Search

Background Although gender may be one of the important factors modifying phenotypic expression in hypertrophic cardiomyopathy (HCM), there has been little information on it. Methods and results We investigated gender differences in the clinical features of HCM caused by cardiac myosin-binding protein C gene ( MYBPC3 ) mutations. Sixty-one subjects (28 families) carrying MYBPC3 mutations were studied. Of the 61 subjects with MYBPC3 mutations, 50 patients including 23 female patients were phenotype-positive by echocardiography. Disease penetrance in subjects aged ≤40 years old was 92% in males and 67% in females. Females showed delayed onset of left ventricular hypertrophy compared with males in subjects who were genotype-positive. Female patients were more symptomatic at diagnosis than were males (mean New York Heart Association class: 1.7 ± 0.8 versus 1.2 ± 0.4, p = 0.012). From a longitudinal point of view by age, no significant gender difference in cardiovascular deaths or cardiovascular events was found. During the follow-up period after diagnosis of HCM (13 ± 8 years), female patients who were phenotype-positive had significantly more frequent heart failure events than did phenotypically affected male patients ( p = 0.028). Conclusions Although females with MYBPC3 mutations showed later onset of the disease, female patients were more symptomatic at diagnosis and had more frequent heart failure events once they had developed hypertrophy. [ABSTRACT FROM AUTHOR]

Aims Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. Methods and results Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca2+]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca2+]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. Conclusion We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal-dominant disorder mainly caused by mutations in sarcomere genes. Recently, a phenotype-based genetic test prediction score for patients with HCM was introduced by Mayo Clinic. The genotype score was derived on the basis of the predictive effect of 6 clinical markers, and the total score was shown to be correlated with the yield of genetic testing. However, it has not been determined whether this prediction model is useful in Japanese HCM patients., Methods and results: The utility of the Mayo Clinic HCM genotype predictor score in 209 Japanese unrelated patients with a clinical diagnosis of HCM who had undergone genetic testing for 6 sarcomere genes was assessed. Overall, 55 patients (26%) had pathogenic or likely pathogenic variants (60% being genotype-positive in familial cases). We divided the patients into 6 groups (groups with scores of from -1 to 5) according to the prediction score. The yields of genetic testing in the groups with scores of -1, 0, 1, 2, 3, 4, and 5 were 8%, 16%, 24%, 48%, 50%, 100%, and 89%, respectively, with an incremental increase in yield between each of the score subgroups (P<0.001)., Conclusions: The Mayo Clinic HCM genotype predictor score is useful for predicting a positive genetic test result in Japanese HCM Patients.

Background: Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomere genes. Regarding the clinical implications of genetic information, little is known about the lifelong clinical effect of sarcomere mutations in Japanese HCM patients., Methods and results: We studied 211 consecutive Japanese patients with HCM who had agreed to genetic testing between 2003 and 2013. Genetic analyses were performed by direct DNA sequencing in the 6 common sarcomere genes (MYH7,MYBPC3,TNNT2,TNNI3,TPM1,ACTC). Through variant filtering, 21 mutations were identified in 67 patients. After excluding 8 patients whose variants were determined as having uncertain significance, finally 203 patients (130 men, age at study entry: 61.8±14.1 years) were investigated for clinical presentation and course. At the time of study entry, patients with mutations were younger, had more frequent non-sustained ventricular tachycardia, had greater interventricular wall thickness, were more frequently in the dilated phase and less frequently had apical HCM. Through their lifetimes, a total of 98 HCM-related morbid events occurred in 72 patients. Survival analysis revealed that patients with sarcomere gene mutations experienced those morbid events significantly more frequently, and this tendency was more prominent for lethal arrhythmic events., Conclusions: In our HCM cohort, patients with sarcomere gene mutations had poorer lifelong outcome. Genetic information is considered important for better management of HCM.