Abstract Body (Do not enter title and authors here): Background: End-stage hypertrophic cardiomyopathy (HCM), characterized by left-ventricular systolic dysfunction, represents the most advanced manifestation of HCM. Patients with pathogenic sarcomeric variants exhibit a higher rate of progression to end-stage HCM; however, further stratification has stalled through genetic analysis focused on sarcomeric genes. Recently, the concept has emerged that phenotype is significantly influenced by a combination of rare variants with large effect sizes, common variants with small effect sizes, and acquired factors serving as multiple hits.
Hypothesis: There are overlooked genetic factors as potential modifiers alongside sarcomeric variants, contributing to phenotypic diversity in HCM.
Aims: To elucidate whether the coexisting other cardiovascular disease (CVD)-related variants are associated with progression to end-stage HCM in patients with sarcomeric HCM.
Methods: Genetic analysis of 83 CVD-related genes was performed on patients with HCM from a Japanese multicentre cohort. Pathogenic variants in eight major sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, MYL2, MYL3, and ACTC1) were defined as ‘sarcomeric variants’. Additionally, pathogenic variants associated with other CVDs, such as dilated cardiomyopathy and arrhythmogenic cardiomyopathy, were referred to as ‘other CVD-related variants’.
Results: Among 394 patients with HCM, 139 had sarcomeric variants. Of these, 10 (7.2%) had other CVD-related variants, 6 (4.3%) had multiple sarcomeric variants, and 123 (88.5%) had single sarcomeric variants. Despite similar baseline characteristics, patients harbouring other CVD-related variants alongside sarcomeric variants exhibited a higher incidence of progression to end-stage HCM (log-rank p=0.015). In multivariable Cox regression analysis, multiple sarcomeric variants (adjusted hazard ratio (aHR): 3.37; 95% confidence interval (CI): 1.26–9.00; p=0.016) and coexisting other CVD-related variants (aHR: 3.05; 95% CI: 1.26–7.36; p=0.013) were independently associated with progression to end-stage HCM. Coexisting other CVD-related variants were also associated with heart-failure events (aHR: 2.44; 95% CI: 1.08–5.50; p=0.032).
Conclusions: Coexisting other CVD-related variants modify phenotypes and clinical outcomes in individuals with sarcomeric HCM. Comprehensive surveillance of CVD-related variants in patients with sarcomeric HCM contribute to risk stratification and comprehend mechanisms underlying end-stage HCM.