Monica Chivulescu1, Øyvind H. Lie1, Kristina H. Haugaa1, Ruxandra Jurcut2,3
1 Center for Cardiological Innovation, Oslo University Hospital, Norway
2 Emergency Institute for Cardiovascular Diseases „Prof. Dr. C. C. Iliescu”, Bucharest, Romania
3 University of Medicine and Pharmacy „Carol Davila”, Bucharest, Romania
Since its clinical description in 19821, arrhythmogenic cardiomyopathy (AC) has been recognized as an im-portant cause of sudden cardiac death (SCD) in young adults, especially in association with athletic activity2. Young adults engaging in competitive sports have an increased risk of SCD although sport is not the cause of cardiac arrest but rather acts as a trigger in the presence of an underlying heart disease predisposing to life-threatening ventricular arrhythmias (VA)3.
AC is an inheritable heart disease predominantly caused by mutation of genes encoding cardiac desmo-somes, proteins responsible of connection between cardiac myocytes4. Under increased wall stress, dys-functional desmosomes are unable to maintain cellular adhesion resulting in cell detachment, abnormal cell-to-cell signaling and finally apoptosis. Death myocytes are replaced by fibro fatty tissue and the fi bro-fatty scar becomes a substrate for life-threatening VA and SCD often in young individuals5. Progressive myocar-dial atrophy leads to aneurysmal formation, ventricu-lar dilatation and dysfunction. The disproportionate load imposed by exercise on the right ventricle (RV) thinner wall has been proposed as an explanation for the negative effects of strenuous physical activity in a disorder that predominantly affects the RV6.
EFFECTS OF EXERCISE IN ARRHYTHMOGENIC CARDIOMYOPATHY
The hypothesis that AC phenotype is accelerated by strenuous training was fi rst studied in mice7. Hete-rozygous deletion of plakoglobin led to accelerated development of RV enlargement, dysfunction and arrhythmias in mice7. First, clinical studies on desmosomal mutation carriers confirmed the infl uence of exercise on the outcome of patients with AC suggesting that exerci-se may be a trigger of phenotypical penetrance8. Both in probands and in asymptomatic mutation positive family members, athletic activity increases risk of life threatening arrhythmic events and biventricular myo-cardial dysfunction; furthermore, exercise accelerates onset of symptoms and life threatening VA9.
PHYSICAL ACTIVITY RECOMMENDATIONS
Therefore it seemed reasonably to recommend com-petitive sports restriction in AC patients and mutati-on carriers family members, except for low intensity sports like archery, bowling, cricket, golf and rifle sho-oting10. As SCD from AC may occur unexpectedly in healthy asymptomatic young people, especially athle-tes, implementation of screening programs in athletes has been proposed but are controversial. Indeed, pre-participation screening program in young competitive athletes led to a decline in fatal events and in a conco-mitant increase of number of athletes successfully dia-gnosed and disqualified from competition, the greatest decline being noticed in death rates from AC11.
Instead, physicians are often confronted with di-lemma of making recommendation for patients who want to have physically active lifestyles by participa-ting in recreational and leisure-time activities. When compared to sedentary patients, recreational exercise was not associated with the same deleterious effects as competitive sports in AC probands12. A dose-de-pendent relationship between athletic history and phenotypic severity is supported by a recent study that found that PKP2 mutation positive family members who limited exercise dose to the upper bound for what is recommended for healthy life style13 were less likely to develop AC diagnosis and arrhythmias14. The positive relationship between exercise amount and outcome of patients with AC has been recently meticulously explored15. It have been shown that pre-valence of VA and degree of structural alterations is directly proportional with exercise dose and that out-come in AC patients is more dependent on exercise intensity than exercise duration15. Although these fin-ding could be used to make further recommendati-ons, the safety of low-intensity exercise remains to be determined.
For now, there is no definite recommendations re-garding recreational physical activity for AC patients; consensus documents states that clinicians should in-dividualize exercise prescription according to the cli-nical status10.
Probands12 and mutation carriers individuals8 who continue to exercise competitively after AC diagno-sis have an adverse arrhythmic outcome. Furthermo-re, following first life threatening arrhythmic event, reducing exercise level from competitive to either recreational or inactive didn’t protect against future arrhythmic events as the absolute risk of ventricular arrhythmias and SCD remains high in AC indepen-dent of physical activity, but still decreased the rate of arrhythmias during follow-up12. Nevertheless, the impact of exercise restriction on non-arrhythmic out-come and development of full AC phenotype has ne-ver been studied.
MUTATION NEGATIVE ARRHYTHMOGENIC CARDIOMYOPATHY
It has been hypothesized that in „gene elusive” pati-ents, greater exercise dose can be sufficient to cause AC phenotype. This theory has been supported by studies that found lower prevalence of familial disea-se and desmosomal mutations in athletic cohorts16,17. Although strenuous exercise has a clear environmen-tal role on AC development, the impact of genetic determinism on disease penetrance and expression cannot be excluded as some „gene-elusive” patients has clear familial history and only a small proportion of athletes are susceptible17. „Gene-elusive” AC phe-notype can also be caused by mutations in unknown genes or by low penetrant variants of desmosomal and other genes17.
The hypothesis of disproportional exercise-indu-ced RV remodeling18 as a substrate for arrhythmias has been explored both in experimental19 and in cli-nical studies20. It has been proposed that a continuum from genetically inherited AC in which dysfunctional desmosomes can be prone to spontaneous rupture to exercise-induced AC phenotype in which extreme do-ses of exercise can disrupt even normal desmosomes in the vulnerable host exists21. If intact desmosomes can be damaged by high RV wall stress in the absence of any genetic predisposition is still questionable.
DIFFERENTIATING ATHLETE´S HEART FROM RIGHT HEART CARDIOMYOPATHY
History of exposure to competitive physical activity has physiologic cardiac effects known as „athlete´s heart”22 that sometimes can be confounded with car-diac pathological states. Endurance training promotes RV dilatation with consistent increase of the RV in-flow and outflow segments. According to 2010 Revi-sed Task Force criteria23, AC diagnosis is only fulfilled when dimensional criteria are accompanied by regi-onal wall motion abnormalities. Nevertheless it has been proposed to use only major indexed dimensional criteria to define RV enlargement compatible with AC in athletes24. There are some other imaging criteria that may help in differential diagnosis between AC and physiologic RV adaptation. In AC patients we often ob-serve predominant increase of the RV outflow tract, a ratio of RV inflow dimension/left ventricle (LV) di-mension >0.9 on echocardiography, regional akinesia/ dyskinesia, aneurysmal deformation and global systolic RV dysfunction25 (RV fractional area change ≤40% and RV longitudinal strain of the lateral RV free wall worse than -23 26).
Furthermore, integrating clinical finding in the de-cision algorithm can be of great help. Family history of SCD/AC, anterior T wave inversion on ECG, VA with left bundle branch block (LBBB) morphology and exercise induced ventricular tachycardia are additional arguments for AC25.
Whenever AC is suspected, clinician should ask the patient about exercise habits in order to make a cor-rect diagnosis and to appropriately assess the risk in AC.
Conflict of interest: none declared.
1. Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Ma-lergue C, et al. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65(2):384-98.
2. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. The New Eng-land journal of medicine. 1988;318(3):129-33.
3. Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? Journal of the American College of Cardiology. 2003;42(11): 1959-63.
4. Haugaa KH, Haland TF, Leren IS, Saberniak J, Edvardsen T. Arrhyth-mogenic right ventricular cardiomyopathy, clinical manifestations, and diagnosis. Europace: European pacing, arrhythmias, and cardiac electrophysiology: journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2016;18(7):965-72.
5. Corrado D, Basso C, Judge DP. Arrhythmogenic Cardiomyopathy. Circulation research. 2017;121(7):784-802.
6. La Gerche A, Heidbuchel H, Burns AT, Mooney DJ, Taylor AJ, Pfl uger HB, et al. Disproportionate exercise load and remodeling of the athlete’s right ventricle. Medicine and science in sports and ex-ercise. 2011;43(6):974-81.
7. Kirchhof P, Fabritz L, Zwiener M, Witt H, Schafers M, Zellerhoff S, et al. Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-defi-cient mice. Circulation. 2006;114(17):1799-806.
8. James CA, Bhonsale A, Tichnell C, Murray B, Russell SD, Tandri H, et al. Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-asso-ciated desmosomal mutation carriers. Journal of the American Col-lege of Cardiology. 2013;62(14):1290-7.
9. Saberniak J, Hasselberg NE, Borgquist R, Platonov PG, Sarvari SI, Smith HJ, et al. Vigorous physical activity impairs myocardial function in patients with arrhythmogenic right ventricular cardiomyopathy and in mutation positive family members. European journal of heart failure. 2014;16(12):1337-44.
10. Pelliccia A, Corrado D, Bjornstad HH, Panhuyzen-Goedkoop N, Urhausen A, Carre F, et al. Recommendations for participation in competitive sport and leisure-time physical activity in individuals with cardiomyopathies, myocarditis and pericarditis. European jour-nal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemi-ology & Prevention and Cardiac Rehabilitation and Exercise Physiol-ogy. 2006;13(6):876-85.
11. Corrado D, Basso C, Pavei A, Michieli P, Schiavon M, Thiene G. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. Jama. 2006;296(13):1593-601.
12. Ruwald AC, Marcus F, Estes NA, 3rd, Link M, McNitt S, Polonsky B, et al. Association of competitive and recreational sport participation with cardiac events in patients with arrhythmogenic right ventricular cardiomyopathy: results from the North American multidisciplinary study of arrhythmogenic right ventricular cardiomyopathy. European heart journal. 2015;36(27):1735-43.
13. Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the Amer-ican Heart Association. Circulation. 2007;116(9):1081-93.
14. Sawant AC, Te Riele AS, Tichnell C, Murray B, Bhonsale A, Tandri H, et al. Safety of American Heart Association-recommended min-imum exercise for desmosomal mutation carriers. Heart rhythm. 2016;13(1):199-207.
15. Lie ØH, Dejgaard LA, Saberniak J, Rootwelt C, Stokke MK, Edvard-sen T, et al. Harmful Effects of Exercise Intensity and Exercise Dura-tion in Patients With Arrhythmogenic Cardiomyopathy. JACC: Clin-ical Electrophysiology. 2018.
16. La Gerche A, Robberecht C, Kuiperi C, Nuyens D, Willems R, de Ravel T, et al. Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhyth-mias of right ventricular origin. Heart (British Cardiac Society). 2010; 96(16):1268-74.
17. Sawant AC, Bhonsale A, te Riele AS, Tichnell C, Murray B, Rus-sell SD, et al. Exercise has a disproportionate role in the pathogen-esis of arrhythmogenic right ventricular dysplasia/cardiomyopathy in patients without desmosomal mutations. Journal of the American Heart Association. 2014;3(6):e001471.
18. La Gerche A, Burns AT, Mooney DJ, Inder WJ, Taylor AJ, Bogaert J, et al. Exercise-induced right ventricular dysfunction and structur-al remodelling in endurance athletes. European heart journal. 2012; 33(8):998-1006.
19. Benito B, Gay-Jordi G, Serrano-Mollar A, Guasch E, Shi Y, Tardif JC, et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation. 2011;123(1):13-22.
20. Heidbuchel H, Hoogsteen J, Fagard R, Vanhees L, Ector H, Wil-lems R, et al. High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias. Role of an electro-physiologic study in risk stratification. European heart journal. 2003; 24(16):1473-80.
21. Heidbuchel H, Prior DL, La Gerche A. Ventricular arrhythmias asso-ciated with long-term endurance sports: what is the evidence? Brit-ish journal of sports medicine. 2012;46 Suppl 1:i44-50.
22. Galderisi M, Cardim N, D’Andrea A, Bruder O, Cosyns B, Davin L, et al. The multi-modality cardiac imaging approach to the Ath-lete’s heart: an expert consensus of the European Association of Cardiovascular Imaging. European heart journal cardiovascular Imag-ing. 2015;16(4):353.
23. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/ dysplasia: proposed modification of the Task Force Criteria. Euro-pean heart journal. 2010;31(7):806-14.
24. D’Ascenzi F, Pisicchio C, Caselli S, Di Paolo FM, Spataro A, Pelliccia A. RV Remodeling in Olympic Athletes. JACC Cardiovascular imag-ing. 2017;10(4):385-93.
25. Pelliccia A, Caselli S, Sharma S, Basso C, Bax JJ, Corrado D, et al. Eu-ropean Association of Preventive Cardiology (EAPC) and European Association of Cardiovascular Imaging (EACVI) joint position state-ment: recommendations for the indication and interpretation of car-diovascular imaging in the evaluation of the athlete’s heart. European heart journal. 2017.
26. Haugaa KH, Basso C, Badano LP, Bucciarelli-Ducci C, Cardim N, Gaemperli O, et al. Comprehensive multi-modality imaging approach in arrhythmogenic cardiomyopathy-an expert consensus document of the European Association of Cardiovascular Imaging. European heart journal cardiovascular Imaging. 2017;18(3):237-53.