Arrhythmogenic right ventricular dysplasia/cardiomyopathy: arrhythmogenesis in the apparently normal heart?

This editorial refers to ‘Phenotypic expression is a prerequisite for malignant arrhythmic events and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy’ by A. Zorzi et al., on pages 1086–1094. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by ventricular arrhythmias, predominantly right ventricular dysfunction, and sudden cardiac death (SCD). Sustained ventricular arrhythmias in ARVD/C are frequently stable monomorphic ventricular tachycardia (VT) episodes with left bundle branch block morphology, associated with structural heart disease due to fibro-fatty alteration. Sudden cardiac death due to ventricular fibrillation (VF) may occur at all disease stages, either as deterioration of monomorphic VT or as primary event. Importantly, SCD may occur as first manifestation of ARVD/C. Sudden cardiac death is frequently observed in young individuals. Quarta et al.1 studied the age distribution in 45 individuals dying suddenly from pathologically proven ARVD/C. In half of these individuals, SCD occurred at ≤30 years of age, and in 14 of them at ≤20 years (youngest 14 years). In our recent transatlantic study by Bhonsale et al.,2 out of 577 ARVD/C-associated mutation carriers, 36 individuals presented with SCD as the first disease manifestation. Monomorphic VT was the first presentation in 131 patients. The median age in those presenting with SCD vs. monomorphic VT was 23 and 36 years, respectively, which was significantly different (P < 0.001). The youngest individual dying suddenly in this study was 13 years of age. These results were confirmed in a larger ARVD/C study of 1001 individuals, including both patients with and without identified mutation.3 The cause of this age-related difference in arrhythmia manifestation is not clear. The differences in the arrhythmogenic substrate, as well as participation in sports activities may be important. Recent studies in cellular and mouse models suggest that fibro-fatty changes may be preceded by gap-junction remodelling mediating electrical coupling and by reduction of amplitude of the sodium current, giving rise to slow conduction and increased propensity for ventricular arrhythmias.4 These molecular mechanisms in mouse models could occur in the absence of detectable structural disease, suggesting their role in the occurrence of SCD in the early concealed disease stage in young individuals. In the clinical setting of ARVD/C, evidence of arrhythmogenesis in the apparently normal heart is still poor. Sustained ventricular arrhythmias in ARVD/C-associated mutation carriers with a normal or unspecific abnormal electrocardiogram (ECG) have been reported as a rare phenomenon, and always in the presence of other abnormalities.5 Since life-threatening ventricular arrhythmias frequently occur unexpectedly, many patients with evidence of ARVD/C, as well as pathogenic mutation carriers underwent implantable cardioverter-defibrillator (ICD) implantation for primary prevention.6 In addition, because of identification of a mutation in the proband cascade screening in their relatives reveal many, often asymptomatic, mutation carriers. These factors have promoted research in risk stratification, first in patients with ICD for primary prevention.7,8 These studies revealed proband status, non-sustained VT, syncope,7 high number of ventricular premature complexes, and high-risk ECG features,8,9 inducible sustained VT/VF, and combinations of these factors,8 as important determinants of arrhythmic risk. Data on the apparently normal heart are missing. Te Riele et al.10 studied the outcome of 69 ARVD/C-associated mutation carriers without sustained VT/VF. After a mean follow-up of nearly 6 years, 11 patients experienced sustained ventricular arrhythmias, and all of them had both electrical and structural disease. The study by Zorzi et al.11 in this issue of Europace is a logic continuation of authors' previous work in the more limited ARVD/C group of ICD carriers.7 They studied prospectively 116 desmosomal mutation carriers without prior sustained VT or VF. In only 13 patients (11%), an ICD was implanted. After a mean follow-up of 8.5 years, 10 patients (9%) had a sustained arrhythmic event (0.9%/year). The event rate was 2.3%/year in patients with definite ARVD/C and only 0.2%/year in those with borderline ARVD/C or phenotype negatives. In patients with definite ARVD/C, those with ≥1 risk factor had an event rate of 4.1%/year. Only two patients died (one SCD and one heart failure). The authors concluded that the vast majority of sustained arrhythmic events occurred in patients with overt disease and major risk factors. Implantation of an ICD for primary prevention could be limited to this high-risk subgroup. Two cases in this study need specific attention. One patient died suddenly at the age of 15 years. Clinical evaluation including ECG and echocardiography 2 years and again 8 months before the event showed no abnormalities. However, at autopsy subepicardial scar in the postero-lateral left ventricular wall was identified. The other patient had also normal ECG and echocardiography findings. However, late enhancement was identified in the left ventricle with cardiac magnetic resonance (CMR) analysis. Thus, these two patients had structural heart disease. Both patients appeared to have a desmoplakin (DSP) mutation. Left-dominant disease is a frequent finding in DSP carriers.12 In our transatlantic cohort, first presentation with SCD occurred four-fold more often in DSP than in other desmosomal mutation carriers, supporting the more malignant character of DSP.2 These observations indicate the need for CMR with late enhancement analysis in the routine evaluation of ARVD/C patients, their relatives, and patients with ventricular arrhythmias of uncertain aetiology. Further studies from large ARVD/C databases in mutation-carrying family members are needed to identify if, similar as in experimental mouse studies, malignant ventricular arrhythmias and SCD may occur in the apparently normal human heart, or not.