P1243Comparison of long-term clinical course and outcome of MYBPC3 - versus MYH7 - related hypertrophic cardiomyopathy

Introduction The presence of sarcomere mutations is a powerful predictor of heart failure-related outcomes in Hypertrophic Cardiomyopathy (HCM). However, whether the prevalence of left ventricular (LV) dysfunction differs in patients with mutations in the two most prevalent HCM-associated genes (i.e. MYBPC3 and MYH7) is unclear. Purpose To ascertain lifetime trends in prevalence of LV dysfunction in HCM associated with pathogenic or likely-pathogenic MYBPC3 versus MYH7 mutations. Methods Clinical and instrumental records of 402 HCM patients with MYBPC3 (N=251) or MYH7 (N=151) mutations were retrospectively reviewed. Presence of systolic dysfunction (ejection fraction [EF] <50%) and diastolic dysfunction (Grade II and III) were assessed for each patient. In vitro analysis of septal myectomy samples was performed to further compare electro-mechanic properties of MYBC3 and MYH7 patients. Results Patients were diagnosed at a mean age of 39±17 years and 63% were men. At first evaluation MYBPC3-HCM patients were less frequently obstructive (15% vs 26% in MYH7; p=0.005) and had lower LVEF (61±11% vs 64±9%; p=0.01). Prevalence of diastolic dysfunction increased with age and was lowest in MYBPC3 patients <40 years at diagnosis (19.5% vs 35.4% in MYH7, p=0.043). At a mean follow-up (FU) of 13±11 years, patients developed comparable left atrium enlargement (MYBPC3 52±29 ml/m2 vs 41±18 at baseline, p<0.001; MYH7 54±25ml/m2 vs 45±22, p=0.003). Prevalence of diastolic dysfunction was also similar. MYBPC3 patients had lower LVEF at final evaluation (61±11% vs 64±9% in MYH7, p=0.01) with greater prevalence of overt systolic dysfunction (EF<50%, MYBPC3 vs MYH7: 15% vs 5%, OR: 2.3 95% CI: 1.2–5.8, p=0.013). No significant differences were observed in terms of NYHA class change, atrial fibrillation, stroke, heart failure, appropriate ICD intervention or cardiovascular death. However, prevalence of NSVT was higher for MYBPC3 (39% vs 14% in MYH7, p<0.0001). At Cox multivariable analysis independent predictors of systolic dysfunction at follow-up were MYBPC3 positive status (HR 2.53 95% CI: 1.09–5.82, p=0.029) and age at initial evaluation (HR 1.03 95% CI 1.00–1.06, p=0.027). In vitro cross-sectional evaluation of myocardial samples taken during septal myectomy at different ages showed a decline in contraction-relaxation properties after age 40 in MYPBC3 carriers, but preserved function in MYH7 patients (Figure). Kinetic of myosin cross-bridges Conclusions In HCM patients, mutations in the MYBPC3 gene and early diagnosis are associated with slowly progressing systolic impairment leading to overt dysfunction in 15% compared to 5% in MYH7-HCM. However, outcome was similar in the two subsets. These differences in lifetime myocardial performance between the two most common HCM-associated genes suggest diverse pathways of disease progression, potentially amenable to requiring different molecular approaches.