What is the clinical evidence from this study?

Study design: Cohort. Population: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (n=118). Intervention: Desmoglein-2 (DSG2) mutation vs. Plakophilin-2 (PKP2) mutation. Primary outcome: Cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (p=<0.001).

February 21, 2019Open Access

High Risk of Heart Failure Associated with Desmoglein-2 Mutations Compared to Plakophilin-2 Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

Q: What are the key findings of this study?

Desmoglein-2 (DSG2) mutation carriers had a significantly higher risk of cardiac transplantation or heart failure-related death compared to PKP2 mutation carriers (log-rank P<0.001).

Q: What does this research mean for the field?

Desmoglein-2 (DSG2) mutation carriers with arrhythmogenic right ventricular cardiomyopathy/dysplasia have a significantly higher risk of cardiac transplantation or heart failure-related death compared to plakophilin-2 (PKP2) mutation carriers. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

Desmoglein-2 (DSG2) mutation carriers had a significantly higher risk of cardiac transplantation or heart failure-related death compared to PKP2 mutation carriers (log-rank P<0.001).

Study Design

Type

Cohort (n=118)

Multicenter

Yes

Structured PICO

Does the presence of a DSG2 mutation compared to a PKP2 mutation increase the risk of adverse outcomes in patients with ARVC/D?

Population

118 patients from 78 families with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) carrying a pathogenic mutation in PKP2 or DSG2, selected from a national registry.

Intervention

Desmoglein-2 (DSG2) mutation

Comparator

Plakophilin-2 (PKP2) mutation

Outcome

Cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (HF)hard clinical

In patients with ARVC/D, carrying a DSG2 mutation is associated with a significantly higher risk of end-stage heart failure and left ventricular dysfunction at diagnosis compared to carrying a PKP2 mutation.

Main Result

p-value: p=<0.001

Abstract

BACKGROUND: Previous studies suggested that genetic status affects the clinical course of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients. The aim of this study was to compare the outcome of desmoglein-2 (DSG2) mutation carriers to those who carry the plakophilin-2 (PKP2) mutation, the most common ARVC/D-associated gene. METHODS AND RESULTS: Consecutive ARVC/D patients carrying a pathogenic mutation in PKP2 or DSG2 were selected from a national ARVC/D registry. The cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (HF) during follow-up was assessed, compared between PKP2 and DSG2, and predictors for ventricular arrhythmia and HF events determined. Overall, 118 patients from 78 families were included: 27 (23%) carried a DSG2 mutation and 91 (77%) a PKP2 mutation. There were no significant differences between DSG2 and PKP2 mutation carriers concerning gender, proband status, age at diagnosis, T-wave inversion, or right ventricular dysfunction at baseline. DSG2 patients displayed more frequent epsilon wave (37% vs. 17%, P = 0.048) and left ventricular dysfunction at diagnosis (54% vs. 10%, P < 0.001). During a median follow-up of 5.6 years (2.5-16), DSG2 and PKP2 mutation carriers displayed a similar risk of sustained ventricular arrhythmia (log-rank P = 0.20), but DSG2 mutation carriers were at higher risk of transplantation/HF-related death (log-rank P < 0.001). The presence of a DSG2 mutation vs. PKP2 mutation was a predictor of transplantation/HF-related death in univariate Cox analysis (P = 0.0005). CONCLUSIONS: In this multicentre cohort, DSG2 mutation carriers were found to be at high risk of end-stage HF compared to PKP2 mutation carriers, supporting careful haemodynamic monitoring of these patients. The benefit of early HF treatment needs to be assessed in DSG2 carriers.