The validity of genotype:phenotype correlation studies in human hypertrophic cardiomyopathy (HCM) has recently been questioned, yet animal models and in vitro studies suggest distinct effects for different mutations. The aims of this study were to investigate whether distinct HCM-mutations have different consequences for cardiac structure and function in the absence of the confounding effects of hypertrophy.Methods and results
Individuals aged 20–65 belonging to 21 R92WTNNT2, R403WMYH7, or A797TMYH7 mutation-bearing families were investigated with 2D, M-mode, and Doppler echocardiography. Cardiac structural and functional parameters were compared between prehypertrophic mutation-carriers and their non-carrier family members, with concomitant adjustment for appropriate covariates. Findings were evaluated against existing animal and in vitro functional data. The distinct functional effect of the R92WTNNT mutation was a relative increase in systolic functional parameters, that of the A797TMYH7 mutation was reduced diastolic function, while the R403WMYH7 mutation reduced both systolic and diastolic function. The observed early effects of the R92WTNNT2 mutation mechanistically fit with prolonged force-transients precipitated by increased Ca2+ sensitivity of the thin filament, and that of the MYH7 mutations with local ATP depletion.Conclusion
Evaluation of the impact of the mutations on cardiac structure and function in prehypertrophic mutation-carriers, relative to the baseline norm provided by their non-carrier family members, best recapitulated existing animal and in vitro functional data, while inclusion of mutation-carriers with hypertrophy obscured such findings. The results prompt speculation that timely treatment aimed at ameliorating Ca2+ sensitivity for R92WTNNT2-carriers, and energy depletion for MYH7 mutation-carriers, may offer a plausible approach for preventing progression from a preclinical into a decompensated state.