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

Aims Hypertrophic cardiomyopathy (HCM) is an inherited cardiomyopathy mainly 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. Little is known about genotype-specific differences. Mice lacking Mybpc3 exhibited reduced left ventricular ejection time (LVET). 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 and results LVET was measured by echocardiography and adjusted for heart rate (LVET index, LVETI) in 173 patients carrying MYBPC3 or MYH7 pathogenic variant. There was a discovery cohort (Hamburg; 46 MYBPC3, 31 MYH7) and a validation cohort (“Valsartan in Attenuating Disease Evolution in Early Sarcomeric HCM”; 55 MYBPC3 , 41 MYH7 ). Data were compared with 44 healthy controls from Hamburg. Variant carriers were stratified for overt (G+LVH+) or subclinical left ventricular hypertrophy (G+LVH-). LVETI was lower in MYBPC3 and higher in MYH7 G+LVH+ patients than in controls in the discovery, validation and pooled cohorts (pooled: 385 ± 23 ms MYBPC3 , 436 ± 38 ms MYH7, 411 ± 15 ms controls). Similar findings were seen in G+LVH-. Conclusion 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.