Value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy.

Value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy.

de Brouwer R, Bosman LP, Gripenstedt S, Wilde AAM, van den Berg MP, Peter van Tintelen J, de Boer RA, Te Riele ASJM; Netherlands ACM Registry. Heart Rhythm. 2022 Oct;19(10):1659-1665. doi: 10.1016/j.hrthm.2022.05.038. Epub 2022 Jun 7.PMID: 35688345

Take Home points:

  • Arrhythmogenic right ventricular cardiomyopathy (ARVC), the right dominant subform of arrhythmogenic cardiomyopathy (ACM), is characterized by fibrofatty replacement of cardiomyocytes leading to ventricular dysfunction and an increased risk of malignant ventricular arrhythmia (MVA).
  • ARVC is often familial with incomplete penetrance and variable expressivity; diagnostic value of genetic testing is disappointing.
Dr Khyati Pandya

Commentary by Dr. Khyati Pandya (Augusta, GA, USA) Congenital and Pediatric Cardiac EP section editor:  

 The current study was one of the largest studies – 402 subjects – of individuals with ARVC, from Netherlands Arrhythmogenic Cardiomyopathy Registry.

The investigators sought to determine the incremental value of genetic testing on the diagnostic yield for ARVC and the clinical impact of the testing on patient outcomes.

Of the 216 probands, 121 (56%) harbored a pathogenic or likely pathogenic ARVC gene variant, most commonly PKP2. Without genetic testing, 5% of probands would have lost their ARVC diagnosis and 10% would have experienced a delay in diagnosis 30 days. Over a follow up period of 13 years, none of the undiagnosed patients would have experienced a malignant ventricular arrhythmia during follow-up and 3% of the patients with diagnostic delay would have experienced a malignant ventricular arrhythmia during the period of delay.

Similarly, for the 186 relatives, 60% harbored a (likely) pathogenic variant. Removal of genetic testing from the diagnostic criteria would have led to a loss of diagnosis in 4% and delay in diagnosis of 0.5%. None of these patients would have experienced a malignant ventricular arrhythmia as a result of the lack of genetic testing.

Figure 2 Survival curve of patients with arrhythmogenic right ventricular cardiomyopathy: pathogenic variant carriers vs noncarriers, showing no significant difference in time from the initial diagnosis to the first malignant ventricular arrhythmia. TFC -Task Force Criteria; VA – ventricular arrhythmia


As mentioned by the authors, a focused analysis on the relationship between genetic testing results and MVA may shed light on the clinical value of genetic testing results in the management of patients with ARVC. The overall yield for genetic testing was good, however the clinical impact of the genetic testing was questioned by the authors of this study.

The current study comprised of a Dutch population, however, studies conducted at various centers across the world have described a similar incidence of ARVC in individuals with various ethnic backgrounds. Findings such as age at presentation, preponderance of male gender, genetic yield, preponderance of PKP2 gene etc. are comparable with studies across other populations.

Although malignant ventricular arrhythmias occurred only in 1% of the patients with a delayed diagnosis of ARVC and although these were not fatal, this finding underscores the importance of continuing to include genetic findings in the TFC.

A biomarker for ARVC may help identify disease in its initial stages, thereby overcoming the suboptimal genetic yield and identifying a greater number of individuals at risk for developing the disease. This may overcome the problems related to a low genetic yield and also help identify individuals with ARVC in the concealed phase of disease who may still be at risk for development of malignant ventricular arrhythmias. Until such time, inclusion of genetic findings in the TFC is likely expedite cascade testing and prevent onset of malignant ventricular arrhythmias in the vast majority, albeit at the cost of psychosocial well-being in those that may never develop the disease.

Future directions and limitations

The 2010 Task Force Criteria are still used to establish a clinical diagnosis of ARVC; however, these criteria do not incorporate other arrhythmogenic cardiomyopathies, leading to a potential underdiagnosis. It remains to be seen if the Padua Criteria, recently being developed by an international expert panel for arrhythmogenic cardiomyopathies, will offer a higher diagnostic accuracy for ARVC as well. There are ongoing studies to evaluate the proposed Padua Criteria in larger cohorts.

Multicenter studies conducted simultaneously in various centers across the world and presented as pooled data may help identify genetic heterogeneity in relation to disease causation in patients with ARVC with varying ethnic backgrounds.

As highlighted by the authors a selection bias may have affected the findings owing to the retrospective nature of the study. Of note, tissue criteria are not available for comment in the primary cohort. Further, details of cardiac MRI if included, would have provided better correlation between severity of disease and onset of malignant ventricular arrhythmias in a background of genetic. As such, larger and prospective studies are required to address limitations related to the current study.