A frameshift deletion mutation in the cardiac myosin-binding protein C gene associated with dilated phase of hypertrophic cardiomyopathy and dilated cardiomyopathy.

OBJECTIVES: A few studies reported that some mutations in the cardiac myosin-binding protein C (MyBPC) gene were associated with dilated phase of hypertrophic cardiomyopathy (D-HCM) resembling dilated cardiomyopathy (DCM). We studied 5 unrelated cardiomyopathy probands caused by an identical mutation in the MyBPC gene. The results of clinical and genetic investigations in these patients are presented in this paper. METHODS: We analyzed MyBPC gene in DCM patients as well as patients with HCM. RESULTS: An R945fs/105 mutation, 2-base deletion at nucleotides 18,535 and 18,536, was identified in 4 of the 176 HCM probands and in 1 of the 54 DCM probands. Genetic analysis in relatives of those probands revealed another one member with this mutation. A total of 6 subjects had R945fs/105 mutation. The mean age of these six patients at diagnosis was 61 years. At initial evaluation, three of them were diagnosed as having HCM with normal left ventricular (LV) systolic function. The other two patients already had D-HCM. The remaining one patient was diagnosed as having DCM because of reduced LV systolic function (ejection fraction=31%) without increased LV wall thickness. During follow-up (7.6 years), all three patients with impaired LV systolic function were admitted for treatment of heart failure and/or sustained ventricular tachycardia. Finally, one patient with the diagnosis of D-HCM died of heart failure. CONCLUSIONS: The patients with this mutation may develop LV systolic dysfunction and suffer from cardiovascular events through mid-life and beyond.

Improvement in prognosis of dilated cardiomyopathy in the elderly over the past 20 years.

BACKGROUND AND PURPOSE: Although dilated cardiomyopathy (DCM) had a poor prognosis in the past, recent studies have shown better survival. However, little is known about the improvement of prognosis in the elderly. This study sought to clarify the changes in prognosis in elderly patients with DCM over the past 20 years. METHODS AND SUBJECTS: We studied 54 consecutive patients with DCM (38 men and 16 women, aged 65-83 years) who were diagnosed at over 65 years of age. The patients were divided into two groups (group A: 12 patients diagnosed before 1990; group B: 42 patients diagnosed after 1990) because after 1990, based on growing evidence from large-scale, randomized clinical studies, we intentionally increased the use of angiotensin-converting enzyme inhibitors (ACEI) and then beta-blockers at our hospital. RESULTS: There were no significant differences in age, gender, NYHA functional class, and the prevalence of atrial fibrillation and ventricular tachycardia between the two groups. Left ventricular (LV) size assessed by echocardiography was larger (LV end-diastolic diameter, 67+/-5.9 versus 62+/-6.6 mm; p=0.039) and LV ejection fraction measured by left ventriculography was lower (ejection fraction, 24+/-9 versus 35+/-10%; p=0.004) in group A. ACEI/angiotensin II type 1 receptor blockers (ARB) (0% versus 88%) or beta-blockers (0% versus 52%) were more frequently used in group B. Antiarrhythmics (class Ia or Ib) (75% versus 14%) were less often used in group B. The 5- and 10-year event-free survival rates for cardiac death were 75.4% and 22.0% in group A versus 81.2% and 71.3% in group B (log-rank test, p=0.014). CONCLUSIONS: The prognosis of DCM patients in the elderly has significantly improved over the past 20 years. The advances in the pharmacologic treatment and earlier diagnosis may have contributed to the better survival.

Hypertrophic cardiomyopathy with mild left ventricular remodeling: echocardiographic assessment using left ventricular wall motion score.

OBJECTIVES: The present study sought to investigate the echocardiographic features of hypertrophic cardiomyopathy (HCM) with mild left ventricular (LV) remodeling, particularly in relation to wall motion abnormalities. METHODS: Among the 137 consecutive patients with HCM, 13 patients (mean age 52 +/- 13 years) who progressed to mild LV systolic dysfunction (LV ejection fraction (LVEF) of 35-50%) were studied. By reviewing the echocardiograms of these patients, wall motion score index (WMSI) was scored using 16 segments model. RESULTS: HCM patients with mild LV systolic dysfunction exhibited mild LV dilatation, mild left atrial dilatation, septal hypertrophy, and LV wall motion impairment localized in the septal and apical regions (septal WMSI 1.94 +/- 0.33 vs. total WMSI 1.51 +/- 0.25 and posterior WMSI 1.02 +/- 0.07; p < 0.001). During follow-up, further deterioration of LV systolic function (LVEF< 35%) was noted in five patients, who had less severe hypertrophy at the initial echocardiograms. These patients developed progressive LV cavity enlargement and more severe and extensive wall motion abnormalities, accompanied by septal akinesis and wall thinning, although posterolateral wall motion impairment was relatively mild (posterior WMSI 1.80 +/- 0.27 vs. septal WMSI 2.95 +/- 0.11; p < 0.001). CONCLUSIONS: Septal and apical wall motions are reduced in HCM with mild LV remodeling. As LV dysfunction progresses, septal akinesis and wall thinning develop and LV cavity enlargement becomes more prominent, though posterolateral wall motion impairment is relatively mild.

Left ventricular remodeling of hypertrophic cardiomyopathy: longitudinal observation in rural community.

BACKGROUND: The purpose of the present study was to assess the clinical long-term course of hypertrophic cardiomyopathy (HCM) in a rural Japanese cohort. METHODS AND RESULTS: A total of 137 consecutive HCM patients (mean age at diagnosis: 52+/-13 years) were enrolled. During a follow-up period of 11.4+/-5.7 years, 28 patients died of HCM-related causes. Eleven patients died suddenly, 10 died of progressive heart failure, 6 died of stroke associated with atrial fibrillation and 1 died of a postoperative complication of alcohol septal ablation. For the overall study group, 5-, 10- and 15-year cumulative survival rates were 91%, 88% and 79%, respectively. Although sudden death was the predominant cause of HCM-related death during the follow-up period of <10 years, heart failure death increased after follow-up period of >10 years. Fifteen (13%) of 114 patients who had follow-up echocardiography became ;end-stage' HCM and 8 patients died of severe and refractory heart failure. They already showed minimally dilated left ventricular (LV) dimension and lower LV fractional shortening at initial evaluation. CONCLUSIONS: Although HCM patients in a Japanese rural community showed relatively benign clinical course (the same as cohorts in the developed world), heart failure death because of LV remodeling became equally important to sudden death when they were followed for more than 10 years.

Long-term prognosis of dilated cardiomyopathy revisited: an improvement in survival over the past 20 years.

BACKGROUND: Because of their favorable prognostic effects, angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and beta blockers have become background therapy in dilated cardiomyopathy (DCM). However, there are few reports concerning the long-term prognosis of Japanese patients with DCM in relation to these treatments. METHODS AND RESULTS: One hundred and fifty patients with DCM were divided into 2 groups: group A (n=46) (diagnosis: 1982-1989) and group B (n=104) (diagnosis: 1990-2002). During follow-up period of 6.9+/-4.8 years, 62 patients died and 1 patient had a heart transplant. The survival rate at 5 and 10 years was 60.9% and 34.8%, respectively, in group A patients, and 80.9% and 65.3%, respectively, in group B patients (p=0.0079). In group A patients, ACEI/ARB or beta blockers were less frequently used (p<0.0001), whereas antiarrhythmics (class Ia or Ib) were more often used (p<0.0001). The patients treated with ACEI/ARB and beta blockers showed a better survival rate than those without (p<0.0001). The patients with antiarrhythmics showed a worse survival rate than those without (p<0.0001). CONCLUSION: The prognosis of Japanese patients with DCM has significantly improved over the past 20 years. This improvement may be explained partly through the increased use of ACEI/ARB and beta blockers and a declining use of antiarrhythmics.

Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC. METHODS AND RESULTS: We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC. CONCLUSIONS: In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC.

[Discrete subaortic stenosis with pressure recovery: a case report].

A 54-year-old woman with subvalvular aortic stenosis was admitted to our hospital. The pressure gradient across the left ventricular outflow tract was estimated as 88 mmHg (peak) and 45 mmHg (mean) by Doppler echocardiography, but only 14 mmHg (peak to peak) and 31 mmHg (mean) by cardiac catheterization. We considered this discrepancy attributable to the presence of moderate aortic regurgitation and the pressure recovery phenomenon. Pressure recovery has clinical relevance particularly in a patient with tunnel-like stenosis, with gradual lumen re-expansion beyond the limiting orifice. Therefore, if Doppler echocardiography shows significant left ventricular outflow tract gradient, precise evaluation of the stenosis geometry is required to investigate the effect of pressure recovery.

Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac Myosin-binding protein C gene among Japanese.

OBJECTIVES: We studied the longitudinal evolution of hypertrophic cardiomyopathy (HCM) caused by a founder frameshift mutation in the cardiac myosin-binding protein C (MyBPC) gene. BACKGROUND: Mutations in the MyBPC gene have been associated with delayed expression of HCM and a good prognosis. Few studies, however, demonstrated the phenotype-genotype correlations in the longitudinal study. METHODS: We studied long-term evolution of clinical features of 15 unrelated families who were found to have an identical frameshift mutation in the MyBPC gene: a one-base deletion of a thymidine at nucleotide 11645 (V592fs/8). RESULTS: Thirty-nine individuals in 15 families were genotype-positive. Thirty of the 39 individuals with the mutation were phenotype-positive. The disease penetrance was 100% in subjects > or =50 years and 65% in those <50 years. "End-stage" HCM (ejection fraction <50%) was observed in 7 (18%) of the 39 genotype-positive individuals (7 [23%] of the 30 phenotype-positive patients); 6 of them were 60 years or older. Seven patients were hospitalized for treatment of repeated congestive heart failure, and four patients died or had implantable cardioverter-defibrillator discharge (13%; incidence, 1.4%/year) during a mean follow-up period of 9.2 +/- 5.5 years. CONCLUSIONS: Elderly patients with a V592fs/8 mutation in the MyBPC gene may evolve into the "end-stage" HCM, characterized by left ventricular systolic dysfunction, cavity dilation, and irreversible heart failure. The clinical course in patients with this mutation is not benign in the long run, with progressive left ventricular remodeling with advancing age.

Prognostic significance of post-exercise blood pressure response in patients with dilated cardiomyopathy.

BACKGROUND AND OBJECTIVES: The occurrence of an abnormal cardiovascular response during exercise in patients with chronic heart failure is well known. Post-exercise blood pressure response is also useful in assessing the severity of heart failure and impaired exercise capacity. This study evaluated the prognostic significance of post-exercise blood pressure response in patients with dilated cardiomyopathy. METHODS: Thirty patients with dilated cardiomyopathy (left ventricular ejection fraction: 32 +/- 9%) were studied and the relationship between post-exercise blood pressure response and cardiac events (sudden death, heart failure death and readmission for heart failure) were evaluated. The post-exercise blood pressure response was defined as PBP3 (systolic blood pressure at 3 min after exercise divided by peak systolic blood pressure during exercise). RESULTS: Seven cardiac events (one sudden death, two deaths for heart failure and four readmissions from heart failure) were observed during the follow-up period (3.3 +/- 1.8 years). The PBP3 in patients with these cardiac events was higher than that in patients without cardiac events (0.95 +/- 0.09 vs 0.84 +/- 0.10, p < 0.05). The area under the curve for the receiver-operating characteristic curve with PBP3 used to predict the cardiovascular events was 0.79 (95% confidence interval: 0.62-0.97, p = 0.02). CONCLUSIONS: Post-exercise blood pressure response is a simple and useful predictor of adverse cardiac events in patients with dilated cardiomyopathy.

Comparison of prevalence of apical hypertrophic cardiomyopathy in Japan and the United States.

The morphologic apical form of hypertrophic cardiomyopathy (HC), in which left ventricular (LV) wall thickening is confined to the most distal region at the apex, has been regarded as a phenotypic expression of nonobstructive HC largely unique to Japanese patients. To investigate this question further, we directly compared unselected and regional hospital-based cohorts of adult patients with HC ( > or =18 years of age) from Japan (Kochi; n=100) and from the United States (US) (Minneapolis; n=361). Japanese and American patients with HC had similar clinical features and did not differ significantly with regard to the severity of symptoms and frequency of outflow obstruction. Although Japanese and American patients also showed similar maximum LV thickness, they differed significantly with respect to the distribution of LV hypertrophy. In particular, the segmental form of HC, with hypertrophy confined to the LV apex, was more frequent in Japanese patients (i.e., apical HC, 15% in Japan vs 3% in US, p<0.0001). Giant negative T waves were also more common in Japanese patients with HC (26% vs 2%, p<0.001), including those with the apical form (64% vs. 30%, p<0.05). Each patient with apical HC had either no or only mild symptoms, and all survived. The morphologic form of nonobstructive HC with hypertrophy limited to the LV apex (apical form of HC) was 5 times more common in an unselected Japanese population. These findings document variability in the phenotypic expression of HC between countries and races, which may be due to differences in environmental factors or genetic background. Patients with the apical form of HC had a benign clinical course.