Phenotypic spectrum and prognostic stratification in desmoglein-2-associated arrhythmogenic cardiomyopathy: Results from a pooled analysis.

BACKGROUND

Increasing knowledge of genotype-phenotype correlations in arrhythmogenic cardiomyopathy (ACM) is leading to more refined diagnostic and risk stratification strategies, encompassing both arrhythmic outcomes and heart failure (HF) progression. Desmoglein-2 (DSG2) mutations represent a clinically relevant genetic subset, taking into consideration both their relative prevalence and their association with severe phenotypic expression.

OBJECTIVE

We aimed to provide a comprehensive characterization of DSG2-associated ACM in terms of clinical presentation, phenotypic expression, and predictors of adverse outcomes.

METHODS

Clinical and genetic data from patients carrying pathogenic or likely pathogenic DSG2 variants were pooled with individual-level data extracted from previously published series. Demographic features, clinical history, phenotypic expression, and outcome measures during follow-up were harmonized and analyzed.

RESULTS

The final cohort included 202 patients, 64.8% males and 60.9% probands. Life-threatening ventricular arrhythmias (LTVAs) were the most common clinical presentation (25.8%). Most of the patients exhibited a right-dominant (38.1%) or biventricular (31.2%) phenotype. After a median follow-up of 92.8 months, 35.3% of patients experienced LTVAs, and 10.9% developed HF. Patients with LTVAs had more severe right ventricular dysfunction, whereas those developing HF exhibited biventricular involvement. Probands exhibit a more severe phenotype in comparison to first-degree relatives, with a trend toward a higher rate of major adverse cardiovascular events (MACEs). Non-sustained ventricular tachycardia on Holter monitoring was the only independent predictor of MACE.

CONCLUSION

DSG2-related ACM is characterized by a high arrhythmic burden, both at clinical onset and during follow-up. HF development is associated with biventricular involvement, and non-sustained ventricular tachycardia represents an independent predictor of MACE, supporting its role in early risk stratification.