Key result
Pathogenic or likely pathogenic cardiomyopathy variants linked to ~130% greater heart failure risk versus noncarriers.
Why the study?
The study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine their risk of adverse clinical outcomes.
Does the presence of pathogenic/likely pathogenic cardiomyopathy variants increase the risk of heart failure, cardiomyopathy, and arrhythmias in a multiancestry US adult population?
Cohort (n=167,435)
Yes
Does the presence of pathogenic/likely pathogenic cardiomyopathy variants increase the risk of heart failure, cardiomyopathy, and arrhythmias in a multiancestry US adult population?
Effect estimate: HR 2.30 (95% CI 2.04-2.60)
Absolute Event Rate: 3.05% vs 1.37%
Pathogenic/likely pathogenic cardiomyopathy variant carriers have a significantly increased risk of heart failure, cardiomyopathy, and arrhythmias, suggesting potential benefits of targeted genetic screening.
BACKGROUND: This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes. METHODS: This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic variant carriers with noncarriers as the reference group. RESULTS: Among 167 435 individuals (median age, 55.2 [39.5-66.3] years; 61.7% female; 40.7% non-European ancestry) included, the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers was 0.7% in the overall population and 0.8%, 0.8%, 0.5%, and 1.2% among European, African, East Asian, and South Asian ancestry individuals, respectively. Over their lifetime, there were 12 867 heart failure events (205 in carriers and 12 662 in noncarriers), with an incidence rate of 3.05 (95% CI, 2.66-3.49) per 1000 person-years in carriers and 1.37 (95% CI, 1.35-1.40) in noncarriers (adjusted hazard ratio, 2.30 [95% CI, 2.04-2.60]). Cardiomyopathy occurred in 5164 (161 in carriers and 5003 in noncarriers), with an incidence rate of 2.38 (95% CI, 2.04-2.78) per 1000 person-years among carriers and 0.54 (95% CI, 0.53-0.56) in noncarriers (adjusted hazard ratio, 4.31 [95% CI, 3.73-4.97]). There were 19 405 arrhythmia events (263 in carriers and 19 142 in noncarriers), with an incidence rate of 3.93 (95% CI, 3.48-4.44) per 1000 person-years among carriers and 2.09 (95% CI, 2.06-2.12) in noncarriers (adjusted hazard ratio, 2.12 [95% CI, 1.78-2.53]). CONCLUSIONS: Pathogenic/likely pathogenic cardiomyopathy variant carriers have an increased risk of heart failure, cardiomyopathy, and arrhythmias. Despite the modest overall prevalence, the associated risks suggest potential benefits of targeted genetic screening for early detection and management.
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Shetty et al. (2025) conducted a cohort in Cardiomyopathies (n=167,435). Pathogenic/likely pathogenic cardiomyopathy variant carriers vs. Noncarriers was evaluated on Heart failure (HR 2.30, 95% CI 2.04-2.60). Pathogenic/likely pathogenic cardiomyopathy variant carriers had an increased risk of heart failure compared with noncarriers (HR 2.30; 95% CI 2.04-2.60).
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