USC 13.2

Volume 13 • Issue 2 • Winter 2019

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Effect of the Extent of Cardiac Damage on Transcatheter Aortic Valve Replacement Outcome: A New Aortic Stenosis Staging System Miho Fukui, MD, and João L Cavalcante, MD

Baroreflex Activation Therapy for Resistant Hypertension and Heart Failure Anna Meta Dyrvig Kristensen, MB, Manan Pareek, MD, PhD, Michael Hecht Olsen, MD, PhD, DMSc, and Deepak L Bhatt, MD, MPH

Artificial Intelligence in Cardiac Imaging Karthik Seetharam, MD, Sirish Shrestha, MSc, and Partho P Sengupta, MD, DM

Clinical Features and Outcomes of Patients with Chemotherapyinduced Takotsubo Syndrome Katelyn Storey, BA, and Scott W Sharkey, MD

Transcatheter aortic valve removal and replacement

Human heart angioplasty

Digital technologies in cardiac imaging

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Volume 13 • Issue 2 • Winter 2019

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

Section Editor (Interventional/Structural)

Section Editor (Imaging)

Section Editor (Preventive Cardiology)

Rishi Puri, MD, PhD, FRACP

Akhil Narang, MD, FACC

Aditya Khetan, MD

Cleveland Clinic, Cleveland, OH

Northwestern University, Chicago, IL

Case Western Reserve University, Cleveland, OH

Section Editor (Electrophysiology)

Section Editor (Heart Failure)

Section Editor (Heart Failure)

Sourbha S Dani, MD, FACC

Amin Yehya, MD, MS, FACC, FHFSA

Andrew J Sauer, MD

Eastern Maine Medical Center, Bangor, ME

Sentara Heart, Norfolk, VA

The University of Kansas Medical Center, Kansas City, KS

Associate Editors Sahil Khera MD, MPH

Rajalakshmi Santhanakrishnan, MBBS

Columbia University, New York City, NY

Wright State University, Dayton, OH

Yogesh Reddy, MD, MSc

Bruce Stambler, MD

Mayo Clinic, Rochester, MN

Piedmont Healthcare, Atlanta, GA

Editorial Board Ralph G Brindis, MD

Bernard J Gersh, MB, ChB, DPhil

Leo Buckley, PharmD

Bill Gogas, MD, PhD

University of California, San Francisco, CA Virginia Commonwealth University, Richmond, VA

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

Donald E Cutlip, MD

Harvard Medical School, Boston, MA

Emory University School of Medicine, Atlanta, GA

Michael R Gold, MD

Duane Pinto, MD, MSc Harvard Medical School, Boston, MA

Medical University of South Carolina, Charleston, SC

Krishna Pothineni, MD

Thomas A Haffey, MD, DO

University of Arkansas for Medical Sciences, Little Rock, AR

Western University of Health Sciences, Pomona, CA

Dinesh K Kalra, MD, FACC, FSCCT, FSCMR

NA Mark Estes III, MD

Morton J Kern, MD

Tufts University School of Medicine, Boston, MA

Jackson J Liang, MD, DO Hospital of the University of Pennsylvania, Philadelphia, PA

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

Cover images © AdobeStock and Shutterstock

Mayo Clinic, Rochester, MN

Rush University Medical Center, Chicago, IL

Rahul Sharma, MD, FACP, FACC, FSCAI Virginia Tech Carilion School of Medicine, Roanoke, VA

W Douglas Weaver, MD

University of California at Irvine, Orange, CA

Wayne State University, Detroit, MI

Editorial

Accounts

Managing Editor Rosie Scott | Production Editor Aashni Shah Publishing Director Leiah Norcott | Senior Designer Tatiana Losinska Contact rosie.scott@radcliffe-group.com

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Published by Radcliffe Cardiology.

All information obtained by Radcliffe Cardiology and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Cardiology and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use 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

© RADCL IFFE CA RD IO LO G Y 2019

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Established: March 2016 | Frequency: Bi-annual | Current issue: Winter 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.

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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.

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• 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 & Electrophysiology Review, Cardiac Failure Review, Interventional Cardiology Review and European Cardiology Review.

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© R A DC LI FFE C AR DI OLOGY 2019

Contents

Foreword Ankur Kalra, MD, FACP, FACC, FSCAI

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DOI: https://doi.org/10.15420/usc.2019.13.2.ED1

Cardiovascular Imaging Effect of the Extent of Cardiac Damage on Transcatheter Aortic Valve Replacement Outcome: A New Aortic Stenosis Staging System

69

Miho Fukui, MD, and João L Cavalcante, MD DOI: https://doi.org/10.15420/usc.2019.9.1

Cardiomyopathies Clinical Features and Outcomes of Patients with Chemotherapy-induced Takotsubo Syndrome

74

Katelyn Storey, BA, and Scott W Sharkey, MD DOI: https://doi.org/10.15420/usc.2019.10.1

Peripheral Interventions Baroreflex Activation Therapy for Resistant Hypertension and Heart Failure

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Anna Meta Dyrvig Kristensen, MB, Manan Pareek, MD, PhD, Michael Hecht Olsen, MD, PhD, DMSc, and Deepak L Bhatt, MD, MPH DOI: https://doi.org/10.15420/usc.2019.13.2

Structural Heart Between a Rock and a Hard Place: How to Use Antithrombotics in Patients Undergoing Transcatheter Aortic Valve Replacement

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Kelsey Grossman, MD, Mathew R Williams, MD, and Homam Ibrahim, MD DOI: https://doi.org/10.15420/usc.2019.01

Congenital Heart Disease Single-Ventricle Physiology

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Lydia Taranto, MD, and Tabitha Moe, MD DOI: https://doi.org/10.15420/usc.2019.20.2

Coarctation: A Review

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Marc G Cribbs, MD, FACC DOI: https://doi.org/10.15420/usc.2019.15.2

Annual Meetings Major Cardiovascular Advances: Highlights from the 2019 American College of Cardiology Annual Scientific Session

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Hisham A Badreldin, PharmD, BCPS, ASH-CHC, Khalid bin Saleh, PharmD, BCPS, and Majed Al Yami, PharmD, BCPS, ASH-CHC DOI: https://doi.org/10.15420/usc.2019.11.2

Trends Artificial Intelligence in Cardiac Imaging

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Karthik Seetharam, MD, Sirish Shrestha, MSc, and Partho P Sengupta, MD, DM DOI: https://doi.org/10.15420/usc.2019.19.2

Catheterization Etiquettes Strategies to Reduce Radiation Exposure in Electrophysiology and Interventional Cardiology

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Sandeep Shankar, MD, DM, Deepak Padmanabhan, MD, DM, Avinash Chandrashekharaiah, BE and Saurabh Deshpande, MD, DM DOI: https://doi.org/10.15420/usc.2019.21.2

Corrigendum Corrigendum to: Value of MitraClip in Reducing Functional Mitral Regurgitation

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Mehmet Ali Elbey, MD, Luis Augusto Palma Dallan, MD, and Guilherme Ferragut Attizzani, MD DOI: https://doi.org/10.15420/usc.2019.13.2.CG1

© RADCLIF F E CARD IO L O G Y 2019

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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.

H

appy 2020! We are in the new decade. As I present to all of you yet another issue of US Cardiology Review (USC), I want to take this opportunity to share our vision for 2020. Our aim is to present contemporary clinical data in a digestible, readyto-implement format for the busy, bedside clinician. USC is your go-to resource for quick, concise, and accurate reviews of relevant clinical topics that you can read on the go during lunch breaks or down time. To facilitate content delivery and continuing medical education for our colleagues, we have also put together a cardiology podcast show, Parallax, to supplement review article content in the format of audio articles that you can access from your device anytime and listen to during your commute to work or while preparing meals or exercising.

I am thrilled to present issue 13.2 of USC. In this issue of the journal, Miho Fukui and João L Cavalcante discuss the extent of cardiac damage in aortic stenosis patients and the role of imaging in classifying aortic stenosis in the era of transcatheter valve therapies.

Next, Katelyn Storey and Scott W Sharkey discuss clinical features and outcomes of patients with chemotherapy-induced takotsubo syndrome. Anna Meta Dyrvig Kristensen et al. discuss baroreflex activation therapy for resistant hypertension and heart failure. In structural heart diseases, Kelsey Grossman et al. write about antithrombotic choices in patients undergoing transcatheter aortic valve replacement. In our congenital heart disease section, Lydia Taranto and Tabitha Moe dive into single-ventricle physiology, and Marc G Cribbs discusses coarctation. In the annual meetings review section, Hisham A Badreldin et al. present highlights from the American College of Cardiology Annual Scientific Sessions 2019. We conclude this issue with a state-of-the-art article on artificial intelligence in cardiac imaging by Karthik Seetharam et al. and radiation safety by Sandeep Shankar et al.

I sincerely hope you enjoy reading this issue as much as we have enjoyed putting it together for you.

If you wish to join our dynamic team of editors and content developers at USC, please do not hesitate to write to me directly at akalra@alumni.harvard.edu. Also, if you listen to Parallax on various podcast platforms, including Apple Podcasts, SoundCloud, and Spotify, please take a moment to review and rate us. We personally go through all your reviews, and it helps us immensely to improve our content and its delivery, based on your feedback.

Thank you for reading, listening, and following us across all online and social media platforms.

DOI: https://doi.org/10.15420/usc.2019.13.2.ED1

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© RADCLIFFE CARDIOLOGY 2019

Cardiovascular Imaging

Effect of the Extent of Cardiac Damage on Transcatheter Aortic Valve Replacement Outcome: A New Aortic Stenosis Staging System Miho Fukui, MD, 1 and João L Cavalcante, MD 1,2 1. Valve Science Center, Minneapolis Heart Institute Foundation, Minneapolis, MN; 2. Minneapolis Heart Institute, Abbott Northwestern Hospital, Allina Health, Minneapolis, MN

Abstract Severe aortic stenosis (AS) causes chronic pressure overload of the left ventricle (LV), resulting in progressive cardiac change that can extend beyond the LV. A new AS staging classification has been recently proposed encompassing the extent of cardiac changes in AS. The AS staging classification has important prognostic implications for clinical outcomes after aortic valve replacement. This article introduces the AS staging system and demonstrates the association of the extent of cardiac change with outcomes after transcatheter aortic valve replacement.

Keywords Aortic stenosis, classification, prognosis, readmission, Society of Thoracic Surgeons Predicted Risk of Mortality score, transcatheter aortic valve replacement Disclosure: JLC has received research funding from Medtronic and Abbott Vascular, and consultant fees from Medtronic, Circle Cardiovascular Imaging, and Siemens. MF has no conflicts of interest to declare..

Received: 11 March 2019 Accepted: 16 July 2019 Citation: US Cardiology Review 2019;13(2):69–73. DOI: https://doi.org/10.15420/usc.2019.9.1 Correspondence: João L Cavalcante, Director, Cardiac MRI, Structural CT and Cardiovascular Imaging Core Lab, Minneapolis Heart Institute, Abbott Northwestern Hospital, Valve Science Center, Minneapolis Heart Institute Foundation, 800 E 28th Street, Suite 300, Minneapolis, MN 55407, US. E: Joao.Cavalcante@allina.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.

Degenerative calcific aortic stenosis (AS) is one of the most common valvular heart diseases, affecting >3% of those aged >65 years in the West.1 As a result of an aging population, the prevalence of AS is expected to increase. Severe AS causes chronic pressure overload of the left ventricle (LV), resulting in LV hypertrophy (LVH), diastolic dysfunction, an increase in the size of the left atrium, development of mitral and tricuspid regurgitation, and an increase in pulmonary artery pressure.2 AS is characterized not only by a restriction of aortic valve opening, but also by progressive myocardial changes that can sometimes extend beyond the LV. A new staging classification system characterizing the extent of cardiac changes was recently proposed by Généreux et al. for patients with severe AS undergoing surgical or transcatheter aortic valve replacement (AVR) as part of the Placement of AoRTic TraNscathetER Valves (PARTNER 2) trial.3 As the number of transcatheter (TAVR) procedures continues to grow, it will be important to determinate whether prior findings can be replicated and validated in the real-world cohort of patients who have received TAVR. We hypothesized that AS staging would be associated with 2-year all-cause mortality and post-TAVR hospitalization. This review introduces the AS classification system and demonstrates the association between the extent of cardiac changes and outcomes after TAVR using a large and homogeneous cohort of patients with severe AS who received TAVR.

© RADCLIFFE CARDIOLOGY 2019

Newly Proposed Aortic Stenosis Staging Classification System The pathophysiologic process of severe AS has both valvular and extravalvular involvement. Previous studies have clearly shown that the presence of extravalvular cardiac changes are prognostic in patients with severe AS.4–7 However, the indications for AVR in patients with AS remain primarily centered on the severity of AS, the symptoms related to AS, and reduced LV systolic function, defined by LV ejection fraction (LVEF) <50%.8–10 Using data from the PARTNER 2A and 2B trials, which include a large contemporary population of patients with symptomatic severe AS undergoing either surgical AVR or TAVR, Généreux et al. proposed the first framework for an integrated staging system to quantify the extent of anatomical and functional cardiac changes associated with AS prior to AVR.3 They classified patients with severe AS undergoing AVR into five stages depending on the presence or absence of extravalvular cardiac changes or dysfunction, as detected by transthoracic echocardiography before AVR (Figure 1) as follows: stage 0, no other cardiac damage detected; stage 1, LV damage, as defined by the presence of LVH (LV mass index >95 g/m2 for women, >115 g/m2 for men), severe LV diastolic dysfunction (E/eʹ >14), or LV systolic dysfunction (LVEF <50%); stage 2, damage to or dysfunction of the left atrium or mitral valve, as defined by the presence of an enlarged left atrium volume index (>34 ml/m2), the

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Cardiovascular Imaging Figure 1: Aortic Stenosis Staging Classification System

Stage 0

Stage 1

Stage 2

Stage 3

Stage 4

No cardiac damage

LV damage

LA or mitral damage

Pulmonary vasculature or tricuspid damage

RV damage

Increased LV mass index: >115 g/m2 in males, >95 g/m2 in females

Indexed LA volume >34 ml/m2

Systolic pulmonary hypertension ≥60 mmHg

Moderate–severe RV dysfunction

E/e´ >14

Moderate–severe mitral regurgitation

Moderate–severe tricuspid regurgitation

LVEF <50%

AF

Stages/criteria

Echocardiogram

The stages are defined according to the extent of cardiac damage as detected by transthoracic ECG. LA = left atrial; LV = left ventricular; LVEF = left ventricular ejection fraction; RV = right ventricular.

Source: Généreux et al.3 Reproduced with permission from Oxford University Press.

presence of AF, or the presence of moderate or severe mitral regurgitation; stage 3, damage to or dysfunction of the pulmonary artery vasculature or tricuspid valve, as defined by the presence of systolic pulmonary hypertension (systolic pulmonary artery pressure ≥60 mmHg) or the presence of moderate or severe tricuspid regurgitation; and stage 4, right ventricular damage, as defined by the presence of moderate or severe right ventricular dysfunction.3 Patients were hierarchically classified in a given stage (worst stage) if at least one of the proposed criteria was met within that stage.

safe in low-risk patients with symptomatic severe AS with regard to short-term outcomes.13 Given the potential expansion of TAVR into the lower (surgical) risk cohort and an increasing aging population, TAVR rates are expected to increase. However, other important risk factors, such as the presence of concomitant mitral or tricuspid regurgitation, pulmonary hypertension, and right ventricular dysfunction, may not be entirely correlated with AVR. Thus, it is important to have better ways to identify patients suitable for AVR and to evaluate risk stratification in patients with severe AS.

Using a cohort of 1,661 trial patients with comprehensive echocardiographic assessment before AVR, Généreux et al. demonstrated that there is a strong association between the newly proposed anatomic and functional cardiac damage staging system and 1-year mortality in patients receiving either surgical AVR or TAVR.3 For each stage increment, 1-year mortality risk increased by approximately 45%. Even after adjusting for several well-established predictors of worse outcomes after AVR, including patient frailty and the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score, the association with 1-year mortality remained significant.

Validation of Aortic Stenosis Staging

Association of the Aortic Stenosis Staging System With Outcomes After TAVR We sought to confirm the reproducibility of the proposed AS staging system (by applying the same proposed classification into a separate homogeneous cohort of patients who received TAVR from another institution), particularly in patients who had undergone TAVR. TAVR has become a breakthrough therapeutic advance in the treatment of symptomatic patients with severe AS classified as being at intermediate, high, and extreme surgical risk.11,12 In the US and many other countries, TAVR has become the most common method for aortic valve replacement. Furthermore, TAVR has been confirmed as

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Using a large and homogeneous cohort of patients with symptomatic severe AS who had undergone TAVR within a large, integrated healthcare system, we sought to expand prior findings by performing survival analysis up to 2 years after TAVR and evaluating the association between AS staging and both cardiac and non-cardiac post-TAVR readmissions. In all, 689 patients were included in the final analysis (351 [50.9%] men; mean [±SD] age 82.4 ± 7.6 years; mean STS-PROM score 8.2 ± 4.7%). Of the 689 patients, 13%, 62%, 21%, and 4% were classified as stage 1, 2, 3, and 4, respectively. These results are similar to those reported by Généreux et al.3 Mean patient age, the prevalence of hypertension, and STS-PROM scores increased from stage 1 to 3, but decreased in stage 4 patients (Table 1). In terms of the ECG characteristics used for the staging classification, patients in stages 3 and 4 had the worst findings (i.e. greater LV mass index, worse LVEF, and concomitant valvular disease). Of note, the prevalence of LV and then right ventricular dysfunction (typically a late finding in severe AS) increased with worsening AS stage. Pulmonary artery systolic pressure increased from stage 1 to 3, but decreased in stage 4, likely due to right ventricular dysfunction and significant valvular disease. The prevalence of low-flow, low-gradient AS (known as a higher-risk phenotype) increased from stage 1 through to 4.

US CARDIOLOGY REVIEW

New Aortic Stenosis Staging System Table 1: Baseline Characteristics Total

Stage 1

Stage 2

Stage 3

Stage 4

p-value

No. patients

689

93

426

142

28

Male sex

351 (50.9)

42 (45.2)

229 (53.8)

60 (42.3)

20 (71.4)

0.009

Age (years)

82.4±7.6

81.1±7.2

82.8±7.4

83.2±6.7

76.6±12.9

<0.001

Diabetes

283 (41.1)

37 (39.8)

170 (39.9)

61 (43.0)

15 (53.6)

0.509

Hypertension

617 (89.6)

81 (87.1)

379 (89.0)

135 (95.1)

22 (78.6)

0.030

Previous CABG

199 (28.9)

24 (25.8)

129 (30.3)

34 (23.9)

12 (42.9)

0.159

Previous MI

263 (38.2)

31 (33.3)

171 (40.1)

46 (32.4)

15 (53.6)

0.092

NYHA ≥3

543 (78.8)

69 (74.2)

338 (79.3)

116 (81.7)

20 (71.4)

0.806

STS-PROM score (%)

8.2±4.7

6.6±4.0

8.2±4.7

9.3±5.1

8.5±4.1

<0.001

Pre-TAVR AF/flutter

321 (46.6)

0 (0.0)

211 (49.5)

91 (64.1)

19 (67.9)

<0.001

LVMI (g/m2)

155±43

141±36

157±42

157±47

163±30

0.009

SVI (ml/m2)

36.3±11.3

37.3±9.7

37.4±10.6

34.4±13.1

23.3±7.9

<0.001

LVEF (%)

54.2±13.0

58.1±10.6

55.4±11.6

51.8±14.3

31.8±13.3

<0.001

PASP (mmHg)

43.3±16.1

36.0±10.6

37.9±10.9

61.2±16.4

54.7±19.2

<0.001

TAPSE <1.7 (cm)

208 (30.2)

18 (19.4)

110 (25.8)

57 (40.1)

23 (82.1)

<0.001

Moderate–severe MR

88 (12.8)

0 (0.0)

49 (11.5)

29 (20.4)

10 (35.7)

<0.001

Moderate–severe TR

108 (15.7)

0 (0.0)

0 (0.0)

94 (66.2)

14 (50.0)

<0.001

0.65±0.18

0.67±0.17

0.66±0.18

0.61±0.18

0.56±0.16

0.001

LAVI (ml/m2)

47.8±17.2

27.5±5.0

49.6±15.4

54.3±19.0

53.0±14.8

<0.001

Low-flow, low-gradient AS*

117 (18.6)

10 (11.2)

63 (16.2)

29 (23.0)

15 (62.5)

<0.001

AVA

(cm2)

ml/m2

Unless indicated otherwise, data are given as number (percentage) or as the mean±SD. *Low-flow, low-gradient aortic stenosis was defined as stroke volume index <35 and aortic valve mean gradient <40 mmHg. AVA = aortic valve area; CABG = coronary artery bypass graft; LAVI = left atrial volume index; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass index; MR = mitral regurgitation; NYHA = New York Heart Association; PASP = pulmonary artery systolic pressure; STS-PROM = Society of Thoracic Surgeons Predicted Risk of Mortality; TAPSE = tricuspid annular plane systolic excursion; TAVR = transcatheter aortic valve replacement; TR = tricuspid regurgitation.

Figure 2: Unadjusted Survival Curves According to Aortic Stenosis Stages

0.8

0.8

0.8

0.6 0.4 Log-rank chi-squared: 25.0, p<0.001 0.2 0.0 0

3

6

0.6 0.4 Log-rank chi-squared: 12.8, p=0.005 0.2

Stage 1 Stage 2 Stage 3 Stage 4

12

15

18

21

0

24

Months after TAVR Stage 1 Stage 2 Stage 3 Stage 4

93 80 83 72 62 57 48 43 36 426 401 381 338 305 282 246 219 185 142 127 115 104 91 74 67 59 49 28 26 23 22 19 19 14 13 11

3

0.6 0.4 Log-rank chi-squared: 12.6, p=0.006 0.2

Stage 1 Stage 2 Stage 3 Stage 4

0.0 9

Cumulative survival

C 1.0

Cumulative survival

B 1.0

Cumulative survival

A 1.0

0.0

6

9

12

15

18

21

0

24

Months after TAVR Stage 1 Stage 2 Stage 3 Stage 4

Stage 1 Stage 2 Stage 3 Stage 4

93 79 66 56 47 41 36 34 29 426 342 313 266 235 206 171 143 114 142 102 88 70 60 46 39 32 26 28 22 20 18 14 13 11 11 9

3

6

9

12

15

18

21

24

Months after TAVR Stage 1 Stage 2 Stage 3 Stage 4

93 81 70 60 52 45 40 36 30 426 356 328 282 248 218 179 154 123 142 105 92 76 66 51 44 36 30 28 22 20 18 15 14 11 11 9

All-cause mortality (A) and composite outcomes of deaths and readmissions for all causes (B) or cardiac causes (C) after transcatheter aortic valve replacement (TAVR) increased with each stage of worsening cardiac dysfunction. Numbers reflect the number of patients per each stage without the event (at-risk) at each time point. Source: Fukui et al.22 Reproduced with permission from the American Medical Association.

Kaplan–Meier analysis revealed a strong graded association between the AS staging system and all-cause mortality up to 2 years follow-up (Figure 2A), which extends the original observations reported by Généreux et al. 3 This separation persisted even after adjustment for

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the STS-PROM score (Figure 3A), with an increased HR for all-cause mortality at each stage (Table 2). That is, AS patients presenting with stage 4 (significant right ventricular dysfunction) had the highest risk of mortality after undergoing TAVR, followed by stage 3 patients,

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Cardiovascular Imaging Table 2: Association Between Aortic Stenosis Stages and Outcomes Unadjusted

Adjusted for STS-PROM score

HR [95% CI]

p-value

HR [95% CI]

p-value

• Stage 1 (Reference)

1.00 [Reference]

–

1.00 [Reference]

–

• Stage 2

1.51 [0.89–2.56]

0.118

1.37 [0.81–2.31]

0.248

• Stage 3

2.68 [1.54–4.67]

< 0.001

2.24 [1.28–3.92]

0.005

• Stage 4

3.37 (1.66–6.83)

< 0.001

2.83 [1.39–5.76]

0.004

• Stage 1 (Reference)

1.00 [Reference]

–

1.00 [Reference]

–

• Stage 2

1.23 [0.83–1.81]

0.305

1.14 [0.77–1.69]

0.513

• Stage 3

1.83 [1.20–2.82]

0.006

1.64 [1.06–2.54]

0.025

• Stage 4

1.34 [0.68–2.61]

0.396

1.22 [0.62–2.38]

0.568

• Stage 1 (Reference)

1.00 [Reference]

–

1.00 [Reference]

–

• Stage 2

1.41 [0.91–2.19]

0.126

1.30 [0.83–2.03]

0.246

• Stage 3

2.09 [1.29–3.37]

0.003

1.84 [1.13–3.00]

0.014

• Stage 4

1.66 [0.81–3.41]

0.167

1.49 [0.73–3.07]

0.277

All-cause mortality:

All-cause readmission:

Cardiac-cause readmission:

STS-PROM = Society of Thoracic Surgeons Predicted Risk of Mortality. Source: Fukui et al.22 Reproduced with permission from the American Medical Association.

Figure 3: Adjusted Survival Curves According to Aortic Stenosis Stages

0.8

0.8

0.8

0.6 0.4 Log-rank chi-squared: 54.8; p<0.001 0.2 0.0 0

3

6

0.6 0.4 Log-rank chi-squared: 29.8; p<0.001 0.2

Stage 1 Stage 2 Stage 3 Stage 4

12

15

18

21

0

24

Months after TAVR Stage 1 Stage 2 Stage 3 Stage 4

93 90 83 72 62 57 48 43 36 426 401 381 338 305 282 246 219 185 142 127 115 104 91 74 67 59 49 28 26 23 22 19 19 14 13 11

3

0.6 0.4 Log-rank chi-squared: 32.8; p<0.001 0.2

Stage 1 Stage 2 Stage 3 Stage 4

0.0 9

Cumulative survival

C 1.0

Cumulative survival

B 1.0

Cumulative survival

A 1.0

0.0

6

9

12

15

18

21

0

24

Months after TAVR Stage 1 Stage 2 Stage 3 Stage 4

Stage 1 Stage 2 Stage 3 Stage 4

93 79 66 56 47 41 36 34 29 426 342 313 266 235 206 171 143 114 142 102 88 70 60 46 39 32 26 28 22 20 18 14 13 11 11 9

3

6

9

12

15

18

21

24

Months after TAVR Stage 1 Stage 2 Stage 3 Stage 4

93 81 70 60 52 45 40 36 30 426 356 328 282 248 218 179 154 123 142 105 92 76 66 51 44 36 30 28 22 20 18 15 14 11 11 9

A: Even after adjusting for the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score, there was a strong graded association of aortic stenosis (AS) stages with all-cause mortality after transcatheter aortic valve replacement (TAVR). B, C: Regarding post-TAVR readmission rates, despite adjustment for the STS-PROM score, patients with Stage 3 AS also had the highest risk of composite outcomes of all-cause death and readmissions for all causes (B) or cardiac causes (C). Numbers reflect the number of patients per each stage without the event (at-risk) at each time point.

Source: Fukui et al.22 Reproduced with permission from the American Medical Association.

whereas stage 2 AS patients did not have a significantly greater risk than those in stage 1.

captured by the staging system was associated with the composite outcomes (Figure 3B and 3C).

Another important finding of our analysis is the association of AS staging with the post-TAVR readmission rate for either any cause or cardiac causes (Table 2). Stage 3 patients who presented with significant pulmonary hypertension or tricuspid valvular damage not only had a higher mortality risk, but were also at higher risk of composite outcomes of all-cause death and readmissions for any cause (Figure 2B) or cardiac causes (Figure 2C). Even after adjustment for STS-PROM scores, the extent of cardiac changes

The findings of the present study support those reported by Généreux et al. by showing that the results of the staging system are reproducible and prognostically sound in an independent cohort of patients who underwent TAVR.3 In addition, we expand on the findings of Généreux et al. by showing that the association of AS staging with all-cause mortality persists up to 2 years of follow-up, and by demonstrating the association between AS staging and post-TAVR readmission rates in real-world patients with symptomatic severe AS who underwent TAVR.

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US CARDIOLOGY REVIEW

New Aortic Stenosis Staging System Study Limitations Although this newly proposed staging classification would offer considerable advantages in terms of patient selection for AVR, the present study has some limitations. First, although risk factors such as concomitant valvular disease, pulmonary hypertension, and RV dysfunction are known to be important for patients presenting with symptomatic severe AS, both the present study and the study of Généreux et al. are retrospective studies, whereby the classification system was not used as part of the original decisionmaking process.3 Second, the cardiac damage proposed at each stage is not progressive and/or not necessarily a direct result of severe AS. Rather, the classification reflects the presence of other comorbidities in addition to severe AS. For example, in a stage 1 patient with severe AS (LV damage, LVEF <50%) may be related to coexisting coronary artery disease, or those in a stage 2 patient (severe AS plus mitral regurgitation plus left atrial dilation) could be related to primary mitral regurgitation with flail mitral leaflet. This newly proposed staging classification is about risk stratification of other coexisting comorbidities, and not a pathophysiological explanation of AS progression. Third, a more detailed classification between stages 0 and 1 is needed. Although reduced LVEF (<50%) is one of the classification criteria for stage 1 and an indication for AVR in patients with severe AS because of its relationship with poor outcome,14–16 LVEF alone is not sufficient to detect myocardial dysfunction at early stages of AS. Indeed, LVEF does not improve in some patients, despite AVR, and adversely affects mortality. Fourth, we have only investigated the classification system using baseline parameters.

It is possible that staging changes in patients, and post-TAVR staging could be equally important. More data are needed to clarify this point.

AS despite preserved LVEF.18–21 These parameters could expand and potentially improve the proposed AS staging system, but are not currently incorporated into the routine clinical assessment of such patients.

The newly proposed staging system could also be particularity important for follow-up care after TAVR. Specifically, patients presenting in stages 3 or 4 may still derive symptomatic benefit from aortic valve intervention, but this benefit could be reduced by the presence of other comorbidities that may increase mortality risks and readmission rates. Such patients may require close follow-up care, and continued surveillance of their pulmonary hypertension, tricuspid regurgitation, and right ventricular dysfunction.

With the potential expansion of TAVR into lower risk and asymptomatic cohorts, the burden of extracardiac comorbidities and frailty may be lessened, thus emphasizing the importance of comprehensive anatomical and functional evaluation of cardiac changes before AVR. Although TAVR may be the correct choice in many patients, those with concomitant regurgitant valve lesions could derive benefit from simultaneous surgical correction.

Conclusion

Future Directions

The newly proposed staging classification system demonstrates a strong and graded association of the extent of cardiac change with mortality and readmission rate in patients with severe AS after AVR. In addition, patients with baseline moderate-to-severe pulmonary hypertension and/ or significant tricuspid regurgitation have higher post-TAVR readmission rates for both cardiac and non-cardiac causes.

In patients with severe AS despite normal LVEF, subclinical myocardial dysfunction detected by ECG-derived global longitudinal strain is very common and can be associated with poor outcomes.14,17 In addition, the presence of myocardial fibrosis identified by cardiac MRI has been shown to be independently associated with mortality in patients with

Inclusion of this staging system should be considered in the development of future TAVR risk stratification models and for shared decision-making. Further studies are required to prospectively validate this classification system.

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onow RO, Greenland P. Population-wide trends in aortic B stenosis incidence and outcomes. Circulation 2015;131:969–71. https://doi.org/10.1161/CIRCULATIONAHA.115.014846; PMID: 25691712.

2. Cavalcante JL. Watchful waiting in aortic stenosis: are we ready for individualizing the risk assessment? Eur Heart J 2016;37:724–6. https://doi.org/10.1093/eurheartj/ehv578; PMID: 26537619.

3. Généreux P, Pibarot P, Redfors B, et al. Staging classification of aortic stenosis based on the extent of cardiac damage. Eur Heart J 2017;38:3351–8. https://doi.org/10.1093/eurheartj/ehx381; PMID: 29020232.

4. Cavalcante JL, Simon MA, Chan SY. Comprehensive right-sided assessment for transcatheter aortic valve replacement risk stratification: time for a change. J Am Soc Echocardiogr 2017;30:47–51. https://doi.org/10.1016/j.echo.2016.11.006; PMID: 28063482.

5. Sultan I, Cardounel A, Abdelkarim I, et al. Right ventricle to pulmonary artery coupling in patients undergoing transcatheter aortic valve implantation. Heart 2019;105:117–21. https://doi. org/10.1136/heartjnl-2018-313385; PMID: 30093545.

6. Asami M, Lanz J, Stortecky S, et al. The impact of left ventricular diastolic dysfunction on clinical outcomes after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11:593–601. https://doi.org/10.1016/j.jcin.2018.01.240; PMID: 29501544.

7. Asami M, Stortecky S, Praz F, et al. Prognostic value of right ventricular dysfunction on clinical outcomes after transcatheter aortic valve replacement. JACC Cardiovasc Imaging 2019;12:577–87. https://doi.org/10.1016/j.jcmg.2017.12.015; PMID: 29454762.

8. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease. Circulation 2014;129:e521–643. https://doi.org/10.1161/

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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.

Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. https://doi.org/10.1056/NEJMoa1103510; PMID: 21639811.

Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609–20. https://doi.org/10.1056/NEJMoa1514616; PMID: 27040324.

Waksman R, Rogers T, Torguson R, et al. Transcatheter aortic valve replacement in low-risk patients with symptomatic severe aortic stenosis. J Am Coll Cardiol 2018;72:2095–105. https://doi. org/10.1016/j.jacc.2018.08.1033; PMID: 30170075.

Ng ACT, Prihadi EA, Antoni ML, et al. Left ventricular global longitudinal strain is predictive of all-cause mortality independent of aortic stenosis severity and ejection fraction. Eur Heart J Cardiovasc Imaging 2018;19:859–67. https://doi.org/10.1093/ ehjci/jex189; PMID: 28950306.

Ito S, Miranda WR, Nkomo VT, et al. Reduced left ventricular ejection fraction in patients with aortic stenosis. J Am Coll Cardiol 2018;71:1313–21. https://doi.org/10.1016/j.jacc.2018.01.045; PMID: 29566814.

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Kusunose K, Goodman A, Parikh R, et al. Incremental prognostic value of left ventricular global longitudinal strain in patients with aortic stenosis and preserved ejection fraction. Circ Cardiovasc Imaging 2014;7:938–45. https://doi.org/10.1161/ CIRCIMAGING.114.002041; PMID: 25320287.

Dweck MR, Joshi S, Murigu T, et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. Am J Coll Cardiol 2011;58:1271–9. https://doi. org/10.1016/j.jacc.2011.03.064; PMID: 21903062.

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Cardiomyopathies

Clinical Features and Outcomes of Patients with Chemotherapy-induced Takotsubo Syndrome Katelyn Storey, BA, and Scott W Sharkey, MD Minneapolis Heart Institute and Foundation, Minneapolis, MN

Abstract Chemotherapy treatment of malignancy accounts for 1–2% of takotsubo syndrome (TS) triggers. Women comprise 60–70% of patients with chemotherapy-associated TS, a distinctly lower prevalence than the 90% female prevalence in TS overall. Fluorouracil is the most commonly reported TS-triggering chemotherapeutic agent, although this must be interpreted in the context of the frequency of worldwide use of this agent. The onset of TS relative to chemotherapy initiation is quite variable, ranging from the initial administration to subsequent chemotherapy cycles several weeks beyond initiation. Limited information suggests chemotherapy can be safely reinitiated once the patient has recovered from the initial TS event. Having a TS event in the setting of chemotherapy treatment for malignancy is associated with substantial mortality.

Keywords Takotsubo syndrome, chemotherapy, cardio-oncology Disclosure: Funding: Minneapolis Heart Institute Foundation, Minneapolis, MN, US. Received: 19 March 2019 Accepted: 18 June 2019 Citation: US Cardiology Review 2019;13(2):74–82. DOI: https://doi.org/10.15420/usc.2019.10.1 Correspondence: Scott W Sharkey, MD, Minneapolis Heart Institute Foundation, 920 East 28th St., Suite 620, Minneapolis, MN 55407. E: scott.sharkey@allina.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.

During the past 25 years, takotsubo syndrome (TS) has emerged as an important form of acute myocardial injury characterized by a distinctive regional left ventricular (LV) contraction abnormality, often with marked reduction of the LV ejection fraction, and typically completely reversible. At presentation, TS is often indistinguishable from acute coronary syndrome, yet its occurrence is independent of epicardial coronary artery obstruction. 1–4 Other features include a predilection for older women and an association with antecedent stressful event acting as the TS trigger. During the early experience with this condition, these triggering events were largely related to emotional trauma.5–10 As experience has expanded, a greater association with physical stressors has emerged. 3,4,11–13 The increased association with a physical trigger likely reflects greater awareness of secondary TS complicating acute illness. Within the realm of physical triggers, a number of reports have documented pharmacological agents as TS triggers, including cocaine, nortriptyline, venlafaxine, albuterol, flecainide, epinephrine, duloxetine, and a number of chemotherapeutic agents. 14 In this article, we examine the association of chemotherapeutic agents with TS.

Takotsubo Syndrome and Malignancy Surprisingly little information is available regarding the association of chemotherapy with TS triggering. The most commonly used chemotherapeutic agents for malignancy among Medicare recipients

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Access at: www.USCjournal.com

in the US are listed in Table 1. A 2015 international systematic review of 1,109 TS patients reported malignancy as a comorbid condition in 10%, although malignancy itself was not necessarily the TS trigger and no information was provided regarding chemotherapy use.15 A 2010–2014 analysis of 1,067,977 adult chemotherapy-related admissions from the US National Inpatient Sample database noted 562 patients (average age 63 ± 12 years, 69% female) with a TS diagnosis, representing an incidence of 37.0 (female) and 16.6 (male) per 100,000 chemotherapy-related hospitalizations.16 The annual incidence of chemotherapy-associated TS is increasing by an estimated 8.6 per 100,000 patients. 16 A 2008–2014 analysis from a tertiary cancer center noted 30 patients (average age 65 ± 9 years, 73% female) with cancer and TS. Among these patients, cancer treatment was identified as the TS trigger in 17 (57%), dominated by surgical procedures in 10 (33%), with chemotherapy as the apparent trigger in only 5 (17%) patients.17 The International Takotsubo Registry (1,750 patients) noted malignancy in only 1.3% of 630 patients (8 individuals) with physical TS triggers, although details regarding use of chemotherapy were not provided.12 Therefore, examining the association of chemotherapy with TS is limited by the relatively small number of patients and the lack of detail surrounding these events.

© RADCLIFFE CARDIOLOGY 2019

Takotsubo Syndrome and Chemotherapy Methods A computer-assisted search of the electronic database MEDLINE (1996– January 2019) was conducted. References were also examined for relevant articles, including review papers. The main search terms were: “takotsubo cardiomyopathy”, “takotsubo syndrome”, “chemotherapy”, “stress cardiomyopathy”, “apical ballooning syndrome”, and “cancer”.

Published case reports of TS and chemotherapy were chosen. We excluded studies in which cancer itself (not chemotherapy) was reported as the primary physical stressor.

Results From 2007 to 2018, we identified 36 unique patients with chemotherapyassociated TS (female patients 19 [61%], average age 64 ± 13 years, range 24–85 years; Table 2). ST-elevation was the most frequent initial ECG finding, present in 56% of reports providing this detail, and the average initial ejection fraction was 28 ± 12%. The onset of TS relative to initiation of chemotherapy was highly variable, ranging from the initial administration to subsequent chemotherapy cycles several weeks beyond initiation. In some cases, the temporal delay between chemotherapy administration and TS onset was lengthy, raising the question of whether the chemotherapeutic agent was actually the TS trigger.

The antimetabolite class of drugs (5-fluorouracil, capecitabine and cytarabine) represented the agents most commonly reported as TS triggers (Table 2). A variety of other chemotherapeutic classes were also represented, including tyrosine kinase inhibitors (sunitinib, axitinib, and pazopanib), HER2 monoclonal antibodies (trastuzumab and pertuzamab), angiogenesis inhibitors (bevacizumab), CD20 monoclonal antibodies (rituximab), microtubule-targeting drugs (paclitaxel and combretastatin), and anthracyclines (doxorubicin and daunorubicin). The TS event was associated with the use of a single chemotherapeutic agent in 69% of patients. Among patients with chemotherapy-associated TS, the most frequent malignancies were colorectal (n=10, 28%), leukemia (n=4, 11%), lymphoma (n=3, 8%), and renal (n=3, 8%).

Additional Considerations Chemotherapeutic agents have a long-established reputation for cardiotoxicity, including left ventricular dysfunction and heart failure, acute myocardial ischemia and infarction, thromboembolism, hypertension, and arrhythmia.47 Several of these drugs (e.g., fluorouracil, capecitabine, paclitaxel, docetaxel, bevacizumab, erlotinib, and sorafenib) have been associated with an acute MI-like syndrome that may be difficult to distinguish from a TS event.

Acute Myocarditis Mimicking Takotsubo Syndrome Recently, immune checkpoint inhibitors have been associated with acute myocarditis characterized by onset of new cardiovascular symptoms, troponin elevation, and abnormal ECG, typically within days to weeks of treatment initiation.48 Acute myocarditis and TS share clinical features, including presentation, ischemic ECG changes, troponin release, and absent acute coronary artery obstruction. In rare circumstances, acute myocarditis may result in a TS-like regional LV contraction abnormality, in which case it may be challenging to distinguish the two conditions.49 In this setting, cardiac MRI may be useful because TS is characterized by myocardial edema in a transmural distribution (T2-weighted imaging) without late gadolinium enhancement.50,51

US CARDIOLOGY REVIEW

Table 1: US Medicare Claims Chemotherapy Drugs 2016 Drug

Typical Use

Medicare Claims in 2016 (n)

Methotrexate

Multiple

2,480,000

Anastrozole

Breast cancer

1,370,000

Tamoxifen

Breast cancer

475,000

Hydroxyurea

Multiple

381,000

Fluorouracil

Multiple

380,000

Revlimid® (lenalidomide)

Multiple

239,000

Prostate cancer

101,000

Imbruvica® (ibrutinib)

Multiple

101,000

Zytiga® (abiraterone)

Prostate cancer

96,800

Ibrance® (palbociclib)

Breast cancer

95,400

Gleevecv (imatinib mesylate)

Chronic myeloid leukemia

76,500

Cyclophosphamide

Multiple

9,565

Rituxan®

Xtandi®

(enzalutamide)

Non-Hodgkins lymphoma

4,867

Avastin® (bevacizumab)

(rituximab)

Colorectal cancer

4,594

Velcade® (bortezomib)

Multiple myeloma and mantle cell lymphoma

2,734

Carboplatin

Multiple

2,487

Herceptin® (trastuzumab)

Breast and gastric cancer

2,450

Paclitaxel

Multiple

1,666

Acute Coronary Syndrome Mimicking Takotsubo Syndrome The apical LV ballooning phenotype is not pathognomonic of TS and urgent coronary angiography is necessary to exclude an unstable coronary obstruction that would require revascularization.3,4 In particular, TS-like apical ballooning may be the consequence of acute myocardial ischemia in the setting of proximal stenosis involving the left anterior descending (LAD) coronary artery, which extends beyond the LV apex to supply the inferior wall (‘wrap around’ LAD).52 In uncertain situations, such as late presentation, suspected coronary embolism, or when coronary angiographic findings are equivocal, CMR is useful because late gadolinium enhancement is rarely evident in TS, but frequently present in a vascular distribution in patients with ischemic injury from coronary artery obstruction.3,4,53

Outcomes In the largest study to date, all-cause in-hospital mortality was substantially greater among chemotherapy-treated patients with versus without a TS event (18.3% versus 3.2% respectively; p<0.001).16 Advanced age (>85 years), sepsis, fluid–electrolyte disorders, respiratory failure, and cardiogenic shock were univariate predictors of in-hospital mortality in patients with chemotherapy-associated TS. Metastatic cancer was present in only 17%.16 There is limited information regarding the safety of continuing or reinitiating chemotherapy after a TS event. A study involving a small number of patients (n=30) noted the majority of patients were able to resume chemotherapy cancer treatment after normalization of LV ejection fraction (generally within 3 weeks of the TS event), without TS recurrence.54

Discussion The current body of information regarding chemotherapy-triggered TS reveals a patient profile that differs from that of the larger TS

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Cardiomyopathies experience. In particular, women account for only 60–70% of patients with chemotherapy-associated TS, yet comprise > 90% of all TS cases,3 an anomaly without an obvious explanation. In women, the five most common malignancies are breast, lung, colorectal, uterine, and thyroid, versus prostate, lung, colorectal, bladder, and melanoma in men.55 Although publication bias may explain some of these findings, it is possible that men have a particular TS vulnerability in the setting of malignancy and chemotherapy. In fact, physical TS triggers are more common in men, and men have a higher 1-year TS-related mortality than women.56 The frequency of reports noting 5-fluorouracil as a TS trigger is curious.

This drug is on the WHO’s list of essential medicines for cancer; therefore, fluorouracil likely represents one of the most commonly used chemotherapy agents worldwide.57 Consequently, the frequency of fluorouracil-associated TS may be driven by exposure of a greater number of patients to this agent (Table 1). Alternatively, fluorouracil may

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Sharkey SW, Maron BJ. Epidemiology and clinical profile of Takotsubo cardiomyopathy. Circ J 2014;78:2119–28. https://doi. org/10.1253/circj.CJ-14-0770; PMID: 25099475.

Ghadri JR, Wittstein IS, Prasad A, et al. International expert consensus document on takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology. Eur Heart J 2018;39:2032–46. https://doi.org/10.1093/eurheartj/ehy076; PMID: 29850871.

Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005;111:472–9. https://doi.org/10.1161/01.

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Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. J Am Coll Cardiol 2001;38:11–18. PMID: 11451258.

Kurisu S, Sato H, Kawagoe T, et al. Tako-tsubo-like left ventricular dysfunction with ST-segment elevation: a novel cardiac syndrome mimicking acute myocardial infarction. Am Heart J 2002;143:448–55. PMID: 11868050.

Abe Y, Kondo M, Matsuoka R, et al. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003;41:737–42. PMID: 12628715.

Wittstein IS, Thiemann DR, Lima JA, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med 2005;352:539–48. https://doi.org/10.1056/NEJMoa043046; PMID: 15703419.

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Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373:929–38. https://doi.org/10.1056/NEJMoa1406761; PMID: 26332547.

Kurisu S, Kihara Y. Tako-tsubo cardiomyopathy: clinical presentation and underlying mechanism. J Cardiol 2012;60:429– 37. https://doi.org/10.1016/j.jjcc.2012.06.015; PMID: 23078863.

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Desai R, Abbas SA, Goyal H, et al. Frequency of takotsubo cardiomyopathy in adult patients receiving chemotherapy (from a 5-year nationwide inpatient study). Am J Cardiol 2019;123:667–73. https://doi.org/10.1016/j.amjcard.2018.11.006; PMID: 30538037.

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have pharmacological properties that can trigger a TS event. For example, there is evidence that fluorouracil is an arterial vasoconstrictor,40 and coronary microvascular vasoconstriction is proposed as a mechanism in TS pathophysiology.58

Conclusion Chemotherapy treatment of malignancy is a relatively uncommon TS trigger, with a significantly greater proportion of men than is typically observed with TS. Fluorouracil is the most commonly reported chemotherapeutic agent, although this must be interpreted in the context of the frequency of worldwide use of this agent.

Whether certain chemotherapeutic agents are more likely to trigger TS is unresolved. Based on limited information, chemotherapy can be safely reinitiated, with careful observation, once the patient has recovered from the initial TS event. A TS event in the setting of chemotherapy treatment of malignancy is associated with substantial mortality.

Coll Cardiol 2016;68:1143–4. https://doi.org/10.1016/j. jacc.2016.06.027; PMID: 27585514.

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Goel S, Sharma A, Garg A, et al. Chemotherapy induced Takotsubo cardiomyopathy. World J Clin Cases 2014;2:565. https:// doi.org/10.12998/wjcc.v2.i10.565; PMID: 25325068.

Franco TH, Khan A, Joshi V, et al. Takotsubo cardiomyopathy in two men receiving bevacizumab for metastatic cancer. Ther Clin Risk Manag 2008;4:1367–70. PMID: 19337443.

Damodaran S, Mrozek E, Liebner D, et al. Focal takotsubo cardiomyopathy with high-dose interleukin-2 therapy for malignant melanoma. J Ntl Compr Canc Netw 2014;12:1666–70. https://doi.org/10.6004/jnccn.2014.0168; PMID: 25505207.

Basselin C, Fontanges T, Descotes J, et al. 5-fluorouracil-induced tako-tsubo-like syndrome. Pharmacotherapy 2011;31:226. https:// doi.org/10.1592/phco.31.2.226; PMID: 21275498.

Malley T, Watson E. A case of takotsubo cardiomyopathy after chemotherapy. Oxf Med Case Reports 2016;2016:55-58. https://doi. org/10.1093/omcr/omw014; PMID: 27066260.

Coen M, Rigamonti F, Roth A, et al. Chemotherapy-induced Takotsubo cardiomyopathy: a case report and review of the literature. BMC Cancer 2017;17:394. https://doi.org/10.1186/ s12885-017-3384-4; PMID: 28578653.

Baumann S, Huseynov A, Goranova D, et al. Takotsubo cardiomyopathy after systemic consolidation therapy with high-dose intravenous cytarabine in a patient with acute myeloid leukemia. Oncol Res Treat 2014;37:487–90. https://doi. org/10.1159/000365536; PMID: 25231689.

Coli S, Pigazzani F, Gaibazzi N. Midventricular takotsubo cardiomyopathy after oxaliplatin infusion: an unreported side effect. J Cardiovasc Med 2015;16:646–9. https://doi.org/10.2459/ JCM.0000000000000204; PMID: 25333375.

Lees C, Yazdan‐Ashoori P, Jerzak KJ, et al. Takotsubo cardiomyopathy during anti‐HER2 therapy for metastatic breast cancer. Oncologist 2019;24:e80-e82. https://doi.org/10.1634/ theoncologist.2018-0285; PMID: 30389744.

Giza DE, Lopez-Mattei J, Vejpongsa P, et al. Stressinduced cardiomyopathy in cancer patients. Am J Cardiol 2017;120:2284–8. https://doi.org/10.1016/j.amjcard.2017.09.009; PMID: 29096885.

Kobayashi N, Hata N, Yokoyama S, et al. A case of takotsubo cardiomyopathy during 5-fluorouracil treatment for rectal adenocarcinoma. J Nippon Med Sch 2009;76:27–33. https://doi. org/10.1272/jnms.76.27; PMID: 19305108.

Geisler BP, Raad RA, Esaian D, et al. Apical ballooning and cardiomyopathy in a melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. J Immunother Cancer 2015;3:4. https://doi.org/10.1186/s40425-015-0048-2; PMID: 25705383.

Lim SH, Wilson SM, Hunter A, Hill J, et al. Takotsubo cardiomyopathy and 5-fluorouracil: getting to the heart of the matter. Case Rep Oncol Med 2013;2013:206765. https://doi. org/10.1155/2013/206765; PMID: 24368954.

Van de Donk NW, America YG, Zelissen PM, et al.

Takotsubo cardiomyopathy following radioiodine therapy for toxic multinodular goitre. Neth J Med 2009;67:350–2. PMID: 19915229.

34. N umico G, Sicuro M, Silvestris N, et al. Takotsubo syndrome in a patient treated with sunitinib for renal cancer. J Clin Oncol 2012;30:e218–20. https://doi.org/10.1200/JCO.2012.42.4911; PMID: 22802320.

35. Ovadia D, Esquenazi Y, Bucay M, et al. Association between takotsubo cardiomyopathy and axitinib: case report and review of the literature. J Clin Oncol 2014;33:e1–3. https://doi. org/10.1200/JCO.2013.48.7280; PMID: 24567431.

36. Shams Y, Tornvall P, Törnerud M, et al. Capecitabine caused cardiogenic shock through induction of global Takotsubo syndrome. Cardiovasc Revasc Med 2013;14:57–61. https://doi. org/10.1016/j.carrev.2012.10.001; PMID: 23218901.

37. Gianni M, Dentali F, Lonn E. 5 flourouracil-induced apical ballooning syndrome: a case report. Blood Coagul Fibrinolysis 2009;20:306–8. https://doi.org/10.1097/MBC.0b013e328329e431; PMID: 19300240.

38. White AJ, LaGerche A, Toner GC, et al. Apical ballooning syndrome during treatment with a vascular endothelial growth factor receptor antagonist. Int J Cardiol 2009;131:e92–4. https:// doi.org/10.1016/j.ijcard.2007.07.066; PMID: 17920711.

39. Khanji M, Nolan S, Gwynne S, et al. Tako-Tsubo syndrome after trastuzumab: an unusual complication of chemotherapy for breast cancer. Clin Oncol 2013;25:329. https://doi.org/10.1016/j. clon.2012.12.007; PMID: 23434354.

40. Smith SA, Auseon AJ. Chemotherapy-induced takotsubo cardiomyopathy. Heart Fail Clin 2013;9:233–42. https://doi. org/10.1016/j.hfc.2012.12.009; PMID: 23562124.

41. Stewart T, Pavlakis N, Ward M. Cardiotoxicity with 5‐fluorouracil and capecitabine: more than just vasospastic angina.

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42. Bhakta S, Flick SM, Cooney MM, et al. Myocardial stunning following combined modality combretastatin‐based chemotherapy: two case reports and review of the literature.

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43. Ng KH, Dearden C, Gruber P. Rituximab-induced takotsubo syndrome: more cardiotoxic than it appears? BMJ Case Rep 2015;2015. https://doi.org/10.1136/bcr-2014-208203; PMID: 25733089.

44. Ozturk MA, Ozveren O, Cinar V, et al. Takotsubo syndrome: an underdiagnosed complication of 5-fluorouracil mimicking acute myocardial infarction. Blood Coagul Fibrinolysis 2013;24:90–4. https://doi.org/10.1097/MBC.0b013e3283597605; PMID: 23249567.

45. Kim L, Karas M, Wong SC. Chemotherapy-induced takotsubo cardiomyopathy. J Invasive Cardiol 2008;20:E338–40. PMID: 19057042.

46. Fernandez SF, Basra M, Canty JM. Takotsubo cardiomyopathy following initial chemotherapy presenting with syncope and cardiogenic shock-a case report and literature review.

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48. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71:1755–64. https://doi.org/10.1016/j. jacc.2018.02.037; PMID: 29567210.

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50. Eitel I, Schuler G, Thiele H. Myocarditis mimicking Takotsubo cardiomyopathy or Takotsubo cardiomyopathy with secondary inflammation? Eur J Heart Fail 2009;11:809, author reply 810. https://doi.org/10.1093/eurjhf/hfp089; PMID: 19605454.

51. Ghadri JR, Wittstein IS, Prasad A, et al. International expert consensus document on Takotsubo syndrome (part II): diagnostic workup, outcome, and management. Eur Heart J 2018;39:2047–62. https://doi.org/10.1093/eurheartj/ehy077; PMID: 29850820.

52. Chao T, Lindsay J, Collins S, et al. Can acute occlusion of the left anterior descending coronary artery produce a typical ‘takotsubo’ left ventricular contraction pattern? Am J Cardiol

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53. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011;306:277–86. https:// doi.org/10.1001/jama.2011.992; PMID: 21771988.

54. Giza DE, Lopez-Mattei J, Vejpongsa P, et al. Stressinduced cardiomyopathy in cancer patients. Am J Cardiol 2017;120:2284–8. https://doi.org/10.1016/j.amjcard.2017.09.009; PMID: 29096885.

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gov/data-software/documentation/seerstat/ (accessed 9 July 2019).

56. Murugiah K, Wang Y, Desai NR, et al. Trends in short-and long-term outcomes for takotsubo cardiomyopathy among medicare fee-for-service beneficiaries, 2007 to 2012. JACC Heart Fail 2016;4:197–205. https://doi.org/10.1016/j.jchf.2015.09.013; PMID: 26746377.

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58. Sharkey SW, Maron BJ, Kloner RA. The case for takotsubo cardiomyopathy (syndrome) as a variant of acute myocardial infarction. Circulation 2018;138:855–7. https://doi.org/10.1161/ CIRCULATIONAHA.118.035747; PMID: 30354447.

77

78 1

1

1

2

1

1

Case report

Case report, review

Case report

Case report

Case report

Case report

Voit et al.

201818

Grunwald et al. 201219

Goel et al.

201420

Franco et al.

200821

Damodaran et al. 201422

Basselin et al. 201123

Age

1

1

Case report

Case report

Malley and Watson 201624

Voit et al.

201818

24

73

48

55

76,61

55

60

24

Patients (Years)

Unique

Study Type

Authors

M

F

M

F

M

M

F

M

Sex

Acute myeloid leukemia

Tonsillar stage IV B diffuse large B-cell lymphoma

Colic adenocarcinoma

Malignant melanoma

Colon cancer, metastatic nonsmall-cell lung cancer

Acute myeloid leukemia

Stage III colon cancer

Acute myeloid leukemia

Malignancy

Table 2: Takotsubo Syndrome and Chemotherapy

Daunorubicin and cytarabine

Lomustine, cytarabine, cyclophosphomide, etoposide (LACE)

5-fluorouracil, oxaliplatin, calcium folinate (FOLFOX protocol)

High-dose IL-2

Bevacizumab

Cytarabine and daunorubicin

Fluorouracil, leucovorin, oxaliplatin

Daunorubicin and cytarabine

Chemotherapy

No

No

Yes

No

Yes

Yes

Yes

No

25

45

15

45

30

10

25

ST-elevation EF

Chemotherapy

Underwent 7 days of chemotherapy prior to TS event

Underwent first round of chemotherapy, ~24 h later, developed chest pain and EKG abnormalities; recurrence after third round of chemotherapy

Admitted for course two, cycle 1 of highdose IL-2, T-wave inversions were seen on EKG after initiation

Patient 1: 2 days PTA started receiving chemotherapy Patient 2: at 3 weeks prior to admission, patient had received second chemotherapy dose

Day 6 of chemotherapy

Chemotherapy, was 26 h into planned 46 h infusion when developed chest pain

Chemotherapy

Circumstances

Triggering

Echocardiography 3 weeks later revealed improvement of EF to 63%

No adverse events in follow-up

4 months later, discovery of liver metastasis led to new chemotherapy regimen including irinotecan and bevacizumab under close monitoring No recurrence of cardiac manifestations was subsequently noted

Complete resolution of LV function

At approximately 1 month, echocardiography showed significant recovery of LV function

20 days after event, patient had EF of 50% with mild anterolateral and anterobasal hypokinesia

At 16-month follow-up had not experienced any additional cardiac events.

However, colon cancer recurred 5 months after the episode of TS

Echocardiography 3 weeks later revealed improvement of EF to 63%

Outcome

Given the complete recovery of LVEF within 12 weeks of presentation, concluded consistent with TS (Continued)

First case of TS in a patient receiving LACE chemotherapy

Interesting case because patient had recurrent TS after third round of chemotherapy, which was the next dose of FOLFOX protocol

First reported instance of TS with high-dose IL-2

Bevacizumab is a novel chemotherapeutic agent that inhibits VEGF

Anthracycline agents may have especially cardiotoxic effects

Contributes to growing literature on TS that occurs with fluorouracil, which is frequently administered for colorectal cancers

Given the complete recovery of LVEF within 12 weeks of presentation, concluded consistent with TS

Authorsâ&#x20AC;&#x2122; Conclusions

Cardiomyopathies

US CARDIOLOGY REVIEW

Takotsubo Syndrome and Chemotherapy

Study Type

Table 2: Cont.

Authors Case report, review

Case report

Research letter/case report

Case report

Coen et al.

201725

Baumann et al. 201426

Coli et al.

201527

Lees et al.

201828

Unique

Age

63

67

58

45

Patients (Years) 1

1

1

1

ST-elevation EF

20

20

Triggering Developed TS after receiving intra-arterial and intravenous polychemotherapy

circumstances

Authorsâ&#x20AC;&#x2122; Conclusions

Chemotherapy

Outcome

Malignancy

EF normalized. Was not rechallenged with intraarterial chemotherapy

TS is a rare and unpredictable event among oncologic patients.

Patients under significant stress (physical or psychological) and those with cardiovascular risk factors complaining of cardiac symptoms should be carefully examined for signs of TS

Sex

During 18 months of followup, no hospitalization or clinical signs of heart failure occurred

TS can occur in patients with acute myeloid leukemia under systemic chemotherapy, which possibly represents a triggering factor for TS development

30

No

After receiving intravenous cytarabine, developed severe dyspnea at rest, with cardiogenic shock after central venous catheter was removed

Yes

Yes

Represents the first description of TS induced by oxaliplatin during combined capecitabine and oxaliplatin regimen

F

Cytarabine

Oxaliplatin

1 month later, MRI showed complete recovery of regional and global LV function. Patient restarted capecitabine monotherapy only, and did not experience any other adverse events

5-fluorouracil and mitomycin C

Acute myeloid leukemia

Local advanced colon cancer

At end of third session of oxaliplatin infusion, patient reported chest pain, dyspnea, jugular constriction

Patient ultimately pursued comfort care and died in palliative care unit ~1 month later

Locally advanced epidermoid carcinoma of the anal canal

M

F

F

Metastatic HER2positive breast cancer

After completing third cycle of pertuzumab + trastuzumab, presented to ED with progressive dyspnea

Dual anti-HER2 Yes therapy (pertuzumab + trastuzumab in addition to nabpaclitaxel chemotherapy)

First reported case of TS associated with pertuzumab + trastuzumab combination therapy. Given these agents are relatively novel, clinicians might consider TS as differential diagnosis upon severe cardiac presentation in these patients

(Continued)

79

US CARDIOLOGY REVIEW

80 1

1

1

1

Case report

Case report

Case report

Case report

Geisler et al.

201531

Lim et al.

201332

van de Donk et al. 200933

Numico et al.

201234

Case report

1

Case report

Kobayashi et al. 200930

Ovadia et al.

201435

5

Research article

Age

1

71

57

73

66

83

62

41–77

Patients (Years)

Giza et al.

201729

Unique

Study Type

Authors

Table 2: Cont.

F

F

M

F

F

F

N/A

Sex

Renal cell carcinoma

Clear-cell renal cancer

Toxic multinodular goiter

Rectal adenocarcinoma

Metastatic melanoma

Rectal adenocarcinoma

64% either advanced malignancy or recurrent disease

Malignancy

Axitinib

Sunitinib

Radioiodine therapy (iodine-131)

5-fluorouracil

Ipilimumab

5-fluorouracil

3 patients after treatment with paclitaxel, 1 patient after bevacizumab and capecitabine, and 1 patient after 5-fluorouracil

Chemotherapy

Yes

Yes

Yes

No

Yes

Yes

No

20

15

25

30

50

28

≤50%

ST-elevation EF

Within 24 h of administration of axitinib, patient developed chest pain and shortness of breath

During treatment with sunitinib at a dose of 12.5 mg/day for 4 weeks every 6 weeks

At 4 weeks after radiodine therapy, presented with rapidly progressive dyspnea and significant increase in free thyroxin

Presented to ED after third week of chemotherapy, had been feeling unwell since the third day after this dose

Had received four standard doses of ipilimumab in the 3 weeks prior to admission

4 weeks after start of chemotherapy, intermittent shortness of breath and slight chest pain developed, progressively worsened

Occurred during chemotherapy session

Circumstances

Triggering

EF 50% at 3 weeks after initial presentation

No sign of cardiomyopathy at 3-month evaluation

Echocardiography after just 4 days showed significant LVEF improvement to 57%

Died 2 years later from complications of cancer

N/A

N/A

No in-hospital immediate mortality or cardiac-related mortality occurred

Outcome

US CARDIOLOGY REVIEW

(Continued)

The presumed association between the initiation of axitinib therapy and TS deserves further prospective clinical observation

To their knowledge, only one other reported case exists of TS with sunitinib

First report of TS provoked by thyrotoxicosis resulting from radiation thyroiditis induced by radioiodine.

Suggest determination of thyroid function in all patients with TS

TS has been increasingly noted to occur in association with 5-fluorouracil.

Oncologists and cardiologists need to recognize TS as a potential toxicity of this drug

First reported case of TS in patient treated with ipilimumab. Post-marketing surveillance should capture cases of ipilimumab cardiac toxicity and physicians should be aware of this potential adverse event

The cause of heart failure in this patient (i.e., TS induced by multivessel coronary vasospasm including microcirculation disorders only during 5-fluorouracil administration) is notable

Compared with the general population, TS is more common in cancer patients

Authors’ Conclusions

Cardiomyopathies

Takotsubo Syndrome and Chemotherapy

Study Type

Table 2: Cont.

Authors Case report

Case report, review

Case report

Case report

Case report/ letter

Case report

Case report

Shams et al.

201336

Gianni et al.

200937

White et al.

200938

Khanji et al.

201339

Smith and Auseon 201340

Stewart et al.

201041

Bhakta et al.

200942

Unique

Age

71, 78

81

60

50

61

79

55

Patients (Years) 1

1

1

1

1

1

2

Triggering

Acute onset of chest pain after 5-fluorouracil therapy

During infusion of rituximab, ST-elevation seen on EKG (she was asymptomatic)

Circumstances

Authors’ Conclusions

ST-elevation EF

Outcome

Chemotherapy

1 week after admission, EF >55%

A case of capecitabineinduced global TS presenting with cardiogenic shock and STEMI

Malignancy 15

Chest pain started ~ 28 h after beginning oral capecitabine therapy

First report of TS secondary to chemotherapy with fluorouracil for colon cancer

Sex

34

4 weeks later EF improved to 70% with no akinesis

Successful treatment with a beta-blocker in a case of TS complicated by severe LV outflow tract obstruction

Yes

Yes

Last chemotherapy had been administered 2 weeks prior to presentation

Repeat echocardiography 3 weeks later showed normal LV function

Capecitabine

Yes

Had been taking pazopanib for 8 weeks, at a dose of 800 mg daily

N/A

Association of trastuzumab with TS has not been previously reported, and whether patients should be rechallenged with the drug is unclear

Adenocarcinoma of cecum

Colorectal cancer 5-fluorouracil with metastatic involvement of liver

No

During 11th infusion of trastuzumab, developed crushing chest pain and T-wave inversion

Rituximab was discontinued, LVEF 1 month later was 42%

40, 50

35

20

Although exact mechanisms behind cardiotoxic effects of chemotherapeutic agents remain unclear, there is an association with a small cohort of medications

No

No

Yes

1 week later, LVEF normalized to 60%

Although vasospasm is a well‐recognized side‐effect of this class of chemotherapeutic agent, broader cardiotoxicity is commonly seen and an increased awareness of the range of toxicity is necessary if repeat toxicity is to be avoided

M

F

Renal cell carcinoma with pulmonary metastases

Combretastatin

5-fluorouracil

Rituximab

Trastuzumab

Pazopanib

M

Breast cancer

Stage III colorectal cancer

Gray-zone lymphoma

F

F

F

F

Anaplastic thyroid carcinoma in both patients

Patient 1: follow-up echocardiography 1 month later showed EF = 55% Patient 2: follow-up echocardiography 1 month later showed EF = 60%

These patients are unique for several reasons because they did not have emotional stressors and remained asymptomatic. Patients who develop cardiac events following combretastatin should be followed closely

Patient 1: 18 h after day 6 of combretastatin Patient 2: after combretastatin therapy, complained of nausea followed by left breast pressure

(Continued)

81

US CARDIOLOGY REVIEW

82 1

1

2

1

Case report

Case report

Case report

Case report, review

Ozturk et al.

201344

Kim et al.

200845

Fernandez et al. 201146

Age

F

M, F

M

M

Sex Rituximab

Chemotherapy

Patient 1: laryngeal squamous cell carcinoma Patient 2: colon cancer

No

Yes

15

40

ST-elevation EF

Rituximab, cyclophosphamide, liposomal doxorubicin, vincristine

Yes

20

Patient 1: cetuximab Patient 1: yes 20, 35 Patient 2: oxaliplatin and Patient 2: no capecitabine

Metastatic gastric 5-fluorouracil cancer

Chronic lymphocytic leukemia

Malignancy

Underwent first cycle of chemotherapy in an outpatient setting, 5 days later had chest pain, dizziness, diaphoresis

Patient 1: 3 days after single dose of cetuximab, while having MRI of brain, became acutely hypoxic, then developed pulseless electrical activity arrest. Patient 2: immediately following first chemotherapy session with new regimen experienced acute onset of severe dyspnea

At the 34th hour of the planned 46-h infusion, patient developed tachycardia followed by dyspnea

Within 40 min of infusion, developed acute shortness of breath, spikes in temperature

Circumstances

Triggering

8 months later, echocardiography was completely normal

Patient 1: repeat echocardiography 2 weeks later showed EF = 45% Patient 2: follow-up echocardiography 2 weeks later showed EF = 59%

Repeat echocardiography 27 days later with EF = 50%.

Died of complications from cancer 13.5 months later

No recurrence of cardiac symptoms

Outcome

TS may represent as a form of cardiac dysfunction within the spectrum of chemotherapy-induced cardiac toxicity. Emphasize that rechallenging should only be considered if no other viable option

The exact mechanism remains unclear and the possible link between chemotherapy and TS needs to be further examined

TS appears to occur more frequently than was previously thought, especially in relation to chemotherapy. Need to increase awareness

First case at the time of rituximab with TS, exceptional case because most TS and chemotherapylinked reactions have occurred during initial infusions, but this patient had already completed treatments with rituximab

Authorsâ&#x20AC;&#x2122; Conclusions

ED = emergency department; EF = ejection fraction; EKG = electrocardiography; HER2 = human epidermal growth factor receptor 2; IL = interleukin; N/A = not available; TS = takotsubo syndrome; VEGF = vascular endothelial growth factor.

85

67, 75

48

66

Patients (Years)

Ng et al.

201543

Unique

Study Type

Authors

Table 2: Cont.

Cardiomyopathies

US CARDIOLOGY REVIEW

Peripheral Interventions

Baroreflex Activation Therapy for Resistant Hypertension and Heart Failure Anna Meta Dyrvig Kristensen, MB, 1 Manan Pareek, MD, PhD, 1,2 Michael Hecht Olsen, MD, PhD, DMSc, 3 and Deepak L Bhatt, MD, MPH 2 1. Department of Cardiology, North Zealand Hospital, Hilleroed, Denmark; 2. Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA; 3. Cardiology Section, Department of Internal Medicine, Holbaek Hospital, Holbaek, Denmark

Abstract Hypertension and heart failure are important contributors to global morbidity and mortality. Despite therapeutic lifestyle and pharmacological measures, a significant proportion of people with hypertension do not reach treatment targets. Patients with resistant or poorly controlled hypertension are at significantly increased risk of cardiovascular events, including heart failure. Since dysfunction of the sympathetic nervous system appears to play a key role in the development and progression of both hypertension and heart failure, these patients may benefit from treatment modalities aimed at reducing sympathetic function. The purpose of this paper is to provide an overview of baroreflex activation therapy as a potential treatment strategy in patients with resistant hypertension or heart failure.

Keywords Baroreflex, blood pressure, cardiovascular diseases, heart failure, hypertension Disclosure: MP is on the advisory board for AstraZeneca; and has received speaker’s fees from AstraZeneca, Bayer, and Boehringer Ingelheim. MHO has received a parttime clinical research grant from the Novo Nordisk Foundation. DLB is on the advisory board for Cardax, Cereno Scientific, PhaseBio, Regado Biosciences; the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (PORTICO trial, funded by St Jude Medical), Cleveland Clinic (including the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology, Baim Institute for Clinical Research (RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Duke Clinical Research Institute (clinical trial steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications, Society of Cardiovascular Patient Care, WebMD (CME steering committees); Other: Clinical Cardiology, NCDR-ACTION Registry Steering Committee, VA CART Research and Publications Committee; Research funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Site Co-Investigator: Biotronik, Boston Scientific, St Jude Medical, Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. The other authors have no conflicts of interest to declare.

Received: 9 April 2019 Accepted: 18 June 2019 Citation: US Cardiology Review 2019;13(2):83–7. DOI: https://doi.org/10.15420/usc.2019.13.2 Correspondence: Deepak L Bhatt, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, 75 Francis St, Boston, MA 02115, US. E: dlbhattmd@post.harvard.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.

Hypertension is an important contributor to global morbidity and mortality and is a major burden on healthcare systems.1,2 More than 20% of the world’s population has high blood pressure when defined by conventional criteria: systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg.3,4 Even with therapeutic lifestyle and pharmacological measures, blood pressure remains poorly controlled in a significant proportion of these people.5–10 The European Society of Cardiology/European Society of Hypertension (ESC/ESH) define treatment-resistant hypertension when office blood pressure cannot be reduced to <140/90 mmHg despite optimal doses of appropriate medications (usually three).11 The American College of Cardiology/American Heart Association (ACC/AHA) define resistant hypertension as an office blood pressure ≥130/80 mmHg in patients on ≥3 antihypertensive medications at optimal doses or <130/80 mmHg in

© RADCLIFFE CARDIOLOGY 2019

patients on ≥4 agents.12,13 Formal diagnosis requires confirmation using out-of-hospital measurements and exclusion of both pseudo-resistant hypertension and secondary hypertension.11–13 Hypertension is significantly associated with subclinical and clinical cardiovascular disease, including left ventricular remodeling and overt heart failure.14–16 This risk is considerably greater among patients with resistant or poorly controlled hypertension, particularly if the condition is persistent.5,6,8,17–20 By extension, many patients with heart failure remain symptomatic and limited in their daily activities despite guideline-recommended drug and device therapy.21,22 Since dysfunction of the sympathetic nervous system appears to play a key role in the development and progression of hypertension and heart failure, treatment modalities aimed at reducing sympathetic function may

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Peripheral Interventions Figure 1: The Baroflex Activation Therapy System

sham control, particularly found in trials of second-generation renal denervation systems.27,28 By extension, the purpose of this paper is to provide an overview of baroreflex activation therapy (BAT) as a potential treatment strategy in patients with resistant hypertension or heart failure, respectively.

Role of the Sympathetic Nervous System in Hypertension and Heart Failure

The baroreflex activation therapy system consists of an implantable pulse generator, a lead, and an electrode similar to a pacemaker system. An external computer-based system is used for programming. Source: Hoppe et al. 2012.35 Reproduced with permission from Wolters Kluwer Health.

Imbalances in the autonomic nervous system may also result in impaired left ventricular function and clinical heart failure. 25,31,32 The compensatory mechanisms that are recruited lead to more inappropriate and excessive activity of the sympathetic nervous system and consequently, adverse cardiac remodeling, heart rate elevation, and salt and water retention.24,25 Indeed, Cohn et al. found lower survival in patients with heart failure who had higher circulating norepinephrine concentrations.33 Baroreflex sensitivity is also independently associated with prognosis in this setting.34

Figure 2: Baroflex Activation Therapy Pathway

Sensory nerves BS

Carotid baroreceptor stimulation

The pathogenesis of essential hypertension is complex and multifactorial, but the sympathetic nervous system may be particularly and persistently overactive in patients with resistant hypertension, exerting direct effects on not only the heart and vasculature, but also the renin– angiotensin–aldosterone system, glomerular filtration and renal tubular sodium reabsorption.25,29,30 Baroreflex impairment appears to be a crucial component in the dysfunction of the sympathetic nervous system, probably through an abnormally reduced ability to exert sympathoinhibition.29,30

The Concept of Baroreflex Activation Therapy Carotid sinus Vagus nerve

SA node

Vagus nerve stimulation

Sympathetic cardiac nerve

AV node

Sympathetic nerve

Carotid BAT consists of leads placed adjacent to the carotid sinus, an implantable pulse generator, and an external programming system (Figure 1).35 Electronic stimulation of the baroreceptors elicit the baroreflex, resulting in reduced sympathetic and increased vagal tone (Figure 2).36,37 Blood pressure reduction and improvements in cardiac structure and function ensue.38 The first experiments in humans were performed more than 60 years ago when Carlsten et al. observed that direct stimulation of the carotid sinus nerve resulted in an acute decline in blood pressure in patients undergoing surgery for neck cancer.39 In 1967, Braunwald et al. extended the possible uses of BAT as they found instantaneous relief of otherwise incapacitating angina pectoris using carotid stimulation.40 Although BAT received little or no attention for decades thereafter, primarily due to successful drug development, an increasing need for alternative treatment approaches for resistant hypertension and heart failure has prompted renewed research in this area.35,41–43

Baroreflex Activation Therapy in Resistant Hypertension The pathway activated by baroreflex activation therapy through electrical stimulation of the carotid baroreceptors. The reflex arc originates in the baroreceptors in the carotid sinus (and aortic arch), stimulated by arterial distension as a result of increased pressure and flow. Afferent nerve fibers then modulate brainstem activity, ultimately resulting in inhibition of efferent sympathetic output and activation of parasympathetic (vagal) output to the effector organs.

AV = atrioventricular; BS = brainstem; SA = sinoatrial. Source: Gronda et al. 2017.38 Reproduced with permission from Elsevier.

be beneficial.23–25 Padmanabhan et al. recently published a review of one such intervention, renal denervation.26 Renal denervation may be associated with significant blood pressure reductions compared with

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Feasibility studies of the first-generation Rheos® Baroreflex Hypertension Therapy System (CVRx) (Figure 3), such as the non-randomized Device Based Therapy in Hypertension Trial (DEBuT-HT), showed substantial and sustained reductions in both systolic and diastolic blood pressures.36,41,44,45 In the subsequent Rheos Pivotal Trial, patients with office systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥80 mmHg taken after ≥1 month of maximally tolerated therapy with ≥3 antihypertensive drugs underwent device implantation and underwent blinded randomization 2:1 to immediate (1 month after implantation; n=181) or deferred (7 months

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Baroreflex Activation Therapy after implantation; n=84) activation.46 Although lead implantation was bilateral, 75% of patients only required unilateral activation. All participants were followed for an additional 6 months. The investigators tested five co-primary endpoints of which sustained efficacy, BAT safety and device safety were met. However, acute efficacy (≥10 mmHg systolic blood pressure reduction at 6 months with immediate versus deferred activation, 54% versus 46%; p=0.97) and procedural safety endpoints were not met. Blood pressure reductions were maintained beyond the duration of the trial.47,48 Due to these shortcomings, the second-generation, minimally invasive Barostim neo system (CVRx) was developed and examined in an openlabel trial (Figure 3).35,36 The device was implanted in 30 patients with systolic blood pressure ≥140 mmHg despite taking ≥3 antihypertensive drugs and deemed compliant with their regimen. Only unilateral carotid sinus exposure was required. The primary efficacy endpoint was reduction in office systolic blood pressure compared with baseline.

System- and procedure-related complications comprised the primary safety endpoint. At 6 months, average systolic and diastolic blood pressures had decreased by 26 mmHg and 12 mmHg, respectively (p<0.001 for both). Three complications occurred within 30 days after surgery, and beyond this perioperative period, one system-related complication was reported. Interestingly, six of 30 participants in the Barostim neo trial had undergone unsuccessful renal denervation but achieved blood pressure reductions with BAT that were comparable to those who had not undergone renal denervation.

Several observational studies have since examined the Barostim neo device and have consistently shown it to achieve reductions in blood pressure. For example, Halbach et al. included 17 patients in an open-label, single-arm study and found mean systolic and diastolic blood pressure reductions of 32 mmHg and 14 mmHg during on/off testing with unilateral BAT.49 Wallbach et al. demonstrated significant 6-month reductions in 24-hour ambulatory blood pressure (mean systolic blood and diastolic pressure reductions, 8 mmHg and 5 mmHg; p<0.01 for both) in 44 patients with resistant hypertension.50 The specific matter regarding patients with prior renal denervation was assessed by the same group of investigators who reported significant reductions in blood pressure (mean office systolic blood pressure reduction, 19 mmHg; p<0.01) and albuminuria (median reduction, 29%; p=0.02) in 28 people treated with BAT.51 The number of antihypertensive drugs remained unchanged over the course of the study.

A recent systematic review and meta-analysis of the efficacy and safety of BAT for resistant hypertension found that although device therapy significantly lowered blood pressure, the evidence was limited by a high risk of bias, small sample size, and the fact that only one randomized controlled trial (the Rheos Pivotal Trial) was included in the analysis.52 Indeed, regression towards the mean and placebo effect may, at least in part, have been responsible for the results obtained from observational studies.

Baroreflex Activation Therapy in Heart Failure Gronda et al. implanted the Barostim neo system in 11 patients who had New York Heart Association (NYHA) class III heart failure, a left ventricular ejection fraction (LVEF) ≤40%, and no indication for cardiac resynchronization therapy.53 The patients’ 6-minute walking distance

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Figure 3: The Rheos and Barostim Neo Devices

The Rheos device (left) and the Barostim neo device (right). Source: Gassler and Bisognano, 2014.36 Reproduced with permission from Springer Nature.

increased significantly at 6 months, with an average of approximately 50 m (p=0.05). Favorable effects were also seen for LVEF, NYHA class, and quality of life (p<0.05 for all) and were maintained beyond the initial 6-month study period.54,55 However, no significant changes were observed for systolic or diastolic blood pressure.

The larger, controlled, open-label Barostim Hope for Heart Failure (HOPE4HF) study randomized patients with NYHA class III heart failure and LVEF ≤35% to receive either BAT (Barostim neo) plus guidelinedirected medical therapy (n=76) or medical therapy alone (n=70) for 6 months.42 The primary safety endpoint, system- and procedure-related major adverse neurological and cardiovascular events, occurred in 2.8% of patients in the BAT group. Changes in NYHA class, quality of life, and 6-minute walk distance comprised the co-primary efficacy endpoints, all of which were significantly improved with BAT (p<0.05) and results were maintained at 12 months.56 The effects of BAT were more prominent in patients without a cardiac resynchronization therapy device, but did not differ between those with or without coronary artery disease.57,58 BAT has also been found to be cost-effective compared with optimal medical treatment in patients with NYHA class III heart failure who are not eligible for cardiac resynchronization therapy.59

Safety Concerns BAT implantation is generally well tolerated.35,41,42 It is associated with complications similar to those observed with cardiac pacemaker implantations, including device pocket hematoma, pneumothorax, and pain. Complication rates also appear to mimic those seen with permanent pacemaker implantation. In a cohort of 42 patients, Wallbach et al. reported that almost all experienced mild adverse events in the first 6 months after implantation and activation of the Barostim neo apparatus, but most could be resolved by optimization of device parameters, that is, amplitude, impulse width, and stimulation frequency.60 One patient experienced a stroke with recovery and another a contralateral carotid artery stenosis during the perioperative period. One died during the observational period of 12 months. In a separate study, Heusser et al. noted that stimulation intensities had to be lowered in 12 of 18 patients,

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Peripheral Interventions resulting in lower efficacy.61 As with any other invasive therapy, safety is expected to improve over time. Finally, the pulse generator battery needs to be replaced approximately every 3 years.

Finally, the Economic Evaluation of Baroreceptor STIMulation for the Treatment of Resistant HyperTensioN (ESTIM-rHTN; NCT02364310) is examining the cost-effectiveness of using Barostim neo compared with standard care in patients with resistant hypertension.

Guidelines Due to the paucity of evidence, contemporary ESC/ESH guidelines do not routinely recommend BAT for the treatment of hypertension (class of recommendation III, level of evidence B).11 The ACC/AHA guidelines also consider device therapy investigational and as such, provide no recommendation.12,13

Ongoing Studies The double-blind, randomized trial, the Effect of Baroreflex Activation Therapy on Blood Pressure and Sympathetic Function in Patients with Resistant Hypertension (The Nordic BAT Study), aims to recruit about 100 participants and examine whether use of the Barostim neo device reduces 24-hour systolic ambulatory blood pressure compared with pharmacotherapy alone (NCT02572024).62 Additionally, the open-label Baroreflex Activation Therapy for Heart Failure (BeAT-HF) trial (NCT02627196) will randomize patients with NYHA class II or III heart failure and LVEF ≤35% to either BAT with Barostim neo or guideline-directed medical therapy alone and assess the primary endpoint of cardiovascular mortality or heart failure morbidity. A total of 938 participants have been recruited and will be followed until 2021.

1.

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Investigations of a closely related, even less invasive, concept are also ongoing.63 The endovascular baroreceptor amplification device (carotid bulb expansion device), MobiusHD™ (Vascular Dynamics) was evaluated in the Controlling and Lowering Blood Pressure With the MOBIUSHD (CALM-FIM_EUR) study, including 30 patients with office systolic blood pressure ≥160 mmHg despite ≥3 antihypertensive drugs.64 Mean office blood pressure was reduced by 24/12 mmHg at 6 months (p<0.001 for both systolic and diastolic blood pressure), with a total of five safety events. The US arm of the study, Controlling and Lowering Blood Pressure with the MOBIUSHD™ (CALM-FIM_US) (NCT01831895), is currently ongoing. The related Controlling and Lowering Blood Pressure with the MobiusHD™ (CALM-2) study (NCT03179800) aims to examine the safety and efficacy of the MobiusHD device in a prospective, randomized, double-blind, sham-controlled fashion.

Conclusion BAT is a potential treatment modality for patients with resistant hypertension and heart failure. However, long-term follow-up from larger randomized, sham-controlled, blinded studies is needed to properly assess its efficacy and safety.

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Chunbin W, Fu S, Jing H. Efficacy and safety of baroreflex activation therapy for treatment of resistant hypertension: a systematic review and meta-analysis. Clin Exp Hypertens 2018;40:501–8. https://doi.org/10.1080/10641963.2016.

1273943; PMID: 29624472.

Gronda E, Seravalle G, Brambilla G, et al. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proofof-concept study. Eur J Heart Fail 2014;16:977–83. https://doi. org/10.1002/ejhf.138; PMID: 25067799.

Gronda E, Seravalle G, Trevano FQ, et al. Long-term chronic baroreflex activation: persistent efficacy in patients with heart failure and reduced ejection fraction. J Hypertens 2015;33:1704–

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8. https://doi.org/10.1097/HJH.0000000000000603; PMID: 26132760.

Dell’Oro R, Gronda E, Seravalle G, et al. Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report. J Hypertens 2017;35:2532–6. https://doi.org/10.1097/HJH.0000000000001498; PMID: 28816745.

Weaver FA, Abraham WT, Little WC, et al. Surgical experience and long-term results of baroreflex activation therapy for heart failure with reduced ejection fraction. Semin Thorac Cardiovasc Surg 2016;28:320–8. https://doi.org/10.1053/j.semtcvs.2016.04.017; PMID: 28043438.

Zile MR, Abraham WT, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. Eur J Heart Fail 2015;17:1066–74. https://doi.org/10.1002/ejhf.299; PMID: 26011593.

Halbach M, Abraham WT, Butter C, et al. Baroreflex activation therapy for the treatment of heart failure with reduced ejection fraction in patients with and without coronary artery disease. Int J Cardiol 2018;266:187–92. https://doi.org/10.1016/ j.ijcard.2018.04.075; PMID: 29705650.

Borisenko O, Muller-Ehmsen J, Lindenfeld J, et al. An early analysis of cost-utility of baroreflex activation therapy in advanced chronic heart failure in Germany. BMC Cardiovasc Disord 2018;18:163-018-0898-x. https://doi.org/10.1186/s12872-0180898-x; PMID: 30092774.

Wallbach M, Bohning E, Lehnig LY, et al. Safety profile of baroreflex activation therapy (NEO) in patients with resistant hypertension. J Hypertens 2018;36:1762–9. https://doi. org/10.1097/HJH.0000000000001753; PMID: 29677053.

Heusser K, Tank J, Brinkmann J, et al. Acute response to unilateral unipolar electrical carotid sinus stimulation in patients with resistant arterial hypertension. Hypertension 2016;67:585–91. https://doi.org/10.1161/HYPERTENSIONAHA.115.06486; PMID: 26831195.

Gordin D, Fadl Elmula FEM, Andersson B, et al. The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study. Blood Press 2017;26:294–302. https://doi.org/10.1080/08037051.2017.13324 77; PMID: 28595464. van Kleef MEAM, Bates MC, Spiering W. Endovascular baroreflex amplification for resistant hypertension. Curr Hypertens Rep 2018;20:46. https://doi.org/10.1007/s11906-018-0840-8; PMID: 29744599.

Spiering W, Williams B, Van der Heyden J, et al. Endovascular baroreflex amplification for resistant hypertension: a safety and proof-of-principle clinical study. Lancet 2017;390:2655– 61. https://doi.org/10.1016/S0140-6736(17)32337-1; PMID: 28870716.

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Structural Heart

Between a Rock and a Hard Place: How to Use Antithrombotics in Patients Undergoing Transcatheter Aortic Valve Replacement Kelsey Grossman, MD, 1 Mathew R Williams, MD, 2 and Homam Ibrahim, MD 2 1. Department of Medicine, NYU Langone Health, New York, NY; 2. Departments of Surgery and Medicine, NYU Langone Health, New York, NY

Abstract Transcatheter aortic valve replacement (TAVR) has become the preferred method for management of severe aortic stenosis in patients who are at high and intermediate surgical risk, and has recently gained approval from the Food and Drug Administration in the US for use in patients at low risk for surgery. Thrombocytopenia and thromboembolic events in patients undergoing TAVR is associated with increased morbidity and mortality, and yet there is insufficient evidence supporting the current guideline-mediated therapy for antithrombotics post-TAVR. In this article, the authors review current guidelines for antithrombotic therapy in patients undergoing TAVR, studies evaluating antiplatelet regimens, and studies evaluating the use of platelet function testing after TAVR. They also offer a potential link between thrombocytopenia and antiplatelet treatments in patients undergoing TAVR.

Keywords Transcatheter aortic valve replacement, thrombocytopenia, thrombology, antiplatelets, antithrombotics Disclosure: The authors have no conflicts of interest to declare.

Received: 8 September 2019 Accepted: 21 November 2019 Citation: US Cardiology Review 2019;13(2):88–93. DOI: https://doi.org/10.15420/usc.2019.01 Correspondence: Kelsey Grossman, NYU Langone Health, 530 1st Ave, Skirball Suite 9V, New York, NY 10016. E: Kelsey.Grossman@nyulangone.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.

Transcatheter aortic valve replacement (TAVR) has become the preferred method for management of severe aortic stenosis in patients who are at high and intermediate surgical risk. Short-term data have been presented from two studies comparing TAVR versus surgical aortic valve replacement (SAVR) in low surgical risk patients. The Placement of Aortic Transcatheter Valves 3 (PARTNER 3) trial compared TAVR using a balloon expandable valve with standard SAVR. The primary endpoint was a composite of all-cause mortality, stroke, or re-hospitalization at 1 year post-procedure. There was a near 50% reduction in the primary endpoint in the TAVR group.1 The Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients (EVOLUT) trial showed similar results using a self-expanding platform. The primary endpoint of all-cause mortality or disabling stroke at 2 years was similar in the TAVR and SAVR groups, meeting criteria for non-inferiority.2 These landmark trials indicate that TAVR will soon become standard of care for a much larger patient population in the US, adding to the need for more data about peri-TAVR care, including pharmacological management to reduce the risk of thrombotic and bleeding complications associated with the procedure. Specifically, there is a gap in the evidence supporting the current guideline-mediated therapy for antithrombotics post-TAVR. Thrombocytopenia in patients undergoing TAVR is associated with increased mortality and morbidity. The poorly understood phenomenon forms a fertile ground for future research.

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Access at: www.USCjournal.com

In this article, we review current guidelines for antithrombotic therapy in patients undergoing TAVR, studies evaluating antiplatelet regimens, and studies evaluating the use of platelet function testing following TAVR. We also offer a potential link between thrombocytopenia and antiplatelet treatments in patients undergoing TAVR.

TAVR-associated Thrombocytopenia and Thrombotic Events About 40–70% of patients undergoing TAVR develop thrombocytopenia, and the proportion can be as high as 87%.3,4 Additionally, post-TAVR patients experience an average decrease in platelet count by about 40% from baseline.5 Severe thrombocytopenia, defined as a platelet count ≤50 × 109/l, is an independent risk factor for long-term mortality postTAVR, as it is associated with higher rates of both strokes and major bleeding events.6 Dvir et al. found 1-year mortality rates in patients with severe thrombocytopenia post-TAVR ranged from 20–67%, a vast increase from baseline rates in patients with no or mild thrombocytopenia.5 Platelet count reaches a nadir 2–3 days after TAVR and spontaneously recovers by days 5 and 6 after the procedure. While the exact mechanism of thrombocytopenia is not known, the spontaneous recovery suggests a consumptive mechanism by means of potential platelet activation and aggregation at the level of the valve prosthesis.3,7 Another potential mechanism is heparin-induced thrombocytopenia

© RADCLIFFE CARDIOLOGY 2019

Antithrombotics in TAVR (HIT). However, Jilaihawi et al. found no evidence that either HIT or bioprosthetic function contributed to early major or persistent thrombocytopenia. Additionally, there was no association between TAVR approach and the magnitude of post-TAVR thrombocytopenia.3 New data suggest that P2Y12 inhibition prior to the procedure may blunt the severity of TAVR-associated thrombocytopenia.8

DAPT correlates with the incidence of HALT. Given the correlation between HPR and increased risk of post-percutaneous coronary intervention (PCI) ischemic events, some researchers have sought to clarify the role of HPR specifically in patients undergoing TAVR.19 Other studies have explored the relationship between platelet reactivity, antiplatelet drugs, and the incidence of HALT, with variable results.

In‐hospital and early thromboembolic event rates after TAVR range between 2–4%.9 More than 70% of these events occur within 2 days of the procedure.10 Data from studies investigating cerebral protection devices have demonstrated that acute thrombi, rather than calcified or valvular debris, were the most frequently captured material by these devices (~99%).11 It is conceivable that platelets are being consumed in forming these acute thrombi. In addition to strokes, new imaging techniques have also led to improved visualization of the recently described phenomenon of hypoattenuated leaflet thickening (HALT).12 It is speculated that this reflects a process invoked by the inflammatory milieu triggered during valve replacement that causes platelet activation on the surface of the prosthetic valves. It may be the case that this thromboinflammatory reaction to valve prostheses is the inciting factor for perioperative thrombocytopenia, though this understudied area is in need of greater investigation.7 The prevalence of HALT in TAVR patients was found to be 18% in a study by Nührenberg et al. looking at the effects of dual anti-platelet therapy (DAPT) on the prevention of subclinical leaflet thrombosis.13 While the study found that rates of symptomatic thrombosis occurred in only 1–2% of patients, it remains unclear if the high rates of subclinical HALT portend adverse long-term clinical outcomes.13 In one study with longitudinal follow-up after TAVR, patients with HALT had lower platelet counts at discharge, 6 months and 1 year after TAVR compared with those without HALT.14

One of the first studies in this area is the Assessment of Platelet REACtivity After Transcatheter Aortic Valve Replacement trial, a randomized, prospective multicenter study investigating platelet reactivity profiles among patients undergoing TAVR treated with acetylsalicylic acid (ASA) and clopidogrel compared with those with HPR placed on ASA and ticagrelor.20 Data from 59 patients were included. Extrapolated from the PCI population, a cut-off value of 208 P2Y12 reactivity units was used to define HPR. More than two-thirds of the 68 participants (n=48) had HPR on clopidogrel at baseline, a prevalence slightly higher than has been described in PCI data among elderly patients (≥75 years).21,22 Unexpectedly, more than one-third of patients who responded to clopidogrel at baseline were found to have HPR 30 days post-TAVR. This observation raises questions about physiologic changes occurring postTAVR that may contribute to the increased incidence of HPR beyond that seen in PCI data. Of note, ticagrelor showed highly effective suppression of platelet activity, with <10% HPR at 6 hours and 100% responders at 5 days, which remained consistent throughout the 3 months. The sample size was too small to allow any conclusions regarding ticagrelor’s safety in this population.

While the majority of patients undergoing TAVR develop thrombocytopenia, the exact mechanism of thrombocytopenia after TAVR has not been elucidated. Additionally, it is unknown whether or not this phenomenon is associated with increased platelet turnover (i.e. higher levels of immature platelets). It is well-documented that immature platelets are more active than senescent platelets in thrombus formation. Changes in the von Willebrand factor (vWF) mutimeric structure during and shortly after TAVR may offer a possible explanation for TAVR-associated thrombocytopenia.

Von Willebrand factor is the major circulating macromolecule that regulates platelet adhesion and aggregation in response to shear forces.15 High molecular weight multimers of vWF have the highest affinity to bind to platelets.16 It is conceivable that the recovery of these multimers is associated with increased interaction with platelets during and shortly after TAVR, resulting in platelet clumping and a decrease in platelet counts. In vitro studies have shown that rapid phosphorylation of adenosine diphosphate and P2Y12 blockade inhibits shear-induced platelet aggregation, a phenomenon thought to cause unfolding of vWF.17 This interaction appears to be resistant to aspirin.18 Hence, aspirin monotherapy is unlikely to have any effect on TAVR‐associated thrombocytopenia.

However, a separate study by Nührenberg et al. concluded that DAPT had no effect on the rates of HALT seen post-TAVR, regardless of clinical outcomes.13 This was a study of all-comers, including those with a prior indication for oral anticoagulation (OAC), who were placed on either DAPT with ASA plus clopidogrel or OAC plus clopidogrel. Platelet function testing was performed at the start of the procedure and patients were evaluated using 4D CT 5 days after valve implantation to assess the association between baseline platelet reactivity and HALT. HPR was defined as >468 aggregation units × minute. The investigators found no relationship between HPR and incidence of HALT, with considerable risk for HALT even among subjects who responded well to clopidogrel.

Ongoing studies to elucidate the optimal pharmacological therapy to reduce leaflet thrombosis are listed in Table 1.

Platelet Reactivity and Thrombotic Events in Trancatheter Aortic Valve Replacement

The main concern with studies evaluating HPR in TAVR patients is the extrapolation of HPR cut-off values from PCI populations. Although it is well-established that HPR correlates with ischemic events, including stent thrombosis, measuring platelet reactivity to guide clinical decisions is no longer routine practice during or after PCI in the era of newer generation drug-eluting stents. Furthermore, thrombotic events in the TAVR population may have a different mechanistic explanation. Most notably, the role of vWF has not been established in the PCI population, as well as platelet activation and aggregation on the valve surface.23 Dedicated on-treatment platelet reactivity studies in TAVR patients are needed. Those studies should focus on identifying HPR cut-offs that correlate with TAVR-specific ischemic events (stroke and HALT).

Two relatively unexplored areas in the debate surrounding antiplatelet and antithrombotic regimens in people who have had TAVR are the significance of high platelet reactivity (HPR) and whether or not HPR and response to

While Nührenberg et al. concluded that DAPT has no effect on the rates of HALT post-TAVR, certain patient factors were associated with impaired

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Structural Heart Table 1: Recently Completed and Ongoing Trials Evaluating Antiplatelet and Anticoagulation Regimens on Leaflet Thrombosis in the Post-transcatheter Aortic Valve Replacement Population Studies Evaluating Strategies to Reduce Leaflet Thrombosis in Patients Without Underlying Indication for Chronic OAC Available Data and Ongoing Trials

Antiplatelet and Anticoagulation

Primary Endpoints

Timeframe

Status

Strategies ADAPT-TAVR (NCT03284827)

Edoxaban versus ASA + clopidogrel

Incidence of leaflet thrombosis on 4D volume-rendered cardiac CT imaging.

6 months

Recruiting

GALILEO-4D41 (NCT02833948)

Rivaroxaban + ASA (3 months) followed by rivaroxaban alone versus ASA + clopidogrel (3 months) followed

by ASA alone

Rate of patients with at least one prosthetic leaflet with >50% motion reduction as assessed by cardiac 4D CT scan.

3 months

Completed

ASA = acetylsalicylic acid; OAC = oral anticoagulation.

response to antiplatelet therapy, as measured by a high on-treatment PR, leading to increased risk of thrombotic and ischemic events. These factors included advanced age, diabetes, polypharmacy, and low BMI.24 Considering that the current population of TAVR recipients are those patients at intermediate and high risk of surgical complications, they are more likely to exhibit factors that alter response to antiplatelet therapy. In addition, the current TAVR population is also at high risk of major bleeds, at rates of up to 16% in the first year.25 The decisions surrounding antithrombotic management are further complicated by the large proportion of patients undergoing TAVR who require anticoagulation for concomitant AF, which is seen in about 30% of the TAVR population.26 While current post-TAVR antithrombotic recommendations support DAPT unless prior OAC is indicated, the evidence to support this practice is limited. A 2019 study of patients with AF and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥65 or ≥75 years, diabetes, stroke/transient ischemic attack, vascular disease, sex category) score ≥2 from the PARTNER 2 cohort showed a decreased rate of stroke at 2 years post-TAVR in patients on antiplatelet therapy (single or dual) even without OAC.27 The study did not, however, address the addition of an antiplatelet to anticoagulation versus anticoagulation alone. Several ongoing studies discussed below seek to clarify the most appropriate regimens.

Antithrombotic Therapy Before and During Transcatheter Aortic Valve Replacement The main question before a TAVR procedure is whether or not to preload patients with P2Y12 inhibitors. Pre-procedural P2Y12 loading was found to decrease the severity of thrombocytopenia in a single-center study.7 Whether pre-procedural P2Y12 inhibition has any effect on clinical events remains to be determined. As far as intraprocedural antithrombotic management, unfractionated heparin (UFH) remains the gold standard.

In the randomized open-label, Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement Phase 3 trial, 802 patients at high surgical risk who were scheduled for transfemoral TAVR were randomized to receive either bivalirudin (n=404) or UFH (n=398). The trial was designed to show superiority of bivalirudin in regard to bleeding events. The co-primary endpoints were major bleeding (defined as Bleeding Academic Research Consortium type ≥3b), either within 48 hours or before hospital discharge, whichever occurred first, and 30-day net adverse cardiovascular events (NACE). Bivalirudin for procedural anticoagulation did not significantly reduce the primary outcomes. At 30

90

days, NACE rates were 14.4% in the bivalirudin group and 16.1% in the UFH group (p=0.50).28 Figure 1 shows the current antithrombotic practice at our center based on the available data. We use a clopidogrel loading dose of 300 mg on the day of the procedure. We recommend clopidogrel monotherapy for 3 months after TAVR. After that, the patient can be transitioned to aspirin if they have an indication for aspirin.

Current Antithrombotic Recommendations after Transcatheter Aortic Valve Replacement The current guidelines for antithrombotic management peri-TAVR have been extrapolated from data obtained from other areas in the field, namely in a post-PCI population. The data behind the use of DAPT versus other antithrombotic regimens specific to TAVR patients are limited.

Guidelines from the American College of Cardiology and the American Heart Association recommend DAPT with aspirin and clopidogrel for 6 months unless there is another indication for OAC, followed by lifelong aspirin monotherapy (class IIb recommendation based on level C evidence). The European Society of Cardiology and the European Association for Cardio-Thoracic Surgery similarly recommends 3–6 months of DAPT followed by lifelong single antiplatelet therapy (IIa–C). The Canadian Cardiovascular Society guidelines suggest treating with low-dose aspirin along with 1–3 months of a thienopyridine based on consensus of expert opinion. The evidence behind these guidelines is based on empiric treatment in the initial clinical trials’ protocols for TAVR, but to date, DAPT has not demonstrated benefit in larger randomized trials.29,30

Available Data and Limitations As mentioned previously, many of the current recommendations and guidelines surrounding antithrombotic strategies in TAVR patients are based on empiric regimens and extrapolated from studies looking at patients undergoing PCI, as well as initial trials comparing TAVR with SAVR. With new data from PARTNER 3 and EVOLUT suggesting benefits of TAVR in low-risk patients, there is an even greater need to clarify appropriate treatment and potentially alter current practices based on a changing patient population.

There are multiple ongoing clinical trials investigating different antithrombotic regimens in patients undergoing TAVR (Table 2). In the Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve

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Antithrombotics in TAVR Table 2: Recently Completed and Ongoing Trials Evaluating Antiplatelet and Anticoagulation Regimens in the Posttrancatheter Aortic Valve Replacement Population Available Data

Antiplatelet and OAC

and Ongoing Trials

Strategies

Primary Endpoints

Timeframe

Status

Patients without Underlying Indication for OAC ARTE29 (NCT01559298)

ASA versus ASA + clopidogrel

Death, MI, stroke or TIA, or major or life-threatening bleeding.

12 months

Stopped early due to lack of funding. Underpowered for clinical endpoints, though showed decrease in major or life-threatening bleeding with SAPT versus DAPT, without increasing MI or stroke.

GALILEO37 (NCT02556203)

Rivaroxaban + ASA (3 months) followed by rivaroxaban alone versus ASA + clopidogrel (3 months) followed by ASA alone

Death or first adjudicated thromboembolic event (stroke, MI, symptomatic valve thrombosis, PE, DVT, non-CNS systemic embolism), as well as life-threatening, disabling or major bleeding.

25 months

Stopped early due to increased all-cause mortality, bleeding, and thromboembolism in rivaroxaban group.

AUREA (NCT01642134)

ASA + clopidogrel versus VKA

Evaluate the effectiveness of DAPT versus OAC for prevention of cerebral thromboembolism by the detection of new areas of cerebral infarction by MRI.

3 months

Recruiting

Patients with Underlying Indication for OAC ENVISAGE-TAVI AF38 (NCT02943785)

Edoxaban versus VKA

Number of participants experiencing all-cause death, MI, ischemic stroke, systemic embolic events, valve thrombosis, and major bleeding.

36 months

Recruiting

AVATAR (NCT02735902)

VKA or DOAC alone versus VKA or DOAC + ASA

Composite outcome of death from any cause, MI, stroke all causes, valve thrombosis, and hemorrhage â&#x2030;Ľ2.

12 months

Recruiting

ATLANTIS39 (NCT02664649)

Apixaban versus standard of care (VKA or antiplatelet therapy)

Composite of death, MI, stroke, systemic embolism, intracardiac or bioprosthesis thrombus, any episode of deep vein thrombosis or pulmonary embolism, life-threatening or disabling or major bleeding.

12 months

Active, not recruiting

POPular-TAVI40 (NCT02247128)

ASA + clopidogrel versus ASA monotherapy or VKA + clopidogrel versus VKA monotherapy

Safety endpoint defined as freedom of all bleeding complications. Co-primary outcome is the safety endpoint defined as freedom of non-procedure-related bleeding complications.

12 months

Active, not recruiting

All-comers

ASA = acetylsalicylic acid; DAPT = dual antiplatelet therapy; DOAC = direct-acting oral anticoagulant; OAC = oral anticoagulation; SAPT = single antiplatelet therapy; TIA = transient ischemic attack; VKA = vitamin K antagonist.

Implantation (ARTE) trial, aspirin monotherapy was compared with DAPT, though the trial was terminated early due to a greater number of major or life-threatening bleeding events in the DAPT arm (10.8% versus 3.6%; p=0.038).29 These event rates were similar to the bleeding event rates seen in the 2011 PARTNER trial, with major bleeding occurring in 9.3% of subjects (32 of 348) at 30 days, all of whom received DAPT.31 With the data obtained from the 222 patients enrolled in the ARTE trial, single antiplatelet therapy (SAPT) had lower rates of major bleeding while showing no increase in risk for MI or stroke. However, this small study was underpowered for clinical endpoints and larger randomized trials are needed to substantiate these results.

In a 2017 meta-analysis by Verdoia et al. looking at safety and efficacy of antithrombotic strategies in post-TAVR patients, DAPT did provide an overall mortality benefit (12.2% versus 14.4%; OR, 0.81) compared with SAPT.32 Additionally, DAPT showed slight benefit compared with SAPT for stroke. However, the similar rates of bleeding between the DAPT and SAPT arms call into question the validity of the study results. This meta-analysis supports the current use of DAPT post-TAVR with SAPT

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plus OAC reserved for patients with prior indications for anticoagulation.

However, there are several limitations to this study mostly related to the small size of the studies included in the meta-analysis, as well as the non-randomized design. Additionally, the majority of patients involved in the study were placed on DAPT (>70%) with the remainder receiving SAPT Âą OAC, leading to a possible amplification of the benefits associated with this treatment. Given the lack of randomization of these studies, it is also possible that the SAPT arm included a disproportionate number of patients who had greater frailty or were at greater risk of adverse events than those placed on DAPT. Finally, there were inconsistent long-term data from the individual studies, with some only providing in-hospital events, potentially missing or under-reporting events after hospitalization.

Other studies that have tried to further elucidate the best antithrombotic regimens post-TAVR include those looking at various antiplatelet combinations, as well as those investigating anticoagulation versus antiplatelet agents. In the Global Study Comparing a rivAroxabanbased Antithrombotic Strategy to an antipLatelet-based Strategy After Transcatheter aortIc vaLve rEplacement to Optimize Clinical Outcomes

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Structural Heart Figure 1: Current Antithrombotic Practice for Patients Undergoing Transcatheter Aortic Valve Replacement at NYU Langone Health

Before the procedure

During the procedure

After the procedure

No indications for anticoagulation: • P2Y12 inhibitor loading dose 300–600 mg

Heparin with target activated clotting time 200–250 seconds

No indication for anticoagulation: • Recent PCI: dual antiplatelet therapy (PCI indications) • No recent PCI: P2Y12 inhibitor monotherapy daily

Indication for anticoagulation: • Without indication for antiplatelets: hold anticoagulation for 48–72 hours prior to TAVR without bridging with enoxaparin • With recent PCI: hold anticoagulation and continue P2Y12 inhibitor

Indication for anticoagulation: • Without indication for antiplatelets: anticoagulation only • With recent PCI: anticoagulation and continue P2Y12 inhibitor

We use P2Y12 inhibitor loading dose of 300 mg on the day of the procedure and recommend P2Y12 inhibitor monotherapy for 3 months after TAVR. After that, the patient can be transitioned to aspirin if they have an indication for aspirin. PCI = percutaneous coronary intervention; TAVR = transcatheter aortic valve replacement.

(GALILEO) trial, anticoagulation regimens were compared with or without the addition of an antiplatelet agent. Specifically, rivaroxaban plus aspirin was compared with standard DAPT treatment. This trial was prematurely stopped due to an increase in all-cause mortality in the rivaroxaban group (6.8% versus 3.3%), as well as increased bleeding (4.2% versus 2.4%) and thromboembolism (11.4% versus 8.8%).33,34 Although there is a lack of publicly available data after the termination of this study, one possible explanation for the increase in bleeding and thromboembolism in this case is the highly frail TAVR population who is at increased risk of both bleeding and thrombosis. Additionally, the increased mortality rate most likely mirrored the increase in bleeding events.

One study that focused on patients with an indication for anticoagulation compared anticoagulation using warfarin only with anticoagulation plus SAPT and DAPT in patients undergoing TAVR. During 13 months of followup, patients who received warfarin and any combination of antiplatelet therapy had higher rates of major and life-threatening bleeding with no significant reduction in thrombotic events.35 However, another study

by Kosmidou et al. showed ischemic benefit of adding antiplatelets to oral anticoagulation after TAVR. The main issue with this study is that patients with AF who received antiplatelets alone had lower rates of stroke than those who received anticoagulation alone (4.2% versus 8.3%), which contradicts the known superiority of anticoagulation in preventing strokes in these patients.27 Furthermore, one recent study found no difference in bleeding events between warfarin and non-vitamin K oral anticoagulants (NOACS) in terms of bleeding events.36 These studies have been the basis of our strategy to omit antiplatelet agents in patients undergoing TAVR who require anticoagulation. At our center, patients who are on any anticoagulant without indications for antiplatelets do not receive any antiplatelet drugs before or after TAVR. The choice of anticoagulation is discussed with each patient individually, given there are no major differences between warfarin and NOACs (Figure 1).

Future Directions The field of antithrombotics in TAVR patients is still in its infancy. The optimal antithrombotic regimen in patients undergoing TAVR is yet

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to be identified. The rationale for DAPT following TAVR is to decrease the risk of thromboembolic events associated with this procedure, especially cerebrovascular events.26 This issue is further complicated with about 30% of patients undergoing TAVR requiring anticoagulation for concomitant AF. Recent studies have suggested that a single antiplatelet drug after TAVR may be as effective with a better safety profile. However, which antiplatelet drug is still to be determined.

Studies evaluating SAPT versus DAPT have conventionally investigated aspirin in the SAPT arm.29 The fact that P2Y12 inhibition appears to blunt the severity of thrombocytopenia in patients undergoing TAVR may offer P2Y12 monotherapy as an alternative to DAPT and to aspirin monotherapy in these patients. This is particularly useful in the era of shrinking indications of aspirin for primary prevention of cardiovascular disease, especially in those aged ≥70 years, where aspirin is no longer recommended for primary prevention.

Whether patients with an indication for anticoagulation should receive one, two, or any antiplatelet therapies at all remains to be determined in large studies. Although one recent study showed ischemic benefit of adding antiplatelets to anticoagulation in patients with AF undergoing TAVR, other studies suggest that warfarin-only therapy may be safer and as effective as warfarin with one or two antiplatelet agents.27,35 While no difference in terms of bleeding events was seen between warfarin and NOACs, it appears that anticoagulation with rivaroxaban for all TAVR patients carries more harm than benefit, which lead to the termination of the GALILEO trial.36 With a rapidly expanding TAVR population, there is a pressing need for research into the pathophysiology of the thrombocytopenia associated with TAVR and the optimal antiplatelet strategies to minimize the risk of subsequent thrombosis. Prospective studies are also needed to determine the best antithrombotic combination for patients with AF who undergo TAVR. Finally, the development of bleeding risk scores that are specific to TAVR population and tailoring antithrombotic therapy based on individual bleeding risk, the safety and efficacy of intraprocedural intravenous P2Y12 inhibition, and the use of platelet turnover markers (i.e. immature platelet levels) to guide antithrombotic therapy in patients undergoing TAVR all require investigation.

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Antithrombotics in TAVR 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

ack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticM valve replacement with a balloon-expandable valve in lowrisk patients. N Engl J Med 2019;380:1695–705. https://doi. org/10.1056/NEJMoa1814052; PMID: 30883058.

Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi.org/10.1056/ NEJMoa1816885; PMID: 30883053.

Jilaihawi H, Doctor N, Chakravarty T, et al. Major thrombocytopenia after balloon-expandable transcatheter aortic valve replacement: Prognostic implications and comparison to surgical aortic valve replacement. Catheter Cardiovasc Interv 2015;85:130–7. https://doi.org/10.1002/ ccd.25430; PMID: 24677617.

Sexton TR, Wallace EL, Chen A, et al. Thromboinflammatory response and predictors of outcomes in patients undergoing transcatheter aortic valve replacement. J Thromb Thrombolysis 2016;41:384–93. https://doi.org/10.1007/s11239-015-1326-z; PMID: 26743061.

Dvir D, Généreux P, Barbash IM, et al. Acquired thrombocytopenia after transcatheter aortic valve replacement: clinical correlates and association with outcomes. Eur Heart J 2014;35:2663–71. https://doi.org/10.1093/eurheartj/ehu082; PMID: 24598983.

De Larochellière H, Puri R, Eikelboom JW, Rodés-Cabau J. Blood disorders in patients undergoing transcatheter aortic valve replacement: a review. JACC Cardiovasc Interv 2019;12:1–11. https://doi.org/10.1016/j.jcin.2018.09.041; PMID: 30621965.

Mitrosz M, Chlabicz M, Hapaniuk K, et al. Thrombocytopenia associated with TAVI – the summary of possible causes. Adv Med Sci 2017;62:378–82. https://doi.org/10.1016/j.advms.2017.04.003; PMID: 28550795.

Ibrahim H, Vapheas E, Shah B, et al. Preprocedural P2Y12 inhibition and decrease in platelet count following transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2019;1–6. https://doi.org/10.1002/ccd.28320; PMID: 31062487.

Kleiman NS, Maini BJ, Reardon MJ, et al. Neurological events following transcatheter aortic valve replacement and their predictors: a report from the CoreValve trials. Circ Cardiovasc Interv 2016;9:e003551. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.003551; PMID: 27601429.

Kapadia S, Agarwal S, Miller DC, et al. Insights into timing, risk factors, and outcomes of stroke and transient ischemic attack after transcatheter aortic valve replacement in the partner trial (placement of aortic transcatheter valves). Circ Cardiovasc Interv 2016;9:e002981. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.002981; PMID: PMID: 27601428.

Schmidt T, Leon MB, Mehran R, et al. Debris heterogeneity across different valve types captured by a cerebral protection system during transcatheter aortic valve replacement. JACC Cardiovasc Interv 2018;11:1262–73. https://doi.org/10.1016/j. jcin.2018.03.001; PMID: 29976363.

Makkar RR, Fontana G, Jilaihawi H. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015;373:2015–24. https://doi.org/10.1056/NEJMoa1509233; PMID: 26436963.

Nührenberg TG, Hromek J, Kille A, et al. Impact of on-clopidogrel platelet reactivity on incidence of hypoattenuated leaflet thickening after transcatheter aortic valve replacement.

JACC Cardiovasc Interv 2019;12:12–8. https://doi.org/10.1016/j. jcin.2018.08.008; PMID: 30621972.

Yanagisawa R, Hayashida K, Yamada Y, et al. Incidence, predictors, and mid-term outcomes of possible leaflet thrombosis after TAVR. JACC Cardiovasc Imaging 2017;10:1–11. https://doi.org/10.1016/j.jcmg.2016.11.005;

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PMID: 28017712.

15. M oake JL, Rudy CK, Troll JH, et al. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982;307:1432–5. https://doi.org/10.1056/ NEJM198212023072306; PMID: 6813740.

16. Moake JL, Turner NA, Stathopoulos NA, et al. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986;78:1456–61. https://doi. org/10.1172/JCI112736; PMID: 3491092.

17. Turner NA, Moake JL, Mclntire LV. Blockade of adenosine diphosphate receptors P2Y 12 and P2Y 1 is required to inhibit platelet aggregation in whole blood under flow. Blood 2001;98:3340–5. https://doi.org/10.1182/blood.V98.12.3340; PMID: 11719372.

18. Moake JL, Turner NA, Stathopoulos NA, et al. Shear-induced platelet aggregation can be mediated by vWF released from platelets, as well as by exogenous large or unusually large vWF multimers, requires adenosine diphosphate, and is resistant to aspirin. Blood 1988;71:1366–74. https://doi.org/10.1182/blood.

V71.5.1366.1366; PMID: 3258770.

19. Stone GW, Witzenbichler B, Weisz G, et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drugeluting stents (ADAPT-DES): A prospective multicentre registry study. Lancet 2013;382:614–23. https://doi.org/10.1016/S01406736(13)61170-8; PMID: 28288963.

20. Jimenez Diaz VA, Tello-Montoliu A, Moreno R, et al. Assessment of platelet REACtivity after Transcatheter Aortic Valve Replacement: the REAC-TAVI trial. JACC Cardiovasc Interv 2019;12:22–32. https://doi. org/10.1016/j.jcin.2018.10.005; PMID: 30621974.

21. Capodanno D. Tailoring antiplatelet therapy in patients undergoing transcatheter aortic valve replacement. JACC Cardiovasc Interv 2019;12:33–7. https://doi.org/10.1016/j. jcin.2018.10.047; PMID: 30621975.

22. Silvain J, Cayla G, Hulot JS, et al. High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study. Eur Heart J 2012;33:1241–50. https://doi.org/10.1093/ eurheartj/ehr407; PMID: 22067090.

23. Heper G, Namik Murat S, Durmaz T, Kalkan F. Prospective evaluation of von Willebrand factor release after multiple and single stenting. Angiology 2004;55:177–86. https://doi. org/10.1177/000331970405500210; PMID: 15026873.

24. Cavender MA, Kim SM. Utility of dual antiplatelet therapy for the prevention of subclinical leaflet thrombosis: now is not the time to HALT the use of dual antiplatelet therapy. JACC Cardiovasc Interv 2019;12:19–21. https://doi.org/10.1016/j.jcin.2018.09.040; PMID: 30621973.

25. Ibrahim H, Rondina MT, Kleiman NS. Von Willebrand factor and the aortic valve: concepts that are important in the transcatheter aortic valve replacement era. Thromb Res 2018;170:20–7. https:// doi.org/10.1016/j.thromres.2018.07.028; PMID: 30092557.

26. Ibrahim H, Rondina M, Welt FGPP. Antithrombotic drugs in cardiovascular medicine: a year in review. Curr Opin Cardiol 2018;33:369–74. https://doi.org/10.1097/ HCO.0000000000000530; PMID: 29708890.

27. Kosmidou I, Liu Y, Alu MC, et al. Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve replacement in patients with atrial fibrillation. JACC Cardiovasc Interv 2019;12:1580–9. https://doi.org/10.1016/j.jcin.2019.06.001; PMID: 31439338.

28. Dangas GD, Lefèvre T, Kupatt C, et al. Bivalirudin versus heparin anticoagulation in transcatheter aortic valve replacement: the randomized BRAVO-3 trial. J Am Coll Cardiol 2015;66:2860–8. https://doi.org/10.1016/j.jacc.2015.10.003; PMID: 26477635.

29. R odés-Cabau J, Masson JB, Welsh RC, et al. Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloonexpandable valve: the ARTE (aspirin versus aspirin + clopidogrel following transcatheter aortic valve implantation) randomised controlled trial. JACC Cardiovasc Interv 2017;10:1357–65. https:// doi.org/10.1016/j.jcin.2017.04.014; PMID: 28527771.

30. Al Halabi S, Newman J, Farkouh ME, et al. Meta-analysis of studies comparing dual- versus mono-antiplatelet therapy following transcatheter aortic valve implantation. Am J Cardiol 2018;122:141–8. https://doi.org/10.1016/j.amjcard.2018.03.019; PMID: 29779587.

31. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187–98. https://doi.org/10.1056/NEJMoa1103510; PMID: 21639811.

32. Verdoia M, Barbieri L, Nardin M, et al. Dual versus single antiplatelet regimen with or without anticoagulation in transcatheter aortic valve replacement: indirect comparison and meta-analysis. Rev Esp Cardiol (Engl Ed) 2018;71:257–66. https://doi.org/10.1016/j.rec.2017.06.012; PMID: 28734880.

33. Windecker S, Tijssen J, Giustino G, et al. Trial design: rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: rationale and design of the GALILEO study. Am Heart J 2017;184:81–7. https://doi. org/10.1016/j.ahj.2016.10.017; PMID: 27892890.

34. Todd N. GALILEO trial of rivaroxaban after TAVR stopped early for harm. TCTMD 9 October 2018. Available at: https://www. tctmd.com/news/galileo-trial-rivaroxaban-after-tavr-stoppedearly-harm (accessed 5 December 2019).

35. Abdul-Jawad Altisent O, Durand E, Muñoz-García AJ, et al. Warfarin and antiplatelet therapy versus warfarin alone for treating patients with atrial fibrillation undergoing transcatheter aortic valve replacement. JACC Cardiovasc Interv 2016;9:1706–17. https://doi.org/10.1016/j.jcin.2016.06.025; PMID: 27539691.

36. Jochheim D, Barbanti M, Capretti G, et al. Oral anticoagulant type and outcomes after transcatheter aortic valve replacement. JACC Cardiovasc Interv 2019;12:1566–76. https://doi.org/10.1016/j.jcin.2019.03.003; PMID: 31202946.

37. Dangas GD, Tijssen JGP, Wöhrle J, et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement.

N Engl J Med 2019. https://doi.org/10.1056/NEJMoa1911425; PMID: 31733180; epub ahead of press.

38. Van Mieghem NM, Unverdorben M, Valgimigli M, et al. EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation in Atrial Fibrillation – rationale and design of the ENVISAGE-TAVI AF trial. Am Heart J 2018;205:63–9. https://doi. org/10.1016/j.ahj.2018.07.006; PMID: 30172099.

39. Collet JP, Berti S, Cequier A, et al. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: the randomized ATLANTIS trial. Am Heart J 2018;200:44–50. https:// doi.org/10.1016/j.ahj.2018.03.008; PMID: 29898848.

40. Nijenhuis VJ, Bennaghmouch N, Hassell M, et al. Rationale and design of POPular-TAVI: antiPlatelet therapy fOr Patients undergoing Transcatheter Aortic Valve Implantation. Am Heart J 2016;173:77–85. https://doi.org/10.1016/j.ahj.2015.11.008; PMID: 26920599.

41. Makkar RR, Fontana G, Jilaihawi H. Possible subclinical leaflet thrombosis in bioprosthetic aortic valves. N Engl J Med 2015;373:2015–24.https://doi.org/10.1056/NEJMoa1509233; PMID: 26436963.

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Congenital Heart Disease

Single-Ventricle Physiology Lydia Taranto, MD, 1 and Tabitha Moe, MD 2,3 1. HonorHealth Hospitals, Scottsdale, AZ; 2. Arizona Cardiology Group, Phoenix, AZ; 3. Phoenix Children’s Hospital, Phoenix, AZ

Abstract Single-ventricle physiology occurs in patients with hypoplastic ventricular heart defects, either on the right or left, who have undergone stepwise palliation surgeries ending with the Fontan procedure. After Fontan completion, these patients are dependent on passive venous return to the pulmonary circulation. The implications of passive flow are potentially devastating to the patient. We discuss some of the basic changes to the patient’s experience after a Fontan procedure, as well as the common complications. We also touch on some of the emerging management strategies for the common complications.

Keywords Fontan, single-ventricle physiology, Fontan physiology, Fontan heart failure, Fontan-associated liver disease, protein losing enteropathy, plastic bronchitis Disclosure: The authors have no conflicts of interest to declare.

Received: 24 May 2019 Accepted: 24 October 2019 Citation: US Cardiology Review 2019;13(2):94–8. DOI: https://doi.org/10.15420/usc.2019.20.2 Correspondence: Tabitha Moe, Arizona Cardiology Group, 340 E Palm Lane #A175, Phoenix, AZ 85004. E: tmoe@azcard.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.

As we approach 50 years since the original publication describing the Fontan procedure for palliation of single-ventricle congenital heart disease, we review the basics of Fontan circulation, and the current literature concerning long-term complications. Surgical interventions have allowed children with former lethal defects to survive into adulthood and we recognize that this has led to a new cohort. Their physiology is divergent from people with two ventricles and their clinical complications highlight the directions for further research to give them a higher quality of life. In this article, we discuss some of the basic physiological changes in single-ventricle physiology regarding the Fontan operation, and introduce the common physiological complications.

Dynamics of the Fontan Procedure The Fontan procedure is the final stage in the stepped palliation of singleventricle disease.1,2 It was initially described by Fontan and Baudet in 1971 as a corrective intervention for tricuspid atresia, and while it is now seen as palliative, it has been applied to most forms of single-ventricle defects.3–5 The Fontan is a method of diverting the systemic venous return away from the right side of the heart directly into the pulmonary artery, through a series of stepwise operations, until all the systemic venous blood flows passively and without ventricular thrust into the pulmonary circulation.3,6–8 The principle behind this concept was the discovery that the pulmonary vascular bed had a much lower pressure than systemic venous pressure.

The pressure gradient between the two vascular beds was enough to allow blood to flow forward without ventricular thrust.8 Conversely, this

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implies that pulmonary vascular resistance, diaphragmatic excursion, and thoracic cage mobility all contribute to a complicated process determining cardiac output.8,9 This operation places the pulmonary and the systemic vasculature in series, with the systemic ventricle effectively functioning as the only pump. In this sense, the Fontan procedure is a palliation, rather than a physiological cure, which would both imply and require a pulmonary circulation pump. This change has profound implications for preload, afterload, cardiac output, and stroke volume.7,8 This system is inherently one of decreased preload and increased afterload. People who have had the procedure are dependent on passive venous return due to the pressure gradient between systemic venous vasculature and pulmonary vasculature, with the skeletal muscle pump and ventilation mechanics supporting secondarily.6–8 Additionally, as the systemic circulation and the pulmonary circulation are placed in series, systemic venous pressures are increased and exceed the upper normal pressure limit by two to three times. Thus, these patients face significantly increased afterload. Having both a decreased preload and an increased afterload, with only a single ventricular pump, creates a challenge for cardiac output and leaves these patients with little hemodynamic reserve.8 After the Fontan procedure, patients are almost entirely dependent on heart rate and atrioventricular conduction to increase their cardiac

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Single-Ventricle Physiology output, and thus they have very little hemodynamic tolerance for decreases in venous return. They are largely dependent on skeletal muscle pump and ventilation mechanics during exercise to increase their venous return and stroke volume.7,8 It has been demonstrated that in adults with Fontan circulation, nearly 30% of their venous flow through the pulmonary artery is dependent on respiration, whereas in patients with two ventricles this number is closer to 15%.8,10 Due to the increase in their venous vasculature resistance, people with Fontan circulation also have a diminished venous capacitance.8,11 In people with two ventricles, approximately 70% of total blood volume is stored in the venous vasculature.8,12 Fontan patients do not have this reserve immediately available to them and this makes them susceptible to decreases in intravascular volume, or to agents that may decrease their vascular tone, either of which can decrease their pulmonary return and cardiac output.8 Pulsatile flow is partially responsible for recruiting pulmonary capillaries, which reduces pulmonary vasculature resistance and increases compliance. Without this pulsatile flow, studies have shown reduced vascular recruitment and impaired lung growth, both of which serve to increase overall pulmonary vascular resistance and decreased compliance.8,13,14 This increase in pulmonary resistance causes a decreased preload and cardiac output. Exogenously administered vasodilators, such as oral sildenafil and baseman have shown some benefit in certain situations, such as cardiovascular exercise, a physiological situation that single-ventricle patients have little tolerance for.8,13â&#x20AC;&#x201C;15

Survival Outcomes after a Fontan Procedure Survival outcomes have varied, with reduced survival in patients who underwent the original Fontan procedure (atriopulmonary connection), and improved survival rates in those who underwent revised Fontan procedures (total cavopulmonary connections). Survival is significantly affected by the long-term complications of the operation, as detailed below. In the largest cohort analyses, survival has been shown to be 90% at 30 years and 80% at 40 years, with significantly worse survival for people who had atriopulmonary connection.16 The analysis found that most patients (65%) had systemic left ventricular morphology. The survival rates of hypoplastic left heart syndrome had significantly worse outcomes, with survival ranging from 72% to 85% at 10 years.7

Heart Failure after a Fontan Procedure Heart failure in people who have had the Fontan procedure is fundamentally different from heart failure in patients with two ventricles.7,17 While heart failure in people with two ventricles helps provide a framework to understand heart failure in the single ventricle, it is essential that we understand where and how the two types of patient diverge.

There are four types of heart failure described in people who have had the Fontan procedure and in each case the circulation is no longer able to meet the metabolic demands of the body.7 Type 1 heart failure in Fontan patients is also called Fontan failure with reduced ejection fraction. It is the most common type seen in children and it presents with consistent signs and symptoms of heart failure with reduced EF, such as pulmonary edema, hepatic congestion, and

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ascites.7,17 This closely resembles systolic heart failure in patients with two ventricles.17 Type 2 heart failure in Fontan patients, known as Fontan failure with preserved ejection fraction, presents with a preserved ejection fraction, with signs and symptoms of pulmonary venous congestion and hepatic congestion, with elevated venous pressures.7,17 This type of heart failure in some way mirrors HFpEF in patients with two ventricles.

Type 3 heart failure in Fontan patients, also known as Fontan failure with normal pressures, presents with right-sided congestion, such as hepatosplenomegaly, ascites, and portal venous outflow obstruction, but with normal ejection fraction and hemodynamics.7,17 Multisystem organ failure in the setting of good hemodynamics is frequently seen, making it challenging to treat.17 Type 4 heart failure in Fontan patients, known as Fontan failure with abnormal lymphatics, will present with normal hemodynamics, but signs and symptoms of lymphatic failure, such as plastic bronchitis and protein-losing enteropathy.7,17 Patients will often have normal Fontan hemodynamics.17

Risk of Arrhythmia after Fontan Procedure Patients with single-ventricle Fontan physiology have multiple risk factors for developing tachyarrhythmias, particularly AF.7,18 With classic Fontan, the surgical interventions lead to fibrosis near the sinus node and atria and are subject to dilation even to the point of atrial gigantism, both of which can predispose to AF.7 Sick sinus syndrome, atypical atrial flutter, and incisional interatrial reentrant atrial tachycardia are also seen. People with Fontan circulation have a reduced tolerance to AF and are more prone to hemodynamic instability at elevated heart rates.

They are also far less responsive to single-agent anti-arrhythmic drug therapy. Amiodarone continues to be considered the most effective antiarrhythmic drug in this patient population.

Catheter ablations can be attempted but are fraught with increased risk due to difficult access. Surgical ablations are considered the gold standard. Therefore, anytime a Fontan patient is scheduled for open heart surgery, surgical ablation should be discussed. Although there is currently no consensus on which anticoagulants to use, clinicians typically agree on the use of anticoagulation for atrial arrhythmia in people who have had a Fontan procedure. Recent studies suggest that aspirin alone is not inferior to vitamin K antagonist, and novel oral anticoagulants have not yet been formally evaluated.7,18,19

The Impact of the Fontan Procedure on the Hepatic System All patients who undergo Fontan operations have some degree of Fontan-associated liver disease (FALD), regardless of their clinical status.6,7 The FALD spectrum ranges from mild fibrosis to fulminant liver failure. As the liver is placed immediately before the heart in the venous return pathway, having systemically elevated central venous pressures impedes venous flow and leads to chronic venous congestion, to which the liver is particularly susceptible. It is this congestion that is believed to lead to the hepatic fibrosis that all Fontan patients experience.6 Research has demonstrated that it is the chronicity of this

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Congenital Heart Disease central venous pressure, rather than the severity of it, that increases the risk of hepatic fibrosis. It has been noted that irreversible hepatic dysfunction may occur as early as the teenage years.7 Unfortunately, the mechanisms leading to this pathology also change the nature of it, both distinguishing it from classic liver fibrosis, and making it more challenging to detect and manage.

While symptoms are often subclinical, manifestations, such as mild hepatomegaly and ascites, are commonly seen. Mild elevation of liver transaminases and mild thrombocytopenia are common, although synthetic function is usually preserved.6,7 Significant increases in liver enzymes are generally not seen due to the low-grade chronic inflammation with only mild hepatocyte damage.8 Changes in varices are often not seen due to the long-standing elevated systemic venous pressures; varices are a manifestation of a high-pressure hepatic system decompressing in a lower pressure venous system.6 People who have had the Fontan procedure have no lower pressure venous systems, and thus the etiology of hepatic fibrosis prevents the complication of varices.

Primary portal hypertension is rarely found.7 Given that synthetic function is generally preserved and that transaminases may only be mildly elevated, even in the setting of advanced cirrhosis, the traditional model for end-stage liver disease (MELD) score holds limited clinical value in staging and prognosis for these patients. The MELD-XI, a MELD score excluding the international normalized ratio is more appropriate. Cardiac MRI, which is frequently used to monitor these patients, captures a portion of the liver and has been used to trend hepatic dimensions, inferior vena cava size, and spleen size. However, cardiac MRI is limited in patients with epicardial pacemaker leads and intra-abdominal generators as the device limits the interpretation of the imaging.

Abdominal ultrasound with elastography can assess hepatic texture and stiffness, but is limited by its difficulty in distinguishing fibrosis from edema.7 FibroSure is a biomarker test that has been used to screen patients in these patients with some success as a non-invasive measure of disease progression.20 More efficacious surveillance options and treatments remain a top research priority in this population.7,17 The most devastating complication of FALD remains hepatocellular carcinoma (HCC), and it has been previously recognized as a long-term complication of the Fontan procedure.7,21 In a recent retrospective study, it was found that 1.3% of 2,470 cases (n=33) had biopsy-proven HCC, with the average age at time of diagnosis being 30 years, and the average length of time from Fontan operation to HCC diagnosis being 22 years.21 Of the 33 patients identified, 18 (55%) died within 26 months.

However, in contrast to other patients with HCC, only 50% of the singleventricle patients diagnosed with HCC previously carried a diagnosis of hepatic cirrhosis, in contrast to 80% of patients with two ventricles developing HCC.21,22 This suggested either an underdiagnosis of hepatic cirrhosis in patients with Fontan circulation, or an increased risk of HCC in non-cirrhotic livers in these patients. Unfortunately, advanced tumor burden at time of diagnosis gives many patients only the option of palliative care. Given the risk of HCC and increased incidence of it, 6-month managing surveillance and alpha fetoprotein serum monitoring is recommended in patients with known FALD.7,21

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The Impact of the Fontan Procedure on the Gastrointestinal System Protein losing enteropathy (PLE) is a well-known complication of Fontan physiology, in which the mucosal integrity of the gastrointestinal lining is compromised and highly proteinaceous material, including immune globulins and clotting factors, is spilled into the lumen.6,7 Its manifestations are seen when the rate of loss exceeds the body’s ability to produce the same proteins. It occurs in about 5–15% of Fontan patients, on average 3–8 years after Fontan surgery, most commonly seen in children. Symptoms typically manifest as diarrhea; however, even without diarrhea the manifestations can be seen. Symptoms such as ascites, weight loss or gain, fatigue, peripheral edema, pleural or pericardial effusions, muscle tetany, and thromboembolism can all be seen and taken as evidence of PLE.6,23 The mechanisms leading to PLE are thought to be a function of chronic hypoperfusion of the gastrointestinal tract due to the chronically low cardiac output of the Fontan physiology, in conjunction with the effects of elevated central venous pressure on the lymphatic system. Over time, chronic hypoperfusion of the gastrointestinal tract leaves the mucosa chronically inflamed and subject to integrity compromise.7,24 Diagnosis can be accomplished by testing for alpha 1 antitrypsin (A1AT) in the stool. A1AT is normally excreted in small amounts in the stool and an elevated level found in a 24-hour stool collection can indicate intestinal protein leak. Decreased serum protein levels, including decreased levels of serum A1AT, can reinforce the diagnosis.7 PLE is currently treated in a variety of ways with varying degrees of success. Approaches include scheduled albumin infusions, use of enteral budesonide, use of heparin, loop diuretics, spironolactone, sildenafil, and digoxin.25 There is considerable variation regarding treatment, and only budesonide has demonstrated benefits in a study assessing survival to time of heart transplant.25 Rapid atrial pacing has been employed in the setting of PLE to help support cardiac output.26 Embolization of tortuous lymphatic vessels contributing to PLE is also currently being studied.6,7

The Impact of the Fontan Procedure on the Pulmonary System Pulmonary vascular changes are not uncommon. Passive flow through the pulmonary vascular bed is a principle and mechanism of the Fontan single-ventricle state. Any impedance to this can result in worsening venous congestion, elevated central venous pressures, reduced ventricular preload, decreased cardiac output, and worsen all subsequent secondary pathologies. Often children born with singleventricle physiology have abnormal pulmonary flow patterns; after operative intervention, the body appears to have a compensatory mechanism for passive aorto-pulmonary flow and develops significant aorto-pulmonary collateralization. These collaterals can further impede the flow through the pulmonary vascular bed, contribute to worsening central venous pressure systemic symptoms, and add an additional complicating factor of ventricular overload to the single functioning ventricle.6–8 Testing pulmonary function in patients with single-ventricle disease reveals a restrictive pattern, likely due to the multiple operative

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Single-Ventricle Physiology interventions and post-surgical changes to the thoracic wall. Reduced forced vital capacity and functional capacity during exercise testing are seen, consistent with restrictive lung disease.7 Therapeutic approaches with flutter valves, respiratory exercises, and vocal training are strategies currently being evaluated.27 Plastic bronchitis is a rare but serious complication in which bronchial mucofibrinous casts develop, resulting in airway obstruction. It can be difficult for patients to expectorate these casts, and if large casts develop, it can result in an urgent, life-threatening event including asphyxiation.28 This pathology is thought to be secondary to the similar pathology derangements that cause PLE; severe lymphatic distortions leading to protein leak into low-pressure systems, such as the gastrointestinal lumen and the bronchioles.7,23,29

The Impact of the Fontan Procedure on the Lymphatic System While the changes involved in the lymphatic system are not well understood, they have been partially characterized and implicated in the serious conditions of plastic bronchitis and PLE.30 The lymphatic system drains into the innominate vein, which is under high pressure after the Fontan procedure, due to increased systemic central venous pressure.6,31 This leads to increased lymphatic fluid production and decreased lymphatic drainage, causing lymphatic insufficiency. Lymphangiography in these patients has revealed dilated, tortuous lymphatic channels throughout the body.31 When these channels are overwhelmed, they open and spill their contents into areas of low pressure, such as the bronchial tree or the gastrointestinal lumen, contributing to the serious complications of plastic bronchitis and protein-losing enteropathy. New treatments, such as glue embolization of these channels, are being developed to help mitigate this process.6,7,32

The Risk of Thrombosis Single-ventricle patients have a multiplicity of risk factors that promote thrombosis, and it has been shown that thromboembolic events may affect up to 33% of patients, contributing to nearly 25% of mortalities, including death from pulmonary embolism and cerebrovascular accidents.7,33,34 The underlying risk factors include the very crux of the Fontan, the passive, non-pulsatile venous flow through the pulmonary bed. Also included are chronic venous congestion, low cardiac output, dilated atrium, cardiac arrhythmia, and PLE. This list is not exhaustive, but it illustrates the increased risk that this patient group has for

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Int J Cardiol 2014;173:277–83. https://doi.org/10.1016/j. ijcard.2014.03.001; PMID: 24650660.

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thrombotic complications. To this end, research has supported the long-term use of anticoagulation agents in these patients, regardless of prior history of thrombotic events. Current data suggest that the use of aspirin is non-inferior to vitamin K antagonists and has less risk of bleeding complications. The use of novel oral anticoagulants is promising; however, studies concerning their benefit in Fontan patients have yet to completed.7,33–36

Renal system Patients who have had a Fontan procedure are at higher risk of renal injury, and often have a lower estimated glomular filtration rate (eGFR) than counterparts with two ventricles. The underlying mechanism for this is thought to be secondary to decreased cardiac output and chronically elevated central venous pressures. Of note, these patients deviate here from their double-ventricle counterparts, because using serum creatinine overestimates their eGFR. The use of cystatin C or urinary biomarkers gives a more accurate indication of their eGFR.7,37

Surveillance Guidelines People with single-ventricle disease are the most complex congenital heart patients and it is critical that these patients maintain continuity of care with congenital heart disease providers. The Adult Congenital Heart Disease (ACHD) certification exam now establishes physicians’ competence to care for these complex patients. Routine follow-up every 6–12 months with associated testing is recommended; at these visits it is recommended to obtain repeat ECG, transthoracic ECHO, pulse oximetry, Holter monitor study, and at extended intervals to obtain cardiac CT and exercise testing.38

Future Directions Research is ongoing on the timing and appropriateness of both singleorgan and dual-organ transplants for people with a single ventricle, and the future of stem cell research, as well as single-ventricle assist devices, is on the horizon. The Rodefeld Fontan pump is one device that may potentially assist a failing Fontan as a portable right ventricular implantable device.39 Registries, as well as biobanks, are allowing cumulative data to assist with informed decision-making and treatment planning.40 The Adult Congenital Heart Association is now building a registry for adult congenital heart disease – the Quality Enhancement Research Initiative ACHD Registry. Ongoing efforts to keep patients in care are going to be crucial to strategies in the long-term preventive approach to managing risks and complications for this patient group.

Rychik, J. The relentless effects of the Fontan paradox. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 19:37–43. https://doi. org/10.1053/j.pcsu.2015.11.006; PMID: 27060041.

7. Kay WA, Moe T, Suter B, et al. Long term consequences of the Fontan procedure and how to manage them. Prog Cardiovasc Dis 2018;61:365–76. https://doi.org/10.1016/j.pcad.2018.09.005; PMID: 30236751.

8. Jolley M, Colan S, Rhodes J, et al. Fontan physiology revisited.

Anesth Analg 2015;121:172–82. https://doi.org/10.1213/ ANE.0000000000000717; PMID: 26086514.

9. Gewillig M, Brown SC, Eyskens D, et al. The Fontan circulation: who controls cardiac output? Interact Cardiovasc Thorac Surg 2010;10:428–33. https://doi.org/10.1510/icvts.2009.218594; PMID: 19995891.

10. Hsia TY, Khambadkone S, Redington AN, et al. Effects of respiration and gravity on infradiaphragmatic venous flow in normal and Fontan patients. Circulation 2000 (19 Suppl 3);102:III148–53. https://doi.org/10.1161/01.CIR.102.suppl_3.III148; PMID: 11082378.

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capacitance in patients with univentricular hearts after the Fontan operation. Am J Cardiol 1995;76:158–63. https://doi. org/10.1016/S0002-9149(99)80049-6; PMID: 7611151.

Tyberg JV. How changes in venous capacitance modulate cardiac output. Pflugers Arch 2002;445:10–7. https://doi. org/10.1007/s00424-002-0922-x; PMID: 12397381.

Presson RG Jr, Baumgart WA Jr, Peterson AJ, et al. Pulmonary capillaries are recruited during pulsatile flow. J Appl Physiology (1985) 2002;92:1183–90. https://doi.org/10.1152/ japplphysiol.00845.2001; PMID: 11842057.

Raj JU, Kaapa P, Anderson J. Effect of pulsatile flow on microvascular resistance in adult rabbit lungs. J Appl Physiol (1985) 1992;72:73–81. https://doi.org/10.1152/jappl.1992.72.1.73; PMID: 1537745.

Ovaert C, Thijs D, Dewolf D, et al. The effect of bosentan in patients with a failing Fontan circulation. Cardiol Young 2009;19:331–9. https://doi.org/10.1017/S1047951109990023; PMID: 19519964.

Dennis M, Zannino D, du Plessis K, et al. Clinical outcomes in adolescents and adults after the Fontan procedure.

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Book, W, Gerardin J, Saraf A, et al. Clinical phenotypes of Fontan failure: implications for management. Congenit Heart Dis 2016;11:296–308. https://doi.org/10.1111/chd.12368; PMID: 27226033.

Moe T, Abrich V, Rhee EK. Atrial fibrillation in patients with congenital heart disease. J Atr Fibrillation 2017;10:1612. https:// doi.org/10.4022/jafib.1612; PMID: 29250225.

Wals EP, Cecchin F. Arrhythmias in adult patients with congenital heart disease. Circulation 2007;115:534–45. https://doi. org/10.1161/CIRCULATIONAHA.105.592410; PMID: 17261672.

Wu F, Earing M, Aboulhosn J, et al. Predictive value of biomarkers of hepatic fibrosis in adult Fontan patients. J Heart Lung Transplant 2017;36:211–9. https://doi.org/10.1016/j. healun.2016.07.011; PMID: 27592026.

Egbe, A. Hepatocellular carcinoma after Fontan operation.

Circulation 2018;138:746–8. https://doi.org/10.1161/ CIRCULATIONAHA.117.032717; PMID: 30359134.

Van Meer S, van Erpecum KJ, Sprengers D, et al. Hepatocellular carcinoma in cirrhotic versus noncirrhotic livers: results from a large cohort in the Netherlands. Eur J Gastroenterol Hepatol 2016;28:352–9. https://doi.org/10.1097/MEG.0000000000000527; PMID: 26629867.

John AS, Johnson JA, Khan M, et al. Clinical outcomes and improved survival in patients with protein-losing enteropathy after the Fontan operation. J Am Coll Cardiol 2014;64:54–62. https://doi.org/10.1016/j.jacc.2014.04.025; PMID: 24998129.

Johnson JN, Driscoll DJ, O’Leary PW. Protein-losing enteropathy and the Fontan operation. Nutr Clin Pract 2012;27:375–84. https://doi.org/10.1177/0884533612444532; PMID: 22516942.

Johnson J, Yu S, Lowery R, et al. Treatment variation and its implication for severe Fontan-associated protein losing

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Cohen M, Rhodes L, Wernovsky G et al. Atrial pacing: an alternative treatment for protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 2001;121:582–3. https://doi.org/10.1067/mtc.2001.110681; PMID: 11241095.

Cordina RL, O’Meagher S, Karmali A, et al. Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology. Int J Cardiol 2013;168:780–8. https://doi.org/10.1016/j.ijcard.2012.10.012; PMID: 23154055.

Brogan TV, Finn LS, Pyskaty DJ Jr, et al. Plastic bronchitis in children: a case series and review of the medical literature.

Pediatr Pulmonol 2002;34:482–7. https://doi.org/10.1002/ ppul.10179; PMID: 12422347.

Caruthers RL, Kempa M, Loo A, et al. Demographic characteristics and estimated prevalence of Fontan-associated plastic bronchitis. Pediatr Cardiol 2013;34:256–61. https://doi. org/10.1007/s00246-012-0430-5; PMID: 22797520.

Don Y, Zviman MM, Itkin M. Dynamic contrast-enhanced MR lymphangiography: feasibility study in swine. Radiology 2014;273:410–6. https://doi.org/10.1148/radiol.14132616; PMID: 24988434.

Dori Y, Keller MS, Fogel MA, et al: MRI of lymphatic abnormalities after functional single-ventricle palliation surgery.

AJR Am J Roentgenol 2014;203:426–31. https://doi.org/10.2214/ AJR.13.11797; PMID: 24848564.

Dori Y, Keller MS, Rychick J, et al. Successful treatment of plastic bronchitis by selective lymphatic embolization in a Fontan patient. Pediatrics 2014;134:e590–5. https://doi.org/10.1542/ peds.2013-3723; PMID: 25002668.

Faircloth JM, Roe O, Alsaied T, et al. Intermediate term thrombotic risk in contemporary total cavopulmonary connection for single

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Alsaied T, Alsidawi S, Allen C, et al. Strategies for thromboprophylaxis in Fontan circulation: a meta-analysis. Heart 2015;101:1731–7. https://doi.org/10.1136/heartjnl-2015-307930; PMID: 26319122.

Takeuchi D, Inai K, Shinohara T, et al. Blood coagulation abnormalities and the usefulness of D-dimer level for detecting intracardiac thrombosis in adult Fontan patients. Int J Cardiol 2016;224:139–44. https://doi.org/10.1016/j.ijcard.2016.09.017; PMID: 27648983.

Yang H, Bouma B, Mulder B. Is initiating NOACs for atrial arrhythmias safe in adults with congenital heart disease?

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Opotowsky AR, Baraona FR, McCausland FR, et al. Estimated glomerular filtration rate and urine biomarkers in patients with single-ventricle Fontan circulation. Heart 2017;103:434–42. https://doi.org/10.1136/heartjnl-2016-309729; PMID: 27670967.

Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC guideline for the management of adults with congenital heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e637–97. https://doi.org/10.1161/ CIR.0000000000000602; PMID: 30586768.

Rodefeld M, Coats B, Fisher T, et al. Cavopulmonary assist for the univentricular Fontan circulation: von Karman viscous impeller pump. J Thorac Cardiovasc Surg 2010;140:529–36. https:// doi.org/10.1016/j.jtcvs.2010.04.037; PMID: 20561640.

Optowsky A, Loukas B, Ellervik C, et al. Design and implementation of a prospective adult congenital heart disease biobank. World J Pediatr Congenit Heart Surg 2016;7:734–43. https:// doi.org/10.1177/2150135116672648; PMID: 27834768.

US CARDIOLOGY REVIEW

Congenital Heart Disease

Coarctation: A Review Marc G Cribbs, MD, FACC Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, US

Abstract Coarctation of the aorta occurs in 0.04% of the population, and accounts for approximately 10% of lesions in adults with congenital heart disease. It can occur as an isolated lesion or as a part of a complex defect, and is most commonly associated with bicuspid aortic valve, ventricular septal defect, and mitral valve abnormalities. Since the first surgical repair in 1944, the available treatment options have expanded greatly. Perhaps one of the most important advances in the management of coarctation of the aorta has been the development of transcatheter therapy for both native and especially recurrent coarctation of the aorta. Late complications, even after apparently successful treatment, are not uncommon. For this reason, lifelong follow-up is vital.

Keywords Congenital heart disease, coarctation of the aorta, adults with congenital heart disease, transcatheter therapy, systemic hypertension Disclosure: Financial support for this study was provided by Division of Cardiovascular Medicine funds, University of Alabama at Birmingham, Birmingham, Alabama.

Received: 6 May 2019 Accepted: 3 July 2019 Citation: US Cardiology Review 2019;13(2):99–104. DOI: https://doi.org/10.15420/usc.2019.15.2 Correspondence: Marc G Cribbs, Division of Cardiovascular Disease, University of Alabama at Birmingham, 1700 6th Avenue South, Suite 9100, Birmingham, AL 35233, US. E: mgcribbs@uabmc.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 congenital heart disease (CHD) is slightly less than 1% of all live births.1 With extensive medical and surgical innovation over the past 50 years, and the high-quality care received in childhood, 85–90% of children with CHD in the US survive into adulthood. As a result, the number of adults with congenital heart defects in the US now exceeds 1 million, with a projected continued growth rate of 5% per year.1,2 Coarctation of the aorta (CoA), considered a moderately complex form of CHD, was first described by Morgagni in 1760.3 It occurs in approximately 0.04% of the population, and accounts for approximately 5% of all congenital heart defects.4 It makes up approximately 10% of lesions in adults with CHD (ACHD), and occurs twofold to fivefold more often in men than in women.5 CoA can occur as an isolated lesion or as a part of a complex defect in the presence of other intracardiac lesions. Most commonly, this includes bicuspid aortic valve (≤85%), mitral valve abnormalities, or ventricular septal defects. Others include transposition of the great arteries, Taussig– Bing anomaly, and hypoplastic left heart syndrome. Patients with Turner’s, Noonan’s, and Williams–Beuren syndromes can have CoA, and various gene deletions have been described. One such gene mutation involves the NOTCH1 gene.6-10

Morphology The morphology of CoA is a spectrum, and varies widely based on the age at presentation. For example, transverse arch and isthmus hypoplasia is most commonly seen in the newborn period, whereas discrete localized

© RADCLIFFE CARDIOLOGY 2019

stenosis or membrane-like obstruction just beyond the left subclavian artery is more often encountered in older children and adults.11,12 More unusual locations include the ascending aorta and abdominal aorta. The etiology of CoA remains unclear. The primary mechanism is thought to be medial thickening and intimal hyperplasia that leads to the formation of a posterolateral ridge that encircles the aortic lumen, resulting in the CoA segment. Another theory is that of aberrant ductal tissue and abnormal intrauterine blood flow through the aortic arch.8,9

Presentation Although most cases of CoA are diagnosed in infancy, some patients may not present until later childhood, adolescence, or adulthood (Figure 1).

The age at presentation is primarily dependent upon the degree of stenosis across the coarcted segment. For example, severe CoA can lead to heart failure and shock upon closure of the ductus arteriosus in infancy.13 Milder forms, in contrast, may not be detected until the patient is much older.

Patients with extensive collateral vessels that bypass the area of CoA can remain asymptomatic for many years.14,15 Indeed, although the natural history of untreated CoA is associated with a mean life expectancy of approximately 35 years, there are reports of untreated patients living to 92 years.16 The most common presenting finding is systemic hypertension measured in the upper extremities. Others can include cardiac failure or endocarditis.10,11,17 Older patients may complain of symptoms, such as headache, dizziness, tinnitus, abdominal angina, and exertional leg fatigue.

Access at: www.USCjournal.com

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Congenital Heart Disease Figure 1: Coarctation MRI

such as systemic hypertension, heart failure, and coronary artery disease. Complications from coarctation surgery can include spinal cord damage, pleural effusions, phrenic, or laryngeal nerve paralysis, paradoxical hypertension, and infection.23 As a result, such older patients are often best managed by non-surgical approaches.

Transcatheter Treatment

Coarctation

Collateral vessel

Transcatheter treatment of CoA became popular with the advent of balloon angioplasty by Lock et al. in 1983.24 In fact, for patients aged >4 years or weighing >15 kg, transcatheter therapy for both native and especially recurrent CoA has become the standard of care in the majority of institutions.25 Guidelines published in 2011 by the American College of Cardiology/American Heart Association for transcatheter treatment for primary and recurrent CoA further allowed for balloon angioplasty and/ or stenting when a peak-to-peak gradient of â&#x2030;Ľ20 mmHg at the time of cardiac catheterization was evident. It should be noted, however, that interventions may be warranted with less severe gradients if there is systemic hypertension with imaging evidence of a significant narrowing.20

Balloon Angioplasty

aorta nv.,

Ascending aorta

Doppler ere CoA

oA

Successful relief of stenosis by balloon angioplasty is accomplished by damage to the aortic intima and media, the degree of which is often difficult to control. The major drawbacks are recoil of the vessel with recurrence of stenosis and vascular injury with consequent vessel dissection or aneurysm formation.26 In addition, elastic fiber fragmentation, underlying fibrosis, cystic medial necrosis, and vascular calcification may predispose patients to dissection, aneurysm formation, or even rupture at the time of repair.12,27

Bare Metal Stent Placement Cardiac MRI of a 53-year-old patient with severe coarctation and evidence of collateral flow.

Management Several treatment options for CoA are now available, and include both surgical and transcatheter interventions. The decision on the optimal treatment method can be complicated, and there is no evidencebased standard of care. In general, management is guided by the age at presentation, and the complexity of the coarctation and/or associated defects.

Surgical Intervention The first surgical repair of CoA was performed in 1944 by Crafoord and Nylin. 18 Over the ensuing 40 years, refinement in surgical techniques expanded the available surgical options and included patch augmentation, end-to-end anastomosis, and even the insertion of a Gore-Tex bypass graft with more complex anatomy.12 Another surgical approach was the subclavian flap, whereby augmentation of the coarcted segment was performed using the subclavian artery as a surgical flap.19 Today, the surgical risk is estimated to be <1% in patients with simple CoA, and surgery remains the preferred method of treatment in infants. In the critically ill infant, older child, or adolescent, however, a less invasive method employing transcatheter treatment is often favored.20â&#x20AC;&#x201C;22 This is particularly true after the third or fourth decade of life, when intraoperative morbidity and mortality increases as a result of degenerative aortic wall changes and comorbid conditions,

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Intravascular bare metal stent placement was first performed by Oâ&#x20AC;&#x2122;Laughlin et al. in 1993 and, at many centers, became the treatment of choice for children and adults with native CoA.28 The goal of using bare metal stents was to avoid dissection, excessive dilation, and elastic recoil of the aorta. It was also believed to result in less vascular injury than balloon angioplasty alone.29 In a study comparing surgical repair, balloon angioplasty, and stent treatment of native CoA in children, stented patients had significantly lower acute complications compared with those who had undergone surgical or balloon angioplasty repair.30 Bare metal stents were also shown to be more effective at achieving acute and sustained reductions in blood pressure gradients. As a result, stent therapy for CoA became the preferred intervention over balloon angioplasty for older children and adults.31 Nevertheless, although rare, complications such as aneurysm formation, stent malposition, vascular complications, death, and the need for emergency surgery can occur.32,33

Covered Stent Placement To this end, perhaps one of the most important advances in the management of CoA has been the development of covered stent technology (Figure 2). First used in 1999 to treat coexistent CoA and aneurysm of the aorta in a young man, it has since been used in a variety of settings, and an array of covered stents have become available for clinical use.34,35 Indications for the use of covered stents are now wideranging and continue to expand. In CoA patients, they are preferentially

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Coarctation: A Review deployed in a number of situations, including the treatment of associated aneurysms, native CoA with near-interruption, associated patent ductus arteriosus, and in older patients due to the potential for aortic disruption (Figure 1).36,37 In addition, where exclusion of the left subclavian artery is anticipated, wire perforation of the covered stent followed by balloon angioplasty through a stent cell has allowed for a recannulized vessel.38 Covered stents can also be used as a rescue treatment in patients with stent complications and in patients with complex CoA anatomy. Potential physiological benefits following stenting include mid-term left ventricular mass regression, ventricular function improvement, and improvement in central aortic function with reduction of daytime ambulatory systolic blood pressure such that anti-hypertensive medication can often be discontinued.39,40 Follow-up with CT examination suggests that the overall development of aneurysms continues to be low.36,41–44 Despite all the potential advantages seen with covered stents, aggressive surveillance remains necessary to screen for long-term complications.

Figure 2: Coarctation Angiogram with Stent

Covered stent

Descending aorta

Ascending aorta

Long-term Complications While symptoms and survival are improved after surgical or transcatheter intervention, the long-term survival of CoA patients continues to be lower than in the general population.10 Late complications can include systemic hypertension, recurrent CoA, aneurysm formation at the site of previous repair, early coronary artery disease, and intracranial aneurysm.

Systemic hypertension, even after excellent repair, remains common, and can lead to stroke, myocardial infarction, and heart failure. The estimated prevalence ranges from 25% to 68%, and is especially common in patients with concomitant aortic arch hypoplasia or in patients who underwent repair at a later age.45 It is believed that systemic hypertension results from increased aortic stiffness, decreased baroreceptor sensitivity, raised plasma concentrations of epinephrine and norepinephrine, or coexisting essential hypertension.46,47 Another factor may be a hypoplastic aortic arch that was not corrected at the time of initial treatment. As hypertension may not be evident at rest or during the routine clinic visit, ambulatory blood pressure monitoring and exercise testing to evaluate for exercise-induced hypertension are often employed.48 Even in the absence of early complications with good initial relief of obstruction, recurrent CoA and aneurysm formation at the site of coarctation repair are seen. Recoarctation at the site of previous repair or residual coarctation are important causes of morbidity, as it can lead to worsening systemic hypertension, coronary artery disease, or systolic and diastolic heart failure. Studies have found the rate of recoarctation to be between 3% and 15%.16,49–51 While recoarctation or residual stenosis may occur with all surgical techniques, a study by Choudary et al. demonstrated a lower rate of significant recoarctation with the end-to-end anastomosis repair.52 Indeed, the extended end-to-end anastomosis is typically preferred, as it allows resection of the coarctation while avoiding prosthetic material and is less prone to restenosis.20 Aneurysm and pseudoaneurysm formation, both of the ascending aorta and in the region of the aortic isthmus, if left untreated, can lead to

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Aortic angiogram in a 54-year-old patient shows severe coarctation of the aorta status-post delivery of a Cheatham-platinum-covered stent (NuMed, Inv., Hopkington, NY, US; 8-Zig 34 mm on 16 mm × 3.5 mm BIB).

rupture with rates up to 100% within 15 years.19 The incidence of early and late aneurysm formation after balloon angioplasty has been reported to be between 5% and 11.5%.29,53 It is felt that associated bicuspid aortic valve, aortic wall changes, and systemic hypertension are largely responsible for aneurysm formation in the ascending aorta.54 Aneurysm formation at the region of the aortic isthmus does not appear to be related to the presence of an intimal tear at the time of the initial procedure and, indeed, the majority of aneurysms tend to be small and discrete. Still, intervention is required for late aneurysm formation in patients after balloon dilation of native recurrent CoA.55 As with recoarctation, most surgical types carry a risk of aneurysm formation.

It is felt, however, that the end-to-end anastomosis repair may carry the lowest risk.52 Because of the risk of recoarctation, residual stenosis, and aneurysm formation, all patients need careful follow-up after coarctation repair. While evidence of recoarctation may be detected by a clinical examination and echocardiography (Figure 3A–C), cardiac MRI (CMR) (Figure 1) or CT angiography (CTA) (Figure 4) are recommended to evaluate for aneurysm and/or pseudoaneurysm formation.56 Early coronary artery disease (CAD) is also described.12,57,58 The etiology of CAD is not well understood, but thought to be related to long-standing hypertension. In a study from the Mayo Clinic, CAD was the most common cause of late postoperative death.59 A Canadian study later found that CoA was not a sole predictor for the development of coronary artery disease, and called into question the prevalence of CAD in patients with a history of CoA.60

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Congenital Heart Disease Figure 3: Coarctation Echocardiogram and Angiogram

Transverse aortic arch

Figure 4: Coarctation CT Image

Descending aortic arch

Coarctation

Coarctation

Ascending aorta

Descending aorta

200

0 + c m 200 / s _ CT angiography in a 54-year-old patient with severe coarctation of the aorta.

400

600 Ascending aorta

Transverse arch

size tends to increase with age, and uncontrolled hypertension increases the risk of rupture.62 Given this, screening for cerebrovascular aneurysms is recommended. 56 It should be noted, however, that routine screening for aneurysms remains a matter of debate amongst some practitioners.63

Follow-up Assessment

Coarctation

Descending aorta

(A) Echocardiography of 54-year-old patient with severe coarctation of the aorta and (B) mean Doppler gradient of nearly 42 mmHg. (C) Aortic angiogram in same patient shows severe coarctation of the aorta with a minimal diameter of 7 mm.

Finally, there is an association of CoA and extracardiac lesions, mainly intracranial aneurysms (i.e. berry aneurysm of the circle of Willis) in up to 10% of patients.10 The reason for this is not clear, but might be a consequence of e has been found to be a risk factor.61 Aneurysm

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Whether the patient has undergone a surgical or transcatheter treatment, follow-up care is required such that long-term complications can be identified and treated. The type and frequency of testing is largely guided by symptoms and the clinical examination, although often includes additional testing to evaluate for issues that may not be evident by physical findings or echocardiography alone. Resting blood pressure, measured in the upper and lower extremities, is important, as a systolic blood pressure discrepancy along with a delay between the brachial to femoral pulses and/or vascular murmur heard between the scapulae could hint toward recoarctation or residual stenosis.13,64 As hypertension may not be evident at rest or during the routine clinic visit, ambulatory blood pressure monitoring and exercise testing to evaluate for exercise-induced hypertension are often employed.48 Electrocardiography may demonstrate left atrial or ventricular pressure load or left ventricular strain. Chest radiography, while non-specific in the young patient, may demonstrate â&#x20AC;&#x2DC;the figure of 3â&#x20AC;&#x2122; sign beneath the aortic knob, which is characteristic of native or recoarctation. Rib notching due to dilated intercostal arteries may also be present in older patients.22,65 Given the widespread availability and ease of use, the mainstay of the imaging evaluation remains the echocardiogram (Figure 3A and 3B). From the suprasternal notch view, the anatomy of the site of CoA is often well visualized, and a mean Doppler gradient

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Coarctation: A Review >20 mmHg or mean Doppler gradient >10 mmHg in the setting of left ventricular systolic dysfunction or aortic valve regurgitation suggests that intervention may be necessary.48,66,67 To further delineate the anatomy, the echocardiographic evaluation should be coupled with advanced imaging, such as CMR or CTA (Figure 4). Indeed, CMR and CTA have become the preferred non-invasive means to evaluate coarctation before and after operative and transcatheter treatment in adults. This is particularly important to evaluate for the presence of aneurysm and/ or pseudoaneurysm formation. At cardiac catheterization, a significant coarctation is defined as a peak-to-peak gradient >20 mmHg across the coarctation in the absence of significant collateral circulation. While this type of diagnostic testing was frequently used in the past, it is now primarily reserved for intervention or where additional hemodynamic information is required.55,65

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Connolly HM, Huston J 3rd, Brown RD Jr, et al. Intracranial aneurysms in patients with coarctation of the aorta: a prospective magnetic resonance angiographic study of 100 patients. Mayo Clin Proc 2003;78:1491–9. https://doi. org/10.4065/78.12.1491; PMID: 14661678.

Kenny D, Hijazi ZM. Coarctation of the aorta: from fetal life to adulthood. Cardiol J 2011;18:487–95. https://doi.org/10.5603/ CJ.2011.0003; PMID: 21947983.

Qureshi SA. Use of covered stents to treat coarctation of the aorta. Korean Circ J 2009;39:261–3. https://doi.org/10.4070/ kcj.2009.39.7.261; PMID: 19949609.

Ward KE, Pryor RW, Matson JR, et al. Delayed detection of coarctation in infancy: implications for timing of newborn follow-up. Pediatrics 1990;86:972–6. PMID: 2251033.

Steffens JC, Bourne MW, Sakuma H, et al. Quantification of collateral blood flow in coarctation of the aorta by velocity encoded cine magnetic resonance imaging. Circulation 1994;90:937–43. https://doi.org/10.1161/01.CIR.90.2.937; PMID: 8044965.

Leschka S, Alkadhi H, Wildermuth S. Collateral circulation in aortic coarctation shown by 64 channel multislice computed tomography angiography. Heart 2005;91:1422. https://doi. org/10.1136/hrt.2004.054346; PMID: 16230439.

Perloff J, Child J, Aboulhosn J. Congenital Heart Disease in Adults.

3rd ed. Philadelphia, PA: Saunders Elsevier, 2008.

Webb G. Treatment of coarctation and late complications in the adult. Semin Thorac Cardiovasc Surg 2005;17:139–42. https://doi.org/10.1053/j.semtcvs.2005.03.001; PMID: 16087083.

Crafoord C, Nyhlin G. Congenital coarctation of the aorta and its surgical treatment. J Thorac Surg 1945;14:347–61. von Kodolitsch Y, Aydin MA, Koschyk DH, et al. Predictors of aneurysmal formation after surgical correction of aortic

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Conclusion CoA is a complex lifelong heterogeneous disease process with multiple associated complications both with and without treatment. Although significant advances in the recognition and treatment of patients with CoA have taken place, continued and aggressive screening and management of patients with CoA are vital. Follow-up needs to include thorough evaluation for late complications, including systemic hypertension, coronary artery disease, recurrent obstruction, and aneurysm formation.

Given the limitation of clinical examination and echocardiography alone, advanced imaging techniques, including CMR or CTA, are necessary.

A thorough evaluation is particularly important whenever systemic hypertension is present to ensure that recoarctation or residual stenosis is not present. Treatment, if necessary, should be performed in centers with extensive experience with CoA.

coarctation. J Am Coll Cardiol 2002;39:617–24. https://doi. org/10.1016/S0735-1097(01)01784-3; PMID: 11849860.

Feltes TF, Bacha E, Beekman RH 3rd, et al. Indications for cardiac catheterization and intervention in pediatric cardiac disease: a scientific statement from the American Heart Association. Circulation 2011;123:2607–52. https://doi. org/10.1161/CIR.0b013e31821b1f10; PMID: 21536996.

Kische S, D’Ancona G, Stoeckicht Y, et al. Percutaneous treatment of adult isthmic aortic coarctation: acute and long-term clinical and imaging outcome with self-expandable uncovered nitinol stent. Circ Cardiovasc Interv 2015;8:e001799. https://doi.org/10.1161/CIRCINTERVENTIONS.114.001799; PMID: 25582143.

Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines (Writing Committee to develop guidelines on the management of adults with congenital heart disease). J Am Coll Cardiol 2008;52:e143–263. https://doi.org/10.1016/j.jacc.2008.10.001; PMID: 19038677.

Bouchart F, Dubar A, Tabley A, et al. Coarctation of the aorta in adults: surgical results and long-term follow-up. Ann Thorac Surg 2000;70:1483–8. https://doi.org/10.1016/S0003-4975(00)01999-8; PMID: 11093474.

Lock JE, Bass JL, Amplatz K, et al. Balloon dilation angioplasty of aortic coarctations in infants and children. Circulation 1983;68:109–16. https://doi.org/10.1161/01.CIR.68.1.109; PMID: 6221828.

Turner DR, Forbes TJ. Interventional therapy for coarctation of the aorta. Cardiac Interventions Today 2009:50–5.

Butera G, Piazza L, Chessa M, et al. Covered stents in patients with congenital heart defects. Catheter Cardiovasc Interv 2006;67:466–72. https://doi.org/10.1002/ccd.20652; PMID: 16502401.

Isner JM, Donaldson RF, Fulton D, et al. Cystic medial necrosis in coarctation of the aorta: a potential factor contributing to adverse consequences observed after percutaneous balloon angioplasty of coarctation sites. Circulation 1987;75:689–95. https://doi.org/10.1161/01.CIR.75.4.689; PMID: 2951035.

O’Laughlin MP, Slack MC, Grifka RG, et al. Implantation and intermediate-term follow-up of stents in congenital heart disease. Circulation 1993;88:605–14. https://doi.org/10.1161/01.

CIR.88.2.605; PMID: 8339424.

Mendelsohn AM, Lloyd TR, Crowley DC, et al. Late follow-up of balloon angioplasty in children with a native coarctation of the aorta. Am J Cardiol 1994;74:696–700. https://doi. org/10.1016/0002-9149(94)90312-3; PMID: 7942528.

Forbes TJ, Kim DW, Du W, et al. Comparison of surgical, stent, and balloon angioplasty treatment of native coarctation of the aorta: an observational study by the CCISC (Congenital Cardiovascular Interventional Study Consortium). J Am Coll Cardiol 2011;58:2664–74. https://doi.org/10.1016/j.jacc.2011.08.053; PMID: 22152954.

Zabal C, Attie F, Rosas M, et al. The adult patient with native coarctation of the aorta: balloon angioplasty or primary stenting? Heart 2003;89:77–83. https://doi.org/10.1136/ heart.89.1.77; PMID: 12482798.

Forbes TJ, Garekar S, Amin Z, et al. Procedural results and acute complications in stenting native and recurrent coarctation of the aorta in patients over 4 years of age: a multi-institutional study. Catheter Cardiovasc Interv 2007;70:276–85. https://doi. org/10.1002/ccd.21164; PMID: 17630670.

Forbes TJ, Moore P, Pedra CA, et al. Intermediate follow-up following intravascular stenting for treatment of coarctation of the aorta. Catheter Cardiovasc Interv 2007;70:569–77. https://doi. org/10.1002/ccd.21191; PMID: 17896405.

34. G unn J, Cleveland T, Gaines P. Covered stent to treat co-existent coarctation and aneurysm of the aorta in a young man.

Heart 1999;82:351. https://doi.org/10.1136/hrt.82.3.351; PMID: 10455088.

35. Ewert P, Schubert S, Peters B, et al. The CP stent -- short, long, covered -- for the treatment of aortic coarctation, stenosis of pulmonary arteries and caval veins, and Fontan anastomosis in children and adults: an evaluation of 60 stents in 53 patients.

Heart 2005;91:948–53. https://doi.org/10.1136/hrt.2004.040071; PMID: 15958369.

36. Kenny D, Margey R, Turner MS, et al. Self-expanding and balloon expandable covered stents in the treatment of aortic coarctation with or without aneurysm formation. Catheter Cardiovasc Interv 2008;72:65–71. https://doi.org/10.1002/ ccd.21559; PMID: 18412235.

37. Tan JL, Mullen M. Emergency stent graft deployment for acute aortic rupture following primary stenting for aortic coarctation.

Catheter Cardiovasc Interv 2005;65: 306–9. https://doi.org/10.1002/ ccd.20370; PMID: 15900549.

38. Tsai SF, Hill SL, Cheatham JP. Treatment of aortic arch aneurysm with a NuMED-covered stent and restoration of flow to excluded left subclavian artery: perforation and dilation of e-PTFE can be done! Catheter Cardiovasc Interv 2009;73:385–9. https://doi.org/10.1002/ccd.21825; PMID: 19133685.

39. Chen SS, Donald AE, Storry C, et al. Impact of aortic stenting on peripheral vascular function and daytime systolic blood pressure in adult coarctation. Heart 2008;94:919–24. https://doi. org/10.1136/hrt.2006.109389; PMID: 17686804.

40. Lam YY, Kaya MG, Li W, et al. Effect of endovascular stenting of aortic coarctation on biventricular 392 function in adults.

Heart 2007;93:1441–7. https://doi.org/10.1136/hrt.2006.106377; PMID: 17575331.

41. Tzifa A, Ewert P, Brzezinska-Rajszys G, et al. Covered Cheathamplatinum stents for aortic coarctation: early and intermediateterm results. J Am Coll Cardiol 2006;47:1457–63. https://doi. org/10.1016/j.jacc.2005.11.061; PMID: 16580536.

42. Chakrabarti S, Kenny D, Morgan G, et al. Balloon expandable stent implantation for native and recurrent coarctation of the aorta – prospective computed tomography assessment of stent integrity, aneurysm formation and stenosis relief. Heart 2010;96:1212–6. https://doi.org/10.1136/hrt.2009.170928; PMID: 19744966.

43. Pedra CA, Fontes VF, Esteves CA, et al. Use of covered stents in the management of coarctation of the aorta. Pediatr Cardiol 2005;26:431–9. https://doi.org/10.1007/s00246-004-0814-2; PMID: 15549617.

44. Tanous D, Collins N, Dehghani P, et al. Covered stents in the management of coarctation of the aorta in the adult: initial results and 1-year angiographic and hemodynamic followup. Int J Cardiol 2010;140:287–95. https://doi.org/10.1016/j. ijcard.2008.11.085; PMID: 19100637.

45. Canniffe C, Ou P, Walsh K, et al. Hypertension after repair of aortic coarctation: a systematic review. Int J Cardiol 2013;167:2456–61. https://doi.org/10.1016/j.ijcard.2012.09.084; PMID: 23041096.

46. Kaemmerer H, Hager A, Hess J. Coarctation of the aorta in adults. SA Heart 2007;4:4–12. https://doi.org/10.24170/4-4-2064.

47. Vriend JW, Zwinderman AH, de Groot E, et al. Predictive value of mild, residual descending aorta narrowing for blood pressure and vascular damage in patients after repair of aortic coarctation. Eur Heart J 2005;26:84–90. https://doi.org/10.1093/ eurheartj/ehi004; PMID: 15615804.

48. Hager A, Kanz S, Kaemmerer H, et al. Coarctation Long-term Assessment (COALA): significance of arterial hypertension in a cohort of 404 patients up to 27 years after surgical repair of isolated coarctation of the aorta, even in the absence

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Connelly MS, Webb GD, Somerville J, et al. Canadian consensus conference on adult congenital heart disease 1996. Can J Cardiol 1998;14:395–452. PMID: 9551034.

Adams EE, Davidson Jr WR, Swallow NA, et al. Long-term results of the subclavian flap repair for coarctation of the aorta in infants. World J Pediatr Congenit Heart Surg 2013;4:13–8. https://doi. org/10.1177/2150135112466878; PMID: 23799749.

Pandey R, Jackson M, Ajab S, et al. Subclavian flap repair: review of 399 patients at median follow-up of fourteen years.

Ann Thorac Surg 2006:81:1420–8. https://doi.org/10.1016/j. athoracsur.2005.08.070; PMID: 16564285.

Choudary P, Canniffe C, Jackson DJ, et al. Late outcomes in adults with coarctation of the aorta. Heart 2015;101:1190–5. https://doi.org/10.1136/heartjnl-2014-307035; PMID: 25810155.

Rao PS, Galagl O, Smith PA, et al. Five- to nine-year followup results of balloon angioplasty of native aortic coarctation in infants and children. J Am Coll Cardiol 1996;27:462–70. https://doi.org/10.1016/0735-1097(95)00479-3; PMID: 8557921.

Niwa K, Perloff JK, Bhuta SM, et al. Structural abnormalities of great arterial walls in congenital heart disease: light and electron microscopic analyses. Circulation 2001;103:393–400. https://doi.org/10.1161/01.CIR.103.3.393; PMID: 11157691.

Forbes T, Matisoff D, Dysart J, et al. Treatment of coexistent coarctation and aneurysm of the aorta with covered stent in a pediatric patient. Pediatr Cardiol 2003;24:289–91. https://doi.

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56. S tout KK, Daniels CJ, Aboulhosn JA, et al. 2018 ACC/AHA guidelines on adult congenital heart disease: Executive summary: A report of the American College of Cardiology/ American Heart Association task force on clinical practice guidelines. Circulation 2019;139:e637–e697. https://doi. org/10.1161/CIR.0000000000000602; PMID: 30586768.

57. Clarkson PM, Nicholson MR, Barratt-Boyes BG, et al. Results after repair of coarctation of the aorta beyond infancy: a 10 to 28 year follow-up with particular reference to late systemic hypertension. Am J Cardiol 1983;51:1481–8. https://doi.org/10.1016/0002-9149(83)90661-6; PMID: 6846181.

58. Kenny D, Polson JW, Martin RP, et al. Hypertension and coarctation of the aorta: an inevitable consequence of developmental pathophysiology. Hypertens Res 2011;34:543-7. https://doi.org/10.1038/hr.2011.22; PMID: 21412243.

59. Cohen M, Fuster V, Steele PM, et al. Coarctation of the aorta.

Long-term follow-up and prediction of outcome after surgical correction. Circulation 1989;80:840–5. https://doi.org/10.1161/01.

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60. Roifman I, Therrien J, Ionescu-Ittu R, et al. Coarctation of the aorta and coronary artery disease: fact or fiction?

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61. Cook SC, Hickey J, Maul TM, et al. Assessment of the cerebral circulation in adults with coarctation of the aorta. Congenit Heart Dis 2013;8:289–95. https://doi.org/10.1111/chd.12024; PMID: 23279961.

62. W u MH, Chen HC, Kao FY, et al. Risk of systemic hypertension and cerebrovascular accident in patients with aortic coarctation aged >60 years (from a national database study). Am J Cardiol 2015;116:779–84. https://doi.org/10.1016/j.amjcard.2015.05.052; PMID: 26100586.

63. Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103–10. https://doi.org/10.1016/S0140-6736(03)138603; PMID: 12867109.

64. Strafford MA, Griffiths SP, Gersony WM. Coarctation of the aorta: a study in delayed detection. Pediatrics 1982:69:159–63.

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65. Karaogmanoglu AD, Khawaja RD, Onur MR, et al. CT and MRI of aortic coarctation: pre- and post-surgical findings. AJR Am J Roentgenol 2015:204:W224–33. https://doi.org/10.2214/ AJR.14.12529; PMID: 25714305.

66. Holzer R, Qureshi S, Ghasemi A, et al. Stenting of aortic coarctation: acute, intermediate, and long-term results of a prospective multi-institutional registry – Congenital Cardiovascular Interventional Study Consortium (CCISC).

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67. Brown JW, Ruzmetov M, Hoyer MH, et al. Recurrent coarctation: is surgical repair of recurrent coarctation of the aorta safe and effective? Ann Thorac Surg 2009;88:1923–30. https://doi.org/10.1016/j.athoracsur.2009.07.024; PMID: 19932264.

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Annual Meetings

Major Cardiovascular Advances: Highlights from the 2019 American College of Cardiology Annual Scientific Session Hisham A Badreldin, PharmD, BCPS, ASH-CHC, Khalid bin Saleh, PharmD, BCPS, and Majed Al Yami, PharmD, BCPS, ASH-CHC King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Abstract The 69th American College of Cardiology Annual Scientific Session and Expo was held in New Orleans, Louisiana on March 16–18, 2019. For many years this meeting has gathered together an enormous number of participants, abstracts, oral presentations, poster presentations, educational sessions, late-breaking clinical trial results, and clinical practice guidelines under one roof. The authors have selected and summarized the key points from a number of key landmark trials, featured clinical research results and clinical practice guidelines that were presented during this year’s meeting.

Keywords American College of Cardiology, late-breaking clinical trials, clinical practice guidelines Disclosure: The authors have no conflicts of interest to declare Received: April 1, 2019 Accepted: May 14, 2019 Citation: US Cardiology Review 2019;13(2):105–9. DOI: https://doi.org/10.15420/usc.2019.11.2 Correspondence: Hisham A Badreldin, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, PO Box 3660, Riyadh 11481, Saudi Arabia; E: hbadreldin@gwmail.gwu.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.

WRAP-IT The Worldwide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT) was a prospective multicenter study to determine the safety and efficacy of an absorbable surgical mesh envelope containing two antibiotics (minocycline and rifampin) in reducing infection incidence in patients with cardiac implantable electronic devices compared to standard care.1 Approximately 7,000 patients were included in this trial. The primary composite endpoint was infection resulting in device removal or revision, long-term antibiotic therapy with infection recurrence, or mortality within 12 months after the implantation procedure.

primary endpoint (all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen at 6 months). In their study, Bundgaard et al. reported that in the longterm POET follow-up, at a median of 3.5 years, the primary outcome had occurred in 26.4% of the oral antibiotics group compared with 38.2% of the intravenous antibiotics group (p=0.01).3 Interestingly, all-cause mortality at the end of follow-up was 16.4% in the oral antibiotics group versus 27.1% in the intravenous antibiotics group (p<0.05). The results of this trial might ultimately reduce hospital length of stay as well as peripherally inserted central catheter-related complications.

HoT-PE During his presentation, Tarakji et al. announced that the primary endpoint had been met in 0.7% of the envelope group and 1.2% of the control group (HR 0.60; 95% CI [0.36–0.98]; p=0.04).1 Given the high envelope price, a rationale would be helpful to determine which patient population with cardiac implantable electronic devices might benefit from the implantation of that envelope.

POET Long-term Follow-up The original Partial Oral Treatment of Endocarditis (POET) trial was a multicenter randomized, non-inferiority trial comparing the efficacy of intravenous antibiotics with oral antibiotics in stable patients with infective endocarditis of the left side of the heart.2 Overall, there was no difference between the two groups with regards to the composite

© RADCLIFFE CARDIOLOGY 2019

The prospective, multicenter, single-arm Home Treatment of Pulmonary Embolism (HoT-PE) trial assessed the safety and efficacy of early discharge and out-of-hospital treatment with rivaroxaban 15 mg twice daily in 525 patients with low-risk pulmonary embolism.4 The majority of participants were Caucasian (98.5%) and the patients had an average age of 56.7 years. The primary outcome was recurrent symptomatic venous thromboembolism or death due to recurrent pulmonary embolism within 3 months. According to Konstantinides et al., of the 525 patients included in the interim analysis, three patients developed symptomatic non-fatal venous thromboembolism recurrence (0.6%; one-sided upper 99.6% CI [2.1%]), Major bleeding occurred in 6 (1.2%) patients. Of note, the median length of hospital stay was 34 hours, with 93.6% of the patients being discharged within 48 hours.4

Access at: www.USCjournal.com

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Annual Meetings These results support the initiation of rivaroxaban in the emergency department and the early discharge of low-risk pulmonary embolism patients without the need for parenteral anticoagulation or extended hospital stay.

PARTNER 3 and Evolut Transcatheter The results from two studies on the safety and efficacy of transcatheter valves in low-risk patients with aortic stenosis were presented: the Safety and Effectiveness of the SAPIEN 2 Transcatheter Heart Valve in Low Risk Patients with Aortic Stenosis (PARTNER 3) and Medtronic Evolut Transcatheter Aortic Valve Replacement in Low Risk Patients study.

PARTNER 3 compared transfemoral transcatheter aortic valve replacement (TAVR) with surgery in 1,000 patients. Participants had severe aortic stenosis and a low risk of surgery, and were randomly assigned to undergo balloon-expandable TAVR or surgical aortic valve replacement in this multicenter study.5 The average age of participants in both groups was 73 years and the average Society of Thoracic Surgeons risk score was 1.9%. The primary endpoint included a composite of death from any cause, rehospitalization, and stroke at 1 year.

Mack et al. informed delegates that the PARTNER 3 results favored TAVR, with 8.5% of the TAVR group versus 15.1% of the surgical group experiencing the primary endpoint (absolute difference −6.6 percentage points; 95% CI [−10.8 to −2.5]; p<0.001 for non-inferiority; HR 0.54; 95% CI [0.37–0.79]; p=0.001 for superiority). Of note, Mack et al. also revealed that patients who underwent TAVR had statistically significantly lower rates of stroke, death, or stroke, and new-onset AF at 30 days.5 The Medtronic Evolut Transcatheter Aortic Valve Replacement in Low Risk Patients trial assessed the efficacy and safety of using TAVR with a self-expanding supraannular bioprosthesis versus surgical aortic-valve replacement in patients with severe aortic stenosis deemed to have a low risk for surgery.6 A total of 1,403 patients were enrolled, 65% were men, with an average age of 74 years. The primary endpoint was a composite outcome of death or disabling stroke at 24 months.

It was reported that the primary endpoint occurred in 5.3% of the TAVR group and 6.7% of the surgical aortic-valve replacement group. Popma et al. stated that this met the statistical significance margin for noninferiority but not for superiority; TAVR was therefore the better treatment option in this patient group.6 Hopefully, the Centers for Medicare and Medicaid will provide coverage for this management modality in low-risk patients once the Food and Drug Administration approves its use in this patient population as a result of the positive outcomes of these two trials.5 According to Reardon et al., it might be reasonable to consider moving TAVR in low-risk patients with severe aortic stenosis to a class I guideline indication.7 The results of these two trials may alter the entire level of aortic stenosis management.7

MOMENTUM-3 Final Report Mehra et al. presented the final report from the open-label Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3; NCT02224755). In this trial, approximately 1,000 patients with advanced heart failure from more

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than 60 different sites were randomized to receive either the centrifugalflow pump HeartMate 3 or the axial-flow pump HeartMate 2 between September 2014 and August 2016.8 The average age of patients was 59.5 years, and two-thirds were men. Almost half of these patients had heart failure as a result of an ischemic event. All patients had reduced ejection fraction. Destination therapy was intended for >50% of patients enrolled in both groups.

The composite primary endpoint of survival free from disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years occurred in 76.9% of the HeartMate 3 group and 64.8% of the HeartMate 2 group, according to Mehra et al.8 Both the non-inferiority criterion and the superiority criterion were statistically significantly in favor of the HeartMate 3. The results of this study will improve quality of life for patients with advanced heart failure, as well as adding many years to their lifespan.

Hopeful Heart In the Blended Collaborative Care for Heart Failure and Co-Morbid Depression (Hopeful Heart; NCT02044211) study, investigators randomized 500 patients with heart failure and depression to receive blended collaborative care for heart failure and depression or collaborative care for heart failure alone. At 12 months, the blended collaborative care for depression and heart failure significantly improved mental health-related quality of life and mood symptoms, according to Herbeck Belnap et al.

However, blended collaborative care did not have an impact on the incidence of readmission or mortality. The results of this study reinforce the role of blended collaborative care in managing cardiac patients suffering from other comorbidities.9

CODIACS-QOL In the COmparison of Depression Identification after Acute Coronary Syndrome: Quality of Life and cost outcomes (CODIACS-QOL; NCT01993017) trial, investigators randomized 1,500 patients with recent acute coronary syndrome (ACS) to receive either depression screening, depression screening and treatment, or no depression screening.

At 18 months, this study failed to detect any statistical difference in quality-adjusted life-years from baseline between the three groups. It was therefore concluded that screening patients with recent ACS for depression was not beneficial.

PANACHE Trial In the Trial to Study Neladenoson Bialanate Over 20 Weeks in Patients with Chronic Heart Failure with Preserved Ejection Fraction (PANACHE; NCT03098979), investigators randomized more than 300 patients with heart failure with preserved ejection fraction to receive either neladenoson (an adenosine A1 receptor agonist) or placebo. At 20 weeks, there was no significant difference between the groups in terms of the primary endpoint, which was change in 6-minute walking distance.

Apple Heart Study Over 400,000 individuals with an Apple Watch and iPhone were enrolled in the Apple Heart Study to evaluate the ability of the optical sensor in the Apple Watch to identify pulse irregularity (AF) and make a subsequent clinical evaluation (NCT03335800). The average age of participants was 41 years, almost 60% were men, and 13% had a CHA2DS2-VASc score of >2.

US CARDIOLOGY REVIEW

Major Cardiovascular Advances Turakhia, who presented the results of this study, revealed that <1% (n=2,161) of those enrolled had received notification that they had an irregular rhythm. The majority of those who had received the notification were elderly and men. Following notification, 658 participants were sent a Food and Drug Administration-approved ECG patch analysis; AF was detected in 34% of these patches.10 For patients wearing both an ECG patch and their watch simultaneously, the positive predictive values for the tachogram and the notification were 0.71 (95% CI [0.69–0.74]) and 0.84 (95% CI [0.76–0.92]), respectively. Approximately 20% of these patients were found to have AF all of the time, and almost 90% had AF durations of at least 1 hour. Of the 2,161 individuals who received a notification, around 30% were started on a new medication, 30% were referred to a specialist, and the remaining individuals required additional investigation and testing.

The investigators concluded that the use of this technology was associated with a low proportion of notification. However, in those who were notified, the relatively high positive predictive values may support the ability to identify pulse irregularity correctly. Turakhia pointed out that the results of this study should not be the sole determinant of pulse irregularity, and that clinicians should continue to look for other risk factors, provide thorough physical examinations and take a good history.10

PIONEER-HF In their study, Velazquez et al. reported the results of the Comparison of Sacubitril/Valsartan versus Enalapril on Effect on NT-proBNP in patients Stabilized from an Acute Heart Failure Episode (PIONEER-HF) trial.11 The investigators randomized more than 800 patients with acute decompensated heart failure to receive either sacubitril/valsartan (target dose, 97 mg sacubitril with 103 mg valsartan twice daily) or enalapril (target dose, 10 mg twice daily).11 The average age of individuals enrolled in this study was 61 years, and almost 70% were men. The median NT-proBNP at baseline was 4,800 pg/ml. At 8 weeks, the primary endpoint of time-averaged reduction in NT-proBNP was −46.7% for sacubitril/ valsartan and −25.3% for enalapril (HR 0.71, 95% CI [0.63–0.81], p<0.001).

There was also a significant reduction in rehospitalization for heart failure in patients receiving sacubitril/valsartan.

According to Velazquez et al., after being approved in patients with reduced ejection fraction, this trial might expand the use of sacubitril/ valsartan to include patients with acute decompensated heart failure.11

be beneficial, especially for those individuals with high LDL cholesterol despite statin or ezetimibe therapy who are unable able to afford or receive proprotein convertase subtilisin/kexin type 9 inhibitors.

CREOLE In the Comparison of Combination Therapies in Lowering Blood Pressure in Black Africans (CREOLE) trial, investigators randomized 728 patients with hypertension to receive a daily regimen of amlodipine 5 mg plus hydrochlorothiazide 12.5 mg or amlodipine 5 mg plus perindopril 4 mg or perindopril 4 mg plus hydrochlorothiazide 12.5 mg.13 The average age of individuals enrolled in this study was 51 years, and almost 65% were women. Investigators excluded patients with a history of cardiovascular disease and those with secondary hypertension.

In their study, Ojji et al. revealed that at 6 months the use of a combination of amlodipine with either hydrochlorothiazide or perindopril was superior in terms of change in 24-hour systolic blood pressure.13 The results of this trial therefore might provide further insight into potential hypertension treatment options for black patients.

INFINITY In the Intensive Versus Standard Blood Pressure Lowering to Prevent Functional Decline in Older People (INFINITY; NCT01650402) trial, investigators randomized approximately 200 hypertensive patients with cerebrovascular disease to receive intensive (systolic blood pressure ≤130 mmHg) or standard (systolic blood pressure 145 mmHg) ambulatory blood pressure lowering to assess the effect of blood pressure control on mobility and cognitive function.14 In his study, White announced that at 3 years there was a significant difference in the percentage change from baseline to end of study white matter hyperintensity (0.29% in the intensive group and 0.48% in the standard group; p=0.03).14 There was no significant difference in gait speed between the two groups during the study (p=0.91). White therefore concluded that intensive systolic blood pressure lowering was not associated with improved mobility or cognitive function. Notably, however, patients in the intensive group had significantly fewer non-fatal cardiovascular events compared to the standard group (4.1% versus 17%, respectively; p<0.01).14

TREAT CLEAR WISDOM Ballantyne et al. reported on the Evaluation of Long-Term Efficacy of Bempedoic Acid (ETC-1002) in Patients with Hyperlipidemia at High Cardiovascular Risk (CLEAR WISDOM; NCT02991118) trial.12 Investigators enrolled more than 700 patients with documented atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia to receive either bempedoic acid 180 mg or placebo once daily. They also enrolled patients with baseline LDL cholesterol ≥2.6 mmol/l (100 mg/dl) at screening and ≥1.8 mmol/l (70 mg/dl) following placebo run-in, while receiving maximally tolerated statin therapy.

At 52 weeks, bempedoic acid significantly reduced LDL cholesterol from baseline in comparison with placebo (−15.1% versus 2.4%, p<0.001).

Despite this reduction, Ballantyne et al. reported that there was no difference in clinical outcomes between the groups.12 This agent could

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The Ticagrelor in Patients with ST Elevation Myocardial Infarction Treated with Pharmacological Thrombolysis (TREAT) trial compared the efficacy and safety of ticagrelor versus clopidogrel in patients with ST-segment elevation MI (STEMI) who were treated with fibrinolytic therapy.15 A total of 3,799 patients aged <75 years were randomized to receive either ticagrelor (180 mg loading dose followed by 90 mg twice daily) or clopidogrel (300–600 mg loading dose followed by 75 mg per day). The primary outcome was time to first major bleeding event (thrombolysis in MI). The secondary outcomes were a composite of cardiovascular mortality, MI or stroke, as a measure of efficacy, and bleeding events, which determined safety.

According to Berwanger et al., at 12 months there was a non-significant reduction in time to first major bleeding events in patients who

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Annual Meetings received ticagrelor (6.7%) compared with (7.3%) in patients who received clopidogrel.15 In terms of safety, there were no differences in the rates of major, fatal, and intracranial bleeding between ticagrelor and clopidogrel following fibrinolytic therapy in patients with STEMI. The results of this trial might expand the indications of ticagrelor to include individuals with STEMI treated with fibrinolytic therapy.

AUGUSTUS The Study of Apixaban in Patients with Atrial Fibrillation, not Caused by a Heart Valve Problem, Who are at Risk for Thrombosis (Blood Clots) due to having had a Recent Coronary Event, such as a Heart Attack or a Procedure to Open the Vessels of the Heart (AUGUSTUS) was conducted to evaluate the efficacy of antithrombotic therapy after ACS or PCI in patients with AF.18

STOPDAPT-2 ACS and SMART-CHOICE The results of two large trials examining the use of dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary intervention (PCI) were presented on the last day of the American College of Cardiology (ACC) meeting. These trials were ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-2 Study for Patients with Acute Coronary Syndrome (STOPDAPT-2 ACS; NCT03462498) and the Comparison Between P2Y12 Antagonist Monotherapy and Dual Antiplatelet Therapy after DES (SMARTCHOICE; NCT02079194). Both trials compared the efficacy and safety of varying lengths of DAPT treatment.

The STOPDAPT-2 ACS trial was conducted to evaluate the efficacy and safety of 1 month of DAPT compared with 12 months of DAPT in patients undergoing PCI.The trial included 3,045 adult patients undergoing PCI with a cobalt chromium everolimus-eluting stent. Patients were randomized to receive either 1 month of DAPT followed by clopidogrel monotherapy for 5 years (n=1,523) or 12 months of DAPT followed by aspirin monotherapy for 5 years (n=1,522). The primary efficacy outcome was a composite of death, MI, stent thrombosis, stroke, and thrombolysis in MI major/minor bleeding at 1 year. Watanabe et al. reported that the use of DAPT for 1 month significantly reduced the chance of the primary outcome (2.4%) compared with 12 months of DAPT (3.7%).16 The SMART-CHOICE trial randomized 2,993 patients who had undergone PCI with a drug-eluting stent to receive DAPT for 3 months (n=1,495) or 12 months (n=1,498), and had a primary outcome was a composite of allcause mortality, MI, or stroke. Hahn et al. announced that short-duration DAPT was non-inferior to a longer duration of DAPT in terms of the primary composite outcome (2.9% versus 2.5%, respectively). However, bleeding rates were significantly lower in those taking DAPT for 1 month (2%) compared with those taking DAPT for 12 months (3.4%).17 The results of STOPDAPT-2 ACS and SMART-CHOICE provide further evidence in favor of shorter-duration antiplatelet therapy in patients undergoing PCI.

1.

2.

3.

4.

5.

T arakji KG, Mittal S, Kennergren C, et al. Antibacterial envelope to prevent cardiac implantable device infection. N Engl J Med 2019;380:1895–905. https://doi.org/10.1056/NEJMoa1901111; PMID: 30883056.

Iversen K, Ihlemann N, Gill SU, et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 2019;380:415–24. https://doi.org/10.1056/NEJMoa1808312; PMID: 30152252.

Bundgaard H, Ihlemann N, Gill SU, et al. Long-term outcomes of partial oral treatment of endocarditis. N Engl J Med 2019;380:415–24. https://doi.org/10.1056/NEJMc1902096; PMID: 30883059.

Konstantinides S. Home Treatment of patients with lowrisk Pulmonary Embolism with the oral factor Xa inhibitor rivaroxaban (HoT-PE). Available at: www.unimedizin-mainz.de/ cth/clinical-studies/hot-pe.html?L=1 (accessed May 28, 2019).

Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aorticvalve replacement with a balloon-expandable valve in low-risk

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6.

7.

8.

9.

A total of 4,614 patients with AF and a recent ACS or PCI and who were planning to take of a P2Y12 inhibitor were enrolled. They were randomized to receive apixaban 5 mg twice daily (n=2,306) or vitamin K antagonist with an international normalized ratio goal of 2–3 (n=2,308) and to receive aspirin 81 mg daily (n=2,307) or matching placebo (n=2,307). The primary outcome was major or clinically relevant non-major bleeding.

The rates of the primary outcome reported by Lopes et al. were significantly lower in the apixaban group (10.5%) compared with the VKA group (14.7%).18 He also stated that bleeding events occurred in a significantly higher proportion of patients who had received aspirin (16.1%) compared with placebo (9%).

The results of this trial have highlighted an additional advantage of using direct oral anticoagulants over VKA. Despite the positive results of this trial, clinicians should be cautious not to extrapolate the results of AUGUSTUS with apixaban to other direct oral anticoagulants.

Primary Prevention Guidelines The updated ACC/American Heart Association primary prevention of cardiovascular disease guidelines were launched at the ACC meeting.

These emphasize the importance of adopting a healthy lifestyle, eating a healthy diet, engaging in physical activities, and smoking cessation, and for healthcare professionals to take a team-based care approach.19 For people with type 2 diabetes already on metformin and who have made lifestyle modifications, the new guidelines suggest initiating a sodium-glucose cotransporter-2 inhibitor or a glucagon-like peptide-1 receptor agonist. This is due to their effectiveness, in terms of improving glycemic control and reducing cardiovascular disease risk.

Given the lack of net benefit, the updated guidelines recommend against the use of low-dose aspirin for the primary prevention of atherosclerotic cardiovascular disease among adults >70 years of age or adults of any age who are at increased risk of bleeding.

patients. N Engl J Med 2019;380:1695–705. https://doi.org/10.1056/ NEJMoa1814052; PMID: 30883058.

Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aorticvalve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019;380:1706–15. https://doi.org/10.1056/ NEJMoa1816885; PMID: 30883053.

PARTNER 3 and EVOLUT Confirm Benefits of TAVR Over Surgery in Low-Risk Patients. www.acc.org/latest-in-cardiology/ articles/2019/03/08/15/32/sun-8am-partner3-tavr-savr-acc-2019 (accessed 21, June 2019).

Mehra MR, Uriel N, Naka Y, et al. A fully magnetically levitated left ventricular assist device – final report. N Engl J Med 2019;380:1618–27. https://doi.org/10.1056/NEJMoa1900486; PMID: 30883052.

Herbeck Belnap B, Anderson A, Abebe KZ, et al. Blended collaborative care to treat heart failure and comorbid depression: rationale and study design of the Hopeful Heart Trial. Psychosom Med 2019;81:495-505. https://doi.org/10.1097/

PSY.0000000000000706; PMID: 31083056.

10. T urakhia M. Apple Heart Study: Assessment of wristwatchbased photoplethysmography to identify cardiac arrhythmias.

Presented at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, US, 18 March 2019.

11. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin– neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539–48. https://doi.org/10.1056/NEJMoa1812851; PMID: 30415601.

12. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol 2019. https://doi. org/10.1177/2047487319864671; PMID: 31357887; epub ahead of press.

13. Ojji DB, Mayosi B, Francis V, et al. Comparison of dual therapies for lowering blood pressure in black Africans. N Engl J Med 2019.

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Major Cardiovascular Advances https://doi.org/10.1056/NEJMoa1901113; PMID: 30883050; epub ahead of press.

14. White WB. Intensive vs. Standard Ambulatory Blood Pressure Lowering to Lessen Functional Decline in the Elderly – INFINITY. Presented at the American College of Cardiology Annual Scientific Session (ACC 2019), New Orleans, LA, US, 18 March 2019.

15. Berwanger O, Lopes RD, Moia DDF, et al. Ticagrelor versus clopidogrel in patients with stemi treated with fibrinolytic therapy: TREAT Trial. J Am Coll Cardiol 2019;73:2819–28. https://doi.org/10.1016/j.jacc.2019.03.011; PMID: 30898608.

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16. W atanabe H, Domei T, Morimoto T, et al. Effect of 1-month dual antiplatelet therapy followed by clopidogrel vs 12-month dual antiplatelet therapy on cardiovascular and bleeding events in patients receiving pci: the STOPDAPT-2 randomized clinical trial.

JAMA 2019;321:2414–27. https://doi.org/10.1001/jama.2019.8145; PMID: 31237644.

17. Hahn JY Song YB, Oh JH, et al. Effect of P2Y12 inhibitor monotherapy vs dual antiplatelet therapy on cardiovascular events in patients undergoing percutaneous coronary intervention: the SMART-CHOICE randomized clinical trial. JAMA 2019;321:2428–37. https://doi.org/10.1001/jama.2019.8146;

PMID: 31237645.

18. Lopes

RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med 2019;380:1509–24. https://doi.org/10.1056/NEJMoa1817083; PMID: 30883055.

19. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease : a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019. https://doi.org/10.1016/j.jacc.2019.03.010; PMID: 30894318; epub ahead of press.

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Trends

Artificial Intelligence in Cardiac Imaging Karthik Seetharam, MD, Sirish Shrestha, MSc, and Partho P Sengupta, MD, DM Division of Cardiology, West Virginia University Heart and Vascular Institute, Morgantown, WV

Abstract Machine learning (ML), a subset of artificial intelligence, is showing promising results in cardiology, especially in cardiac imaging. ML algorithms are allowing cardiologists to explore new opportunities and make discoveries not seen with conventional approaches. This offers new opportunities to enhance patient care and open new gateways in medical decision-making. This review highlights the role of ML in cardiac imaging for precision phenotyping and prognostication of cardiac disorders.

Keywords Machine learning, artificial intelligence, cardiac imaging, precision phenotyping, deep learning, convolutional neural network Disclosure: PPS is a consultant for HeartSciences and Ultromics. All other authors have no conflicts of interest to declare.

Received: 21 May 2019 Accepted: 6 November 2019 Citation: US Cardiology Review 2019;13(2):110â&#x20AC;&#x201C;6. DOI: https://doi.org/10.15420/usc.2019.19.2 Correspondence: Partho Sengupta, Division of Cardiology, Heart and Vascular Institute, West Virginia University, One Medical Center Drive, Morgantown, WV 26506.

E: Partho.Sengupta@wvumedicine.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.

Numerous advances in cardiovascular imaging technology paralleled by the simultaneous growth in wearable technology, mobile health devices, and electronic medical record integration have encouraged increasingly complex and large multi-dimensional data acquisition.1 The influx of data with each scan is exponentially rising in all cardiovascular imaging modalities and will exceed the capabilities of current statistical software.2 Artificial intelligence (AI) has sparked remarkable progress in various aspects of technology from speech recognition to automated driving.3,4 Machine learning (ML), a subset of AI, can harvest information from this vast data matrix to improve disease prognostications and survival prediction.2,5 The current model of image acquisition and interpretation has led to a number of issues in timing, efficiency, and inaccurate diagnosis.6 ML can help transcend the gap between the rapid growth of cardiac imaging and clinical care by improving image acquisition, interpretation, subsequent decision-making, and reducing costs. 6 Furthermore, ML facilitates a number of opportunities for data-driven discoveries and innovation not typically seen with conventional statistical approaches.7 In this article, we review several contributions that ML can make in cardiac imaging.

Types of Machine Learning ML algorithms strive to learn and find natural patterns in data to support decisions, automation, and risk mitigation to enable generalizability.1,7 It generally results in better performance if the algorithm learns from large heterogeneous datasets for prediction from an unlearnt dataset, such as one that has not been subjected to ML. It aspires to learn the data in multiple different ways that can be broadly subdivided into supervised,

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unsupervised, semi-supervised, and reinforcement learning (Table 1 and Figure 1). Recent investigations have shown the ability to use supervised and unsupervised ML for cardiac imaging.8,9 Supervised and unsupervised learning are the commonly used approaches.10 Supervised learning works with datasets with labeled variables or classified outcomes, where it is trained to build a model from a select feature derived from any imaging data sample and clinical variables along with the outcome of interest.11 It reacts to the feedback based on corresponding labels from modalities, such as ECG, CCT, and cardiac MRI (CMR). This subsequently contributes to prediction and risk stratification of cardiovascular diseases. In contrast to supervised learning, an unsupervised learning algorithm must decipher the data without labels or interventions.11 Semi-supervised learning is a type of learning process that has a mixture of labeled and unlabeled classes within the dataset.2 It has a role in speech and image recognition.

Reinforcement learning uses reward criteria, like human psychology, learning through trial and error. Although reinforcement learning has had limited development in cardiology, there is a growing interest in these techniques in clinical and research settings.2 Physicians must remain constantly aware of their data to prevent bias creeping into the models.10 For example, sampling bias can creep in if the training data do not accurately represent the heterogeneity in the cardiovascular diseases. Prejudicial bias may occur if the sample is affected by cultural, ethnic, or gender factors. Measurement bias can also occur. It can occur if the model is trained on incorrect and noisy image data or inaccurate measurements from various modalities.

Š RADCLIFFE CARDIOLOGY 2019

Artificial Intelligence in Cardiac Imaging Deep learning is a subset of ML and has sparked much interest in the health sector.10 Deep learning uses several layers similar to neuronal architecture in the human brain that enables reasoning and interpretation. Information is progressively processed through this neuronal-like hierarchy to analyze and interpret information. It learns through a series of iterations where it extrapolates predictive properties which are superior to conventional ML algorithms.10 Unlike other ML algorithms, the performance of deep learning improves with larger datasets.5 Deep learning is becoming increasingly popular due to paralleled growth in cloud infrastructures and improving computer performance.3 It is frequently used in image segmentation, and uses associations based on previous experience to increase the chances of correct classification by the ML algorithm.

There is great potential for deep learning to have significant impact on cardiovascular imaging in the future.1 There are algorithms within deep learning. Convolutional neural network (CNN) algorithms are the most frequently used.12 CNN algorithms consist of a convolutional part and a fully connected part. The convolutional part enables feature extraction to occur and the fully connected part allows classification or regression.12 The convolutional part allows the generation of feature maps based on the parameters used in the analysis. The commonly used Googlenet and ResNet are based on CNNlike architectures.12

Machine Learning in Echocardiography Echocardiography frequently serves as the first line of diagnostic imaging and is an integral part of cardiology practice.1 There are numerous echocardiographic variables, and this, along with the development of vector flow mapping and speckle tracking have overwhelmed a clinician’s ability to properly evaluate results.13 ML can use the vast amount of information present in echocardiography to uncover valuable information and has seen exponential growth in the use of various algorithms in different modalities in cardiac imaging research (Figure 2).7 Most studies have emphasized the use of a supervised ML framework for developing diagnostic predictions. For example, Zhang et al. used a CNN for automatic interpretation of ECG in 14,035 ECGs over a span of 10 years.14 The authors showed that the ML measurements were superior to manual measurements across numerous standards, such as the correlation of left atrial and ventricular volumes. Some aspects of this study must be interpreted with caution and require further validation.

The algorithm may have correlated well with manual measurements, but there were wider limits.15 This emphasizes the variability of ECG findings in daily practice, and the lack of gold standard metrics, such as CMR, cannot be used for comparison.

Supervised ML has also been used for predicting future adverse cardiac events using echocardiography data. Samad et al. used the random forest ML algorithm to predict survival after ECG in a population of 171,510 patients.16 The model was compared with the logistic regression model using three different inputs involving a variety of ECG and clinical parameters by mean area under the curve (AUC). The random forest algorithm achieved superior prediction accuracy (all AUC >0.82) against common clinical risk scores (AUC 0.69–0.79). Additionally, it outclassed logistic regression models (p<0.001 and all survival durations). However, a unique feature demonstrated by Samad et al. was pursuing a broad

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Table 1: Types of Machine Learning Algorithms 2,3 Supervised learning

Data are labeled with classes and outcomes. This helps the algorithm to infer prediction

This type of learning comprises of logistic regression, ridge regression, elastic net regression, least absolute shrinkage and selection operator regression, Bayesian networks, random forests, and artificial neural networks

Unsupervised learning

The data are not labeled, it can be considered agnostic.

The algorithm recognizes vital relationships within datasets

It encompasses hierarchical clustering, k-means clustering, and principal component analysis

Semi-supervised learning

A type of learning process that works with data containing labeled and unlabeled fields

This includes both labeled and unlabeled outcomes and classes. Primarily used in image and speech recognition

Reinforcement learning

A type of process similar to human psychology, uses rewards criteria

It is more commonly seen in medical imaging, analytics disease screening, and prescription selection

initial hypothesis, rather than contemporary hypothesis-driven research.17 This can help overcome gaps in knowledge by revising initial inquiry or by leading to new questions.18 Similarly, Madani et al. applied a CNN algorithm to 267 transthoracic ECGs with 15 standard views to showcase real-life variation.19 The overall test accuracy was 97.8% for the ML model across 12 views. Among low-resolution images, there was a 91.7% accuracy for the ML algorithm in relation to 70.2–84.0% for board certified echocardiographers. In another report by Madani et al., they used deep learning classifiers for automatic interpretation of ECGs.19 Madani et al. obtained an accuracy of 94.4% for 15 echocardiographic view classifications of still images and 91.2% accuracy for binary left ventricular (LV) hypertrophy view classification. Afterwards, the researchers used a semi-supervised generative adversarial network model that showed 80% accuracy in view classification and 92.3% accuracy for LV hypertrophy.19

Machine Learning in Nuclear Cardiology The potential of ML in nuclear cardiology is vast and can greatly shape decision-making for cardiologists.5 Arsanjani et al. investigated the accuracy of myocardial perfusion imaging (MPI) for coronary artery disease (CAD) prediction by using a supervised learning algorithm in 957 studies using perfusion and functional variables.20 The outcomes of the ML algorithm were compared with automatic quantification software and two experienced readers. The sensitivity and specificity of ML were superior (p<0.005) to the quantification software and two experienced readers. The receiver operating curve (ROC) area under the curve for the ML algorithm (0.92) was statistically superior to both readers (0.87 and 0.88, p<0.03). Arsanjani et al. conducted another study to predict CAD by incorporating clinical and imaging data in 1,181 patients with ML algorithms to improve single-photon emission computed tomography (SPECT) accuracy.21 A supervised ML algorithm or LogitBoost was used.

The ROC curve for the ML architecture (0.94 ± 0.01) was statistically superior to the total perfusion deficit and used two readers (p<0.001).

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Trends Figure 1: Types of Machine Learning with Examples of Respective Use Insights

Fraud detection

Predictions Anomaly Detection

Optimization Regression

Recommendation

Forecasting Clustering

SUPERVISED LEARNING

Diagnostics Disease classification

UNSUPERVISED LEARNING

Patient similarity Targeted patient management

Classification Dimensionality Reduction

Image classification

Structure discovery

Visualization

Feature selection TYPES OF MACHINE LEARNING

Speech recognition

Genetic sequencing Real-time decision

REINFORCEMENT LEARNING

SEMI-SUPERVISED LEARNING

Disease classification

Robot navigation Learning tasks

Haro Alonso et al. developed an ML algorithm to predict the risk of cardiac death derived from a combination of adenosine myocardial perfusion using myocardial perfusion SPECT (MPS) and clinical data in 8,321 patients and 551 cases of cardiac death.22 This was compared with logistic regression. Remarkably, the logistic regression was outperformed by all ML approaches (AUC 0.76; 14 features). The support vector machine demonstrated greatest accuracy (AUC 0.83; p <0.0001; 49 features).

The ML algorithm was superior to logistic regression by providing the best AUC for showing the risk of cardiac death. The authors clearly demonstrated the superiority of ML models to improve prognostic value from multi-dimensional MPS and clinical variables while simultaneously increasing interpretability. However, this should not underscore our preference towards ML models over conventional statistical models, rather it changes our previous beliefs regarding the inability to integrate high-dimensional data and identify unique properties which may otherwise affect our perception of parameters.4 Nonetheless, the study was retrospective and did not occur in real time.4

Machine Learning in Cardiac CT Motwani et al. investigated the use of an ML algorithm to predict 5-year mortality in CT scans in reference to conventional cardiac metrics in 10,030 patients with possible CAD.23 The ML algorithm demonstrated a

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statistically significant (p<0.001) higher AUC (0.79) than fractional flow reserve (0.61) or CT severity scores (segmental stenosis score 0.64, segment involvement score 0.64, Duke index 0.62) for predicting 5-year all-cause mortality. Although the study offers exciting opportunities, there are a number of hurdles to overcome to successfully implement these approaches in clinical practice, and institutions will require dedicated IT teams to manage the data that need to be anonymized.24 There are significant costs associated with management and regulation. Clinical trials may be required to determine the effectiveness of these various ML processes.

Rosandael et al. explored the use of an ML algorithm in 8,844 patients to predict major cardiovascular events using only CT variables in evaluation to CT severity scores for patients with suspected CAD.25 Remarkably, the AUC for the ML algorithm (0.77) was far better than CT severity scores (0.69â&#x20AC;&#x201C;0.70) with a statistical significance (p<0.001) for prediction of major cardiovascular events.

Zreik et al. used a CNN algorithm to automatically calculate fractional flow reserve from coronary CT angiography in 166 patients who underwent invasive coronary angiography.26 The area under the ROC was 0.74 (Âą0.02). When sensitivity levels measured 0.60, 0.70, and 0.80, the equivalent specificity was 0.77, 0.71, and 0.59.

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Artificial Intelligence in Cardiac Imaging Figure 2: Use of Machine Learning Techniques in Cardiac Imaging Publications

40 Cumulative publications

Cumulative publications

40

30

20

10

30

20

10

0

0 2000

2005

2010

2015

2000

2005

2010

2015

Year

Year Echocardiogram

Support vector machine (SVM)

Decision trees

Nuclear cardiology

Neural networks

Hierarchical clustering

Cardiac CT

AdaBoost

Random forest

Cardiac MRI

Principal component analysis

The data were collected from PubMed between 1998 and 2017. They show the cumulative usage of machine-learning techniques in cardiac imaging publications and cumulative publication counts of machine learning algorithms used in echocardiography. Source: Sengupta and Shrestha, 2019.7 Used with permission from Elsevier.

Machine Learning in Cardiac MRI The application of ML learning in CMR is quite limited and there is significant opportunity for growth. However, there has been some notable works that demonstrate the viability of ML in CMR. For example, Winther et al. used a deep learning ML algorithm for automatic segmentation of the right ventricular (RV) and LV endocardium and epicardium for assessing cardiac mass and function parameters from a variety of datasets.27 They found that learning architecture accomplished a comparable outcome in relation to human experts. Nevertheless, the findings must be taken with a degree of caution due to small sample sizes.

Bai et al. applied a fully convolutional network for automated analysis of CMR images from a large database consisting of 93,500 images in 5,000 patients for measuring left and RV mass and volumes.28 On the short axis image test of 600 patients, the Dice metric measured 0.94 for LV cavity, 0.88 for LV myocardium, and 0.90 for RV cavity. In addition, the average Dice metric measured 0.93 for the left atrial cavity in two chamber view, 0.95 for left atrial cavity in four chamber view, and 0.96 in right atrial cavity in two chamber view. Bai et al. demonstrated ML automated methods had values comparable with human experts.28 Tan et al. assessed the function of a convolutional network, a supervised learning approach for automatic segmentation of the left ventricle in all short axis slices.29 It was applied to a number of publicly available datasets which included the LV segmentation challenge dataset consisting of 200 CMR imaging sets with unique cardiac pathology. They obtained a Jaccard index of 0.77 in the LV segmentation challenge dataset. Furthermore, they obtained a continuous ranked probability score of 0.0124 with the Kaggle Second Annual Data Science Bowl. Findings from Tan et al. showed the potential of the ML algorithm in automatic LV segmentation in CMR.29

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Machine Learning for Identifying Cardiac Phenotypes The exponential rise in data size and complexity will make it difficult for physicians to analyze data in a clinically meaningful manner. In DNA analysis, phenomapping is used to comprehend vast quantities of data by subdividing subjects into various categories. Recently, ML algorithms have expanded the role of phenomapping in cardiac imaging.

Tabassian et al. explored the role of ML in assessing the timing and amplitude of the LV long-axis myocardial motion and deformation at stress and rest in 100 prospectively recruited patients by using unsupervised and supervised learning.30 This was compared with conventional measurements in patients with heart failure with preserved ejection fraction (HFpEF), healthy, breathless, and hypertensive people. The learnt strain rate parameters showed the highest accuracy for categorizing subjects into four groups (overall 57%; HFpEF patients 81%) and into two classes (asymptomatic versus symptomatic; AUC 0.89; accuracy 85%; sensitivity 86%, specificity 82%). When comparing ML with conventional measurement for strain, it demonstrated the highest improvement in accuracy for the two-class task (+23%, p<0.001), comparison with +11% (p<0.001) using velocity and +4% (p<0.05) using strain.

Tabassian et al. encountered an issue with their data, which consisted of 36 segmental curves for each patient with 208 and 123 time points at rest and exercise, respectively.30 They used unsupervised learning to break down the complexity of the data into reduced dimensions.

It is an approach to represent data with fewer features, potentially to reduce noise and multicollinearity, from high-dimensional data obtained from imaging modalities and clinical data. Subsequently, they used a supervised classification algorithm to categorize patients into one of four

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Trends Figure 3: The Patient-similarity Network: Ejection Fraction

50 Ejection Fraction 75

M

Reduced EF

AS ate er d o

the mild and severe AS on right and left sides, respectively (p<0.001; Figure 3). These two regions were connected from the top and the bottom by moderate AS. The region of severe AS showed greatly elevated risk of balloon valvuloplasty and transcatheter aortic valve replacement.

After surgical intervention, many patients were in the regions of mild and moderate AS. The results were further validated in mouse models with similar results. The authors showed that ML has the potential to facilitate precise recognition of phenotypic patterns of the left ventricle during AS. The model was able to show the movement of the patients from severe to mild pre- and post-aortic valve replacement (Figure 4). Further studies and clinical trials will be required to validate these findings.

Role of Deep Learning in Cardiac Imaging

M il

ere A S

d AS

Sev

Mo

derate AS

Preserved EF The patient-similarity network showing preserved and reduced ejection fractions in the patients with aortic stenosis. Red nodes represent abnormal values and blue represents the normal malady in the disease space. AS = aortic stenosis; EF = ejection fraction. Source: CasaclangVerzosa et al. 2019.32 Used with permission from Elsevier.

groups. Though it may appear unique, this can affect the modelâ&#x20AC;&#x2122;s efficacy and relatability to the real world, since a small sample size may not show the heterogeneous nature of HFpEF.11 Data imputation may introduce errors and it may not reflect the patient population.

Similarly, the potential of ML in HFpEF for phenotyping patients with diastolic dysfunction has been explored. Lancaster et al. used a clustering algorithm to assess LV dysfunction by exploring a number of key echocardiographic variables in 866 patients.31 Cluster and standard classifications were used to compare major adverse cardiovascular events and complications. It identified diastolic dysfunction in 559 of 866 patients and recognized two unique groups. There was moderate agreement with conventional classification (kappa 0.41, p<0.0001).

Subsequently, additional cluster analysis was done in 387 patients to classify the severity of diastolic dysfunction. Similarly, it showed good agreement with the traditional classification (kappa 0.619, p<0.001).

Recently we used a patientâ&#x20AC;&#x201C;patient similarity network using multiple features of LV structure and function in patient with aortic stenosis (AS).32 This was done through the application of a novel data analytic method known as topological data analysis. It clusters patients and visualizes a similarity network to obtain insights regarding pathological mechanisms.

Casaclang-Verzosa et al. used a topological data analysis from crosssectional echocardiographic data in 246 AS patients, and it was compared with a mouse model of 155 animals with AS at various time points.32 A loop was created by the topological map which significantly separated

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Deep learning has unprecedented potential to revolutionize the field of cardiac imaging. Steady and progressive advances in computer processing capabilities and cloud infrastructure have propelled the growth of deep learning.3 Betancur et al. led a multicenter investigation assessing automatic prediction of CAD obstruction in 1,638 patients by MPI implemented through deep learning in relation to total perfusion deficit.33 These patients underwent stress Tc-Sestambi or tetrofosmin MPI, and invasive coronary artery angiography was done within 6 months. Only 1,018 (62%) had obstructive CAD among the total population. Deep-learning ML showed a higher AUC than total perfusion deficit for CAD prediction (per patient: 0.80 versus 0.78; per vessel 0.76 versus 0.73: p<0.01). If the ML matched the total perfusion deficit specificity, per-patient sensitivity (79.8% to 82.3%, p<0.05) and per-vessel (64.4% to 69.8%, p<0.01) sensitivity increased. Although Betancur et al. performed a remarkable feat, there are still issues that need to be addressed.34 The sensitivity could be higher for the algorithm. The relationship between epicardial anatomy and cellular perfusion is not ideal. As a result, the study did not focus on a definite endpoint, such as MI or death. In reality, it is also very difficult to define who is an expert and who is not.

Yang et al. explored the role of deep learning ML for left ventricle segmentation in publicly available datasets which included SATA-13 and LV-09.35 Sometimes accurate segmentation of the left ventricle from CMR can be challenging due to significant variation in intensity levels, structural shape issues, and respiratory movement artefacts. The deeplearning ML showed a 0.83 in averaged Dice metric on SATA-13 dataset and 0.95 averaged Dice metric for the LV-09 dataset. As a result, it compared satisfactorily with other automatic segmentation approaches.

Issues to be Resolved Before Machine Learning is Widely Adopted Although the promise and early fruits of ML in cardiology have been encouraging, it is far from straightforward. In parallel with the rapid growth of ML, many steps must be taken to facilitate the transition of ML into clinical practice so that patient care can benefit.

A universal reference standard may need to be adopted by institutions to fully validate and assess the accuracy of ML learning approaches for each diagnostic modality.36 Depending on the standard chosen for evaluation, ML might show differing results. Furthermore, some form of a universal approach is mandatory for data standardization. There

US CARDIOLOGY REVIEW

Artificial Intelligence in Cardiac Imaging Figure 4: The Patient-similarity Network: Aortic Stenosis

10.0

AV Mean Gradient

40.0

S

Age: Sex: AVA: MG:

80 yrs Female 0.6 cm2 29 mmHg

Moderate A

EF: 51% LVMi: 85 g/m2 RWT: 0.47 E/e’: 11.7

S

Moderate A

EF: 57% LVMi: 91 g/m2 RWT: 0.5 1st Echo E/e’: 15

Mild AS

67 yrs Male 0.5 cm2 59 mmHg

Mild AS

Severe AS

Age: Sex: AVA: MG:

Severe AS

1st Echo

2nd Echo

LVMi: 76 g/m2 EF: 66% AVA: 2.1 cm2 RWT: 0.34 MG: 15 mmHg E/e’: 23.5 2nd Echo

M

od

M

S erate A

ode

S rate A

LVMi: 85 g/m2 EF: 60% AVA: 1.7 cm2 RWT: 0.52 MG: 8.9 mmHg E/e’: 8.9

The patient-similarity network containing patients who had aortic valve replacement as delineated in the network with brown-colored nodes. The accompanying figure shows the movement of the representative patient who had severe aortic stenosis to mild region after aortic valve replacement. AS = aortic stenosis. Source: Casaclang-Verzosa et al. 2019.32 Used with permission from Elsevier.

are discrepancies between each institution. Each center has their own classification, protocol, and different acquisition protocols.4 If ML algorithms are universally accepted, there are subsequent difficulties in clinical implementation, and maintenance of data quality. Some form of homogenization of clinical data recording and imaging protocols may become necessary to serve as a common input for the use of ML.6 In addition, information from electronic health records needs to be streamlined with imaging databases.

Another prevailing issue in ML adoption is cost.6 For ML algorithms to thrive in any institution, significant investment is needed. A surrounding IT team and ecosystem may be needed to help institutions during ML training, and development. As ML technology continues to grow and evolve, more investments will be needed to keep up with trends and development.

Large data are pivotal for ML training, and accuracy increases proportionately.2 For any single institution, it can be difficult to obtain data large enough to reach any meaningful conclusion with any ML algorithm. As a result, some form of data sharing needs to be established between centers to improve ML accuracy. For successful data sharing, certain issues need to be resolved: the datasets need to be completely anonymized, and multiple institutional review board approvals are needed to for the sharing of data among institutions and this can be laborious.5 If datasets are publicly available, this can significantly help the growth of ML.

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Another important issue for the adoption of ML in academic centers is the ethics of AI. For discussion’s sake, AI has no moral compass.37 Unintentionally, AI can make errors in judgement when confronted with unusual scenarios. Its ‘black box’ nature is not easily understood.10 These properties can be an issue in the real world because of the flawed and imperfect nature of the world. Engineering cannot address every issue in the design of these algorithms. Key attributes need to be decided before using and designing any algorithm. One way of addressing these issues is to have AI classes introduced into medical school curricula to help trainee doctors to responsibly use and comprehend AI. Physicians need to constantly update themselves regarding advances in AI to fully tap its potential.

As ML continues to expand across academic institutions, there are potential benefits. This technology facilitates the possibility of reducing the clinical burden by mitigating repetitive activities, such as measurements, data preparation, or quality control.15 As a result, more dedicated time can be steered toward medical interpretation and complex decisionmaking. Furthermore, ML can supplement and aid the clinical acumen of physician by offering more possibilities. This can allow physicians to ask patients vital diagnostic questions which can foster improved patient care. These possibilities of ML point towards a healthier harmony between physician and patient in years to come.

Conclusion ML has revolutionary potential to completely alter current clinical guidelines in diagnostic evaluation and decision-making. It provides

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Trends limitless possibilities for analyzing data. As data continue to become larger and more complex, ML will become pivotal. In this data-driven era, traditional beliefs in statistics must evolve with changing times and

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Shameer K, Johnson KW, Glicksberg BS, et al. Machine learning in cardiovascular medicine: are we there yet? Heart 2018;104:1156–64. https://doi.org/10.1136/heartjnl-2017-311198; PMID: 29352006.

Johnson KW, Torres Soto J, Glicksberg BS, et al. Artificial intelligence in cardiology. J Am Coll Cardiol 2018;71:2668–79. https://doi.org/10.1016/j.jacc.2018.03.521; PMID: 29880128.

Shrestha S, Sengupta PP. Machine learning for nuclear cardiology: The way forward. J Nucl Cardiol 2018;26:1755–8. https://doi.org/10.1007/s12350-018-1284-x; PMID: 29679221.

Seetharam K, Shrestha S, Mills JD, Sengupta PP. Artificial intelligence in nuclear cardiology: adding value to prognostication. Curr Cardiovasc Imaging Rep 2019;12:5 https://doi. org/10.1007/s12410-019-9490-8.

Dey D, Slomka PJ, Leeson P, et al. Artificial intelligence in cardiovascular imaging: JACC state-of-the-art review.

J Am Coll Cardiol 2019;73:1317–35. https://doi.org/10.1016/j. jacc.2018.12.054; PMID: 30898208.

Sengupta PP, Shrestha S. Machine learning for data-driven discovery: the rise and relevance. JACC Cardiovasc Imaging 2019;12:690–2. https://doi.org/10.1016/j.jcmg.2018.06.030; PMID: 30553684.

Omar AMS, Narula S, Abdel Rahman MA, et al. Precision phenotyping in heart failure and pattern clustering of ultrasound data for the assessment of diastolic dysfunction.

JACC Cardiovasc Imaging 2017;10:1291–303. https://doi. org/10.1016/j.jcmg.2016.10.012; PMID: 28109936.

Sengupta PP, Kulkarni H, Narula J. Prediction of abnormal myocardial relaxation from signal processed surface ECG. J Am Coll Cardiol 2018;71:1650–60. https://doi.org/10.1016/j. jacc.2018.02.024; PMID: 29650121.

Seetharam K, Shrestha S, Sengupta PP. Artificial intelligence in cardiovascular medicine. Curr Treat Options Cardiovasc Med 2019;21:25. https://doi.org/10.1007/s11936-019-0728-1; PMID: 31089906.

Shrestha S, Sengupta PP. The mechanics of machine learning: from a concept to value. J Am Soc Echocardiogr 2018;31:1285–7. https://doi.org/10.1016/j.echo.2018.10.003; PMID: 30522604.

Bizopoulos P, Koutsouris D. Deep learning in cardiology.

IEEE Rev Biomed Eng 2019;12:168–93. https://doi.org/10.1109/ RBME.2018.2885714; PMID: 30530339.

Cho JS, Ashraf M, Shrestha S, et al. The classification of intracardiac vortex structure and function using the patient similarity analysis. J Am Coll Cardiol 2019;73(Suppl 1):1436. https:// doi.org/10.1016/S0735-1097(19)32042-X. Zhang J, Gajjala S, Agrawal P, et al. Fully automated echocardiogram interpretation in clinical practice.

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embrace data-driven discoveries.7 At the same time, cardiologists must evaluate the legal and ethical ramifications and develop a set of reference standards for the successful implementation of ML in clinical care.

Circulation 2018;138:1623–35. https://doi.org/10.1161/ CIRCULATIONAHA.118.034338; PMID: 30354459.

Sengupta PP, Adjeroh DA. Will artificial intelligence replace the human echocardiographer? Circulation 2018;138:1639–42. https:// doi.org/10.1161/CIRCULATIONAHA.118.037095; PMID: 30354473.

Samad MD, Ulloa A, Wehner GJ, et al. Predicting survival from large echocardiography and electronic health record datasets: optimization with machine learning. JACC Cardiovasc Imaging 2019;12:681–9. https://doi.org/10.1016/j.jcmg.2018.04.026; PMID: 29909114.

Sengupta PP, Shrestha S. Machine learning for data-driven discovery: the rise and relevance. JACC Cardiovasc Imaging.

2019;12:690–2. https://doi.org/10.1016/j.jcmg.2018.06.030.

PMID: 30553684.

Narula S, Shameer K, Salem Omar AM, et al. Machine-learning algorithms to automate morphological and functional assessments in 2D echocardiography. J Am Coll Cardiol 2016;68:2287–95. https://doi.org/10.1016/j.jacc.2016.08.062; PMID: 27884247.

Madani A, Arnaout R, Mofrad M, Arnaout R. Fast and accurate view classification of echocardiograms using deep learning.

NPJ Digit Med 2018;1 2018;1:pii6. https://doi.org/10.1038/s41746017-0013-1; PMID: 30828647.

Arsanjani R, Xu Y, Dey D, et al. Improved accuracy of myocardial perfusion SPECT for the detection of coronary artery disease using a support vector machine algorithm. J Nucl Med 2013;54:549–55. https://doi.org/10.2967/jnumed.112.111542; PMID: 23482666.

Arsanjani R, Xu Y, Dey D, et al. Improved accuracy of myocardial perfusion SPECT for detection of coronary artery disease by machine learning in a large population. J Nucl Cardiol 2013;20:553–62. https://doi.org/10.1007/s12350-013-9706-2; PMID: 23703378.

Haro Alonso D, Wernick MN, Yang Y, et al. Prediction of cardiac death after adenosine myocardial perfusion SPECT based on machine learning. J Nucl Cardiol 2018. 26(5):1746–54. https://doi. org/10.1007/s12350-018-1250-7; PMID: 29542015.

Motwani M, Dey D, Berman DS, et al. Machine learning for prediction of all-cause mortality in patients with suspected coronary artery disease: a 5-year multicentre prospective registry analysis. Eur Heart J 2017;38:500–7. https://doi. org/10.1093/eurheartj/ehw188; PMID: 27252451.

Schoenhagen P, Mehta N. Big data, smart computer systems, and doctor-patient relationship. Eur Heart J 2016;38:508–10. https://doi.org/10.1093/eurheartj/ehw217; PMID: 27354057. van Rosendael AR, Maliakal G, Kolli KK, et al. Maximization of the usage of coronary CTA derived plaque information using a machine learning based algorithm to improve risk stratification; insights from the CONFIRM registry. J Cardiovasc Comput Tomogr 2018;12:204–9. https://doi.org/10.1016/j.jcct.2018.04.011; PMID: 29753765.

26. Z reik M, Lessmann N, van Hamersvelt RW, et al. Deep learning analysis of the myocardium in coronary CT angiography for identification of patients with functionally significant coronary artery stenosis. Med Image Anal 2018;44:72–85. https://doi. org/10.1016/j.media.2017.11.008; PMID: 29197253.

27. Winther HB, Hundt C, Schmidt B, et al. ν-net: deep learning for generalized biventricular mass and function parameters using multicenter cardiac MRI data. JACC Cardiovasc Imaging 2018;11:1036–8. https://doi.org/10.1016/j.jcmg.2017.11.013; PMID: 29361481.

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29. Tan LK, Liew YM, Lim E, McLaughlin RA. Convolutional neural network regression for short-axis left ventricle segmentation in cardiac cine MR sequences. Med Image Anal 2017;39:78–86. https://doi.org/10.1016/j.media.2017.04.002; PMID: 28437634.

30. Tabassian M, Sunderji I, Erdei T, et al. Diagnosis of heart failure with preserved ejection fraction: machine learning of spatiotemporal variations in left ventricular deformation. J Am Soc Echocardiogr 2018;31:1272–84. https://doi.org/10.1016/j. echo.2018.07.013; PMID: 30146187.

31. Lancaster MC, Salem Omar AM, Narula S, et al. Phenotypic clustering of left ventricular diastolic function parameters: patterns and prognostic relevance. JACC Cardiovasc Imaging 2018;12:1149–61. https://doi.org/10.1016/j.jcmg.2018.02.005; PMID: 29680357.

32. Casaclang-Verzosa G, Shrestha S, Khalil MJ, et al. Network tomography for understanding phenotypic presentations in aortic stenosis. JACC Cardiovasc Imaging 2019;12:236–48. https:// doi.org/10.1016/j.jcmg.2018.11.025; PMID: 30732719.

33. Betancur J, Commandeur F, Motlagh M, et al. Deep learning for prediction of obstructive disease from fast myocardial perfusion SPECT: a multicenter study. JACC Cardiovasc Imaging 2018;11:1654–63. https://doi.org/10.1016/j.jcmg.2018.01.020; PMID: 29550305.

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36. Slomka PJ, Dey D, Sitek A, et al. Cardiac imaging: working towards fully-automated machine analysis and interpretation.

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Catheterization Etiquettes

Strategies to Reduce Radiation Exposure in Electrophysiology and Interventional Cardiology Sandeep Shankar, MD, DM, 1 Deepak Padmanabhan, MD, DM, 1 Avinash Chandrashekharaiah, BE 2 and Saurabh Deshpande, MD, DM 1 1. Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, Karnataka, India; 2. BMS College of Engineering, Bengaluru, Karnataka, India

Abstract Clinical diagnosis sometimes involves the use of medical instruments that employ ionizing radiation. However, ionizing radiation exposure is a workplace hazard that goes undetected and is detrimental to patients and staff in the catheterization laboratory. Every possible effort should be made to reduce the amount of radiation, including scattered radiation. Implementing radiation dose feedback may have a role in reducing exposure. In medicine, it is important to estimate the potential biologic effects on, and the risk to, an individual. In general, implantation of cardiac resynchronization devices is associated with one of the highest operator exposure doses due to the proximity of the operator to the radiation source. All physicians should work on the principle of as low as reasonably achievable. Methods for reducing radiation exposure must be implemented in the catheterization laboratory. In this article, we review the available tools to lower the radiation exposure dose to the operator during diagnostic, interventional, and electrophysiological cardiac procedures.

Keywords Radiation exposure, electrophysiology, interventional cardiology, ionizing radiation, workplace hazard, cardiac resynchronization devices Disclosure: The authors have no conflicts of interest to declare.

Received: 17 July 2019 Accepted: 22 December 2019 Citation: US Cardiology Review 2019;13(2):117–22. DOI: https://doi.org/10.15420/usc.2019.21.2 Correspondence: Deepak Padmanabhan, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bannerghatta Main Rd, Phase 3, Jayanagara 9th Block, Jayanagar, Bengaluru, Karnataka 560069, India. E: deepak.padmanabhan@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.

Ionizing radiation is a workplace hazard that goes undetected. In the cardiac catheterization laboratory, where various interventional and electrophysiological procedures are done, physicians and other staff are exposed to ionizing radiation daily. The amount of radiation exposure in the catheterization laboratory is exponentially more compared to other departments using X-ray and fluoroscopy, which increases even more in complex cases. Staff are at a higher lifetime risk of various medical conditions, ranging from cataracts to malignancies. The two major sources of radiation exposure to staff in the cardiac catheterization laboratory are scattered X-ray photons and X-ray tube leakage.

As per the original definitions given by International Commission on Radiological Protection, radiation effects were classified into stochastic (random) and non-stochastic (or deterministic). Currently, the classification has been changed to stochastic and tissue reactions, but there is an overlap of common reactions, such as thyroid cancer and cataracts, into both types.1 Radiation in the catheterization laboratory is generated using two different modes: fluoroscopy or cine angiography (cine). Fluoroscopy is used for catheter placement and involves 95% of the total X-ray operation time, but only causes 40% of the total radiation exposure to staff and patients.2

© RADCLIFFE CARDIOLOGY 2019

Cine is used to acquire diagnostic images and to generate a permanent record of the procedure, and although representing only 5% of the total X-ray tube operation time, 60% of the total radiation exposure to staff and patients occur during cine. This is primarily due to the use of a relatively high dose required to record onto film.

It has been revealed that there may be an excess risk of brain tumors among interventional cardiologists.3,4 The lens of the eye is a region of particular interest, with several studies showing an increased incidence of cataracts among catheterization laboratory staff.5–7 A recent study of radiation-induced cataracts documented that 52% of interventional cardiologists had posterior subcapsular cataracts, citing radiation as the cause.6 The occupational effective dose limit to radiation workers is 20 mSv per year averaged over 5 years, and the dose limit for the eye has recently been reduced from 150 to 20 mSv a year to further protect against the rising number of radiation-induced cataracts.8 Recent evidence suggests that even protracted low-dose radiation exposure could be associated with leukemia, carotid artery atherosclerosis, and early vascular aging.9,10 Physicians need to keep the dose as low as reasonably achievable (ALARA),11 regardless of occupational dose

Access at: www.USCjournal.com

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Catheterization Etiquettes Table 1: Radiation Quantities Commonly Encountered in the Catheterization Laboratory Quantity

Description

SI Unit

Reference air kerma

The energy released per unit of mass of air at the interventional reference point, which is located 15 cm from the isocenter toward the X-ray tube

Gy

Organ-absorbed dose

Integral or average absorbed dose over a whole organ mass

Gy

Dose area product or kerma area product

The integral of air kerma multiplied by the irradiated field area

Gy.cm2

Effective dose

A tissue-weighted sum of the absorbed dose in irradiated organs and a representation of the patient stochastic risk

Sv

Peak skin dose

The accumulated absorbed dose to the highest irradiated area of the skin

Gy

limits. Radiation-attenuating materials, such as lead and lead-free materials (i.e. antimony and bismuth) have been used as a component of protective equipment to decrease the amount of radiation exposure.

This includes aprons, glasses, gloves, and movable shields. With appropriate use, these will lower radiation exposure. Implementing radiation dose feedback may also have a role in reducing exposure.

In this article, we review all the available tools to lower the radiation exposure dose to the operator during diagnostic, interventional, and electrophysiological cardiac procedures.

Basic Nomenclature in Radioprotection Radiation exposure can be expressed as absorbed dose or kerma, which represents the energy of absorbed radiation by an organ or tissue per unit of mass, typically measured in milligray. Equivalent dose takes into account the radiation weighting factor relevant to the biologic effect of the absorbed radiation. In medicine, it is important to estimate the potential biologic effects on and the risk to an individual. The amount of radiation that an individual is exposed to is calculated by effective dose in millisieverts (Table 1). There are variables, including genetic and dietary variables, that affect radiation exposure and they vary between individuals. It is possible to combine effective doses of individual organs to obtain a global quantity (effective dose). Modern X-ray equipment detail information regarding the amount of radiation exposure to the patient by a measurement referred to as the kerma area product or dose area product (DAP).2

Magnitude of Radiation Exposure Modern cardiac interventional procedures, such as coronary angiography and percutaneous coronary intervention (PCI), have been shown to generate radiation exposure to 2–16 mSv and 7–57 mSv, respectively.

Values for patient radiation vary from 3.2 mSv for a simple diagnostic electrophysiological study to higher values in more complex ablation procedures, such as in the treatment of AF, for which the reported median dose is 16.6 mSv (Table 2). Cardiac resynchronization device implantation is associated with the highest radiation exposure, with patients’ mean effective dose reported to reach 22 mSv per procedure.12,13

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Estimating the amount of radiation dose to the physician in general is much more difficult due to the many variables involved from the energy source to the individual clinician. There is an impact of the hardware (detector size, image quality settings), procedure-specific factors (tube angulations, collimation, patient BMI), laboratory setup (use of protective lead lining, the position of the operator), and operator factors (use of personal protection).14 As a general rule, approximately 10–20% of photons are scattered.

Adequate lead lining above and below the patient table is capable of blocking upwards of 80% of this scatter.15 A worst-case estimate of total physician dose in this setting would be 5% of the total estimated patient dose. The highest exposure during implantation of cardiac resynchronization devices was found to be 1.2 mSv (mean of up to 9 mSv) in one study.16 During structural interventions, the radiation exposure, as measured with DAP, was not found to be significantly greater than for single-vessel PCI.17 In structural heart disease laboratories, the radiation exposure to the operators performing transesophageal echocardiography has found to be at least as high as the primary operator.18 The amount of radiation exposure is significantly higher in endovascular interventions, especially with greater use of digital subtraction angiography runs, oblique angulations, and in thoracic procedures.19 The concept of the hybrid operating room involves radiation exposure to the surgical team and interventional cardiologists.20 The exposure can be minimized by various methods, as described later in this article.

Radiation exposure during pregnancy has been a cause for concern for many years. The maximum allowable total radiation dose in pregnancy is 500 mrem (100 mrem = 1 mSv), and the maximum monthly limit is 50 mrem.21 The effect on the fetus is based on gestational age. Exposure of up to 50 mrem in utero reduces the probability of malformation or cancer in live births from 95.93% to 95.92%, according to the National Council on Radiation Protection and Measurements.22

Methods of Reducing Radiation Exposure Only procedures that have a valid scientific basis and are known to benefit a patient should be done. There needs to be responsible use of radiation-minimizing exposure time using the least amount of images. All physicians should work to the principle of ALARA.11

Physician Training in Radiation Protection All staff should be trained to limit the dose of radiation and in radiation protection.12,23 Radiation protection and comprehensive training in the correct use of all available protection measures should be part of the curriculum of all trainees in interventional cardiology/specialized electrophysiology/device training programs.12 Careful attention should be paid to the correct use of protective shielding, and personal protection using an adequate lead apron, as well as the constant use of the radiation dosimeters in the correct position, should be implemented.24 Recognition of radiation exposure for both patient and operator/staff needs to be governed by the ALARA principle at all times, particularly for pediatric patients.11,25

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Radiation Exposure in Electrophysiology and Interventional Cardiology Work Adaptations Reducing Time of Radiation Exposure The average procedure time for a diagnostic coronary angiogram is approximately 30 minutes and an interventional procedure (PCI or electrophysiology procedure/pacing) is between 90 and 120 minutes.

However, the fluoroscopic and cine screening times are highly variable and depend on the nature of the procedure and the experience of the operator. The lower the amount of time spent in a radiation area, the lower the exposure.

Compared with acquisition cine imaging, fluoroscopy accounts for approximately 40% and 66% of the total air kerma dose in diagnostic catheterization and PCI, respectively.26 Fluoroscopy should be performed in short intervals, rather than continuously. The use of intravascular ultrasonography could also result in radiation dose reduction.26,27 Fluoroscopy storing is available in newer X-ray systems and also reduces the dose of radiation exposure.28 Virtual collimation, when available, reduces the radiation dose.28,29 Every effort should be made by the operating cardiologist to minimize fluoroscopy and cine screening time.

Table 2: Typical Value of Patient Radiation Exposure for Common Electrophysiological Procedures Study Type

Median Radiation

Range (mSv)

Exposure (mSv) Diagnostic electrophysiology study

3.2

1.3–23.9

Ablation procedures

15.2

1.6–59.6

• AF ablation

16.6

6.6–59.6

• AT-AVNRT-AVRT

4.4

1.6–25.0

• VT

12.5

3.0–45.0

Pacemaker (VVI/DDD)/ICD implantation

4.0

1.4–17.0

CRT implantation

22.0

2.2–95.0

Coronary angiography

7.0

2.0–16.0

Percutaneous coronary intervention

15.0

7.0–57.0

AT = atrial tachycardia; AVNRT = atrioventricular nodal re-entrant tachycardia; AVRT = atrioventricular reciprocating tachycardia; CRT = cardiac resynchronization therapy; VT = ventricular tachycardia; VVI/DDD = three-letter code to designate common type of pacemakers implanted in an electrophysiology laboratory.

Magnification and Collimation Increasing Distance of Operator from Radiation Beam Increasing the distance from the radiation beam decreases the risk of exposure.30 Doubling the distance between the primary beam and operator reduces the exposure by a factor of four. Radiation exposure also varies according to the angle at which the camera is projected. Oblique views (left and right anterior oblique) and steep angulations increase radiation exposure, which are often employed to improve visualization.

Angulations of 60 degrees give up to three times the operator dose than 30-degree angulations.14 The second operator or assistant is generally less exposed to radiation compared to the first operator, but is at greater risk than other staff in the operating room .

X-ray Angulation and Patient Positioning Increasing the angulation of the imaging equipment (i.e. from 30 to 60 degrees) also increases radiation dose during both fluoroscopy and cine imaging.30 Proper positioning of both the patient and the operator is important for reducing radiation exposure. Radiation scatter is the primary mechanism of operator and staff exposure. Several factors can substantially affect radiation scatter, including the thickness of the X-ray beam, patient position, patient body surface area, access site, fluoroscopy and acquisition settings, filtration, shielding, and gantry angulation.29 Radial access increases exposure by reducing the distance between the X-ray beam and the operator; therefore, it is important to use manifold extensions and position the operator as close to the feet of the patient as possible.31 The height of the patient table can significantly affect scatter. The image receptor should be as close to the patient as possible.

Reducing magnification reduces the amount of radiation exposure.

Newer X-ray systems offer features, such as storing fluoroscopy images, last image hold, and virtual collimation.29 There is a quasi-linear reduction in radiation dose with a reduction in the irradiated surface area.

Cine Acquisition During cine, radiation exposure is five times higher than during fluoroscopy.27 The use of cine should be limited as much as possible. It is recommended that fluoroscopy images are stored in place of cine images.

Other available dose-reduction technologies include low pulse rate fluoroscopy, lower frame rate imaging, lower dose per frame, spectral beam filtration, and high X-ray beam energy.29

Robotic Percutaneous Coronary Intervention Future modalities, such as the use of robotic systems to perform PCI, will result in a drastic reduction in operator exposure. The CorPath 200 robotic system was used in a study with eight patients and total radiation exposure was reduced by 97%.33,34 Remote-controlled robotic systems were developed to address the occupational hazards for interventionalists, such as chronic radiation exposure and orthopedic injuries, from long hours of standing while wearing heavy radiation protection gear. A prospective, multicenter study, Percutaneous Robotically-Enhanced Coronary Intervention Study (PRECISE) was carried out to compare robotic-assisted PCI to conventional PCI. The radiation exposure was 95.2% lower in the former. 34

Adjusting X-ray Settings and Fluoroscopy Rate In most catheterization systems, the default setting for acquisition is 15 frames per second (FPS). During most interventional and electrophysiological procedures, the frame rate is kept at 7.5 FPS. By decreasing the fluoroscopy frame rate, radiation exposure is reduced by 30% and DAP by 19%.32 Most electrophysiological procedures can be done at 3.5 FPS, and often even at one FPS. During transseptal puncture and ablation near the atrioventricular node, higher frame rates are desirable.

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Non-fluoroscopic Guidance Systems on Electrophysiology Non-fluoroscopic mapping systems commonly used in electrophysiology are Carto, Ensite–NavX, and MediGuide.35 In supraventricular tachycardia ablation, including Wolff–Parkinson– White syndrome, atrial flutter/atrial tachycardia, and AF, the Carto

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Catheterization Etiquettes Ceiling-mounted Shields

and Ensite-NavX systems reduced the fluoroscopy time and radiation dose.36–39 AF ablation can be done without radiation using the NavX system.40 MRI-guided catheter ablation offers minimal radiation with high resolution, but is still under development.

Ceiling-mounted shields, if positioned correctly, reduce the radiation dose to the operator’s head and neck.15,48,57 The shield should be as close as possible to the patient to reduce scatter at the source.

Radiation Shielding

Table Lead Skirts

Lead Caps

The lower region of the operator receives the most exposure during the procedure. Protecting the lower trunk protects the reproductive organs, which are radiosensitive. Wearable aprons provide the majority of radiation protection, but using a table lead skirt reduces the radiation dose by 90%.15,58

Brain tumors due to radiation have raised concerns regarding appropriate shielding of the head.3,4,41,42 The use of lead caps has been shown to reduce the dose to the head compared to ceiling-mounted lead shields.43,44 However, the weight of lead caps leads to neck and back pain. Lightweight lead-equivalent caps containing barium sulfate and bismuth oxide composite were found to reduce radiation dose by 90%; these caps weigh about 125 g and are comfortable to wear.45

Patient Drapes Radiation drapes placed on top of the patient are important to prevent scatter radiation to the operator. RADPAD is a commercially available nonlead disposable shield that has been shown to reduce the operator radiation dose by 80% without increasing the radiation dose to the patient.59–61

Gloves Hands are exposed to a significant amount of radiation (45–1,500 mSv per procedure) because they are unshielded and close to the radiation source.46 Lead gloves reduce the dexterity of operators’ hands. The use of lead-free radiation-attenuating latex gloves can reduce radiation by 58%.47 The best way to protect the hands is to shield them from the primary beam. Single-use unleaded radiation-protective gloves are recommended.

Eyewear Catheterization laboratory staff and operating physicians are at high risk of radiation-induced cataracts. Studies have shown that using lead glasses lowers the dose of lens radiation by 98%.46–48 The use of non-lead glasses reduces the radiation dose by 36% compared to 87% with lead glasses. A lead acrylic face mask that protects the corners the eyes has been shown to reduce radiation exposure by 97%.49–51

Wearable Aprons Lead aprons are effective in reducing the amount of radiation to the operator and are adapted as a standard of practice in all laboratories.

The fit of the apron is important, as large gaps can increase radiation exposure to breast tissue in women.52 As they weigh a minimum of about 7 kg, their use can cause back problems.53 A custom-fit apron is recommended. Newer lead aprons made from lead composite or lead-free materials are about 20–40% lighter (around 4 kg) and offer similar protection to lead aprons.54 Lead-free bismuth-based materials provide good shielding, but are slightly less effective than standard lead aprons.54,55 Aprons should be quality checked annually to ensure that there are no cracks in the radioprotective layer. Aprons should be handled carefully and stored in purpose-designed racks to maintain the integrity of the radioprotective layer. Aprons should not be folded or creased during storage.

Thyroid Collar The thyroid is a radiosensitive organ and has been linked to an increased risk of carcinogenesis with radiation exposure.56 It receives a significant amount of scattered radiation if it is not protected. Thyroid shields should be worn, and there should not be a significant gap between the thyroid shield and lead apron. They should be quality checked every year.

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Zero-gravity Radiation Protection System The ceiling-suspended gantry system is available to support a walk-in lead-lined suit that eliminates the weight of lead aprons. These lead aprons have a 1-mm lead equivalency from the thyroid to groin, which is about twice the protection compared to standard lead aprons. It also provides 0.5 mm of protection where previously none was available.

Combined with table-side shielding, a ceiling-suspended lead screen reduces radiation to the primary operator by 76.8%, 81.9%, and 93.5% when placed close to the patient phantom, at the left side, and close to the primary operator, respectively, and reduces the radiation dose to the assistant by 70.3%, 76.7%, and 90%, respectively.62

EggNest Radiation Protection The EggNest-XR system is a carbon fiber sledge platform with flexible shielding for radiation protection, which conforms to the patient’s body to allow 360 degrees of gantry motion. Significant reduction in radiation is achieved both to the patient and operator by this system. Compared to standard shielding, the EggNest reduces total room scatter radiation at all angiographic angles tested (average 92% reduction) and significantly reduces scatter radiation exposure at each of the six positions around the table at each angulation.63

Radiation Monitoring Personal dosimeters are the gold standard to measure the dose of radiation to the operator. Two dosimeters are generally recommended to be worn: at the thyroid collar and under the protective apron. Eye dose can be measured by a dedicated eye lens dosimeter. The effective dose per interventional cardiologist varies from 1 to 4 mSv per year.29 Real-time monitoring of radiation exposure is a novel approach to reduce radiation exposure to modify the behavior of the operator. Bleeper Sv is a radiation detector that beeps at a rate proportional to radiation intensity.

It helps to modify the behavior of the operator, and reduces radiation exposure according to the RadiCure study.64 The DoseAware System is designed to measure radiation exposure in real time and provides visual graphs to show per procedure, and daily and cumulative radiation exposure.65

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Radiation Exposure in Electrophysiology and Interventional Cardiology Conclusion Ionizing radiation is beneficial to neither patients nor staff in the catheterization laboratory. Every possible effort should be made to reduce the amount of radiation exposure, including scattered radiation.

including procedural modifications, optimizing catheterization laboratory equipment, using a lower frame rate, and minimizing cine exposure and changing vascular access, will reduce the operator radiation dose. This should be done without compromising patient or therapeutic outcomes.

Staff should use protective equipment to ensure that occupational radiation exposure is as low as reasonably possible. Unprotected areas, such as the head, neck, eyes, and hands, should also be protected using appropriate radiation shielding. A combination of tools,

Staff training and education are important to achieve these goals. There should be a regular audit of each individual’s radiation exposure in the cardiac catheterization laboratory and each should be educated on how to minimize the dose of radiation.

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Corrigendum

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

Citation: US Cardiology Review 2019;13(2):123. DOI: https://doi.org/10.15420/usc.2019.13.2.CG1 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.

In the article by Elbey et al. entitled “Value of MitraClip in Reducing Functional Mitral Regurgitation” (US Cardiology Review 2019;13(1):30–4. https://doi.org/10.15420/usc.2018.19.1), the following correction should be made for the second author: “Luis Augusto Palma Dalan” should be “Luis Augusto Palma Dallan”.

The authors apologise for this error.

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