A new challenge for diagnostic and therapeutic strategies for acute pulmonary thromboembolism in Japan.
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Acute Disease↗
Biomedical subjects
Minoru Hongo
Publications and source records attributed to Minoru Hongo.
Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction.
Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34+/Flk-1+ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI.
Animals↗
Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats.
Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH.
Animals↗
In vitro fibrin clot formation and fibrinolysis using heterozygous plasma fibrinogen from gammaAsn319, Asp320 deletion dysfibrinogen, Otsu I.
INTRODUCTION: We have reported a heterozygous dysfibrinogenemia, fibrinogen Otsu I, caused by the deletion of gammaAsn319 and gammaAsp320, which was originally identified in the dysfibrinogen Vlissingen/Frankfurt IV (V/FIV) associated with thrombosis. Unlike the V/FIV family, the Otsu propositus showed no thrombotic tendencies. To analyze the relationship between thrombosis and the heterozygous plasma variant fibrinogen, we used purified plasma fibrinogen from the Otsu patient and compared it with a normal control. MATERIALS AND METHODS: Thrombin-induced fibrin clot formation and clot structure were observed by fibrin polymerization and scanning electron microscopy, respectively. For in vitro observation of fibrinolysis, plasmin generation and clot lysis assays were performed by the addition of tissue type plasminogen activation (tPA) and plasminogen. RESULTS AND CONCLUSIONS: Polymerization of Otsu was markedly impaired, while fibrin fibers were much thicker and the density of the bundles of fibrin fibers was less and porous compared with normal. Lysis of the Otsu clot was not significantly different from normal when a tPA and plasminogen mixture was overlaid onto the clots. For Otsu, the penetration of the tPA/plasminogen mixture into the clot was much faster than normal and the protection against plasmin cleavage was impaired; however, tPA-induced plasmin activation of the Otsu fibrin was slower than that of normal fibrin, resulting in a clot lysis of Otsu similar to normal.
Afibrinogenemia↗
Characteristics of metabolic and lifestyle risk factors in young Japanese patients with coronary heart disease: a comparison with older patients.
Coronary heart disease (CHD) is recognized as a lifestyle-related disease and is the second leading cause of death in Japan. However, the cardiac risk factor profile of young patients with CHD has not been clarified in suburban areas of Japan. Our study aimed to determine metabolic and lifestyle risk factors in young patients and compare them with older patients living in suburban areas of Nagano Prefecture. A multicenter study was conducted in 86 young (aged less than 40 years) and 91 older (aged 50 years and over) patients diagnosed with CHD from 1992 to 2002. There was a strong association between obesity and the occurrence of CHD events in young patients (odds ratio = 3.61, P = 0.006). Lifestyle in the young patients was characterized by a lack of physical activity and regular physical activity was found to decrease the risk of the CHD events in these patients (odds ratio = 0.31, P = 0.030). In older patients, hypertension was identified as an independent risk factor for CHD events. The results of the present study have demonstrated that obesity and a lack of regular physical exercise are independent risk factors for CHD events in younger patients. Thus, the data may be useful for the effective screening of high-risk individuals and the development of educational programs for the prevention of CHD, especially in younger Japanese.
Adult↗
Human amniotic mesenchymal cells have some characteristics of cardiomyocytes.
BACKGROUND: Cellular cardiomyoplasty (CCM) is a major method for the treatment of heart failure because adult cardiomyocytes do not regenerate after ischemic injury, which results in heart failure. There is a great deal of interest in finding suitable new cell sources for use in CCM. Here, we report that human amniotic mesenchymal cells (hAMC), which are multipotent cells derived from fetal mesoderm, may be a suitable cell source for CCM. METHODS: Freshly isolated hAMC were examined to detect the expression of cardiac-specific genes by reverse-transcription polymerase chain reaction and immunocytochemistry. hAMC were cocultivated with neonatal rat heart explants and transplanted into myocardial infarcts in the rat heart. RESULTS: hAMC expressed cardiac-specific transcription factor GATA4, cardiac-specific genes, such as myosin light chain (MLC)-2a, MLC-2v, cTnI, and cTnT, and the alpha-subunits of the cardiac-specific L-type calcium channel (alpha1c) and the transient outward potassium channel (Kv4.3). After stimulation with basic fibroblast growth factor (bFGF) or activin A, hAMC expressed Nkx2.5, a specific transcription factor for the cardiomyocyte and cardiac-specific marker atrial natriuretic peptide. In addition, the cardiac-specific gene alpha-myosin heavy chain was detected after treatment with activin A. Coculture experiments confirmed that hAMC were able to both integrate into cardiac tissues and differentiate into cardiomyocyte-like cells. After transplantation into the myocardial infarcts in rat hearts, hAMC survived in the scar tissue for at least 2 months and differentiated into cardiomyocyte-like cells. CONCLUSION: The results of the present study suggest that hAMC possess some characteristics of cardiomyocytes.
Amnion↗
Mycophenolate mofetil prevents the development of experimental autoimmune myocarditis.
Experimental autoimmune myocarditis (EAM) is characterized by the appearance of multinucleated giant cells. EAM leads to severe myocardial damage and is a useful model of human giant cell myocarditis. We investigated whether mycophenolate mofetil (MMF), which is a potent immunosuppressant, prevents the development of myocarditis in a rat EAM model, and focused on the role of osteopontin (OPN) in the pathogenesis of this disorder. Adult Lewis rats were immunized with porcine cardiac myosin to establish EAM. The early MMF treatment completely prevented the development of EAM, and the late MMF treatment was also effective even against established EAM. Echocardiogram demonstrated that left ventricular function was also improved by the treatment with MMF. Real-time RT-PCR analysis showed that both early and late MMF treatments significantly inhibited myocarditis-induced OPN mRNA expression in the heart. Immunohistochemistry revealed that OPN expression was prominent in the myocardium on day 14, whereas expression was observed in the infiltrated macrophages on day 21. Mycophenolic acid (MPA) did inhibit agonist-induced OPN expression in cultured cardiomyocytes. These results show the therapeutic potential of MMF for autoimmune myocarditis and provide new insights into the pathogenesis of this disease.
Animals↗
Effects of nicorandil on monocrotaline-induced pulmonary arterial hypertension in rats.
We investigated whether nicorandil might prevent and reverse monocrotaline (MCT)-induced pulmonary arterial hypertension. Rats were injected with 50 mg/kg of MCT subcutaneously and randomized to either 7.5 mg/kg/d of nicorandil in drinking water or placebo for 3 weeks. Animals that were treated with MCT and survived for 3 weeks were assigned to either nicorandil or placebo. Nicorandil markedly attenuated pulmonary arterial hypertension with severe structural remodeling of the pulmonary vessels. The survival rate at 3 weeks after treatment was significantly increased in the nicorandil group compared with the placebo group (73% versus 39%, P<0.05). In the placebo group, endothelial nitric oxide synthase (eNOS) protein was significantly decreased, the numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen-positive cells were increased in the lung tissue, and P-selectin was intensely expressed on the endothelium of the pulmonary arteries. These features were prevented by nicorandil. Late treatment with nicorandil did not palliate established pulmonary arterial hypertension nor improved survival. Thus, nicorandil inhibited development of MCT-induced pulmonary arterial hypertension but failed to reverse it. These effects were associated with marked up-regulation of diminished lung eNOS protein along with improvement of pulmonary vascular endothelial activation and anti-inflammatory and anti-proliferative effects in the lung tissue.
Animals↗
Seasonal difference in onset of coronary heart disease in young Japanese patients: a comparison with older patients.
BACKGROUND: The aim of the present multicenter study was to investigate whether there is a seasonal difference in the onset of coronary heart disease (CHD) in young patients compared with older patients living in Nagano Prefecture, Japan. METHODS AND RESULTS: The study group comprised 101 young (aged < or = 40 years) and 94 older (aged > or =50 years) patients diagnosed with CHD from 1992 to 2002. In young patients, the prevalence of the onset of CHD events was significantly higher from June to September than from December to March (odds ratio =2.23, p=0.035). Obesity was found in 56%, hypertension in 29%, dyslipidemia in 54%, diabetes in 24%, smoking history in 82%, and habitual physical activity in 13% in young patients. There was a trend for an association between the presence of acute myocardial infarction (p=0.082) and history of smoking and the onset of CHD events during the summer months in young patients (p=0.077). CONCLUSIONS: There is a seasonal difference in the onset of CHD events, with an increase in the prevalence during the summer months in young patients. The data may provide insights into preventive approaches to CHD in the young population.
Adult↗
Trends over the last 20 years in the clinical background of young Japanese patients with coronary artery disease.
BACKGROUND: The prevalence, pathogenesis, and clinical background of coronary artery disease (CAD) in patients aged 40 years or less in Japan are not well understood. METHODS AND RESULTS: Temporal trends in the clinical background, including growth from childhood, of young patients with CAD over the last 20 years were examined. The study group comprised 38 patients who were 40 years of age or less (7 patients in 1980-84, phase I; 10 patients in 1985-89, phase II; 10 patients in 1990-94, phase III; 11 patients in 1995-99, phase IV). Among the classic coronary risk factors, obesity significantly increased in prevalence. An increase in patients with multiple risk factors was seen (0, 10%, 20%, and 36% in phases I, II, III, and IV, respectively). There was no significant change in the prevalence of familial hypercholesterolemia, sequelae of Kawasaki disease or vasospastic angina. All phase III and IV patients with multiple risk factors had moderate to severe obesity, and 83% had been overweight since childhood. CONCLUSIONS: These results suggest that the number of young patients with CAD because of multiple risk factors has been increasing, and most of them have been overweight since childhood. Thus, for primary prevention it is essential to control cardiovascular risk factors in overweight children.
Adolescent↗
Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats.
OBJECTIVES: It has been reported that serotonin (5-HT) is involved in the development of pulmonary arterial hypertension (PAH) with pulmonary vascular remodeling. The purpose of the present study was to examine the role of a 5-HT2A receptor antagonist, sarpogrelate hydrochroride, in preventing or reversing monocrotaline (MCT)-induced PAH in rats. METHODS: Rats were injected with 40 mg/kg of MCT subcutaneously and randomized to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for 3 weeks. Animals treated with MCT and survived for 3 weeks were assigned to either sarpogrelate (50 mg/kg, intraperitoneally) or placebo for next 3 weeks. The animals had pressure measurement of the pulmonary artery, and then underwent histologic, immunohistochemical, and Western blot analyses of the lung tissue. Survival rate was also assessed after treatment. RESULTS: Sarpogrelate immediately following MCT injection suppressed PAH with severe pulmonary vascular remodeling and right-sided heart failure. The survival rate was significantly increased in the sarpogrelate-treated group compared with the placebo group (71% vs. 44%, p<0.05). Intense expression of P-selectin was found on the endothelium of the pulmonary arteries in the placebo group, and it was markedly attenuated in the sarpogrelate-treated group. The numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen (PCNA)-positive cells in the lung tissue were significantly increased in the placebo group, and the increases in these cells were prevented by sarpogrelate. Endothelial nitric oxide synthase (eNOS) expression in the lung tissue was markedly decreased in the placebo group, but it was prevented by sarpogrelate (p<0.001). In contrast, late treatment with sarpogrelate failed to reverse established PAH. CONCLUSIONS: Specific 5-HT2A receptor blockade with sarpogrelate immediately after MCT inhibited PAH and prolongs survival in rats. These effects were accompanied by anti-inflammatory and anti-proliferative effects in the lung tissue and marked improvement of pulmonary vascular endothelial dysfunction and activation.
Animals↗
Effects of Hct and norepinephrine on segmental vascular resistance distribution in isolated perfused rat livers.
We studied the effects of blood hematocrit (Hct), blood flow, or norepinephrine on segmental vascular resistances in isolated portally perfused rat livers. Total portal hepatic venous resistance (Rt) was assigned to the portal (Rpv), sinusoidal (Rsinus), and hepatic venous (Rhv) resistances using the portal occlusion (Ppo) and the hepatic venous occlusion (Phvo) pressures that were obtained during occlusion of the respective line. Four levels of Hct (30%, 20%, 10%, and 0%) were studied. Rpv comprises 44% of Rt, 37% of Rsinus, and 19% of Rhv in livers perfused at 30% Hct and portal venous pressure of 9.1 cmH2O. As Hct increased at a given blood flow, all three segmental vascular resistances of Rpv, Rsinus, and Rhv increased at flow >15 ml/min. As blood flow increased at a given Hct, only Rsinus increased without changes in Rpv or Rhv. Norepinephrine increased predominantly Rpv, and, to a smaller extent, Rsinus, but it did not affect Rhv. Finally, we estimated Ppo and Phvo from the double occlusion maneuver, which occluded simultaneously both the portal and hepatic venous lines. The regression line analysis revealed that Ppo and Phvo were identical with those measured by double occlusion. In conclusion, changes in blood Hct affect all three segmental vascular resistances, whereas changes in blood flow affect Rsinus, but not Rpv or Rhv. Norepinephrine increases mainly presinusoidal resistance. Ppo and Phvo can be obtained by the double occlusion method in isolated perfused rat livers.
Animals↗
T-wave alternans in patients with right ventricular tachycardia.
Microvolt T-wave alternans has been proposed as a new risk marker for ventricular arrhythmias. However, the clinical significance of T-wave alternans in patients with ventricular tachycardia (VT) originating from the right ventricle has been unknown. The study population consisted of 20 patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic VT. T-wave alternans was measured during bicycle exercise testing using the CH 2000 system. Of the 7 patients with ARVC, 6 (86%) were positive for T-wave alternans. On the other hand, only 1 (8%) of 13 patients with idiopathic VT originating from the right-ventricular outflow tract was positive for T-wave alternans.
Adipocytes↗
Fibrinogen Otsu I:A gammaAsn319,Asp320 deletion dysfibrinogen identified in an asymptomatic pregnant woman.
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Adult↗
Effects of angiotensin-converting enzyme inhibition on changes in left ventricular myocardial creatine kinase system after myocardial infarction: their relation to ventricular remodeling and function.
We assessed the effects of angiotensin-converting enzyme (ACE) inhibition on changes in the myocardial intracellular creatine kinase (CK) system in relation to left ventricular (LV) remodeling and function in heart failure after myocardial infarction (MI) in rats. We compared the findings at 4 weeks after MI to those at 12 weeks after MI. LV weight and chamber size were significantly increased and percent fractional shortening (%FS) was decreased in untreated MI rats compared with normal control animals both at 4 and 12 weeks after MI. Animals with MI and treated with the ACE inhibitor temocapril showed significantly reduced LV weight and chamber size and increased %FS compared with untreated MI rats at 12 weeks after MI, but not at 4 weeks after MI. At 4 weeks after MI, no significant changes were found in the total creatine and relative distribution of each CK isoenzyme in either the temocapril-treated or untreated animals with MI compared with the normal controls. In contrast, at 12 weeks after MI, untreated MI rats showed significant reductions in the total creatine and mitochondrial and MM-CK fractions and increases in the MB- and BB-CK fractions compared with the controls. The alterations in the mitochondrial and MB-CK fractions were significantly attenuated after 12 weeks of ACE inhibition. Thus, LV myocardial energy metabolism is progressively impaired and its alteration is not related to the magnitude of geometric changes and LV dysfunction after MI. Most of the beneficial effects of ACE inhibition were observed at 12 weeks after MI. Our results may provide an insight into the therapeutic strategy of ACE inhibition in chronic heart failure after MI.
Angiotensin-Converting Enzyme Inhibitors↗
Iodine-123 metaiodobenzylguanidine scintigraphic analysis of myocardial sympathetic innervation in patients with AL (primary) amyloidosis.
BACKGROUND: Although a high incidence of myocardial adrenergic denervation has been reported in patients with familial amyloid polyneuropathy, assessment of cardiac sympathetic nerve function has not been available in patients with AL (primary) amyloidosis. METHODS: To test the hypothesis that myocardial sympathetic nerve innervation might be impaired and variable according to the presence or absence of clinical autonomic abnormalities and congestive heart failure in AL amyloidosis, we examined 25 patients by use of iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: Ten of the 16 patients without autonomic symptoms and 5 of the 9 patients with autonomic neuropathy showed congestive heart failure. The heart/mediastinal activity (H/M) ratio (1.53 +/- 0.06 vs 1.29 +/- 0.05 at 3 hours, P <.001) and myocardial washout ratio (41.5% +/- 4.8% vs 30.8% +/- 4.0%, P <.001) of MIBG were significantly increased in patients without autonomic symptoms compared with patients showing autonomic neuropathy. In patient groups with and without autonomic dysfunction, patients demonstrating congestive heart failure exhibited a significantly decreased H/M ratio and increased washout compared with patients with no heart failure, and left ventricular fractional shortening was positively correlated with the H/M ratio and inversely correlated with the washout ratio. There were significant correlations between the low-frequency component of the heart rate variability and the H/M ratio and washout ratio in the entire patient population. CONCLUSIONS: Patients with AL amyloidosis and no autonomic dysfunction showed variable degrees of enhanced cardiac adrenergic neuronal activity with presynaptic sympathetic dysfunction. In contrast, patients with AL amyloidosis and autonomic neuropathy exhibited prominent myocardial adrenergic denervation with normal or impaired sympathetic neural function of the heart. This study demonstrates that myocardial uptake and turnover of MIBG in patients with AL amyloidosis are heterogeneous and dependent on the presence or absence of congestive heart failure and cardiac autonomic dysfunction.
3-Iodobenzylguanidine↗
The high zero-flow pressure phenomenon in coronary circulation: a simulation study.
A dynamic simulation was performed in order to study the high zero-flow pressure phenomenon by using an electronic model of the coronary vessel. The objective of this study was to establish a relationship between the diastolic arterial pressure and diastolic arterial flow. The simulated study showed that this relationship is approximately linear with a zero flow pressure intercept of approximately 40 mmHg. This result is consistent with the results obtained in animal experimentation conducted by others.
Arteries↗
Diurnal variation in QT dispersion in patients with chronic heart failure.
QT dispersion is defined as the difference in QT interval among the different leads of the standard 12-lead electrocardiogram and reflects inhomogeneity of myocardial repolarization. Dispersion of repolarization is an important electrophysiologic feature that is considered fundamental for the initiation of ventricular fibrillation. However, no data exist regarding the diurnal variation of QT dispersion measured from simultaneous 12-lead recording in chronic heart failure patients. The aim of this study was to identify diurnal variation in QT dispersion in patients with chronic heart failure. QT dispersion was measured in the 12-lead standard electrocardiogram in 11 patients with chronic heart failure. QT dispersion in these patients was increased in the afternoon compared to the morning. It is concluded that QT dispersion has a clear diurnal variation in patients with chronic heart failure. These findings have potentially significant implications for therapy and prevention of sudden cardiac death in patients with chronic heart failure.
Adult↗