CLINICAL REVIEW
The long-QT syndrome and exercise practice: The never-ending debate
Giuseppe Mascia MD, PhD,
Elena Arbelo MD, PhD,
Francesco Solimene MD,
Marzia Giaccardi MD,
Ramon Brugada MD, PhD,
Josep Brugada MD, PhD,
Corresponding Author
Giuseppe Mascia MD, PhD
Electrophysiology Unit, Clinica Montevergine, Mercogliano, Italy
Correspondence
Giuseppe Mascia, MD, PhD, Electrophysiology Unit, Clinica Montevergine Via Mario Malzoni, 83013 Mercogliano (AV), Italy.
Email: [email protected]
Search for more papers by this authorElena Arbelo MD, PhD
Arrhythmia Section, Cardiology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
Search for more papers by this authorFrancesco Solimene MD
Electrophysiology Unit, Clinica Montevergine, Mercogliano, Italy
Search for more papers by this authorMarzia Giaccardi MD
Cardiology and Electrophysiology Unit, Department of Internal Medicine, Santa Maria Nuova Hospital, Florence, Italy
Search for more papers by this authorRamon Brugada MD, PhD
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, Girona, Spain
Search for more papers by this authorJosep Brugada MD, PhD
Arrhythmia Section, Cardiology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
Search for more papers by this authorGiuseppe Mascia MD, PhD,
Elena Arbelo MD, PhD,
Francesco Solimene MD,
Marzia Giaccardi MD,
Ramon Brugada MD, PhD,
Josep Brugada MD, PhD,
Corresponding Author
Giuseppe Mascia MD, PhD
Electrophysiology Unit, Clinica Montevergine, Mercogliano, Italy
Correspondence
Giuseppe Mascia, MD, PhD, Electrophysiology Unit, Clinica Montevergine Via Mario Malzoni, 83013 Mercogliano (AV), Italy.
Email: [email protected]
Search for more papers by this authorElena Arbelo MD, PhD
Arrhythmia Section, Cardiology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
Search for more papers by this authorFrancesco Solimene MD
Electrophysiology Unit, Clinica Montevergine, Mercogliano, Italy
Search for more papers by this authorMarzia Giaccardi MD
Cardiology and Electrophysiology Unit, Department of Internal Medicine, Santa Maria Nuova Hospital, Florence, Italy
Search for more papers by this authorRamon Brugada MD, PhD
Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, Girona, Spain
Search for more papers by this authorJosep Brugada MD, PhD
Arrhythmia Section, Cardiology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain
Search for more papers by this authorSection Editor: Bruce D. Lindsay, MD
Disclosures: None.
Abstract
Today, understanding the true risk of adverse events in long-QT syndrome (LQTS) populations may be extremely complex and potentially dependent on many factors such as the affected gene, mutation location, degree of QTc prolongation, age, sex, and other yet unknown factors. In this context, risk stratification by genotype in LQTS patients has been extremely difficult, also during exercise practice, especially due to the lack of studies that would lead to a better understanding of the natural history of each mutation and its impact upon athletes. The creation of individualized guidelines for sport participation is a goal yet to be achieved not only due to the complexity of genotype effect on the phenotype in this patient population, but also due to penetrance in genotype-positive patients. This article summarizes current knowledge and raises questions concerning the difficult relationship between exercise practice and LQTS.
REFERENCES
- 1Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957; 54: 59–68.
- 2Romano C, Gemme G, Pongiglione R. Rare cardiac arrhythmias of the pediatric age. II. Syncopal attacks due to paroxysmal ventricular fibrillation. (Presentation of 1st case in Italian pediatric literature). Clin Pediatr (Bologna). 1963; 45: 656–683.
- 3Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964; 54: 103–106.
- 4Ackerman MJ. Cardiac channelopathies: It's in the genes. Nat Med. 2004; 10: 463–464.
- 5Liu JF, Jons C, Moss AJ, et al. International Long QT Syndrome Registry. Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome. J Am Coll Cardiol. 2011; 57: 941–950.
- 6Basavarajaiah S, Wilson M, Whyte G, Shah A, Behr E, Sharma S. Prevalence and significance of an isolated long QT interval in elite athletes. Eur Heart J. 2007; 28: 2944–2949.
- 7Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991; 252: 704–706.
- 8Priori SG, Wilde AA, Horie M, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013; 10: e85–108.
- 9Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: Clinical impact. Circulation. 1999; 99: 529–533.
- 10Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011; 124: 2181–2184.
- 11Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update Circulation. 1993; 88: 782–784.
- 12Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: Clinical implications. J Intern Med. 2006; 259: 39–47.
- 13Sy RW, Van der Werf C, Chattha IS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation. 2011; 124: 2187–2194.
- 14Schwartz PJ, Crotti L, Insolia R. Long QT-syndrome. From genetics to management. Circ Arrhythm Electrophysiol. 2012; 5: 868–877.
- 15Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003; 348: 1866–1874.
- 16Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: Teach the tangent. Heart Rhythm. 2008; 5: 1015–1018.
- 17Talbot S. QT interval in right and left bundle-branch block. Br Heart J. 1973; 35: 288–291.
- 18Jouven X, Hagege A, Charron P, et al. Relation between QT duration and maximal wall thickness in familial hypertrophic cardiomyopathy. Heart. 2002; 88: 153–157.
- 19Napolitano C, Bloise R, Priori SG. Long QT syndrome and short QT syndrome: How to make correct diagnosis and what about eligibility for sports activity. J Cardiovasc Med (Hagerstown). 2006; 7: 250–256.
- 20Diercks DB, Shumaik GM, Harrigan RA, Brady WJ, Chan TC. Electrocardiographic manifestations: Electrolyte abnormalities. J Emerg Med. 2004; 27: 153–160.
- 21Kuppermann N, Park J, Glatter K, Marcin JP, Glaser NS. Prolonged QT interval corrected for heart rate during diabetic ketoacidosis in children. Arch Pediatr Adolesc Med. 2008; 162: 544–549.
- 22Lesinskiene S, Barkus A, Ranceva N, Dembinskas A. A meta-analysis of heart rate and QT interval alteration in anorexia nervosa. World J Biol Psychiatry. 2008; 9: 86–91.
- 23Viskin S, Rosovski U, Sands AJ, et al. Inaccurate electrocardiographic interpretation of long QT: The majority of physicians cannot recognize a long QT when they see one. Heart Rhythm. 2005; 2: 569–574.
- 24Levine E, Rosero SZ, Budzikowski AS, Moss AJ, Zareba W, Daubert JP. Congenital long QT syndrome: Considerations for primary care physicians. Cleve Clin J Med. 2008; 75: 591–600.
- 25Fagard R. Athlete's heart. Heart. 2003; 89: 1455–1461.
- 26Swan H, Viitasalo M, Piippo K, Laitinen P, Kontula K, Toivonen L. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. J Am Coll Cardiol. 1999; 34: 823–829.
- 27Takenaka K, Ai T, Shimizu W, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation. 2003; 107: 838–844.
- 28Kapplinger JD, Tester DJ, Salisbury BA, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009; 6: 1297–1303.
- 29Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation. 2001; 103: 89–95.
- 30Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: Possible therapy implications. Circulation. 2006; 114: 2096–2103.
- 31Fujiki A, Nishida K, Mizumaki K, Nagasawa H, Shimono M, Inoue H. Spontaneous onset of torsade de pointes in long-QT syndrome and the role of sympathovagal imbalance. Jpn Circ J. 2001; 65: 1087–1090.
- 32Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT syndrome. Curr Opin Cardiol. 2002; 17: 43–51.
- 33Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001; 104: 569–580.
- 34Tseng GN, Xu Y. Understanding the microscopic mechanisms for LQT1 needs a global view of the I(Ks) channel. Heart Rhythm. 2015; 12: 395–396.
- 35Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long QT syndrome: Effects of b-adrenergic agonists and antagonists and sodium channels blockers on transmural dispersion of repolarization and torsade de pointes. Circulation. 1998; 98: 2314–2322.
- 36Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman MJ. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation. 2004; 110: 2119–2124.
- 37Priori SG, Napolitano C, Cantù F, Brown AM, Schwartz PJ. Differential response to Na+ channel blockade, beta-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long-QT syndrome. Circ Res. 1996; 78: 1009–1015.
- 38Aziz PF, Wieand TS, Ganley J, et al. Genotype- and mutation site-specific QT adaptation during exercise, recovery, and postural changes in children with long-QT syndrome. Circ Arrhythm Electrophysiol. 2011; 4: 867–873.
- 39Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol. 1999; 33: 327–332.
- 40Liu J, Laurita KR. The mechanism of pause-induced torsade de pointes in long QT syndrome. J Cardiovasc Electrophysiol. 2005; 16: 981–987.
- 41Shimizu W, Ohe T, Kurita T, et al. Early after-depolarizations induced by isoproterenol in patients with congenital long QT syndrome. Circulation. 1991; 84: 1915–1923.
- 42Shimizu W, Antzelevitch C. Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Coll Cardiol. 2000; 35: 778–786.
- 43Viswanathan PC, Rudy Y. Pause induced early after-depolarizations in the long QT syndrome: A simulation study. Cardiovasc Res. 1999; 42: 530–542.
- 44Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation. 1996; 94: 1996–2012.
- 45Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias; impact on clinical management. Eur Heart J. 1999; 20: 174–195.
- 46Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998; 339: 960–965.
- 47Mitchell JH, Haskell W, Snell P, Van Camp SP. Task Force 8: Classification of sports. J Am Coll Cardiol. 2005; 45: 1364–1367.
- 48Pelliccia A, Fagard R, Bjørnstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: A consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J. 2005; 26: 1422–1445.
- 49Heidbüchel H, Corrado D, Biffi A, et al. Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part II: Ventricular arrhythmias, channelopathies and implantable defibrillators. Eur J Cardiovasc Prev Rehabil. 2006; 13: 676–686.
- 50Pelliccia A, Zipes DP, Maron BJ. Bethesda Conference #36 and the European Society of Cardiology Consensus Recommendations revisited a comparison of U.S. and European criteria for eligibility and disqualification of competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol. 2008; 52: 1990–1996.
- 51Johnson JN, Ackerman MJ. Return to play? Athletes with congenital long QT syndrome. Br J Sports Med. 2013; 47: 28–33.
- 52Aziz PF, Sweeten T, Vogel RL, et al. Sports participation in genotype positive children with long QT syndrome. JACC Clin Electrophysiol. 2015; 1(1-2): 62–70.
- 53Ackerman MJ, Zipes DP, Kovacs RJ, Maron BJ. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 10: The cardiac channelopathies: A scientific statement from the American Heart Association and American College of Cardiology. Circulation. 2015; 132: e326–9.
- 54Maron BJ, Zipes DP. Introduction: Eligibility recommendations for competitive athletes with cardiovascular abnormalities-general considerations. J Am Coll Cardiol. 2005; 45: 1318–1321.
- 55Lampert R, Olshansky B, Heidbuchel H, et al. Safety of sports for athletes with implantable cardioverter-defibrillators: Results of a prospective, multinational registry. Circulation. 2013; 127: 2021–2030.
- 56Zipes DP, Link MS, Ackerman MJ, Kovacs RJ, Myerburg RJ. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 9: Arrhythmias and conduction defects: A scientific statement from the American Heart Association and American College of Cardiology. Circulation. 2015; 132: e315–25.
- 57Dorostkar PC, Eldar M, Belhassen B, Scheinman MM. Long-term follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing. Circulation. 1999; 100: 2431–2436.
- 58Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000; 101: 616–623.
- 59Wilde AA, Moss AJ, Kaufman ES, et al. Clinical aspects of type 3 long-QT syndrome: An international multicenter study. Circulation. 2016; 134: 872–882.
- 60Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation. 2007; 116: 1137–1144.
- 61Mazzanti A, Maragna R, Faragli A, et al. Gene-specific therapy with mexiletine reduces arrhythmic events in patients with long QT syndrome type 3. J Am Coll Cardiol. 2016; 67: 1053–1058.
- 62Chockalingam P, Crotti L, Girardengo G, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: Higher recurrence of events under metoprolol. J Am Coll Cardiol. 2012; 60: 2092–2099.
- 63Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004; 109: 1826–1833.
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