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Biomedical subjects

Takayoshi Tsutamoto

Publications and source records attributed to Takayoshi Tsutamoto.

At least 19 recordsLinked to original sources
PubMed2006

Relationship between renal function and plasma brain natriuretic peptide in patients with heart failure.

OBJECTIVES: This study sought to evaluate the relationship between brain natriuretic peptide (BNP), renal function, and the severity of congestive heart failure (CHF). BACKGROUND: Both BNP and renal function are prognostic predictors in CHF patients. METHODS: We measured the plasma BNP level in the aortic root and coronary sinus in 366 consecutive patients with CHF. Estimated glomerular filtration rate (eGFR) by the Cockcroft-Gault equation was used as an indicator of renal function. RESULTS: By stepwise multivariate analyses, hemodynamic parameters such as left ventricular ejection fraction (LVEF) and left ventricular end-diastolic pressure (LVEDP) but not eGFR were independent predictors of a transcardiac increase (coronary sinus-aortic root) in BNP. Regarding the plasma level of BNP in the aortic root, not only LVEF (p < 0.0001) and LVEDP (p < 0.0001) but also eGFR (p < 0.0001) were independent predictors. Patients were divided into two groups, patients with an eGFR > or =60 ml/min (group 1, n = 229) and patients with an eGFR <60 ml/min (group 2, n = 137). There was no difference in LVEF, LVEDP, or the transcardiac gradient of BNP between the two groups, but the plasma level of BNP in the aortic root was approximately two-fold greater in group 2 than in the group 1. CONCLUSIONS: These findings suggest that decreased clearance from the kidney contributes to the elevated BNP in CHF patients with renal dysfunction, especially in patients with an eGFR <60 ml/min.

Aged↗
PubMed2006

Proteomic analysis reveals significant alternations of cardiac small heat shock protein expression in congestive heart failure.

BACKGROUND: Because congestive heart failure (CHF) is a complex syndrome with many different underlying mechanisms of worsening of heart function, it is important to recognize the global alternations in protein expression associated with the processes of CHF. METHODS AND RESULTS: The purpose of our study was to use a proteomic approach to investigate global alternations in protein expression in tachycardia induced CHF dogs. We compared the 2-dimensional electrophoresis protein patterns of left ventricular samples from the normal with those from failing myocardium. Differentially expressed cardiac proteins showed approximately 500 cardiac protein spots. A total of 20 spots (14 increased, 6 decreased) was altered in CHF, whereas the more distinguishably increased spots in CHF were identified by using mass spectrometry as alpha B crystallin, heat shock protein (HSP) 27, and HSP20, which maintain both the morphologic and functional integrity of the cardiomyocytes and increase tolerance against various types of stress. Because phosphorylation is one of the most important posttranslational modifications, we evaluated whether or not the overexpressed small HSPs were phosphorylated in CHF. Phosphoprotein staining and Western blotting demonstrated that the phosphorylation of alpha B crystallin at serine (Ser)-59 site and of HSP27 at both Ser-78 and Ser-82 sites increased in CHF. CONCLUSION: Proteomics studies can provide new insights into molecular mechanisms in CHF and phosphorylated small HSPs may be involved in preventing cardiac dysfunction.

Animals↗
PubMed2006

Serum level of uric acid, partly secreted from the failing heart, is a prognostic marker in patients with congestive heart failure.

BACKGROUND: A recent study suggested that xanthine oxidase is activated in congestive heart failure (CHF). However, whether uric acid (UA) is secreted from the failing heart remains unknown, so it is currently unclear whether serum UA can provide prognostic information independent of brain natriuretic peptide (BNP). METHODS AND RESULTS: Serum UA was measured in the aortic root (AO) and the coronary sinus (CS) of 74 patients with CHF. The serum UA level was significantly higher in the CS than in the AO. The transcardiac gradient of UA (CS-AO) increased with the severity of CHF, inversely correlated with left ventricular ejection fraction (LVEF) and positively correlated with left ventricular end-diastolic volume index. The plasma levels of norepinephrine, BNP, UA, and LVEF were monitored prospectively in 150 CHF patients for a mean follow-up of 3 years. High plasma levels of UA (p<0.001) and BNP (p<0.001) were shown by multivariate stepwise analysis to be independent predictors of mortality. CONCLUSIONS: High plasma UA level, partly secreted from the failing heart, is a prognostic predictor independent of BNP in patients with CHF. Monitoring a combination of BNP and UA may be useful for the management of patients with CHF.

Aged↗
PubMed2006

Prediction of mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in patients with dilated cardiomyopathy.

BACKGROUND: The prognostic role of serum C-reactive protein (CRP) in chronic heart failure (CHF) patients, especially those with nonischemic dilated cardiomyopathy (DCM), remains unknown. In the present study, whether CRP provides prognostic information in DCM patients was evaluated. METHODS AND RESULTS: Neurohumoral factors and hemodynamics in 84 consecutive DCM patients were measured and these patients were followed up for a mean period of 42 months. During the follow-up period, 23 patients developed cardiac events and 18 patients died of cardiac causes. Using stepwise multivariate Cox proportional hazards regression analyses, log brain natriuretic peptide (BNP) (p = 0.007) and high-sensitivity CRP (hsCRP) > 1 mg/L (p = 0.008) were significant independent predictors of cardiac events. The patients were stratified into 4 groups based on the normal serum concentration of hsCRP (1 mg/L) and median plasma concentration of BNP (110 pg/ml). Survival rates were significantly higher in patients with hsCRP < 1 mg/L and BNP < 110 pg/ml. The hazard ratio of patients with BNP > 110 pg/ml and hsCRP > 1 mg/L was 15.8 (95% confidence interval, 1.9-127.2) compared with those with BNP < 110 pg/ml and hsCRP < 1 mg/L for cardiac death. CONCLUSIONS: Serum hsCRP level is an independent prognostic predictor in patients with DCM and the combination of hsCRP and BNP may be useful for the management of CHF patients with DCM.

C-Reactive Protein↗
PubMed2005

Inhibition of aldosterone and endothelin-1 by carperitide was attenuated with more than 1 week of infusion in patients with congestive heart failure.

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.

Aldosterone↗
PubMed2005

Myocardial creatine concentration in various nonischemic heart diseases assessed by 1H magnetic resonance spectroscopy.

BACKGROUND: Previous (31)P magnetic resonance spectroscopy (MRS) studies demonstrated that the myocardial phosphocreatine-to-ATP ratio offered important information concerning the degree of dysfunction and prognosis in patients with cardiomyopathy. In the present study, we investigated total creatine (CR) levels in various diseased hearts using 1H MRS. METHODS AND RESULTS: Fourteen patients with the following conditions were examined: cardiac amyloidosis (n = 2); hypertensive heart disease (4); valvular disease (2); hypertrophic cardiomyopathy (2); dilated cardiomyopathy (2); restrictive cardiomyopathy (1); and post-operative atrial septal defect (1). Myocardial CR was measured using 1H MRS with point-resolved spectroscopy localization. Overall, myocardial CR levels in diseased hearts were significantly lower than those in the control group [16.5+/-6.0 (n = 14) vs 27.1+/-3.2 micromol/g (n = 10), p < 0.001]. There was a positive correlation between myocardial CR and left ventricular ejection fraction (42.9+/-13.8%, range 19.5-69.1%) despite the different mechanisms of cardiac dysfunction (r = 0.60, p < 0.05). Myocardial CR levels in patients who were hospitalized due to heart failure within 1 year were significantly lower than those in other patients [11.3+/-1.0 (n = 4) vs 18.6+/-5.9 micromol/g (n = 10), p < 0.05]. CONCLUSIONS: Noninvasive measurement of myocardial CR using 1H MRS may be valuable in the assessment of disease severity and prediction of clinical course in various forms of heart disease.

Adult↗
PubMed2004

Transcardiac increase in tumor necrosis factor-alpha and left ventricular end-diastolic volume in patients with dilated cardiomyopathy.

BACKGROUND: It remains unclear whether tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) are secreted from the failing heart and whether there is a relationship between the transcardiac gradients of these cytokines and left ventricular (LV) remodeling. AIMS: This study evaluated the relationship between transcardiac gradients of cytokines and LV volume and function in congestive heart failure patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: We measured the plasma levels of TNF-alpha and IL-6 in the aortic root (Ao) and the coronary sinus (CS) in 60 patients with DCM. There was no difference in plasma IL-6 between the Ao and the CS. However, the plasma TNF-alpha level was significantly higher in the CS than that in the Ao. There was a significant correlation between the transcardiac gradient of plasma TNF-alpha and the LV end-diastolic volume index (LVEDVI) and LV ejection fraction. According to stepwise multivariate analyses, the transcardiac increase of TNF-alpha showed an independent and significantly positive relationship with a large LVEDVI. CONCLUSIONS: These results indicate that the elevated plasma TNF-alpha is partly derived from the failing heart in patients with DCM and that TNF-alpha plays a potential role in structural LV remodeling in patients with DCM.

Adult↗
PubMed2004

Long-term treatment with a phosphodiesterase type 5 inhibitor improves pulmonary hypertension secondary to heart failure through enhancing the natriuretic peptides-cGMP pathway.

In advanced heart failure (HF), the compensatory pulmonary vasodilation is attenuated due to the relative insufficiency of cGMP despite increased secretion of natriuretic peptides (NPs). Phosphodiesterase type 5 (PDE5) inhibitors prevent cGMP degradation, and thus may potentiate the effect of the NPs-cGMP pathway. We orally administered a specific PDE5 inhibitor, T-1032 (1 mg/kg; twice a day, n = 7) or placebo (n = 7) for 2 weeks in dogs with HF induced by rapid pacing (270 bpm, 3 weeks) and examined the plasma levels of atrial natriuretic peptide (ANP), cGMP, and hemodynamic parameters. We also examined the hemodynamic changes after injection of a specific NPs receptor antagonist, HS-142-1 (3 mg/kg), under treatment with T-1032. T-1032 significantly increased plasma cGMP levels compared with the vehicle group despite low plasma ANP levels associated with improvement in cardiopulmonary hemodynamics. HS-142-1 significantly decreased plasma cGMP levels in both groups, whereas it did not change all hemodynamic parameters in the vehicle group. In contrast, in the T-1032 group, HS-142-1 significantly increased pulmonary arterial pressure and pulmonary vascular resistance. These results indicated that long-term treatment with a PDE5 inhibitor improved pulmonary hypertension secondary to HF and the NPs-cGMP pathway contributed to this therapeutic effect.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Endogenous bradykinin suppresses myocardial fibrosis through the cardiac-generated endothelin system under chronic angiotensin-converting enzyme inhibition in heart failure.

In congestive heart failure, angiotensin-converting enzyme inhibitors (ACEIs) may prevent cardiac fibrosis via interaction with both angiotensin II and endothelin-1, which enhance myocardial collagen synthesis. However, whether endogenous bradykinin with an ACEI modifies the cardiac collagen architecture, affecting the endothelin system, has not yet been fully elucidated. We evaluated the changes in circulating hormonal factors, myocardial fibrosis and cardiac gene expression closely linked with heart failure, using an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg/day, n = 6), with an ACEI, enalapril (1 mg/kg/day), in dogs with tachycardia-induced congestive heart failure (270 p.p.m., 22 days) and compared the effects with enalapril alone (n = 6). Although there were no differences observed in blood pressure, plasma renin activity, aldosterone and endothelin-1 levels, combined FR173657 significantly increased the cardiac expression of preproendothelin- 1 mRNA (P < 0.05) and collagen type I and type III mRNA (P < 0.05), and cardiac collagen deposits (P < 0.05), and decreased eNOS gene expression (P < 0.05) in the left ventricle compared with the ACEI-treated group. Furthermore, there was a significant negative correlation between the expression of preproendothelin- 1 and eNOS mRNA levels (r = -0.708, P < 0.001). In conclusion, bradykinin may prevent cardiac fibrosis in part via suppression of the local endothelin system in the failing heart through the enhancement of nitric oxide production under chronic angiotensin-converting enzyme inhibition.

Aldosterone↗
PubMed2004

Contribution of vascular NAD(P)H oxidase to endothelial dysfunction in heart failure and the therapeutic effects of HMG-CoA reductase inhibitor.

BACKGROUND: The vascular NAD(P)H oxidase-derived superoxide anion (O(2)-) plays a crucial role in the pathological progression of hypertension and atherosclerosis, and HMG-CoA reductase inhibitors (statins) have vascular antioxidant effects. However, it is unclear whether the vascular NAD(P)H oxidase is involved in the endothelial dysfunction of congestive heart failure (CHF) and whether HMG-CoA reductase inhibitors (statins) exert their vasoprotective effects in CHF. The present study examined both the involvement of vascular NAD(P)H oxidase in endothelial dysfunction in dogs with tachycardia-induced CHF and the therapeutic effect of a statin (pitavastatin). METHODS AND RESULTS: Femoral blood flow (FBF) responses to acetylcholine was significantly impaired in the CHF group, but were improved by pitavastatin. Vascular O(2)- production, NAD(P)H oxidase activity and Nox4 and p47phox expression were significantly elevated in CHF compared with the normal group. The elevated O(2)-production in the CHF group was suppressed by the NAD(P)H oxidase inhibitor, apocynin, to the normal level. In contrast, neither the gene expression nor the activity of endothelial nitric oxide synthase (eNOS) differed significantly between the normal and CHF groups. However, pitavastatin significantly suppressed O(2)- production, NAD(P)H oxidase activity and Nox4 and p47phox expression and increased eNOS expression and activity compared with the CHF group. CONCLUSIONS: The activated vascular NAD(P)H oxidase contributes to endothelial dysfunction in CHF, which was partly improved by pitavastatin via its inhibition of NAD(P)H oxidase.

Acetylcholine↗
PubMed2004

Rationale for the use of combination angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy in heart failure.

BACKGROUND: The present multicenter study investigated whether the combination of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) is more beneficial for preventing left ventricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone. METHODS AND RESULTS: One hundred and six patients with mild-to-moderate congestive heart failure treated in 26 Japanese institutes were randomly assigned to the combination therapy or monotherapy. Changes in physical activity (New York Heart Association functional classes, Specific Activity Scale (SAS)), concentrations of neurohumoral factors (plasma renin activity, angiotensin II, aldosterone, and brain natriuretic peptide (BNP)), and cardiac function for 6 months were compared between the 2 groups. It was found that the combination therapy, which was administered at doses standard in Japan, increased the SAS score (4.5 +/- 1.5 to 4.9 +/- 1.5, p<0.05) and decreased the plasma BNP concentration (183 +/- 163 to 135 +/- 118 pg/ml, p<0.05). In contrast, there were no changes in SAS score (4.5 +/- 1.4 to 4.6 +/- 1.4, NS) or BNP concentration (156 +/- 157 to 151 +/- 185 pg/ml, NS) in the patients receiving monotherapy. CONCLUSIONS: The results of the study demonstrate that the combination therapy, even at the standard doses for Japan, improves physical activity and plasma BNP concentration more than the monotherapy. A larger study is required to assess the effects of the combination therapy on major clinical outcomes.

Adrenergic beta-Antagonists↗
PubMed2004

Mineralocorticoid receptor antagonist spironolactone improves left ventricular remodeling in patients with congestive heart failure and acute myocardial infarction.

Randomized aldactone evolution study (RALES) and eplerenone post-AMI heart failure efficacy and survival study (EPHESUS) had shown that aldosterone blockade (AB) with standard therapy resulted in a reduction in mortality in patients with congestive heart failure (CHF) and acute myocardial infarction (AMI). However, the mechanism for the beneficial effect of AB remains unknown. To evaluate the effect of spironolactone (Spi) on left ventricular (LV) remodeling, 34 CHF patients with DCM were randomly divided into the Spi (+) or Spi (-) groups. Four months of treatment with Spi improved the LV volume and mass. To evaluate the effect of Spi on post-infarct LV remodeling, 134 patients with first anterior AMI were randomly divided into the Spi (+) or Spi (-) groups after revascularization. LV ejection fraction was significantly improved after 1 month in the Spi (+) group compared with that in the Spi (-) group. LV end-diastolic volume index was significantly suppressed in the Spi (+) group compared with that in the Spi (-) group. Transcardiac extraction of aldosterone through the heart was significantly suppressed in the Spi (+) group and was significant lower in the Spi (+) group compared with the Spi (-) group. These findings indicate that AB combined with standard therapy can prevent LV remodeling in patients with CHF and AMI, suggesting that the failing heart is the target organ of the aldosterone.

Adolescent↗
PubMed2004

[Brain natriuretic peptide].

Plasma levels of various neurohumoral factors are activated and have an important role of the pathophysiology of congestive heart failure (CHF). Atrial natriuretic peptide (ANP) and brain (or B-type) natriuretic peptide (BNP) are secreted from cardiomyocytes in response to atrial or ventricular wall stretch. The natriuretic peptides have a fundamental role in cardiovascular remodeling, volume homeostasis, and the response to myocardial injury. Clinical investigations of these peptides have focused on their diagnostic usefulness for heart failure and left ventricular dysfunction and their prognostic usefulness after acute coronary syndromes and heart failure. In patients with left ventricular systolic dysfunction, a high plasma BNP level is an independent prognostic predictor of CHF patients, suggesting that the compensatory activity of the cardiac natriuretic peptide system is attenuated as mortality increases in chronic CHF patients with high plasma levels of ANP and BNP. BNP is more useful than ANP for diagnosis and management of CHF. Recently, rapid BNP assay is available in our country, rapid measurement of BNP in the emergency department may improve the evaluation and treatment of patients with acute dyspnea and thereby reduced the time to discharge and the total cost of treatment. In addition, BNP-guided treatment of heart failure may reduce total cardiovascular events, and delayed time to first event combination with intensive clinically guided treatment.

Biomarkers↗
PubMed2003

Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy.

OBJECTIVES: This study noninvasively examined total creatine (CR) of the myocardium in dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) using proton magnetic resonance spectroscopy ((1)H-MRS). BACKGROUND: Abnormalities in CR metabolism in failing hearts have been reported. A biochemical study suggested that myocardial metabolic changes are very similar in DCM and HCM despite the different heart failure (HF) mechanisms. METHODS: Using cardiac-gated (1)H-MRS with magnetic resonance image (MRI)-guided point-resolved spectroscopy (PRESS) localization, we quantitatively measured septal CR. Patients with either DCM (n = 11) or HCM (n = 7) and age-matched normal subjects (n = 14) were examined. RESULTS: Myocardial CR was significantly lower in DCM patients (16.1 +/- 4.5 micromol/g wet weight [range 10.2 to 22.9], p < 0.05) than that in subjects with normal hearts (27.6 +/- 4.1 micromol/g [range 21.4 to 36.2]). Myocardial CR in HCM patients (22.6 +/- 8.1 micromol/g [range 12.2 to 34.5]) was significantly lower than that in subjects with normal hearts (p < 0.05) but was significantly higher than that in DCM patients (p < 0.05). In 18 patients with either DCM or HCM, myocardial CR correlated positively with left ventricular ejection fraction (LVEF) (y = 0.22x + 9.8, r = 0.73, p = 0.0006) but correlated negatively with plasma B-type natriuretic peptide (BNP) levels (y = -0.012x + 22.4, r = -0.54, p = 0.022). CONCLUSIONS: This study showed that (1)H-MRS can noninvasively detect CR depletion associated with the severity of HF in cardiomyopathy.

Adult↗
PubMed2003

Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure.

BACKGROUND: Angiotensin (Ang) II, which plays a crucial role in the cardiac remodeling process, is generated via angiotensin-converting enzyme (ACE); however, an alternative generation pathway, chymase, which is stored in the mast cells, also exists in the heart. Cardiac chymase is insensitive to ACE inhibitors (ACEIs), and heart chymase promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor-beta in vitro. Therefore, selective chymase blockade seems to be an important strategy in the prevention of cardiac remodeling METHODS AND RESULTS: We evaluated the effects of a specific chymase inhibitor, SUNC8257 (Chy I; 10 mg/kg twice a day; n=7), on changes in cardiac structures, Ang II levels, and gene expressions, which are characterized as molecular markers for fibrosis, in dogs with tachycardia induced heart failure (HF). In HF, the number of chymase enzyme-positive mast cells increased in the left ventricle (LV) compared with the normal group; however, Chy I significantly decreased the mast cell density and cardiac Ang II levels. Despite no significant differences in LV systolic function compared with the vehicle group, Chy I decreased LV end-diastolic pressure and shortened the prolongation of tau. Chy I suppressed collagen-type I and III and transforming growth factor-beta mRNA levels and decreased fibrosis in the LV compared with the vehicle. CONCLUSIONS: The chymase pathway may be critical for cardiac diastolic dysfunction accompanied with fibrosis. Chronic chymase inhibition may therefore become an important strategy in the prevention of cardiac remodeling in HF.

Angiotensin II↗