Yohei Tanada

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.

Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats.

AIMS Heart failure (HF) is associated with changes in energy metabolism of the heart, as well as in extra-cardiac organs such as the skeletal muscles. Cardiac cachexia is a common complication and is associated with poor prognosis. Branched-chain amino acids (BCAAs) reportedly improve sarcopenia and cancer cachexia. We tested the hypothesis that BCAA ameliorates HF with cardiac cachexia. MAIN METHODS We used Dahl salt-sensitive (DS) rats fed a high-salt diet as a model of HF. DS rats fed a low-salt diet were used as a control. BCAA were administered in drinking water from 11weeks of age, when cardiac hypertrophy was established but the cardiac function was preserved. Survival and the cardiac function were monitored, and animals were sacrificed at 21weeks of age and analyzed. KEY FINDINGS In HF rats, BCAA treatment decreased the heart rate, preserved the cardiac function, and prolonged survival. BCAA also prevented body weight loss, associated with preservation of the skeletal muscle weight. Moreover, gene expression related to mitochondrial biogenesis and function was increased with BCAA in skeletal muscles. SIGNIFICANCE BCAA preserved the body weight and cardiac function and prolonged survival in HF rats. The expression of genes involved in mitochondrial biogenesis and function in skeletal muscles was increased by BCAA.

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.

Persistent Overexpression of Phosphoglycerate Mutase, a Glycolytic Enzyme, Modifies Energy Metabolism and Reduces Stress Resistance of Heart in Mice

Background Heart failure is associated with changes in cardiac energy metabolism. Glucose metabolism in particular is thought to be important in the pathogenesis of heart failure. We examined the effects of persistent overexpression of phosphoglycerate mutase 2 (Pgam2), a glycolytic enzyme, on cardiac energy metabolism and function. Methods and Results Transgenic mice constitutively overexpressing Pgam2 in a heart-specific manner were generated, and cardiac energy metabolism and function were analyzed. Cardiac function at rest was normal. The uptake of analogs of glucose or fatty acids and the phosphocreatine/βATP ratio at rest were normal. A comprehensive metabolomic analysis revealed an increase in the levels of a few metabolites immediately upstream and downstream of Pgam2 in the glycolytic pathway, whereas the levels of metabolites in the initial few steps of glycolysis and lactate remained unchanged. The levels of metabolites in the tricarboxylic acid (TCA) cycle were altered. The capacity for respiration by isolated mitochondria in vitro was decreased, and that for the generation of reactive oxygen species (ROS) in vitro was increased. Impaired cardiac function was observed in response to dobutamine. Mice developed systolic dysfunction upon pressure overload. Conclusions Constitutive overexpression of Pgam2 modified energy metabolism and reduced stress resistance of heart in mice.

Measurement of Technetium-99m Sestamibi Signals in Rats Administered a Mitochondrial Uncoupler and in a Rat Model of Heart Failure

Background Many methods have been used to assess mitochondrial function. Technetium-99m sestamibi (99mTc-MIBI), a lipophilic cation, is rapidly incorporated into myocardial cells by diffusion and mainly localizes to the mitochondria. The purpose of this study was to investigate whether measurement of 99mTc-MIBI signals in animal models could be used as a tool to quantify mitochondrial membrane potential at the organ level. Methods and Results We analyzed 99mTc-MIBI signals in Sprague-Dawley (SD) rat hearts perfused with carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler known to reduce the mitochondrial membrane potential. 99mTc-MIBI signals could be used to detect changes in the mitochondrial membrane potential with sensitivity comparable to that obtained by two-photon laser microscopy with the cationic probe tetramethylrhodamine ethyl ester (TMRE). We also measured 99mTc-MIBI signals in the hearts of SD rats administered CCCP (4 mg/kg intraperitoneally) or vehicle. 99mTc-MIBI signals decreased in rat hearts administered CCCP, and the ATP content, as measured by 31P magnetic resonance spectroscopy, decreased simultaneously. Next, we administered 99mTc-MIBI to Dahl salt-sensitive rats fed a high-salt diet, which leads to hypertension and heart failure. The 99mTc-MIBI signal per heart tissue weight was inversely correlated with heart weight, cardiac function, and the expression of atrial natriuretic factor, a marker of heart failure, and positively correlated with the accumulation of labeled fatty acid analog. The 99mTc-MIBI signal per liver tissue weight was lower than that per heart tissue weight. Conclusion Measurement of 99mTc-MIBI signals can be an effective tool for semiquantitative investigation of cardiac mitochondrial membrane potential in the SD rat model by using a chemical to decrease the mitochondrial membrane potential. The 99mTc-MIBI signal per heart tissue weight was inversely correlated with the severity of heart failure in the Dahl rat model.

Left ventricular end-diastolic pressure and ejection fraction correlate independently with high-sensitivity cardiac troponin-T concentrations in stable heart failure.

BACKGROUND Cardiac troponin is widely accepted as a biomarker of myocyte injury in patients with myocardial ischemia. Patients with congestive heart failure are also associated with elevated cardiac troponin and it is a very sensitive prognostic marker. However, the mechanisms of troponin elevation in patients with heart failure are not fully understood. Decompensated state itself is suggested as a factor contributing to elevated cardiac troponin-T. However comparison between invasive hemodynamic parameters and cardiac troponin-T is insufficient. METHODS Data were collected from 167 patients in stable, chronic HF, without acute coronary syndrome, recent revascularization, mitral stenoses, hemodialysis, or clinically significant right HF. We evaluated the correlations and 95% confidence intervals (CI) between invasive hemodynamic measurements and serum high-sensitivity (hs) concentrations of cTnT. RESULTS The serum cTnT concentration was equal to or more than the detection threshold (0.003ng/ml) in all patients. The serum cTnT concentration was equal to or more than the cut-off value of 0.014ng/ml in 46% of patients. By multiple variable analysis, left ventricular (LV) end-diastolic pressure (EDP; adjusted coefficient=0.014; 95% CI 0.0003-0.029; P=0.046) was positively correlated, while hemoglobin (adjusted coefficient=-0.079; 95% CI -0.140 to -0.018; P=0.012), estimated glomerular filtration rate (adjusted coefficient=-0.008; 95% CI -0.013 to -0.003; P=0.004), and LV ejection fraction (EF; adjusted coefficient=-0.011; 95% CI -0.018 to -0.003; P=0.004) were negatively correlated with hs-cTnT concentrations. CONCLUSION In patients with stable chronic HF, LVEDP and LVEF correlate with the serum concentrations of hs-cTnT, independently of other correlates of elevated plasma concentrations of hs-cTnT.

Serial measurements of high sensitive cardiac troponin I in patients with acutely decompensated heart failure treated with carperitide or nitrates.

BACKGROUND In patients with acutely decompensated heart failure (ADHF), elevated serum concentration of cardiac troponin is an independent predictor of adverse cardiac events. In ADHF with a preserved systolic blood pressure, treatment with intravenous vasodilator is recommended. However, the effect of vasodilators on troponin concentrations has not been elucidated well. METHODS AND RESULTS Serial high sensitive cardiac troponin I (hs-TnI) was measured in 36 patients presenting with ADHF and preserved systolic blood pressure, of whom 20 were treated with atrial natriuretic peptide (ANP) and 16 with nitrates. The concentrations of hs-TnI ranged from 0.069+/-0.114ng/ml at baseline to 0.076+/-0.121ng/ml at 5h, 0.062+/-0.106ng/ml at 1 day, and 0.056+/-0.089ng/ml at day 7 (n=36,ns). The relative change in hs-TnI between baseline and at 5h, day 1 and day 7 were 1.13+/-0.43, 0.95+/-0.44 and 0.93+/-0.64 in patients treated with ANP, and 1.02+/-0.19, 0.95+/-0.31 and 1.19+/-1.38 in patients treated with nitrates (ns; ANP versus nitrates). On day 7, a hs-TnI change, >20% decrease from baseline, was observed in 55% patients with ANP versus 56% patients with nitrates (ns). The cardiac event rates were similar in both groups. CONCLUSIONS In ADHF patients with preserved systolic blood pressure, the administration of intravenous vasodilators did not decrease hs-TnI over the first 7 days. Treatments with ANP and nitrates were associated with similar short-term decreases in hs-TnI and long-term adverse cardiac events.

The metabolic profile of a rat model of chronic kidney disease

Background The kidney is always subjected to high metabolic demand. The aim of this study was to characterize metabolic profiles of a rat model of chronic kidney disease (CKD) with cardiorenal syndrome (CRS) induced by prolonged hypertension. Methods We used inbred male Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from six weeks of age (high-salt; HS group) or a 0.3% NaCl diet as controls (low-salt; LS group). We analyzed function, pathology, metabolome, and the gene expression related to energy metabolism of the kidney. Results DS rats with a high-salt diet showed hypertension at 11 weeks of age and elevated serum levels of creatinine and blood urea nitrogen with heart failure at 21 weeks of age. The fibrotic area in the kidneys increased at 21 weeks of age. In addition, gene expression related to mitochondrial function was largely decreased. The levels of citrate and isocitrate increased and the gene expression of alpha-ketoglutaratedehydrogenase and succinyl-CoA synthetase decreased; these are enzymes that metabolize citrate and isocitrate, respectively. In addition, the levels of succinate and acetyl Co-A, both of which are metabolites of the tricarboxylic acid (TCA) cycle, decreased. Conclusions DS rats fed a high-salt diet were deemed a suitable model of CKD with CRS. Gene expression and metabolites related to energy metabolism and mitochondria in the kidney significantly changed in DS rats with hypertension in accordance with the progression of renal injury.

Prognostic significance of changes in cystatin C during treatment of acute cardiac decompensation

BACKGROUND The long-term prognostic significance of in-hospital worsening renal function (WRF) during treatment of acute cardiac decompensation (ACD) remains controversial. METHODS We analyzed data from 100 patients (mean age=75 years; 53% men) presenting with ACD, in whom the serum cystatin C (Cys-C) concentration was measured upon admission to the hospital and 4 days later. We examined the relationship between changes in Cys-C and primary study endpoint of risk of death and re-hospitalization for management of ACD, up to 180 days, searched for predictors by multiple variable analysis and calculated the hazard ratios (HR) and 95% confidence intervals (CI). RESULTS A median (25th to 75th percentile) increase in Cys-C from 1.29 (0.88-1.66)mg/l on day 1 to 1.31 (1.00-1.84)mg/l on day 4, observed in 66% of all patients, was associated with a significant decrease (p=0.040) in the 180-day incidence of primary study endpoint. By multiple variable regression analysis, an increase in Cys-C was an independent predictor of death and re-hospitalization for management of ACD (HR 0.415; 95% CI 0.193-0.885; p=0.023). CONCLUSIONS An increase in serum Cys-C concentration after hospitalization for management of ACD was associated with a decreased, long-term incidence of primary study endpoint.

Cardiac effects of acute administration of a protonophore in a rat model

Excessive use of uncoupling agents, previously used as weight loss agents, has led to the increase in body temperature and death. The aim of the present study was to evaluate the acute cardiac effects of mitochondrial protonophore in a rat model at a high dose, and its specific influence on cardiac substrate uptake.