Arrhythmogenic Cardiomyopathy: Towards Genotype Based Diagnoses and Management

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a genetically heterogeneous inherited cardiomyopathy with an estimated prevalence of 1:5000-10 000 that predisposes patients to life-threatening ventricular arrhythmias (VA) and sudden cardiac death (SCD). ACM diagnostic criteria and risk prediction models, particularly for arrhythmogenic right ventricular cardiomyopathy (ARVC), the most common form of ACM, are typically genotype-agnostic, but numerous studies have established clinically meaningful genotype-phenotype associations. Early signs of ACM onset differ by genotype indicating the need for genotype-specific diagnostic criteria and family screening paradigms. Likewise, risk factors for SCD vary by genetic subtype, indicating that genotype-specific guidelines for management are also warranted. Of particular importance, genotype-specific therapeutic approaches are being developed. Results from a randomized controlled trial for flecainide use in ARVC patients are currently pending. Research in a plakophilin-2-deficient mouse model suggests this antiarrhythmic drug may be particularly useful for patients with likely pathogenic or pathogenic (LP/P) PKP2 variants. Additionally, the first gene therapy clinical trials in ARVC patients harboring LP/P PKP2 variants are currently underway. This review aims to provide clinicians caring for ACM patients with an up-to-date overview of the current literature in genotype-specific natural history of disease and management of ACM patients and describe scientific advances that have led to upcoming clinical trials.

Keywords: ACM; ARVC; cardiac arrest/sudden death; clinical:electrophysiology; gene‐specific; genotype‐specific.