Assessing the Role of Rare Genetic Variation in Patients With Heart Failure

Area of Science:

• Cardiovascular Genetics
• Genomics and Precision Medicine
• Heart Failure Pathophysiology

Background:

• Genetic variants are known causes for specific heart failure (HF) subtypes like hypertrophic or dilated cardiomyopathy.
• The contribution of rare, high-impact genetic variants to all-cause HF, especially when ischemic heart disease is the primary cause, remains under-investigated.

Purpose of the Study:

• To determine the role of rare genetic variants in all-cause heart failure (HF).
• To assess the contribution of these variants in patients with and without reduced left ventricular ejection fraction.

Main Methods:

• Retrospective analysis of clinical trials (CHARM, CORONA) and prospective data (UK Biobank).
• Whole-exome sequencing and gene-based collapsing approach to compare rare variant burden in HF patients and controls.
• Investigation of pathogenic variants in known cardiomyopathy genes for diagnostic yield.

Main Results:

• Significant enrichment of protein-truncating variants in the TTN gene in HF patients compared to controls (OR, 2.54).
• Similar enrichment observed in UK Biobank data (OR, 4.97).
• Pathogenic variants in cardiomyopathy genes were identified in 3.4% of HF patients, with ischemic heart disease being the most common etiology (60.2%).

Conclusions:

• An increased burden of diagnostic mendelian cardiomyopathy variants exists in a broad spectrum of HF patients, including those with ischemic heart disease.
• Mendelian genetic conditions may constitute a significant subset of complex late-onset diseases like heart failure, regardless of clinical presentation.