Arrhythmogenic cardiomyopathy and sports: from mice to humans

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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.

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.

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.

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.

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.

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