Biomedical subjects
Kunio Hiwada
Publications and source records attributed to Kunio Hiwada.
Efficacy and safety of the selective aldosterone blocker eplerenone in Japanese patients with hypertension: a randomized, double-blind, placebo-controlled, dose-ranging study.
Approximately 40% of Japanese patients with essential hypertension, including low-renin hypertension, are inadequately managed. Low-renin hypertension generally responds poorly to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, but may respond more optimally to diuretics, calcium channel blockers, and aldosterone blockers. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study evaluated the efficacy and safety of the selective aldosterone blocker eplerenone in 193 Japanese patients with essential hypertension. Although not a study inclusion criterion, baseline active plasma renin levels were consistently low (5.7-10.1 mU/L); most patients met the criteria for low-renin hypertension (< or =42.5 mU/L; normal range, 7-76 mU/L). Patients received placebo or eplerenone 50, 100, or 200 mg once daily for 8 weeks. Systolic blood pressure decreased significantly (-6.8 to -10.6 mm Hg vs. -2.1 mm Hg; p< or =0.0022 vs. placebo). Eplerenone offers significant blood pressure reduction with good tolerability in Japanese patients with hypertension, including those with low-renin hypertension.
17-year follow-up study of a patient with obstructive hypertrophic cardiomyopathy with a deletion mutation in the cardiac myosin binding protein C gene.
A 60-year-old Japanese man with obstructive hypertrophic cardiomyopathy was found to have a mutation in the cardiac myosin binding protein C gene: a single base deletion of a thymidine residue at nucleotide 11645 (codon 593) in exon 18. He was diagnosed at the age of 43 and has been followed for 17 years. During this follow-up period, echocardiograms and mechanocardiograms revealed progressive hypertrophy until the age of 54, then gradual dilation of the left ventricle associated with a decrease in the obstruction. Paroxysmal atrial fibrillation occurred at the age of 52 and progressed to chronic atrial fibrillation at the age of 53. He had congestive heart failure at the age of 58.
Ischemia in the territory of the first major septal perforator branch anomalously originating from the first diagonal branch leads to a transient leftward shift of the QRS axis in the frontal plane: a case report.
A patient with non-Q wave myocardial infarction had severe luminal narrowing in the first major septal perforator branch, which arose anomalously from the first diagonal branch. In this case, an exercise ECG showed a transient leftward QRS axis shift.
Guidelines for treatment of hypertension in the elderly--2002 revised version.
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Serum cystatin C level is a marker of end-organ damage in patients with essential hypertension.
High urinary albumin excretion rate (AER) has been associated with the presence of atherosclerotic vascular damages and is an independent risk factor for all causes of death and cardiovascular morbidity and mortality in essential hypertensive patients. Serum cystatin C (s-CC) is a recently identified nonglycosylated 13-kD basic protein that has been suggested to be a useful marker of glomerular filtration rate. In the present study, we investigated the relationship between s-CC level and end-organ damages in the kidney, heart, and vessels of patients with essential hypertension. Sixty patients with essential hypertension participated in the present study. Patients with renal failure were excluded. Serum-CC level was measured by a particle-enhanced turbidimetric assay. Left ventricular mass index (LVMI) and intima media thickness (IMT) in the common carotid arteries were evaluated by ultrasound images. Twenty-four-hour blood pressure was measured by a cuff-oscillometric method. Serum-CC level was negatively correlated with creatinine clearance (r=-0.617, p<0.0001). It was also correlated with mean 24-h systolic blood pressure (24h-SBP) (r=0.308, p= 0.0167), LVMI (r=0.528, p<0.0001), and IMT (r=0.539, p<0.0001). Both AER and s-CC level were independently associated with mean 24h-SBP. AER but not s-CC level was associated with HDL-cholesterol. The present study was the first to demonstrate that s-CC level is a useful and convenient parameter of renal function, and may also prove to be an early marker of the severity of end-organ damage in patients with essential hypertension.
[Successful treatment of bronchiolitis obliterans organizing pneumonia with cyclosporin and steroids].
A 71-year-old woman with fever and dry cough was admitted to our hospital. Chest computed tomography, bronchoalveolar lavage and transbronchial lung biopsy were performed, and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed. The patient was treated with corticosteroid, and marked improvement was noted. However, when the dosage was tapered, the BOOP recurred. We increased the dosage of corticosteroid and also put the patient on a daily regimen of cyclosporin. The cyclosporin was administered orally, and was effective, so that we could gradually decrease the dosage of corticosteroid. We concluded that cyclosporin may be useful in the treatment of refractory BOOP.
Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma.
CCAAT/enhancer-binding proteins (C/EBPs) upregulate transcription of various inflammatory cytokines and acute phase proteins, such as interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and cyclooxygenase-2. Recent studies have demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma is present in atherosclerotic lesions, and negatively regulates expression of these genes. Interestingly, PPAR-gamma gene promoter has tandem repeats of C/EBP-binding motif, and C/EBP-delta plays a pivotal role in transactivation of PPAR-gamma gene. It has been well known that the interaction between C/EBPs and PPAR-gamma plays a central role in maintaining adipocyte differentiation and glucometabolism; however, the relationship between PPAR-gamma and C/EBPs in the vessel wall remains unclear. In the present study, we showed that a high level of C/EBP-delta expression induced by inflammation positively regulated transcription and protein expression of PPAR-gamma in vascular smooth muscle cells (VSMCs). On the other hand, PPAR-gamma ligands troglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibited IL-1beta-induced IL-6 expression at a transcriptional revel in VSMCs. Functional promoter analysis revealed that PPAR-gamma ligands inhibited IL-1beta-induced transactivation of IL-6 gene via suppression of not only nuclear factor-kappaB but also C/EBP-DNA binding. Moreover, PPAR-gamma ligands suppressed protein expression and transcription of C/EBP-delta through dephosphorylation of signal transducer and activator of transcription 3. These findings strongly suggest that C/EBP-delta is negatively autoregulated via transactivation of PPAR-gamma. This feedback mechanism probably downregulates transcription of inflammatory cytokines and acute phase proteins, and modulates inflammatory responses in the early process of atherosclerosis.
Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation.
BACKGROUND: In vitro studies suggest that angiotensin II type 1 and type 2 (AT1 and AT2) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT1a in vascular remodeling. METHODS AND RESULTS: Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT1a-null (AT1aKO), AT2-null (AT2KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT2KO mice, but they were both suppressed in AT1aKO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT1aKO mice but decreased in AT2KO mice. Reverse transcriptase-polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT2KO mice. On the other hand, the expression of bcl-2 and bcl-x(L) mRNA was enhanced in AT2KO mice but attenuated in AT1aKO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results. CONCLUSIONS: Our results suggest that AT2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT1a in the process of neointimal formation after vascular injury.
Comparison of effects of carvedilol versus metoprolol on cytokine levels in patients with idiopathic dilated cardiomyopathy.
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Mechanism of oxidative stress-induced GADD153 gene expression in vascular smooth muscle cells.
Oxidative stress plays a critical role in normal functioning of cardiac and vascular cells as well as in the pathogenesis of cardiovascular disease. Growth arrest and DNA damage-inducible gene 153 (GADD153), which is upregulated by oxidative stress, regulates the cell cycle and apoptosis. Previously an AP-1 was reported to contribute significantly to GADD153 gene transcriptional activation by oxidative stress. Recently, we have reported that GADD153 gene promoter activity is negatively regulated by nuclear factor 1 (NF1), in vascular smooth muscle cells (VSMCs). The aim of this study was to elucidate the roles of AP-1 and NF1 in GADD153 gene induction by oxidative stress in VSMCs. H(2)O(2) induced GADD153 mRNA and reduced NF1 mRNA expression. In the electromobility shift assay, H(2)O(2) induced AP-1-binding activity and reduced NF1-binding activity. Overexpression of NF1 significantly suppressed the induction of the GADD153 gene after treatment with H(2)O(2). These results revealed that induction of the GADD153 gene by oxidative stress is regulated mainly by two nuclear factors, NF1 and AP-1.
Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases.
KL-6, surfactant protein (SP)-A, SP-D, and monocyte chemoattractant protein-1 (MCP-1) are reported to be sensitive markers for interstitial lung diseases (ILD). However, each marker has been studied independently. The aim of this study was a comparative analysis of the diagnostic values of these markers. Subjects consisted of 33 patients with ILD (21 cases of idiopathic pulmonary fibrosis and 12 associated with collagen vascular diseases) and 82 control subjects (12 cases of bacterial pneumonia and 70 healthy volunteers). Receiver operating characteristic curves revealed that KL-6 was superior to the other markers. The cut-off levels for these markers that resulted in the highest diagnostic accuracy were determined to be 465 U/ml for KL-6, 48.2 ng/ml for SP-A, 116 ng/ml for SP-D, and 1080 pg/ml for MCP-1. The sensitivity, specificity, and diagnostic accuracy were 93.9%, 96.3%, and 95.7% for KL-6; 81.8%, 86.6%, and 85.2% for SP-A; 69.7%, 95.1%, and 87.8% for SP-D; and 51.5%, 92.7%, and 80.9% for MCP-1; respectively. The serum levels of SP-A and SP-D, but not of KL-6, were significantly higher in patients with bacterial pneumonia than in healthy volunteers. These results suggest that of the markers studied, KL-6 is the best serum marker for ILD.
Relation between angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic cardiomyopathy.
Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/ deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3-7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM.
Carotid hemodynamic alterations in hypertensive patients with insulin resistance.
BACKGROUND: Insulin resistance (IR) is implicated in the pathogenesis of atherosclerosis. One mechanism is thought to be the impaired vasodilation, which can lead to a reduction in peripheral blood flow. Hypertensive patients with IR have greater intima-media thickness (IMT) in the common carotid artery (CCA) than those without IR. However, the relationship between IR and hemodynamic alterations of the CCA has not been clarified. METHODS: Seventy patients with essential hypertension (EHT) and 11 normotensive controls (NT) participated in this study. The IMT, number of plaques, and internal dimensions of the CCA were evaluated by ultrasound imaging. Mean diastolic (Vd) and systolic (Vs) velocity were determined by the Doppler flow method, and other parameters such as Vd/Vs and the cross-sectional distensibility coefficient (CSDC) were further calculated. When the homeostasis model assessment (HOMA) index exceeded 2.0, the subject was considered to have IR. RESULTS: The IMT was positively correlated with the HOMA index in all subjects. The Vd/Vs and CSDC were significantly decreased in EHT patients with IR compared to NT and EHT patients without IR. The Vd/Vs and CSDC were negatively correlated with the HOMA index. A stepwise regression analysis revealed that age, HDL-cholesterol, and the HOMA index were independently associated with IMT in patients with EHT. Age, the HOMA index, and mean blood pressure (MBP) were independently associated with CSDC, and the first two factors were independently associated with Vd/Vs. CONCLUSIONS: Decreased distensibility of the arterial wall and ensuing low diastolic perfusion are possible mechanisms of atherosclerotic changes in the CCA in EHT patients with IR.
Soluble Fas ligand and atherosclerosis in hypertensive patients.
BACKGROUND: The Fas-Fas ligand (FasL) system is involved in apoptosis in many types of cells. Recently, the expression of FasL on endothelial cells was reported. FasL is cleaved by a metalloproteinase and released in serum as soluble FasL (sFasL). Vasoactive substances, including metalloproteinase, are modulated by endothelial dysfunction. Advanced atherosclerosis and impaired endothelial function are seen in hypertensive patients. The inflammatory response has an important role in the development of atherosclerosis, whereas C-reactive protein (CRP) is associated with the presence and severity of atherosclerosis. OBJECTIVE: To measure the intima-media thickness of the common carotid artery and evaluate the relationship between atherosclerosis and serum sFasL concentrations in hypertensive patients. PATIENTS AND MAIN OUTCOME MEASURES: Forty-seven patients with hypertension participated in the study. The intima-media thickness of the common carotid artery was evaluated by ultrasound imaging. Serum concentrations of sFasL were measured by enzyme-linked immunosorbent assay. RESULTS: Intima-media thickness correlated positively with age (r = 0.362, P = 0.012) and sFasL concentrations (r =0.332, P = 0.022), and negatively with creatinine clearance (r = -0.399, P = 0.0055). A general linear model analysis with atherosclerotic risk factors and sFasL revealed that age, sFasL, high-density lipoprotein-cholesterol and systolic blood pressure were significantly associated with intima-media thickness. Furthermore, we demonstrated that serum sFasL is directly associated with CRP concentration (r = 0.316, P = 0.030). CONCLUSIONS: These results indicated that serum sFasL concentration is associated with atherosclerosis and inflammatory disease, in patients with hypertension.
Production of eosinophilic chemokines by normal pleural mesothelial cells.
Eosinophilic pleural effusion occurs in many diseases. The mechanisms of eosinophil accumulation are not well understood. We showed previously that eotaxin was readily detectable in most pleural effusions, and its concentration significantly correlated with eosinophil number. To test the hypothesis that pleural eotaxin is produced by resident mesothelial cells, we examined its production by normal pleural mesothelial cells (NPMC). Eotaxin was induced by tumor necrosis factor (TNF)-alpha or interleukin (IL)-4 and was drastically increased by their combination. In contrast, interferon (IFN)-gamma inhibited eotaxin production. Regulated on activation, normal T cells expressed and secreted (RANTES) was also induced by TNF-alpha and was drastically increased by the addition of IFN-gamma. These effects were observed at both protein and mRNA levels. Stabilization of RANTES mRNA was observed with IFN-gamma but not IL-4; neither cytokine stabilized eotaxin mRNA. Eosinophil chemoattractant activity in culture supernatants of NPMC stimulated with TNF-alpha plus IL-4 was diminished by an anti-eotaxin antibody; that induced by TNF-alpha plus IFN-gamma was attenuated by an anti-RANTES antibody. Thus, NPMC can produce eotaxin, and different cytokines act on NPMC to induce different chemokines by different mechanisms. IFN-gamma, a Th1 cytokine, acts at least at the posttranscriptional level to induce RANTES production, but it inhibits eotaxin production. In contrast, IL-4, a Th2 cytokine, acts at the transcriptional level to induce eotaxin.
Attenuation of biventricular pressure gradients by cibenzo-line in an 18-year-old patient with hypertrophic obstructive cardiomyopathy.
An 18-year-old male patient with biventricular hypertrophic obstructive cardiomyopathy (HOCM) had successful reduction of the pressure gradients by cibenzoline. At 11 months after birth, he was first diagnosed with cardiac murmurs and by the age of 5 years, he was diagnosed with subpulmonic infundibular stenosis with a pressure gradient of 10 mmHg by cardiac catheterization. At the age of 14, re-catherterization revealed hypertrophic cardiomyopathy with isolated obstruction of the right ventricular outflow tract, with a pressure gradient of 70 mmHg, but no obstruction in the left ventricle. He began daily treatment with 30 mg propranolol. At the age of 18, he was admitted for cardiac evaluation. An echocardiogram revealed left mid-ventricular and subpulmonic obstructions associated with pressure gradients of 88 mmHg and 65 mmHg, respectively. A single oral dose of 200 mg of cibenzoline decreased the pressure gradients in the left and right ventricles (38 mmHg and 36 mmHg, respectively). He was then given 300 mg daily of cibenzoline, and both pressure gradients remained low without any complications 8 months later at the time of discharge.
Postprandial elevation of remnant lipoprotein leads to endothelial dysfunction.
Recent studies have demonstrated that elevated levels of cholesterol in the form of remnant-like particles (RLP-C) induce deterioration of endothelial function during the fasting state, but it is not known whether postprandial RLP-C elevation has the same effect. The objective of this study was to assess the effect of postprandial RLP-C elevation on endothelial function in 24 fasting normolipidemic subjects. Flow-mediated dilatation (FMD) during reactive hyperemia in the brachial artery was investigated. Serum lipids and lipoproteins during fasting and 4h after regular fat-loading were measured. Subjects were divided into 2 groups: the high responders (postprandial RLP-C level >7.5mg/dl, n=8) and the normal responders (postprandial RLP-C level < or =7.5mg/dl, n=16). Significant increases in the level of both triglycerides and RLP-C were observed in the high responders. Basal FMD in the high responders (4.3+/-3.0%) was significantly lower than that in the normal responders (8.3+/-2.4%) (p<0.01), but FMD after the fat-loading in both groups did not change significantly. The change in RLP-C levels during the fat-loading test correlated significantly with basal FMD (r=-0.588, p<0.01). Multiple regression analysis showed a significant correlation between basal FMD and the change in RLP-C levels (r=-0.488, p<0.02). The results of this study suggest that postprandial RLP-C elevation could be associated with atherosclerotic progression even in normolipidemic subjects.