Yukihito Sato

Biochemical markers of myocyte injury in heart failure

This review discusses the role of biochemical markers of myocyte injury in patients with chronic congestive heart failure. Heart specific assays have been developed for the measurement of cardiac troponin T (cTnT), cardiac troponin I (cTnI), heart type fatty acid binding protein (H-FABP), and myosin light chain 1 (MLC-1). Concentrations of these biochemical markers increase in the absence of ischaemic events in the subset of patients with heart failure whose long term outcomes are most adverse. The markers are easy to measure serially and it is therefore easy to follow patients without inter-observer variability. The serial clinical use of these markers, separately or in combination, will sharpen our understanding of the state of heart failure.

Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy

Objective To identify new prognostic indicators in idiopathic dilated cardiomyopathy (DCM) and secondary cardiomyopathy. Design and patients Serum concentrations of aminoterminal propeptides of type III procollagen and the 7S domain of type IV collagen (7S collagen)—which have recently been used as indicators of collagen matrix turnover in other diseases—and of cardiac troponin T were measured in 17 consecutive patients with DCM and in four patients with secondary cardiomyopathy (one associated with hyperthyroidism, two with chronic renal failure, one with amyloidosis), confirmed by endomyocardial biopsy. The correlation of these variables with short term prognosis was then assessed prospectively. Results 11 of the patients were positive for type III procollagen, 7S collagen, or troponin T even though their creatine kinase concentrations were within the normal range. These patients had a poor short term prognosis (p < 0.001). Conclusions Within the DCM and secondary cardiomyopathy groups, there was a subgroup of patients with raised concentrations of serum collagen and troponin T, for whom short term prognosis was poor. Although it is unclear whether these serum peptide levels reflect ongoing myocyte degeneration and interstitial fibrosis, they may serve as useful new prognostic indicators for cardiomyopathy.

Beneficial effects of amlodipine in a murine model of congestive heart failure induced by viral myocarditis. A possible mechanism through inhibition of nitric oxide production.

BACKGROUND Although calcium channel blockers have not been shown to be beneficial for the treatment of patients with heart failure, a recent clinical trial demonstrated a favorable effect of amlodipine on the survival of patients with heart failure resulting from nonischemic dilated cardiomyopathy. We investigated the effects of amlodipine on a murine model of congestive heart failure induced by the M variant of encephalomyocarditis virus (EMCV). METHODS AND RESULTS Four-week-old male DBA/2 mice were inoculated with EMCV and administered amlodipine, diltiazem, or vehicle PO for 2 weeks. The heart weight-to-body weight ratio and the histopathological grades of myocardial lesions were significantly lower and survival was significantly increased in the amlodipine-treated group (P < .01, P < .05, and P < .05, respectively) than in the control group. In vitro, amlodipine added to murine J774A.1 macrophages concomitant with EMCV inhibited nitrite formation in a concentration-dependent manner, but diltiazem did not. Furthermore, NG-monomethyl-L-arginine, an inhibitor of NO synthesis, decreased myocardial lesions significantly in this murine model. Immunohistochemistry revealed that the number of cells stained with antibody against an inducible NO synthase decreased significantly in the amlodipine-treated group compared with that in the control group (P < .01). CONCLUSIONS Amlodipine appears to have a protective effect against myocardial injury in this animal model of congestive heart failure. The therapeutic effect of amlodipine may be in part resulting from inhibition of overproduction of NO.

Epidemiologic and Clinical Characteristics of Cardiomyopathies in Japan

Nationwide clinico-epidemiological surveys of cardiomyopathies in Japan were carried out. Disorders surveyed included idiopathic dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular dysplasia (ARVD), mitochondrial disease, Fabrys disease of the heart and prolonged Q-T interval syndrome. The total number of patients was estimated at 17,700 for DCM, 21,900 for HCM, 300 for RCM, 520 for ARVD, 640 for mitochondrial disease, 150 for Fabrys disease of the heart, and 1,000 for prolonged Q-T interval syndrome. The prevalence of both DCM and HCM was higher in men than women: the male-to-female ratios were 2.6 and 2.3 for DCM and HCM, respectively. Detailed data on patients with DCM or HCM were collected by a follow-up survey. In 1 year more patients with DCM (5.6%) died than with HCM (2.8%): congestive heart failure (CHF) and arrhythmias were the leading causes of death for DCM and HCM, respectively. Angiotensin converting enzyme inhibitors (64.6%) and β-adrenergic blockers (40.9%) are commonly used to treat the CHF complicating DCM and may be associated with the clinical improvement in a significant number of DCM patients. Thus, the nationwide surveys of Japanese patients have yielded important current epidemiological and clinical information on the characteristics of cardiomyopathies in Japan. (Circ J 2002; 66: 323 - 336)

Measurements of baseline and follow-up concentrations of cardiac troponin-T and brain natriuretic peptide in patients with heart failure from various etiologies.

Since chronic heart failure (CHF) is a complex clinical syndrome, a single biomarker may not reflect all of its characteristics. In this study, the clinical significance of combination and serial measurement of biochemical markers of myocyte injury and myocardial load in patients with CHF from various etiologies was examined. Serum concentrations of cardiac troponin-T (cTnT) and plasma concentrations of brain natriuretic peptide (BNP) were measured simultaneously in 190 patients with CHF, including dilated cardiomyopathy (DCM) (n = 41), ischemic heart disease (n = 40), valvular or congenital disease (n = 53), hypertensive heart disease (n = 16), and hypertrophic cardiomyopathy (HCM) (n = 22). Serum cTnT concentrations ≥0.01 ng/ml were found in 46/190 patients (24%) at baseline (20% in DCM, 42% in ischemic heart disease, 21% in valvular or congenital disease, 43% in hypertensive heart disease, and 9% in HCM). Follow-up samples were obtained in 137 patients after a mean treatment period of 31.8 days. Although BNP decreased significantly in each disease category (P < 0.0001: DCM; P < 0.005: ischemic heart disease; P < 0.05: valvular or congenital disease; P < 0.005: hypertensive heart disease; P < 0.05: HCM), cTnT remained high in 36/137 patients (26%) (19% in DCM, 39% in ischemic heart disease, 25% in valvular or congenital disease, 38% in hypertensive heart disease, and 19% in HCM). The rate of adverse cardiac events was significantly higher in patients with high cTnT than in patients with low cTnT concentrations (P < 0.0001) (P < 0.05: DCM; P < 0.05: ischemic heart disease; P < 0.01: valvular or congenital disease). Multivariate analysis showed that both cTnT and BNP are independent prognostic factors, and patients with elevations of both cTnT and BNP had the poorest prognosis (P < 0.0001). In patients with CHF, the evolution and prognostic value of cTnT and BNP are different. The combined measurements of these markers should refine our understanding of the state and evolution of CHF.

Biochemical markers in heart failure

In industrialized countries, chronic heart failure (HF) is a major illness and cause of death. However, because of the paucity of specific clinical manifestations of HF, its early diagnosis and management might be challenging. Therefore, biochemical markers of HF are now being closely scrutinized. An ideal biochemical marker should be a prognostic indicator, should assist in the early diagnosis, reflect the therapeutic response, and help grading the risk associated with each stage of HF. This review summarizes our current understanding of biochemical markers of HF.

High-sensitivity cardiac troponin T in essential hypertension

BACKGROUND Myocyte injury might be involved in the progression of essential hypertension (EHT) toward heart failure (HF). However, in the absence of high-sensitivity (hs) assay, cardiac troponin T (TnT) in EHT has not been measurable. METHODS AND RESULTS We studied 236 consecutive ambulatory patients (mean age=65.5 years; 110 men) with treated EHT (mean systolic blood pressure=134.3 mmHg, mean serum N-terminal pro-B-type natriuretic peptide=86.6 pg/ml) for mean 65.6 months. Patients with a history of HF were excluded. Single and multiple variable analyses were performed in search of clinical correlates of elevated hs-TnT (≥0.003 ng/ml). Serum concentration of hs-TnT was ≥0.003 ng/ml (mean=0.008 ng/ml) in 184 patients. By single variable analysis, age, uric acid, log-transformed N-terminal pro-B-type natriuretic peptide, brachial-ankle pulse wave velocity, Cornell electrocardiographic (ECG) voltage, and number of antihypertensive medications were associated with log-transformed hs-TnT, while hemoglobin and estimated glomerular filtration rate (eGFR) were inversely correlated with log-transformed hs-TnT. By multivariate analysis, age, eGFR and Cornell voltage were independent correlates of log-transformed hs-TnT, even after adjustment for clinical backgrounds including known prognostic biomarkers of EHT. CONCLUSIONS hs-TnT was ≥0.003 ng/ml in 78% of patients presenting with treated EHT and independently correlated with age, renal function, and ECG voltage of hypertrophy.

Cardiac troponin and heart failure in the era of high-sensitivity assays

The Joint European Society of Cardiology-American College of Cardiology Foundation-American Heart Association-World Heart Federation Task Force for the Redefinition of Myocardial Infarction recommends cardiac troponin (cTn)-T as a first-line biomarker, and suggests the use of the 99th percentile of a reference population with acceptable precision (i.e. a coefficient of variance≤10%) as a cut-off for the diagnosis of acute myocardial infarction. Recently developed troponin assays fulfill this analytical precision. While conventional cTnT assays have often been used as a positive or negative categorical variable, stepwise rises in high sensitivity (Hs)-cTnT in patients presenting with chronic heart failure (HF) have been associated with a progressive increase in the incidence of cardiovascular events. Similar observations have been made in the general population. Hs-cTnT at baseline and during follow-up is a powerful predictor of cardiac events in patients with HF and in the general population. Whether it is the ideal biomarker remains to be confirmed, however. We review the potential contributions of TnT assays in the assessment of risk of HF, in HF, and in myocardial diseases that cause HF.

In patients with heart failure and non-ischemic heart disease, cardiac troponin T is a reliable predictor of long-term echocardiographic changes and adverse cardiac events

BACKGROUND The relationships between (1) serum concentration of cardiac troponin T (cTnT) and clinical hemodynamic profiles, (2) cTnT versus B-type natriuretic peptide (BNP) and long-term echocardiographic changes, and (3) cTnT versus BNP and echocardiographic changes, and rates of adverse cardiac events, have not been well elucidated. METHODS Retrospective analysis of 100 consecutive patients with heart failure, left ventricular ejection fraction < 50%, and non-ischemic heart disease was performed. RESULTS Baseline cTnT was > or = 0.01 ng/ml in 30 patients. By multiple variable logistic regression analysis, diabetes mellitus [DM; odds ratio (OR) 7.5; p=0.014], serum creatinine (OR 25.9; p=0.0157), and pulmonary capillary wedge pressure (PCWP; OR 1.12; p=0.0214) were independent predictors of baseline elevation of cTnT. At a follow-up of 40.6+/-20.6 months, echocardiograms and cTnT and BNP measurements were available in 93 patients, of whom 23 experienced an adverse cardiac event. By multiple variable analyses, elevated cTnT at follow-up was negatively correlated with echocardiographic improvements in cardiac function (OR 0.10; p=0.019), and was a significant predictor of adverse cardiac events after adjustment for covariables, including follow-up BNP and echocardiographic changes (hazard ratio 5.6; p=0.0046). CONCLUSIONS DM, serum creatinine, and PCWP were correlated with elevated baseline serum cTnT concentrations. cTnT concentration during follow-up might be a surrogate marker of heart failure.

Early Evolution and Correlates of Urine Albumin Excretion in Patients Presenting with Acutely Decompensated Heart Failure

Background—Urine albumin excretion is an important predictor of adverse cardiovascular events in various populations. Its correlation in patients with acute heart failure has not been described. Methods and Results—This prospective, observational study included 115 patients presenting with acute heart failure. The urine albumin/creatinine ratio (UACR) was measured from spot urine samples collected on days 1 and 7 of hospitalization. Median UACR decreased from 83 to 22 mg/gCr on days 1 and 7, respectively (P<0.0001). The proportion of patients with normoalbuminuria (UACR <30 mg/gCr) increased from 31% on day 1 to 60% on day 7, whereas the proportion with microalbuminuria (UACR between 30 and 299 mg/gCr) and macroalbuminuria (UACR ≥300 mg/gCr) decreased, respectively, from 42% and 27% on day 1 to 30% and 10% on day 7 (P<0.0001). These changes in UACR were correlated with changes in serum bilirubin and N-terminal pro b-type natriuretic peptide concentrations (correlation coefficients 1.087 and 0.384, respectively; 95% confidence interval, 0.394–1.781 and 0.087–0.680, respectively; and P=0.003 and 0.013, respectively), although they were not correlated with change in estimated glomerular filtration rate. Conclusions—In this sample of patients presenting with acute heart failure, urine albumin excretion was often increased at admission to the hospital and decreased significantly within 7 days of treatment. The decrease was correlated with serum N-terminal pro b-type natriuretic peptide and bilirubin concentrations, although neither with baseline nor with changes in indices of renal function.