Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and the impact of gene variants on clinical outcomes are not well understood.
• Understanding these relationships is crucial for predicting disease progression and patient prognosis.

Purpose of the Study:

• To investigate the prognostic significance of genetic variant carrier status in a large cohort of DCM patients.
• To identify specific gene variants associated with adverse clinical outcomes in DCM.

Main Methods:

• Next-generation sequencing was used to analyze 487 DCM patients.
• Patients were categorized by functional gene groups, and outcomes including all-cause mortality, heart failure events, and sudden cardiac death were assessed.
• Composite outcomes included heart failure-related death, heart transplantation, or ventricular assist device implantation (DHF/HTx/VAD), and sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF).

Main Results:

• Pathogenic/likely pathogenic variants were identified in 37% of patients, with Titin, sarcomeric genes, LMNA, and desmosomal genes being frequently implicated.
• No significant difference in all-cause mortality was observed between variant carriers and noncarriers.
• A trend towards worse outcomes for SCD/VT/VF and DHF/HTx/VAD was noted in carriers, with desmosomal and LMNA variants showing the highest rates of SCD/VT/VF, independent of left ventricular ejection fraction.

Conclusions:

• Desmosomal and LMNA gene variants are key indicators for identifying DCM patients at elevated risk for sudden cardiac death and life-threatening ventricular arrhythmias.
• These findings are significant regardless of the patient's left ventricular ejection fraction, offering a critical prognostic marker.