Yuichi Baba

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.

Serum tenascin-C levels as a prognostic biomarker of heart failure events in patients with hypertrophic cardiomyopathy

BACKGROUND AND PURPOSE Although serum tenascin-C (TN-C) levels are related to left ventricular (LV) remodeling in patients with myocardial infarction and are useful as a prognostic biomarker of heart failure in patients with dilated cardiomyopathy, the clinical significance of TN-C levels has not yet been studied in patients with hypertrophic cardiomyopathy (HCM). Therefore, the purpose of this study is to elucidate whether serum TN-C levels are a prognostic biomarker for heart failure in patients with HCM. METHODS The relationship between serum TN-C levels and heart failure events was studied in 36 patients with HCM during follow-up. RESULTS Levels of serum TN-C were 28±13 ng/ml (range 11-80 ng/ml). Although patients with LV systolic impairment showed higher TN-C levels than those with preserved LV systolic function (33±11 ng/ml vs. 27±14 ng/ml; p=0.16), TN-C levels were not related to any echocardiographic parameters. During the follow-up period of 4.8±1.4 years, heart failure events were observed in six patients and TN-C levels in patients with events were higher than those in patients without events. Kaplan-Meier analysis showed that the prognosis was worse in patients with high TN-C levels (≥39.2 ng/ml) than in those with low TN-C levels. CONCLUSIONS Heart failure events were more frequently observed in patients with high serum TN-C levels than in those with low TN-C levels. Serum TN-C levels may be a new prognostic biomarker for heart failure in patients with HCM.

A novel cardiac myosin-binding protein C S297X mutation in hypertrophic cardiomyopathy

BACKGROUND Mutations in the cardiac myosin-binding protein C gene (MYBPC3) have been reported to be associated with delayed expression of hypertrophic cardiomyopathy (HCM) and a relatively good prognosis. PURPOSE The aim of this study was to evaluate clinical manifestations in patients with familial HCM caused by a novel nonsense mutation, S297X, in MYBPC3. METHODS We analyzed the sarcomere protein genes in 93 probands with HCM. RESULTS The nonsense mutation S297X in MYBPC3 was present in nine subjects from two unrelated families. Eight of those nine subjects with this mutation were found to be phenotype-positive and the remaining individual was not affected phenotypically. The age range at diagnosis was 9-75 years. There was no family history of sudden death in either family. At presentation, there were various left ventricular hypertrophy (LVH) patterns, including Maron type III hypertrophy from the LV base to apex, hypertrophy confined to the anterolateral wall at the basal LV wall. Two patients showed a significant LV outflow tract gradient and one patient showed intra-right-ventricular obstruction. During follow-up, one patient was repeatedly hospitalized for the treatment of heart failure after development of paroxysmal atrial fibrillation at the age of 86 years and the remaining eight subjects were in relatively stable condition and did not require hospitalization for the treatment of HCM-related events. CONCLUSION The novel mutation S297X in MYBPC3 causes HCM in a broad range of ages and heterogeneous clinical manifestations, though the clinical course in patients with this mutation seems to be benign.

Plasma metalloproteinase levels and left ventricular remodeling in hypertrophic cardiomyopathy in patients with an identical mutation

BACKGROUND AND PURPOSE Although it has been reported that matrix metalloproteinases (MMPs) are associated with left ventricular (LV) remodeling in patients with hypertrophic cardiomyopathy (HCM), the impact of plasma MMP levels in patients with HCM is somewhat vague. METHODS AND SUBJECTS Plasma levels of MMP-2, MMP-9, and clinical/echocardiographic findings were evaluated in 16 HCM patients with preserved LV ejection fraction (defined as LV ejection fraction more than 50%) caused by an identical frameshift mutation (S593fs: a one-base deletion of a thymidine at nucleotide 11,645) in the cardiac myosin-binding protein C gene. RESULTS MMP-2 levels were inversely related to LV ejection fraction (r(2)=-37, p=0.01). MMP-9 levels were inversely related to LV end-diastolic dimension (r(2)=-0.24, p=0.06) and positively related to the maximum LV wall thickness (r(2)=0.25, p=0.04). During follow-up period of 4.1 ± 1.2 years, LV ejection fraction decreased from 68.5 ± 7.4% to 64.9 ± 9% (p=0.03). Among clinical, echocardiographic findings at baseline and levels of biomarkers, high MMP-9 levels were only related to the decrease of LV ejection fraction from baseline to follow-up (r(2)=0.39, p=0.009). CONCLUSIONS MMP-2 levels are related to reduced LV systolic function in HCM patients with preserved LV ejection fraction caused by an identical cardiac myosin-binding protein C gene abnormality. On the other hand, MMP-9 levels are associated with small LV size and the degree of LV hypertrophy and related to the deterioration in LV systolic function during follow-up. These results suggest that MMPs are important in the process of LV remodeling in HCM.

Prevalence and clinical features of Fabry disease in Japanese male patients with diagnosis of hypertrophic cardiomyopathy.

BACKGROUND The prevalence of Fabry disease (FD) in Japanese patients presenting with unexplained left ventricular hypertrophy (LVH) has remained unclear. METHODS We measured plasma α-galactosidase A activity in 177 men with a diagnosis of hypertrophic cardiomyopathy (HCM) (maximum LV wall thickness ≥15mm). RESULTS Two patients (1.1%) showed very low α-galactosidase A activity [0.0 and 0.3nmol/hr/ml (normal range: 3.6-17.6nmol/hr/ml)], and a clinical diagnosis of cardiac variant of FD was finally made. One patient was a 55-year-old man who came to our hospital because of abnormal results of electrocardiography and showed concentric LVH in echocardiography. A missense mutation, R112L, was identified. The other was a 74-year-old man who had been diagnosed with HCM at the age of 60 years in another hospital and was referred for evaluation of repeated hospitalization for heart failure. Although echocardiography revealed asymmetric septal hypertrophy (ASH) with interventricular septal wall thickness of 16mm and posterior wall thickness of 11mm and reduced LV ejection fraction with hypokinetic posterior wall motion, his echocardiographic findings at the initial diagnosis of HCM were not ASH but concentric LVH with normal LV systolic function. A splicing mutation, IVS4+919G>A, was identified. CONCLUSIONS The prevalence of FD in Japanese male patients with a clinical diagnosis of HCM was found to be 1.1%. These patients showed late onset and concentric LVH at initial presentation.

Gender differences in the clinical features of hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations

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.

Erythrocyte creatine as a marker of intravascular hemolysis due to left ventricular outflow tract obstruction in hypertrophic cardiomyopathy

BACKGROUND Erythrocyte creatine, a marker of erythrocyte age that increases with shortening of erythrocyte survival, has been reported to be a quantitative and reliable marker for intravascular hemolysis. We hypothesized that hemolysis could also occur due to intraventricular obstruction in patients with hypertrophic cardiomyopathy (HCM). The purpose of this study was to examine the presence of subclinical hemolysis and the relation between intravascular hemolysis and intraventricular pressure gradient (IVPG). METHODS AND RESULTS We measured erythrocyte creatine in 92 HCM patients. Twelve patients had left ventricular outflow tract obstruction (LVOTO), 4 had midventricular obstruction (MVO), and the remaining 76 were non-obstructive. Erythrocyte creatine levels ranged from 0.92 to 4.36μmol/g hemoglobin. Higher levels of erythrocyte creatine were associated with higher IVPG (r=0.437, p<0.001). If erythrocyte creatine levels are high (≥1.8μmol/g hemoglobin), subclinical hemolysis is considered to be present. Half of LVOTO patients and no MVO patients showed high erythrocyte creatine levels. Although non-obstructive patients did not show significant intraventricular obstruction at rest, some showed high erythrocyte creatine levels. When LVOT-PG was measured during the strain phase of the Valsalva maneuver in 20 non-obstructive patients, 7 of those 20 patients showed LVOTO. In the 20 patients, there was no relation between erythrocyte creatine levels and LVOT-PG before the Valsalva maneuver (r=0.125, p=0.600), whereas there was a significant correlation between erythrocyte creatine and LVOT-PG provoked by the Valsalva maneuver (r=0.695, p=0.001). CONCLUSIONS There is biochemical evidence of subclinical hemolysis in patients with HCM, and this hemolysis seems to be associated with LVOTO provoked by daily physical activities.

Clinical Significance of High-Sensitivity Cardiac Troponin T in Patients With Dilated Cardiomyopathy

Although conventional cardiac troponin T (cTnT) and I (cTnI) markers have been reported to predict adverse outcome in dilated cardiomyopathy (DCM), the usefulness of a new-generation high-sensitivity assay of cardiac troponin T (hs-cTnT) compared with these conventional biomarkers is unclear.We performed clinical evaluation including measurements of troponin markers in 54 patients with DCM under a clinically stable condition. At baseline, the serum concentration of hs-cTnT was 0.014 ± 0.016 ng/mL and 17 (31%) of the patients showed abnormal hs-cTnT values (> 0.014 ng/mL). During a mean follow-up period of 5.1 ± 1.6 years, there were 16 cardiac events: heart failure death in 6 patients, sudden cardiac death in 2 patients, and hospitalization for heart failure in 8 patients. Patients with abnormal hs-cTnT or abnormal cTnT (> 0.01 ng/mL) values had significantly more frequent cardiac events than did those with normal hs-cTnT or cTnT values. On the other hand, abnormal cTnI (> 0.03 ng/mL) value did not reach statistical significance for these adverse events. Multivariate analysis showed that only an abnormal hs-cTnT value was an independent predictor of all cardiac events (HR: 5.68, P = 0.003). When the patients were divided into 4 groups according to the degree of hs-cTnT levels, the clinical course was significantly worse in patients with higher hs-cTnT values.These results suggest that the serum concentration of hs-cTnT provides better risk stratification in DCM patients.

Prognostic Significance of Non-Dilated Left Ventricular Size and Mitral Regurgitation in Patients With Dilated Phase of Hypertrophic Cardiomyopathy

Although a subtype of hypertrophic cardiomyopathy (HCM), dilated phase of HCM (D-HCM) characterized by left ventricular (LV) systolic dysfunction, has been reported to have a poor prognosis, some patients with D-HCM survive for a relatively long period. The degree of LV dilatation and functional mitral regurgitation (MR) are generally thought to be important predictors of poor prognosis in patients with LV systolic dysfunction. However, there is little information available on the relations among LV size, presence of significant MR, and prognosis in D-HCM patients.We retrospectively studied 31 patients with D-HCM to determine whether echocardiographic assessment of LV size and MR provides incremental prognostic information.During a follow-up period of 5.6 ± 4.2 years, there were 13 cardiovascular deaths. When the patients were divided into two groups by LV size at diagnosis of D-HCM, a non-dilated LV group (LV end-diastolic diameter (LVEDD) < 50 mm, n = 9) and a dilated LV group (LVEDD ≥ 50 mm, n = 22), the clinical course in the non-dilated LV group was significantly worse. As for the clinical impact of MR, no patient in the non-dilated LV group showed significant MR and 7 of the patients with dilated LV size showed significant MR during follow-up. Once significant MR was reached, cardiovascular deaths were significantly more frequent in patients with MR.Patients with D-HCM, particularly those with less LV dilatation at diagnosis of dilated phase and with significant MR during follow-up, have a poor prognosis.

Giant Left Atrial Myxoma in a Nonagenarian

To the Editor: An independent 90-year-old man presented with progressive shortness of breath. A left atrial mass had been accidentally found on chest computed tomography at another hospital 2 years earlier. He had declined further investigation and treatment for the mass. He had been asymptomatic until 3 months earlier. He had undergone a unilateral nephrectomy for renal cell carcinoma 17 years before and had been free of recurrence after surgery. His family history was unremarkable. On physical examination, his pulse rate was 63 beats per minute, and blood pressure was 132/62 mmHg. He had bilateral leg edema and a distended jugular vein. An accentuated first heart sound without tumor plop or diastolic murmur was heard. Breath sounds were diminished. Electrocardiogram was unremarkable. Chest X-ray showed bilateral pleural effusion. Transthoracic and transesophageal echocardiography revealed a mobile and pedunculated mass in the left atrium attached to the interatrial septum (Figure 1A). The mass prolapsed into the left ventricle across the mitral valve, resulting in mitral valve obstruction and pulmonary hypertension. Tricuspid regurgitation was mild, with a pressure gradient of 53 mmHg. The inferior vena cava was 18 mm in diameter, with low respiratory change. The mitral valve appeared structurally normal, and mitral regurgitation was trivial. The left ventricle was normal in size and function. He was open to the prospect of surgical removal of the mass and accepted after obtaining the details of the surgery and discussing matters with us and his family. He underwent surgical resection of the mass (Figure 1B). Histologic examination confirmed a diagnosis of myxoma. Postoperatively, pressure gradient calculated from tricuspid regurgitation decreased to 27 mmHg. He recovered without major complication and was discharged. Figure 1 (A) Transesophageal echocardiogram showing an atrial mass prolapsing into the left ventricle. (B) The excised myxoma (3.5 × 4.5 × 7 cm).