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Biomedical subjects

Masahiko Kinoshita

Publications and source records attributed to Masahiko Kinoshita.

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↗
PubMed2005

Incidence of acute myocardial infarction in Takashima, Shiga, Japan.

BACKGROUND: The incidence and mortality from ischemic heart disease (IHD) in Japan seem to be among the lowest of all the industrialized countries, but there are few reliable registers of acute myocardial infarction (AMI). METHODS AND RESULTS: To assess the incidence of AMI in Takashima County, Shiga, Japan, from 1988 to 1998 and compare the data with similar registers in the world, cases of AMI or sudden death presumed from myocardial ischemia were registered. The criteria of AMI were based on the WHO MONICA Projects. The medical records of all the hospitals inside as well as outside the county, the original death records in the health center, and the ambulance records in the county were investigated and 291 cases were registered (190 males, 101 females; average age (mean +/- SD), 69.5+/-12.2). The 28-day and 24-h case fatality was 38.1% and 33.0%, respectively. Age-adjusted annual incidence of AMI per 100,000 population aged between 25 and 74 years were 58.2 for men and 18.0 for women. The incidence of AMI showed a constant trend from 1988 to 1998. CONCLUSION: The results confirmed that Japan has the lowest incidence of AMI among the industrialized countries.

Adult↗
PubMed2004

Targeted gene delivery to sinusoidal endothelial cells: DNA nanoassociate bearing hyaluronan-glycocalyx.

Liver sinusoidal endothelial cells (SECs) possess unique receptors that recognize and internalize hyaluronic acid (HA). To develop a system for targeting foreign DNA to SECs, comb-type polycations having HA side chains were prepared by coupling HA to poly(L-lysine) (PLL). The HA-grafted-PLL copolymer (PLL-g-HA) thus formed was mixed with DNA in 154 mM NaCl to form soluble nanoassociates bearing hydrated hyaluronate shells. Agarose gel retardation assays revealed selective interaction of the PLL backbone with DNA despite the presence of polyanionic HA side chains. To determine whether the PLL-g-HA/DNA complexes were recognized by SEC HA receptors in vivo, we injected Wistar rats i.v. via the tail vein with PLL-g-HA complexed to a beta-galactosidase expression plasmid (pSV beta-Gal) labeled with 32P. One hour postinjection, >90% of the injected radioactivity remained in the liver. Administration of the PLL-g-HA complexed to an FITC-labeled DNA revealed that the carrier-DNA complex was distributed exclusively in SECs. A large number of SECs expressing beta-galactosidase was detected along the sinusoidal lining after transfection with PLL-g-HA/pSV beta-Gal. Moreover, PLL-g-HA effectively stabilized DNA triplex formation. In conclusion, the new PLL-g-HA/DNA carrier system permits targeted transfer of exogenous genes selectively to the SECs.

Animals↗
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

Endothelial modulation and tolerance development in the vasorelaxant responses to nitrate of rabbit aorta.

We investigated the endothelial modulations in nitrate tolerance in isolated rabbit aorta. Nitrate tolerance was induced by a 72-h treatment with transdermal nitroglycerin (NTG, 0.4 mg/h) in conscious rabbits, which was verified by a 20-fold increase in the EC50 values [NTG tolerance (6.1 +/- 0.8) x 10(-7) M vs control (3.0 +/- 0.6) x 10(-8) M]. The relaxations to NTG in tolerant and nontolerant aortic strips were enhanced when their endothelia were denuded [E(-)]. In the presence of endothelium [E(+)], NTG-tolerant vessels were not tolerant to acetylcholine (ACh), which can release endothelial nitric oxide (NO), exogenous NO or 8-bromo (Br)-cGMP. In NTG-tolerant and nontolerant vessels with endothelium, concentration-response curves for NO were the same as those in endothelium-absent tolerant vessels. In both NTG-tolerant and nontolerant vessels, treatment with superoxide dismutase (SOD, 20 units/ml), an O2-. scavenger, unaffected the responses to NTG reduced in the presence of endothelium, but treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), an NO synthase (NOS) inhibitor, reversed these reductions. Thus, our data did not indicate that an increased endothelial superoxide O2-. production contributes to nitrate tolerance. Our study suggested that (i) an impaired biotransformation process from NTG to NO is responsible for the occurrence of nitrate tolerance and (ii) vascular response to NTG enhanced by endothelial removal is related to blocked endothelial NO release.

Acetylcholine↗
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↗
PubMed2003

Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction.

BACKGROUND: Aldosterone (ALD) has been shown to stimulate cardiac collagen synthesis and fibroblast proliferation via activation of local mineralocorticoid receptors. In patients with acute myocardial infarction, we demonstrated that ALD was extracted through the infarct heart and extracting ALD-stimulated post-infarct left ventricular (LV) remodeling. METHODS AND RESULTS: To evaluate the effect of mineralocorticoid receptor antagonist (MRA) spironolactone on post-infarct LV remodeling, 134 patients with first anterior acute myocardial infarction were randomly divided into the MRA (n=65) or non-MRA (n=69) groups after revascularization. All patients were administered angiotensin-converting enzyme (ACE) inhibitor and study drug just after revascularization. Left ventriculography with contrast medium was performed at the acute stage and after 1 month to evaluate LV remodeling. ALD was measured at aortic root and coronary sinus. There was no difference in the baseline characteristics including infarct size and LV performance between the two groups. However, LV ejection fraction was significantly improved in the MRA group compared with that in the non-MRA group (46.0+/-0.6% to 53.2+/-0.8% versus 46.5+/-0.8% to 51.0+/-0.8%, Pinteraction=0.012). LV end-diastolic volume index was significantly suppressed in the MRA group compared with that in non-MRA group (86.5+/-1.0 to 90.6+/-2.4 versus 87.5+/-1.3 to 106.8+/-3.5 mL/m2, Pinteraction=0.002). Transcardiac extraction of ALD through the heart was significantly suppressed in the MRA group (Pinteraction=0.001), and plasma procollagen type III aminoterminal peptide level, a biochemical marker of fibrosis, was significant lower in the MRA group compared with the non-MRA group (Pinteraction=0.002). CONCLUSIONS: These findings indicate that MRA combined with ACE inhibitor can prevent post-infarct LV remodeling better than ACE inhibitor alone in association with the suppression of a marker of collagen synthesis.

Adrenergic beta-Antagonists↗
PubMed2003

Angiotensin-converting enzyme inhibition but not angiotensin II type 1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients.

OBJECTIVES: We compared the effects of perindopril and losartan on endothelium-dependent coronary vasomotor and fibrinolytic function. BACKGROUND: The renin-angiotensin system regulates the vascular fibrinolytic balance. However, the effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists on coronary fibrinolytic function have not been compared in hypertensive patients. METHODS: Forty-five patients with hypertension were randomly assigned to three groups: 16 patients were treated with perindopril (4 mg/day) for four weeks; 15 were treated with losartan (50 mg/day) for four weeks; and 14 were not treated with either perindopril or losartan (control group). Graded doses of bradykinin (BK) (0.2, 0.6, and 2.0 microg/min) were administered into the left coronary artery. Coronary blood flow (CBF) was evaluated by Doppler flow velocity measurement. RESULTS: Bradykinin induced dose-dependent increases in CBF in all groups. The increases in CBF induced by BK in the perindopril and losartan groups were significantly greater than those in the control group. Net coronary tissue-type plasminogen activator (t-PA) release was enhanced by BK in all groups, and the increase in the perindopril group was greater than that in the losartan and control groups. Bradykinin did not alter plasminogen activator inhibitor type 1 levels in any of the groups. CONCLUSIONS: Perindopril and losartan similarly augment BK-induced coronary vasodilation. Perindopril may have a greater potential to enhance the BK-induced coronary release of t-PA than losartan.

Aged↗
PubMed2003

Noninvasive assessment of significant right coronary artery stenosis based on coronary flow velocity reserve in the right coronary artery by transthoracic Doppler echocardiography.

BACKGROUND: Coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography (TTDE) has been reported to be useful for the noninvasive assessment of coronary stenosis in the left anterior descending artery. However, the measurement of CFVR in the right coronary artery by TTDE has not yet been validated in a clinical study. OBJECTIVE: The aim of this study was to evaluate whether CFVR by TTDE can detect significant stenosis in the right coronary artery. METHODS: We studied 50 patients who underwent coronary angiography. Coronary flow velocity in the posterior descending branch of the right coronary artery (PD) was measured by TTDE both at baseline and during hyperemia induced by the intravenous infusion of adenosine triphosphate. CFVR was calculated as the hyperemia/baseline (average diastolic peak velocity). RESULTS: Adequate spectral Doppler recordings in the PD were obtained in 36 patients including 26 patients who were given an echocardiographic contrast agent to improve Doppler spectral signals. The study population was divided into 2 groups with (Group A;n = 11) and without (Group B;n = 25) significant stenosis in the right coronary artery. CFVR in Group A was significantly smaller than that in Group B (1.6+/-0.3versus2.5+/-0.4; P < 0.0001). The sensitivity of a CFVR of <2.0 for predicting the presence of significant stenosis in the right coronary artery was 91%, and the specificity was 88%. CONCLUSIONS: The measurement of CFVR in the PD by TTDE is useful for the noninvasive assessment of significant stenosis in the right coronary artery.

Adenosine Triphosphate↗
PubMed2002

Plasma oxidized low-density lipoprotein as a prognostic predictor in patients with chronic congestive heart failure.

OBJECTIVES: The aim of this study was to evaluate the relationship between plasma oxidized low-density lipoprotein (oxLDL), a marker of oxidative stress, and the prognosis of patients with chronic congestive heart failure (CHF). BACKGROUND: Oxidative stress appears to play a role in the pathophysiology of CHF. We have recently reported the usefulness of plasma oxLDL as a marker of oxidative stress in CHF patients with dilated cardiomyopathy. METHODS: We measured the plasma level of oxLDL by sandwich enzyme-linked immunosorbent assay using a specific monoclonal antibody against oxLDL in 18 age-matched normal subjects and in 84 patients with chronic CHF (New York Heart Association functional class II to IV) and monitored them prospectively for a mean follow-up period of 780 days. RESULTS: Plasma oxLDL level was significantly higher in severe CHF patients than in control subjects and mild CHF patients. A significant negative correlation existed between the plasma level of oxLDL and left ventricular ejection fraction (LVEF) and a significant positive correlation between the plasma level of oxLDL and plasma norepinephrine level. Twenty-six patients had cardiac events; 14 had cardiac death and 12 were hospitalized for heart failure or other cardiovascular events. Among 10 variables including LVEF and neurohumoral factors, only high plasma levels of brain natriuretic peptide and oxLDL were shown to be independent predictors of mortality. CONCLUSIONS: These results indicate that the plasma level of oxLDL is a useful predictor of mortality in patients with CHF, suggesting that oxidative stress plays an important role in the pathophysiology of CHF.

Adolescent↗
PubMed2002

Genetic variation in aldehyde dehydrogenase 2 and the effect of alcohol consumption on cholesterol levels.

UNLABELLED: Moderate drinkers with a defective alcohol dehydrogenase type 3 (ADH3) genotype have higher high-density lipoprotein (HDL) levels and a decreased risk of coronary artery disease (CAD). We examined the interaction between the aldehyde dehydrogenase type 2 (ALDH2), alcohol intake, and HDL levels in 826 men and 1295 women in a rural town in Japan. The ALDH2 genotype of each subject was determined by polymerase chain reaction (PCR) analysis. HDL was adjusted for the alcohol intake, age, body mass index, smoking status, total cholesterol, triglycerides and HbA1c levels. None of the subjects had a history or ECG suggestive of CAD. The proportions of ALDH2, *1/*1, *1/*2, and *2/*2 (defective homozygote) were 45.8, 46.0, and 8.2%, respectively, for men. Drinking more than two drinks daily was associated with lower HDL levels in men with the defective genotypes compared with men with a normal genotype (55.6+/-0.9 vs. 51.2+/-0.9 mg/dl, mean+/-S.E., P<0.0001). Also, drinking more than 0.5 drinks daily was not associated with beneficial effects on HDL levels in women with defective ALDH2 genotypes. CONCLUSIONS: Alcohol intake did not have beneficial effects on HDL levels in the defective ALDH2 genotype and may not protect against CAD in subjects with defective ALDH2 genotypes.

Adult↗
PubMed2002

Endothelin stimulates an endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, in experimental heart failure.

Congestive heart failure (CHF) is characterized by increased peripheral vascular resistance. Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor, is present at increased concentrations in the plasma and contributes to the regulation of vascular tone in CHF. An endothelium-derived relaxing factor, nitric oxide (NO), also regulates vascular tone, but endothelium-dependent NO-mediated vasodilation is blunted in CHF. An endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), which inhibits NO production and endothelium-dependent relaxation, is present at increased levels in the plasma and plays a role in impaired endothelial function in CHF. However, at present, the relationship between ET-1 and impaired vascular relaxation in CHF is not well known. We hypothesized that ET-1 inhibits NO-mediated vasodilation via increased ADMA production in CHF, and that an endothelin receptor antagonist can prevent this increase in plasma ADMA levels. In the present study, we first examined whether circulating ADMA levels were increased in a dog model of CHF induced by 3 weeks of rapid ventricular pacing (n=5; 270 beats/min) compared with normal dogs (n=5). After 3 weeks of pacing, cardiac output had decreased significantly (1.56+/-0.16 compared with 2.93+/-0.25 litres/min; P<0.01) and systemic vascular resistance had increased (4653+/-374 compared with 3227+/-396 dyn.s.cm(-5); P<0.01) in dogs with CHF compared with normal dogs. Plasma levels of both ET-1 (4.95+/-0.83 compared with 2.12+/-0.39 pg/ml; P<0.05) and ADMA (3.27+/-0.49 compared with 1.91+/-0.25 nmol/ml; P<0.05) were significantly increased in CHF dogs. A significant positive correlation was observed between plasma ET-1 and ADMA levels (r=0.72, P<0.05). Secondly, we chronically administered an ET(A) receptor antagonist, TA-0201 (0.3 mg/kg; n=5), to paced CHF dogs. Drug administration started on day 8 of pacing and continued throughout the experiment. TA-0201 significantly increased cardiac output (2.58+/-0.24 litres/min; P<0.01) and suppressed the increases in plasma ADMA levels and systemic vascular resistance (2.36+/-0.30 nmol/ml and 2423+/-188 dyn.s.cm(-5) respectively; P<0.05 for each) compared with CHF dogs without TA-0201 treatment. In conclusion, ET-1 contributes to the regulation of vascular tone due, in part, to increased levels of an endogenous NO synthase inhibitor in CHF, and an ET(A) receptor antagonist can prevent the inhibition of NO production and the increased peripheral vascular resistance observed in CHF.

Animals↗