All other authors have no conflicts of interest to declare. Received: June 30, 2018 Accepted: October 23, 2018 Citation: US Cardiology Review, 2019;13(1):21–9. DOI: https://doi.org/10.14520/usc.2018.7.2 Correspondence: Chad A Kliger, Director, Valve and Structural Heart Center, Lenox Hill Heart and Lung, 130 East 77th Street, Suite 4th Floor, New York, NY 10075, USA. E: ckliger@northwell.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transcatheter aortic valve replacement (TAVR) has been established as a therapeutic option for patients with severe symptomatic aortic stenosis who are considered to be of intermediate, high or prohibitive surgical risk.1–5 As a result of favorable TAVR outcomes and substantial improvements in transcatheter heart valve (THV) technologies and implantation techniques, the feasibility of broadening applications to the low-risk population is being evaluated. Despite periprocedural complications being reduced with newer THV generations, the occurrence of conduction abnormalities and the need for permanent pacemaker implantation (PPI) remain the most frequent complications. 6,7 Rates of PPI have not been significantly reduced but rather, with some technologies, have increased.8 The long-term implications of PPI in the TAVR patient population remain unclear, and applicability in low-risk patients is a further consideration. In addition, short-term implications may jeopardize the minimalist TAVR approach, with increased use of electrophysiological studies and continuous EKG monitoring devices (i.e. Holter monitors, event monitors, or implantable loop recorders), and subsequent prolonged length of hospital stay.9–12 This article highlights conduction abnormalities after TAVR with a focus on basic conduction system anatomy in relation to the aortic valve, the

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mechanism, incidence, predisposing factors for occurrence, impact on mortality, and finally, proposed treatment algorithms for management.

Anatomy of the Conduction System The atrioventricular node (AVN) is located within the triangle of Koch, which is demarcated by the tendon of Todaro, the septal leaflet attachment of the tricuspid valve, and the orifice of the coronary sinus (Figure 1). The AVN continues as the His bundle, tracking through the septum leftward to the central fibrous body. The central fibrous body is the area within the heart where the membranous septum (MS), the atrioventricular valves, and the aortic valve join in continuity. The left bundle branch exits within this area between the non-coronary cusp (NCC) and right coronary cusp (RCC) leaflets and travels along the septal surface of the left ventricular septum.13,14 The close relationship of the AVN and left bundle branch to the subaortic region explains the potential conduction abnormalities after percutaneous THV insertion.

Conduction Abnormalities after Surgical Aortic Valve Replacement The most common conduction abnormality after surgical aortic valve replacement (SAVR) is left bundle branch block (LBBB). The incidence of new LBBB after SAVR has been reported to range from 6% to 32%.15–17 It is caused by injury to the conduction system at the interleaflet

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Interventional Cardiology: Structural Heart Figure 1: Schematic Illustration of Intracardiac Anatomy and Relationship to Atrioventricular Node Tendon of Todaro

Right atrium

AV N CS

Triangle of Koch Right ventricle

His Purkinje located in membranous septum

of et afl alve e l v al pt pid Se icus tr

Left bundle branch originates at lower border of membranous septum

Right bundle branch Interventricular septum

triangle of the NCC/RCC leaflets from direct surgical trauma during decalcification, mechanical compression, hemorrhage, or ischemia.15–17 New LBBB after SAVR was found to be associated with worse 1-year survival, when compared with cases where LBBB did not develop.15,18 SAVR can be performed by using either stented or stentless biological prostheses. Stented biological prostheses can be implanted in a supraannular or intra-annular position; the valve does not generate a radial force that compresses the conduction system if implanted in a supra-annular position. Stentless valve prostheses are designed to achieve a more physiological flow pattern and superior hemodynamics in comparison with stented valves.19 Some generations of stentless valves require only one suture line to secure the valve.19 Recent technological developments have led to an alternative, minimallyinvasive option that avoids the placement of sutures, known as sutureless or rapid-deployment aortic valves (Su-AVR). Su-AVR, which combines features of both SAVR and TAVR, requires removal/decalcification of native leaflets, but depends on its intra-annular stent design with oversizing to anchor the prosthesis.20 Conduction abnormalities associated with this valve type are more similar to with TAVR than SAVR.21

Conduction Abnormalities After Transcatheter Aortic Valve Replacement TAVR prostheses are placed in an intra-annular position in closer proximity to the AVN and left bundle branch. In contrast to surgical valves, they are anchored into the aortic annulus and their stent frames generate a radial force expansion that may compress the conduction system.21 Slight oversizing is necessary in implant technique to secure the THV and reduce paravalvular regurgitation; however, excessive oversizing can result in increased compression of the conduction system.22 Overall, TAVR patients have a higher incidence of conduction abnormalities than patients who have conventional SAVR.21

Incidence of New-onset Left Bundle Branch Block and Permanent Pacemaker Insertion New-onset LBBB is the most frequent complication after TAVR.6 The incidence of new-onset LBBB ranges from 4% to 57%, with the rate of PPI ranging from 2% to 51%.23,24 The incidence of both new-onset LBBB and PPI are higher after implantation with the self-expanding CoreValve® system (MCV, Medtronic) than with the balloon-expandable SAPIEN or SAPIEN XT systems (ESV, Edwards Lifesciences); new-onset LBBB

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and PPI are 35–65% and 28%, and 3–30% and 6%, for MCV and ESV, respectively.25–34 Table 1 summarizes studies with their associated LBBB and PPI rates. The higher incidence of PPI in the MCV compared with the ESV has been confirmed in a randomized controlled trial.35 Overall, LBBB leads to an increased likelihood of new PPI early after TAVR.36 However, one-fifth to nearly half of new-onset LBBB is temporary.37 Testa et al. studied 1,060 patients treated with MCV; 43.0% developed LBBB after TAVR, and this figure decreased to 27.3% at discharge and remained stable at 30 days.25 Urena et al. reported the rate of new-onset LBBB to be approximately 20.0% after TAVR with ESV and that 50.0% of new-onset LBBB resolved within a few days after TAVR, leading to a rate of new-onset persistent LBBB of approximately 10.0%.38 In another study, Franzoni et al. showed a higher incidence of LBBB following MCV (50.0%) than ESV (13.5%), which reduced by discharge to 32.2% for MCV and 8.6% for ESV, respectively.39 LBBB is also a predictor of late PPI after hospital discharge.40,41 In a recent meta-analysis, a higher rate of PPI at 1-year follow up was observed among patients with new-onset LBBB, compared with those who did not develop LBBB.41 The frequency of LBBB after TAVR has decreased significantly over time, especially with MCV THVs. This has been largely attributed to operator experience and the subsequent reduction in implantation depth.42 Nevertheless, the incidence of PPI has remained unchanged over time and has not been affected by operator experience.42 When interrogation of permanent pacemakers are performed, approximately 50% of patients are continuously paced, 25% are intermittently paced, and 25% have adequate atrioventricular conduction without the necessity of pacing.37 The patient population with persistent LBBB who require PPI and have identifiable need upon followup interrogation still require improved understanding.

Newest Third-generation Transcatheter Heart Valves Increased rates of PPI, ranging from 12.4% to 25.5%, have been reported with the use of the newest third-generation ESV SAPIEN 3, when compared with previous generations.43–49 This finding has been attributed to the incorporation of an external fabric cuff in the inferior part of the valve, intended to minimize paravalvular leak. Moreover, different stent expansion patterns of the SAPIEN 3 compared with the SAPIEN XT may play a role.50 In SAPIEN XT, the expansion area increased from the inflow level, reaching its peak at the outflow level; in contrast, the SAPIEN 3 has its largest expansion at the left ventricular outflow tract (LVOT) end, causing elevated localized pressure within the LVOT and thus higher rates of atrioventricular conduction disturbances.50 A higher (>70% aortic extension) valve depth implantation of this newestgeneration THV may decrease PPI risk.43,44 Also, the next-generation selfexpanding MCV Evolut Pro has been designed with an external pericardial wrap with the intention of reducing paravalvular leak. Early PPI rates in the first 60 patients were reported at 30 days at 11.7%.51 Although 6-month data suggest no significant change in PPI, data for this THV are limited.

Impact of Transcatheter Aortic Valve Replacementinduced Left Bundle Branch Block on Mortality LBBB has been associated with increased morbidity and mortality in a broad population of patients, from healthy individuals to patients who have had MI and have established heart failure.52,53 However,

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Conduction Abnormalities After Valve Replacement Table 1: Summary of Studies Showing the Incidence of LBBB and PPI Following TAVR and Respective Association with Mortality Author

Patients

Valve

Incidence of

(n)

Type

LBBB (%)

PPI (%)

Risk Factors for LBBB/PPI

Association of TAVRinduced LBBB/PPI and

Chamandi et al. 201890

1,629

45% ESV 55% MCV

N/A

19.8% at 30 days N/A post-TAVR (26.9% of MCV, 10.9% of ESV)

PPI was associated with an increased risk of heart failure rehospitalization and lack of LVEF improvement, but not mortality

Fadahunsi et al. 201676 (STS/ACC TVT registry)

9,785

ESV MCV

N/A

6.7% at 30 PPI: age, prior conduction defect, use of days post-TAVR self-expanding valve, large prosthesis, valve (25.0% of MCV oversizing and 4.3% of ESV)

PPI was associated with increased mortality and a composite of mortality or heart failure admission at 1 year

Mauri et al. 201667

229

ESV3

N/A

14.4%

PPI: deep THV implantation, higher LVOT calcium in the area below LCC and RCC, preexisting RBBB

N/A

Van der Boon et al. 201542

549

ESV MCV

New-onset LBBB 33.7%

13.3% (7.6% of TAVR-induced LBBB patients underwent PPI)

LBBB: Use of MCV, transfemoral approach, deep THV implantation

N/A

Nazif et al. 201573 (PARTNER trial and registry)

1,973

ESV

N/A

8.8%

PPI: RBBB, prosthesis/LVOT diameter, LVEDD

PPI was associated with higher repeat hospitalization and mortality or repeat hospitalization at 1 year

Urena et al. 201438

668

ESV

New-onset LBBB 19.2% Persistent LBBB 11.8%

N/A Higher rate of PPI in LBBB group

LBBB: Transapical approach, a 29-mm valve

LBBB did not increase the risk of global or cardiovascular mortality or rehospitalization at 1 year

Nazif at al. 201458 (PARTNER trial and registry)

1,307

ESV

New-onset LBBB 10.5%

N/A Higher rate of PPI in LBBB group

LBBB: Prior CABG

LBBB was not associated with 1-year mortality, cardiovascular mortality, repeat hospitalization, stroke, or MI

Testa at al. 201325

818

MCV

Persistent LBBB 27.4%

N/A PPI: Deep THV implantation Higher rate of (>8 mm) PPI at 30 days in persistent LBBB group

LBBB was not associated with increased all-cause mortality, cardiac mortality, hospitalization for heart failure at 30 days or 1 year.

Franzoni at al.201339

238

63.4% ESV New-onset LBBB 36.6% 26.5% (13.5% MCV ESV, 50.0% MCV) Persistent LBBB: 8.6% ESV, 32.2% MCV

12.7%

LBBB: Use of MCV

LBBB was not associated with overall or cardiovascular mortality

57% MCV 43% ESV

New-onset LBBB 34.3%

N/A

LBBB increased all-cause mortality LBBB was not associated with mortality at 1 year

Mortality

Houthuizen et al. 201226 679 Urena et al. 201233

202

ESV

New-onset LBBB 30.2%

N/A

LBBB: Baseline QRS, deep THV implantation

De Carlo et al. 201227

275

MCV

New-onset LBBB 26.9%

24%

PPI: Deep THV implantation, RBBB, left anterior PPI did not affect 1-year hemiblock, longer PR interval survival

Aktug et al. 201228

139

ESV MCV

New-onset LBBB 29.0% (38.0% in MCV, 16.0% in ESV) Persistent LBBB 12.9%

17.2% (28.0% MCV, 5.0% ESV)

LBBB: Deep THV implantation, use of MCV

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N/A

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Interventional Cardiology: Structural Heart Table 1: Continuted Author

Patients

Valve

Incidence of

(n)

Type

LBBB (%)

PPI (%)

Risk Factors for LBBB/PPI

Association of TAVR-

Laynez et al. 201234

125

ESV

New-onset LBBB 4%

N/A

Khawaja et al. 201131

243

MCV

New-onset LBBB 61%

33.3%

PPI: Periprocedural AVB, balloon predilatation, CoreValve prosthesis, increased interventricular septum diameter, prolonged QRS

N/A

Baan et al. 201077

MCV

New-onset LBBB 65%

20.5% (7/34 patients)

LBBB: Deep THV implantation PPI: Pre-existing conduction abnormalities, narrow LVOT, postprocedural small EOA, more mitral annular calcification

N/A

Piazza et al. 201032

MCV

New-onset LBBB 54%

19%

LBBB: Male sex, pre-existing RBBB, depth of N/A implantation, actual diameter of inflow portion of CoreValve frame PPI: Baseline QRS, septal wall thickness

induced LBBB/PPI and Mortality

AVB = atrioventricular block; CABG = coronary artery bypass graft; EOA = effective orifice area; ESV = Edwards SAPIEN valve; LBBB = left bundle branch block; LCC = left coronary cusp; LVEDD = left ventricular end-diastolic dimension; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; MCV = Medtroic CoreValve; PARTNER = Placement of AoRtic TraNscathetER Valves; PPI = permanent pacemaker implantation; RBBB = right bundle branch block; RCC = right coronary cusp; STS/ACC TVT = Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy; TAVR = transcatheter aortic valve replacement; THV = transcatheter heart valve.

there are conflicting data about the impact of new-onset LBBB on mortality in post-TAVR patients. Several studies have failed to show the relationship between new-onset LBBB and mortality.25,27,32–34,38,54–58 In an analysis from the Placement of AoRtic TraNscathetER Valves (PARTNER) trial, persistent new-onset LBBB occurred in 10.5% of cases and was not associated with all-cause mortality, cardiovascular mortality, stroke, or MI. However, it was associated with a higher rate of repeat hospitalizations, PPI, and lack of improvement in left ventricular ejection fraction (LVEF).58 On the other hand, a large multicenter registry study by Houthuizen et al. reported that TAVR-induced LBBB is one of the strongest predictors of all-cause mortality in TAVR patients,26 and can neutralize the benefit of TAVR. A meta-analysis by Regueiro et al. confirmed a higher risk of cardiac death in patients with TAVR-induced LBBB after 1 year of follow up.41

following TAVR were independently associated with an increased risk of SCD.62 Patients with new-onset persistent LBBB and QRS duration >160 ms had a greater SCD risk and most of them died within 6 months of TAVR.62 No increased risk of SCD was observed in patients with new-onset persistent LBBB and pacemaker implanted before hospital discharge, suggesting HAVB as the main cause of SCD in these patients.62 The ongoing Ambulatory Electrocardiographic Monitoring for the Detection of High-Degree Atrio-Ventricular Block in Patients With New-onset PeRsistent Left Bundle Branch Block After Transcatheter Aortic Valve Implantation (MARE) study, with continuous EKG recording (up to 3 years) in patients with new-onset persistent LBBB following TAVR should provide more information on this issue.

Possible mechanisms of increased mortality for patients with TAVRinduced LBBB are progression to high-grade atrioventricular blocks (HAVB), and the development of dyssynchrony associated with the LBBB.26 LBBB causes left ventricular dyssynchrony, which has a similar effect to chronic right ventricular pacing and can lead to reduction in left ventricular function and remodeling.59,60 Patients who develop left ventricular dysfunction from dyssynchrony are also susceptible to ventricular tachyarrhythmias, which could be another possible explanation for higher mortality in patients with TAVR-induced LBBB.26 One case report of a patient without pre-existing conduction abnormalities who died suddenly in the early phase after discharge, showed autopsy findings of a THV that had compressed the atrioventricular conduction system at the septum.61 Microscopic examination confirmed necrosis of the His bundle and left bundle branch as a result of mechanical compression, supporting progression to HAVB as a possible mechanism of sudden cardiac death (SCD).61

Atrioventricular conduction disorders and LBBB occur after both TAVR and SAVR as a result of the close proximity of the AVN and left bundle branch to the aortic valve.13 The His bundle is located between the MS and the posterior crest of the muscular septum; the lower end of MS is an anatomic landmark for the left ventricular exit point of the His bundle.13 Consequently, the MS length represents the distance between the aortic annulus and the His bundle. Hamdan et al. evaluated 73 patients with severe aortic stenosis who underwent contrast-enhanced CT before TAVR and found that MS length was the most powerful predictor of HAVB and PPI.63 Short MS, insufficient distance between MS length and implantation depth, and the presence of calcification in the basal septum facilitate mechanical compression of the conduction tissue by the TAVR prosthesis.63 On the other hand, a longer MS length may allow accommodation of more device penetration without causing conduction abnormalities.63

Advanced heart failure and SCD account for two-thirds of cardiac deaths in post-TAVR patients.62 LVEF ≤40% and new-onset persistent LBBB

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Mechanism and Risk Factors of TAVR-induced LBBB, HAVB, and PPI

LBBB may develop before actual insertion of the valve device in >50% of cases. This can be caused by contact of the guidewire or compression of the LVOT by balloon dilatation.29,56 Patient- and procedure-related

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Conduction Abnormalities After Valve Replacement factors such as septal wall thickness, NCC thickness, depth of valve implantation within the LVOT, post-implantation dilatation, and large size and type of THV predicts LBBB or new conduction abnormalities after TAVR.38,54–56,64 Deep THV implants, greater than or equal to 6 mm, are associated with increased conduction abnormalities and pacemaker rate.39,65,66 Moreover, higher ratio between prosthesis valve size and the annulus, (that is, oversizing) in the MCV is considered to be a predictor of new LBBB.39 Mauri et al. identified risk factors for PPI following TAVR with a balloonexpandable (SAPIEN 3) THV to be a high LVOT calcium volume in the area below the left coronary cusp and RCC, pre-existing right bundle branch block (RBBB), and lower implantation depth (Table 2).67 Tarantini et al. described a relationship between implantation depth and PPI rate after SAPIEN 3 implantation and proposed an implantation technique aimed at a maximum LVOT extension of the stent frame of less than 8 mm, which would result in a ventricular portion of approximately 40.0% depending on prosthesis size.44 Subsequent studies showed that implantation techniques aimed at a ventricular portion of <30.0% and <25.5% were the best discriminatory thresholds for reduced PPI risk.43,67 Optimal implantation depths for MCV and ESV are between 3 mm and 6 mm and 80% aortic:20% ventricular, respectively. The radial force from the THV must be sufficient to ensure valve anchoring, but not interfere with the AVN and disturb the electrical conduction system.68 Radial force produced by the MCV and ESV was studied by Tzamtzis et al.69 In self-expanding THVs, the radial force is dependent on the diameter of LVOT.69 However, the radial force in the balloon-expandable THVs is associated with a more complex mechanism that involves the geometric and material properties of the stent, of the balloon and of the host tissue, as well as the technical aspects of the balloon inflation procedure.69

Pre-existing Right Bundle Branch Block in Patients Undergoing Transcatheter Aortic Valve Replacement Data from the Copenhagen City Heart Study demonstrated that RBBB was associated with an increased risk for all-cause mortality and adverse cardiovascular outcomes in the general population.70 A large meta-analysis of 19 prospective cohort studies confirmed the same findings; RBBB was associated with an increased risk of mortality in the general population and in patients with heart disease.71 RBBB is a well-recognized risk factor for PPI or late bradycardia in post-TAVR patients.24,72,73 Watanabe et al. evaluated the prognostic effect of pre-existing RBBB in patients undergoing TAVR in a substudy of the Optimized Transcatheter Valvular Intervention (OCEAN-TAVI) registry, which used the SAPIEN XT prosthesis.74 Of 749 patients, 102 (13.6%) had pre-existing RBBB, and this group had a higher incidence of PPI than the group without RBBB (17.6% versus 2.9%).74 Patients with RBBB demonstrated an increased risk of cardiovascular mortality after TAVR, and were at higher risk of cardiac death if discharged without pacemakers (HR 2.6).74 A recent study showed a similar result; RBBB was present on baseline EKG in approximately 10% of patients and associated with higher 30-day rates of PPI and death.75 Patients with pre-existing RBBB should be carefully monitored to detect fatal arrhythmic events after discharge and may require prolonged hospitalization.

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Table 2: Risk Factors for TAVR-induced LBBB and PPI Risk Factors for TAVR-induced

Risk Factors for Pacemaker

LBBB

Insertion (PPI)

Patient Characteristics Baseline QRS duration

Age

–

Male sex

–

Baseline conduction disturbances (i.e. RBBB)

Anatomical Considerations Short membranous septum

Short membranous septum

Increased septal wall thickness

Narrow LVOT

Presence of calcification in the basal septum

High LVOT calcium volume below the LCC and RCC

Increased non-coronary cusp thickness

Large annular size

–

Mitral annular calcification

Procedural Characteristics Higher ratio between THV size and annulus (oversizing)

Higher ratio between THV size and annulus (oversizing)

Deep THV implantation

Post-dilatation

Intraprocedural atrioventricular block

Type of THV (self- > balloon-expandable)

Type of THV (self- > balloonexpandable)

LBBB = left bundle branch block; LCC = left coronary cusp; LVOT = left ventricular outflow tract; PPI = permanent pacemaker implantation; RBBB = right bundle branch block; RCC = right coronary cusp; TAVR = transcatheter aortic valve replacement; THV = transcatheter heart valve.

Predictors and Outcomes of Permanent Pacemaker Implantation Following TAVR Positive predictors of PPI post-TAVR are age, male sex, baseline conduction disturbances, intraprocedural atrioventricular block (AVB), narrow LVOT, the severity of mitral annular calcification,and use of self-expanding valve (Table 2).24,76,77 Patients who received PPI were more likely to have larger THVs implanted, higher oversizing, larger left ventricular internal diastolic dimensions, larger aortic valve annular size, larger aortic valve area, and lower aortic valve mean gradient.76 Moreover, septal bulge can result in a smaller LVOT and increased prosthesis:LVOT diameter ratio, which increases risk of PPI.73 PPI was associated with longer hospital and intensive care unit stays,73,76 and significantly increased cost associated with TAVR.78–80 Most studies reported a median time of 3 days from TAVR to PPI, and almost 90% of PPIs were performed within 7 days of TAVR.73,76,81,82 It is believed that conduction abnormalities occurring at a later time are a result of edema and late expansion of the THV prosthesis.83,84 Chronic right ventricular pacing causes electrical and mechanical dyssynchrony, and has been associated with a deleterious effect on left ventricular function and an increased risk of heart failure hospitalizations in patients with pre-existing heart failure.85–87 Among TAVR patients, several studies have shown a negative effect of PPI on left ventricular function at both short- and long-term follow up.30,81,88–90 A retrospective cohort study of patients undergoing TAVR at 229 sites in the US was performed using the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) registry and the Centers for Medicare and Medicaid Services database. The study found that PPI was required within 30 days of TAVR in 6.7% of cases and varied

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Interventional Cardiology: Structural Heart Figure 2: Treatment Algorithms for Management of Conduction Abnormalities Following Transcatheter Aortic Valve Replacement

Baseline EKG

LBBB

Normal QRS

RBBB

TAVR with balloon-expandable valve Unchanged QRS

Widened QRS but <160

Unchanged QRS

QRS >160

Widened QRS

Transient (<24 h)

TVP removal post-procedure

• Maintain TVP 24 h • Avoid BB 3–5 days • Discharge home with event monitor

• Maintain TVP • Avoid BB 3–5 days • EP study

• TVP removal after 24 h • Hold BB 3–5 days

Unchanged RBBB

Complete heart block

Persist (>24 h)

• Maintain TVP • Hold BB 3–5 days • EP study

• Maintain TVP 48 hours. • Consider EP study • Event monitor or ILR if negative EP study • Avoid BB

PPM

Baseline EKG

LBBB

Normal QRS

RBBB

TAVR with self-expanding valve Unchanged QRS

Widened QRS but <120

QRS >120 or new-onset LBBB

Unchanged QRS

Widened QRS Transient (<24 h)

• TVP removal post-procedure • Continue telemetry monitoring

• Maintain TVP 24 h • Avoid BB 3–5 days • Discharge home with event monitor

• Maintain TVP • Avoid BB 3–5 days • EP study

• TVP removal after 24 h • Hold BB 3–5 days

Unchanged RBBB

Complete heart block

Persist >24 h

• Maintain TVP • Hold BB 3–5 days • EP study

• Maintain TVP 48 h • Consider EP study • Event monitor or ILR if negative EP study • Avoid BB

PPM

A: Treatment algorithms for management of conduction abnormalities following TAVR with balloon-expandable valves. B: Treatment algorithms for management of conduction abnormalities following TAVR with self-expanding valves. BB = beta-blocker; EP = electrophysiology; ILR = implantable loop recorder; LBBB = left bundle branch block; PPM = permanent pacemaker; RBBB = right bundle branch block; TVP = transvenous pacemaker.

among those receiving self-expanding THVs (25.1%) versus balloonexpanding THVs (4.3%).76 Early PPI is a common complication following TAVR and was associated with higher mortality and composite endpoint of mortality or heart failure admission at 1 year.76 Conversely, another recent multicenter study showed PPI was associated with an increased risk of heart failure rehospitalization and lack of LVEF improvement, but not total mortality or cardiac mortality, after a median 4-year follow up.90 A meta-analysis by Regueiro et al. also failed to show any association between PPI and mortality (total and cardiovascular),41 which was similar to the Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) trial that did not show any effect of new PPI post-TAVR on 2-year mortality.4

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A study from the PARTNER trial and registry confirmed PPI after TAVR had higher rates of repeat hospitalization and a longer duration of hospitalization, but did not show any association with 1-year mortality.73 Whether more long-term follow-up is needed to better evaluate this risk of PPI on post-TAVR mortality is yet to be determined, particularly as the therapy extends to low-risk aortic stenosis patients.

Management of Conduction Abnormalities After Transcatheter Aortic Valve Replacement Toggweiler et al. evaluated a cohort of 1,064 patients who underwent TAVR; 6.7% of patients developed delayed HAVB, of which most cases occurred within the first 48 hours, and 2.3% had HAVB at 3–8 days post-TAVR.91 The rates of delayed HAVB in patients with complete RBBB,

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Conduction Abnormalities After Valve Replacement LBBB, and without bundle branch block (BBB) are 27%, 11%, and 2%, respectively.91 A first-degree AVB was associated with a higher probability of subsequent HAVB.91 Overall, the presence of conduction disorders (BBB, first-degree AVB, or bradycardia in patients with AF) on the EKG post-TAVR had high sensitivity (99.0%) and negative predictive value (99.7%) for the occurrence of delayed HAVB.91 The authors propose a treatment algorithm for the management of conduction abnormalities post-TAVR (Figure 2).

first 48 hours, patients can be discharged home with an event monitor. In patients with a self-expandable THV, consider electrophysiology study with development of a new LBBB. A HV interval >65 ms may be suggestive of a significant conduction abnormality and warrant PPI; patients with a HV interval <65 ms can be discharged home with an event monitor. Highrisk patients, such as those with baseline RBBB and bifasicular blocks, may warrant long-term monitoring with an implantable loop recorder if early event monitoring is unremarkable.

Without Conduction Disorders

With Post-procedural High-grade Atrioventricular Block

Patients without new BBB and first-degree AVB did not develop HAVB at 30 days post-TAVR.91 Moreover, the rate of HAVB was low in patients with AF without BBB or bradycardia.91 The temporary venous pacemaker (TVP) can be removed immediately post-procedure, and telemetry monitoring and a daily 12-lead EKG can be continued. Patients without new BBB and first-degree AVB may be candidates for early discharge.

PPI is indicated for either third-degree or advanced second-degree AVB at any anatomic level, which is not expected to resolve, or in the presence of sinus node dysfunction and documented symptomatic bradycardia.92

With a New Left Bundle Branch Block or First-degree Atrioventricular Block

TAVR represents a valid option for treatment of severe symptomatic aortic stenosis. Post-TAVR conduction abnormalities are still a common complication following both self- and balloon-expandable THVs. Predictors of TAVR-induced LBBB and PPI depend on baseline patient characteristics such as preoperative EKG pattern, anatomy of the AVN, His bundle, and surrounding structures, as well as intra-procedural technical factors.

The risk of HAVB is highest in patients with pre-existing RBBB, followed by those with LBBB, and first-degree AVB. It is recommended that TVP is maintained in patients with RBBB and LBBB, and that telemetry monitoring and a daily 12-lead EKG is continued. Avoid atrioventricular nodal blocking agents. In patients with a balloon-expandable THV, consider electrophysiology study if there is a worsening PR interval or the PR interval is >200 ms, or QRS duration is >160 ms in the first 48 hours. However, if the PR interval is stable and QRS duration is <160 ms in the

There is no consensus on how to prevent and/or treat post-TAVR conduction abnormalities. Protocols vary among operators and valve centers. New generation THVs and modified techniques for valve implantation may help to reduce the prevalence of PPI. Further studies are required to validate and establish universal algorithms to manage conduction abnormalities following TAVR, irrespective of the prosthesis type.

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Regueiro A, Abdul-Jawad Altisent O, Del Trigo M, et al. Impact of new-onset left bundle branch block and periprocedural permanent pacemaker implantation on clinical outcomes in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis. Circ Cardiovasc Interv 2016;9:e003635. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003635; PMID: 27169577. 42. van der Boon RM, Houthuizen P, Urena M, et al. Trends in the occurrence of new conduction abnormalities after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2015;85:E144– 52. https://doi.org/10.1002/ccd.25765; PMID: 25504891. 43. De Torres-Alba F, Kaleschke G, Diller GP, et al. Changes in the pacemaker rate after transition from Edwards SAPIEN XT to SAPIEN 3 transcatheter aortic valve implantation: the critical role of valve implantation height. JACC Cardiovasc Interv 2016;9:805–13. https://doi.org/10.1016/j.jcin.2015.12.023; PMID: 27017367. 44. Tarantini G, Mojoli M, Purita P, et al. Unravelling the (arte) fact of increased pacemaker rate with the Edwards SAPIEN 3 valve. EuroIntervention 2015;11:343–50. https://doi.org/10.4244/ EIJY14M11_06; PMID: 25405801. 45. Webb J, Gerosa G, Lefevre T, et al. Multicenter evaluation of a next-generation balloon-expandable transcatheter aortic valve. J Am Coll Cardiol 2014;64:2235–43. https://doi.org/10.1016/j. jacc.2014.09.026; PMID: 25456759. 46. Murray MI, Geis N, Pleger ST, et al. First experience with the new generation Edwards Sapien 3 aortic bioprosthesis: procedural results and short term outcome. J Interv Cardiol 2015;28:109–16. https://doi.org/10.1111/joic.12182; PMID: 25689554. 47. Binder RK, Stortecky S, Heg D, et al. Procedural results and clinical outcomes of transcatheter aortic valve implantation in Switzerland: an observational cohort study of Sapien 3 versus Sapien XT Transcatheter heart valves. Circ Cardiovasc Interv 2015;8. https://doi.org/10.1161/CIRCINTERVENTIONS.115.002653; PMID: 26453687. 48. Schymik G, Lefevre T, Bartorelli AL, et al. European experience with the second-generation Edwards SAPIEN XT transcatheter heart valve in patients with severe aortic stenosis: 1-year outcomes from the SOURCE XT Registry. JACC Cardiovasc Interv 2015;8:657–69. https://doi.org/10.1016/j.jcin.2014.10.026; PMID: 25946437. 49. Gilard M, Eltchaninoff H, Iung B, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med

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2012;366:1705–15. https://doi.org/10.1056/NEJMoa1114705; PMID: 22551129. Kazuno Y, Maeno Y, Kawamori H, et al. Comparison of SAPIEN 3 and SAPIEN XT transcatheter heart valve stent-frame expansion: evaluation using multi-slice computed tomography. Eur Heart J Cardiovasc Imaging 2016;17:1054–62. https://doi.org/10.1093/ehjci/ jew032; PMID: 27002141. Forrest JK, Mangi AA, Popma JJ, et al. Early Outcomes With the Evolut PRO Repositionable Self-Expanding Transcatheter Aortic Valve With Pericardial Wrap. JACC Cardiovasc Interv 2018;11:160–8. https://doi.org/10.1016/j.jcin.2017.10.014; PMID: 29348010. Zannad F, Huvelle E, Dickstein K, et al. Left bundle branch block as a risk factor for progression to heart failure. Eur J Heart Fail 2007;9:7–14. https://doi.org/10.1016/j.ejheart.2006.04.011; PMID: 16890486. Zhang ZM, Rautaharju PM, Soliman EZ, et al. Mortality risk associated with bundle branch blocks and related repolarization abnormalities (from the Women’s Health Initiative [WHI]). Am J Cardiol 2012;110:1489–95. https://doi.org/10.1016/j. amjcard.2012.06.060; PMID: 22858187. Gutierrez M, Rodes-Cabau J, Bagur R, et al. Electrocardiographic changes and clinical outcomes after transapical aortic valve implantation. Am Heart J 2009;158:302–8. https://doi. org/10.1016/j.ahj.2009.05.029; PMID: 19619709. Sinhal A, Altwegg L, Pasupati S, et al. Atrioventricular block after transcatheter balloon expandable aortic valve implantation. JACC Cardiovasc Interv 2008;1:305–9. https://doi.org/10.1016/j. jcin.2007.12.009; PMID: 19463318. Piazza N, Onuma Y, Jesserun E, et al. Early and persistent intraventricular conduction abnormalities and requirements for pacemaking after percutaneous replacement of the aortic valve. JACC Cardiovasc Interv 2008;1:310–6. https://doi.org/10.1016/j. jcin.2008.04.007; PMID: 19463319. Godin M, Eltchaninoff H, Furuta A, et al. Frequency of conduction disturbances after transcatheter implantation of an Edwards Sapien aortic valve prosthesis. Am J Cardiol 2010;106:707–12. https://doi.org/10.1016/j.amjcard.2010.04.029; 20723650. Nazif TM, Williams MR, Hahn RT, et al. Clinical implications of new-onset left bundle branch block after transcatheter aortic valve replacement: analysis of the PARTNER experience. Eur Heart J 2014;35:1599–607. https://doi.org/10.1093/eurheartj/ eht376; PMID: 24179072. Yu CM, Chan JY, Zhang Q, et al. Biventricular pacing in patients with bradycardia and normal ejection fraction. N Engl J Med 2009;361:2123–34. https://doi.org/10.1056/NEJMoa0907555; PMID: 19915220. Vernooy K, Verbeek XA, Peschar M, et al. Left bundle branch block induces ventricular remodelling and functional septal hypoperfusion. Eur Heart J 2005;26:91–8. https://doi.org/10.1093/ eurheartj/ehi008; PMID: 15615805. Saji M, Murai T, Tobaru T, et al. Autopsy finding of the Sapien XT valve from a patient who died suddenly after transcatheter aortic valve replacement. Cardiovasc Interv Ther 2013;28:267–71. https://doi.org/10.1007/s12928-012-0153-9; PMID: 23277347. Urena M, Webb JG, Eltchaninoff H, et al. Late cardiac death in patients undergoing transcatheter aortic valve replacement: incidence and predictors of advanced heart failure and sudden cardiac death. J Am Coll Cardiol 2015;65:437–48. https://doi. org/10.1016/j.jacc.2014.11.027; PMID: 25660921. Hamdan A, Guetta V, Klempfner R, et al. Inverse relationship between membranous septal length and the risk of atrioventricular block in patients undergoing transcatheter aortic valve implantation. JACC Cardiovasc Interv 2015;8:1218–28. https://doi.org/10.1016/j.jcin.2015.05.010; PMID: 26292585. Roten L, Wenaweser P, Delacretaz E, et al. Incidence and predictors of atrioventricular conduction impairment after transcatheter aortic valve implantation. Am J Cardiol 2010;106:1473–80. https://doi.org/10.1016/j. amjcard.2010.07.012; PMID: 21059439. Guetta V, Goldenberg G, Segev A, et al. Predictors and course of high-degree atrioventricular block after transcatheter aortic valve implantation using the CoreValve Revalving System. Am J Cardiol 2011;108:1600–5. https://doi.org/10.1016/j. amjcard.2011.07.020; PMID: 21880290. Lenders GD, Collas V, Hernandez JM, et al. Depth of valve implantation, conduction disturbances and pacemaker implantation with CoreValve and CoreValve Accutrak system for Transcatheter Aortic Valve Implantation, a multi-center study. Int J Cardiol 2014;176:771–5. https://doi.org/10.1016/j. ijcard.2014.07.092; PMID: 25147076. Mauri V, Reimann A, Stern D, et al. Predictors of permanent pacemaker implantation after transcatheter aortic valve replacement with the SAPIEN 3. JACC Cardiovasc Interv 2016;9:2200–9. https://doi.org/10.1016/j.jcin.2016.08.034; PMID: 27832845. Jilaihawi H, Chin D, Vasa-Nicotera M, et al. Predictors for permanent pacemaker requirement after transcatheter aortic valve implantation with the CoreValve bioprosthesis. Am Heart J 2009;157:860–6. https://doi.org/10.1016/j.ahj.2009.02.016; PMID: 19376312.

69. T zamtzis S, Viquerat J, Yap J, et al. Numerical analysis of the radial force produced by the Medtronic-CoreValve and Edwards-SAPIEN after transcatheter aortic valve implantation (TAVI). Med Eng Phys 2013;35:125–30. https://doi.org/10.1016/j. medengphy.2012.04.009; PMID: 22640661. 70. Bussink BE, Holst AG, Jespersen L, et al. Right bundle branch block: prevalence, risk factors, and outcome in the general population: results from the Copenhagen City Heart Study. Eur Heart J 2013;34:138–46. https://doi.org/10.1093/eurheartj/ ehs291; PMID: 22947613. 71. Xiong Y, Wang L, Liu W, et al. The prognostic significance of right bundle branch block: a meta-analysis of prospective cohort studies. Clin Cardiol 2015;38:604–13. https://doi.org/10.1002/ clc.22454; PMID: 26436874. 72. Chorianopoulos E, Krumsdorf U, Pleger ST, et al. Incidence of late occurring bradyarrhythmias after TAVI with the selfexpanding CoreValve® aortic bioprosthesis. Clin Res Cardiol 2012;101:349–55. https://doi.org/10.1007/s00392-011-0398-9; PMID: 22179559. 73. Nazif TM, Dizon JM, Hahn RT, et al. Predictors and clinical outcomes of permanent pacemaker implantation after transcatheter aortic valve replacement: the PARTNER (Placement of AoRtic TraNscathetER Valves) trial and registry. JACC Cardiovasc Interv 2015;8:60–9. https://doi.org/10.1016/j. jcin.2014.07.022; PMID: 25616819. 74. Watanabe Y, Kozuma K, Hioki H, et al. Pre-existing right bundle branch block increases risk for death after transcatheter aortic valve replacement with a balloon-expandable valve. JACC Cardiovasc Interv 2016;9:2210–6. https://doi.org/10.1016/j. jcin.2016.08.035; PMID: 27832846. 75. Auffret V, Webb JG, Eltchaninoff H, et al. Clinical Impact of baseline right bundle branch block in patients undergoing transcatheter aortic valve replacement. JACC Cardiovasc Interv 2017;10:1564–74. https://doi.org/10.1016/j.jcin.2017.05.030; PMID: 28734885. 76. Fadahunsi OO, Olowoyeye A, Ukaigwe A, et al. Incidence, predictors, and outcomes of permanent pacemaker implantation following transcatheter aortic valve replacement: analysis from the U.S. Society of Thoracic Surgeons/American College of Cardiology TVT Registry. JACC Cardiovasc Interv 2016;9:2189–99. https://doi.org/10.1016/j.jcin.2016.07.026; PMID: 27832844. 77. Baan J Jr, Yong ZY, Koch KT, et al. Factors associated with cardiac conduction disorders and permanent pacemaker implantation after percutaneous aortic valve implantation with the CoreValve prosthesis. Am Heart J 2010;159:497–503. https://doi.org/10.1016/j.ahj.2009.12.009; PMID: 20211315. 78. Chevreul K, Brunn M, Cadier B, et al. Cost of transcatheter aortic valve implantation and factors associated with higher hospital stay cost in patients of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. Arch Cardiovasc Dis 2013;106:209–19. https://doi.org/10.1016/j.acvd.2013.01.006; PMID: 23706367. 79. 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. https://doi. org/10.1016/j.jcin.2014.04.005; PMID: 25086843. 80. Reynolds MR, Magnuson EA, Lei Y, et al. Cost-effectiveness of transcatheter aortic valve replacement compared with surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results of the PARTNER (Placement of Aortic Transcatheter Valves) trial (Cohort A). J Am Coll Cardiol 2012;60:2683–92. https://doi.org/10.1016/j.jacc.2012.09.018; PMID: 23122802. 81. Urena M, Webb JG, Tamburino C, et al. Permanent pacemaker implantation after transcatheter aortic valve implantation: impact on late clinical outcomes and left ventricular function. Circulation 2014;129:1233–43. https://doi.org/10.1161/ CIRCULATIONAHA.113.005479; PMID: 24370552. 82. Buellesfeld L, Stortecky S, Heg D, et al. Impact of permanent pacemaker implantation on clinical outcome among patients undergoing transcatheter aortic valve implantation. J Am Coll Cardiol 2012;60:493–501. https://doi.org/10.1016/j. jacc.2012.03.054; PMID: 22726632. 83. Steinberg BA, Harrison JK, Frazier-Mills C, et al. Cardiac conduction system disease after transcatheter aortic valve replacement. Am Heart J 2012;164:664–71. https://doi. org/10.1016/j.ahj.2012.07.028; PMID: 23137496. 84. Akin I, Kische S, Schneider H, et al. Surface and intracardiac ECG for discriminating conduction disorders after CoreValve implantation. Clin Res Cardiol 2012;101:357–64. https://doi. org/10.1007/s00392-011-0400-6; PMID: 22179507. 85. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013;368:1585–93. https://doi.org/10.1056/NEJMoa1210356; PMID: 23614585. 86. Steinberg JS, Fischer A, Wang P, et al. The clinical implications of cumulative right ventricular pacing in the multicenter automatic defibrillator trial II. J Cardiovasc Electrophysiol 2005;16:359–65. https://doi.org/10.1046/j.1540-

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Conduction Abnormalities After Valve Replacement

8167.2005.50038.x; PMID: 15828875. 87. M oss 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. https://doi. org/10.1056/NEJMoa013474; PMID: 11907286. 88. Hoffmann R, Herpertz R, Lotfipour S, et al. Impact of a new conduction defect after transcatheter aortic valve implantation on left ventricular function. JACC Cardiovasc Interv 2012;5:1257–63. https://doi.org/10.1016/j.jcin.2012.08.011; PMID: 23257374. 89. Dizon JM, Nazif TM, Hess PL, et al. Chronic pacing and

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adverse outcomes after transcatheter aortic valve implantation. Heart 2015;101:1665–71. https://doi.org/10.1136/ heartjnl-2015-307666; PMID: 26261157. 90. Chamandi C, Barbanti M, Munoz-Garcia A, et al. Long-term outcomes in patients with new permanent pacemaker implantation following transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11:301–10. https://doi.org/10.1016/j. jcin.2017.10.032; PMID: 29413244. 91. Toggweiler S, Stortecky S, Holy E, et al. The Electrocardiogram after transcatheter aortic valve replacement determines the risk for post-procedural high-degree AV Block and

the need for telemetry monitoring. JACC Cardiovasc Interv 2016;9:1269–76. https://doi.org/10.1016/j.jcin.2016.03.024; PMID: 27339844. 92. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/ HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013;61:e6–75. https://doi.org/10.1016/j.jacc.2012.11.007; PMID: 23265327.

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Interventional Cardiology: Structural Heart

Value of MitraClip in Reducing Functional Mitral Regurgitation Mehmet Ali Elbey, MD, Luis Augusto Palma Dalan, MD, and Guilherme Ferragut Attizzani, MD Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH

Abstract Patients with heart failure who have secondary severe mitral regurgitation due to left ventricular dysfunction have a poor prognosis, with high rates of rehospitalization and mortality. Percutaneous mitral valve repair using the MitraClip (Abbott) has been shown to be safe and effective in secondary severe mitral regurgitation with heart failure. The number of MitraClip procedures performed has increased significantly, as recently published large, randomized clinical studies have shown. However, these studies have drawn different conclusions. This review aims to summarize the current evidence for the MitraClip procedure and provide information for its safe and successful implementation, comparing the studies that examined the use of MitraClip versus medical therapy alone or surgical repair for severe secondary mitral regurgitation.

Keywords MitraClip, secondary mitral regurgitation, heart failure, medical therapy Disclosure: Guilherme Attizzani is a consultant for Abbott Vascular. The other authors have no conflicts of interest to declare. Received: December 11, 2018 Accepted: February 8, 2019 Citation: US Cardiology Review 2019;13(1):30–4. DOI: https://doi.org/10.14520/usc.2018.19.1 Correspondence: Guilherme F Attizzani, Harrington Heart and Vascular Institute, University Hospitals, Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106. E: Guilherme.Attizzani@UHhospitals.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The field of mitral valve disease diagnosis and management is in constant change. New understanding of disease pathology and progression, with improvements in and increased use of sophisticated imaging modalities have led to more complex treatments. Transcatheter mitral valve repair with a MitraClip device is resulting in good outcomes in patients with primary mitral regurgitation who are at high surgical risk.1 In primary mitral regurgitation, surgical repair of the mitral valve and its apparatus is the standard of care. However, surgical treatment of secondary mitral regurgitation has not been demonstrated to be better than medical therapy regarding improvement in quality of life or survival, and mitral valve surgery treatment has a weak class IIb recommendation according to 2017 European Society of Cardiology and American Heart Association/American College of Cardiology (ESC/ ACC/AHA) guidelines for the management of patients with valvular heart disease. 2,3 In this paper, we review recently published articles on MitraClip therapy.

Pathophysiology Mitral regurgitation (MR) is classified as either primary or secondary. Primary and secondary MR are two different disease states.3 Primary MR is the result of pathology of one or more components of the mitral valve apparatus. In patients with secondary MR, the chordae tendineae and mitral valve leaflets are structurally normal, and mitral regurgitation results from dilatation or remodeling of the left ventricle, causing either leaflet tethering and/or impaired coaptation. The main cause of

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the disease is the underlying cardiomyopathy, and the regurgitation is probably a signal or marker of the disease; the ventricle, not the valve, is the culprit. The presence of chronic secondary MR is associated with an impaired prognosis. 4–6 Secondary MR is strongly associated with hospitalization for heart failure (HF) and mortality despite treatment with medical therapy alone.7,8 No data have yet demonstrated whether a lack of improvement in left ventricular function affects survival.9,10 In patients with secondary MR, which is mainly a disease of the left ventricle, treatment options have advanced significantly. The use of transcatheter techniques for both repair and replacement is expected to expand substantially in the next few years.1

MitraClip Procedure The percutaneous mitral valve repair procedure involves of the implantation of a dedicated device – the MitraClip – in both mitral cuspids at the same time; attachment of the leaflets helps to reduce regurgitant flow. It is performed under general anesthesia, under the guidance of transesophageal echocardiography (TEE) and fluoroscopy. A trans-septal puncture procedure is performed to gain access to the left atrium. The mitral leaflets are grasped onto the MitraClip and the device is closed, resulting in a fixed approximation of the mitral leaflets. Adequate reduction of mitral regurgitation to a grade of 2+ or less is considered successful according to intraoperative TEE. If the reduction of the degree of mitral regurgitation is still inadequate, a second device may be deployed.11–13 Figure 1 shows the MitraClip.

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MitraClip in Functional Mitral Regurgitation Clinical Studies

Figure 1: MitraClip Procedure and Result

Prospective studies suggest that percutaneous mitral valve repair with a MitraClip may decrease symptoms and improve functional capacity and quality of life in patients with secondary MR.14,15 However, these studies were not randomized controlled trials. Therefore, current guidelines do not strongly recommend percutaneous repair for secondary MR.2,3

The Endovascular Valve Edge-to-Edge Repair Study (EVEREST II) trial randomized 279 relatively low-risk patients (left ventricle ejection fraction >60%, and most with New York Heart Association [NYHA] class II or III symptoms) to a MitraClip device group (184 patients, 73% primary MR, 27% secondary MR) or a mitral valve surgery group (95 patients, 73% primary MR, 27% secondary MR).16 Although the degree of mitral regurgitation reduction was lower with the MitraClip procedure than surgical mitral valve repair, reduction of mitral regurgitation to ≤2+ was observed in most of the MitraClip patients, an effect that was sustained over 5 years. The MitraClip group had similar 1- and 5-year effectiveness as the mitral valve surgery group in the subset of patients with secondary MR, but not in those with primary MR. Patients treated with a MitraClip more commonly required surgery for residual mitral regurgitation during the first year after treatment but, between 1 and 5 years of follow-up, both groups experienced low rates of surgery.17 In the Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation (GRASP) registry, the safety and efficacy of the MitraClip technique were demonstrated in degenerative and secondary MR (3+–4+) in both men and women who could not have repair surgery or were at a high surgical risk.18,19 Its efficiency has also been demonstrated in patients aged over 75 years.20 However, the GRASP Registry was not a randomized controlled clinical study, and there was no control group. In the ACCESS-Europe Two-Phase Observational Study of the MitraClip System in Europe (ACCESS EU) trial, a total of 567 patients with significant mitral valve regurgitation underwent the MitraClip procedure. Patients had NYHA functional class III or IV symptoms. Left ventricular ejection fraction <40% was present in 52.7% of patients, and 5% of patients had an ejection fraction of <20%. The MitraClip device implant rate was 99.6%. There was a reduction in the severity of MR at 12 months, compared with baseline (p< 0.0001), with 78.9% of patients free from MR, and severity of >2+ at 12 months. At 12 months, 71.4% of patients had either NYHA functional class II or class I symptoms. Although the patients undergoing MitraClip therapy were elderly and were at high surgical risk, the MitraClip procedure was demonstrated to be effective, with low rates of adverse events and hospital mortality.21

A: Echocardiogram showing severe mitral regurgitation. B: Echocardiogram showing MitraClip pre-implantation; C: 3D-echocardiogram showing mild mitral regurgitation after MitraClip deployment. D: Final echocardiogram showing mild mitral regurgitation after MitraClip deployment.

either a MitraClip group (152 patients, MitraClip plus medical therapy) or a control group (152 patients, medical therapy alone).10,22 Patients had to have a left ventricular ejection fraction of 15–40% and chronic HF symptoms (NYHA functional class II, III, or IV). In the MitraClip group, implantation was attempted in 144 patients, and technical success in fitting the device was achieved in 138 of these patients (95.8%). At the time of discharge, the patients were evaluated with regard to the severity of MR in the intervention group. Of these patients, 113 (91.9%) had a reduction in MR to 2+ or lower, and 93 patients (75.6%) had a substantial reduction to 1+ or 0. The composite primary outcome of death from any cause or unplanned hospitalization for HF at 12 months occurred in 83 patients (54.6%) in the MitraClip group, and in 78 patients (51.3%) in the control group (p=0.53). At 12 months, there had been 37 deaths (24.3%) in the MitraClip group and 34 (22.4%) in the control group. In the MitraClip group, 74 patients (48.7%) had an unplanned hospitalization for HF, compared with 72 patients (47.4%) in the control group (p=ns).10,22 The MITRA-FR trial investigators concluded that percutaneous mitral valve repair plus medical therapy offered no advantage over medical therapy alone in patients with HF with a reduced ejection fraction and secondary mitral valve regurgitation.

COAPT Trial Recently, two large studies with similar characteristics but with conflicting results were published, and comparing them helps us to better understand what kind of patients should be treated with the transcatheter mitral technique.

MITRA-FR Trial In the MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) trial, a multicenter, randomized controlled study, patients presenting with secondary MR were randomized to

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Another large study, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, evaluated the reduction in risk of HF hospitalization and mortality.11,23 It included 614 patients with HF and moderate to severe or severe functional MR who were randomized to percutaneous mitral valve repair (MitraClip group: n=302; mean age 72 years; 67% men) or medical therapy alone (the control group: n=312; mean age 73 years; 62% men). The primary effectiveness endpoint was all hospitalizations for HF within 24 months of follow-up. Patients had non-ischemic or ischemic cardiomyopathy with a left ventricular ejection

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Interventional Cardiology: Structural Heart Figure 2: Optimal Approach for Secondary Mitral Valve Regurgitation Treatment

non-blinded trial undoubtedly increases the chances of selection bias but may not explain the dramatic effect sizes noted in the COAPT trial.9,24 The two studies are complementary to one another rather than controversial.

Secondary MR

Patient Selection and Follow-up MITRA-FR was the first prospective randomized trial of functional MR catheter-based treatment, and it concluded that percutaneous mitral valve repair was of no benefit. The MitraClip procedure was deemed safe and efficient and it decreased regurgitation but did not improve clinical outcomes according to this study. However, a lot of data on patients’ follow-up echocardiographic results were missing.10 Conversely, in the COAPT trial, the clinical, functional, echocardiographic and health status outcomes were all congruent.23

CAD Rx HF Rx Consider CRT

Symptomatic severe MR (stage D)

Asymptomatic severe MR (stage C)

Progressive MR (stage B)

Persistent NYHA class III–IV symptoms

MitraClip procedure

MV surgery* (IIb)

Periodic monitoring

CAD Rx = coronary artery disease therapy; CRT = cardiac resynchronization therapy; HF Rx = heart failure therapy; MR = mitral regurgitation; MV = mitral valve; NYHA = New York Heart Association. Source: Nishimura et al. 2017.2 Reproduced with permission from Elsevier.

fraction of 20–50%, moderate to severe (grade 3) or severe (grade 4) secondary MR confirmed with echocardiography, and were symptomatic (NYHA functional class II, III, or IV) despite the use of guideline-directed medical therapy at maximally tolerated doses. MitraClip implantation was attempted in 293 of the 302 patients (97.0%) in the device group, with one or more clips implanted in 287 patients. The rate of freedom from device-related complications at 12 months was 96.6%.23 The rate of HF hospitalizations per year was lower in the device group than the control group (35.8% versus 67.9%, p<0.001). In addition, the secondary endpoint of 2–year mortality was significantly lower among MitraClip patients at 29.1% versus 46.1% for the controls. The absolute risk reduction in all-cause mortality in patients receiving the MitraClip in the COAPT trial was 17%, which translates to a number needed to treat of six to prevent one death over 2 years. It was the first therapy shown to improve the prognosis in high-risk patients with secondary MR due to underlying left ventricular dysfunction.

Comparison of MITRA-FR and COAPT Trials MitraClip had been demonstrated as a successful therapy before in patients who were at high surgical risk. The difference in the results of these two randomized studies are likely to be related to patient selection, number of patients, medication changes during the study, duration of follow-up and operator experience. Rigorously screening patients in a

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Safety The MitraClip is a less invasive and a much safer therapy than surgery in this group of patients. An important result of the study was it showed how safe the procedure is. The complication rate was only about 3% in a population with a high mortality risk. Device failure or complication rates were lower than expected.10,18,19,23 The low mortality risk associated with the MitraClip procedure was demonstrated in a recently published meta-analysis that identified 21 studies in high-risk patients, representing real-world experience, where the MitraClip was used in 3,198 patients and mitral surgery in 53,265, with a mean age of 74 years. Procedural success was observed in 96% of patients who underwent MitraClip implantation and 98% in the surgical group.25 The MitraClip procedure is safe, even in a critically ill patient group.13

Hemodynamics The severity of mitral regurgitation accepted in COAPT was substantially greater and the ventricles were not severely dilated in this study. Comparing the control arms of COAPT and MITRA-FR trials at 1-year time points reveal that rates of all-cause mortality were similar (23% and 22% respectively), which suggests the patient population enrolled in the two RCTs were not drastically different. The degree of mitral regurgitation among patients selected in COAPT was more severe than in MITRA-FR. Mean effective regurgitant orifice area was 41 mm2 in COAPT and 31 mm2 in MITRA-FR. The mean ejection fraction in the MitraClip implantation arms was similar (31.3% in COAPT and 33.3% in MITRA-FR). Notably, the indexed left-ventricular end-diastolic volume was higher in MITRA-FR (135 ± 37 ml/m2) than in COAPT (10 ± 34 ml/m2). These are key differences between the trials as far as identifying which patients would benefit the most. However, both these indexed left ventricular volumes would be considered to indicate severely dilated ventricles, as per the echocardiographic guidelines.2 More importantly, subgroup analyses in COAPT in patients with left ventricular volumes similar to MITRA-FR showed similar reductions, so may not explain the discordant results.

Medical Treatment and pro-BNP HF medications were allowed to be changed in the MITRA-FR trial but, in COAPT, patients were on maximally tolerated guideline-directed

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MitraClip in Functional Mitral Regurgitation medical therapy at baseline with few major changes during follow-up. Also N-terminal pro-B-type natriuretic peptide (pro-BNP) levels (a wellaccepted surrogate marker of left ventricular stress) were higher at baseline in the COAPT trial population.9

Volume of Cases and Center Experience Operator experience is important as it affects outcomes. Centers with a higher number of patients treated with MitraClip have the best results; the GRASP registry demonstrated that high-volume centers had more successful results.18,20 The procedure is invasive and difficult, and requires a steep learning curve. According to the MITRA-FR trial investigators, centers were required to be experienced in the MitraClip procedure and to have performed it at least five times before they could be selected as a trial site.21 This may be a limitation of MITRA-FR results. Five cases may not be enough to guarantee adequate experience in carrying out the MitraClip procedure.

Validation Trials and Guidelines Recommendation Following the MITRA-FR and COAPT studies, ESC/ACC/AHA guidelines’ recommendations may change, but the MitraClip will be used in more patients regardless. The results are pending for an ongoing 420-patient study, Clinical Evaluation of the Safety and Effectiveness of the MitraClip System in the Treatment of Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF2; NCT02444338), which randomized patients in a similar way as the COAPT trial and has run since 2015 in Europe.26 If the findings of this study are similar to those of the COAPT trial, it would open doors to performing the MitraClip procedure in appropriately selected patients. Certainly, the COAPT trial results should not be extrapolated to a broader secondary patient population with MR and HF. In a shared decisionmaking model, only carefully selected patients, using a heart-team

ishimura RA, Vahanian A, Eleid MF, Mack MJ. Mitral valve N disease – current management and future challenges. Lancet 2016;387:1324–34. https://doi.org/10.1016/S01406736(16)00558-4; PMID: 27025438. 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. https://doi.org/10.1016/j.jacc.2017.03.011; PMID: 28315732. 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. https://doi.org/10.1093/eurheartj/ehx391; PMID: 28886619. Stone GW, Vahanian AS, Adams DH, et al. Clinical trial design principles and endpoint definitions for transcatheter mitral valve repair and replacement: part 1: clinical trial design principles: a consensus document from the Mitral Valve Academic Research Consortium. J Am Coll Cardiol 2015;66:278–307. https://doi. org/10.1016/j.jacc.2015.05.046; PMID: 26184622. Carabello BA. The current therapy for mitral regurgitation. J Am Coll Cardiol 2008;52:319–26. https://doi.org/10.1016/j. jacc.2008.02.084; PMID: 18652937. Grigioni F, Enriquez-Sarano M, Zehr KJ, et al. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103:1759– 64. https://doi.org/10.1161/01.CIR.103.13.1759; PMID: 11282907. Goliasch G, Bartko PE, Pavo N, et al. Refining the prognostic impact of functional mitral regurgitation in chronic heart failure. Eur Heart J 2018;39:39–46. https://doi.org/10.1093/eurheartj/ ehx402; PMID: 29020337. Levine RA, Schwammenthal E. Ischemic mitral regurgitation on the threshold of a solution: from paradoxes to unifying

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10.

11.

12.

13.

14.

15.

approach, should undergo the MitraClip procedure for treatment of secondary MR. Whether the conflicting results of the MITRA-FR and COAPT trials are down to a case of intervening early or late in the course of the disease remains to be established. Until then, patients with MR secondary to HF who meet the COAPT trial criteria may benefit from a MitraClip. HF specialists need to identify these patients and refer them to the heart team. In the past, this patient population was mostly treated with medical therapy. Now, the MitraClip may become standard care for these patients. It can substantially improve their exercise capacity and quality of life, reduce their need for HF hospitalization, and improve their survival. HF is the first overall cause of morbidity and mortality in developed countries, and has tremendous cost implications for resource utilization. The differences between MITRA-FR and COAPT also allow us to understand this complex disease better. The optimal approach for secondary MR treatment is shown in an algorithm (Figure 2).

Conclusion MitraClip has been demonstrated to be a successful therapy for patients at high surgical risk. The MitraClip procedure can be safely and effectively performed in patients with severe secondary MR. Two recent large randomized studies (the MITRA-FR and COAPT trials) have conflicting results, but they should be interpreted as complementary trials. Although the MITRA-FR trial did not show significant differences between the intervention and control groups, the COAPT trial demonstrated a reduction in hospitalization and mortality rates in patients with HF and secondary MR in the MitraClip group compared with those receiving medical therapy alone. Cardiologists should individualize treatments in accordance with patient characteristics, and select patients who would benefit from the procedure accurately.

concepts. Circulation 2005; 112:745–58. https://doi.org/10.1161/ CIRCULATIONAHA.104.486720; PMID: 16061756. Sorajja P, Vemulapalli S, Feldman T, et al. Outcomes with transcatheter mitral valve repair in the United States: an STS/ ACC TVT Registry report. J Am Coll Cardiol 2017;70:2315–27. https://doi.org/10.1016/j.jacc.2017.09.015; PMID: 29096801. Obadia JF, Messika-Zeitoun D1, Leurent G1, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation. N Engl J Med 2018;379:2297–306. https://doi.org/10.1056/ NEJMoa1805374; PMID: 30145927. Mack MJ, Abraham WT, Lindenfeld J, et al. Cardiovascular outcomes assessment of the MitraClip in patients with heart failure and secondary mitral regurgitation: design and rationale of the COAPT trial. Am Heart J 2018;205:1–11. https://doi. org/10.1016/j.ahj.2018.07.021; PMID: 30134187. Feldman T, Wasserman HS, Herrmann HC, et al. Percutaneous mitral valve repair using the edge-to-edge technique: six-month results of the EVEREST Phase I clinical trial. J Am Coll Cardiol 2005;46:2134–40. https://doi.org/10.1016/j.jacc.2005.07.065; PMID: 16325053. Feldman T, Mehta A, Guerrero M, et al. MitraClip therapy for mitral regurgitation secondary mitral regurgitation. Intervent Cardiol Clin 2016;5:83–91. https://doi.org/10.1016/j. iccl.2015.08.007; PMID: 27852484. Armoiry X, Brochet E, Lefevre T, et al. Initial French experience of percutaneous mitral valve repair with the MitraClip: a multicentre national registry. Arch Cardiovasc Dis 2013;106:287–94. https://doi.org/10.1016/j.acvd.2013.03.059; PMID: 23769403. Baldus S, Schillinger W, Franzen O, et al. MitraClip therapy in daily clinical practice: initial results from the German transcatheter mitral valve interventions (TRAMI) registry. Eur J Heart Fail 2012;14:1050–5. https://doi.org/10.1093/eurjhf/hfs079; PMID: 22685268.

16. F eldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med 2011;364:1395–406. https://doi.org/10.1056/NEJMoa1009355; PMID: 21463154. 17. Feldman T, Kar S, Elmariah S, et al. Randomized comparison of percutaneous repair and surgery for mitral regurgitation: 5–year results of EVEREST II. J Am Coll Cardiol 2015;66:2844–54. https:// doi.org/10.1016/j.jacc.2015.10.018; PMID: 26718672. 18. Grasso C, Capodanno D, Scandura S, et al. One- and twelvemonth safety and efficacy outcomes of patients undergoing edge-to-edge percutaneous mitral valve repair (from the GRASP Registry). Am J Cardiol 2013;111:1482–7. https://doi.org/10.1016/j. amjcard.2013.01.300; PMID: 23433761. 19. Attizzani GF, Ohno Y, Capodanno D, et al. Gender-related clinical and echocardiographic outcomes at 30–day and 12–month follow up after MitraClip implantation in the GRASP registry. Catheter Cardiovasc Interv 2015; 85:889–97. https://doi.org/10.1002/ ccd.25715; PMID: 25367550. 20. Scandura S, Capranzano P, Caggegi A, et al. Percutaneous mitral valve repair with the MitraClip system in the elderly: one-year outcomes from the GRASP registry. Int J Cardiol 2016;224:440–6. https://doi.org/10.1016/j.ijcard.2016.09.076; PMID: 27710781. 21. Maisano F, Franzen O, Baldus S et al. Percutaneous mitral valve interventions in the real world early and 1–year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe. J Am Coll Cardiol 2013;62:1052–61. https://doi.org/10.1016/j.jacc.2013. 02.094; PMID: 23747789. 22. Obadia JF, Armoiry X, Iung B, et al. The MITRA-FR study: design and rationale of a randomised study of percutaneous mitral valve repair compared with optimal medical management alone for severe secondary mitral regurgitation. EuroIntervention 2015;10:1354–60. https://doi.org/10.4244/EIJV10I11A232; PMID: 25798568.

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Interventional Cardiology: Structural Heart 23. S tone GW, Lindenfeld JA, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med 2018;379:2307–18. https://doi.org/10.1056/NEJMoa1806640; PMID: 30280640. 24. Arora G, Patel N, Arora P. Futile MITRA-FR and a positive COAPT trial: Where does the evidence leave the clinicians?

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Int J Cardiol Heart Vasc 2018;22:18–9. https://doi.org/10.1016/j. ijcha.2018.11.003; PMID: 30505928. 25. P hilip F, Athappan G, Tuzcu EM, et al. MitraClip for severe symptomatic mitral regurgitation in patients at high surgical risk: a comprehensive systematic review. Catheter Cardiovasc Interv 2014; 84:581–90. https://doi.org/10.1002/ccd.25564; PMID: 24905665.

26. A clinical evaluation of the safety and effectiveness of the MitraClip system in the treatment of clinical significant functional mitral regurgitation (Reshape-HF2). Clinical Trials. gov identifier: NCT02444338, 2015. Available at: https:// clinicaltrials.gov/ct2/show/NCT02444338 (accessed February 9, 2019).

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Interventional Cardiology: Structural Heart

Transcatheter Edge-to-edge Repair of Severe Tricuspid Regurgitation Shu-I Lin, MD, 1,2 Mizuki Miura MD, PhD, 1 Francesco Maisano, MD, 1 Michel Zuber, MD, 1 Mara Gavazzoni, MD, 1,3 Edwin C Ho, MD, 1,4 Alberto Pozzoli, MD, 1 and Maurizio Taramasso, MD, PhD 1 1. Heart Valve Clinic, University Hospital of Zurich, Zurich, Switzerland; 2. Cardiovascular Center, MacKay Memorial Hospital, Tamsui, Taiwan; 3. Cardiology Department, University of Brescia, Brescia, Italy; 4. Division of Cardiology, St Michael’s Hospital, Toronto, Canada

Abstract Despite the increasing knowledge of the long-term adverse consequence of severe tricuspid regurgitation (TR), most patients with moderateto-severe TR are still treated conservatively because of the high risk of surgery. Percutaneous procedures have emerged as an attractive alternative treatment. Transcatheter edge-to-edge repair is a validated technique to treat mitral regurgitation. In recent years, the same concept has been applied to patients with TR and prohibitive operative risk. Early trials have shown feasibility and safety. More clinical experiences and long-term results are still being gathered. In this article, we provide an overview of transcatheter edge-to-edge repair and look at the current evidence and clinical results regarding procedure.

Keywords Tricuspid valve, tricuspid regurgitation, transcatheter tricuspid valve intervention, transcatheter edge-to-edge repair Disclosure: MT is a consultant for Abbott Vascular, Boston Scientific, CoreMedic, and 4Tech and has received speaker fees from Edwards Lifesciences. Francesco Maisano is a consultant for Abbott Vascular, Medtronic, Edwards Lifesciences, Perifect, Xeltis, Transseptal Solutions, and Cardiovalve. He receives grant support from Abbott Vascular, Medtronic, Edwards Lifesciences, Biotronik, and Boston Scientific Corporation, and royalties from Edwards Lifesciences and 4Tech. MM is a consultant for Japan Lifeline. The other authors have no other conflicts of interest to declare. Received: December 13, 2018 Accepted: January 29, 2019 Citation: US Cardiology Review 2019;13(1):35–40. DOI: https://doi.org/10.15420/usc.2018.20.1 Correspondence: Maurizio Taramasso, Cardiovascular Surgery Department, University Hospital of Zurich, Rämistrasse 100, CH-8091, Zurich, Switzerland. E: Maurizio.Taramasso@usz.ch Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Moderate-to-severe tricuspid regurgitation (TR) is estimated to affect more than 1.6 million people in the US. However, fewer than 8,000 tricuspid valve operations are performed each year.1,2 There is clearly an unmet need for a tricuspid valve (TV) intervention. There has been rapid development in the field of transcatheter aortic and mitral valve interventions and percutaneous management of tricuspid valve disease has also evolved substantially in recent years. With increasing evidence of a poor prognosis associated with untreated severe TR, the once ‘forgotten valve’ has gained more attention.3 In this article, we provide a review of tricuspid regurgitation and transcatheter edge-to-edge repair.

Etiology of Tricuspid Valve Regurgitation The most frequent etiology of tricuspid valve disease is secondary (or functional). In a study of 242 consecutive patients diagnosed with severe TR by echocardiography, 90% of the patients were defined as secondary TR.4 Secondary TR refers to TR with anatomically normal leaflets and chords with regurgitation occurring due to right atrium and ventricle dilatation, annulus dilatation, and leaflet tethering leading to malcoaptation. The common causes of secondary TR are left-side myocardial or valvular heart disease and pulmonary hypertension. Atrial remodeling associated with atrial fibrillation and annulus dilatation is also a notable cause of significant TR5.

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Primary TR accounts for 10% of severe TR, and is caused by the process that directly affect the leaflets of the tricuspid valve. The common causes include congenital abnormality, tricuspid prolapse, trauma, endocarditis, and intragenic injury by myocardial biopsy or intracardiac leads.6,7 Table 1 lists possible causes of TR.

Image Evaluation The primary method of evaluating tricuspid valve regurgitation is echocardiography. Transthoracic echocardiography (TTE) can allow the etiology and severity to be evaluated by measuring the dimension of the right ventricle, right atrium, and tricuspid annulus. Other important information includes tricuspid valve motion, coaptation, Doppler color flow of the TV, right ventricular function, pulmonary artery pressure, and concomitant left-sided valvular or myocardial disease. A comprehensive echocardiographic assessment is crucial to the grading of tricuspid regurgitation severity and will inform the treatment strategy. The European Society of Echocardiography and American Society of Echocardiography have suggested that grading of severity as mild, moderate, or severe should be made by using the combination of structure, qualitative Doppler, semiquantitative, and quantitative measures.8,9 However, in a recent transcatheter trial, patients were

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Interventional Cardiology: Structural Heart Table 1: Etiology of Tricuspid Regurgitation Causes of Primary Tricuspid Regurgitation Chest wall trauma Congenital heart disease (Ebstein’s anomaly, tricuspid valve dysplasia, double orifice tricuspid valve) Connective tissue disorder

tenting distance which shows correlation to TR severity and outcome after surgical repair, tricuspid annulus dimension, right ventricular volumes, and function can all be ascertained using CT.13 Cardiac MRI provides excellent spatial resolution of right heart structures and it is the gold standard method for quantifying right ventricular volumes and function.14

Prognosis

Carcinoid heart disease Rheumatic valve disease Infective endocarditis Ischemic heart disease (caused by papillary muscle dysfunction or rupture) Myxomatous degeneration (tricuspid valve prolapse) Iatrogenic injury (during intracardial intervention in the right ventricle) Intracardial pacing devices (mechanical interference) Degenerated bioprosthesis Cause of Secondary Tricuspid Regurgitation Left-sided valvular disease Left-sided myocardial disease Pulmonary hypertension (independent of left-sided cardiac pathology) Left to right shunt (atrial septal defect, ventricular septal defect, anomalous pulmonary venous return)

TR is independently associated with increased cardiac events and mortality in patients with congestive heart failure.15 In a retrospective study of 5,223 patients, after controlling left ventricular ejection fraction, right ventricular dilation and dysfunction, and pulmonary artery systolic pressure, mortality increased with increasing severity of TR.16 The 1-year survival rate was 91.7% with no TR, 90.3% with mild TR, 78.9% with moderate TR, and 63.9% with severe TR. In patients with left ventricular dysfunction, those who developed severe TR were in a highrisk subset.17 Another study involved 353 patients with isolated TR and excess mortality and cardiac event rates were found to be associated with severe regurgitation.18 These studies indicate that TR has been independently associated with a worse prognosis in patients with or without left ventricular systolic dysfunction and with or without clinical heart failure.

Right ventricular infarction with remodeling

Surgical Treatment

Current guidelines recommend that tricuspid valve surgery is indicated for patients with symptoms of severe primary TR that are not responsive to medical treatment.19 Surgery is also considered in asymptomatic or mildly symptomatic patients with severe primary TR and progressive right ventricular dilatation or dysfunction. However, although the utilization has increased over time, isolated TV surgery remains rare. In a large US national registry, a total of 5,005 isolated TV operations were performed over 10 years with an in-hospital mortality rate of 8.8%.20

Hyperthyroidism

Table 2: Expanded Grading of Tricuspid Valve Regurgitation Variable

Mild

Moderate Severe

Massive

Torrential

VC (biplane) (mm)

3–6.9

7–13

14–20

≥21

EROA (PISA) (mm2)

<20

20–39

40–59

60–79

≥80

75–94

95–114

≥115

3D VCA or quantitative EROA (mm2)

EROA = effective regurgitant orifice area; PISA: proximal isovelocity surface area; VC = vena contracta; VCA = vena contracta area.

enrolled with late stage TR and most of them developed severe rightside heart failure. The current grading system often fails to take into account the ‘torrent’ nature of TR severity in people with advanced diseased. Hahn et al. proposed increasing the grades to include very severe (or massive) and torrential (Table 2) to better characterize the severity of TR.10 Echocardiography measurement also provides information of outcome predictors. Significant annulus dilatation defined as diastolic diameter ≥ 40mm is a predictor of severe late TR after mitral valve surgery.11,12 Transesophageal echocardiography (TEE) is considered when there is an inadequate image found using TTE. The most important role of TEE is to guide steering of the transcatheter device during transcatheter tricuspid valve intervention. CT imaging has an important role in pre-procedural planning for tricuspid valve intervention. Detailed information of the end-diastolic leaflet

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Tricuspid valve surgery is indicated in patients with primary or secondary severe TR undergoing left-sided valve surgery, surgery is also considered in patients with moderate primary TR who are undergoing left-side valve surgery. There is an increasing amount of evidence to support a more aggressive surgical approach for secondary TR. In addition, because of the hazards associated with reoperation, concomitant tricuspid valve repair is reasonable for patients with non-severe TR.21 Current guidelines suggest surgery should be considered in patients with mild to moderate secondary TR undergoing left-side valve surgery with a dilated annulus ≥40mm, and surgery may be considered in the absence of annulus dilatation when previous right-heart failure has been documented.19 After previous left-sided surgery, reoperation should be considered for persistent symptoms or progressive right ventricular dilatation caused by secondary severe TR. Reoperation of the tricuspid valve is associated with poor outcomes and an early mortality rate of 10–25%, probably because this group of patients are usually already in late-stage TR with severe right ventricular dilatation and organ damage.3 Tricuspid annuloplasty with suture or ring is the main technique for secondary TR because annular dilatation is the most common mechanism. Ring annuloplasty is the preferred technique due to increased durability compared with suture technique.22

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Severe Tricuspid Regurgitation Repair Transcatheter Tricuspid Valve Intervention Despite guidelines that suggest surgical treatment, many patients with severe TR are still treated conservatively due to the high risk of surgery. Patients with severe TR and previous open-heart surgery are often deemed at prohibitive operative risk for reoperation. Patients in late stage of secondary TR and progressive right heart dysfunction despite medical treatment are also usually considered as high risk for isolated TR repaired. In recent years, a novel transcatheter valvular treatment option for treating TR has been developed. Patients with prohibitive operative risk may benefit from the transcatheter treatment as an alternative.

Transcatheter Edge-to-edge Repair Multiple technologies for transcatheter tricuspid intervention are currently under preclinical or initial clinical evaluation. Those treatments can be grouped into coaptation, annuloplasty device and valve implantation device (Table 3). Taramasso et al. reported initial results of The TriValve registry suggesting the feasibility of transcatheter tricuspid valve therapy.23 Among those novel transcatheter tricuspid intervention techniques, the edge-to-edge repair with off-label use of MitraClip system (Abbott Vascular) has become the most common choice because of the systemâ&#x20AC;&#x2122;s wide availability and operator familiarity.

Table 3: Transcatheter Tricuspid Intervention Devices Coaptation devices

Description

MitraClip (Abbot Vascular)

Tricuspid edge-to-edge clipping

PASCAL (Edwards Lifesciences)

Edge-to-edge clipping plus a central spacer

FORMA (Edwards Lifesciences)

Spacer to occupy the regurgitant orifice area

Annuloplasty device Trialign (Mitralign)

Bicuspidalization of TV by pledgeted sutures

TriCinch (4Tech)

Reduce tricuspid annulus by cinching and IVC stent

Cardioband (Edwards Lifesciences)

Direct annuloplasty by anchoring a cinchable ring

Millipede IRIS (Millipede)

Direct annuloplasty with a semi-rigid ring

Heterotopic caval valve implantation Sapien (Edwards Lifesciences)

Balloon-expandable aortic valve implanted in IVC

TricValve (P&F)

Self-expandable cava valves implanted in IVC and SVC

Transcatheter tricuspid valve replacement NaviGate (NaviGate Cardiac Structures)

Self-expandable valve designed for TR

Surgical Perspective on Transcatheter Edge-to-edge Repair

IVC = inferior vena cava; SVC = superior vena cava; TV = tricuspid valve.

Surgical edge-to-edge tricuspid repair was reported early by Maisano et al. to treat traumatic tricuspid regurgitation.24 Currently, surgical tricuspid annuloplasty is the foundation of surgical treatment of secondary TR. Two principal methods of surgical annuloplasty are suture and ring techniques. Kay bicuspidization by surgical plication of the posterior leaflet is one cornerstone of suture annuloplasty (Figure 1b).25 The clover technique involves suturing the three leaflets edge to edge and has been used to treat severe TR due to severe prolapse or tethering (Figure 1c).26

quality contributes to the increased technical complexity of TV clipping. A combination of TEE, TTE and intracardiac ultrasound together with fluoroscopy are used to achieve better visualization. Communication between the echocardiographer and interventionalist is fundamental during the procedure and the nomenclature in the tricuspid valve position while steering the device is important. Taramasso et al. proposed to use aortic-posterior and septal-anterior directions in 3D TEE surgical view to better describe the orientation of TV during steering.31

Transcatheter edge-to-edge repair technique can produce similar result as a modified Kay technique or the clover technique. Based on the concept of surgical correcting annular dilatation to improve leaflet coaptation, percutaneous edge-to-edge tricuspid clipping is a sound technique.27 A combination of transcatheter annuloplasty device and edge-to-edge repair is also a possible therapeutic option.

The use of the MitraClip system for the TV raises some issues because the device was designed specifically for the mitral valve. One technical issue is the proximity of the inferior vena cava orifice to the tricuspid valve coaptation line and atrial septum, which makes steering of the MitraClip delivery system perpendicular to the tricuspid valve plane more difficult. Daniel et al. proposed to insert the clip delivery system 90Â° counterclockwise from its standard locking position into the sheath to accommodate the system in the tricuspid valve plane with an orthogonal orientation.32 In the future, the technique must be refined, and the device be modified for dedicated use for tricuspid valve disease.33

Preliminary Experience of Transcatheter Edge-to-edge Repair The first case reports of transcatheter edge-to-edge repair published in 2016 demonstrated its technical feasibility and procedural safety for patients with severe primary or secondary TR with a prohibitive operative risk.28,29 Hammerstingl et al. reported three consecutive patients treated successfully for significant TR in advanced stages of right heart failure and multiorgan damage.30 Reduction of measured effective regurgitation orifice area (EROA) was observed in all the patients. Other clinical benefits included an increase in left ventricular stroke volumes and relief of clinical symptoms.

Image and Technique During Procedure Although preliminary experience has shown the feasibility of tricuspid valve clipping, intraprocedural guidance remains a major issue. Procedural guidance with 3D TEE is a fundamental tool to guide the procedure. However, the three-leaflet configuration of TV and often suboptimal TEE

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The optimal clip position strategy for reducing the EROA by closing the valve remains to be established. In an ex vivo pulsatile heart model study, grasping the septal and anterior leaflets allowed for the best post-procedural outcome.34 Two-clip implantation involving the septalanterior and septal-posterior position also increased cardiac output. Tricuspid bicuspidization using a modified zipping technique has been proposed.32 The first clip is placed into the anteroseptal commissure, which is the easiest to target and the subsequent clips are placed in wards close proximally to the previous clips. A retrospective study of 69 consecutive symptomatic patients with secondary TR treated by MitraClip compared two-clip placement strategies, the triple-

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Interventional Cardiology: Structural Heart Figure 1: Tricuspid Valve and Surgical Intervention A

A: Tricuspid valve before surgical intervention. B: Kay bicuspidization. C: Clover repair. Source: Rodés-Cabau et al. 2016.2 Reproduced with permission from Elsevier.

orifice technique (TOT) and bicuspidization technique.35 Two clips are placed centrally between the septal and anterior tricuspid leaflet, as well as the septal and posterior tricuspid leaflet in TOT. The procedural success rate was 93% in the TOT group and 84% in the bicuspidization group. A persistent reduction of TR ≤2 was demonstrated in both groups and the septolateral tricuspid annulus diameter had a greater reduction in the TOT group.

Patient Selection Based on current studies, most patients who undergo transcatheter edge-to-edge repair were deemed high risk for surgery. In many cases the procedure is performed as a compassionate treatment (the use of a new, unapproved drug to treat a seriously ill patient when no other treatments are available), so it is difficult to assess which patient is the perfect target for transcatheter edge-to-edge repair. Patients with poor echocardiography visualization of the tricuspid valve, with concurrent tricuspid valve stenosis and unsuitable anatomy were excluded from most studies, but there is no established consensus on unsuitable anatomy. A recent study proposed the conditions that make leaflet grasping unlikely: an EROA >1.5 cm2, a TV coaptation defect >15 mm, and TR caused by markedly restricted leaflet mobility due to pacemaker or implantable cardioverter defibrillator leads across the TV.36 Advanced age, severe impaired left or right ventricular dysfunction, pulmonary hypertension, and concomitant mitral regurgitation are not absolute contraindications in current practice. Multidisciplinary discussion by the heart team is mandatory for each case selection.

Current Outcomes from Clinical Experience More than 650 procedures using the MitraClip system in tricuspid valve treatment have been performed worldwide. Increasing evidence has been published that assesses the outcome and safety of the procedure. In a multicenter European registry, 64 high-risk patients with severe TR were treated with the MitraClip system.37 The MitraClip device was successfully implanted in the tricuspid valve in 97% of the cases. TR was reduced by at least one grade in 91% of the patients after the procedure. Significant reduction in EROA, vena contracta width and regurgitation volume were observed. New York Heart Association (NYHA) class and 6-minute walk test distance were improved significantly at 30 days post-procedure. A case series with 18 consecutive patients with symptomatic moderateto-severe TR treated using the MitraClip system was reported.32

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Implantation success was achieved in all patients and no major adverse cardiac events occurred in hospital. There was a significant reduction in the percentage of patients with TR ≥3 from 94% to 33% after the procedure and 89% of patients had an improved NYHA functional class at 30 days. Orban et al. reported 6-month follow-up result of 50 patients with rightsided heart failure and severe TR treated with the MitraClip system.38 Among them, 36 patients received combined mitral valve and tricuspid valve clipping. A persistent reduction of at least one TR grade was achieved in 90% of patients after 6 months. NYHA class improved in 79% of patients, and 6-minute walk distance increased by 44%. The improvement was observed in patients treated with isolated tricuspid valve and concomitant mitral valve plus tricuspid valve repair. Recently, Besler et al. reported median 6-month follow-up of 117 patients who underwent transcatheter edge-to-edge repair with 96% success rate for clip implantation.36 After the procedure, 81% of patients had TR reduction of more than one grade, mean vena contracta reduced from 9 mm to 5 mm (p<0.01) and median TR EROA from 0.5 mm2 to 0.2 mm2 (p<0.01). Improvement of NYHA functional class was shown in 76% of patients and 6-minute walk test distance improved by 29%. In the study, a successful procedure (TR reduction ≥1) was an independent predictor of reduced mortality and heart failure hospitalization. Five echocardiographic parameters were developed to predict procedural success: small TR EROA, a smaller TR tenting area, TR vena contracta, a smaller TV coaptation gap and a central and anteroseptal TR jet location. A coaptation gap of 7.2 mm has been proposed as a cut-off value to assist in deciding whether a patient is anatomically suited for transcatheter clipping. The clinical and procedural features of patients treated with edge-toedge repair mentioned above are outlined in Table 4.

MitraClip XTR Recently, the new generation MitraClip XTR device has been used for tricuspid valve repair. The new device has clip arms and grippers that are 3 mm longer than the MitraClip NTR clip, facilitating easier grasping of the leaflets, making it a preferred choice to treat severe TR with a large coaptation gap. A dedicated tricuspid clip delivery system has been developed and is under evaluation. The evaluation of

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Severe Tricuspid Regurgitation Repair Table 4. Transcatheter Edge-to-edge Therapies: Clinical, Procedural, and Follow-up Data Braun et al. 201732

Nickenig et al. 201737

Orban et al. 201838

Besler et al. 201836

Patients

117

Age (years)

78 ± 7

77 ± 10

77 ± 8

Male

56%

45%

60%

56%

EuroSCORE II (%)

10 ± 8

27.8 ± 16.7

8.8 ± 6.6

6.3

NYHA class ≥III

100%

94%

100%

97%

Secondary TR

95%

88%

98%

97%

TR severity ≥3

94%

100%

98%

94%

Pacemaker leads

33%

30%

28%

33%

EROA (mm)

0.6 ± 0.2

0.9 ± 0.3

0.5

Implantation success

100%

97%

92%

96%

Concomitant clip for MR

66%

34%

72%

63%

Clip numbers for TR

2.3

1.6

1.9

Follow-up time (months)

TR severity ≥3

33%

77%

23%

22%

NYHA class ≥III

33%

63%

36%

NA*

6MWT improvement (m)

MLHFQ

−7.1

−6

EROA (mm)

0.3 ± 0.2

0.4 ± 0.2

0.2

Mortality

16%

21%

Baseline Characteristics

Procedure result

Follow-up data

Values are mean ± SD. Values from Besler et al. are median. *Although there was no specific data available, improvement of NYHA class was observed in 76% of patients. 6MWT = 6-minute walk test; EuroSCORE = European System for Cardiac Operative Risk Evaluation; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NA = not available.

treatment with an Abbott transcatheter clip repair system in patients with moderate or greater tricuspid regurgitation (TRILUMINATE) trial is a prospective, multicenter, single-arm study that has enrolled 85 patients with symptomatic TR treated with a novel Abbott transcatheter tricuspid valve repair system. Early results from the first 30 patients have been reported recently with a 100% device implantation success rate.39 The early results show effectiveness for TR reduction and improvement of symptoms and quality of life after 30 days follow-up. A low rate of major adverse event without mortality through 30 days has been reported.

PASCAL The other transcatheter edge-to-edge repair device is PASCAL (Edwards Lifesciences), which had been developed to treat mitral regurgitation. The device combines a 10 mm central spacer with two paddles and clasps that attach the device to the valve leaflets. The device is repositionable and recapturable. The first-in-human study enrolled 23 patients with moderate-to-severe mitral regurgitation using the PASCAL system showed the feasibility with a high rate of technical success and reduction of mitral regurgitation severity.40 The first 12 cases of using PASCAL to treat severe TR were reported recently.41,42 Among 12 patients, the mean tricuspid septal-lateral annulus diameter is 52.3 mm and mean maximum coaptation gap size is 7.3 mm. After the procedure, 92% of patients had TR reduction of more than one grade. Clinical improvement in NYHA class and reduced mean

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values of TR grade have also been demonstrated. This device offers a new option for patients who have severe TR with large coaptation gaps and leaflet tethering. Further research to evaluate efficacy, safety and durability is needed.

Conclusion Although the growing evidence addresses the clinical importance of significant tricuspid valve regurgitation, there are still an extremely large number of untreated patients with moderate-to-severe TR. Transcatheter tricuspid intervention is an appealing option for the treatment of this group of patients. Transcatheter edge-to-edge repair devices are currently the most popular among these novel technologies for percutaneous treatment of TR. Transcatheter edge-to-edge repair is still at a preliminary stage. Imaging during intervention is a challenge and procedural success is dependent on the experience of the interventionalist and echocardiographer and close interaction between them. Initial results from the procedure have showed feasibility and safety. Increasing data have shown the benefits of the procedure on clinical outcomes. Most studies reported significant improvement in TR grade, symptoms, and quality of life. A recent retrospective study demonstrated lower mortality and hospitalization after a successful procedure.36 We still need more evidence to understand optimal patient selection, correct timing of intervention, durability of the device, and long-term outcome of the treatment.

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Interventional Cardiology: Structural Heart 1.

10.

11. 12.

13.

14.

assileva CM, Shabosky J, Boley T, et al. Tricuspid valve surgery: V the past 10 years from the Nationwide Inpatient Sample (NIS) database. J Thorac Cardiovasc Surg 2012;143:1043–9. https://doi. org/10.1016/j.jtcvs.2011.07.004; PMID: 21872283. Stuge O, Liddicoat J. Emerging opportunities for cardiac surgeons within structural heart disease. J Thorac Cardiovasc Surg 2006;132:1258–61. https://doi.org/10.1016/j.jtcvs.2006.08.049; PMID: 17140937. Taramasso, M, Vanermen H, Maisano F, et al. The growing clinical importance of secondary tricuspid regurgitation. J Am Coll Cardiol 2012;59:703–10. https://doi.org/10.1016/j. jacc.2011.09.069; PMID: 22340261. Mutlak D, Lessick J, Reisner SA, et al. Echocardiography-base spectrum of severe tricuspid regurgitation: the frequency of apparently idiopathic tricuspid regurgitation. J Am Soc Echocardiogr 2007;20:405. https://doi.org/10.1016/j.echo.2006.09.013; PMID: 17400120. Yamasaki N, Kondo F, Kubo T, et al. Severe tricuspid regurgitation in the aged: atrial remodeling associated with long-standing atrial fibrillation. J Cardiol 2006;48:315. PMID: 17243626. Vaturi M, Kusniec J, Shapira Y, et al. Right ventricular pacing increases tricuspid regurgitation grade regardless of the mechanical interference to the valve by the electrode. Eur J Echocardiogr 2010;11:550–3. https://doi.org/10.1093/ejechocard/ jeq018; PMID: 20185527. Höke U, Auger D, Thijssen J, et al. Significant lead-induced tricuspid regurgitation is associated with poor prognosis at long-term follow-up. Heart 2014;100:960–8. https://doi. org/10.1136/heartjnl-2013-304673; PMID: 24449717. Lancellotti P, Tribouilloy C, Hagendorff A, et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14:611–44. https://doi.org/10.1093/ehjci/ jet105; PMID: 23733442. Zoghbi WA, Adams D, Bonow RO, et al. Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr 2017;30:303–71. https://doi. org/10.1016/j.echo.2017.01.007; PMID: 28314623. Hahn RT, Zamorano JL. The need for a new tricuspid regurgitation grading scheme. Eur Heart J Cardiovasc Imaging 2017;18: 1342–3. https://doi.org/10.1093/ehjci/jex139; PMID: 28977455. Hahn RT. Imaging considerations for percutaneous tricuspid intervention. Cardiac Interventions Today 2017;11:40–7. Dreyfus GD, Corbi PJ, Chan KM, et al. Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair? Ann Thorac Surg 2005;79:127–32. https://doi. org/10.1016/j.athoracsur.2004.06.057; PMID: 15620928. Min SY, Song JM, Kim JH, et al. Geometric changes after tricuspid annuloplasty and predictors of residual tricuspid regurgitation: a real-time three-dimensional echocardiography study. Eur Heart J 2010;31:2871–80. https://doi.org/10.1093/ eurheartj/ehq227; PMID: 20601392. Maffessanti F, Gripari P, Pontone G, et al. Three-dimensional dynamic assessment of tricuspid and mitral annuli using cardiovascular magnetic resonance. Eur Heart J Cardiovasc Imaging 2013;14:986–95. https://doi.org/10.1093/ehjci/jet004;

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PMID: 23341146. 15. A gricola E, Stella S, Gullace M, et al. Impact of functional tricuspid regurgitation on heart failure and death in patients with functional mitral regurgitation and left ventricular dysfunction. Eur J Heart Fail 2012;14:902–8. https://doi. org/10.1093/eurjhf/hfs063; PMID: 22552182. 16. Nath J, Foster E, Heidenreich PA. Impact of tricuspid regurgitation on long-term survival. J Am Coll Cardiol 2004;43:405– 9. https://doi.org/10.1016/j.jacc.2003.09.036; PMID: 15013122. 17. Koelling TM, Aaronson KD, Cody RJ, et al. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J 2002;144:524–29. https://doi.org/10.1067/mhj.2002.123575; PMID: 12228791. 18. Topilsky Y, Nkomo VT, Vatury O, et al. Clinical outcome of isolated tricuspid regurgitation. JACC Cardiovasc Imaging 2014;7:1185–94. https://doi.org/10.1016/j.jcmg.2014.07.018; PMID: 25440592. 19. 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. https://doi.org/10.1093/eurheartj/ehx391; PMID: 28886619. 20. Zack CJ, Fender EA, Chandrashekar P, et al. National trends and outcomes in isolated tricuspid valve surgery. J Am Coll Cardiol 2017;70:2953–60. https://doi.org/10.1016/j.jacc.2017.10.039; PMID: 29241483. 21. Rodés-Cabau J, Taramasso M, O’Gara PT. Diagnosis and treatment of tricuspid valve disease: current and future perspectives. Lancet 2016;388:2431–42. https://doi.org/10.1016/ S0140-6736(16)00740-6; PMID: 27048553. 22. Tang GHL, David TE, Singh SK, et al. Tricuspid valve repair with an annuloplasty ring results in improved long-term outcomes. Circulation 2006;114:I577–81. https://doi.org/10.1161/ CIRCULATIONAHA.105.001263; PMID: 16820641. 23. Taramasso M, Hahn RT, Alessandrini H, et al. The International Multicenter TriValve Registry: Which patients are undergoing transcatheter tricuspid repair? JACC Cardiovasc Interv 2017;10:1982–90. https://doi.org/10.1016/j.jcin.2017.08.011; PMID: 28982563. 24. Maisano F, Lorusso R, Sandrelli L, et al. Valve repair for traumatic tricuspid regurgitation. Eur J Cardiothorac Surg 1996;10:867–73. https://doi.org/10.1016/S1010-7940(96)80313-7; PMID: 8911840. 25. Kay JH, Maselli-Campagna G, Tsuji KK. Surgical treatment of tricuspid insufficiency. Ann Surg 1965;162:53–8. https://doi. org/10.1097/00000658-196507000-00009; PMID: 14313519. 26. De Bonis M, Lapenna E, La Canna G, et al. A novel technique for correction of severe tricuspid valve regurgitation due to complex lesions. Eur J Cardiothorac Surg 2004;25:760–5. https://doi. org/10.1016/j.ejcts.2004.01.051; PMID: 15082279. 27. Taramasso M, Maisano F. Novel technologies for percutaneous treatment of tricuspid valve regurgitation. Eur Heart J 2017;38:2707–10. https://doi.org/10.1093/eurheartj/ehx475; PMID: 29044389. 28. Braun D, Nabauer M, Massberg S, et al. Transcatheter repair of primary tricuspid valve regurgitation using the MitraClip system. JACC Cardiovasc Interv 2016;9:e153–4. https://doi.org/10.1016/j. jcin.2016.05.020; PMID: 27423227. 29. Schofer J, Tiburtius C, Hammerstingl C, et al. Transfemoral tricuspid valve repair using a percutaneous mitral valve repair system. J Am Coll Cardiol 2016;67:889–90. https://doi.

org/10.1016/j.jacc.2015.11.047; PMID: 26892424. 30. H ammerstingl C, Schueler R, Malasa M, et al. Transcatheter treatment of severe tricuspid regurgitation with MitraClip system. Eur Heart J 2016;37:849–53. https://doi.org/10.1093/ eurheartj/ehv710; PMID: 26744457. 31. Taramasso M, Zuber M, Kuwata S, et al. Clipping of the tricuspid valve: proposal of a ‘Rosetta Stone’ nomenclature for procedural 3D transesophageal guidance. EuroIntervention 2017;12:e1825-7. https://doi.org/10.4244/EIJ-D-16-00307; PMID: 27916743. 32. Braun D, Nabauer M, Orban Mathias, et al. Transcatheter treatment of severe tricuspid regurgitation using the edge-toedge repair technique. EuroIntervention 2017;12:e1837–44. https://doi.org/10.4244/EIJ-D-16-00949; PMID: 28089953. 33. Taramasso M, Calen C, Guidotti A, et al. Management of tricuspid regurgitation: the role of transcatheter therapies. Interv Cardiol 2017;12:51–5. https://doi.org/10.15420/icr.2017:3:2; PMID: 29588731. 34. Vismara R, Gelpi G, Prabhu S, et al. Transcatheter edgeto-edge treatment of functional tricuspid regurgitation in an ex vivo pulsatile heart model. J Am Coll Cardiol 2016;68: 1024–33 https://doi.org/10.1016/j.jacc.2016.06.022;1024–33. PMID: 27585507. 35. Braun D, Orban M, Orban M, et al. Transcatheter edge-to-edge repair for severe tricuspid regurgitation using the triple-orifice technique versus the bicuspidalization technique. J Am Coll Cardiol 2018;11:1785–92. https://doi.org/10.1016/j.jcin.2018.05.049; PMID: 30170957. 36. Besler C, Orban M, Rommel KP, et al. Predictors of procedural and clinical outcomes in patients with symptomatic tricuspid regurgitation undergoing transcatheter edge-to-edge repair. J Am Coll Cardiol Interv 2018;11:1119–28. https://doi.org/10.1016/j. jcin.2018.05.002; PMID: 29929631. 37. Nickenig G, Kowalski M, Hausleiter J, et al. Transcatheter treatment of severe tricupsid regurgitation with the edgeto-edge MitraClip technique. Circulation 2017;135:1802–14. https://doi.org/10.1161/CIRCULATIONAHA.116.024848; PMID: 28336788. 38. Orban M, Besler C, Braun D, et al. Six-month outcome after transcatheter edge-to-edge repair of severe tricuspid regurgitation in patients with heart failure. Eur J Heart Fail 2018;20:1055–62. https://doi.org/10.1002/ejhf.1147; PMID: 29405554. 39. Nickenig G, von Bardeleben RS, Hausleiter J, et al. MitraClip Tricuspid: growing experience technology and clinical updates. Presented at TCT 2018, San Diego, California, September 21–25 2018. 40. Praz F, Spargias K, Chrissoheris M, et al. Compassionate use of the PASCAL transcatheter mitral valve repair system for patients with severe mitral regurgitation: a multicentre, prospective, observational, first-in-man study. Lancet 2017;390:773–80. https://doi.org/10.1016/S0140-6736(17)316008; PMID: 28831993. 41. Fam NP, Ho EC, Zahrani M, et al. Transcatheter tricuspid valve repair with the PASCAL system. J Am Coll Cardiol Interv 2018;11:407–8. https://doi.org/10.1016/j.jcin.2017.12.004; PMID: 29361449. 42. Fam NP. PASCAL tricuspid: early experience technology and clinical updates. Presented at TCT 2018, San Diego, California, September 21–25 2018.

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Heart Failure and Cardiomyopathies

Diagnosis and Therapy of Cardiac Sarcoidosis: A Clinical Perspective Steven R Sigman, MD, FASNC Nuclear Cardiology, Piedmont Heart Institute, Atlanta, GA

Abstract Cardiac sarcoidosis, either as part of a systemic process or in its isolated form, is an important and increasingly recognized disorder. It is associated with high rates of morbidity and mortality, including sudden cardiac death. Early recognition and prompt initiation of treatment is life-saving. A team approach, involving general cardiologists, cardiac electrophysiologists, cardiac imaging specialists and radiologists, is the key to best diagnose and manage this complex disorder. Advanced cardiac imaging with PET and MRI is useful for both diagnosis and managment of therapy. Treatment for this disorder involves immunosuppresant therapy, ICDs, and guideline-directed medical therapy of congestive heart failure.

Keywords Cardiac sarcoidosis, cardiac MRI, PET, ICDs, cardiomyopathy Disclosure: The author has no conflicts of interest to declare. Received: December 17, 2017 Accepted: April 4, 2018 Citation: US Cardiology Review 2019;13(1):41–5. DOI: https://doi.org/10.15420/usc.2018.3.1 Correspondence: Steven Sigman, 275 Collier Road Suite 500, Atlanta, Georgia 30309. E: steven.sigman@piedmont.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Although less common than other forms of cardiomyopathy, cardiac sarcoidosis (CS), both as part of a systemic process and in its isolated form, is an important, and increasingly recognized disorder. This is felt to be due, in part, to advances in cardiac imaging and heightened awareness of the disorder.1,2 CS is associated with high rates of morbidity and mortality, including sudden cardiac death. The early recognition of CS and prompt initiation of treatment is of the utmost importance. Generally a systemic process, sarcoidosis is an idiopathic, inflammatory, granulomatous disorder generally involving the lung and lymph nodes, but it can also occur in ocular, cutaneous, neurological, musculoskeletal, and cardiac forms. The incidence of systemic sarcoidosis varies among populations, with rates ranging from 10 per 100,000 in a primarily white group in Minnesota, to 30 and 39 per 100,000 in African–American men and women, respectively, in a more racially mixed population.3,4 Overt cardiac disease occurs in 2.3–7% of patients with systemic disease, however, autopsy studies and studies in patients undergoing cardiac MRI show evidence of CS in about 25% of patients with systemic sarcoidosis.5–9 Isolated CS, with disease determined to be localized to the heart based on clinical and imaging characteristics, may have a more malignant course.2 A rare subgroup of patients with CS has a rapidly progressive, fulminant course characterized by intractable congestive heart failure (CHF) with limited response to therapy.10 These patients may require cardiac transplantation. Patients with CS may present with classic symptoms of CHF, such as dyspnea, orthopnea, and fatigue, along with signs, such as peripheral

USC_Sigman_FINAL.indd 41

edema and rales. They can also have arrhythmic symptoms, such as palpitations, light-headedness, or syncope, due to involvement of the cardiac conduction system. A high index of suspicion for CS by health care providers is important as treatment may need to be started swiftly.

Diagnosis Several guidelines for the diagnosis of CS have been published.11-13 The first step in the diagnosis of CS is a thorough history and physical examination. Symptoms of mild light-headedness can be of critical importance for the identification possible arrhythmias. ECG is key for detection of conduction disturbances such at right bundle, bifasicular, or varying degrees of atrioventicular (AV) block. In addition, frequent premature ventricular contractions (PVCs) may be seen. Unexplained advanced AV block or ventricular tachycardia (VT), particularly in younger patients, may be important indicators of CS.14,15 Chest X-ray or computerized tomograhy (CT) of the chest are used for the detection of hilar or mediastinal lymphadenopathy. Laboratory tests may demonstrate elevation of angiotensin-converting enzyme levels, as well as hypercalemia or hypercalciuria, particularly in patients with systemic disease. However, these test are somewhat non-specific, and cannot be relied on for the diagnosis or exclusion of CS. Cardiac echocardiography is another important element in the evaluation of the patient with suspected CS. Characteristic findings include reduced left or right ventricular function, wall motion abnormalities not in the normal distribution of the coronary arteries, aneurysmal segments, or thinning of the basal portions of the septum. Mid and basal septal

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Heart Failure and Cardiomyopathies hypertrophy can be seen, and may mimic hypertrophic cardiomyopathy. Valvular abnormalities, particularly mitral regurgitation, may be present if the infiltrative process affects the papillary muscles.

group experienced one or more of the hard endpoints of death, aborted s udden cardiac death, or appropriate ICD discharge as opposed to only one patient who died among the 114 patients without LGE.

Occasionally, single photon emission computed tomograhy (SPECT) myocardial perfusion imaging may be useful indentifying patients with CS. Typical finding are fixed defects suggesting scarring, particulary when localized to the base of the septum or lateral wall.

Murtagh et al. followed 205 patients with extracardiac sarcoidosis who underwent cardiac MRI as part of their evlaution and who had an EF>50%.20 20% of patients (n=41) had evidence of LGE. Over a mean follow-up period of 36Âą18 months, 24% (10/41) experienced death/ sustained VT. Patients with LGE had a 20-fold higher risk of adverse events compared to those without LGE. Scar burden was the most important predictor of events. Ekstrom followed 59 patients with CS as defined by Heart Rhythm Society crieteria who underwent cardiac MRI. 39% (n=23) reached the primary endoints, which was either death, transplant, or life threatening arrhythmias. The median time of follow in this subgroup was 15 months. They found that the extent of LGE as a percentage of left ventricular mass was the most important predictor of events, with LGE >22% having best predictive value.21

Ambulatory event recording or Holter monitoring are important in screening for arrhythmias, particularly in patients with symptoms of light-headedness or near syncope. Although obtaining cardiac tissue for analysis is considered the gold standard for the diagnosis of CS, the yield of endomyocardial biopsy is low, 19.2% in a study of 26 patients by Uemura et al.,16 but may be improved when biopsy is coupled with electroanatomic maping.17 Biopsy of extracardiac sites where sarcoidosisis suspected remains the primary method of diangnosis for most patients. This may be accomplished by mediastinoscopy with lymph node biopsy or endobronchial ultrasound-guided needle biopsy. Coronary angiography may be important to rule out an atypical presentation of coronary heart disease.

Advanced Cardiac Imaging Multimodality cardiac imaging using a team approach involving cardiac imagers and radiologists is the key to best diagnosis and management of CS, and is an example of how cardiac MRI and PET may be complementary. Advanced cardiac imaging is suggested for patients with extracardiac sarcoidosis with symptoms of CHF, possible arrhythmia, along with an abnormal ECG and/echo.18 Patients without known extracardiac sarcoidosis but with new unexplained CHF associated with conduction disturbances such as AV block, or ventricular arrhythmias, such as ventricular tachycardia, may also be candidates for advanced imaging.

Cardiac MRI For most patients, cardiac MRI with the use of late gadolinium enhancement (LGE), is the favored method of initial diagnosis of CS.19 This is primarily due to its superior spatial resolution, which allows improved sensitivity to detect and localize even small areas of fibrosis characteristic of CS. Cardiac MRI findings include focal, bright, patchy areas of LGE, particularly at the base of the anterior septal, inferior or lateral walls, in a non-coronary distribution. Other findings are papillary muscle or right ventricular LGE, areas of wall thinning, left ventricular aneurysms, or septal hypertrophy. In addition to its diagnostic use, cardiac MRI may yield important prognostic information. A prospective, observational study by Greulilch et al. followed 155 patients with systemic sarcoidosis who underwent cardiac MRI, of which 153 were available for follow-up (median follow-up time 2.6 years).9 LGE was present in 25% (n=39) of patients and 28% (n=11) of this

USC_Sigman_FINAL.indd 42

Quantitative assessment of myocardial tissue characteristics using T1 and T2 mapping techniques can be a useful adjunct to observations of LGE alone when diagnosing CS. In a study by Greulich et al., 61 patients with systemic CS had higher median elevations of native T1 and T2, higher extracellular volume, and lower post-contrast T1 compared with 26 healthy controls.22 These findings were present even in patients without LGE, suggesting it could be used to detect early cardiac disease. A study by Puntman et al. of 53 patients with systemic sarcoidosis, yielded similar findings of higher native T1 and T2 compared with controls.23 Follow-up cardiac MRI performed on 40 patients demonstrated a significant reduction in native T1 and T2 levels in patients receiving anti-inflammatory treatment compared with those who did not.

PET Improvements in imaging and patient preparation techniques, as described in recent consensus statements, along with an evolving body of data, have brought PET imaging to the forefront for both initial diagnosis and management of CS.18,24 Pooled estimates of accuracy of PET for the diagnosis of CS from a meta-analysis of seven studies has demonstrated sensitivities of 89% and specificities of 78%.25 PET imaging is based on the principle of uptake of the glucose analog FDG in areas of intense inflammation, characteristic of active sarcoidosis. Lack of uptake of radioisotope suggests extensive fibrosis, inactive disease, or successfully treated disease. PET images are acquired and registered to CT images for co-localization. Rest myocardial perfusion imaging, generally performed with RB-82 or 13N-ammonia, is also performed to detect areas of decreased activity suggestive of acute inflammation or scarring. A key component to optimal imaging is meticulous adherence to a pre-procedural diet that is high in protein and fat and very low in carbohydrates, followed by at least a 4â&#x20AC;&#x201C;12-hour fast.26 The resultant low glucose, low insulin, high fatty acid milieu suppresses uptake of glucose in area of normal myocardium and enhances imaging of areas of inflammation. PET imaging is preferred for patients with relative contraindications to MRI, including those with older cardiac implantable electronic devices, renal insufficiency, obesity, or claustrophobia. An example of a patient who

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Cardiac Sarcoidosis: Diagnosis and Therapy underwent both PET/FDG and cardiac MRI as part of an evaluation for CS is shown in Figure 1. It should be noted that the types of abnormalities appearing on either cardiac MRI and/or PET are not completely specific to CS; the differential diagnosis includes myocarditis in its various forms, including giant cell, lymphocytic, and eosinophilic,27 as well as arrhythmogenic right ventricular cardiomyopathy.28 Further, physiologic uptake of FDG, particularly in the lateral wall of the left ventricle, may occur in normal and abnormal patients, despite best efforts to suppress with preprocedural diet protocols. Specific findings on PET imaging can provide important prognostic information. In a study of 118 patients undergoing PET for evaluation of CS, Blankstein et al. identified specific PET imaging patterns associated with death or sustained VT.29 They found annualized event rates of 7.3% in patients with normal perfusion and metabolism, 18.4% in patients with either perfusion or metabolic abnormalities, and 31.9% in patients with perfusion and metabolic abnormalities (median follow-up 1.5 years).29 Patients demonstrating right ventricular uptake of FDG had an annualized event rate of 55.2%.

Combination of Cardiac MRI and PET A good approach to the management of CS may use both techniques: cardiac MRI to make the initial diagnosis and assess prognosis and PET to document an active inflammatory process as well as to further assess prognosis and monitor response to therapy. Further, PET may be useful in cases of an indeterminate cardiac MRI and vice versa. Vita et al. used an imaging rubric combining cardiac PET and MRI findings based on specific imaging characteristics to develop the likelihood criteria for the diagnosis of CS.27 They then compared these findings to a pre-specified reference criteria based on clinical data and consensus statement recommendations. Combination imaging helped reclassify 48 (45%) of the patients into higher or lower probabibility categories, most of them (80%) being correctly re-classified when compared with final diagnosis. This reclassification had important clinical implications, with initiation or modification of immunosuppressive therapies being more likely among patients in the higher probability groups.30 Wicks et al., following 51 consecutive patients with suspected CS as defined by Japanese Ministry of Health and Welfare criteria (JMHW), found superior sensitivity for the diagnosis of CS using simultaneous imaging with a hybrid PET/MRI scanner compared with stand-alone PET or MRI.31 This study also provided important prognostic information, demonstrating 18 (35%) adverse events over the median follow-up of 2.2 years. Of the 17 patients with abnormalities on both PET and MRI, 71% (n=12) had adverse events.31

Medical Therapy Immunosuppressant therapy remains the mainstay of treatment for CS and is longstanding practice despite incomplete validation and lack of randomized clinical trials.32 Although there are no formal guidelines for medical treatment of CS, an expert consensus statement11 and treatment protocols from major sarcoidosis centers have been published.1,33–35 Survival or improvement in LVEF with corticosteroid therapy has been demonstrated in some studies, but not others.33,36,37 Treatment

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Figure 1: Patient with Active Cardiac Sarcoidosis A

A: Axial PET-fluorodeoxyglucose images in a patient with active cardiac sarcoidosis, demonstrating characteristic bright patchy areas of fluorodeoxyglucose uptake in the mid and basal septum, base of lateral wall, apex, and portions of the right ventricle (arrows). B: Axial cardiac MRI images in the same patient, with corresponding areas of bright, patchy late gadolinium enhancement suggestive of fibrosis in septum and lateral wall (arrows). The patient had a cardiac arrest a few weeks after this study and was resuscitated by a discharge from a wearable defibrillator.

protocols vary between centers, but generally prednisone, initially at higher doses (40 mg/day) is initiated, then gradually tapered over 6–12 months, depending on clinical response. Methotrexate, along with folic acid, may be added if clinical response inadequate, or if evidence of persistent inflammation on follow-up PET. Methotexate may also permit down titration of prednisone dose. Azathioprine, mycophenolate, or hydroxychloroquine may also be added as adjuncts or used as alternatives, to either allow reduction in dose of prednisone, or when clinical improvement is not seen.1,34 It is strongly recommended that treatment be managed by healthcare providers and pharmacologists familiar with these medications in dedicated clinics, to minimize the high potential for complications. Patients with CHF should be treated with standard guideline-directed medical therapy including beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone blockers. Antiarrhythmic agents such as amiodarone are used to maintain normal sinus rhythm in patients with atrial arrhythmias or symptomatic VT. Anticoagulation should be strongly considered in patients with risk factors for stroke. Although there are no standardized protocols for follow up, cardiac PET may be performed 3-6 months after initiation of immunosuppressant therapy to assess response.18,24,35 The degree of cardiac inflammation can be quantified by measurement of the specific uptake value of FDG in areas of myocardial uptake.24 Evidence of reductions in inflammation using these measurements have been shown to correlate with improvements in ejection fraction.38 If evidence of decreased inflammation is observed, immunosuppression may be slowly tapered off over a period of months. Once this is accomplished, a chronic suppressive dose of 5–10 mg prednisone daily can be prescribed. If inflammation persists, the addition of other immunosuppressant agents can be considered. PET imaging may again be performed 3–6 months later to reassess response. Once clinical stability is achieved, a reasonable approach is to follow patients using echo to monitor for relapse. This may be done every 6–12 months. It is important that patients receive careful follow-up by a team that is familiar with managing this disorder, in a dedicated clinic if available. An example of a patient who had a good response to immunosuppressant therapy is shown in Figure 2.

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Heart Failure and Cardiomyopathies Figure 2: Patient with Cardiac Sarcoidosis Before and After Immunosuppressant Therapy

management of atrial and ventricular arrhythmias, and recommendations for ICD implantation.11

Prognosis

Axial PET/CT images of a patient with cardiac sarcoidosis prior to treatment (A), and following a 6 month course of prednisone (B). Note intense uptake of FDG uptake in inferior-septal and lateral walls, and papillary muscle, suggestive of active inflammation (panel A, arrow). There is subsequent complete resolution following treatment (panel B). The faint FDG uptake present in the blood pool of the left and right ventricular cavities is normal

Interventional Therapy Patients with CS are at high risk for sudden cardiac death (SCD). Episodes of non-sustained and sustained VT with syncope are common. In a study of 45 patients with CS and an ICD by Betensky et al., 37.8% (n=17) had a least one important arrhythmic event requiring therapy during a mean follow-up time of 2.6±2.7 years after device implantation. Notable in this study was the finding that a significant number of serious events occurred in patients with a LVEF >35%, higher than that generally recommended for placement of an ICD for primary prevention of sudden cardiac death in patients with other types of cardiomyopathy.39 Patients with isolated CS are at particularly risk for arrhythmias. Kron et al. reported on a retrospective multicenter review of 235 patients with CS and ICD in place. Of this group, 5.5% of patients (n=13) were felt to have definite or suspected isolated CS. Over a mean follow-up of 4.2 years, 69% (n=9) of these patients had appropriate ICD therapy, a much higher percentage than patients with CS as part of a systemic process, 33.8% (n=222).40 In 2014, the Heart Rhythm Society, in conjunction with six major cardiology organizations, published an expert consensus statement regarding diagnosis and management of patients with arrhythmias associated with CS. Included are recommendations for diagnosis, screening, management of conduction abnormalities,

andolin R, Lehtonen J, Airaksinen J, et al. Cardiac sarcoidosis: K epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation 2015;131:624–32. https://doi. org/10.1161/CIRCULATIONAHA.114.011522; PMID: 25527698. Okada D, Bravo P, Vita T, et al. Isolated cardiac sarcoidosis: a focused review of an under-recognized entity. J Nucl Cardiol 2016;25:1136–46. https://doi.org/10.1007/s12350-016-0658-1; PMID: 27613395. Ungprasert P, Carmona E, Utz J, et al. Epidemiology of sarcoidosis 1946–2013: A population-based study. Mayo Clinic Proc 2016;91:183–8. https://doi.org/10.1016/j.mayocp.2015.10.024; PMID: 26727158. Rybicki B, Major M, Popovich J, et al. Racial differences in sarcoidosis incidence: a five-year study in a health maintenance organization. Am J Epidemiol 1997;145:234–41. https://doi. org/10.1093/oxfordjournals.aje.a009096; PMID: 9012596. Baughman R, Teirstein A, Judson M, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164:1885–9. https://doi.org/10.1164/ ajrccm.164.10.2104046; PMID: 11734441. Johns C, Michele T. The clinical management of sarcoidosis: a 50-year experience at the Johns Hopkins hospital. Medicine 1999;78:65–111. https://doi.org/10.1097/00005792-19990300000001; PMID: 10195091. Silverman K, Hutchins G, Bulkley B. Cardiac sarcoid: a clinicopathologic study of 84 unselected patients with systemic sarcoidosis. Circulation 1978;58:1204–11. https://doi. org/10.1161/01.CIR.58.6.1204; PMID: 709777.

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Prognostic information regarding CS differs due variations in the evidence base regarding definitions, diagnosis, degree of cardiac involvement, treatment protocol used, and use of current guideline-directed electophysiologic and medical therapy for CHF. Earlier studies suggested a poor outcome, particularly in patients with reduced LVEF or patients who did not receive immunosuppressant therapy.36,37 More recent studies, using aggressive treatment protocols and advanced cardiac imaging, suggest a much better prognosis. Kandolin’s important study of 110 Finnish patients with CS followed over a period of 25 years, reported transplant-free survivals of 97% at 1 year, 90% at 5, and 83% at 10 years.1 The subgroup of patients who presented with CHF had somewhat worse outcomes, with transplant-free survivals of 90%, 75%, and 53% at 1, 5, and 10 years, respectively. This series was also notable for aggressive treatment with immunosuppressant and judicious use of ICDs among patients, along with advanced cardiac imaging to monitor the condition. A retrospective study by Zhou et al. of 73 patients with CS, also receiving state of the art care, demonstrated survivals of 95% at 5 years, and 93.4% at 10 years.41

Conclusion CS is an important and increasingly recognized cause of cardiomyopathy, both as part of a systemic process or isolated to the heart. It is characterized by elements of CHF, cardiac conduction disturbances and potentially fatal arrhythmias. Optimal diagnosis and treatment rely strongly on a high clinical index of suspicion. Cardiac imaging with cardiac MRI and PET is key for best diagnosis and monitoring of therapy. Although data are inconclusive, immunosuppression may be useful in improving symptoms, prognosis and LVEF. Judicious use of ICDs, even in patients with LVEF >35%, can be lifesaving. Finally, it should be emphasized that strong collaboration among cardiologists, cardiac electrophysiologists, cardiac imagers, radiologists and pulmonologists is of the utmost importance for the optimal care of patients with this complex condition.

atel M, Cawley P, Heitner J, et al. Detection of myocardial P damage in patients with sarcoidosis. Circulation 2009;120:1969– 77. https://doi.org/10.1161/CIRCULATIONAHA.109.851352; PMID: 19884472. Greulich S, Deluigi C, Gloekler S, et al. CMR imaging predicts death and other adverse events in suspected cardiac sarcoidosis. JACC Cardiovasc Imaging 2013;6:501–11. https://doi. org/10.1016/j.jcmg.2012.10.021; PMID: 23498675. Stewart RE, Graham DM, Godfrey GW, et al. Rapidly progressive heart failure resulting from cardiac sarcoidosis. Am Heart J 1988;115:1324–6. https://doi.org/10.1016/0002-8703(88)90035-X; PMID: 3376855. Birnie D, Sauer W, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm 2014;11:1305– 23. https://doi.org/10.1016/j.hrthm.2014.03.043; PMID: 24819193. Ishida Y, Yoshinaga K, Miyagawa M, et al. Recommendations for 18F-fluorordeoxyglucose positron emission tomography imaging for cardiac sarcoidosis: Japanese Society of Nuclear Cardiology Recommendations. Ann Nucl Med 2014;28:393–403. https://doi. org/10.1007/s12149-014-0806-0; PMID: 24464391. Judson MA, Costabel U, Drent M, et al. The WASOG sarcoidosis organ assessment instrument: an update of a previous clinical tool. Sarcoidosis Vasc Diffuse Lung Dis 2014;31:19–27. PMID: 24751450. Nery P, Beanlands R, Nair G, et al. Atrioventricular block as the initial manifestation of cardiac sarcoidosis in middle-aged

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adults. J Cardiovasc Electrophysiol 2014;25:875–81. https://doi. org/10.1111/jce.12401; PMID: 24602015. Nery P, McArdle B, Redpath C, et al. Prevalence of cardiac sarcoidosis in patients presenting with monomorphic ventricular tachycardia. Pacing Clin Electrophysiol 2014;37:364–74. https://doi.org/10.1111/pace.12277; PMID: 24102263. Uemura A, Morimoto S, Hiramitsu S, Kato Y, Ito T, Hishida H. Histologic diagnostic rate of cardiac sarcoidosis; evaluation of endomyocardial biopsy. Am Heart J 1999;138;229-302. PMID: 10426842. Liang JJ, Hebl VB, DeSimone CV, et al. Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis. JACC Heart Fail 2014;2:466–73. https://doi. org/10.1016/j.jchf.2014.03.015; PMID: 25194292. Slart RHJA, Glaudemans AWJM, Lancellotti P, et al. A joint procedural position statement on imaging in cardiac sarcoidosis: from the Cardiovascular and Inflammation & Infection Committees of the European Association of Nuclear Medicine, the European Association of Cardiovascular Imaging, and the American Society of Nuclear Cardiology. J Nucl Cardiol 2018;25:298–319. https://doi.org/10.1007/s12350-017-1043-4; PMID: 29043557. Bozkurt B, Colvin M, Cook J, et al. Current diagnostic and treatment strategies for specific dilated cardiomyopathies – a scientific statement from the American Heart Association. Circulation 2016;134:e579–e646; https://doi.org/10.1161/ CIR.0000000000000455; PMID: 27832612.

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Cardiac Sarcoidosis: Diagnosis and Therapy

20. M urtagh G, Laffin L, Beshai J, et al. Prognosis of myocardial damage in sarcoidosis patients with preserved left ventricular ejection fraction. Circ Cardiovasc Imaging 2016;9:e003738. https:// doi.org/10.1161/CIRCIMAGING.115.003738; PMID: 26763280. 21. Ekstrom K, Lehtonen J, Hanninen H, et al. Magnetic resonance imaging as a predictor of survival free of life-threatening arrhythmias and transplantation in cardiac sarcoidosis. J Am Heart Assoc 2016;5:e003040. https://doi.org/10.1161/JAHA.115.003040; PMID: 27139734. 22. Greulich S, Kitterer D, Latus J, et al. Comprehensive cardiovascular magnetic resonance assessment in patients with sarcoidosis and preserved left ventricular ejection fraction. Circ Cardiovasc Imaging 2016;9:e005022. https://doi.org/10.1161/ CIRCIMAGING.116.005022; PMID: 27903537. 23. Puntmann VO, Isted A, Hinojar R, et al. T1 and T2 mapping in recognition of early cardiac involvement in systemic sarcoidosis. Radiology 2017;285;63–72. https://doi.org/10.1148/ radiol.2017162732; PMID: 28448233. 24. Chareonthaitawee P, Beanlands RS, Chen W, et al. Joint SNMMIASNC expert consensus document of the role of 18F-FDG PET/ CT in cardiac sarcoid detection and therapy monitoring. J Nucl Cardiol 2017;24:1741–58. https://doi.org/10.1007/s12350-0170978-9; PMID: 28770463. 25. Youssef G, Leung E, Mylonas I, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: A systematic review and metaanalysis including the Ontario experience. J Nucl Med 2012;53:241–8. https://doi.org/10.2967/jnumed.111.090662; PMID: 22228794. 26. Osborne M, Hulten E, Murthy V, et al. Patient preparation for cardiac fluorine-18 fluorordeoxyglucose positron emission tomography imaging of inflammation. J Nucl Cardiol 2017;24:86– 99. https://doi.org/10.1007/s12350-016-0502-7; PMID: 27277502. 27. Kadkhodayan A, Chareonthatitawee P, Raman S, et al.

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Imaging of inflammation in unexplained cardiomyopathy. JACC Cardiovascular Imaging 2016;9(5):603-617. https://doi.org/10.1016/j. jcmg.2016.01.010; PMID: 27151523. Philips B, Madhavan S, James C. Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. Circ Arrhythm Electrophysiol. 2014;7:230-236. https://doi.org/10.1161/ CIRCEP.113.000932; PMID: 24585727. Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014;63:329–36. https://doi.org/10.1016/j.jacc.2013.09.022; PMID: 24140661. Vita T, Okada D, Veillet-Chowdhury M, et al. Complementary value of cardiac magnetic resonance imaging and positron emission tomography/computed tomography in the assessment of cardiac sarcoidosis. Circ Cardiovasc Imaging 2018;11:e007030. https://doi.org/10.1161/CIRCIMAGING.117.007030; PMID: 29335272. Wicks EC, Menezes LJ, Barnes A, et al. Diagnostic accuracy and prognostic value of simultaneous hybrid 18F-fluorodeoxyglucose positron emission tomography/ magnetic resonance imaging in cardiac sarcoidosis. Eur Heart J Cardiovasc Imaging 2018;19:757–67. https://doi.org/10.1093/ehjci/ jex340; PMID: 29319785. Sadek MM, Yung D, Birnie DH, et al. Corticosteroid therapy for cardiac sarcoidosis: A systematic review. Can J Cardiol 2013;29:1034– 41. https://doi.org/10.1016/j.cjca.2013.02.004; PMID: 23623644. Nagai S, Yokomatsu T, Tanizawa K, et al. Treatment with methotrexate and low-dose corticosteroids in sarcoidosis patients with cardiac lesions. Intern Med 2014;53:427–33. https://doi. org/10.2169/internalmedicine.53.0794; PMID: 24583430. Lynch J, Hwang J, Bradfield J, et al. Cardiac involvement in

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sarcoidosis: evolving concepts in diagnosis and treatment. Semin Respir Crit Care Med 2014;35:372–90. https://doi. org/10.1055/s-0034-1376889; PMID: 25007089. Birnie D, Nery P, Ha A, et al. Cardiac sarcoidosis. J Am Coll Cardiol 2016;68:411–21. https://doi.org/10.1016/j.jacc.2016.03.605; PMID: 27443438. Yazaki Y, Isobe M, Hiroe M, et al. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001;88:1006–10. https://doi. org/10.1016/S0002-9149(01)01978-6; PMID: 11703997. Chiu A, Nakatani S, Zhang G, et al. Prevention of left ventricular remodeling by long-term corticosteroid therapy in patients with cardiac sarcoidosis. Am J Cardiol 2005;95:143–6. https://doi. org/10.1016/j.amjcard.2004.08.083; PMID: 15619415. Osborne M, Hulten E, Singh A, et al. Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014;21:166–74. https://doi.org/10.1007/s12350013-9828-6; PMID: 24307261. Betensky B, Tschabrunn C, Zado E, et al. Long-term followup of patients with cardiac sarcoidosis and implantable cardioverter-defibrillators. Heart Rhythm 2012;9:884–91. https:// doi.org/10.1016/j.hrthm.2012.02.010; PMID: 22338670. Kron J, Sauer W, Mueller G, et al. Outcomes of patients with definite and suspected isolated cardiac sarcoidosis treated with an implantable cardiac defibrillator. J Interv Card Electrophysiol 2015;43:55–64. https://doi.org/10.1007/s10840-015-9978-3; PMID: 25676929. Zhou Y, Lower E, Hui-ping L, et al. Cardiac sarcoidosis – the impact of age and implanted devices on survival. Chest 2017;151:139–48. https://doi.org/10.1016/j.chest.2016.08.1457; PMID: 27614001.

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Cardiometabolic Disorders

Diabetic Cardiomyopathy: Five Major Questions with Simple Answers Miguel Alejandro Rodriguez-Ramos, MD Servicio de Cardiología, Hospital General Docente Camilo Cienfuegos, Sancti-Spiritus, Cuba

Abstract Diabetes is a major risk factor for heart disease. Diabetic cardiomyopathy is a long-lasting process that affects the myocardium in patients who have no other cardiac conditions. The condition has a complex physiopathology which can be subdivided into processes that cause diastolic and/or systolic dysfunction. It is believed to be more common than reported, but this has not been confirmed by a large study. Diagnosis can involve imaging; biomarkers cannot be used to identify diabetic cardiomyopathy at an early stage. In people with diabetes, there should be a focus on prevention and, if diabetic cardiomyopathy develops, the objective is to delay disease progression. Further studies into identifying and managing diabetic cardiomyopathy are essential to reduce the risk of heart failure in people with diabetes.

Keywords Diabetic cardiomyopathy, diabetes, metabolic disease, heart failure, myocardial dysfunction Disclosure: The author has no conflicts of interest to declare. Received: November 25, 2018 Accepted: February 5, 2019 Citation: US Cardiology Review 2019;13(1):46–8. DOI: https://doi.org/10.15420/usc.2018.18.2 Correspondence: Miguel Rodriguez-Ramos, Servicio de Cardiología, Hospital General Docente Camilo Cienfuegos, Sancti-Spiritus, Cuba. E: mialero@infomed.sld.cu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Type 2 diabetes is a major risk factor for the development of heart disease.1 At the beginning of the last century, or even before, several authors described a possible association between diabetes and heart failure (HF).2 However, according to the Heart Failure Association of the European Society of Cardiology guideline for the treatment of type 2 diabetes and HF, the first report of this association, excluding other risk factors, was published in 1954.3 Lundbaek et al. stated that a heart condition could occur without hypertension or coronary artery disease.3 Later, in 1972, Rubler et al. reported a series of pathological changes in myocardial tissue in four patients with diabetic glomerulosclerosis. 4 They described diffuse fibrotic strands extending between bundles of muscles and and myofibrillar hypertrophy. Soon after, researchers working on the Framingham Heart Study demonstrated a higher incidence of HF in women and men with diabetes, with an increased prevalence of cardiovascular complications.5 A search of Medline for ‘diabetic cardiomyopathy’ in November 2018 retrieved 1,002 articles published in the past 5 years (almost 50% of total published articles), which indicates that interest in diabetic cardiomyopathy (DCM) is growing. However, the condition continues to be unrecognized. Several technological advances are needed to make an accurate diagnosis, and this technology that may not be available in middle- and low-income countries, where the prevalence of diabetes is increasing, while effective treatment is lacking, predisposing these patients to DCM.

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What is Diabetic Cardiomyopathy? Rubler et al. are believed to be the first to describe DCM. 4 However, those findings are not useful from a clinical point of view because pathological findings are not a suitable way to diagnose this condition. Descriptions of the condition, with varying degrees of complexity, have been published. 1,6,7 They all have something in common: a disease of a heart muscle develops in patients with diabetes who have no other cardiac conditions such as valvular, ischemic, or hypertensive disease. A novel definition has been proposed: DCM is a long-term process that affects the myocardium from the early stage of metabolic changes. 8 Nevertheless, others have reported that it is purely a combination of molecular myocardial abnormalities that predispose a person to develop myocardial dysfunction, starting with type 1 or type 2 diabetes, which is a metabolic disease. These metabolic changes elicit cardiac functional abnormalities and, ultimately, cardiac dysfunction.9

Is Diabetic Cardiomyopathy Common or Rare? Unfortunately, the definition of DCM can cause problems in answering this question. Patients with a history of hypertensive or ischemic disease cannot be diagnosed with DCM. Observational registries show that epicardial coronary stenosis of clinical importance occurs in 90% of patients with diabetes, and others report more than three-quarters of patients with diabetes have hypertension.10,11 As a result, the prevalence of DCM in the whole diabetic population is less than 8%, but this figure is likely to be wrong. Diastolic dysfunction can be present in up to 25% of

Diabetic Cardiomyopathy patients with diabetes, as several clinical trials have shown, rising to 60% in patients with type 1 diabetes.12,13 According to recent data, around 600 million people are living with type 2 diabetes.12 The prevalence of DCM is not clear because of a lack of large study outcomes from different populations with type 2 diabetes.13

acid, procollagen 3 N-terminal peptide, and brain natriuretic peptide.13 Although tests for these have been approved by Food and Drug Administration for the screening of heart diseases, none can be used to identify DCM at an early stage.20

Can Treatment be Improved? Does Diabetic Cardiomyopathy Have a Simple Physiopathology? Unfortunately, the answer is no. DCM is a complex condition that can affect the heart in several ways.14 Type 2 diabetes involves impaired glucose levels with an increase in insulin resistance. This systemic condition produces changes in the metabolism of cardiomyocytes, which increase their metabolism of fatty acids.15 This leads to fibrosis and a loss of contractile properties, which decrease the compliance of the heart so cause diastolic dysfunction. The hexosamine biosynthetic pathway, protein kinase C pathway, advanced glycation end-products pathway, and polyol flux pathway secondary to an increase of hyperglycemia can all produce contractile dysfunction, which can lead to systolic HF in a patient with DCM.16,17

Yes. Although diagnosis in the early stage is not easy, metabolic changes can be identified using nuclear imaging and MRI.12 Echocardiography is also useful in the first stage. Several degrees of diastolic dysfunction may appear with the use of longitudinal and circumferential strains.18 In the later stages, complementary imaging can produce more information. In the middle stage, echocardiography can be used to determine the mass and diameter of the left ventricle and the diastolic patterns described above. MRI can detect changes in blood flow and ventricular filling patterns.19 In the final stages, several degrees of systolic dysfunction become apparent. Perfusion changes can be seen in nuclear imaging. Cardiac tomography can detect calcification and systolic dysfunction; the latter can also be detected by MRI. Echocardiography can show several degrees of contractile dysfunction through alterations of strain rate and global, regional, and ventricular strain.12,18,19 Several biomarkers can give additional information, including matrix metalloproteinases (MMPs), tissue inhibitors of MMPs, microribonuleic

J ia GG, Hill MA, Sowers JR. Diabetic cardiomyopathy. An update of mechanisms contributing to this clinical entity. Circ Res 2018;122:624–38. https://doi.org/10.1161/ CIRCRESAHA.117.311586; PMID: 29449364. Glezeva N, Chisale M, McDonald K, et al. Diabetes and complications of the heart in Sub-Saharan Africa: an urgent need for improved awareness, diagnostics and management. Diabetes Res Clin Pract 2018;137:10–19. https://doi.org/10.1016/j. diabres.2017.12.019; PMID: 29287838. Seferović PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:853–72. https://doi.org/10.1002/ejhf.1170; PMID: 29520964. Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomeruloscierosis. Am J Card 1972;30:595–602. https://doi.org/10.1016/00029149(72)90595-4; PMID: 4263660. Jia GH, Whaley-Connell A, Sowers JR. Diabetic cardiomyopathy: a hyperglycaemia and insulin-resistance-induced heart disease.

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Hypoglycemic agents are the cornerstone of type 2 diabetes treatment. However, none of them had been shown to decrease the risk of HF until the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and CANagliflozin cardioVascular Assessment Study (CANVAS) trialS, which examined empagliflozin and canagliflozin respectively.6,22 Other strategies proposed for DCM treatment include lifestyle modifications, vasoactive medications (such as beta-blockers and angiotensin-converting enzyme inhibitors), lipid-lowering drugs (such as statins), and metabolic modulators.8,23,24

Can Diagnosis be Improved?

Yes. Given that the Detection of Ischemia in Asymptomatic Diabetics (DIAD) trial stated that screening to detect subclinical DCM had failed, further studies into the development of novel strategies are essential to reduce the risk of HF in people with diabetes.1,21

A classification for DCM has been created, using similar categories to the New York Heart Association (NYHA) system. Patients with grade 3 DCM can be categorized as having NYHA grade 2 or 3 and DCM grade 4 can have a NYHA classification of 3 or 4. The difference between these two classifications is that while NYHA is a clinical classification for HF, DCM grades depend on the metabolic status: impaired glucose tolerance (grade 1), chronic hyperglycemia (grade 2), insulin resistance or microangiopathic complications (grade 3), and macroangiopathic complications (grade 4). Treatment depends on the grade or type of HF and DCM.25,26

Conclusion DCM is a long-lasting process that affects the myocardium in absence of valvular, hypertensive, or ischemic heart diseases. It seems that it is more frequent than reported, but a large study is needed for confirmation. The condition has a complex physiopathology which can be divided into processes that cause diastolic and/or systolic dysfunction. Diagnosis can be improved by suspecting it in patients with diabetes. There should be a focus on prevention (by tight metabolic control) and, once DCM develops, the objective should be to delay disease progression.

Diabetologia 2018;61:21–8. https://doi.org/10.1007/s00125-0174390-4; PMID: 28776083. Joubert M, Manrique A, Cariou B, Prier X. Diabetes-related cardiomyopathy: The sweet story of glucose overload from epidemiology to cellular pathways. Diabetes Metab 2018;pii:S1262– 3636(18)30124–1. https://doi.org/10.1016/j.diabet.2018.07.003; PMID: 30078623. Sathibabu Uddandrao VV, Brahmanaidu P, Nivedha PR, et al. Beneficial role of some natural products to attenuate the diabetic cardiomyopathy through Nrf2 pathway in cell culture and animal models. Cardiovasc Toxicol 2018;18:199–205. https://doi.org/10.1007/s12012-017-9430-2; PMID: 29080123. Marcinkiewicz A, Ostrowski S, Drzewoski J. Can the onset of heart failure be delayed by treating diabetic cardiomyopathy? Diabetol Metab Syndr 2017;9:21. https://doi.org/10.1186/s13098017-0219-z; PMID: 28396699. Mizamtsidi M, Paschou SA, Grapsa J, Vryonidou A. Diabetic cardiomyopathy: a clinical entity or a cluster of molecular heart changes? Eur J Clin Invest 2016;46:947–53. https://doi. org/10.1111/eci.12673; PMID: 27600276.

10. Z apolski T, Kamińska A, Konarski Ł, Wysokiński A. [The left atrium volume index: a biomarker of left atrium remodelling – methods of assessment and predictive value]. Kardiol Pol 2013;71:191–7 [in Polish]. https://doi.org/10.5603/KP.2013.0016; PMID: 23575716. 11. Colosia AD, Palencia R, Khan S. Prevalence of hypertension and obesity in patients with type 2 diabetes mellitus in observational studies: a systematic literature review. Diabetes Metab Syndr Obes 2013;17:327–38. https://doi.org/10.2147/DMSO. S51325; PMID: 24082791. 12. Lorenzo-Almorós A, Tuñón J, Orejas, M, et al. Diagnostic approaches for diabetic cardiomyopathy. Cardiovasc Diabetol 2017;16(1):28. https://doi.org/10.1186/s12933-017-0506-x; PMID: 28231848. 13. Lee WS, Kim J. Diabetic cardiomyopathy: where we are and where we are going. Korean J Intern Med 2017;32:404–21. https://doi.org/10.3904/kjim.2016.208; PMID: 28415836. 14. Hu X, Bai T, Xu Z, et al. Pathophysiological fundamentals of diabetic cardiomyopathy. Compr Physiol 2017;7:693–711. https://doi.org/10.1002/cphy.c160021; PMID: 28333387. 15. Carpentier AC: Abnormal myocardial dietary fatty acid metabolism

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16.

17.

18.

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and diabetic cardiomyopathy. Can J Cardiol 2018;34:605–14. https://doi.org/10.1016/j.cjca.2017.12.029; PMID: 29627307. Varma U, Koutsifeli P, Benson VL, et al. Molecular mechanisms of cardiac pathology in diabetes – experimental insights. Biochim Biophys Acta Mol Basis Dis 2018;1864:1949–59. https://doi. org/10.1016/j.bbadis.2017.10.035; PMID: 29109032. Singh RM, Waqar T, Howarth FC, et al. Hyperglycemia-induced cardiac contractile dysfunction in the diabetic heart. Heart Fail Rev 2018;23:37–54. https://doi.org/10.1007/s10741-017-9663-y; PMID: 29192360. Negishi K. Echocardiographic feature of diabetic cardiomyopathy: where are we now? Cardiovasc Diagn Ther 2018;8:47–56. https://doi.org/10.21037/cdt.2018.01.03; PMID: 29541610. Marwick TH, Ritchie R, Shaw JE, Kaye D. Implications of underlying mechanisms for the recognition and management of

diabetic cardiomyopathy. J Am Coll Cardiol 2018;71:339–51. https://doi.org/10.1016/j.jacc.2017.11.019; PMID: 29348027. 20. Palomer X, Pizarro-Delgado J, Vázquez-Carrera M. Emerging actors in diabetic cardiomyopathy: heartbreaker biomarkers or therapeutic targets? Trends Pharmacol Sci 2018;39:452–67. https://doi.org/10.1016/j.tips.2018.02.010; PMID: 29605388. 21. Young LH, Wackers FJ, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009;301:1547–55. https://doi.org/10.1001/ jama.2009.476; PMID: 19366774. 22. Borghetti G, von Lewinski D, Eaton DM, et al. Diabetic cardiomyopathy: current and future therapies. Beyond glycemic control. Front Physiol 2018;9:1514. https://doi.org/10.3389/

fphys.2018.01514; PMID: 30425649. 23. A lonso N, Moliner P, Mauricio D. Pathogenesis, clinical features and treatment of diabetic cardiomyopathy. Adv Exp Med Biol 2018;1067:197–217. https://doi.org/10.1007/5584_2017_105; PMID: 28980272. 24. Sivasankar D, George M, Sriram DK. Novel approaches in the treatment of diabetic cardiomyopathy. Biomed Pharmacother 2018;106:1039–45. https://doi.org/10.1016/j.biopha.2018.07.051; PMID: 30119169. 25. Gilca GE, Stefanescu G, Badulescu O, et al. Diabetic cardiomyopathy: current approach and potential diagnostic and therapeutic targets. J Diabetes Res 2017;2017:1310265. https://doi. org/10.1155/2017/1310265; PMID: 28421204. 26. Maisch B, Alter P, Pankuweit S. Diabetic cardiomyopathy – fact or fiction? Herz 2011;36:102–15. https://doi.org/10.1007/s00059011-3429-4; PMID: 21424347.

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Everything in Moderation: Investigating the U-Shaped Link Between HDL Cholesterol and Adverse Outcomes Marc P Allard-Ratick, MD, 1 Pratik B Sandesara, MD, 2 Arshed A Quyyumi, MD, FACC, FRCP, 2 and Laurence S Sperling, MD, FACC, FAHA, FACP, FASPC 2 1. Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA; 2. Division of Cardiology, Department of Internal Medicine, Emory University School of Medicine, Atlanta, GA

Abstract Despite historical evidence suggesting an inverse association between HDL cholesterol (HDL-C) and adverse cardiovascular events, pharmacological efforts to increase HDL-C and improve outcomes have not been successful. Recently, a U-shaped association between HDL-C and adverse events has been demonstrated in several population cohorts, further complicating our understanding of the clinical significance of HDL. Potential explanations for this finding include genetic mutations linked to very high HDL-C, impaired HDL function at high HDL-C levels, and residual confounding. However, our understanding of this association remains premature and needs further investigation.

Keywords HDL cholesterol, very high HDL cholesterol, adverse cardiovascular events, HDL function, lipids Disclosure: The authors have no conflicts of interest to declare. Received: January 27, 2019 Accepted: February 5, 2019 Citation: US Cardiology Review 2019;13(1):49–53. DOI: https://doi.org/10.14520/usc.2019.3.2 Correspondence: Marc Allard-Ratick, 49 Jesse Hill Drive, SE, Floor 4, Office 444, Atlanta, GA, 30303. E: mallard@emory.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Historically, HDL cholesterol (HDL-C) has been inversely associated with adfverse cardiovascular outcomes such as MI, stroke, and cardiovascular death.1–3 This led to widespread belief that HDL-C, in addition to LDL cholesterol (LDL-C), was a modifiable risk factor for cardiovascular disease. However, efforts to increase HDL-C in high-risk patients with wellcontrolled LDL-C values have not demonstrated a reduction in adverse cardiovascular outcomes.4,5 These have included the administration of cholesteryl ester transfer protein (CETP) inhibitors, which dramatically raise HDL-C, but have failed to demonstrate a meaningful reduction in adverse cardiovascular events.6–9 Subsequent analyses of several large population cohorts suggested a plateauing of the inverse association between HDL-C and adverse cardiovascular events at high levels of HDL-C. More recently, a U-shaped association has been demonstrated between HDL-C and adverse events, including all-cause mortality, suggesting that, at very high levels, HDL-C may correlate with increased cardiovascular events and all-cause death. The aim of this article is to outline the data regarding very high HDL-C and adverse outcomes, to explore potential explanations for this seemingly paradoxical association, and to provide clinically relevant applications.

Exploring HDL Cholesterol and Adverse Outcomes Assessment of HDL Cholesterol and Cardiovascular Risk in Large Population Cohorts Identification of HDL-C as a potential protective factor in atherosclerotic cardiovascular disease (ASCVD) gained significant attention after analysis of the Framingham Heart Study cohort. This study demonstrated an inverse association between HDL-C levels and incidence of CHD in more than 2,800 men and women without known cardiovascular disease after a follow-up of 12 years.1 These findings remained significant after multivariate adjustment for other common cardiovascular risk factors including tobacco use, hypertension, obesity, and age.1 Of note, however, HDL-C categories for analysis were broken into quartiles (<1.04 mmol/l, 1.04–1.27 mmol/l, 1.30–1.53 mmol/l, and >1.55 mmol/l), which may have limited the ability to detect adverse outcomes in a small subset of patients with very high HDL-C values. Analysis from the more recent Emerging Risk Factor Collaboration, a combination of 68 long-term prospective cohorts involving over 300,000 individual patient records from across the world, supported this inverse linear association between HDL-C and adverse cardiovascular events.3 When the population was separated into quintiles, there was notable attenuation of the inverse relationship between HDL-C and adverse cardiovascular events among patients in the highest quintile.3 However, it

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Cardiometabolic Disorders is challenging to draw definite conclusions from this study as it involved analysis from numerous prospective studies with differing inclusion and exclusion criteria as well as recorded covariates. Analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort provided one of the first signals that very high HDL-C may be correlated with adverse cardiovascular outcomes.10 The study included more than 5,500 community-dwelling men and women at low inherent risk for cardiovascular disease and excluded those on cholesterol-lowering medication. Initial analysis of HDL-C levels (broken down into quartiles) and CHD event rate suggested an inverse linear relationship as had been demonstrated previously.10 However, a fifth HDL-C category of >2.07 mmol/l was analyzed separately and was notable for an increased risk of CHD events (HR 2.59; 95% CI [1.11–6.02]) compared to the reference HDL-C range.10 While these results remained significant after multivariate regression, alcohol intake was not included in the adjustment, which is a potential confounder as alcohol is associated with both increased HDL-C and adverse events.

Very High HDL Cholesterol and Adverse Events in Patients at Low Risk of Cardiovascular Disease Given that HDL-C values >2.07 mmol/l are relatively rare among people at low risk of cardiovascular disease, it was hypothesized that much larger patient samples would be necessary to confirm a significant association between very high HDL-C and adverse cardiovascular events. The Cardiovascular Health in Ambulatory Care Research Team (CANHEART) dataset, which involves more than 600,000 individuals from Ontario, Canada, without known cardiovascular disease, was analyzed after a median follow-up of 5 years in an attempt to understand the relationship between HDL-C and cause-specific mortality.11 The results demonstrated a statistically significant increased risk of allcause mortality in men with HDL-C levels >2.07 mmol/l and HDL-C levels <0.78 mmol/l compared to reference HDL-C levels of 1.04–1.30 mmol/l, after adjusting for covariates including heavy alcohol use.11 Interestingly, this significant increase in mortality for HDL-C values >2.07 mmol/l was driven by non-cardiac, non-cancer related deaths, although there was a non-significant trend towards an increased risk of cardiac death.11 There was no statistically significant increase in all-cause mortality in women in the highest HDL-C category (>2.33 mmol/l) but there was a significant increase in non-cancer, non-cardiac associated death.11

Study cover two longitudinal, non-overlapping cohorts at a relatively low risk for cardiovascular disease. The two cohorts were analyzed in combination to generate a population sample of more than 50,000 men and 60,000 women who were followed for a median of 6 years. Primary endpoints included all-cause mortality and cardiovascular death. Secondary endpoints included incidence of ischemic heart disease, MI, and ischemic stroke. When HDL-C was assessed as a continuous variable using restricted spline curves, there was a significant ‘U-shaped’ association with all-cause mortality in both men and women (Figure 1), although the association was stronger in men. Analysis of HDL-C categories demonstrated a significantly increased risk of all-cause death at HDL-C values of >2.51 mmol/l in men (HR 1.36; 95% CI [1.09–1.70] and >3.50 mmol/l in women (HR 1.68; 95% CI [1.09–2.58] 95%) as well as <1.04 mmol/l in both sexes compared to the lowest risk HDL-C categories for each sex. Cardiovascular death was also demonstrated to have a U-shaped association with HDL-C values in both men and women. The risks of CHD, MI, and ischemic stroke were not significantly greater in the highest HDL-C categories than in reference values, although there was a plateauing of the inverse relationship between these variables at very high HDL-C levels.12 All findings remained significant after multivariate adjustment, which included degree of alcohol use, hormone replacement therapy for women, and physical activity level, all of which have previously been shown to increase HDL-C levels.13–15 Further sensitivity analysis stratifying alcohol use did not demonstrate a significant difference in the results previously stated. These data provide compelling evidence of an epidemiologic link between very high HDL-C levels and both all-cause death and cardiovascular death in a low-risk population.11,16 While the study involved a rather homogenous population in one geographic area, this U-shaped association was also noted in the CANHEART study in Ontario, Canada, described above, and in a more recent population-based study from Japan, suggesting generalizability to low-risk populations across the globe.11,16

Very High HDL Cholesterol and Adverse Events in Patients at High Risk of Cardiovascular Disease The majority of data linking very high HDL-C levels and adverse events have been obtained in populations at relatively low risk for cardiovascular disease, and data in higher risk individuals are limited.

While this analysis of the CANHART dataset did not include major adverse cardiovascular events as an endpoint, the higher non-cardiac death rates observed in patients with very high HDL-C levels is surprising. This could reflect a limitation of analyzing mortality rates in a large dataset, as cause-specific mortality was obtained from patient death certificates, which can misclassify the cause of death. Alternatively, these findings could support that the HDL molecule is crucial to broader systemic pathophysiologic processes.

Van der Steeg et al. analyzed the association between HDL-C and adverse cardiovascular events in two distinct populations – the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial (IDEAL) and EPIC (European Prospective Investigation of Cancer)-Norfolk cohorts.17 The IDEAL cohort involved 8,888 patients with a prior coronary event randomized to receive high-intensity versus moderate-intensity statin therapy. EPIC-Norfolk was a cohort at low risk for cardiovascular disease and involved patients enrolled at community practices in Norfolk, UK.

Perhaps the best evidence to date detailing the link between very high levels of HDL-C and increased adverse events comes from an analysis of two general population cohorts in Copenhagen, Denmark.12 The Copenhagen City Heart Study and the Copenhagen General Population

Analysis of these two cohorts included all 8,888 patients from IDEAL and a 1:2 case-control study of the EPIC-Norfolk cohort involving those who developed coronary artery disease (CAD) during the follow-up period (858 patients) and matched controls (1,491 patients). Results were

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HDL Cholesterol and Adverse Outcomes

In the EPIC-Norfolk cohort, there was an inverse association between HDL-C values and the primary endpoint of fatal or non-fatal CAD after adjusting for common risk factors (excluding alcohol use). These data may suggest that patients with prior cardiovascular disease and very high HDL-C levels are at higher risk for subsequent events than patients with similar HDL-C levels who are at lower cardiovascular risk at baseline. However, limitations in this two-cohort analysis include differing study design involving two different primary endpoints, and the lack of adjustment for alcohol use in the IDEAL cohort. Furthermore, there was no analysis of mortality data, which has demonstrated the strongest correlation with very high HDL-C levels as detailed above.

Figure 1: HDL Cholesterol and All-cause Mortality

All-cause mortality

broken down by cohort. In the IDEAL cohort, there was an increased risk of the combined primary endpoint of coronary death, non-fatal MI, and resuscitation after cardiac arrest in patients with HDL-C levels <1.04 mmol/l and >2.07 mmol/l compared to the lowest risk HDL-C range (1.55–1.80 mmol/l) after adjusting for common risk factors (this did not include alcohol use).17

HDL cholesterol (mg/dl) U-shaped association between HDL cholesterol levels and all-cause mortality.

Recently, preliminary data presented at the European Society of Cardiology included 5,965 individuals enrolled in the Emory University cardiovascular biobank in Atlanta, Georgia, who had either known CAD or were at high risk for cardiovascular disease, who were followed for a median of 3.9 years to assess the relationship between elevated HDL-C levels and adverse events.18 The two co-primary endpoints were a combination of cardiovascular death or non-fatal MI and all-cause mortality. Results demonstrated there was a U-shaped association between HDL-C levels and both all-cause mortality and cardiovascular death or non-fatal MI when using restricted cubic spline regression.18 There was a significantly increased risk of all-cause mortality at HDL-C levels of >2.07 mmol/l and <1.17 mmol/l, and an increased risk of the combination of cardiovascular death and non-fatal MI at HDL-C levels >2.60 mmol/l and <1.17 mmol/l after adjustment for common covariates including alcohol use.18 These data, albeit preliminary, suggest there is a correlation between very high HDL-C levels and all-cause mortality in a high-risk population, adding to a growing evidence base. Given the U-shaped association between these two variables, two important questions arise: • Is this correlation causative? • What are potential explanations for this finding?

similar increase in HDL-C have also been analyzed with mixed results. One study involving more than 9,000 community-dwelling men and women and over 900 men and women with ischemic heart disease found a significantly increased risk of ischemic heart disease in women only, with a specific single nucleotide polymorphism (SNP) of the CETP gene that led to a mild mean increase (~0.13 mmol/l) in HDL-C levels among the affected population.20 However, other SNPs of the CETP gene that lead to a similar mean increase in HDL-C have been found to have an inverse association with ischemic cardiovascular disease.21 It is important to note that these mutations of the CETP gene do not exclusively affect HDL-C values, and also lead to mild reductions in LDL-C, triglycerides, and apolipoprotein B. Therefore, the associations demonstrated may be confounded by these additional effects of CETP mutation. To address this, deLemos et al. performed a genome-wide association study that identified several variants of the endothelial lipase gene (LIPG) that were exclusively associated with HDL-C.22 Of these variants, one particular loss of function SNP (Asn396Ser) was associated with significantly increased HDL-C and decreased endothelial lipase activity in vitro.23 As part of a Mendelian randomization analysis, carriers of this SNP of LIPG were found to have higher levels of HDL-C (mean 1.41 mmol/l) but similar levels of other lipids compared with non-carriers.24 In addition,

Genetic Variants Associated with Elevated HDL-C

carriers of the Asn396Ser SNP did not demonstrate any association with the risk of MI in a prospective cohort involving six population-based trials and more than 50,000 participants.24

Several gene mutations associated with altering HDL-C levels in vivo have been identified.19 CETP facilitates the exchange of cholesteryl esters for triglycerides between HDL and remnant lipoproteins. Inhibition of this action leads to significant increases in HDL-C, which has prompted several trials of pharmacological CETP inhibitors with the intention of reducing residual cardiovascular risk in patients at high risk. Unfortunately, these trials have not demonstrated a consistent reduction in cardiovascular risk, with one trial even suggesting an increased risk.6–9

Scavenger receptor class B type 1 (SR-BI) is a major receptor for HDL that promotes the transfer of cholesterol from the HDL molecule to the liver. Mutations of the SR-BI gene (SCARB1) have been found to be associated with increased HDL-C without significant association with other lipid measures.25 Among a population of >300,000 individuals, a specific SNP of SCARB1 (P376L) was found to be associated with significantly increased HDL-C levels, with a large effect size (beta = 0.22 mmol/l).25 A case-control

Given the inconsistent results of these pharmacological trials, loss of function genetic mutations in the CETP gene that may translate to a

analysis of 137,995 patients with and without CHD demonstrated a significantly increased risk of CHD in carriers of the P376L allele compared to non-carrier controls.25 However, this specific mutation was rare in the

Possible Explanations for the HDL Paradox

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Cardiometabolic Disorders large population studied, limiting its general applicability to patients with very high HDL-C. A subsequent case-control analysis of 36,886 patients with identified CAD from the National University Hospital of Iceland and 306,268 control individuals from the Icelandic genealogical database did not demonstrate any association with CAD among carriers of three novel SNPs of the SCARB1 gene.26 Of note, the P376L mutation was not one of the three variants included in this analysis.26 The evidence to support a genetic cause of very high HDL-C and an association with adverse cardiovascular events is mixed. This outcome variability, at least in part, is likely to come from the different genes and numerous SNPs within the genes examined. Additionally, genes that also affect other risk factors for cardiovascular disease, such as CETP, provide limited evidence because of potential confounding. Furthermore, few studies used all-cause mortality as an endpoint. As the association between very high HDL-C and all-cause mortality has the strongest epidemiologic link, further investigation is needed.

HDL Function at High HDL-C Levels Pursuit of the potential causative relationship between HDL-C and adverse events has shifted investigative attention to the function of the HDL molecule. At present, there are two main validated measurable assays of HDL function: the cholesterol efflux capacity (CEC); and the HDL inflammatory index. CEC is a dynamic assessment of the rate and magnitude of cholesterol movement from the peripheral tissues to the liver, otherwise known as reverse cholesterol transport. This process is mediated by the HDL molecule, so impairment of CEC is suggestive of dysfunctional HDL. To date, several studies have demonstrated an inverse relationship between CEC and adverse cardiovascular events.27,28 Furthermore, CEC has been shown to be a superior marker for incident adverse cardiovascular events than HDL-C, and improves net reclassification indices for predicting cardiovascular risk in a primary prevention population.27,28 When analyzed in a population of patients with very high HDL-C levels (mean 2.23 mmol/l) and CHD, CEC was markedly impaired compared to age, sex, and HDL-C-matched controls.29 While these data suggest an inverse correlation between CEC and adverse cardiovascular events, likely outperforming HDL-C as an independent risk factor, they also elucidate whether CEC becomes impaired at very high levels of HDL-C exclusive of incident cardiovascular disease. A study by Agarwala et al. investigated a population of patients with very high HDL-C and CHD. HDL-C values were similar in matched controls free from cardiovascular disease and had superior CEC.29 Whether very high HDL-C levels affect CEC directly is unknown.

normal range compared to age and sex-matched controls. There was a marked increase in CFA and MCA values in the CHD experimental group compared to the controls (MCA 1.38 versus 0.38 p<1.5x10−5, CFA 1.19 versus 0.53 p<7.4x10–14).30 A second study group involving 20 patients with incident CHD and very high HDL-C values (>2.18 mmol/l) demonstrated a similar increase in CFA and MCA values in the experimental group (MCA 1.28 versus 0.35 p<1.7x10−14, CFA 1.37 versus 0.66 p<4.4x10−12).30 These data suggest that, in patients with established cardiovascular disease, HDL is more likely to be pro-inflammatory than in similar control populations. While this finding was demonstrated in a population of patients with very high HDL-C, the results are confounded by the presence of CHD. Statistical comparison of the two populations with incident CHD but different mean HDL-C levels was not completed, although raw data did not suggest a difference between these two groups. HDL may play a role in immune system modulation, which could in part be tied to its pro- and anti-inflammatory properties.31 In patients with severe sepsis, HDL-C was inversely associated with other markers of systemic inflammation, and low levels of HDL-C were predictive of poor outcomes in a small prospective study.32 Recently, Madsen et al. analyzed the Copenhagen General Population Study and Copenhagen City Heart Study to understand the association between HDL-C and infection risk.33 The association between HDL-C and risk of any infectious disease was U-shaped, although the absolute highest risk for infectious disease remained at very low levels of HDL-C.A similar association was noted between HDL-C and death related to infectious disease.33 Other lipids measures, including LDL-C and triglycerides, did not share this U-shaped association.33 While these data provide evidence that HDL-C at extreme levels correlates with infectious disease risk, they do not provide a causative link. Several other functions of the HDL molecule have been suggested by researchers, including roles in endothelial function, cellular apoptosis, and regulation of endothelial progenitor cells.34–36 While HDL clearly plays a role in many systemic processes in the human body, there is not significant data nor enough readily available measures of these functions to conclude that dysfunctional HDL causes adverse outcomes. Furthermore, no study to date has accurately assessed the functional status of the HDL molecule when HDL-C is at very high levels, despite recent data suggesting an association with increased infection risk at very high HDL-C levels. Therefore, the question of whether dysfunctional HDL is an explanation for the epidemiological association between very high HDL-C and adverse outcomes requires further exploration.

Residual Confounding A second functional assessment of HDL, the HDL inflammatory index, measures the degree of LDL oxidation via a cell free assay (CFA) and LDL mediated monocyte chemotactic activity (MCA) as influenced by HDL compared to control LDL. Pro-inflammatory and pro-oxidant HDL will increase MCA and CFA values (>1.0) compared to control LDL (reference 1.0). Alternatively, anti-inflammatory and antioxidant HDL will decrease MCA and CFA values (<1.0). Ansell et al. conducted a small prospective study involving patients who presented with incident CHD and age- and sex-matched controls. 30 The initial study group involved 26 patients with incident CHD and HDL-C values in the

The association between very high HDL-C and other risk factors for adverse events has been studied insufficiently, leading to the possibility of residual confounding in the epidemiological studies described. While excessive alcohol use is one known risk factor that may confound results, this was adequately accounted for in several of the more recent population based studies, and is unlikely to be a sufficient explanation for the correlation between very high HDL-C and adverse events. However, there may be other risk factors, similar to alcohol, that are associated with both elevated HDL-C levels and adverse events but have not been identified and accounted for.

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HDL Cholesterol and Adverse Outcomes Conclusion The inverse association between HDL-C and adverse outcomes has recently been challenged by the results of several large, population-based studies that have suggested that this relationship is instead U-shaped. These contemporary findings used large sample sizes to correctly power the studies to detect significant event rates in the small portion of the general population with very high HDL-C values. The findings suggest that very high HDL-C is correlated most with an increased risk of all-cause death, rather than cardiovascular death or adverse cardiovascular events. The understanding behind this epidemiologic link remains unclear. Possible explanations include genetic mutations linked to very high HDLC, impaired HDL function at high levels of HDL-C, and the possibility of residual confounding. While several genes, when mutated, are associated with increased HDL-C – such as CETP, SCARB1, and LIPG – studies of patients who carry these mutated alleles have not demonstrated a clear increased risk of all-cause mortality or adverse cardiovascular events. Whether the HDL molecule becomes dysfunctional at very high HDL-C levels still remains unknown. To date, no study has clearly linked very high HDL-C levels with impaired HDL function, despite available ways to assess HDL function, such as CEC and the HDL inflammatory index assays. The role of HDL in immune system modulation and infection regulation provides our best insight into a potential explanation. The results of

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astelli WP, Garrison RJ, Wilson PW, et al. Incidence of C coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986;256:2835–8. https://doi. org/10.1001/jama.1986.03380200073024; PMID: 3773200. Ridker PM, Genest J, Boekholdt SM, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy. Lancet 2010;376:333–9. https://doi. org/10.1016/S0140-6736(10)60713-1; PMID: 20655105. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993– 2000. https://doi.org/10.1001/jama.2009.1619; PMID: 19903920. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255–67. https://doi.org/10.1056/ NEJMoa1107579; PMID: 22085343. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extendedrelease niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203–12. https://doi.org/10.1056/NEJMoa1300955; PMID: 25014686. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017;376:1933–42. https://doi.org/10.1056/NEJMoa1609581; PMID: 28514624. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089–99. https://doi.org/10.1056/NEJMoa1206797; PMID: 23126252. Bowman L, Hopewell JC, Chen F, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217–27. https://doi.org/10.1056/NEJMoa1706444; PMID: 28847206. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–22. https://doi.org/10.1056/NEJMoa0706628; PMID: 17984165. Mackey RH, Greenland P, Goff DC, Jr, et al. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2012;60:508–16. https://doi.org/10.1016/j.jacc.2012.03.060; PMID: 22796256. Ko DT, Alter DA, Guo H, et al. High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: the CANHEART study. J Am Coll Cardiol 2016;68:2073–83. https://doi.org/10.1016/j. jacc.2016.08.038; PMID: 27810046. Madsen CM, Varbo A, Nordestgaard BG. Extreme high highdensity lipoprotein cholesterol is paradoxically associated with high mortality in men and women. Eur Heart J 2017;38:2478–86. https://doi.org/10.1093/eurheartj/ehx163; PMID: 28419274. Gökmen O, Yapar Eyi EG. Hormone replacement therapy and lipid-lipoprotein concentrations. Eur J Obstet Gynecol Reprod Biol 1999;85:31–41. https://doi.org/10.1016/S0301-2115(98)00279-6;

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a large retrospective analysis in Copenhagen, Denmark, suggest that very high (and very low) HDL-C levels correlate with both increased risk of infection and death related to infectious disease. This may provide insight as to why very high HDL-C levels correlate better with all-cause mortality than cardiovascular endpoints, but a causative link has not yet been proven. Finally the possibility of residual confounding remains, given the lack of other definitive answers to this paradox. Given the complexity of the HDL molecule and the diverse roles it plays in the human body, using HDL-C as a tool for cardiovascular risk prediction may no longer be an effective clinical strategy, especially when HDL-C is significantly elevated. Use of other HDL-related measures, such as HDL particle concentration or apolipoprotein A1, or assessments of HDL function, such as CEC, may better predict adverse events.17,27,37 At present, given the limited data verifying a causative link between HDL-C and adverse events, pharmacological treatment of HDL-C, whether it is too low or perhaps too high, should not be considered an initial therapy for risk reduction. Until more is uncovered through research, patients should focus on modifying other well-established risk factors for cardiovascular disease, such as elevated LDL-C, hypertension, and smoking.

PMID: 10428319. 14. D e Oliveira E Silva ER, Foster D, McGee Harper M, et al. Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II. Circulation 2000;102:2347–52. https://doi.org/10.1161/01.CIR.102.19.2347; PMID: 11067787. 15. O’Donovan G, Stensel D, Hamer M, Stamatakis E. The association between leisure-time physical activity, low HDL-cholesterol and mortality in a pooled analysis of nine population-based cohorts. Eur J Epidemiol 2017;32:559–66. https://doi.org/10.1007/s10654-017-0280-9; PMID: 28667447. 16. Hirata A, Sugiyama D, Watanabe M, et al. Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals. J Clin Lipidol 2018;12:674–84. e5. https://doi.org/10.1016/j.jacl.2018.01.014; PMID: 29506864. 17. van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol 2008;51:634–42. https://doi.org/10.1016/j.jacc.2007.09.060; PMID: 18261682. 18. Allard-Ratick M, Khambhati J, Topel M, et al. Elevated HDL-C is associated with adverse cardiovascular outcomes. Eur Heart J 2018;39:ehy564.50. https://doi.org/10.1093/eurheartj/ehy564.50. 19. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707–13. https://doi.org/10.1038/nature09270; PMID: 20686565. 20. Agerholm-Larsen B, Nordestgaard BG, Steffensen R, et al. Elevated HDL cholesterol is a risk factor for ischemic heart disease in white women when caused by a common mutation in the cholesteryl ester transfer protein gene. Circulation 2000;101:1907–12. https://doi.org/10.1161/01.CIR.101.16.1907; PMID: 10779455. 21. Johannsen TH, Frikke-Schmidt R, Schou J, et al. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J Am Coll Cardiol 2012;60:2041–8. https://doi.org/10.1016/j.jacc.2012.07.045; PMID: 23083790. 22. deLemos AS, Wolfe ML, Long CJ, et al. Identification of genetic variants in endothelial lipase in persons with elevated highdensity lipoprotein cholesterol. Circulation 2002;106:1321–6. https://doi.org/10.1161/01.CIR.0000028423.07623.6A; PMID: 12221047. 23. Edmondson AC, Brown RJ, Kathiresan S, et al. Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J Clin Invest 2009;119:1042–50. https://doi.org/10.1172/JCI37176; PMID: 19287092. 24. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 2012;380:572–80. https://doi. org/10.1016/S0140-6736(12)60312-2; PMID: 22607825. 25. Zanoni P, Khetarpal SA, Larach DB, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases

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risk of coronary heart disease. Science 2016;351:1166–71. https://doi.org/10.1126/science.aad3517; PMID: 26965621. Helgadottir A, Sulem P, Thorgeirsson G, et al. Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease. Eur Heart J 2018;39:2172–8. https://doi.org/10.1093/eurheartj/ehy169; PMID: 29596577. Khera AV, Demler OV, Adelman SJ, et al. Cholesterol efflux capacity, high-density lipoprotein particle number, and incident cardiovascular events. Circulation 2017;135:2494–504. https://doi. org/10.1161/CIRCULATIONAHA.116.025678; PMID: 28450350. Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014;371:2383–93. https://doi.org/10.1056/NEJMoa1409065; PMID: 25404125. Agarwala AP, Rodrigues A, Risman M, et al. High-density lipoprotein (HDL) phospholipid content and cholesterol efflux capacity are reduced in patients with very high HDL cholesterol and coronary disease. Arterioscler Thromb Vasc Biol 2015;35:1515–9. https://doi.org/10.1161/ATVBAHA.115.305504; PMID: 25838421. Ansell BJ, Navab M, Hama S, et al. Inflammatory/ antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than highdensity lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003;108:2751–6. https:// doi.org/10.1161/01.CIR.0000103624.14436.4B; PMID: 14638544. Catapano AL, Pirillo A, Bonacina F, Norata GD. HDL in innate and adaptive immunity. Cardiovasc Res 2014;103:372–83. https://doi. org/10.1093/cvr/cvu150; PMID: 24935428. Lekkou A, Mouzaki A, Siagris D, et al. Serum lipid profile, cytokine production, and clinical outcome in patients with severe sepsis. J Crit Care 2014;29:723–7. https://doi.org/10.1016/j. jcrc.2014.04.018; PMID: 24891152. Madsen CM, Varbo A, Tybjærg-Hansen A, Frikke-Schmidt R, Nordestgaard BG. U-shaped relationship of HDL and risk of infectious disease. Eur Heart J 2018;39:1181–90. https://doi. org/10.1093/eurheartj/ehx665; PMID: 29228167. Mineo C, Deguchi H, Griffin JH, Shaul PW. Endothelial and antithrombotic actions of HDL. Circ Res 2006;98:1352–64. https:// doi.org/10.1161/01.RES.0000225982.01988.93; PMID: 16763172. Riwanto M, Rohrer L, Roschitzki B, et al. Altered activation of endothelial anti- and proapoptotic pathways by highdensity lipoprotein from patients with coronary artery disease. Circulation 2013;127:891–904. https://doi.org/10.1161/ CIRCULATIONAHA.112.108753; PMID: 23349247. Feng Y, Jacobs F, Van Craeyveld E, et al. Human ApoA-I transfer attenuates transplant arteriosclerosis via enhanced incorporation of bone marrow-derived endothelial progenitor cells. Arterioscler Thromb Vasc Biol 2008;28:278–83. https://doi. org/10.1161/ATVBAHA.107.158741; PMID: 18063807. Mora S, Glynn RJ, Ridker PM. High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy. Circulation 2013;128:1189–97. https://doi.org/10.1161/ CIRCULATIONAHA.113.002671; PMID: 24002795.

Electrophysiology

The Next 10 Years in Atrial Fibrillation Jeffrey L Turner, DO, and Nassir Marrouche, MD Comprehensive Arrhythmia and Research Management Center, University of Utah School of Medicine, Salt Lake City, UT

Abstract Predicting future advancements in arrhythmia management – specifically AF – with any certainty is impossible. The clinical approach to AF has changed markedly since the turn of the century in ways that could never have been foreseen, but the current methods of identification and treatment remain far from perfect. Over the next decade we expect significant continued progress in AF management. However, if asked to forecast the future, we consider it wise to predict advancements in the nearer term. We believe there will be widespread expansion in digital health and mobile devices, altering the way we detect and monitor the arrhythmia. We expect substantial growth in advanced MRI to aid in early detection, evaluation, and possibly non-invasive treatment of AF substrate. We imagine there will be increasing focus on individual populations to identify at-risk groups and personalize early management. We also anticipate improvement in anticoagulation employment and left atrial appendage modification. Finally, recognizing the benefit of improvement in modifiable risk factors such as mandatory tobacco cessation and weight loss in obese patients, we predict that reimbursement will be dependent on successfully addressing modifiable risk. For now, several questions remain unanswered, and while no one can predict the next 10 years in AF, there is, without doubt, an abundance of opportunity.

Keywords Atrial fibrillation, catheter ablation, arrhythmia, antiarrhythmic drugs, mobile cardiac telemetry, atrial fibrosis, cardiac MRI Disclosure: NM is a consultant and speaker for Medtronic, Abbot, Biotronik, Biosense Webster, Siemens, and Vytronus. JT has no conflicts of interest to declare. Received: December 18, 2018 Accepted: February 11, 2019 Citation: US Cardiology Review 2019;13(1):54–7. DOI: https://doi.org/10.15420/usc.2018.21.2 Correspondence: Nassir Marrouche, Division of Cardiovascular Medicine, University of Utah Health Sciences Center, 30 North 1900 East, Room 4A100, Salt Lake City, UT 84132. E: nassir.marrouche@hsc.utah.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The incidence of AF is on the rise.1–3 This is secondary not only to increasing prevalence but also a focus on increased recognition of occult AF for primary thromboembolic (TE) prevention.4 How we identify and treat these patients with AF is constantly in flux. While it is possible that a novel procedure or antiarrhythmic drug could create sweeping changes in AF management overnight, here we will focus on where we believe the most predictable changes in the approach to AF will occur in the near future.

Personal, Everyday Monitoring We expect widespread advances in the area of mobile cardiac telemetry. Many currently available monitors are bulky and inconvenient, with some requiring removal for routine daily activities and others sometimes causing skin irritation that may result in low patient adherence rates.5 We expect current monitors will be replaced by personally owned and operated smart devices. Devices such as the Apple Watch™ (Apple Inc.) running apps like Cardiogram™ (Cardiogram) currently have the capability of identifying AF with sensitivity and specificity of 98% and 90%, respectively, against reference 12-lead electrocardiography in patients undergoing cardioversion.6 Ambulatory results, while not as promising, with improvement may revolutionize the way we use ambulatory monitoring.6 We predict these devices will cause a significant increase in the identification of occult AF. This will lead to an increase in the

Access at: www.USCjournal.com

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overall incidence of AF, perhaps temporarily increasing healthcare costs. However, a resultant decline in population-wide embolic cerebrovascular events with appropriate anticoagulant treatment may lead to a long-term overall decrease in costs for the healthcare system. Technological advancements in this area will likely also extend to embedded rhythm monitors such as pacemakers and implanted loop recorders. With improvement in wireless communication, a patient may be able to routinely trigger rhythm recording from their implanted devices if or when they have symptoms. This could potentially identify rhythms that were under-detected because of lower rates or duration as well as providing reassurance in the case of normal rhythm findings. With the amount of data collected from these devices, we may even be able to clarify the temporal relationship between paroxysms of AF and embolic events leading to a treatment strategy that may limit the lifelong, continuous use of systemic anticoagulation with all of its inherent risks.4,7,8 We believe growth in personally owned devices capable of ambulatory rhythm monitoring will be exponential and practice changing.

The Role of MRI The use of cardiac MRI (CMR) in the management of AF is becoming standard of care at some large electrophysiology centers. It has the

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The Next 10 Years in Atrial Fibrillation ability to quantify myocardial morphology, function and structure with high spatial and temporal resolution.9 In addition, it can identify areas of scar, or fibrosis, which may provide the substrate for developing and maintaining AF (Figure 1).10,11 It has been shown that tissue fibrosis, estimated by delayed enhancement MRI, is independently associated with the likelihood of recurrent atrial arrhythmia after the ablation procedure.12 There is ongoing investigation into whether targeted catheter ablation in areas of fibrosis in addition to standard pulmonary vein isolation (PVI) will result in improved procedural success rates (efficacy of DE-MRI-guided ablation versus Conventional catheter Ablation of Atrial Fibrillation [DECAAF-II; NCT02529319). If the DECAAF-II study is positive or another treatment modality is found more effective, than standard ablation techniques, randomized controlled trials will need to be repeated comparing it against current medical therapies. The degree of atrial fibrosis as seen on CMR has also shown to be associated with increased major cardiovascular and cerebrovascular event risk, primarily as a result of an increase in transient ischemic attack/stroke.13 Currently no imaging parameter of the left atrium is part of the risk scoring system. Atrial fibrosis and other left atrial parameters may be used in the future to guide the use of systemic anticoagulation independent from or in addition to the CHADS2-VASc score.14 If we can predict the ideal candidate for an ablation procedure based on objective myocardial-based substrate findings, we could restrict potential complications only to patients who may derive the most benefit.

Substrate Modification Catheter ablation is currently the most commonly used invasive technique to modulate the cardiac electrical system in AF. Developed in the early 2000s, the success rate of current PVI catheter ablation procedures are modest at best, with only approximately half of patients having 2-year of freedom from arrhythmia.15 Targeted ablation strategies such as roof lines and complex fractionated electrogram ablations have not shown significant improvement in addition to the standard PVI technique.16–19 One promising alternative lies in uniting CMR findings with targeted ablation techniques such as fibrosis- or substrate-guided ablation mentioned previously.9 Other less invasive strategies such as external stereotactic body radiation therapy (SBRT) may have a role in the treatment of AF in the future. Despite being in its very preliminary stages, SBRT has been shown to be effective in the treatment of ventricular tachycardia in heart failure patients as well as being capable of non-invasive atrio-ventricular node ablation.20–22 While it is recognized that left atrial substrate is notably different from even the right atrium, it is reasonable that advances in SBRT could make this feasible.23,24 This is especially promising in high-risk individuals who are poor candidates for invasive procedures.

Population-based Care It is well recognized that different populations have variable response to treatment of AF.25 Recently, for example, the Catheter Ablation versus Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation (CASTLE-AF) trial demonstrated that patients with symptomatic congestive heart failure with ejection fraction <35% obtain mortality benefit and reduction in heart failure

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Figure 1: 3D Model of Left Atrial Tissue Fibrosis

3D model showing areas of quantified left atrial fibrosis (white and green) in contrast to normal atrial tissue (blue) rendered from high-resolution delayed enhancement MRI of the left atrium.

hospitalizations with catheter ablation.26 This was also suggested in the intention-to-treat primary endpoint (all cause mortality, disabling stroke, serious bleeding, cardiac arrest) sub-group analysis of not only heart failure patients, but also patients aged <65 years and those in minority populations in the Catheter ABlation versus ANtiarrhythmic drug therapy for Atrial fibrillation (CABANA) trial.27 Catheter ablation is now a Class IIB recommendation in those with systolic heart failure.28 So should we be ablating all patients with AF and systolic heart failure? The answer still seems unclear as both CABANA and CASTLE-AF had limitations such as significant treatment group crossover and high use of amiodarone. We need more data, but based on these trials we predict there will be more evidence available for early use of catheter ablation techniques in heart failure and other yet-to-be-determined patient populations.

Anticoagulation and Left Atrial Appendage Modification Anticoagulation to reduce TE risk is currently the only widely accepted prognostic intervention in AF, therefore appropriate and judicious use is an important area of improvement.29 The widespread use of oral anticoagulation (OAC) including direct OACs and vitamin K antagonists, while significantly decreasing the risk of TE events, conversely confers a significant increase in bleeding of around 2–4% annually and contraindications to these drugs leaves a large population of untreated patients at risk.29–34 Atrial appendage occlusion is a developing area of innovation in AF management, particularly in those patients unable to tolerate long-term anticoagulation.35,36 Most recently this has been shown to have benefits beyond reduction in TE risk, improving success rates of catheter ablation in addition to standard ablation procedures.37,38 Unfortunately these devices come with a complication rate as high as 5–10% in some studies, although this seems to improve with operator experience.35,36 The question of whether these devices should only be used in those with a contraindication to OAC or implanted when patients are at low embolic risk but able to take OAC temporarily in order to reduce a lifetime dependence on OAC will likely be answered in the next few years, as will long-term complications – if any – of these devices.

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Electrophysiology The Story of Modifiable Risk and a Healthier Future

increasingly common especially in teenagers – will affect the prevalence of AF and other cigarette-related conditions is not well understood.50

AF is strongly attributable to modifiable risk factors such as obesity and substance abuse; therefore, the prevalence of AF is largely tied to the incidence of these risk factors. 39–41 In recent decades there has been a steady incline in the rate of obesity, rising nearly 10% in adults aged >20 years from the late 1990s to the early 2010s.42 For the first time, the American Heart Association/American College of Cardiology/Heart Rhythm Society task force has included weight loss in the guidelines for AF management.28 There is strong evidence to include risk-factor modification in the guidelines. Obesity rates and subsequent peri/epicardial fat have been found to correlate with the degree of atrial fibrosis – a known surrogate for AF and success of AF ablation.43,44 It is also known that weight loss and exercise can dramatically change cardiac structure and lower AF burden in these obese patients.45–48 Therefore, obesity rates are an important marker of the future global impact of AF. If obesity rates continue to rise, rates of AF will rise concordantly. Coupled with an aging population, the healthcare burden of AF will continue to be an important expenditure in the next decade. Cigarette use in the US, another known risk factor for AF, is generally stable or declining.49,50 How the use of nicotine vaping – which is

J anuary CT, Wann LS, 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. https://doi. org/10.1016/j.jacc.2014.03.022; PMID: 24685669. 2. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N-9N. https:// doi.org/10.1016/S0002-9149(98)00583-9; PMID: 9809895. 3. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation 2015;131:e29–322. https://doi. org/10.1161/CIR.0000000000000152; PMID: 25520374. 4. Andrade JG, Field T, Khairy P. Detection of occult atrial fibrillation in patients with embolic stroke of uncertain source: a work in progress. Front Physiol 2015;6:100. https://doi.org/10.3389/ fphys.2015.00100; PMID: 25883570. 5. Zimetbaum P, Goldman A. Ambulatory arrhythmia monitoring: choosing the right device. Circulation 2010;122:1629–36. https://doi.org/10.1161/CIRCULATIONAHA.109.925610; PMID: 20956237. 6. Tison GH, Sanchez JM, Ballinger B, et al. Passive detection of atrial fibrillation using a commercially available smartwatch. JAMA Cardiol 2018;3:409–16. https://doi.org/10.1001/ jamacardio.2018.0136; PMID: 29562087. 7. Miller CS, Grandi SM, Shimony A, et al. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012;110:453-60. https://doi.org/10.1016/j. amjcard.2012.03.049; PMID: 22537354. 8. Gieling EM, van den Ham HA, van Onzenoort H, et al. Risk of major bleeding and stroke associated with the use of vitamin K antagonists, nonvitamin K antagonist oral anticoagulants and aspirin in patients with atrial fibrillation: a cohort study. Br J Clin Pharmacol 2017 Aug;83(8):1844–59. https://doi.org/10.1111/ bcp.13265; PMID: 28205318. 9. Slavin GS, Bluemke DA. Spatial and temporal resolution in cardiovascular MR imaging: review and recommendations. Radiology 2005;234:330–8. https://doi.org/10.1148/ radiol.2342031990; PMID: 15601895. 10. Gal P, Marrouche NF. Magnetic resonance imaging of atrial fibrosis: redefining atrial fibrillation to a syndrome. Eur Heart J 2017;38:14–9. https://doi.org/10.1093/eurheartj/ehv514; PMID: 26409008. 11. Zghaib T, Nazarian S. New insights into the use of cardiac magnetic resonance imaging to guide decision making in atrial fibrillation management. Can J Cardiol 2018;34:1461-1470. https:// doi.org/10.1016/j.cjca.2018.07.007; PMID: 30297256. 12. Marrouche NF, Wilber D, Hindricks G, et al. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study.

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We anticipate that clinically guided risk-factor modification will become increasingly important over the next decade, with payment potentially linked to these goals. In the most extreme scenario, perhaps similar to bariatric surgery, successfully demonstrated weight loss and tobacco cessation will be required before procedures with the potential for complications and poorer predicted success rates are reimbursed. This could make modifiable risk factors a target of contention between payers and healthcare providers in the near future.

Conclusion There is abundant opportunity for the advancement of AF care. Given the current epidemic of atrial arrhythmia and the associated healthcare costs, we expect significant continued advancement in AF identification, risk stratification, and treatment.51 It is possible that new technologies such as the collimated ultrasound ablation system or painless optogenetic defibrillation techniques could change practice overnight.52–55 However, for now the narrative remains: rhythm or rate, ablate or medicate. These questions will hopefully be answered clearly in the coming years or reimbursement for costly and potentially hazardous procedures is at risk.

JAMA 2014;311:498–506. https://doi.org/10.1001/jama.2014.3; PMID: 24496537. King JB, Azadani PN, Suksaranjit P, et al. Left atrial fibrosis and risk of cerebrovascular and cardiovascular events in patients with atrial fibrillation. J Am Coll Cardiol 2017;70:1311–21. https:// doi.org/10.1016/j.jacc.2017.07.758; PMID: 28882227. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest 2010;137:263–72. https://doi.org/10.1378/chest.09-1584; PMID: 19762550. Kaba RA, Cannie D, Ahmed O. RAAFT-2: Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation. Glob Cardiol Sci Pract 2014;2014:53–5. https://doi. org/10.5339/gcsp.2014.26; PMID: 25405179. Oral H, Knight BP, Ozaydin M, et al. Segmental ostial ablation to isolate the pulmonary veins during atrial fibrillation: feasibility and mechanistic insights. Circulation 2002;106:1256–62. PMID: 12208802. Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: a new anatomic approach for curing atrial fibrillation. Circulation 2000;102:2619–28. PMID: 11085966. Arbelo E, Guiu E, Ramos P, et al. Benefit of left atrial roof linear ablation in paroxysmal atrial fibrillation: a prospective, randomized study. J Am Heart Assoc 2014;3:e000877. https://doi. org/10.1161/JAHA.114.000877; PMID: 25193295. Wong KC, Paisey JR, Sopher M, et al. No benefit of complex fractionated atrial electrogram ablation in addition to circumferential pulmonary vein ablation and linear ablation: Benefit of complex ablation study. Circ Arrhythm Electrophysiol 2015;8:1316–24. https://doi.org/10.1161/CIRCEP.114.002504; PMID: 26283145. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive cardiac radiation for ablation of ventricular tachycardia. N Engl J Med 2017;377:2325–36. https://doi.org/10.1056/NEJMoa1613773; PMID: 29236642. Lehmann HI, Deisher AJ, Takami M, et al. External arrhythmia ablation using photon beams: ablation of the atrioventricular junction in an intact animal model. Circ Arrhythm Electrophysiol. 2017;10:e004304. https://doi.org/10.1161/CIRCEP.116.004304; PMID: 28408649. Kim EJ, Davogustto G, Stevenson WG, et al. Non-invasive cardiac radiation for ablation of ventricular tachycardia: a new therapeutic paradigm in electrophysiology. Arrhythm Electrophysiol Rev 2018;7:8–10. https://doi.org/10.15420/ aer.7.1.EO1; PMID: 29636967. Park JH, Lee JS, Ko YG, et al. Histological and biochemical comparisons between right atrium and left atrium in patients with mitral valvular atrial fibrillation. Korean Circ J 2014;44:233–42. https://doi.org/10.4070/kcj.2014.44.4.233; PMID: 25089135. Ng SY, Wong CK, Tsang SY. Differential gene expressions in

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atrial and ventricular myocytes: insights into the road of applying embryonic stem cell-derived cardiomyocytes for future therapies. Am J Physiol Cell Physiol 2010;299:C1234–49. https://doi. org/10.1152/ajpcell.00402.2009; PMID: 20844252. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017;33:369–409. https://doi.org/10.1016/j. joa.2017.08.001; PMID: 29021841. Marrouche NF, Brachmann J, Andresen D, et al. CASTLE-AF Investigators. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018;378:417–27. https://doi.org/10.1056/ NEJMoa1707855; PMID: 29385358. Packer DL, et al. Catheter ablation vs. anti-arrhythmic drug therapy for atrial fibrillation trial (CABANA). NCT00911508. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 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 Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2019; S1547–5271:30037–2. https://doi. org/10.1016/j.hrthm.2019.01.024; PMID: 30703530; epub ahead of press. European Heart Rhythm Association, Heart Rhythm Society, Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2006;48:854– 906. https://doi.org/10.1016/j.jacc.2006.07.009; PMID: 16904574. Ezekowitz MD, Nagarakanti R, Noack H, et al. Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy). Circulation 2016;134:589– 98. https://doi.org/10.1161/CIRCULATIONAHA.115.020950; PMID: 27496855. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2015;132:624–32. https://doi.org/10.1161/ CIRCULATIONAHA.114.014807; PMID: 26106009. Patel MR, Mahaffey KW, Garg J, et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. https://doi.org/10.1056/ NEJMoa1009638. PMID: 21830957. Birman-Deych E, Radford MJ, Nilasena DS, Gage BF. Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation. Stroke 2006;37:1070–4. https://doi.org/10.1161/01. STR.0000208294.46968.a4; PMID: 16528001. Petersen P, Boysen G, Godtfredsen J, et al. Placebo-controlled,

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The Next 10 Years in Atrial Fibrillation

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randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet 1989;1:175–9. https://doi. org/10.1016/S0140-6736(89)91200-2; PMID: 2563096. Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus longterm warfarin therapy: the PREVAIL trial. J Am Coll Cardiol 2014;64:1–12. https://doi.org/10.1016/j.jacc.2014.04.029; PMID: 24998121. Holmes DR, Reddy VY, Turi ZG, et al. PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534–42. https://doi.org/10.1016/S01406736(09)61343-X; PMID: 19683639. Litwinowicz R, Bartus M, Burysz M, et al. Long term outcomes after left atrial appendage closure with the LARIAT device-Stroke risk reduction over five years follow-up. PLoS One 2018;13:e0208710. https://doi.org/10.1371/journal. pone.0208710; PMID: 30566961. Lakkireddy D, Sridhar Mahankali A, Kanmanthareddy A, et al. Left atrial appendage ligation and ablation for persistent atrial fibrillation: the LAALA-AF registry. JACC Clin Electrophysiol 2015;1:153–160. https://doi.org/10.1016/j.jacep.2015.04.006; PMID: 29759358. Wong CX, Sullivan T, Sun MT, et al. Obesity and the risk of incident, post-operative, and post-ablation atrial fibrillation. JACC Clinical Electrophysiol 2015; 1:139–152. https://doi.org/10.1016/j. jacep.2015.04.004; PMID: 29759357. Hatem SN, Redheuil A, Gandjbakhch E. Cardiac adipose tissue and atrial fibrillation. Cardiovasc Res 2016;109:502–9. https://doi.

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org/10.1093/cvr/cvw001; PMID: 26790475. 41. W hitman IR, Agarwal V, Nah G, et al. Alcohol abuse and cardiac disease. J Am Coll Cardiol 2017;69:13–24. https://doi.org/10.1016/j. jacc.2016.10.048; PMID: 28057245. 42. Flegal KM, Kruszon-Moran D, Carroll MD, et al. Trends in obesity among adults in the United States, 2005 to 2014. JAMA 2016;315:2284–91. https://doi.org/10.1001/jama.2016.6458; PMID: 27272580. 43. Wong CX, Mahajan R, Pathak R, et al. The role of pericardial and epicardial fat in atrial fibrillation pathophysiology and ablation outcomes. J Atr Fibrillation 2013;5:790. https://doi.org/10.4022/ jafib.790; PMID: 28496816. 44. Wong CX, Abed HS, Molaee P, et al. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol 2011;57:1745–51. https://doi.org/10.1016/j. jacc.2010.11.045; PMID: 21511110. 45. Pathak RK, Elliott A, Middeldorp ME, et al. Impact of CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals With Atrial Fibrillation: the CARDIO-FIT study. J Am Coll Cardiol 2015;66:985–96. https://doi.org/10.1016/j. jacc.2015.06.488; PMID: 26113406. 46. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014;64:2222–31. https://doi.org/10.1016/j. jacc.2014.09.028; PMID: 25456757. 47. Pathak RK, Middeldorp ME, Meredith M, et al. Long-term effect of goal-directed weight management in an atrial fibrillation Cohort: a long-term follow-up study (LEGACY). J Am Coll Cardiol 2015;65:2159–69. https://doi.org/10.1016/j.jacc.2015.03.002; PMID: 25792361. 48. Abed HS, Nelson AJ, Richardson JD, et al. Impact of weight

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reduction on pericardial adipose tissue and cardiac structure in patients with atrial fibrillation. Am Heart J 2015;169:655–62.e2. https://doi.org/10.1016/j.ahj.2015.02.008; PMID: 25965713. Chamberlain AM, Agarwal SK, Folsom AR, et al. Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study. Heart Rhythm 2011;8:1160–6. https://doi.org/10.1016/j.hrthm.2011.03.038; PMID: 21419237. Jamal A, Phillips E, Gentzke AS, et al. Current cigarette smoking among adults – United States, 2016. MMWR Morb Mortal Wkly Rep 2018;19;67:53–9. http://dx.doi.org/10.15585/mmwr.mm6702a1; PMID: 29346338. Bajpai A, Camm AJ, Savelieva I. Epidemiology and economic burden of atrial fibrillation. US Cardiology Review 2007;4:14–7. Koruth JS, Schneider C, Avitall B, et al. Pre-clinical investigation of a low-intensity collimated ultrasound system for pulmonary vein isolation in a porcine model. JACC Clin Electrophysiol 2015;1:306–14. https://doi.org/10.1016/j.jacep.2015.04.011; PMID: 29759318. Vogt CC, Bruegmann T, Malan D, et al. Systemic gene transfer enables optogenetic pacing of mouse hearts. Cardiovasc Res 2015;106:338–43. https://doi.org/10.1093/cvr/cvv004; PMID: 25587047. Nussinovitch U, Shinnawi R, Gepstein L. Modulation of cardiac tissue electrophysiological properties with light-sensitive proteins. Cardiovasc Res 2014;102:176–87. https://doi.org/10.1093/ cvr/cvu037; PMID: 24518144. Bingen BO, Engels MC, Schalij MJ, et al. Light-induced termination of spiral wave arrhythmias by optogenetic engineering of atrial cardiomyocytes. Cardiovasc Res 2014;104:194–205. https://doi.org/10.1093/cvr/cvu179; PMID: 25082848.

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Editor’s Pick

Can Early Management of Hypertension by General Practitioners Improve Outcome? Deborah L Nadler, MD, 1 and Athena Poppas, MD FACC 2 1. Department of Internal Medicine, Brown University, Providence, Rhode Island; 2. Lifespan, Brown University, Miriam Hospital, Providence, Rhode Island

Abstract Hypertension and its cardiovascular sequelae remain one of the major causes of death and disability worldwide, and the prevalence of hypertension in the US and Europe is high. Hypertension is a leading modifiable risk factor for cardiovascular events. Pharmacological approaches and lifestyle modification to treat hypertension early have been consistently shown to improve cardiovascular outcomes in primary and secondary prevention. Recent guidelines recommend initiating treatment at lower blood pressure levels, with normal blood pressure being defined as <120/80 mmHg. Calculating risk using a score such as the Atherosclerotic Cardiovascular Disease Risk Calculator is important to enable the general practitioner to give appropriate, individualized care.

Keywords Hypertension, prevention, risk factors, cardiovascular outcomes Disclosure: The authors have no conflicts of interest to declare. Received: January 31, 2019 Accepted: February 4, 2019 Citation: US Cardiology Review 2019;13(1):58–60. DOI: https://doi.org/10.15420/usc.2019.5.1 Correspondence: Athena Poppas, Miriam Hospital, 164 Summit Avenue, Fain Building, Providence, Rhode Island, 02906. E: APoppas@Lifespan.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Hypertension was the leading cause of death worldwide in 2010 (Figure 1). Its scope is broad: hypertension and its sequelae account for the leading cause of disability-adjusted life years and for more cardiovascular deaths than any other modifiable cardiovascular risk factor, and 25% of all cardiovascular events can be attributed to hypertension.1–3 Targeting hypertension with early management is crucial for population and individual health and can improve cardiovascular outcomes. The prevalence of hypertension in the US alone is staggering. According to Wenger et al., 29% of all adults have hypertension, and it is present in 64.9% of people >60 years and 7.3% of those aged 19–39.4 These realities demonstrate a large population in which general practitioners can make real and effective change. These trends are not confined to the US and there is also a high prevalence of hypertension in Europe. As in the US, there are regional variations in hypertension rates and its attendant cardiovascular morbidity and mortality, with eastern European countries still seeing higher disease prevalence and rates of modifiable risk factors. Targeted treatment of blood pressure in several European nations has led to a decline in mean systolic blood pressure (SBP) over the past four decades.5

The Importance of Treating Hypertension The risk of cardiovascular disease increases significantly for adults with hypertension, and improving or eliminating this risk factor affects overall cardiovascular disease prevalence.

Access at: www.USCjournal.com

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Research using data from the Cardiovascular Health Study and the Health, Ageing and Body Composition (ABC) study investigated 4,409 older people (mean age 72.9 years) who were based in the community, did not have heart failure and had not been treated with anti-hypertensives.6 Investigators looked at the primary outcome of first hospitalization for heart failure. Participants were divided into prehypertension (SBP 120–139 mmHg), stage 1 hypertension (SBP 140–159 mmHg), and stage 2 hypertension (SBP ≥160 mmHg). There was a continuous positive association between SBP and heart failure risk. More than half (51.7%) the incidents of heart failure were in people whose SBP was <140 mmHg. In a study of more than 10,000 adults followed from the age of 30 years, hypertension (SBP >140 mmHg) resulted in a higher lifetime risk of cardiovascular disease overall and heart failure in particular.7 Pharmacological treatment of hypertension has been clearly shown to result in real and sustained reductions in SBP and diastolic blood pressure (DBP) and improved primary and secondary outcomes.8,9 A meta-analysis of eight trials of blood pressure lowering as a determinant of cardiovascular outcome, which included 12,903 young patients (30–49 years old), 14,324 elderly (60–79 years old), and 1,209 very elderly (>80 years old), looked at the pooled results of using antihypertensive drugs against placebo or no treatment.10 Antihypertensive treatment reduced SBP/DBP by 8.3/4.6 mmHg in young patients, by 10.7/4.2 mmHg in older patients, and by 9.4/3.2 mmHg in very elderly patients, resulting in DBP:SBP lowering rations of 0.55, 0.39, and 0.32, respectively (p=0.004). Despite the differential lowering of SBP and DBP, antihypertensive

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Early Management of Hypertension treatment reduced the risk of all cardiovascular events, stroke and MI in the three age groups to a similar extent. Absolute benefit increased with age and with lowering of DBP:SBP ratio. Similarly, the Systolic Blood Pressure Intervention Trial (SPRINT) involved 9,361 participants with an SBP >130 mmHg and an increased cardiovascular risk without diabetes.11 They were divided into two groups: those who had a target SBP <120 mmHg were in the intensive treatment group, and those who had a goal of <140 mmHg were in the standard treatment group. Intensive treatment was found to be superior for the secondary outcomes of heart failure incidence (p=0.002), and death from cardiovascular disease (p=0.005). The primary composite outcome was MI, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes, and intensive treatment also significantly reduced the incidence of these outcomes (p<0.001).

Table 1: Definition of Hypertension in Adults Categories of Blood Pressure Normal: SBP/DBP <120/<80 mmHg Elevated: SBP 120–129 mmHg; DBP <80 mmHg for DBP Stage 1 hypertension: SBP 130–139 mmHg or DBP 80–89 mmHg. Stage 2 hypertension: SBP ≥140 mmHg or DBP ≥90 mmHg. DBP = diastolic blood pressure; SBP = systolic blood pressure. Adapted from: Whelton et al. 2018.12 Used with permission from Elsevier.

Figure 1: Deaths in Women Attributable to Risk Factors Deaths attributable to individual risks (thousands) in women –50

Non-Pharmacological Approaches to Reducing Blood Pressure There are some non-pharmacological approaches to reducing blood pressure, including weight loss for patients who are overweight or obese, a heart-healthy diet, such as the Dietary Approaches to Stop Hypertension (DASH) diet, sodium reduction, potassium supplementation, increased physical activity, and a reduction in alcohol consumption. Obesity is closely tied to hypertension; weight loss of 5–10% will lower blood pressure. Diet and physical activity are strongly related. A DASH diet can result in a BP that is 10 mmHg lower, while physical inactivity doubles a patient’s CVD risk. Similarly, increasing exercise can lower blood pressure by 5–8 mmHg and halve CVD risk.12

Primary and Secondary Prevention Primary prevention includes treating high-risk adults who have an estimated 10-year risk >10% of developing CVD and an SBP >130 mmHg or DBP >80 mmHg. Secondary prevention is treatment to avoid recurrent CVD events in patients that have clinical CVD and an SBP >130 mmHg or DBP >80 mmHg (Table 1). Estimation of risk can be calculated using the Atherosclerotic Cardiovascular Disease (ASCVD) Risk Calculator.13 This uses pooled data to assess risk factors and guide treatment options. It is important to note that patients have multiple interrelated risk factors, some of which are modifiable, such as cholesterol levels, blood pressure, smoking, diabetes, obesity/sedentary lifestyle, and some of which are not, such as age, gender and family history. However, using a risk calculator with pooled cohorts can help to identify and stratify patients based on modifiable and non-modifiable risk factors.

Setting a Target In patients with known CVD or a 10-year risk that is >10%, the blood pressure goal would be <130/80 mmHg. In those patients who have an intermediate risk or do not have additional markers of increased CVD risk, a target of <130/80 mmHg is also reasonable.

150

250

Hypertension Smoking Physical inactivity Overweight and obesity (high BMI) High blood glucose High dietary sodium (salt) High LDL cholesterol Low dietary omega-3 fatty acids (seafood) High dietary trans fatty acids Low intake of fruits and vegetables Alcohol use Low PUFA (in place of SFA) Cardiovascular

Cancer

Diabetes

Respiratory

Other NCDs

Injury

NCDs = non=comminicable diseases; PUFA = polyunsaturated fatty acids; SFA = saturated fatty acids. Source: Wenger et al. 2018.4 Reproduced with permission from Elsevier.

enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs). Notably, none of these drugs have been shown to be clearly superior to another. In patients who fail to meet their blood pressure control target, combination drug therapy may be beneficial. Physicians can elect to use two first-line agents if the patient has stage 2 hypertension and has an average blood pressure of >20/10 mmHg above target. It is reasonable to use monotherapy if the patient has stage 1 hypertension with a blood pressure goal of <130/80 mmHg. Doses can be titrated accordingly with sequential addition of other agents to achieve target blood pressure.

Heart Failure Hypertension poses a significant risk of heart failure. In fact, 75% of those with congestive heart failure have had antecedent hypertension.14 In those adults with an increased risk of heart failure, the optimal blood pressure for those with hypertension is less than 130/80 mmHg. In fact, large scale randomized controlled trials have shown that antihypertensive drug therapy reduces the incidence of heart failure in patients with hypertension. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial, chlorthalidone reduced the risk of heart failure with reduced ejection fraction (HFrEF) more than amlodipine and doxazosin, however it was similar to lisinopril.12,13 Of note, non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, have negative inotropy and are therefore not recommended for patients at risk of heart failure.

Pharmacological Approaches First-line agents for pharmacological treatment for hypertension include thiazide diuretics, calcium channel blockers, angiotensin-converting

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In the instance of heart failure with preserved ejection fraction (HFpEF), hypertension is prevalent in 60–90% of cases. Therefore, preventing

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Editor’s Pick hypertension and/or treating it is critical to reducing the prevalence of HFpEF. Treating hypertension in the setting of heart failure reduces hospitalizations, events, and mortality.15 Diuretics are among the most important agents for reducing blood pressure and improving the success of other agents. In the ALLHAT trial, chlorthalidone demonstrated a decreased incidence of new-onset HFpEF compared with amlodipine, doxazosin, and lisinopril.15

a high burden of comorbid conditions, shared decision making with clinical judgement and a team-based approach are important. In black adults who do not have chronic kidney disease or heart failure, initial antihypertensive treatment includes a thiazide-type diuretic or a calcium channel blocker. Similarly, a drug regimen that includes two or more antihypertensives is recommended to achieve a blood pressure goal <130/80 mmHg, especially in black adults.12

Patients with HFpEF who present with volume overload will require diuretics, which help to lower blood pressure. In persistent hypertension, despite improving volume status for those patients with HFpEF, ACE inhibitors, ARBs, or beta blockers can help reduce blood pressure to a target <130/80 mmHg.

Conclusion

Personalizing Hypertension Treatment Plans In those patients who are 65 years or over, ambulatory and living in the community, the goal remains a SBP <130 mmHg. If older patients have

5. 6.

L im S, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2224–60. https://doi.org/10.1016/S01406736(12)61766-8; PMID: 23245609. Ford, E. Trends in mortality from all causes and cardiovascular disease among hypertensive and nonhypertensive adults in the United States. Circulation 2011;123:1737–44. https://doi.org/ 10.1161/CIRCULATIONAHA.110.005645; PMID: 21518989. Cheng S, Claggett B, Correia A, et al. Temporal trends in the population attributable risk for cardiovascular disease. Circulation 2014;130:820–8. https://doi.org/10.1161/ CIRCULATIONAHA.113.008506; Wenger NK, Arnold A, Bairey N, et al. Hypertension across a woman’s life cycle. J Am Coll Cardiol 2018;71:1797–813. https://doi. org/10.1016/j.jacc.2018.02.033; PMID: 29673470. European Cardiovascular Disease Statistics 2017. http://www. ehnheart.org/cvd-statistics.html. Butler J, Kalogeropoulos AP, Georgiopoulou VV, et al. Systolic blood pressure and incident heart failure in the elderly. The Cardiovascular Health Study and the Health, Ageing and Body Composition Study. Heart 2011;97:1304–11. https://doi. org/10.1136/hrt.2011.225482; PMID: 21636845.

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Overall, early management and treatment of hypertension by general practitioners will improve cardiovascular outcomes. By adhering to the target blood pressure guidelines, assessing CVD risk, encouraging lifestyle changes, and recommending multiple drug regimens as indicated, general practitioners should feel empowered to make a real change in this patient group. In addition, by personalizing the approach depending on ethnicity and heart failure class, they can expect a reduction in cardiac events, hospitalizations, and overall negative outcomes.

apsomaniki E, Timmis A, George J, et al. Blood pressure R and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people. Lancet 2014;383:1899–911. https://doi.org/10.1016/S0140-6736(14)60685-1; PMID: 24881994. 8. Moser M, Hebert P. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. J Am Coll Cardiol 1996;27:1214–8. https://doi.org/10.1016/0735-1097(95)00606-0; PMID: 8609345. 9. Kostis JB, Davis B, Cutler J, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. J Am Med Assoc 1997;278:212–16. https:// doi.org/10.1001/jama.1997.03550030052033; PMID: 9218667. 10. Wang JG, Staessen JA, Franklin SS, et al. Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 2005;45:907–13. https://doi.org/10.1161/ 01.HYP.0000165020.14745.79; PMID: 15837826. 11. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103–16. https://doi.org/10.1056/ NEJMoa1511939; PMID: 26551272. 12. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/

ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines. J Am Coll Cardiol 2018;71:e127–e248. https://doi.org/10.1016/j.jacc.2017.11.006; PMID: 29146535. 13. Grundy SM, Stone NJ, Bailey, AL et al. 2018 AHA/ACC/ AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation 2018. https://doi.org/10.1161/CIR.0000000000000625; PMID: 30586774; epub ahead of press. 14. 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. J Am Coll Cardiol 2017;70:776–803. https://doi.org/10.1016/j. jacc.2017.04.025; PMID: 28461259. 15. Davis BR, Kostis JB, Simpson LM et al. Heart failure with preserved and reduced left ventricular ejection fraction in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Circulation 2008;118:2259–67. https://doi.org/10.1161/ CIRCULATIONAHA.107.762229; PMID: 19001024.

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Foreword