Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy

Elżbieta K Biernacka,Witold Śmigielski,Karolina Borowiec,Alessandra Rampazzo,Olgierd Woźniak,Maria Franaszczyk,Anna Lutyńska,Małgorzata Szperl,Piotr Hoffman,Marta Roszczynko

doi:10.1007/s13353-021-00647-y

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is mainly caused by mutations in genes encoding desmosomal proteins. Variants in plakophilin-2 gene (PKP2) are the most common cause of the disease, associated with conventional ARVC phenotype. The study aims to evaluate the prevalence of PKP2 variants and examine genotype–phenotype correlation in Polish ARVC cohort. All 56 ARVC patients fulfilling the current criteria were screened for genetic variants in PKP2 using denaturing high-performance liquid chromatography or next-generation sequencing. The clinical evaluation involved medical history, electrocardiogram, echocardiography, and follow-up. Ten variants (5 frameshift, 2 nonsense, 2 splicing, and 1 missense) in PKP2 were found in 28 (50%) cases. All truncating variants are classified as pathogenic/likely pathogenic, while the missense variant is classified as variant of uncertain significance. Patients carrying a PKP2 mutation were younger at diagnosis (p = 0.003), more often had negative T waves in V1–V3 (p = 0.01), had higher left ventricular ejection fraction (p = 0.04), and were less likely to present symptoms of heart failure (p = 0.01) and left ventricular damage progression (p = 0.04). Combined endpoint of death or heart transplant was more frequent in subgroup without PKP2 mutation (p = 0.03). Pathogenic variants in PKP2 are responsible for 50% of ARVC cases in the Polish population and are associated with a better prognosis. ARVC patients with PKP2 mutation are less likely to present left ventricular involvement and heart failure symptoms. Combined endpoint of death or heart transplant was less frequent in this group.

Highlights

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease characterized by fibrofatty replacement of the myocardium leading to electrical instability and ventricular arrhythmias and increasing risk of sudden death
Pathogenic variants in plakophilin-2 gene (PKP2) are responsible for 50% of ARVC cases in the Polish population and are associated with a better prognosis
There was no difference between PKP2 mutation-positive and mutation-negative individuals in sex, family history, history of sports activity, and arrhythmia (meaning cardiac arrest, syncope, ventricular tachycardia (VT), premature ventricular beats, supraventricular arrhythmias, ICD implantation, appropriate ICD interventions, and history of VT ablation)

Summary

Introduction

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease characterized by fibrofatty replacement of the myocardium leading to electrical instability and ventricular arrhythmias and increasing risk of sudden death. At least 50% of cases are familial and ARVC is currently considered a genetically determined cardiomyopathy, mainly caused by pathogenic variants in genes encoding desmosomal proteins (Basso et al 2009; Marcus et al 2010). Pathogenic variants in desmosomal genes are being identified in 33 to 63% of probands (Gandjbakhch et al 2018). Defects in the structure of desmosomes result in cardiac myocyte detachment and death, gap junction remodeling, and dysregulation of the Wnt–beta catenin pathway, leading to fibrofatty tissue substitution and electrical instability (Gandjbakhch et al 2018)

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