Toru Kubo

Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations

Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder characterized by impaired filling of the ventricles with reduced volume in the presence of normal or near normal wall thickness and systolic function. The disease may be associated with systemic disease but is most often idiopathic. We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM). Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I (TNNI3) as the likely disease gene. Subsequent mutation analysis revealed a novel missense mutation, which cosegregated with the disease in the family (lod score: 4.8). To determine if idiopathic RCM is part of the clinical expression of TNNI3 mutations, genetic investigations of the gene were performed in an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in six of these nine RCM patients. Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene. This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy is a common cause of heart failure. Half of cases are believed to be hereditary, and mutations in cardiac sarcomeric contractile protein genes have been reported with autosomal dominant inheritance. We used mutation analysis suitable for identification of both dominant and recessive mutations to investigate the sarcomeric gene for cardiac troponin I (TNNI3) in 235 patients with dilated cardiomyopathy. We identified a novel TNNI3 mutation in a family with recessive disease. Functional studies showed impairment of troponin interactions that could lead to diminished myocardial contractility. TNNI3 is the first recessive gene identified for this condition, and we suggest that other such genes could be pinpointed by mutation analyses designed to identify homozygous mutations.

Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy

OBJECTIVES The purpose of this study was to explore a novel disease gene for hypertrophic cardiomyopathy (HCM) and to evaluate functional alterations caused by mutations. BACKGROUND Mutations in genes encoding myofilaments or Z-disc proteins of the cardiac sarcomere cause HCM, but the disease-causing mutations can be found in one-half of the patients, indicating that novel HCM-susceptibility genes await discovery. We studied a candidate gene, ankyrin repeat domain 1 (ANKRD1), encoding for the cardiac ankyrin repeat protein (CARP) that is a Z-disc component interacting with N2A domain of titin/connectin and N-terminal domain of myopalladin. METHODS We analyzed 384 HCM patients for mutations in ANKRD1 and in the N2A domain of titin/connectin gene (TTN). Interaction of CARP with titin/connectin or myopalladin was investigated using coimmunoprecipitation assay to demonstrate the functional alteration caused by ANKRD1 or TTN mutations. Functional abnormalities caused by the ANKRD1 mutations were also examined at the cellular level in neonatal rat cardiomyocytes. RESULTS Three ANKRD1 missense mutations, Pro52Ala, Thr123Met, and Ile280Val, were found in 3 patients. All mutations increased binding of CARP to both titin/connectin and myopalladin. In addition, TTN mutations, Arg8500His, and Arg8604Gln in the N2A domain were found in 2 patients, and these mutations increased binding of titin/connectin to CARP. Myc-tagged CARP showed that the mutations resulted in abnormal localization of CARP in cardiomyocytes. CONCLUSIONS CARP abnormalities may be involved in the pathogenesis of HCM.

Prevalence and clinical significance of systolic impairment in hypertrophic cardiomyopathy

Objectives: To determine the frequency of systolic impairment (SI) and its impact on the natural history of hypertrophic cardiomyopathy (HCM). Methods: 1080 patients (mean (SD) age 43 (15) years, 660 men) with HCM were evaluated. Initial assessment included history, examination, 48 hour Holter monitoring, cardiopulmonary exercise testing, and echocardiography; SI was defined as a fractional shortening (FS) ⩽ 25%. Survival data were collected at clinic visits or by direct communication with patients and their general practitioners. The results of serial echocardiography in 462 patients with normal FS at presentation are also reported. Results: 26 (2.4%) patients (49 (14) years, 18 men) had SI at the initial visit. During follow up (58 (49) months), nine (34.6%) died or underwent cardiac transplantation compared with 108 (10.2%) patients with normal FS (p  =  0.01). Five year survival from death (any cause) or transplantation was 90.1% (95% confidence interval (CI) 87.8 to 92.4) in patients with normal systolic function versus 52.4% (95% CI 25.2 to 79.6, p < 0.0001) in patients with SI. In patients who underwent serial echocardiography, 22 (4.8%, aged 41 (15) years) developed SI over 66 (40) months; the annual incidence of SI was 0.87% (95% CI 0.54 to 1.31). On initial evaluation patients who developed SI had a higher frequency of syncope (67 (15.2%) v 10 (45.5%) of those who did not develop SI, p  =  0.001), non-sustained ventricular tachycardia (91 (20.6%) v 11 (50%), p  =  0.002), and an abnormal blood pressure response on exercise (131 (29.7%) v 15 (68.2%), p  =  0.001). Patients with SI had greater wall thinning (p  =  0.001), left ventricular cavity enlargement (p < 0.0005), and deterioration in New York Heart Association functional class (p  =  0.001) during follow up. Thirteen (59.1%) patients who progressed to SI died or underwent transplantation compared with 38 (8.6%) patients who maintained normal systolic function. Conclusions: SI is an infrequent complication of HCM but, when present, is associated with a poor prognosis.

Significance of high-sensitivity cardiac troponin T in hypertrophic cardiomyopathy.

OBJECTIVES This study investigated the significance of the serum high-sensitivity cardiac troponin T (hs-cTnT) marker for prediction of adverse events in hypertrophic cardiomyopathy (HCM). BACKGROUND Although serum cardiac troponins as sensitive and specific markers of myocardial injury have become well-established diagnostic and prognostic markers in acute coronary syndrome, the usefulness of hs-cTnT for prediction of cardiovascular events in patients with HCM is unclear. METHODS We performed clinical evaluation, including measurements of hs-cTnT in 183 consecutive patients with HCM. RESULTS Of 183 HCM patients, 99 (54%) showed abnormal hs-cTnT values (>0.014 ng/ml). During a mean follow-up of 4.1 ± 2.0 years, 32 (32%) of the 99 patients in the abnormal hs-cTnT group, but only 6 (7%) of 84 patients with normal hs-cTnT values, experienced cardiovascular events: cardiovascular deaths, unplanned heart failure admissions, sustained ventricular tachycardia, embolic events, and progression to New York Heart Association functional class III or IV status (hazard ratio [HR]: 5.05, p < 0.001). Abnormal hs-cTnT value remained an independent predictor of these cardiovascular events after multivariate analysis (HR: 3.23, p = 0.012). Furthermore, in the abnormal hs-cTnT group, overall risk increased with an increase in hs-cTnT value (HR: 1.89/hs-cTnT 1 SD increase in the logarithmic scale, 95% confidence interval: 1.13 to 3.15; p = 0.015 [SD: 0.59]). CONCLUSIONS In patients with HCM, an abnormal serum concentration of hs-cTnT is an independent predictor of adverse outcome, and a higher degree of abnormality in hs-cTnT value is associated with a greater risk of cardiovascular events.

Effect of left ventricular reverse remodeling on long-term prognosis after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and β blockers in patients with idiopathic dilated cardiomyopathy.

It remains unknown whether left ventricular (LV) reverse remodeling (LVRR) after therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and β blockers is correlated with prognosis in patients with idiopathic dilated cardiomyopathy. Forty-two patients with idiopathic dilated cardiomyopathy treated with the therapy were studied. Complete left ventricular reverse remodeling was defined as LV end-diastolic dimension ≤ 55 mm and fractional shortening ≥ 25% at the last echocardiographic assessment. The incidence of complete LVRR was significantly higher in patients who survived than in those who died or underwent heart transplantation. Patients were divided into 3 groups: death or transplantation, alive with complete LVRR, and alive without complete LVRR. Although patients who died or underwent transplantation did not show any LV improvements, those with complete LVRR showed significant improvements at 1 to 6 months after starting the therapy. Patients without complete LVRR also showed small but significant improvements at 1 to 6 months. The decrease in LV end-systolic dimension from the initial value to that at 1 to 6 months was an independent determinant of future cardiac death or transplantation. In conclusion, complete LVRR is related to favorable prognosis in patients with idiopathic dilated cardiomyopathy. The extent of left ventricular reverse remodeling at 1 to 6 months after starting the therapy is predictive of long-term prognosis.

Serum Cardiac Troponin I is Related to Increased Left Ventricular Wall Thickness, Left Ventricular Dysfunction, and Male Gender in Hypertrophic Cardiomyopathy

Serum cardiac troponin I (cTnI) is a sensitive and specific marker of myocardial injury. However, a systematic evaluation of cTnI in hypertrophic cardiomyopathy (HCM) patients has not been performed.

Influences of donepezil on cardiovascular system--possible therapeutic benefits for heart failure--donepezil cardiac test registry (DOCTER) study.

Abstract: To study prospectively influences of donepezil, an acetylcholinesterase inhibitor against Alzheimer disease, on cardiovascular system, we evaluated cardiovascular changes occurring during new initialized treatment with donepezil in 49 dementia patients over 6 months. No patient suffered from cardiovascular events. In clinical changes between baseline and the first evaluation after donepezil treatment, heart rate and plasma brain natriuretic peptide (BNP) levels as a marker for heart failure did not change (BNP: 59.62 ± 62.71 pg/mL at baseline to 53.18 ± 42.34 pg/mL at first evaluation; P = 0.262). We further examined plasma BNP levels in 2 groups into which the patients were divided at baseline according to the cut-off plasma BNP level of 60 pg/mL. In patients with high level of BNP, the BNP levels decreased after administration of donepezil (116.39 ± 76.58 pg/mL at baseline to 82.24 ± 46.64 pg/mL at first evaluation; P = 0.011) with the tendency to be reduced in the follow-up period. BNP did not change in patients with low level of BNP. Donepezil seemed to be safe in patients with dementia without symptomatic heart disease and significantly decreased plasma BNP levels in patients with subclinical chronic heart failure.

Gender-specific differences in the clinical features of hypertrophic cardiomyopathy in a community-based Japanese population: Results from Kochi RYOMA study

OBJECTIVES Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with a broad spectrum of clinical features. Although gender may be one of the important modifying factors in HCM, there has been little information on gender differences. METHODS We investigated gender-specific differences in the clinical features of HCM in a community-based Japanese population. We established cardiomyopathy registration in Kochi Prefecture named Kochi RYOMA study consisting of 9 hospitals as an unselected regional Japanese population. RESULTS 261 patients with diagnosis of HCM were registered. At registration, 88 patients (34%) were women. Female patients were more frequently diagnosed as having HCM at ≥65 years (41% versus 27%) and had a higher ratio of familial HCM (35% versus 19%). More female patients had diagnosis of HCM due to cardiac symptoms (64% versus 40%) and were symptomatic both at diagnosis and at registration. Although the prevalence of atrial fibrillation was not different between males and females, embolic events occurred less frequently in female patients at registration than in male patients (2% versus 10%). In female patients, there were more obstructive HCM patients and fewer patients with apical HCM. Left ventricular and left atrial diameters were smaller and fractional shortening was higher in females than in males. CONCLUSIONS The manifestations of HCM in unselected Japanese patients differed in men and women, which suggest that hormonal, social, and genetic factors may influence the clinical presentation of HCM.

Left Ventricular Reverse Remodeling in Long-Term (>12 Years) Survivors With Idiopathic Dilated Cardiomyopathy

Little is known about left ventricular (LV) reverse remodeling (LVRR) in long-term survivors with idiopathic dilated cardiomyopathy. We studied 59 patients with idiopathic dilated cardiomyopathy who had a potential clinical and echocardiographic follow-up period of >12 years. LVRR was defined as LV end-diastolic dimension ≤ 55 mm and fractional shortening ≥ 25% on the last echocardiogram. Of the 59 patients, 38 died (heart failure in 20, sudden death in 11, and other causes in 7), 2 underwent transplantation, and 19 survived. In the survivors, the LV size had significantly decreased and LV fractional shortening had significantly increased on the last echocardiogram. LVRR occurred in 37% of the survivors. The remaining 63% of the survivors still had LV dysfunction, but the LV end-systolic dimension had decreased significantly. In patients who died or underwent transplantation, the LV size significantly increased. No patient who died or underwent transplantation had LVRR. In conclusion, >60% of the long-term (>12 years) survivors with idiopathic dilated cardiomyopathy still had LV systolic dysfunction, but the LV end-systolic dimension had decreased significantly. In contrast, patients who died or underwent transplantation had significant LV enlargement. These results suggest that LVRR, even if it is not marked, is associated with a favorable prognosis.