Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study

doi:10.1161/CIRCULATIONAHA.123.067590

Observational Study

. 2024 Aug 13;150(7):516-530.

doi: 10.1161/CIRCULATIONAHA.123.067590. Epub 2024 Jul 25.

Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study

Rachel Lampert¹, Sharlene Day^{2

3}, Barbara Ainsworth^{4

5}, Matthew Burg^{1

6}, Bradley S Marino^{7

8}, Lisa Salberg⁹, Maria Teresa Tome Esteban^{10

11}, Dominic J Abrams¹², Peter F Aziz⁷, Cheryl Barth¹, Elijah R Behr^{10

11}, Cheyanne Bell¹³, Charles I Berul¹⁴, Johan M Bos¹³, David Bradley¹⁵, David S Cannom¹⁶, Bryan C Cannon¹³, Maryann Anandi Concannon³, Marina Cerrone¹⁷, Richard J Czosek¹⁸, Anne M Dubin¹⁹, James Dziura¹, Christopher C Erickson²⁰, N A Mark Estes 3rd^{21

22}, Susan P Etheridge²³, Ilan Goldenberg²⁴, Belinda Gray²⁵, Carla Haglund-Turnquist¹³, Kimberly Harmon²⁶, Cynthia A James²⁷, Christopher Johnsrude²⁸, Prince Kannankeril²⁹, Alice Lara³⁰, Ian H Law³¹, Fangyong Li¹, Mark S Link^{21

32}, Silvana M Molossi³³, Brian Olshansky³¹, Peter A Noseworthy³⁴, Elizabeth V Saarel³⁵, Shubhayan Sanatani³⁶, Maully Shah³⁷, Laura Simone¹, Jonathan Skinner³⁸, Gordon F Tomaselli^{27

39}, James Simon Ware^{40

41}, Gregory Webster⁸, Wojciech Zareba²⁴, Douglas P Zipes⁴², Michael J Ackerman¹³

Affiliations

¹ Yale School of Medicine, New Haven, CT (R.L., M.B., C. Barth, J.D., F.L, L.S.).
² University of Pennsylvania, Philadelphia (S.D.).
³ University of Michigan Hospital, Ann Arbor (S.D., M.A.C.).
⁴ School of Exercise and Health, Shanghai University of Sport, China (B.A.).
⁵ College of Health Solutions/Arizona State University, Phoenix (B.A.).
⁶ VA Hospital, West Haven, CT (M.B.).
⁷ Cleveland Clinic, OH (B.S.M., P.F.A.).
⁸ Lurie Children's Hospital, Chicago, IL (B.S.M., G.W.).
⁹ Hypertrophic Cardiomyopathy Association, Denville, NJ (L.S.).
¹⁰ Cardiology Section, Cardiovascular and Genomics Research Institute, St. George's, University of London, UK (M.T.T.E., E.R.B.).
¹¹ Cardiology Department, St. George's University Hospitals NHS Foundation Trust, London, UK (M.T.T.E., E.R.B.).
¹² Boston Children's Hospital, MA (D.J.A.).
¹³ Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN (C. Bell, J.M.B., B.C.C., C.H.-T., M.J.A.).
¹⁴ Children's National Hospital, Washington, DC (C.I.B.).
¹⁵ C.S. Mott Children's Hospital, Ann Arbor, MI (D.B.).
¹⁶ Keck Medicine of USC, Los Angeles, CA (D.S.C.).
¹⁷ Leon H. Charney Division of Cardiology, NYU Grossman Sch of Medicine, New York (M.C.).
¹⁸ The Heart Institute, Cincinnati Children's Hospital Med Center, OH (R.J.C.).
¹⁹ Stanford University School of Medicine, Palo Alto, CA (A.M.D.).
²⁰ University of Nebraska Medical Center, Children's Nebraska, Omaha (C.C.E.).
²¹ Tufts Medical Center, Boston, MA (N.A.M.E., M.S.L.).
²² UPMC, Pittsburgh, PA (N.A.M.E.).
²³ University of Utah, Salt Lake City (S.P.E.).
²⁴ Division of Cardiology, University of Rochester Medical Center, NY (I.G., W.Z.).
²⁵ Faculty of Medicine and Health, University of Sydney/Royal Prince Alfred Hospital, Australia (B.G.).
²⁶ Department of Family Medicine, University of Washington, Seattle (K.H.).
²⁷ Johns Hopkins University, Baltimore, MD (C.A.J.,G.F.T.).
²⁸ University of Louisville School of Medicine, KY (C.J.).
²⁹ Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt and Vanderbilt University, Nashville, TN (P.K.).
³⁰ Sudden Arrhythmia Death Syndrome Foundation, Salt Lake City, UT (A.L.).
³¹ University of Iowa Carver College of Medicine, Iowa City (I.H.L., B.O.).
³² UT Southwestern Medical Center, Dallas, TX (M.S.L.).
³³ Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston (S.M.M.).
³⁴ Department of Medicine/Cardiology, Mayo Clinic, Rochester, MN (P.A.N.).
³⁵ St. Lukes Medical Center/Primary Children's Hospital, Boise, ID (E.V.S.).
³⁶ Institution British Columbia Children's Hospital, University of British Columbia, Vancouver, Canada (S.S.).
³⁷ University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia (M.S.).
³⁸ Cardiac Inherited Disease Group, Starship Children's Hospital, Auckland, New Zealand (J.S.).
³⁹ Albert Einstein College of Medine, Bronx, NY (G.F.T.).
⁴⁰ National Heart & Lung Inst & MRC London Institute of Medical Sciences, Imperial College London, UK (J.S.W.).
⁴¹ Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK (J.S.W.).
⁴² Indiana University School of Medine, Carmel, IN (D.P.Z.).

PMID: 39051104
DOI: 10.1161/CIRCULATIONAHA.123.067590

Free article

Observational Study

Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study

Rachel Lampert et al. Circulation. 2024.

Free article

. 2024 Aug 13;150(7):516-530.

doi: 10.1161/CIRCULATIONAHA.123.067590. Epub 2024 Jul 25.

Authors

Affiliations

¹ Yale School of Medicine, New Haven, CT (R.L., M.B., C. Barth, J.D., F.L, L.S.).
² University of Pennsylvania, Philadelphia (S.D.).
³ University of Michigan Hospital, Ann Arbor (S.D., M.A.C.).
⁴ School of Exercise and Health, Shanghai University of Sport, China (B.A.).
⁵ College of Health Solutions/Arizona State University, Phoenix (B.A.).
⁶ VA Hospital, West Haven, CT (M.B.).
⁷ Cleveland Clinic, OH (B.S.M., P.F.A.).
⁸ Lurie Children's Hospital, Chicago, IL (B.S.M., G.W.).
⁹ Hypertrophic Cardiomyopathy Association, Denville, NJ (L.S.).
¹⁰ Cardiology Section, Cardiovascular and Genomics Research Institute, St. George's, University of London, UK (M.T.T.E., E.R.B.).
¹¹ Cardiology Department, St. George's University Hospitals NHS Foundation Trust, London, UK (M.T.T.E., E.R.B.).
¹² Boston Children's Hospital, MA (D.J.A.).
¹³ Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology and Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, MN (C. Bell, J.M.B., B.C.C., C.H.-T., M.J.A.).
¹⁴ Children's National Hospital, Washington, DC (C.I.B.).
¹⁵ C.S. Mott Children's Hospital, Ann Arbor, MI (D.B.).
¹⁶ Keck Medicine of USC, Los Angeles, CA (D.S.C.).
¹⁷ Leon H. Charney Division of Cardiology, NYU Grossman Sch of Medicine, New York (M.C.).
¹⁸ The Heart Institute, Cincinnati Children's Hospital Med Center, OH (R.J.C.).
¹⁹ Stanford University School of Medicine, Palo Alto, CA (A.M.D.).
²⁰ University of Nebraska Medical Center, Children's Nebraska, Omaha (C.C.E.).
²¹ Tufts Medical Center, Boston, MA (N.A.M.E., M.S.L.).
²² UPMC, Pittsburgh, PA (N.A.M.E.).
²³ University of Utah, Salt Lake City (S.P.E.).
²⁴ Division of Cardiology, University of Rochester Medical Center, NY (I.G., W.Z.).
²⁵ Faculty of Medicine and Health, University of Sydney/Royal Prince Alfred Hospital, Australia (B.G.).
²⁶ Department of Family Medicine, University of Washington, Seattle (K.H.).
²⁷ Johns Hopkins University, Baltimore, MD (C.A.J.,G.F.T.).
²⁸ University of Louisville School of Medicine, KY (C.J.).
²⁹ Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt and Vanderbilt University, Nashville, TN (P.K.).
³⁰ Sudden Arrhythmia Death Syndrome Foundation, Salt Lake City, UT (A.L.).
³¹ University of Iowa Carver College of Medicine, Iowa City (I.H.L., B.O.).
³² UT Southwestern Medical Center, Dallas, TX (M.S.L.).
³³ Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston (S.M.M.).
³⁴ Department of Medicine/Cardiology, Mayo Clinic, Rochester, MN (P.A.N.).
³⁵ St. Lukes Medical Center/Primary Children's Hospital, Boise, ID (E.V.S.).
³⁶ Institution British Columbia Children's Hospital, University of British Columbia, Vancouver, Canada (S.S.).
³⁷ University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia (M.S.).
³⁸ Cardiac Inherited Disease Group, Starship Children's Hospital, Auckland, New Zealand (J.S.).
³⁹ Albert Einstein College of Medine, Bronx, NY (G.F.T.).
⁴⁰ National Heart & Lung Inst & MRC London Institute of Medical Sciences, Imperial College London, UK (J.S.W.).
⁴¹ Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK (J.S.W.).
⁴² Indiana University School of Medine, Carmel, IN (D.P.Z.).

PMID: 39051104
DOI: 10.1161/CIRCULATIONAHA.123.067590

Abstract

Background: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown.

Methods: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis.

Results: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup.

Conclusions: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664.

Keywords: arrhythmias, cardiac; exercise; long QT syndrome.

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Conflict of interest statement

Dr Lampert reports honoraria and research support from Medtronic, Abbott-St. Jude, and Boston Scientific, as well as serving on the Advisory Board for Medtronic. Dr Day received consulting and grant funding from Lexicon Pharmaceuticals, grant funding from Bristol Myers Squibb, and DMC from Cytokinetics. L. Salberg consulted for Biomarin. Dr Tome Esteban consulted for BMS and Cytokinetics. Dr Abrams served on the Scientific Advisory Board for Thryv Therapeutics and consulted for Rocket Pharmaceuticals. Dr Aziz served on the Medtronic Advisory Committee. Dr Behr consulted for Boston Scientific. Dr Berul received research funding from Medtronic. Dr Cerrone provided teaching and CME activities for Abbott and Medtronic. Dr Erickson received funding from Integer. Dr Estes reports consulting for Boston Scientific and Medtronic. Dr Ethridge reports funding from Spauling Research (ECG reading) and UpToDate. Dr James was a consultant for Pfizer and Lexeo Therapeutics and received research funding from Lexeo Therapeutics and StrideBio. Dr Law was a consultant for Medtronic and St. Jude and a speaker for Boston Scientific. Dr Olshansky, AstraZeneca DSMB (Data Safety Monitoring Board). Dr Noseworthy and Mayo Clinic have filed patents related to the application of artificial intelligence to the ECG for diagnosis and risk stratification and have licensed several A-ECG algorithms to Anumana. Dr Noseworthy and Mayo Clinic have a relationship with AliveCor related to the measurement of the QT interval on the Kardia device. Dr Shah was a consultant for Medtronic and Tenaya. Dr Ware received research support and/or consultancy fees from MyoKardia, Bristol Myers Squibb, Foresite Labs, Pfizer, and Health Lumen. Dr Ware is supported by Medical Research Council (UK), British Heart Foundation (RE/18/4/34215), and the NIHR Imperial College Biomedical Research Centre. Dr Ackerman has served as a consultant for Abbott, BioMarin Pharmaceuticals, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Illumina, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and Thryv Therapeutics. The other authors report no conflicts.

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Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study

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Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study

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