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Isao Kubota

Publications and source records attributed to Isao Kubota.

At least 37 records · Page 2Linked to original sources

Expression and localization of diacylglycerol kinase isozymes and enzymatic features in rat lung.

Diacylglycerol kinase (DGK) catalyzes phosphorylation of diacylglycerol to generate phosphatidic acid, and both molecules are known to serve as second messengers as well as important intermediates for the synthesis of various lipids. In this study, we investigated the spatiotemporal expression patterns of DGK isozymes together with the developmental changes of the mRNA expression and enzymatic property in rat lung. Northern blot and RT-PCR analyses showed that mRNAs for DGKalpha, -epsilon, and -zeta were detected in the lung. By immunohistochemical examination, DGKalpha and -zeta were shown to be coexpressed in alveolar type II cells and macrophages. Interestingly, these isozymes were localized at distinct subcellular locations, i.e., DGKalpha in the cytoplasm and DGKzeta in the nucleus, suggesting different roles for these isozymes. In the developing lung, the expression for DGKalpha and -zeta was transiently elevated on embryonic day 21 (E21) to levels approximately two- to threefold higher than on postnatal day 0 (P0). On the other hand, the expression for DGKepsilon was inversely elevated approximately twofold on P0 compared with that on E21. These unique changes in the expression pattern during the perinatal period suggest that each isozyme may play a distinct role in the adaptation of the lung to air or oxygen breathing at birth.

Animals↗

Ongoing myocardial damage relates to cardiac sympathetic nervous disintegrity in patients with heart failure.

UNLABELLED: Iodine-123-metaiodobenzylguanidine (123I-MIBG) has been used to assess the integrity and function of the cardiac sympathetic nervous system in patients with heart failure. Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured, and H-FABP has been recently used as a novel marker for the diagnosis of ongoing myocardial damage. OBJECTIVE: The aim of the present study was to compare cardiac sympathetic nervous activity assessed by 123I-MIBG imaging with serum levels of H-FABP in patients with heart failure. METHODS: Fifty patients with chronic heart failure were studied. 123I-MIBG imaging was carried out at 30 min (early) and 240 min (delayed) after the tracer injection. We measured serum levels of H-FABP using a sandwich enzyme linked immunosorbent assay. RESULTS: Heart to mediastinum (H/M) ratios of 123I-MIBG decreased and washout rate increased with higher New York Heart Association (NYHA) functional class. H-FABP, norepinephrine and brain natriuretic peptide (BNP) levels increased as the severity of NYHA class advanced. Delayed H/M ratio was significantly correlated with H-FABP (r = -0.296, p = 0.029) and BNP (r = -0.335, p = 0.0213). Myocardial washout rate of 123I-MIBG was also correlated with H-FABP (r = 0.469, p < 0.001), norepinephrine (r = 0.433, p = 0.005), and BNP (r = 0.465, p = 0.001). CONCLUSIONS: These data suggest that cardiac sympathetic nervous activation was associated with ongoing cardiomyocyte damage characterized by an elevated serum level of H-FABP in patients with heart failure. 123I-MIBG imaging is an appropriate approach to evaluate non-invasively not only cardiac sympathetic nervous activity, but also latent ongoing myocardial damage in the failing heart.

3-Iodobenzylguanidine↗

C-reactive protein elevation predicts the occurrence of atrial structural remodeling in patients with paroxysmal atrial fibrillation.

It has been poorly understood whether inflammation may contribute to atrial structural remodeling and increase the propensity for atrial fibrillation (AF) to persist. We investigated the relationship between C-reactive protein (CRP) elevation and the development of atrial remodeling in AF. The study population comprised 50 consecutive paroxysmal AF (PAF) patients and 50 control patients without AF. All patients underwent echocardiography, and high-sensitivity CRP was routinely measured. C-Reactive protein was significantly higher in the patients with PAF than control patients (0.231+/-0.176 mg/dl vs 0.055+/-0.041 mg/dl, P<0.001). Other predictors of elevated CRP included left ventricular mass (P<0.05), left ventricular end-systolic diameter (P<0.05), and left atrial (LA) diameter (P<0.001). In a multivariate analysis, only CRP and LA diameter were independent predictors of PAF. Elevated CRP levels correlated with LA diameter (r=0.489, P<0.001). Left atrial diameter was increased in PAF patients compared with control patients (P<0.001). We found that a longer duration of AF is associated with higher CRP levels and a larger LA diameter (duration <30 days: CRP 0.166+/-0.139 mg/dl, LA diameter 38.4+/-8.0 mm; duration >30 days: CRP 0.345+/-0.181 mg/dl, LA diameter 45.6+/-6.6 mm; P<0.001). In conclusion, longer AF duration is associated with CRP elevation and atrial structural remodeling, as approximated by larger LA diameter. However, CRP elevation, while correlating with LA diameter, was not an independent predictor of atrial structural remodeling. Thus, it remains unclear whether CRP and the inflammatory state are contributory to LA remodeling or whether LA remodeling or AF induces elevation in CRP and inflammation.

Aged↗

Prognostic value of elevated circulating heart-type fatty acid binding protein in patients with congestive heart failure.

BACKGROUND: Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured and is a novel marker for the diagnosis of acute myocardial infarction. The purpose of the present study was to examine the clinical significance of increased serum H-FABP levels in patients with congestive heart failure. METHODS AND RESULTS: Serum levels of H-FABP were measured in 179 patients admitted with congestive heart failure and 20 age-matched normal controls by using a sandwich enzyme-linked immunosorbent assay. Patients were prospectively followed during a mean follow-up period of 20 months with the end points of cardiac death and progressive heart failure requiring rehospitalization. Serum levels of H-FABP were higher in patients with congestive heart failure than in control subjects (5.7 +/- 4.8 ng/mL versus 2.7 +/- 0.8 ng/mL, P < .01) and increased with advancing NYHA class (P < .01). The cardiac event rate was markedly higher in patients with elevated H-FABP levels than in those with normal levels (43% versus 7%, P < .0001). Furthermore, the Cox multivariate proportional hazard analysis revealed that the elevated H-FABP level was the only independent predictor for cardiac events (chi2= 7.397, P < .01). CONCLUSIONS: Elevation of H-FABP indicates latent and ongoing cardiomyocyte damage and identifies patients at high risk for future cardiac events in congestive heart failure.

Aged↗

Cystatin C, a novel measure of renal function, is an independent predictor of cardiac events in patients with heart failure.

BACKGROUND: Cystatin C, a novel endogenous marker of glomerular filtration rate, has been reported as more sensitive to detect renal insufficiency than creatinine. The purpose of the present study was to examine the clinical significance of serum cystatin C level in patients with mild to moderate heart failure. METHODS AND RESULTS: Serum levels of cystatin C were measured by an enzyme immunoassay in 140 patients with heart failure and 64 control subjects without heart failure. Patients were prospectively followed during a median follow-up period of 480 days, with the end points of cardiac death and progressive heart failure requiring rehospitalization. Serum levels of cystatin C were higher in patients with heart failure than in control subjects (1.14 +/- 0.60 ng/mL versus 0.72 +/- 0.14 ng/mL, P < .001). The Cox multivariate proportional hazard analysis revealed that a change of 1 standard deviation (SD) in cystatin C level was the one of independent predictor for cardiac events (hazard ratio, 1.94; 95% confidence interval, 1.29-6.64; P < .01). The cardiac event rate was markedly higher in patients with elevated cystatin C level (> or =1.0 ng/mL) than in those with normal level (< or =1.0 ng/mL) (38.7% versus 10.3%, P < 0.001). Furthermore in patients with normal creatinine levels (n = 91), the cardiac event rate was similarly higher in patients with elevated cystatin C than in those with normal levels (29.2% versus 7.5%, P = .002). CONCLUSION: Elevation of serum cystatin C, a new marker of renal function, provides promising prognostic information for clinical outcome in patients with mild to moderate heart failure.

Aged↗

Impaired systemic cell-mediated immunity and increased susceptibility to acute respiratory tract infections in patients with COPD.

Although it has been reported that chronic obstructive pulmonary disease (COPD) is frequently associated with systemic immune disturbances, negative impact of these disturbances on the increased prevalence of acute respiratory tract infections (aRTIs) has remained unclear. We evaluated circulating levels of interferon-gamma (IFN-gamma), soluble interleukin-2 receptor (sIL-2R), neopterin, and soluble intercellular adhesion molecule-1 (sICAM-1) in 35 clinically stable patients with COPD and in 22 age-matched healthy controls, since these molecules are considered to reflect the in vivo status of systemic cell-mediated immunity (CMI). We found that circulating levels of sIL-2R (1.52+/-1.25 vs. 0.97+/-0.48 ng/ml; P<0.05), neopterin (7.23+/-4.24 vs. 4.95+/-1.52 nmol/l; P<0.05), and sICAM-1 (665+/-302 vs. 328+/-164 ng/ml; P<0.0001), but not IFN-gamma (7.55+/-4.72 vs. 6.65+/-1.13 pg/ml; P=NS) were significantly higher in patients with COPD than in the controls. Importantly, follow-up study for 12 months demonstrated that patients in subgroup with relatively higher circulating levels of sIL-2R (2.20+/-1.44 ng/ml, n=18) had significantly higher risk of developing aRTIs (P=0.0204) than those in subgroup with relatively lower circulating levels of sIL-2R (0.80+/-0.23 ng/ml, n=17). These results may suggest that impaired systemic CMI observed in COPD patients is associated with the increased susceptibility to aRTIs in these patients.

Aged↗

Mechanism for atrial tachyarrhythmia in chronic volume overload-induced dilated atria.

UNLABELLED: Mechanism of chronic volume overload-induced AT. INTRODUCTION: Atrial dilatation associated with chronic volume overload (CVO) plays an important role in the development of atrial fibrillation (AF). However, the underlying mechanisms are unknown. METHODS AND RESULTS: CVO-induced atrial dilatation was created in Japanese white rabbits using arteriovenous shunt formation for 6 weeks. Epicardial action potentials were measured from both atria in Langendorff-perfused sham-operated control hearts (n=8) and in CVO hearts (n=8) using high-resolution optical mapping techniques. The left atrial diameter was greater in CVO hearts (16.0+/-0.4 mm) compared to control hearts (11.0+/-0.8 mm). During steady-state pacing, right and left atrial conduction velocities were significantly lower in CVO hearts compared to control hearts (P<0.01). Rapid atrial pacing did not induce atrial tachyarrhythmia (AT) in any control hearts. However, in seven of eight CVO hearts 16 episodes of AT were induced, of which 9 exhibited a single reentrant circuit. The remaining 7 episodes exhibited a focal pattern of excitation without evidence of reentry. Interestingly, the activation rate was higher during reentry (16.1+/-1.5 Hz) compared to focal AT (9.8+/-1.0 Hz). In addition, 15 of 16 episodes occurred in the posterior left atrium (PLA). In all seven CVO hearts, AT was self-sustained for more than 10 minutes. CONCLUSION: CVO caused atrial dilatation, conduction slowing, and AT associated with reentrant and focal excitation originating from the PLA. These results suggest that the PLA may play an important role in AT induction associated with CVO-induced atrial dilation.

Animals↗

Pitavastatin inhibits cardiac hypertrophy in a rat model of progressive renal injury.

Increased cardiovascular mortality is an unresolved problem of chronic renal failure. Cardiac hypertrophy, observed in many patients with chronic renal failure, is a major risk factor for cardiovascular death. The purpose of the present study was to examine the effects of pitavastatin on cardiac hypertrophy in a progressive renal injury rat model by subtotal nephrectomy (SNx). Because we previously reported that angiotensin II played a pivotal role in cardiac hypertrophy of SNx rats, we first investigated the effects of pitavastatin on angiotensin II-induced activation of extracellular signal-regulated kinase (ERK) and serum response element (SRE) DNA-binding activity using neonatal rat cardiomyocytes. Angiotensin II-induced ERK activation was attenuated by pretreatment with pitavastatin. Luciferase assay revealed that angiotensin II-induced increase in SRE DNA-binding activity was inhibited by pitavastatin. We next examined the effect of pitavastatin on cardiac hypertrophy of SNx rats in vivo. Treatment with pitavastatin prevented ERK activation and cardiac hypertrophy in SNx rats without changes in blood pressure. The increased expression of atrial natriuretic factor mRNA in SNx rat hearts was significantly attenuated by the treatment with pitavastatin. These results suggest that pitavastatin has a beneficial effect on cardiac hypertrophy in renal failure through preventing the activation of ERK.

Angiotensin II↗

Combination of heart-type fatty acid binding protein and brain natriuretic peptide can reliably risk stratify patients hospitalized for chronic heart failure.

BACKGROUND: The aim of the present study was to prospectively study whether a combination of markers for myocardial cell injury and left ventricular overload at admission can reliably risk stratify patients hospitalized for chronic heart failure (CHF). METHODS AND RESULTS: Serum concentrations of heart-type fatty acid binding protein (H-FABP) and plasma concentrations of brain natriuretic peptide (BNP) were measured at admission in 186 consecutive patients hospitalized for CHF. During a mean follow-up period of 534+/-350 days, there were 44 cardiac events, including 16 cardiac deaths and 28 readmissions for worsening heart failure. Normal upper limits for H-FABP and BNP values were determined from the receiver operating characteristic curves (4.3 ng/ml for H-FABP and 200 pg/ml for BNP). A stepwise Cox regression analysis demonstrated that high H-FABP (hazard ratio 5.416, p = 0.0002) and high BNP (hazard ratio 2.411, p = 0.0463) were independent predictors of cardiac events. High concentrations of both H-FABP and BNP at admission were associated with the highest incidence of cardiac mortality and cardiac events. Kaplan-Meier analysis also showed that the combination of H-FABP and BNP concentrations could reliably stratify patients for cardiac events. CONCLUSION: Combined measurement of H-FABP and BNP concentrations at admission may be a highly reliable evaluation for risk stratifying patients hospitalized for CHF.

Aged↗

Diminution of angiotensin II-induced contraction of the abdominal aorta isolated from Watanabe heritable hyperlipidemic rabbits.

The purpose of this study was to investigate the changes in vasocontractile responses in atherosclerosis, using abdominal aortic strips isolated from Watanabe heritable hyperlipidemic (WHHL) rabbits and Japanese White (control) rabbits. The aortic strips from WHHL rabbits showed a significantly lower contractile response to angiotensin II than that in strips from control rabbits. The contractile responses to phenylephrine and 5-hydroxytryptamine were not different in WHHL and control groups. The contractile response to angiotensin II was higher in endothelium-denuded aortic strips than in endothelium-intact strips, but to a greater extent in the control group than in the WHHL group. The contractile response to angiotensin II in the absence of the endothelium was also lower in the WHHL group than in the control group. Pretreatment with N(G)-nitro-L-arginine significantly increased the contractile response to angiotensin II in the endothelium-intact aortic strips in both the WHHL and control groups, while pretreatment with diclofenac did not affects the aortic contractile response to angiotensin II. The contractile responses to angiotensin II in the presence of N(G)-nitro-L-arginine and diclofenac were lower in the WHHL group than in the control group. The contractile response to angiotensin II in the presence of PD123319 was also lower in the WHHL group than in the control group. Endothelium-dependent relaxation by acetylcholine occurred to the some extent in the WHHL and control groups. These results suggest that the WHHL rabbit abdominal aorta displays attenuated angiotensin II-induced contraction, mainly due to an abnormality in the angiotensin II-specific contractile pathway of the medial smooth muscle.

Angiotensin II↗

Circulating levels of soluble Fas ligand in cachexic patients with COPD are higher than those in non-cachexic patients with COPD.

OBJECTIVE: Apoptosis may be involved in the pathophysiology of cachexia in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the potential role of the Fas-Fas ligand (FasL) system in cachexic patients with COPD. PATIENTS AND METHODS: We measured the circulating levels of soluble FasL (sFasL), with a newly developed, highly sensitive enzyme-linked immunosorbent assay system in seventy patients with COPD and forty-seven control subjects. RESULTS: The levels of sFasL in the COPD patients were significantly lower than those in the control subjects (46+/-29 vs. 55+/-28 pg/ml; p<0.05), whereas the levels of soluble Fas (sFas) remained unchanged between the two groups. The significant correlation between the levels of sFasL and sFas, observed in the control subjects (r=0.304; p<0.05), was absent in the COPD patients. Cachexic COPD patients with a relatively lower BMI (BMI <20 kg/m(2), n=45) and %fat (%fat <20%, n=34), showed significantly increased levels of sFasL compared to non-cachexic COPD patients with a relatively higher BMI (BMI > or =20 kg/m(2), n=25) and %fat (%fat > or =20%, n=36) (BMI; 51+/-33 vs. 36+/-15 pg/ml; p<0.05. %fat; 55+/-33 vs. 37+/-21 pg/ml; p<0.01), due to the inverse relationships between the body composition measurements and the levels of sFasL observed exclusively in the patients (BMI; r=-0.307; p<0.05. %fat; r=-0.283; p<0.05). CONCLUSION: These results may suggest that the Fas-FasL system does not play a significant role in the potential triggers of enhanced apoptosis leading to skeletal muscle wasting and adipose tissue depletion in cachexic patients with COPD.

Adipose Tissue↗

Serum heart-type fatty acid binding protein predicts cardiac events in elderly patients with chronic heart failure.

BACKGROUND AND OBJECTIVES: Heart-type fatty acid binding protein (H-FABP) is released into the circulation from the damaged myocardium of patients with severe chronic heart failure. Chronic heart failure is the most frequent cause of death and disability in the elderly. However, there are no data for the prognostic value of H-FABP in the elderly population. This study investigated whether H-FABP can effectively predict the prognosis in elderly patients (> or = 70 years) with chronic heart failure. METHODS: Serum H-FABP levels were measured in 90 chronic heart failure patients > or =70 years old (mean age 77 +/- 4 years, range 70-92 years), and patients were followed-up for 421 +/- 326 days. RESULTS: There were 35 cardiac events (38.9%) including cardiac deaths and readmissions for worsening chronic heart failure. Multivariate analysis with the Cox proportional hazard model showed that H-FABP was the only independent predictor of cardiac events (chi2 = 6.640, p = 0.0100). Kaplan-Meier analysis revealed that H-FABP effectively risk stratified elderly patients with chronic heart failure for cardiac events. CONCLUSIONS: These findings suggest that H-FABP is a reliable marker for prognosis in elderly patients with chronic heart failure.

Aged↗

Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice.

BACKGROUND: Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and are involved in the responsiveness to pathogen-associated molecular patterns. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, which may contribute to congestive heart failure. Oxidative stress is one of the major factors in doxorubicin (Dox)-induced cardiac dysfunction. Thus, we hypothesized that TLRs contribute to the pathogenesis of Dox-induced cardiac dysfunction. METHODS AND RESULTS: Cardiac dysfunction was induced by a single injection of Dox (20 mg/kg IP) into wild-type (WT) mice and TLR-2-knockout (KO) mice. Five days after Dox injection, left ventricular dimension at end-diastole was smaller and fractional shortening was higher in KO mice compared with WT mice (P<0.01). Nuclear factor-kappaB activation and production of proinflammatory cytokines after Dox were suppressed in KO mice compared with WT mice (P<0.01). The numbers of TUNEL-positive nuclei and Dox-induced caspase-3 activation were less in KO mice than in WT mice (P<0.01). Survival rate was significantly higher in KO mice than in WT mice 10 days after Dox injection (46% vs 11%, P<0.05). CONCLUSIONS: These findings suggest that TLR-2 may play a role in the regulation of inflammatory and apoptotic mediators in the heart after Dox administration.

Animals↗

Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy.

PURPOSE: Pulmonary microvascular endothelial injury may be involved in the pathogenesis of pulmonary fibrosis (PF). The aim of this study was to evaluate the pulmonary vascular status in patients with PF by lung scintigraphic assessment of 123I-metaiodobenzylguanidine (123I-MIBG), which reflects latent endothelial cell lesions. METHODS: We assessed lung 123I-MIBG kinetics and clinical indices in 23 PF patients and 16 controls. Mean uptake ratios of lung to mediastinum (L/M) were calculated in anterior planar images at 30 (early image) and 270 (delayed image) min after intravenous injection of 123I-MIBG. The pulmonary mean washout rate (WR) of 123I-MIBG was also calculated. RESULTS: The L/M ratio in early images, but not in delayed images, was significantly lower in the PF patients than in the controls (L/M(early) 1.41+/-0.14 vs 1.53+/-0.10, p<0.01; L/M(delayed) 1.28+/-0.10 vs 1.33+/-0.07, p=NS). WR was significantly reduced in the PF patients compared with the controls (28.6%+/-3.1% vs 34.2%+/-5.1%, p<0.001). In the study subjects (PF patients plus controls) there were significant relationships between lung WR of (123)I-MIBG and other diagnostic parameters for the severity of PF, such as vital capacity (r=0.625, p<0.0001), total lung capacity (r=0.691, p<0.0001), carbon monoxide diffusing capacity (r=0.622, p<0.0001), serum angiotensin-converting enzyme activity (r=0.422, p<0.01), carbohydrate antigen KL-6 levels (r=-0.495, p<0.01) and surfactant protein-D levels (r=-0.461, p<0.01). When control subjects were excluded, similar significant correlations were observed between WR and %TLC (r=0.508, p<0.05), DL(CO) (r=0.593, p<0.01) and serum ACE activity (r=0.515, p<0.05) in the PF patients. CONCLUSION: These results suggest that endothelial cell injury plays a significant role in the pathogenesis of PF, and that lung WR of 123I-MIBG, which is a specific marker of endothelial damage, can serve as a novel diagnostic tool to evaluate the functional severity of PF.

3-Iodobenzylguanidine↗

Dynamic and not static change in ventricular repolarization is a substrate of ventricular arrhythmia on chronic ischemic myocardium.

OBJECTIVE: The restitution mechanism has been the focus of attention as the possible mechanism behind ventricular fibrillation (VF). However, its contribution in chronic ischemic heart has not been established. METHODS: We investigated chronic ischemic dogs with occlusion of left anterior descending artery. Sixty unipolar electrograms were simultaneously recorded from an entire cardiac surface. Activation-recovery intervals (ARIs) and QRST deflection area (AQRST) were measured during constant atrial pacing. The ischemic dogs were divided into two groups, five dogs in VF(+) group or seven dogs in VF(-) group, according to VF occurrence by programmed electrical stimulation. RESULTS: When investigating ARI dispersions on an epicardium, there was no difference between VF(+) and VF(-) groups. The relationship between ARIs and diastolic intervals was quantified as an electrical restitution curve. The slopes of the ARI restitution curve for the anterior left ventricle in VF(+) dogs were significantly steeper than those of VF(-) dogs. The amplitude of AQRST alternans were significantly greater in VF(+) dogs than VF(-) dogs. CONCLUSIONS: Combined observation of steep restitution slopes and increased electrical alternans supported the restitution mechanism as being involved in the arrhythmia. Dynamic restitution properties and not static single-beat ARI dispersion may play an important role in the VF arrhythmia in the chronic ischemic heart.

Animals↗

Chronic hypertriglyceridemia in young watanabe heritable hyperlipidemic rabbits impairs endothelial and medial smooth muscle function.

Several studies have suggested that hypertriglyceridemia is a common risk factor for coronary heart disease. Although increasing serum levels of triglyceride correlate with hypercoagulability, little is known about the contribution of hypertriglyceridemia to vascular function. We successfully segregated two lines of rabbits with genetically-determined severely high (TGH; 2764 +/- 413 mg/dl) and moderately high (TGL; 191 +/- 12 mg/dl) levels of triglyceride, but with comparable levels of total cholesterol, from Watanabe heritable hyperlipidemic rabbits. To determine whether hypertriglyceridemia was involved in alterations of vascular function, we conducted isometric tension studies and analyzed protein expression on thoracic aortic rings isolated from young (3-4 month) TGH, TGL and Japanese White rabbit (JW). No difference in percentage of plaque area in the thoracic aorta was found between TGH and TGL. Relaxing responses, evoked by sodium nitroprusside were similar in JW, TGL and TGH, but endothelium-dependent relaxation to acetylcholine was impaired in TGH compared with JW or TGL (maximal relaxation in JW; 83.5 +/- 2.7%, TGL; 79.9 +/- 5.3%, TGH; 59.1 +/- 5.7%, p<0.05). Relaxation to A23187 was also attenuated in TGH compared with JW, but not significantly different between TGL and JW. Endothelium-independent relaxation elicited by isoproterenol in TGH was significantly decreased compared with JW or TGL (maximal relaxation in JW; 95.2 +/- 2.6% TGL; 91.0 +/- 4.9%, TGH; 75.1 +/- 5.2%, p<0.05). Protein expression of angiotensin II type-1 receptor was increased in TGH and that of nitric oxide synthases-3 was attenuated in TGH compared with TGL. This is the first study showing that endothelium-dependent and -independent vascular relaxation under the condition of combined hyperlipidemia was severely impaired as compared to that under only hypercholesterolemia. These results suggest that hypertriglyceridemia aggravates functional impairment induced by hypercholesterolemia in endothelial and smooth muscle cells.

Animals↗

Dynamic 123I-BMIPP single-photon emission computed tomography in patients with congestive heart failure: effect of angiotensin II type-1 receptor blockade.

BACKGROUND: Heart failure is a major and growing public health problem with a high mortality rate. Although recent studies have demonstrated that a variety of metabolic and/or neurohumoral factors are involved in the progression of this syndrome, the precise mechanisms responsible for this complex condition are poorly understood. HYPOTHESIS: To examine 123I-beta-methyl-iodophenylpentadecanoic acid (BMIPP) kinetics in the early phase soon after tracer injection in patients with congestive heart failure (CHF), we performed dynamic single-photon emission computed tomography (SPECT). METHODS: Twenty-six patients with CHF and eight control subjects were examined. The consecutive 15 images of 2-min dynamic SPECT were acquired for 30 min after injection. In the early phase after injection (0-4 min), a significant amount of radioactivity existed in the blood pool. After 6 min, the myocardial 123I-BMIPP image was clear and thus the washout rate of 123I-BMIPP from 6 to 30 min was calculated. RESULTS: The washout rate of 123I-BMIPP from the myocardium was faster in patients with CHF than in the controls (8 +/- 4 vs. -5 +/- 3%, p < 0.01). The washout rate of 123I-BMIPP demonstrated positive correlation with left ventricular (LV) end-diastolic volume index (R = 0.54, p < 0.02) and inverse correlation with LV ejection fraction (R = 0.53, p <0.02). Patients were given the angiotensin II type-1 receptor antagonist candesartan for 6 months, and dynamic SPECT was repeated. The enhanced washout rate of 123I-BMIPP in CHF was reduced after treatment with candesartan (p < 0.05). CONCLUSION: These data suggest that (1) enhanced washout of 123I-BMIPP was observed soon after injection in patients with CHF, (2) the activation of angiotensin II signaling pathway is involved as an intracellular mechanism for enhanced 123I-BMIPP washout in heart failure, and (3) improvement in fatty acid metabolism may represent a new mechanism for beneficial effects of angiotensin II receptor blockade on cardiac function and survival in patients with heart failure. 123I-BMIPP washout in the early phase obtained from dynamic SPECT may be a new marker for evaluating the severity of heart failure and the effects of medical treatment.

Adult↗

Dynamic assessment of myocardial involvement in patients with end-stage renal disease by ultrasonic tissue characterization and serum markers of collagen metabolism.

BACKGROUND: Congestive heart failure is the most common cause of mortality in patients with end-stage renal disease (ESRD). However, noninvasive assessment for cardiac involvement in ESRD has not been established. HYPOTHESIS: Assessment of ultrasonic tissue characterization and serum markers of collagen degradation is useful for defining myocardial involvement in ESRD. METHODS: Cyclic variation of ultrasonic integrated backscatter of the ventricular septum (CV-IBS) and the serum levels of free matrix metalloproteinase-I (MMP-I) and tissue inhibitor of metalloproteinase-I (TIMP-I) were measured in 30 patients with ESRD undergoing routine hemodialysis (HD) and in 40 patients with essential hypertension (HTN). RESULTS: Compared with the group with HTN, ESRD (before HD) showed larger left ventricular (LV) mass index (217 +/- 56 vs. 146 +/- 45 g/m2, p < 0.01), worse LV diastolic function (E/A, 0.6 +/- 0.2 vs. 0.9 +/- 0.3, p < 0.05), smaller CV-IBS (9.0 +/- 1.3 vs. 12.4 +/- 0.9 dB, p < 0.01), and larger TIMP-I/MMP-I (46 +/- 10 vs. 34 +/- 10, p < 0.05), in spite of the comparable ventricular wall thickness. Thus, these indices may possibly reflect myocardial interstitial fibrosis. After HD (after the improvement of myocardial interstitial edema), a negative linear relationship between CV-IBS and TIMP-I/MMP-I was observed (r= -0.52, p < 0.05). CONCLUSIONS: Noninvasive assessment of ultrasonic tissue characterization and serum markers of collagen type I degradation may be a new diagnostic tool for defining myocardial interstitial fibrosis in patients with ESRD and LV hypertrophy.

Biomarkers↗