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Biomedical subjects

Yoshihiro Fukumoto

Publications and source records attributed to Yoshihiro Fukumoto.

At least 19 recordsLinked to original sources
PubMed2006

Inhibitory effects of edaravone on the production of tumor necrosis factor-alpha in the isolated heart undergoing ischemia and reperfusion.

We evaluated the effects of edaravone, a hydroxyl radical scavenging agent, on the production of tumor necrosis factor-alpha (TNF-alpha) in myocardium, and the release of TNF-alpha and P-selectin from myocardium after ischemia-reperfusion injury in isolated Langendorff-perfused rat hearts. Cardiodynamic function at stable points during perfusion and 5, 15, 30, and 60 min after the initiation of reperfusion was evaluated by left ventricular developed pressure, rate of increase in left ventricular pressure and rate of decrease in ventricular pressure, coronary flow, and heart rate. At 60 min after the initiation of reperfusion, myocardial infarct size was estimated microscopically using triphenyltetrazolium chloride staining, and expression of TNF-alpha in myocardium was detected by Western blot and immunohistochemistry. At the same time points as the measurement of cardiodynamic function, TNF-alpha and the soluble form of P-selectin in coronary effluent were measured by enzyme immunoassay. At all time points during reperfusion, edaravone markedly improved cardiodynamic function and reduced myocardial infarct size in comparison to the control. In myocardium in the control, TNF-alpha was detected in the endothelial cells and other cells bearing some resemblance to interstitial cells and monocyte cells. Edaravone suppressed this cytokine expression in the corresponding sites. P-selectin as well as TNF-alpha was found in the coronary effluent of the control, and edaravone significantly decreased soluble P-selectin levels in comparison to the control (P < 0.01). Edaravone might have protective effects on cardiac function through reduction of infarct size via decrease of production of TNF-alpha in myocardium induced by ischemia-reperfusion injury and through reduction of the release of adhesion molecules such as P-selectin from vascular endothelial cells.

Analysis of Variance↗
PubMed2006

Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease.

OBJECTIVE: Prognosis of severe coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting remains poor. We have recently demonstrated that shock wave therapy effectively induces neovascularization and improves myocardial ischemia in a porcine model in vivo. METHODS: With permission from the Ethical Committee of our Institute, we treated nine patients with end-stage coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting (55-82 years old, five men and four women) with our cardiac shock wave therapy (200 shots/spot at 0.09 mJ/mm for 20-40 spots, 3 times a week/series). We followed-up the patients at 1, 3, 6, and 12 months after the therapy to examine the amelioration of myocardial ischemia. When needed, shock wave therapy was performed up to three series at 0, and 1, 3 or 6 months. RESULTS: The cardiac shock wave therapy improved symptoms (Canadian Cardiovascular Society functional class score, from 2.7+/-0.2 to 1.8+/-0.2, P<0.01) and reduced nitroglycerin use (from 5.4+/-2.5 to 0.3+/-0.3/week, P<0.05). The treatment also improved myocardial perfusion as assessed by dipyridamole stress thallium scintigraphy (severity score, 25.2+/-7.2% improvement, P<0.05; extent score, 23.3+/-9.0% improvement, P=0.10; washout rate, 20+/-3 to 34+/-3, P<0.05). Myocardial perfusion was improved only in the ischemic area treated with the therapy. These beneficial effects persisted for 12 months. No procedural complications or adverse effects were noted. CONCLUSION: These results indicate that our extracorporeal cardiac shock wave therapy is an effective and non-invasive treatment for end-stage coronary artery disease, although further careful evaluation is needed.

Aged↗
PubMed2006

Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in mice.

Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells for which no satisfactory treatment has yet been developed. It has been recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis and that long-term inhibition of Rho-kinase markedly ameliorates monocrotaline-induced PH in rats. However, it remains to be examined whether direct inhibition of Rho-kinase also ameliorates PH with a different etiology and whether endothelial nitric oxide synthase (eNOS) is involved in the beneficial effects of Rho-kinase inhibition. This study was designed to address those 2 important issues in a hypoxia-induced PH model using wild-type (WT) and eNOS-deficient (eNOS) mice. Long-term blockade of Rho-kinase with fasudil (100 mg/kg/d) for 3 weeks markedly improved PH and right ventricular hypertrophy in WT mice with a lesser but significant inhibition noted in eNOS mice. Fasudil upregulated eNOS with increased Akt phosphorylation in WT but not in eNOS mice. These results suggest that long-term inhibition of Rho-kinase also ameliorates hypoxia-induced PH in mice, for which eNOS activation may partially be involved.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Fatal case of amiodarone-induced acute respiratory distress syndrome in a patient with severe left ventricular dysfunction due to extensive anterior acute myocardial infarction.

We here report a case of 71-year-old man with acute extensive anterior myocardial infarction, who was complicated with ventricular tachycardia (VT) even after successful percutaneous coronary intervention. As intravenous administration of nifekalant terminated VT, we started oral administration of amiodarone (day 1). We gave 400 mg of amiodarone a day for the first week and 200 mg a day from the second week. The patient was stable with normoxia by day 20, in spite of pulmonary congestion-like infiltrates on chest X-ray. On day 21, he was complicated with acute respiratory distress syndrome. Immediate discontinuance of amiodarone and high-dose pulse glucocorticoid therapy with intubation slightly improved the infiltrations on chest X-ray. However, glucocorticoid therapy induced hyperglycemia with an increase in plasma osmolality, complicated with hypoalbuminemia, and gastrointestinal bleeding. Despite treatment with a large amount of saline, high-doses of catecholamines, and blood transfusion, the patient died on day 28. It is sometimes difficult to diagnose congestive heart failure or amiodarone-induced pulmonary infiltrates in patients with severe left ventricular dysfunction.

Aged↗
PubMed2005

Combination therapy with cerivastatin and nifedipine improves endothelial dysfunction after balloon injury in porcine coronary arteries.

HMG-CoA reductase inhibitors and calcium channel blockers have antiatherogenic effects; however, their mechanisms remain to be elucidated. This study examined the effect of cerivastatin and/or nifedipine on the endothelial dysfunction in porcine balloon-injured coronary arteries. Normal male pigs were randomly divided into the following four groups: control, cerivastatin (1 mg/kg/d PO), nifedipine (4 mg/kg/d PO), and their combination (n = 10 each). We started the treatments 3 days before balloon injury in the proximal left coronary arteries and continued for 4 weeks after the procedure. Then, we examined endothelial vasodilator functions ex vivo in organ chambers and in vitro by Western blotting for eNOS expression. Endothelium-dependent relaxations to serotonin, but not those to bradykinin or the calcium ionophore A23187 or endothelium-independent relaxations to sodium nitroprusside, were significantly impaired by balloon injury. The monotherapy with cerivastatin or nifedipine partially improved, and their combination supernormalized the relaxations to serotonin without affecting those to bradykinin or A23187 or endothelium-independent relaxations to sodium nitroprusside. The expression of eNOS was significantly reduced by balloon injury and normalized by the combination therapy. These results indicate that the combination therapy improves endothelial dysfunction after balloon injury, in which the up-regulation of eNOS may be involved.

Administration, Oral↗
PubMed2005

Coronary microvascular dysfunction in patients with microvascular angina: analysis by TIMI frame count.

We have previously reported that angina pectoris persists in patients with coronary microvascular spasm (MVS) even on calcium channel blockers. Because measurement of myocardial lactate production in the coronary sinus is necessary to diagnose MVS, a more feasible diagnostic method needs to be developed. In this study, we examined the diagnostic significance of Thrombolysis in Myocardial Infarction (TIMI) frame count, a marker of coronary blood flow, in 131 consecutive patients who underwent provocation test for coronary spasm with acetylcholine (ACh). Epicardial coronary spasm (ES) was diagnosed as more than 75% of ACh-induced vasoconstriction noted by coronary angiography. MVS was diagnosed as ACh-induced myocardial ischemia (chest pain, ischemic ECG changes, and myocardial lactate production) without ES. TIMI frame count was significantly increased in patients with MVS alone (n = 35) and those with ES + MVS (n = 16) compared with those with ES alone (n = 53) or those with no myocardial ischemia (Normal, n = 27) either before and after intracoronary ACh and even after intracoronary isosorbide dinitrate (ISDN) in both the left anterior descending (LAD) and the left circumflex coronary artery (LCX). TIMI frame count in LAD correlated well to that in LCX in patients with MVS, suggesting diffuse impaired coronary microcirculation in the myocardium. These results suggest that increased TIMI frame count in response to ACh reflects microvascular dysfunction in MVS and that ISDN may not be enough to relieve MVS. Thus, TIMI frame count may be useful to diagnose MVS without requiring coronary sinus catheterization or myocardial lactate production measurement.

Acetylcholine↗
PubMed2004

Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques.

BACKGROUND: We hypothesized that collagenolytic activity produced by activated macrophages contributes to collagen loss and the subsequent instability of atheromatous lesions, a common trigger of acute coronary syndromes. However, no direct in vivo evidence links collagenases with the regulation of collagen content in atherosclerotic plaques. METHODS AND RESULTS: To test the hypothesis that collagenases influence the structure of atheromata, we examined collagen accumulation in atherosclerotic lesions of apolipoprotein E-deficient mice (apoE-/-) that express collagenase-resistant collagen-I (ColR/R/apoE-/-, n=12) or wild-type collagen-expressing mice (Col+/+/apoE-/-, n=12). Aortic atheromata of both groups had similar sizes and numbers of macrophages, a major source of collagenases. However, aortic intimas from ColR/R/apoE-/- mice contained fewer smooth muscle cells, a source of collagen, probably because of decreased migration or proliferation or increased cell death. Despite reduced numbers of smooth muscle cells, atheromata of ColR/R/apoE-/- mice contained significantly more intimal collagen than did those of Col+/+/apoE-/- mice. CONCLUSIONS: These results establish that collagenase action regulates plaque collagen turnover and smooth muscle cell accumulation.

Amino Acid Substitution↗
PubMed2004

Wild-type but not interferon-gamma-deficient T cells induce graft arterial disease in the absence of B cells.

OBJECTIVE: Interferon-gamma (IFN-gamma), a cytokine produced primarily by T cells and by activated macrophages, plays a central role in the pathogenesis of graft arterial disease (GAD). This study investigated whether T cells can induce GAD in the absence of humoral alloresponses and whether activated macrophages or other host cell types can substitute as sources of IFN-gamma in GAD. METHODS: Wild-type (WT), IFN-gamma-/-, or recombination-activating-gene-1-/- (RAG-1-/-; lacking mature T and B cells) mice received MHC II-disparate hearts. The grafts were harvested 8 weeks post-transplant and histological and immunohistochemical analyses, RNase protection assay (RPA), and flow cytometry were used to evaluate GAD lesions, infiltrating cell populations, and IFN-gamma expression by infiltrating cells. RESULTS: Moderate-to-severe GAD developed in WT recipient allografts, associated with abundant IFN-gamma expression by both infiltrating T cells and macrophages. No GAD developed in IFN-gamma-/- or in RAG-1-/- hosts, nor was any IFN-gamma expression evident. RAG-1-/- hosts receiving naïve WT or IFN-gamma-/- T cells (10(7)) after heart transplantation demonstrated no mature B cells but showed persistence of transferred T cells up to 8 weeks post-transplant. In the complete absence of B cells and alloantibody, transfer of WT T cells into RAG-1-/- recipients yielded GAD, with associated IFN-gamma expression by the transferred T cells and the host macrophages. Transfer of IFN-gamma-/- T cells induced neither GAD nor host macrophage IFN-gamma expression. CONCLUSIONS: T cells, even in the absence of B cells, suffice to induce GAD, and T cell-derived IFN-gamma plays a critical role in GAD pathogenesis.

Adoptive Transfer↗
PubMed2004

Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery.

We have recently demonstrated that fasudil, a Rho-kinase inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the inhibitory effect of fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosorbide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2004

Changing characteristics of patients with vasospastic angina in the era of new calcium channel blockers.

In the 1980s, clinical characteristics and long-term prognosis of patients with vasospastic angina (VSA) were investigated; however, they remain to be updated after the introduction of new calcium channel blockers, benidipine and amlodipine, in 1990s. Our patient cohort registered 726 patients with VSA from January 1980 to December 2002. Before and after 1990, 138 and 527 patients were respectively entered in this study with a follow-up rate of 92%. Most of the patients were treated with calcium channel blockers, while benidipine and amlodipine were used in 28% and 21% of them only after 1990. Survival without cardiovascular events (96% versus 96%) at 5 years remained good before and after 1990. The presence of significant coronary stenosis had a negative prognostic impact both before and after 1990, whereas after 1990, diabetes mellitus, smoking, and a history of myocardial infarction became more influential. Among the calcium channel blockers, benidipine showed a better prognosis. These results suggest that in the era of new calcium channel blockers, the prognosis of patients with VSA remains good with more prognostic impact of diabetes mellitus, smoking, and a history of myocardial infarction and that benidipine might have some better prognostic effects.

Administration, Sublingual↗
PubMed2004

[Inhibition of Rho-kinase by fasudil preventing anginal attacks associated with spastic angina: a case report].

An 86-year-old woman was admitted with unstable angina pectoris. Plain old balloon angioplasty (POBA) was performed for 90% stenosis at segment 7 of the left coronary artery with concomitant treatment with nitrate, calcium antagonists, and nicorandil. Five days after POBA, she again suffered chest pain at rest with ST depression by electrocardiography, despite increased doses of calcium-antagonist and nicorandil. Coronary arteriography showed no evidence of restenosis (50%) at the POBA site. The involvement of coronary artery spasm was considered and intravenous treatment with a Rho-kinase inhibitor, fasudil, was started, which resulted in disappearance of the anginal attacks. She refused to continue the fasudil treatment on day 5, which resulted in reappearance of anginal attacks. Third coronary angiography showed a 90% restenosis at POBA site and percutaneous coronary intervention was again performed. This case suggests that a Rho-kinase inhibitor is potentially effective to prevent anginal attacks in spastic angina.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2003

Long-term inhibition of Rho-kinase suppresses neointimal formation after stent implantation in porcine coronary arteries: involvement of multiple mechanisms.

OBJECTIVE: We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved. METHODS AND RESULTS: Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg per day orally), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. On day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-beta1 expression were noted at the stent site, and all were significantly suppressed by fasudil. On day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis on day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-1and bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil. CONCLUSIONS: These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2003

The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: a prospective study.

BACKGROUND: Cholesterol embolization syndrome is a systemic disease caused by distal showering of cholesterol crystals after angiography, major vessel surgery, or thrombolysis. METHODS: We prospectively evaluated a total of 1,786 consecutive patients 40 years of age and older, who underwent left-heart catheterization at 11 participating hospitals. The diagnosis of CES was made when patients had peripheral cutaneous involvement (livedo reticularis, blue toe syndrome, and digital gangrene) or renal dysfunction. RESULTS: Twenty-five patients (1.4%) were diagnosed as having CES. Twelve patients (48%) had cutaneous signs, and 16 patients (64%) had renal insufficiency. Eosinophil counts were significantly higher in CES patients than in non-CES patients before and after cardiac catheterization. The in-hospital mortality rate was 16.0% (4 patients), which was significantly higher than that without CES (0.5%, p < 0.01). All four patients with CES who died after cardiac catheterization had progressive renal dysfunction. The incidence of CES increased in patients with atherosclerotic disease, hypertension, a history of smoking, and the elevation of baseline plasma C-reactive protein (CRP) by univariate analysis. The femoral approach did not increase the incidence, suggesting a possibility that the ascending aorta may be a potential embolic source. As an independent predictor of CES, multivariate regression analysis identified only the elevation of pre-procedural CRP levels (odds ratio 4.6, P = 0.01). CONCLUSIONS: Cholesterol embolization syndrome is a relatively rare but serious complication after cardiac catheterization. Elevated plasma levels of pre-procedural CRP are associated with subsequent CES in patients who undergo vascular procedures.

Acute Kidney Injury↗
PubMed2002

Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma.

BACKGROUND: Lipid lowering may reduce acute coronary events in patients in part by reducing vascular inflammation. Oxidative stress induces endothelial cell (EC) expression of vascular cell adhesion molecule 1 (VCAM-1) and monocyte chemoattractant protein 1 (MCP-1) and reduces levels of atheroprotective NO, leading to monocyte recruitment and macrophage accumulation. This study tested the hypothesis that lipid lowering decreases oxidative stress and improves EC functions related to inflammatory cell accumulation. METHODS AND RESULTS: Rabbits consumed an atherogenic diet for 4 months to produce atheroma, followed by a purified chow diet for 16 months. Atherosclerotic aortas from hypercholesterolemic rabbits produced high levels of reactive oxygen species. Oxidized LDL (oxLDL) accumulated in atheroma underlying ECs that overexpress VCAM-1. In contrast, few if any ECs in atheroma stained for endothelial NO synthase (eNOS). Lipid lowering reduced reactive oxygen species production, oxLDL accumulation, and plasma levels of anti-oxLDL IgG. After lipid lowering, VCAM-1 and MCP-1 expression decreased, eNOS expression increased, and ECs exhibited a more normal ultrastructure. CONCLUSIONS: These results establish that lipid lowering can reduce oxidative stress and EC activation in vivo. These mechanisms may contribute to improvement in endothelial function and plaque stabilization observed clinically.

Animals↗
PubMed2002

Augmented vasodilator response to L-arginine after coronary angioplasty may attenuate restenosis.

Nitric oxide (NO) plays an important role in the control of vascular tone as well as structure. This study examined the possibility that the extent of restenosis 3 months after percutaneous transluminal coronary angioplasty (PTCA) might be correlated with the magnitude of NO production at the PTCA sites on the day following PTCA. In 23 consecutive patients who underwent PTCA, we examined the coronary artery diameter response to intracoronary administration of L-arginine (1 microg/kg) and isosorbide dinitrate (ISDN, 40 microg/kg) at the sites of PTCA (n = 25) and at untreated sites distal to the PTCA sites approximately 18 h after PTCA. The coronary artery diameter at the PTCA site was determined 3 months after PTCA in all patients. Normalized vasodilator responses to L-arginine (responses to L-arginine/those to ISDN) were greater at the PTCA sites than at the untreated sites (P = 0.05), whereas vasodilator responses to ISDN did not differ between the PTCA and untreated sites. These results suggest a greater production of NO at the PTCA sites despite presumable loss of the endothelium due to the PTCA. Furthermore, the magnitude of normalized vasodilator responses to L-arginine examined at 18 h after PTCA correlated with the coronary artery diameter 3 months after PTCA (r = 0.592, P = 0.002). These results suggest that augmented NO production after PTCA may protect against the development of coronary restenosis. Treatment that enhances local NO production may be clinically useful in preventing restenosis after PTCA.

Angina Pectoris↗