Introduction of Nature And Nurture In Arrhythmogenic Right Ventricular Cardiomyopathy – A Clinical Perspective

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Summary

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare heritable cardiomyopathy characterised by fibro-fatty replacement of the myocardium, which predisposes patients to frequent lifethreatening ventricular arrhythmias and slowly progressive ventricular dysfunction.^1,2 Structural involvement of the right ventricle (RV) generally predominates,^3,4 although left dominant forms of ARVD/C are increasingly well-recognised.⁵ Patients typically present in their second to fifth decade with symptoms associated with ventricular arrhythmias and go on to have an arrhythmic disease course.^6,7 Sudden cardiac death may be the first manifestation in up to 50 % of index cases.⁸

ARVD/C was first described in the modern scientific literature in 1982 in the seminal work of Frank Marcus and colleagues.⁹ In this initial description of 24 patients with ventricular arrhythmias and RV dysfunction from a French tertiary care centre, the authors speculated that ARVD/C resulted from a developmental abnormality of the RV musculature. Indeed, the original name – arrhythmogenic RV dysplasia – reflects this early interpretation. However, soon afterwards, threads of evidence implicating both inherited factors (nature) and exercise (nurture) in ARVD/C pathogenesis emerged. Clustering of ARVD/C within families was appreciated early.¹⁰ Investigators recognised the cardiac phenotype of a rare familial cardio-cutaneous condition, Naxos disease, overlapped with ARVD/C.¹¹ The major discovery that homozygous mutations in junctional plakoglobin (JUP) were the genetic basis of Naxos disease in 2000,¹² led to rapid identification of mutations in each of the desmosomal genes among ARVD/C patients. Simultaneously, articles began appearing calling attention to the fact that many patients with ARVD/C were elite athletes¹³ and that athletic ARVD/C patients appeared to have a particularly high risk of sudden cardiac death.^14,15

These early observations set the stage for research exploring the genetic basis of ARVD/C (nature) and the role of endurance exercise (nurture) in ARVD/C pathogenesis and clinical course. This article will review current evidence regarding the association of genotype, endurance exercise and clinical phenotype of ARVD/C patients and at-risk family members and discuss the emerging paradigm in which genetic predisposition and environmental factors (exercise) interact around a threshold for phenotypic expression of ARVD/C. Excellent reviews have recently been published describing current understanding of the molecular mechanism through which ARVD/C-associated mutations lead to disease.^16,17 Thus, this paper will focus on evidence from clinical research and address three questions: 1) To what extent does genotype predict ARVD/C phenotype? 2) How is endurance exercise associated with ARVD/C phenotype and clinical course? 3) How do exercise and genotype interact in disease pathogenesis?