Phenotypic spectrum and prognostic stratification in desmoglein-2-associated arrhythmogenic cardiomyopathy: Results
Marika Martini1, Luigi Filippo Brizzi1, Serena Pinci1
1Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy.
Insights
Desmoglein-2 (DSG2) mutations in arrhythmogenic cardiomyopathy (ACM) cause significant arrhythmias and heart failure, particularly with biventricular involvement. Non-sustained ventricular tachycardia predicts major adverse cardiovascular events, aiding early risk stratification.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Arrhythmogenic cardiomyopathy (ACM) diagnosis and risk stratification are improving with genotype-phenotype knowledge.
- Desmoglein-2 (DSG2) mutations are a key genetic subset of ACM, linked to severe phenotypes.
Purpose of the Study:
- To comprehensively characterize DSG2-associated ACM.
- To identify clinical presentation, phenotypic expression, and outcome predictors in DSG2-ACM.
Main Methods:
- Pooled individual-level data from 202 patients with pathogenic/likely pathogenic DSG2 variants.
- Harmonized analysis of demographic, clinical, phenotypic, and outcome data.
Main Results:
- Life-threatening ventricular arrhythmias (LTVAs) were the most common presentation (25.8%).
- Right-dominant or biventricular phenotypes were prevalent.
- Follow-up revealed 35.3% experienced LTVAs, 10.9% developed heart failure (HF).
- LTVAs correlated with RV dysfunction; HF with biventricular involvement.
- Non-sustained ventricular tachycardia predicted major adverse cardiovascular events (MACEs).
Conclusions:
- DSG2-ACM presents with a high arrhythmic burden.
- Heart failure development is linked to biventricular involvement.
- Non-sustained ventricular tachycardia is an independent MACE predictor, useful for risk stratification.
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.
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