Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium

R W Roudijk,L Van Den Heuvel,M J Boonstra,T A B Van Veen,M Bourfiss,L P Bosman,I Christiaans,S M Van Der Voorn,P Loh,A S J M Te Riele,C A Remme,F W Asselbergs,F Van Lint,J P Van Tintelen,M P Van Den Berg,K Taha

doi:10.1007/s12471-021-01542-1

Abstract

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.

Highlights

In the Netherlands, pathogenic variants in the plakophilin-2 (PKP2) and phospholamban (PLN) gene are the most prevalent genetic predispositions for familial dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) [1, 2]
Pathogenic variants are found in 40% of DCM index patients and 67% of ACM index patients [2, 4]
Due to increased awareness and improved genetic analysis techniques, the number of identified relatives carrying a pathogenic variant without overt clinical disease—currently estimated at 300,000 individuals—is increasing

Summary

Introduction

In the Netherlands, pathogenic variants in the plakophilin-2 (PKP2) and phospholamban (PLN) gene are the most prevalent genetic predispositions for familial dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) [1, 2]. Due to increased awareness and improved genetic analysis techniques, the number of identified relatives carrying a pathogenic variant without overt clinical disease—currently estimated at 300,000 individuals—is increasing. Despite this genetic risk, only 40–60% of relatives will develop cardiomyopathy; this phenomenon is known as incomplete penetrance of disease [5, 6]. Only 40–60% of relatives will develop cardiomyopathy; this phenomenon is known as incomplete penetrance of disease [5, 6] This variability is presumably caused by a combination of variants in specific genes, epigenetic regulation and environmental factors. In carriers of pathogenic PKP2 variants, which may result in dysfunction of cardiac desmosome proteins, disease penetrance is generally lower (40–60%) [1, 4, 5]

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