Background

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is uncommon but recognized as a cause of sudden cardiac death (SCD) in those with structurally normal hearts. It typically presents with palpitations or syncope during intense physical or emotional stress and may be fatal. Genetic advances in the last decade have allowed for improved diagnosis, risk stratification, and treatment of this disorder. Given the association to intense physical activity, CPVT deserves special consideration in athletes participating in competitive sports.

The incidence of SCD in young competitive athletes is relatively low (1:42,000-200,000 athletes) and is more commonly related to cardiac structural abnormalities such as hypertrophic cardiomyopathy (HCM) and coronary anomalies.^1,2 Contrary to previous belief, a recent study found that the most cause of SCD at autopsy was autopsy-negative sudden unexplained death (ANSUD) (25%) followed by HCM (8%). It is thought that the cause of ANSUD is likely due to unrecognized channelopathies.^3,4 CPVT is an uncommon condition, accounting for about 12% of autopsy-negative sudden deaths and 1.5% of sudden infant deaths.⁵ The true prevalence is unknown, though a possible prevalence of 1 in 10,000 has been quoted in the literature.⁶ There is ongoing controversy regarding the optimal screening and prevention of SCD in athletes. Athletic screening programs are likely to be helped by advances in genetics, novel antiarrhythmic drug strategies, and the management of athletes with implantable cardioverter-defibrillators (ICD).^7,8 Currently, athletes with CPVT are advised physical activity cessation and disqualification from nearly all competitive sports.⁹ The risk of SCD as well as disqualification from sports participation is devastating and has significant impact on quality of life for patients and their families. In the last decade, genetic testing and our understanding of the mechanisms of arrhythmogenesis has significantly improved, novel antiarrhythmic drug strategies have emerged, more epidemiological experience with athletes with inherited channelopathies is available, surveillance of asymptomatic mutation carriers has evolved, and experience with athletes with ICDs has expanded. These factors will likely change our management of athletes with the diagnosis of CPVT.

Genetics

CPVT is a highly malignant inheritable cardiac channelopathy. CPVT was originally described by Coumel et al. in 1978 and later further characterized by Leenhardt et al. in 1995 as a distinct genetic arrhythmogenesis disorder of unknown origin in individuals without structural heart disease and QT prolongation.^10,11 Affected individuals often present in childhood or adolescence with symptoms such as syncope or catecholamine-mediated ventricular arrhythmias that may result in cardiac arrest and sudden death. The untreated mortality rate as high as 50%.^12-14

Based on the early genetic studies, the electrocardiographic pattern of ventricular tachycardia in this disorder closely resembles that of arrhythmias associated with calcium overload and delayed afterdepolarizations observed in digitalis toxicity.^15,16 More specifically, missense mutations involving the human cardiac ryanodine receptor 2 gene (hRyR2) mapped to chromosome 1q42-q43 may be associated with CPVT, with an autosomal dominant pattern of inheritance.¹⁷ Priori et al. specifically showed that CPVT is a clinically and genetically heterogeneous disease presenting beyond the pediatric age with a spectrum of polymorphic arrhythmias.⁵ Probands identified as genotype positive for the RYR2 mutation often present with symptoms earlier with males having a higher risk of cardiac events. Nongenotyped CPVT probands are predominantly women and present later in life. Lahat et al. also identified a missense mutation involving the calsequestrin 2 gene (CASQ2) responsible for the autosomal recessive form.¹⁸

Clinical Presentation

CPVT is widely accepted to be a disease of childhood, with most patients presenting with symptoms (syncope or SCD) before the age of 21, with a median age of 15±10 years (range 2 to 51 years).^12,13 The incidence of cardiac events (syncope under physical or emotional stress, aborted cardiac arrest, appropriate ICD discharges, or SCD) during 4- and 8- year follow-up was 12% and 32% respectively. In other studies, the occurrence of cardiac events varied from 2% to 62% of the patients.^13,19

More recently, a bimodal distribution of symptom onset has been highlighted, with a juvenile type presenting in the first two decades of life and the adult type of CPVT presenting at 32-48 years.^15,20 The adult form tends to present around the age of 40 years, have a female predominance, usually RYR2-genotype negative, and associated with less risk of SCD. Further, Priori et al. showed that variable expressivity of RYR2 mutations was seen in 17% of gene carriers.¹⁵ These patients were phenotype negative for CPVT as well as other inherited arrhythmogenic diseases suggesting that RYR2 CPVT has incomplete penetrance.

Diagnosis

CPVT patients usually have a normal resting ECG. The delay between initial presentation and diagnosis is often between 2 to 9 years.^12,21 A high index of suspicion for CPVT should be held in patients with palpitations or syncope during physical or emotional stress, especially in those who have a family history of premature death.

The diagnosis of CPVT relies on the demonstration of ventricular arrhythmias (VA) during standard noninvasive exercise treadmill testing and epinephrine drug challenge. A positive test is defined when complex ventricular ectopy, bidirectional ventricular tachycardia (VT), and/or polymorphic VT occurs (Figure 1). A negative stress test, however, does not exclude CPVT. Several studies have shown that VA provoked with exercise range from 30%-76% and epinephrine in 82% of patients with CPVT.^22,23 The epinephrine drug challenge may be considered as an alternative to exercise treadmill testing, with sensitivity and specificity of 28% and 98% respectively.²⁴ Holter monitoring, loop recorder monitoring and implanted loop recorders may be useful in this case when exercise testing or drug challenge is either negative or cannot be performed. Genetic testing and family screening should then be performed in affected individuals and asymptomatic genotype positive family members should be treated with β-blockers.

Figure 1

Therapy

β-blockers remain the drug of choice in the treatment and prevention of VA. Their efficacy is modest and may vary with cardio-selective versus non-selective β-blockers, dosage and compliance.^13,25,26 Ca²⁺ channel blockers (CCB), often used in combination therapy with β-blockers, also reduce exercise induced VA.²⁷ Flecainide, a class IC antiarrhythmic sodium channel blocker, has also been studied and shown to reduce VA and defibrillator-induced VT storm in patients refractory to β -blockers and CCB therapy.²⁸ ICD placement currently is a class IIa recommendation for patients with CPVT who have syncope and/or documented sustained VA while receiving β -blockers.²⁹ However, ICD therapies may heighten the catecholamine response resulting in inappropriate shocks and electrical storm in 22% and 18% of cases respectively.¹² In patients who are symptomatic despite high dose β -blockers, intolerant or refractory to drug therapy and or electrical storm, left cardiac sympathetic denervation may be required and has been shown to reduce VA with 1- and 2-year event free survival rates of 87% and 81% respectively.³⁰

Recommendations

Despite strict contemporary guidelines, not all athletes choose to follow these recommendations. Recent data has shown that LQTS patients on a comprehensive treatment program have low risk of events even with continued sports participation. There is emerging data that this may also hold true in CPVT. Currently as outlined by the recent 36th Bethesda Conference (2005) and 2015 AHA/ACC Eligibility and Disqualification Recommendations, an athlete with previously symptomatic CPVT or asymptomatic CPVT with exercise-induced VA, participation in competitive sports is not recommended (except for class 1A sports).^31,32 Non participation is potentially devastating for an athlete and the risks should be carefully discussed with the patient and family. Exceptions to this limitation should be made only after consultation with a CPVT specialist. In a recent study of 63 CPVT patients older than 6 years on good medical therapy, 21 patients were identified as athletes at the start of the study who continued to compete during follow up. Compared to patients in the nonathlete group, there was no difference in event rates including death.³³

Implications

The current recommendation for undiagnosed and untreated CPVT patients is to refrain from all except class 1A sports. There is currently insufficient evidence to allow participation in asymptomatic treated CPVT patients, but the risk in the patients may be lower than previously thought. The decision for patients to compete in sports is complex and should involve the participation of the patient, family members, coaches, and electrophysiologists.

References

1. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation 2009;119:1085-92.
2. Harmon KG, Asif IM, Maleszewski JJ, et al. Incidence, cause, and comparative frequency of sudden cardiac death in national collegiate athletic association athletes: a decade in review. Circulation 2015;132:10-9.
3. Harmon KG, Asif IM, Klossner D, Drezner JA. Incidence of sudden cardiac death in National Collegiate Athletic Association athletes. Circulation 2011;123:1594-600.
4. Maron BJ, Haas TS, Murphy CJ, Ahluwalia A, Rutten-Ramos S. Incidence and causes of sudden death in U.S. college athletes. J Am Coll Cardiol 2014;63:1636-43.
5. Tester DJ, Medeiros-Domoingo A, Will ML, Haglund Cm, Ackerman MJ. Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexpected death referred for postmortem genetic testing. Mayo Clin Proc 2012;87:524-39.
6. van der Werf C, Wilde AA. Catecholaminergic polymorphic ventricular tachycardia: from bench to bedside. Heart 2013;99:497-504.
7. Lampert R, Olshansky B, Heidbuchel H, et al. Safety of sports for athletes with implantable cardioverter-defibrillators: results of a prospective, multinational registry. Circulation 2013;127:2021-30.
8. Johnson JN, Ackerman MJ. Competitive sports participation in athletes with congenital long QT syndrome. JAMA 2012;308:764-5.
9. Ackerman 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. J Am Coll Cardiol 2015;66:2424-8.
10. Coumel P, Fidelle J, Lucet V, Attuel P, Bouvrain Y. Catecholaminergic-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: report of four cases. Br Heart J 1978;40:28-37.
11. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children: a 7-year follow-up of 21 patients. Circulation 1995;91:1512-9.
12. Kawata H, Ohno S, Aiba T, et al. Catecholaminergic polymorphic ventricular tachycardia (CPTV) associated with ryanodine receptor (ryR2) gene mutations - long-term prognosis after initiation of medical treatment. Circ J 2016;80:1907-15.
13. Roston TM, Vinocur JM, Maginot KR, et al. Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhytm Electrophysiol 2015;8:633-42.
14. Hayashi M, Denjoy I, Extramiana F, et al. Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia. Circulation 2009;119:2426-34..
15. Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103:196-200.
16. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106:69-74.
17. Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999;34:2035-42.
18. Lahat H, Pras E, Olender T, et al. A missense mutation in a highly conserved region of CASQ1 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel. Am J Hum Genet 2001;69:1378-84.
19. Sumitomo N, Harada K, Nagashima M, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart 2003;89:66-70.
20. Sumitomo N. Are there juvenile and adult types in patients with catecholaminergic polymorphic ventricular tachycardia? Heart Rhythm 2011;8:872-3.
21. Kozlovski J, Ingles J, Connell V, et al. Delay to diagnosis amongst patients with catecholaminergic polymorphic ventricular tachycardia. Int J Cardiol 2014;176:1402-4.
22. Sy RW, Gollob MH, Klein GJ, et al. Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2011;8:864-71.
23. Haugaa KH, Leren IS, Berge KE, et al. High prevalence of exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia mutation-positive family members diagnosed by cascade genetic screening. Europace 2010;12:417-23.
24. Marjamaa A, Hiippala A, Arrhenius B, et al. Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol 2012;23:194-9.
25. van der Werf C, Zwinderman AH, Wilde AA. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace 2012;14:175-83.
26. Leren IS, Saberniak J, Majid E, Haland TF, Edvardsen T, Haugaa KH. Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2016;13:433-40.
27. Rosso R, Kalman JM, Rogowski O, et al. Calcium channel blockers and beta-blockers versus beta-blockers alone for preventing exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm 2007;4:1149-54.
28. van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244-54.
29. European Heart Rhythm Association, Heart Rhythm Society, Zipes DP, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol 2006;48:e247-346.
30. De Ferrari GM, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation. Circulation 2015;131:2185-93.
31. Maron B. 36th Bethesda Conference: Eligibility recommendation for competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol 2005;45.
32. Maron BJ, Zipes DP, Kovacs RJ. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: preamble, principles, and general considerations: a scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol 2015;66:2343-9.
33. Ostby SA, Bos JM, Owen HJ, Wackel PL, Cannon BC, Ackerman MJ. Competitive sports participation in patients with catecholaminergic polymorphic ventricular tachycardia: a single center's early experience. JACC Clin Electrophysiol 2016;3:253-62.

Keywords: Adolescent, Tachycardia, Ventricular, Ryanodine Receptor Calcium Release Channel, Flecainide, Exercise Test, Anti-Arrhythmia Agents, Ventricular Premature Complexes, Channelopathies, Calsequestrin, Digitalis, Defibrillators, Implantable, Electrocardiography, Ambulatory, Athletes, Physical Exertion, Quality of Life, Follow-Up Studies, Electrocardiography, Syncope, Death, Sudden, Cardiac, Epinephrine, Cardiomyopathy, Hypertrophic, Catecholamines, Heart Arrest, Sports, Sodium Channel Blockers, Genetic Testing, Genotype, Exercise, Sympathectomy, Chromosomes, Stress, Psychological

< Back to Listings