Takashi Fujita

High Incidence of Sudden Cardiac Death With Conduction Disturbances and Atrial Cardiomyopathy Caused by a Nonsense Mutation in the STA Gene

Background—The STA gene encodes emerin and is one of the genes that is affected in Emery-Dreifuss muscular dystrophy (EDMD). Although it has been reported that EDMD caused by the STA gene mutation is associated with X-linked recessive inheritance, the genotype-phenotype correlations, with special reference to cardiac manifestations, are not well defined. Methods and Results—We identified 16 carriers (7 male and 9 female) with a nonsense mutation in exon 6 of the STA gene in 2 EDMD families. Pacemakers were required for treatment of bradyarrhythmias in all 7 male carriers and in 2 of the 9 female carriers. In addition, 2 of the 9 female carriers displayed atrial fibrillation. In these 2 families, 3 males without pacemaker implantation, who were not tested genetically, had died suddenly. In these family members, the majority of carriers with the mutation had not been clinically diagnosed as having EDMD before genetic testing because of extremely mild or nonexistent skeletal myopathy. Conclusions—EDMD caused by this mutation is characterized by atypical clinical features and incomplete penetrance of the clinical phenotype and may result in serious cardiac complications, including sudden death. Approaches to preventing possible sudden death in carriers with the STA gene mutation require further study.

Adult Patient With Isolated Noncompaction of Ventricular Myocardium

A 55-year-old woman was admitted to our hospital because of congestive heart failure despite full medical therapy. She had been diagnosed as having and was treated for cardiomyopathy of unknown cause during an extended period. She had no familial history of cardiovascular diseases or sudden cardiac death. Echocardiograms revealed severely reduced left ventricular (LV) contraction, severe mitral regurgitation, thickened myocardium with prominent trabeculations, and …

Fragmented QRS Predicts Heart Failure Progression in Patients With Hypertrophic Cardiomyopathy

BACKGROUNDnAlthough fragmented QRS complex (frag-QRS) reflecting intra-ventricular conduction delay has been shown to be a prognostic marker for cardiac events, few data exist regarding the impact of frag-QRS on cardiac events in hypertrophic cardiomyopathy (HCM).nnnMETHODS AND RESULTSnNinety-four HCM patients (56 male; mean age, 58 ± 17 years) were retrospectively investigated. Frag-QRS was defined as the presence of various RsR patterns in at least 2 contiguous ECG leads. Major arrhythmic events (MAE) were defined as sudden cardiac death, and combined sustained ventricular tachycardia/ventricular fibrillation. New-onset atrial fibrillation (AF) was diagnosed based on ECG during provisional or routine medical examination. Heart failure (HF) with hospitalization was defined as hospital admission due to subjective or objective symptoms. Frag-QRS was detected in 31 patients (33%).TNNI3 was the most frequent disease-causing gene. Median follow-up was 4.6 years. The 4-year cumulative survival rates of cardiac death, MAE, new-onset AF and HF with hospitalization were 97.6%, 94.6%, 87.5% and 89.3%, respectively. On multivariate analysis, frag-QRS was significantly associated with HF with hospitalization (adjusted hazard ratios [95% confidence intervals]: 5.4 [1.2-36], P=0.03). Moreover, HF-free survival was significantly lower in the frag-QRS (+) group compared to the frag-QRS (-) group (79.0% vs. 95.1%, P=0.03).nnnCONCLUSIONSnFrag-QRS is associated with HF with hospitalization in HCM patients who had a unique distribution of gene mutations.

Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models

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.

Impact of Systolic Dysfunction in Genotyped Hypertrophic Cardiomyopathy

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.

Sarcomere gene mutations are associated with increased cardiovascular events in left ventricular hypertrophy: results from multicenter registration in Japan.

OBJECTIVESnThis study investigated the occurrence of cardiovascular events in patients with hypertensive heart disease (HHD) or hypertrophic cardiomyopathy (HCM) with or without sarcomere gene mutations.nnnBACKGROUNDnAlthough HHD and HCM are associated with left ventricular hypertrophy (LVH), few data exist regarding the difference in prognosis between them.nnnMETHODSnWe enrolled 256 patients with LVH (>13 mm) screened for sarcomere gene mutations. We divided them into 3 groups: the first had HHD without sarcomere gene mutations (group H), the second had sarcomere gene mutations (group G), and the third had neither sarcomere gene mutations nor HHD (group NG). We compared the occurrence of sudden cardiac death, ventricular tachycardia/fibrillation, admission for heart failure, and atrial fibrillation for 1 year.nnnRESULTSnGroup G (nxa0= 78, 36 men; mean age, 53.4 years) experienced more total cardiovascular events than group H (nxa0=xa045, 32 men; mean age, 67.4 years) (pxa0= 0.042) after adjustments for age and sex, although there was no significant difference in total cardiovascular events between groups H and NG (nxa0= 98, 66 men; mean age, 62.0 years). With Kaplan-Meier analysis, group G exhibited a significantly higher incidence of admission for heart failure (pxa0= 0.017) and atrial fibrillation (pxa0= 0.045) than group H in those 50 years of age and older. Additionally, there was a significant difference in total cardiovascular events between groups G and NG (pxa0= 0.021).nnnCONCLUSIONSnThese results demonstrate that HCM with sarcomere gene mutations can be associated with increased cardiovascular events compared with HHD or HCM without sarcomere gene mutations.

Increased extent of myocardial fibrosis in genotyped hypertrophic cardiomyopathy with ventricular tachyarrhythmias

BACKGROUNDnOccurrence 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.nnnOBJECTIVEnWe 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.nnnMETHODS AND RESULTSnWe 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).nnnCONCLUSIONnThese 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.

A novel mutation in the cardiac myosin-binding protein C gene is responsible for hypertrophic cardiomyopathy with severe ventricular hypertrophy and sudden death

It has been demonstrated previously that clinical phenotypes of HCM (hypertrophic cardiomyopathy) caused by mutations in the cardiac MyBP-C (myosin-binding protein C) gene show late onset, low penetrance and favourable clinical course. However, we have encountered severe phenotypes in several carriers of the MyBP-C gene mutations. The aim of the present study was to screen novel MyBP-C gene mutations in patients with HCM and to investigate the genetic differences in affected subjects with severe phenotypes. The MyBP-C gene was screened in 292 Japanese probands with HCM, and a novel c.2067+1G-->A mutation was present in 15 subjects in five families. Clinical phenotypes of carriers of the c.2067+1G-->A mutation were compared with those of a previously identified Arg820Gln (Arg820-->Gln) mutation in the MyBP-C gene. The disease penetrance in subjects aged > or =30 years was 90% in carriers of the c.2067+1G-->A mutation and 61% in carriers of the Arg820Gln mutation. Sudden death occurred in four subjects from three families with the c.2067+1G-->A mutation and in two subjects from one family with the Arg820Gln mutation. Two carriers of the c.2067+1G-->A mutation had substantial hypertrophy (maximal wall thickness > or =30 mm). In contrast, two carriers of the Arg820Gln mutation had end-stage HCM. In conclusion, the c.2067+1G-->A mutation is associated with HCM with substantial hypertrophy and moderate incidence of sudden death, whereas the Arg820Gln mutation is associated with end-stage HCM. These observations may provide important prognostic information regarding the clinical practice of HCM.

Abnormal sympathetic innervation of the heart in a patient with Emery-Dreifuss muscular dystrophy

A 33-year-old man was admitted for general malaise and vomiting. An electrocardiogram showed a complete atrioventricular block and an echocardiogram showed right atrial dilatation and normal wall motion of left ventricle (LV). Gene analysis showed nonsense mutation in the STA gene, which codes for emerin, and Emery-Dreifuss muscular dystrophy was diagnosed. An endomyocardial biopsy of right ventricle showed mild hypertrophy of myocytes. Myocardial scintigraphic studies with Tc-99m methoxyisobutylisonitrile (MIBI) and I-123-betamethyl-p-iodophenylpentadecanoic acid (BMIPP) scintigrams showed no abnormalities. In contrast, I-123 metaiodobenzylguanidine (MIBG) scintigrams showed a diffuse and severe decrease in accumulation of MIBG in the heart. Six months later, his LV wall motion on echocardiograms developed diffuse hypokinesis. These results suggest that the abnormality on I-123 MIBG myocardial scintigrams may predict LV dysfunction in Emery-Dreifuss muscular dystrophy.

J Waves for Predicting Cardiac Events in Hypertrophic Cardiomyopathy

OBJECTIVESnThis study sought to investigate whether the presence of J waves was associated with cardiac events in patients with hypertrophic cardiomyopathy (HCM).nnnBACKGROUNDnIt has been uncertain whether the presence of J waves predicts life-threatening cardiac events in patients with HCM.nnnMETHODSnThis study evaluated consecutive 338 patients with HCM (207 men; age 61 ± 17 years of age). A J-wave was defined as J-point elevation >0.1 mV in at least 2 contiguous inferior and/or lateral leads. Cardiac events were defined as suddenxa0cardiac death, ventricular fibrillation or sustained ventricular tachycardia, or appropriate implantable cardiac defibrillator therapy. The study also investigated whether adding the J-wave in a conventional risk model improved a prediction of cardiac events.nnnRESULTSnJ waves were seen in 46 (13.6%) patients at registration. Cardiac events occurred in 31 patients (9.2%) duringxa0median follow-up of 4.9 years (interquartile range: 2.6 to 7.1 years). In a Cox proportional hazards model, the presence of J waves was significantly associated with cardiac events (adjusted hazard ratio: 4.01; 95% confidence interval [CI]: 1.78 to 9.05; pxa0= 0.001). Compared with the conventional risk model, the model using J waves in addition to conventional risks better predicted cardiac events (net reclassification improvement, 0.55; 95% CI: 0.20 to 0.90; pxa0= 0.002).nnnCONCLUSIONSnThe presence of J waves was significantly associated with cardiac events in HCM. Adding J waves to conventional cardiac risk factors improved prediction of cardiac events. Further confirmatory studies are needed beforexa0considering J-point elevation as a marker of risk for use in making management decisions regarding risk in patients with HCM.