Biomedical subjects
Jitsuo Higaki
Publications and source records attributed to Jitsuo Higaki.
Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II.
Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis. Herein, we describe a novel transcription mechanism through which Ang II inhibits macrophage expression of the ATP-binding cassette transporter A1 (ABCA1), a key regulator of reverse cholesterol transport. We demonstrate that chronic Ang II infusion substantially promotes macrophage infiltration, foam cell formation, and atherosclerosis in low-density lipoprotein receptor-deficient mice and significantly reduces ABCA1 expression in peripheral macrophages. Administration of the Ang II type 1 receptor blocker valsartan inhibited Ang II-induced ABCA1 mRNA repression, macrophage cholesterol accumulation, and atherosclerosis. Ang II treatment reduced ABCA1 promoter activity of in vitro cultured mouse peritoneal macrophages, inducing fos-related antigen 2 (Fra2) protein binding to an ABCA1 promoter E-box motif, a site known to negatively regulate macrophage ABCA1 transcription. Valsartan pretreatment blocked Fra2 binding to the ABCA1 promoter, and Fra2 small interfering RNA pretreatment attenuated Ang II-mediated ABCA1 transcriptional inhibition, confirming the role of Fra2 in this process. This new evidence suggests that Ang II, a well-known proinflammatory and pro-oxidative factor, alters macrophage cholesterol homeostasis by repressing ABCA1 to promote foam cell formation and atherosclerosis.
Black pearl in the LIFE study: angiotensin-II receptor blockade on atrial fibrillation for future personalized medicine.
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Circulating levels of heart-type fatty acid-binding protein and its relation to thallium-201 perfusion defects in patients with hypertrophic cardiomyopathy.
Myocyte loss and replacement fibrosis have been observed in patients with hypertrophic cardiomyopathy (HC) with heart failure. This study was designed to elucidate whether heart-type fatty acid-binding protein (H-FABP), a sensitive biochemical marker for myocardial damage, indicates ongoing myocardial damage in patients with HC. We studied 48 patients with HC and 17 control subjects. Patients with HC were divided into 2 groups according to the New York Heart Association (NYHA) functional class: NYHA I + II (n = 40) and NYHA III + IV (n = 8). Serum H-FABP and myoglobin levels were measured, and extent score was used to assess the extent of thallium-201 perfusion defect. Serum H-FABP levels were significantly higher in patients with HC than in control subjects (3.8 +/- 1.6 vs 2.6 +/- 0.7 ng/ml, p = 0.0032). Furthermore, serum H-FABP levels were significantly higher in NYHA III + IV than in NYHA I + II (5.2 +/- 1.3 vs 3.5 +/- 1.5 ng/ml, p = 0.0043). Serum myoglobin levels showed no significant difference among the 3 groups (control, 46.6 +/- 15.0 ng/ml; NYHA I + II, 55.5 +/- 26.4 ng/ml; NYHA III + IV, 65.1 +/- 33.6 ng/ml, p = 0.2115). Extent score correlated positively with serum H-FABP levels (r = 0.420, p = 0.0026) and negatively with fractional shortening (r = -0.542, p <0.0001). Increased H-FABP levels indicate ongoing myocardial damage, which could result in clinical deterioration in patients with HC.
Effect of beta-blocker therapy on myocardial perfusion defects in thallium-201 scintigraphy in patients with dilated cardiomyopathy.
BACKGROUND: The beneficial effects of beta-blocker therapy in patients with heart failure have been confirmed. However, the effects of beta-blockers on myocardial perfusion defects are unclear. The aim of this study was to evaluate the effect of beta-blockers on myocardial perfusion defects estimated by thallium-201 myocardial scintigraphy in patients with dilated cardiomyopathy (DCM) and to investigate the relationships between beta-blocker treatment and myocardial damage and cardiac function. METHODS: 201Tl and echocardiography were performed in 37 patients before and after 6 months of beta-blocker therapy. Extent score (ES) by 201Tl was used to quantitate myocardial perfusion defects before and after treatment. RESULTS: ES was significantly decreased by beta-blocker therapy. According to the change in ES, DCM patients were classified into three groups, patients who improved, patients showing no change and patients who deteriorated. In the improvement and no-change groups, beta-blocker therapy induced a reduction in left ventricular dimensions and an associated increase in ejection fraction. However, in the deterioration group, left ventricular dimensions and ejection fraction were unchanged. There was a significant relationship between the change in left ventricular dimension at end-diastole and the change in ES. CONCLUSIONS: beta-Blocker therapy could attenuate myocardial perfusion defects in some patients with DCM. The improvement in left ventricular function associated with beta-blocker therapy may be related to the attenuation in myocardial perfusion defects.
Assessment of reperfused acute myocardial infarction with two-phase contrast-enhanced helical CT: prediction of left ventricular function and wall thickness.
PURPOSE: To investigate whether two-phase contrast material-enhanced computed tomographic (CT) findings serve as predictors of changes in left ventricular (LV) function and wall thickness (WT) after acute myocardial infarction (MI) and successful angioplasty. MATERIALS AND METHODS: Ethics committee approval and informed consent were obtained. In 58 patients (51 men and seven women; mean age, 62 years +/- 12 [standard deviation]) who had experienced an acute MI and undergone successful angioplasty, two-phase (acquisitions at 45 seconds and 7 minutes) contrast-enhanced CT was performed in the acute (mean interval between treatment and CT, 37 hours +/- 4) and intermediate (mean interval, 28 days +/- 4) periods and for long-term (mean interval, 12 months +/- 4) follow-up. CT images were reviewed for an early perfusion defect (ED) at 45 seconds and for late enhancement (LE) and a residual perfusion defect (RD) at 7 minutes. Myocardial enhancement patterns and WT were assessed, and LV ejection fraction (LVEF) and percentage decrease in WT were calculated. The patient group was subdivided into three groups according to enhancement pattern: Group 1 included patients with LE but no ED or RD; group 2, patients with ED and LE but no RD; and group 3, patients with ED, LE, and RD. Fisher exact testing was used to measure categorical response. Paired and unpaired t tests were used for comparison between two groups (points); Tukey-Kramer multiple comparison and repeated-measures analysis of variance were used for comparisons between the three groups. P < .05 was considered to indicate a significant difference. RESULTS: In group 3 (n = 36), WT in infarcted area was significantly reduced at the intermediate and long-term CT examinations (P < .001). At the intermediate and long-term examinations, percentage decrease in WT was greater in group 2 (n = 10) than in group 1 (n = 12) (P < .05 for intermediate and P < .001 for long-term examination) and was greatest in group 3 (P < .001 for both examinations). LVEF was poorest in group 3 and best in group 1. CONCLUSION: Two-phase contrast-enhanced CT proved useful in predicting LV functional recovery and WT in patients who had experienced acute MI and undergone successful angioplasty.
Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) in patients with coexistent hypertrophic cardiomyopathy and coronary spastic angina.
Coronary vasospasm appears to play a significant role in the etiology of myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM). Furthermore, the management of patients with coexistent HCM and coronary spastic angina (CSA) presents a therapeutic challenge. The purpose of this study was to examine the Glu298Asp variant of the endothelial nitric oxide synthase (eNOS) gene to determine whether this polymorphism was associated with susceptibility to CSA in patients with HCM. The eNOS gene polymorphism (Glu298Asp) was genotyped in 150 HCM patients by the TaqMan chemical method. Patients were classified into group A (n=12) if they had CSA provoked by intracoronary acetylcholine, and group B (n=138) if they did not. In group A, the frequency of Glu/Glu, Glu/Asp, and Asp/Asp genotypes was 5 (41.7%), 6 (50%), and 1 (8.3%), respectively. In group B, it was 119 (86.2%), 17 (12.3%), and 2 (1.5%), respectively. The frequency of the Asp298 variant was significantly higher in group A than in group B (P<0.001). Multivariate logistic regression analysis showed that the Asp298 variant was a significant risk factor for CSA (odds ratio 11.8; P<0.001) that was independent of age, gender, smoking status or body mass index. Significantly more drugs were used by the patients in group A than those in group B and the patients with the Asp298 variant were treated with significantly more drugs than those without it. In conclusion, the Asp298 variant of the eNOS gene may be associated with CSA in HCM patients. HCM patients with CSA or the Asp298 variant may need more drugs to relieve their symptoms.
Fibrillary glomerulonephritis associated with monoclonal gammopathy of undetermined significance showing lambda-type Bence Jones protein.
A 79-year-old woman was admitted to our hospital because of leg edema due to a nephrotic syndrome. Urinary and serum immunoelectrophoresis showed positive for the lambda type of Bence Jones protein. A bone marrow aspiration test revealed mild plasmacytosis (6.4% of the total cells). These findings confirmed her diagnosis of monoclonal gammopathy of undetermined significance (MGUS). Her renal biopsy specimen revealed mild mesangial cell proliferation and an increase in the mesangial matrix. Immunofluorescence studies showed positive staining for IgG, IgA, C3, and kappa and lambda light chains in the capillary wall and mesangium area. Electron microscopy showed that the electron deposits in the thickened basement membrane were formed by randomly arranged 16- to 18-nm nonbranching fibrils. A Congo red stain for amyloid was negative. These findings corresponded with the diagnosis of fibrillary glomerulonephritis. Therefore, this case showed a rare combination of fibrillary glomerulonephritis and MGUS.
Impact of multi-detector row computed tomography on the tactics of cardiovascular surgery: from qualitative evaluation to quantitative assessment.
OBJECTIVE: We assessed the role of multi-detector row computed tomography in cardiovascular surgery. METHODS: The efficacy of multi-detector row computed tomography was assessed concerning the graft patency of coronary artery bypass, arterial atheromatous degeneration, small vessel imaging, and left ventricular volume measurement. Images were reconstructed using both the volume-rendering and the maximum-intensity-profile methods. Arterial atherosclerotic degeneration was assessed by aortic wall volume and aortic calcification volume. RESULTS: In the assessment of bypass graft patency, multi-detector row computed tomography showed a 98% correct positive ratio with sensitivity and specificity of 98% and 100%, respectively. Atheromatous degeneration showed matching results in more than 70% of cases compared with intraoperative findings. More than 92% of arterial branches with diameters of 3 mm or greater were detected by preoperative multi-detector row computed tomography images, though only 6% of branches with diameters of 2 mm or less could be visualized. There was a positive linear correlation between left ventricular volumes determined by multi-detector row computed tomography and those calculated from cine angiography. CONCLUSION: Multi-detector row computed tomography clearly visualized coronary bypass grafts and aortic arterial branches, providing detailed vascular images. Atheromatous degeneration assessed by multi-detector row computed tomography was equivalent with intraoperative findings in more than 70% of cases. Left ventricular volumes measured by multi-detector row computed tomography correlated closely with those determined by cine-angiography. Multi-detector row computed tomography is an efficient and promising modality in cardiovascular surgery.
Angiotensin I-converting enzyme insertion/insertion genotype as a genetic risk factor for cardiovascular disease.
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Angiotensin-converting enzyme inhibitors as a new therapy for atrial fibrillation? Controversy.
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Relation of genetic predisposition and insulin resistance to left ventricular hypertrophy in hypertension.
BACKGROUND: The aim of the study was to determine whether genetic predisposition to hypertension and insulin resistance are related to left ventricular (LV) hypertrophy in essential hypertension. METHODS: The study included 72 nondiabetic patients with essential hypertension and 15 normotensive control (NC) subjects. The 72 patients were divided into two groups according to genetic predisposition to hypertension. The family history (FH)(+) group included 33 patients with at least one essential hypertensive parent or sibling. The FH(-) group included 39 patients with weak genetic predisposition to hypertension. Insulin resistance was estimated using the homeostasis model assessment (HOMA). Echocardiographically determined LV mass (LVM) and relative wall thickness (RWT) were measured as markers of LV hypertrophy. RESULTS: The HOMA values in the FH(+) group (2.00 +/- 0.89) were significantly higher than those in either the FH(-) group (1.21 +/- 0.44) or NC subject group (0.91 +/- 0.24). The HOMA values in the FH(-) group were significantly higher than those in NC subjects. The LVM and RWT were greatest in the FH(+) group, followed by those in the FH(-) group and NC subjects. There were no significant differences in LVM and RWT between the FH(-) group and NC subjects. By multivariate analysis, HOMA value (P = .0011), male sex (P = .0032), body mass index (P = .0061), systolic blood pressure (P = .0245), and genetic predisposition to hypertension (P = .0441) remained determinants of LVM in nondiabetic patients with essential hypertension. CONCLUSIONS: Genetic predisposition to hypertension and the HOMA value appear to have additive impact on LV hypertrophy. This relation is independent of well-known determinants of LVM such as male sex, overweight, and high blood pressure.
Serum markers of angiogenesis and myocardial ultrasonic tissue characterization in patients with dilated cardiomyopathy.
BACKGROUND AND AIMS: It has been proven that a disturbance in angiogenesis contributes to the progression of myocardial interstitial fibrosis in idiopathic dilated cardiomyopathy (DCM). This study was designed to evaluate the relationship between serum activity of angiogenic factors and myocardial ultrasonic tissue characterization in patients with DCM. METHODS AND RESULTS: We studied 30 patients with DCM and 15 healthy control subjects. Serum levels of vascular endothelial growth factor (VEGF), interleukin (IL)-4 and IL-13 were measured using enzyme-linked immunosorbent assay. We determined calibrated myocardial integrated backscatter (IB) as the value of myocardial interstitial fibrosis using ultrasonic tissue characterization and also quantified the magnitude of cyclic variations in IB (CV-IB). Serum levels of VEGF and IL-13 were significantly higher in patients with DCM than in control subjects (both P<0.05). Calibrated IB was significantly higher and CV-IB was markedly lower in patients with DCM than in control subjects (both P<0.01). In patients with DCM, the levels of IL-13 significantly correlated with calibrated IB (r=0.520, P=0.018). In addition, there was a significant negative correlation between levels of VEGF and CV-IB (r=-0.611, P=0.007). CONCLUSION: The increase in serum VEGF and IL-13 may be closely related to alterations in myocardial texture in DCM.
Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with essential hypertension.
Chronic inflammation is common in hypertension and acts as an independent determinant of arterial blood pressure. Hypertensive patients are reported to have high circulating levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Recently, angiotensin II receptor blockers (ARBs) have been shown to possess benefits in addition to their ability to lower blood pressure, including anti-inflammatory and antioxidative properties within the vasculature. We evaluated the effects of the angiotensin II receptor blocker, valsartan, on these inflammatory cytokines. Thirty-nine patients with essential hypertension participated. These subjects received valsartan, 40 to 80 mg/day. Serum TNF-alpha, IL-6, CRP, and serum amyloid A (SAA) were measured before and after 3 months of treatment with valsartan. Valsartan significantly decreased systolic and diastolic blood pressure (160 +/- 16/92 +/- 11 mm Hg to 147 +/- 21/84 +/- 11 mm Hg, P = 0.001/P = 0.001, respectively). Serum TNF-alpha (9.1 +/- 8.6 pg/mL to 6.1 +/- 1.0 pg/mL, P = 0.006) and IL-6 (9.3 +/- 1.7 pg/mL to 8.9 +/- 1.4 pg/mL, P = 0.005) were significantly reduced after treatment with valsartan. However, C-reactive protein and serum amyloid A did not change. The angiotensin II receptor blocker, valsartan, may inhibit the development of atherosclerosis by lowering serum pro-inflammatory cytokines.
Metastatic renal cell carcinoma presenting as multiple pleural tumours.
A 66-year-old man was admitted with dyspnoea. Chest X-ray and chest computed tomography (CT) demonstrated a left-sided pleural effusion and multiple tumours, suggesting malignant mesothelioma in the left pleural space, but there were no pulmonary lesions. However, abdominal CT revealed a right renal tumour. An ultrasonography-guided needle biopsy of the pleural mass provided evidence of metastatic renal cell carcinoma (RCC). The pleural lesions dramatically decreased in size following right radical nephrectomy and subsequent interferon-alpha treatment. While the thorax is a frequently affected site of RCC, sole pleural metastases are rare and are often secondary to lung involvement. Batson's plexus, a network of vertebral valve-less veins with multiple connections, is likely responsible for the contralateral pleural metastases of RCC.
Thymic carcinoma originating from the mid-posterior mediastinum.
An unusual thymic carcinoma in a 74-year-old woman is described. Initial chest CT revealed a mass at the mid-posterior mediastinum. Transbronchial fine needle biopsy of the mass failed to provide a definite diagnosis. The mass was treated as a malignant mediastinal tumour, and chemoradiotherapy was performed as initial treatment. The patient died 5 years after receiving primary treatment. The results of postmortem microscopic examination, including immunohistochemical study with CD5 antibody, were consistent with thymic carcinoma. This case is interesting in that the mid-posterior mediastinum is the site where thymic carcinoma is least likely to originate.
Exercise-related syncope induced by vasodilator therapy in an elderly hypertensive patient.
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Myocardial perfusion imaging using adenosine triphosphate stress multi-slice spiral computed tomography: alternative to stress myocardial perfusion scintigraphy.
BACKGROUND: The present study was designed to: (i) detect myocardial ischemia in contrast enhanced multi-slice spiral computed tomography (CE-MSCT) using adenosine triphosphate (ATP) pharmacological stress test; and (ii) evaluate the potential of ATP stress CE-MSCT in a clinical setting. METHODS AND RESULTS: Twelve patients underwent ATP stress CE-MSCT and stress thallium-201 myocardial perfusion scintigraphy (MPS) and 9 of the patients received conventional coronary angiography (CAG). Dual CE-MSCT scans were performed for stress and rest images, with and without intravenous infusion of ATP (0.16 mg.kg-1.min-1) at intervals of 20 min. Myocardial perfusion and coronary artery were visually evaluated using MSCT and compared the results obtained from MPS and CAG. Of 36 territories, stress images of CE-MSCT described 26 hypo-perfusion areas and MPS described 22 redistributions. The agreement between MSCT and MPS was 83% (30/36, p<0.05). In 141 coronary artery segments of 9 patients undergoing CAG, rest images of CE-MSCT, which had significantly higher assessability than stress images (89% vs 48%, p<0.05), described 76% (13/17) of culprit coronary stenoses. CONCLUSIONS: Although CT-angiography should be currently assessed using rest images, ATP stress CE-MSCT can describe both ATP-induced myocardial ischemia and coronary artery stenoses in patients with coronary artery disease.