Genetic, echocardiographic and clinical determinants of mitral valve abnormalities in hypertrophic cardiomyopathy

Abstract Background Left ventricular outflow tract obstruction (LVOTO) is a common and prognostically relevant complication in hypertrophic cardiomyopathy (HCM). Elongated residual mitral leaflets past the coaptation point and low distance between the mitral leaflet tip and the ventricular septum (TIS) have been identified as crucial mechanistic prerequisites of LVOTO. Determinants of these mitral valve abnormalities have not been described so far. Purpose To investigate genetic, echocardiographic, and clinical parameters as determinants of mitral valve abnormalities in HCM. Methods This is a cross-sectional analysis of participants of a single-center HCM registry, consecutively enrolled between 2019 and 2024. All individuals with feasible echocardiographic studies and available genetic testing results were included. Echocardiographic parameters were assessed by a trained, blinded investigator using a vendor independent post-processing software . Residual leaflet length (RLL) and TIS were acquired from apical three-chamber views (3CV). Parameters associated with these mitral valve parameters in univariable analyses were included in multivariable linear regression models. Results We included 247 registry participants (42% women, mean ± standard deviation age 58 ± 16 years). Medians (interquartile ranges) of RLL and TIS were 6.3 (2.1 – 12.0) mm and 16.5 (9.7 – 21.6) mm, respectively. Genetic testing was available in 187 participants (75%) and pathogenic or likely pathogenic variants were present in 86 (46%). A strong correlation between RLL and TIS (Spearman r -0.559, P 0.001) was observed. RLL was significantly associated with interventricular septal thickness (IVS) and tended to be lower in genotype positive patients (p=0.073, see Table). In a multivariable linear regression model, RLL remained significantly associated with IVS (adjusted beta=0.172, p=0.036) and estimated glomerular filtration rate (eGFR; beta=0.166, p=0.043). TIS correlated significantly with age, IVS, left ventricular end-diastolic diameter (LVEDD), height, and systolic blood pressure, and was higher in genotype positive patients (p=0.018) and men (p=0.013). In a multivariable model, TIS remained significantly associated with IVS (beta=-0.158, p=0.041) and LVEDD (beta=0.269, p0.001), while there was no significant association with the genotype (p=0.689). Conclusion This single-center registry analysis suggests that mitral valve abnormalities in HCM relate with septal thickness and geometry rather than genotype. Whether this indicates shared mechanisms between RLL elongation and hypertrophy beyond genetic background, such as risk factors like arterial hypertension, should be investigated in future studies.