👤 Akira Funada

Occurrence of malignant ventricular tachyarrhythmias such as ventricular tachycardia and fibrillation (VT/VF) in hypertrophic cardiomyopathy (HCM) can be related to the extent of myocardial fibrosis. Although late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging has been used to detect myocardial fibrosis, few data exist regarding relationships between CMR-determined myocardial fibrosis and VT/VF in genotyped HCM populations. We retrospectively investigated whether the extent of LGE can be increased in HCM patients with VT/VF compared to those without VT/VF in the genotyped HCM population. We studied 35 HCM patients harboring sarcomere gene mutations (TNNI3=22, MYBPC3=12, MYH7=1) who underwent both CMR imaging and 24-h ambulatory electrocardiographic monitoring. VT/VF were identified in 6 patients (2 men, mean age 55.0 years). The extent of LGE was significantly increased in patients with VT/VF (n=6) compared with those without VT/VF (n=29) (18.6±14.4% vs. 8.3±11.4%, p=0.04), although the LGE extent was not an independent predictor for the occurrence of VT/VF. Applying a cut-off point ≥3.25%, episodes of VT/VF were identified with a sensitivity of 100%, specificity of 51.7%, positive predictive value of 30%, negative predictive value of 100%, and the area under the curve of 0.767 (95% confidence interval: 0.590-0.944). These results demonstrate that myocardial fibrosis determined by CMR imaging may be increased in genotyped HCM patients with episodes of VT/VF. A further prospective study will be needed to clarify the association between the LGE extent and arrhythmic events in HCM patients harboring sarcomere gene mutations. Show less

Although most founder mutation carriers of hypertrophic cardiomyopathy (HCM), such as the cardiac myosin-binding protein C gene (MYBPC3), arose from a common ancestor exhibit favorable clinical phenotypes, there still remain small fractions of these carriers associated with increased cardiovascular events. However, few data exist regarding the defining factors that modify phenotypes of these patients, particularly in terms of multiple gene mutations. Therefore, we assessed genotype-phenotype correlations and investigated factors that contribute to phenotypic diversities of mutation carriers from 488 unrelated HCM probands. A prevalent founder mutation (Val762Asp) in MYBPC3 was identified in 33 subjects from 19 families. Among them, 28 carriers harbored an isolated Val762Asp mutation and exhibited a late onset of overt HCM compared with other MYBPC3 mutation carriers (62.8 ± 3.0 vs 50.1 ± 2.6 yr, P < 0.05). In contrast, the remaining five carriers had additional sarcomere gene mutations (3 carriers in MYBPC3 and 2 carriers in the cardiac troponin T gene). Of these five carriers, two carriers showed early disease onset and one carrier exhibited end-stage HCM. These phenotypes were recapitulated in zebrafish models; injection of MYBPC3 Val762Asp alone did not alter ventricular size or function, but ventricular dimension was significantly increased when MYBPC3 Val762Asp mRNA was coinjected with MYBPC3 Arg820Gln mRNA. These results demonstrate that MYBPC3 Val762Asp may be associated with unfavorable HCM phenotypes in some cases when combined with another MYBPC3 mutation. Show less

Some patients with dilated cardiomyopathy (DCM) have mutations of the genes that encode sarcomeric or cytoskeletal proteins of cardiomyocytes, but the prevalence of these mutations in Japan remains unclear. A group of 99 unrelated adult patients with DCM (familial n=27, sporadic n=72) were screened for the following genes: cardiac beta-myosin heavy chain, cardiac myosin-binding protein C (MYBPC3), regulatory and essential myosin light chains, alpha cardiac actin, alpha tropomyosin, cardiac troponin T, cardiac troponin I, cardiac troponin C, dystrophin, and lamin A/C. A mutation (R820Q) in MYBPC3 was found in an aged patient. In addition, dystrophin mutations were identified in 3 male patients (2 with exon 45-48 deletion and 1 with exon 48-52 deletion). The prevalence of dystrophin mutations in male patients with DCM was 4.4% (3 of 68). No mutations involving amino acid changes were identified in the other genes. Although cases of adult patients with DCM caused by mutations of the genes encoding sarcomeric or cytoskeletal proteins of cardiomyocytes are infrequent in Japan, it may be advisable to screen older DCM patients for MYBPC3 mutations, and male patients with familial DCM for dystrophin mutations. Show less