High risk of heart failure associated with desmoglein-2 mutations compared to plakophilin-2 mutations in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Eur J Heart Fail. 2019 Jun;21(6):792-800. doi: 10.1002/ejhf.1423. Epub 2019 Feb 21.


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.

Keywords: Arrhythmogenic right ventricular cardiomyopathy/dysplasia; Cardiac transplantation; Desmoglein-2; Heart failure; Plakophilin-2; Ventricular arrhythmia.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arrhythmogenic Right Ventricular Dysplasia / complications
  • Arrhythmogenic Right Ventricular Dysplasia / genetics
  • Arrhythmogenic Right Ventricular Dysplasia / metabolism
  • DNA / genetics*
  • DNA Mutational Analysis
  • Desmoglein 2 / genetics*
  • Desmoglein 2 / metabolism
  • Electrocardiography
  • Female
  • Follow-Up Studies
  • Heart Failure / etiology
  • Heart Failure / genetics*
  • Heart Failure / metabolism
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Pedigree
  • Phenotype
  • Plakophilins / genetics*
  • Plakophilins / metabolism
  • Retrospective Studies
  • Young Adult


  • DSG2 protein, human
  • Desmoglein 2
  • PKP2 protein, human
  • Plakophilins
  • DNA