[Renin inhibitors].
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Antihypertensive Agents↗
Biomedical subjects
K Hiwada
Publications and source records attributed to K Hiwada.
[To spread and make use of guidelines for hypertension in the elderly--1999 revised version].
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Aged↗
Transcriptional regulation of the platelet-derived growth factor alpha receptor gene via CCAAT/enhancer-binding protein-delta in vascular smooth muscle cells.
Inflammatory cytokines stimulate the proliferation of vascular smooth muscle cells (VSMC) and play a pivotal role in the pathogenesis of vascular diseases including atherosclerosis and restenosis. Mitogenic response of interleukin-1beta (IL-1beta) on VSMC is thought to be mediated by induction of endogenous platelet-derived growth factor (PDGF), especially PDGF-AA. Although the action of PDGF-AA is mediated by its specific receptor, PDGFalpha-receptor (PDGFalphaR), very little is known about the regulatory mechanism of PDGFalphaR gene expression in VSMC. To understand the mechanism, we studied the transcriptional control of the PDGFalphaR gene in VSMC after treatment with IL-1beta. IL-1beta (10 ng/ml) drastically increased both PDGFalphaR and CCAAT/enhancer-binding protein delta (C/EBPdelta) mRNA levels in a time dependent manner. A rapid induction of C/EBPdelta mRNA within 30 min was followed by slower emergence of PDGFalphaR mRNA, which reached the maximum level in 12 h, whereas C/EBPdelta mRNA was detectable at 30 min and reached the maximum level at 3 h. Electromobility shift and supershift assays revealed that IL-1beta markedly increased DNA-protein complex, which was mainly composed of C/EBPbeta and/or -delta. Both Western blotting and immunohistochemistry demonstrated that either C/EBPbeta or -delta expression was induced by IL-1beta exclusively in nuclei of VSMC. On the other hand, overexpression of C/EBPdelta specifically transactivated the promoter activity of the PDGFalphaR gene and significantly enhanced VSMC proliferation in PDGF-treated cells. We conclude that induction of PDGFalphaR expression is mainly mediated by C/EBPdelta expression in VSMC, and a high level of C/EBPdelta expression may be involved in the pathogenesis of atherosclerosis and restenosis.
Animals↗
[Methods for diagnosis of hypertension].
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Humans↗
Relation of left ventricular hypertrophy and geometry to asymptomatic cerebrovascular damage in essential hypertension.
Increased left ventricular (LV) mass and abnormal geometry have a powerful prognostic value for cardiovascular morbidity and mortality including stroke. However, there have been no studies on the association between LV hypertrophy and preclinical brain damage in essential hypertensive patients. In the present study, we investigated the relation between LV hypertrophy and asymptomatic cerebrovascular damage identified by magnetic resonance imaging in 150 essential hypertensive patients, with an emphasis on LV geometry. Patients were divided into the following 4 groups according to their LV mass index and relative wall thickness; normal ventricular geometry (n = 50), concentric remodeling (n = 22), eccentric hypertrophy (n = 44), and concentric LV hypertrophy (n = 34). Lacunar lesions and leukoaraiosis were evaluated. The prevalence of lacunae was significantly higher in patients with LV remodeling than in patients with normal LV (chi-square 19.6, p = 0.0002). The number of lacunae was significantly higher in patients with LV hypertrophy than in patients with normal LV or concentric remodeling (F [3,146] = 8.03, p<0.0001). The severity of leukoaraiosis was also significantly greater in patients with LV hypertrophy than in patients with a normal left ventricle (chi-square 14.5, p = 0.02). Stepwise regression analysis confirmed that LV mass index and relative wall thickness, in addition to age and systolic blood pressure, were independent predictors for asymptomatic cerebrovascular damage, even in the absence of neurologic abnormalities. In hypertensive patients, LV hypertrophy, and especially concentric LV hypertrophy, provides important prognostic information on the presence of pre-clinical brain damage.
Blood Pressure↗
Diagnosis of Thrombus and Blood Flow in Aortic Aneurysm Using Tagging Cine Magnetic Resonance Imaging.
In order to diagnose thrombus and to evaluate blood flow in aortic diseases, we investigated the usefulness of tagging cine magnetic resonance imaging (MRI) in patients with aortic aneurysm and aortic dissection. Six abdominal aortic aneurysms (AAA), two aortic arch aneurysms, and three aortic dissections were examined using tagging cine MRI. Linear tagging bands were 3 or 5 mm wide and established to the long and short axial images of the aortic lesions. Tagging bands were confirmed as the low-intensity signal bands in all patients. The parts of tagging bands of the intraaortic thrombus did not move, whereas the parts of tagging bands of the intraaortic blood flow moved and faded as time passed. Intraaortic thrombi were diagnosed in eight patients (six AAA, one aortic arch aneurysm, and one aortic dissection) in accordance with the stain of the parts of tagging bands. In patients with aortic dissection, the parts of tagging bands in the false lumen moved slowly, whereas the parts of tagging bands in the true lumen moved quickly. Tagging cine MRI has been shown to be useful in the diagnosis of thrombus and blood flow in aortic diseases.
Journal Article↗
Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial banding.
The aim of this study is to investigate whether the cardiomyocyte apoptosis is induced after experimental right-sided pressure overload and whether the expression of proapoptotic factor is altered or not. Ten-week-old male Sprague-Dawley rats were subjected to right ventricular overload by experimental coarctation of the main pulmonary artery. In pulmonary artery-banded rats, TUNEL method revealed that positive nuclei were observed in cardiomyocytes exclusively in the right ventricle, and Northern blot analysis showed that p53 mRNA level in the right ventricle was 6.2-fold higher at the day 1 than that in sham-operated rats and its level decreased gradually. Bax mRNA in the right ventricle was also increased 3.3-fold at the day 1 in pulmonary artery-banded rats and also gradually decreased. The immunohistochemical study revealed that the immunoreactivity of P53 and Bax was observed exclusively in the right ventricle of the pulmonary artery-banded group. These results demonstrated that the occurrence of TUNEL-positive cardiomyocytes in the acute pressure overload was accompanied by the enhanced expression of apoptosis inducers. It is suggested that acute pressure overload is a potent apoptotic stimulus for cardiomyocytes.
Animals↗
Aging but not sodium loading significantly attenuated diurnal change in blood pressure in stroke-prone spontaneously hypertensive rats.
In the present study, we evaluated the effect of aging on diurnal change in blood pressure in stroke-prone spontaneously hypertensive rats (SHRSP/Izm) using a telemetry system. Diurnal changes in blood pressure, heart rate, and locomotor activity were determined in unrestrained, freely moving condition in 24-week-old male SHRSP/Izm (n = 6) and 40-week-old male SHRSP/Izm (n = 6). Diurnal change in blood pressure was also investigated in 40-week-old male spontaneously hypertensive rats (SHR/Izm, n = 6) and Wistar-Kyoto rats (WKY/Izm, n = 5) as age-matched controls of the strain. All rats were kept in a 12-h light/dark cycle (light period from 06:00 to 18:00, and dark period from 18:00 to 06:00). Rats were active in dark phase and inactive in light phase. Mean blood pressures (MBP) were significantly higher in light phase as well as dark phase in old SHRSP/Izm compared with the other three groups. Light/dark phase ratio of MBP was significantly higher in old SHRSP/Izm compared with the other three groups. We observed a significant positive relationship between light/dark phase ratio of MBP and left ventricular mass index in a studied population of rats (r = 0.547, P < .01). Because SHRSP is a salt-sensitive model, the effect of high salt loading on the circadian pattern of blood pressure was also investigated. Male SHRSP/Izm, at the age of 22 weeks, were maintained on high salt (8%) for 2 weeks. High salt exposure significantly increased dark phase as well as light phase MBP in SHRSP/Izm. However, light/dark phase ratio of MBP was not significantly different from normal salt-fed (0.6%) SHRSP/Izm. These results indicate that aging and end-organ damage were associated with the alteration of diurnal change in blood pressure in SHRSP/Izm.
Aging↗
Effect of reflection of arterial pressure on carotid circulation in essential hypertension.
Pressure wave reflection plays a pivotal role in the augmentation of systolic blood pressure. In the present study, the association between reflection of pressure wave and structural and functional alteration, including blood flow, in the common carotid artery was investigated in 70 hospitalized essential hypertensive patients. The reflection of pressure was estimated by the "augmentation index" of the carotid arterial pressure waveform. The carotid augmentation index was significantly related to age (r = 0.36), body height (r = -0.30), intima-media thickening (r = 0.28), number of plaques (r = 0.44), stiffness of the carotid artery (r = 0.38), diastolic carotid flow velocity (r = -0.31), and left ventricular mass index (r = 0.33). Furthermore, the reflection of arterial pressure showed a significant negative correlation with diastolic/systolic ratio of blood flow velocity in the carotid artery (r = -0.41, P = .0005). Stepwise regression analysis revealed that age and left ventricular mass index were independent determinants for the carotid augmentation index. These findings indicate that the reflection of arterial pressure is related to morphological and functional alterations of the carotid artery, including a relative reduction of diastolic blood flow.
Adult↗
Rest-redistribution thallium-201 myocardial scintigraphic study in cardiac amyloidosis.
BACKGROUND: Histopathological study in amyloid heart demonstrates that myocyte destructed by the extracellular deposition of amyloid protein together with viable myocyte is present. We hypothesized that rapid thallium washout may be found in amyloid heart as in regions which have a mixture of viable myocyte and scar tissue in patients with myocardial infarction. Thus, the purpose of this study was to evaluate the extent and severity of myocardial damage due to amyloid deposits using the washout rate of the tracer on rest-redistribution thallium-201 (201Tl) myocardial scans in cardiac amyloidosis patients. METHODS: Rest-redistribution 201Tl myocardial scintigraphy was performed in 5 patients with biopsy-proved systemic amyloidosis with cardiac involvement (amyloidosis group). The initial and delayed images were obtained 15 min and 4 h, respectively, after intravenous injection of the tracer of 111 MBq. Washout rate of the tracer was calculated. Twelve patients with no apparent heart disease served as controls (control group). RESULTS: Mean washout rate of the whole heart was higher in the amyloidosis group than in the control group (56 +/- 9% vs 36 +/- 6%, p < 0.001). Particularly, 4 of the 5 patients in the amyloidosis group presented a very high rate of thallium clearance which ranged from 57 to 61%, and died in less than a year. In the remaining 1 patient who had a normal washout rate of the tracer in the first study, it changed from 40 to 53% during the 5-year follow-up period. CONCLUSIONS: Washout rate in the setting of rest and delayed 201Tl images may represent the severity of amyloid depositions in the myocardium and may provide prognostic information.
Aged↗
Effect of antihypertensive therapy on aortic distensibility in patients with essential hypertension: comparison with trichlormethiazide, nicardipine and alacepril.
To assess the effect of antihypertensive drugs on aortic distensibility, we evaluated the aortic distensibility of 33 hypertensive patients before and after antihypertensive treatment by using cine magnetic resonance imaging. Thirty three hypertensive patients were divided into three groups and treated for 12 weeks with 2-4 mg trichlormethiazide per day (n = 10), 80 mg nicardipine per day (n = 13) and 50 mg alacepril per day (n = 10). There were no significant differences in mean age and mean blood pressure among the three groups. Cine magnetic resonance was performed at ascending and descending aortic levels. Aortic area was measured at the maximum and minimum frames. The effect of antihypertensive therapy on aortic distensibility was evaluated as the percent change from before treatment to after treatment. There were no significant differences in pulse pressure before and after treatment with trichlormethiazide, nicardipine and alacepril. After treatment with these drugs, mean blood pressure in all groups decreased (trichlormethiazide and nicardipine, P < .01; alacepril, P < .05), (the maximum area--the minimum area) and aortic distensibility in all groups increased significantly (each P < .01). Percent changes in aortic distensibility after treatment were significantly higher with nicardipine (ascending, 346.6 +/- 255.9%; descending, 338.8 +/- 246.5%, each P < .05) and alacepril (ascending, 369.7 +/- 238.8%, P < .05; descending, 306.9 +/- 123.3%, P < .01) than with trichlormethiazide (ascending, 146.0 +/- 139.6%; descending, 129.3 +/- 97.5%). In conclusion, nicardipine and alacepril have a beneficial effect on aortic distensibility.
Age Factors↗
Effect of different sensitizing doses of antigen in a murine model of atopic asthma.
The dose of antigen is assumed to be one of the important factors in the polarized development of helper T cell subsets, i.e. Th1 or Th2 cells. We investigated the effect of the sensitizing antigen dose in a murine model of atopic asthma, which involved sensitization with ovalbumin (OVA) followed by repeated exposure to OVA aerosols. BALB/c mice were primed with varying doses of OVA (0, 10, 100 and 1000 microg) plus Al(OH)3 on days 0, 7 and 14, and were challenged with OVA aerosols (50 mg/ml for 20 min) on days 15-20. There were striking antigen dose-related differences in OVA-specific antibodies: high IgE and low IgG2a titres were found in mice sensitized at 10 microg, while low IgE and high IgG2a titres were seen at 1000 microg. The sensitizing dose was inversely correlated with the total cell count and the eosinophil count in bronchoalveolar lavage fluid (BALF), as well as with the extent of histological changes such as goblet cell hyperplasia of the bronchial epithelium and cellular infiltration into bronchovascular bundles. Antigen-induced bronchial hyper-responsiveness (BHR) to methacholine was observed with sensitization at 10 microg but not at 1000 microg. Splenic mononuclear cells (SMNC) obtained from mice sensitized at either dose showed proliferation in response to OVA. Production of IL-4 and IL-5 by OVA-stimulated SMNC was inversely correlated with the dose of sensitizing antigen. High-dose sensitization resulted in general suppression of cytokine production by SMNC, including interferon-gamma (IFN-gamma). The BALF levels of IL-4 and IL-5 were increased by low-dose sensitization, whereas IFN-gamma and IL-12 levels were increased by high-dose sensitization. These results suggest that the dose of sensitizing antigen defines the phenotypic changes in the present murine asthma model, presumably by influencing the pattern of cytokine production.
Animals↗
Clinical implications of circulating soluble Fas and Fas ligand in patients with acute myocardial infarction.
BACKGROUND: Apoptotic cell death is the major form of myocardial damage produced by coronary ischemic events. OBJECTIVE: To assess whether circulating levels of soluble Fas (sFas), an inhibitor of apoptosis, and sFas ligand, an inducer of apoptosis, in patients with coronary artery disease are greater than normal. METHODS: Forty-seven patients [acute myocardial infarction (AMI) in 17, old myocardial infarction (OMI) in 15, stable angina in 15] and 10 normal control subjects participated in this study. Serum levels of sFas and sFas ligand in all patients were measured, and cardiac catheterizations were performed. RESULTS: Serum levels of sFas were greater than normal only in patients with AMI (4.6 +/- 1.6 ng/ml); the levels were significantly higher than those in patients with OMI (2.1 +/- 0.6 ng/ml) and stable angina (2.2 +/- 0.5 ng/ml), and in normal subjects (2.0 +/- 0.6 ng/ml; P < 0.0001). However, there was no difference among serum levels of sFas ligand for all groups. For patients with AMI, there was no significant correlation between serum levels of sFas and peak levels both of plasma creatine phosphokinase and of plasma myosin light chain type I as clinical indexes of infarct size. However, there were significant correlations between serum levels of sFas and both pulmonary artery wedge pressure (r = 0.767, P = 0.0003) and left ventricular end-diastolic pressure (r = 0.629, P = 0.03). CONCLUSIONS: Circulating sFas increases in concentration in relation to the severity of hemodynamic conditions in patients with AMI, but it is independent from size of infarct. Therefore, circulating sFas could play an important role as the marker of pathophysiologic conditions associated with cardiomyocyte apoptosis in AMI.
Aged↗
Contribution of reflection of pressure wave on central systolic blood pressure in older hypertensive patients.
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Adult↗
Novel cis element for tissue-specific transcription of rat platelet-derived growth factor beta-receptor gene.
Platelet-derived growth factor (PDGF) and its receptors are widely expressed in several tissues in the stage of cellular growth and development. In adulthood, PDGF beta-receptor (PDGFbetaR) is mainly detected in pathological conditions such as atherosclerotic lesions and injured vascular wall. The purpose of the present study was to elucidate the underlying mechanism of PDGFbetaR gene expression under pathological conditions in vascular smooth muscle cells (VSMC) and to identify the important cis elements responsible for tissue-specific gene transcription. Gel mobility shift assay and supershift assay indicated that the CCAAT motif located at -67 (C67) was mainly interacted with NF-YC, and this element drove the basal promoter activity of the gene as a putative promoter. On the other hand, another important sequence essential for the basal transcription was found at a 30-bp region (R30) spanning -150 to -121. To test whether R30 actually regulates the tissue-specific transcription of PDGFbetaR gene, electromobility shift pattern was compared between VSMC and hepatoma cell line (HTC). We obtained the result that DNA-protein complex seen only in nuclear extracts from HTC suppressed the promoter activity in HTC in a tissue-specific manner. Furthermore, cis element decoy transfection experiments for C67 and R30 also revealed that both elements were functionally important in mRNA expression of PDGFbetaR in VSMC. From these results, we concluded that the basal activity of PDGFbetaR gene expression was transactivated by the interaction or coordination of both C67 and R30, and the latter one mainly controlled the tissue-specific gene expression in VSMC.
Animals↗
Postprandial hypotension is associated with asymptomatic cerebrovascular damage in essential hypertensive patients.
offelucidate the relationship between postprandial hypotension (PPH) and asymptomatic cerebrovascular damage, we evaluated changes in blood pressure after a meal by 24-hour blood pressure monitoring in 70 hospitalized essential hypertensive patients aged >/=50 years. They received a diet containing standard nutritional ingredients with 120 mmol (7 g) NaCl and were free from medication for at least 1 week. PPH was defined as the mean reduction of systolic blood pressure during 2 hours after a meal. Patients were divided into three groups according to mean values of PPH after 3 meals: PPH-1 (n=16, 5 mm Hg</=PPH<10 mm Hg), PPH-2 (n=18, PPH>/=10 mm Hg), and normal (n=36, PPH<5 mm Hg). As asymptomatic cerebrovascular damage, lacunae and leukoaraiosis were evaluated by magnetic resonance imaging. PPH did not correlate with daytime or nighttime blood pressure or the nondipper phenomenon; however, PPH was significantly related to asymptomatic cerebrovascular damage. The prevalence of lacunae in the normal, PPH-1, and PPH-2 groups was 44%, 69%, and 83%, respectively (chi2=8.22, P<0.05). The number of lacunae in the normal, PPH-1, and PPH-2 groups was 1.0+/-1.3, 1.3+/-1.2, and 1. 9+/-1.4, respectively (F[2,67]=3.2, P<0.05). The prevalence of advanced leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 44%, 50%, and 83%, respectively (chi2=7.63, P<0.05). Severity score of leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 1.5+/-0. 7, 1.7+/-0.8, and 2.1+/-0.7, respectively (F[2,67]=4.3, P<0.05). These findings indicate that elderly hypertensive patients with marked PPH should be considered to have advanced cerebrovascular damage even in the absence of abnormal neurological findings.
Aged↗
Giant unruptured aneurysm of the thoracic aorta--a case report.
An asymptomatic 88-year-old woman underwent a screening medical examination. The chest x-ray film showed a large mediastinal mass with calcification. Both chest computed tomography and nuclear magnetic resonance imaging revealed an unruptured aortic aneurysm, predominantly affecting the ascending aorta and the proximal part of the aortic arch. Its maximum diameter was 10.5 cm. An ascending aortic aneurysm more than 10 cm in diameter is very rare. She died of acute pulmonary embolism unrelated to the aneurysm, and autopsy indicated that the etiology of the aneurysm was atherosclerotic degeneration. Retrospectively, the natural progression of the aneurysm was able to be followed on a series of chest x-ray films obtained over 18 years.
Aged↗
Left ventricular end-systolic wall stress is a potent prognostic variable in patients with dilated cardiomyopathy.
Dilated cardiomyopathy is an important cause of morbidity and mortality among patients with heart failure. Left ventricular dilation is viewed as a compensatory response to maintain stroke volume, and left ventricular dilation is directly related to the increase of wall stress. However, only a few studies have examined whether wall stress can be a prognostic variable in patients with dilated cardiomyopathy. This study was designed to elucidate whether left ventricular systolic wall stress was related to the prognosis in patients with dilated cardiomyopathy. Twenty-five normal control subjects and 68 patients with dilated cardiomyopathy participated in this study. Hemodynamic parameters and left ventricular systolic wall stress were determined using echocardiography. In addition, the extent score determined by thallium-201 myocardial scintigraphy was measured as an index of cumulative loss of myocardium. During the 53-month follow-up period, 13 patients died of cardiac events. In a stepwise multivariable analysis, end-systolic wall stress and fractional shortening were significant predictors of survival. The extent score was markedly greater in the patients who died than in alive patients. There was a significant correlation between end-systolic wall stress and extent score (r=0.501, p=0.0001). Left ventricular end-systolic wall stress is an important predictor of mortality in patients with dilated cardiomyopathy.
Adult↗