Association of Pathogenic/Likely Pathogenic Inherited Cardiomyopathy Variants With Heart Failure: A TOPMed Multiancestry Analysis.

Objective: To evaluate the prevalence of pathogenic/likely pathogenic inherited cardiomyopathy variants and their association with heart failure in the (TOPMed) TransOmic for Precision of Medicine cohorts.

Methods: A retrospective cohort study using the TOPMed cohorts, including multi-ancestry US adults (≥18 years of age) with sequencing data, was conducted. Pathogenic/likely pathogenic inherited cardiomyopathy variant carrier status was determined based on ClinVar variants classified with two or more stars of evidence. Individuals without pathogenic/likely pathogenic variants were used as the reference group. The primary outcome was heart failure , adjudicated by an expert panel. Cox proportional hazards models assessed the association between carrier status and heart failure risk, adjusting for sex, study cohort, coronary artery disease, and genetic ancestry. Age was used as the timescale to account for the effect of variants since birth, and interval censoring was used to handle the uncertainty in the timing of heart failure events.

Results: Among 30,977 individuals (median age, 61.0 years; 71.3% female; 37.0% non-European ancestry), 229 (0.7%) were identified as pathogenic/likely pathogenic inherited cardiomyopathy variant carriers. There were 3,298 events of heart failure (35 in carriers and 3,263 in non-carriers). The heart failure incidence rate was higher in variant carriers (2.06 per 1000 person-years) compared with noncarriers (1.40 per 1000 person-years), with an adjusted hazard ratio of 1.68 (95% CI, 1.29-2.22).

Conclusion: Approximately 1 in 140 US adults carry a cardiomyopathy variant, which increases heart failure risk. Targeted genetic screening may facilitate early identification and preventive interventions to reduce heart failure risk in carriers.