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

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.

Heart failure in arrhythmogenic cardiomyopathy: is phenotypic variability just a matter of genetics?

“…Data by Hermida et al are different from those published by the US–The Netherlands and Italy study groups, who failed to determine HF correlation with the genetic status. Variable prevalence of PKP2 vs. DSP or DSG2 mutation carriers in different study populations, referral bias, variable cohort size and follow‐up period might be some of the reasons explaining the differences in the published series.…”

“…A recent study on a DSG2 founder mutation demonstrated that homozygote DSG2 patients exhibited full disease penetrance, though clinical presentation varied from HF to late‐onset symptoms . Similarly, Hermida and colleagues confirmed the prognostic value of a more complex genetic status in determining end‐stage HF (either death or transplantation) independent of a DSG2 mutation presence, reflecting a variable inheritance disease pattern …”

“…In the era of widespread genetic testing, multiple attempts to correlate genetic background with clinical phenotype, including HF, have been undertaken. To this aim, in the current issue of the Journal, Hermida and colleagues compared 27 DSG2 (20 index cases and 7 family members) to 91 PKP2 (58 index cases and 33 family members) gene mutation carriers of a large multicentre AC registry with a 10‐year follow‐up, providing compelling evidence of a higher risk of end‐stage HF in missense DSG2 mutation carriers and in patients with a more complex genetic status branded by multiple heterozygosis/homozygosis. Noteworthy, in the first investigation demonstrating DSG2 gene mutations in a significant number of AC‐unrelated index cases, cardiac phenotype was characterized clinically by frequent left ventricular involvement; the proband, diagnosed at the age of 55, eventually underwent heart transplantation due to HF at the age of 63 …”

June 2019 at a glance: from genetics to haemodynamics, biomarkers and imaging for the prediction of outcomes

“…Genetic status affects the clinical course of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Hermida et al . compared the outcomes of desmoglein‐2 (DSG2) mutation carriers to those with plakophilin‐2 (PKP2) mutation.…”

“…During a median follow‐up of 5.6 years, DSG2 and PKP2 mutation carriers had a similar risk of sustained ventricular arrhythmia, but DSG2 mutation carriers were at higher risk of transplantation/heart failure (HF)‐related death. Thus, DSG2 mutation is associated with a high risk of end‐stage HF, compared to PKP2 mutation, and careful haemodynamic monitoring is needed in these patients …”