Lower left ventricular ejection time in MYBPC3 variant carriers with overt or subclinical hypertrophic cardiomyopathy

Aims

Hypertrophic cardiomyopathy (HCM) is an inherited cardiomyopathy often caused by pathogenic variants in MYBPC3 and MYH7, encoding myosin-binding protein C3 and myosin heavy chain 7, respectively. These variants can cause increased actin–myosin crossbridge cycling, resulting in ventricular hypercontractility, but mice lacking Mybpc3 exhibited reduced left ventricular ejection time (LVET) as a sign of systolic dysfunction. In this study, we tested whether LVET is specifically altered in patients carrying MYBPC3 variants by retrospective echocardiographic analysis in two genotype-defined HCM cohorts.

Methods

LVET was measured by echocardiography and adjusted for heart rate [LVET index (LVETI)] in 166 patients. Variant carriers were stratified for the presence (LVH+) or absence of left ventricular hypertrophy with septal thickness of ≥13 mm (LVH−). Multivariate analysis of variance (MANOVA) was used to identify differences in LVETI between variant carriers and controls with LVETI as the dependent variable, adjusted for sex, age, left ventricular ejection fraction (LVEF), interventricular septal diameter in diastole (IVSd), diastolic dysfunction, left ventricular outflow tract (LVOT) gradient at rest and medication history as confounders.

Results

In a total of 166 patients carrying MYBPC3 or MYH7 pathogenic variants (38 ± 3 years, 45% female), we compared the discovery cohort (40 MYBPC3 and 31 MYH7) and the validation cohort (‘Valsartan in Attenuating Disease Evolution in Early Sarcomeric HCM’; 54 MYBPC3 and 41 MYH7) with 44 healthy controls. LVETI was lower in MYBPC3 and higher in MYH7 LVH+ patients than in controls in the discovery, validation and pooled cohorts (pooled: MYBPC3 381 ± 19 ms vs. MYH7 437 ± 38 ms, P < 0.001; MYBPC3 vs. controls 411 ± 15 ms, P < 0.001; and MYH7 vs. controls, P < 0.001). Similar findings were seen in LVH− (pooled: MYBPC3 380 ± 16 ms vs. MYH7 437 ± 39 ms, P < 0.001; MYBPC3 vs. controls, P < 0.001). While MYH7 variants were all missense as expected, 87% of the MYBPC3 variants were truncating (including nonsense variants, out-of-frame deletion and splice site variants) and 13% were non-truncating (missense and in-frame deletion). LVETI did not differ between the groups and was significantly lower than the control in both.

Conclusions

The data suggest that variants in MYBPC3 and MYH7 result in distinct biophysical consequences, which can be detected by measuring LVETI in patients. The findings may have implications for potential genotype-specific differences in response to therapies targeting sarcomere function.