Impact of Systolic Dysfunction in Genotyped Hypertrophic Cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a disease of the sarcomere, and approximately 5% of cases of HCM show systolic dysfunction with poor prognosis. Few data exist regarding the systolic dysfunction in a large population of genotyped HCM subjects. Hypothesis: The aim of this study was to assess the systolic dysfunction and prognosis in sarcomere gene mutation carriers. Methods: The study included 157 sarcomere gene mutation carriers from 69 unrelated HCM families (87 males; mean age, 46.5 +/- 20.5 years). After exclusions for systolic dysfunction at baseline, 107 subjects underwent serial echocardiograms. Results: At a mean follow-up of 7.0 years, 12 subjects experienced systolic dysfunction. In multivariate Cox analysis, systolic dysfunction was related to age and ejection fraction at initial evaluation (P < 0.001 and P = 0.020, respectively), and was associated with the absence of mutations in the cardiac myosin-binding protein C gene (MYBPC3) (P = 0.042). When the subjects were divided into MYBPC3 and non-MYBPC3 mutation carriers, and time from birth to development of systolic dysfunction was compared, the rate of systolic dysfunction was higher in the non-MYBPC3 group than in MYBPC3 group (Kaplan-Meier, log-rank test, P = 0.010). After the onset of systolic dysfunction, 11 of 12 subjects died during a mean follow-up of 8.3 years. Conclusions: Non-MYBPC3 mutation carriers developed left ventricular systolic dysfunction more frequently than MYBPC3 mutation carriers, and the majority of sarcomere gene mutation carriers with systolic dysfunction had fatal outcomes during follow-up. This suggests that subjects with mutations in sarcomeric genes require careful management for systolic dysfunction. This work was supported in part by a Grant-in-Aid for Scientific Research, the Ministry of Education, Culture, Sports, Science, and Technology (KAKENHI 16790414, 19590807, 22590808, Tokyo, Japan), and the Research Grant for Cardiovascular Diseases (20C-4) from the Ministry of Health, Labour, and Welfare (Tokyo, Japan). The authors have no other funding, financial relationships, or conflicts of interest to disclose.