新保 昌久

BACKGROUND Short sleep duration has been shown to be associated with cardio/cerebrovascular disease. White matter hyperintensities (WMH) have been associated with an increased risk of stroke. In addition to high ambulatory blood pressure (BP), chronic kidney disease (CKD) is a risk for WMH. In this study, we investigated the relationships among sleep duration, CKD, and WMH in elderly hypertensives. METHODS Ambulatory BP monitoring and brain magnetic resonance imaging were performed in 514 Japanese elderly hypertensives (mean age 72.3 years, males 37%). WMH cases were further divided into deep subcortical white matter lesion or periventricular hyperintensity (PVH). CKD (n = 193) was defined as estimated glomerular filtration rate less than 60 ml/min/1.73 m(2). RESULTS According to sleep duration (< 7.5, a parts per thousand yen7.5 to < 9.5, and a parts per thousand yen9.5 hour per night), significant associations of sleep duration were observed with WMH and PVH. In the regression analysis including age, gender, smoking, antiplatelet agents use, 24-hour systolic BP, nondipper, white coat hypertension and CKD, short sleep duration was significantly positively associated with WMH and PVH when subjects with mid-range sleep duration were used as a reference group. A significant interaction was found between short sleep duration and CKD for PVH. In the non-CKD group, short sleep duration had strong significant positive associations with WMH and PVH. CONCLUSIONS In the present study, short sleep duration was a positive significant determinant for WMH and PVH in elderly hypertensives. Sleep duration might serve as a strong determinant for white matter lesions especially in those without CKD.

Obstructive sleep apneas syndrome (OSAS) is associated with nocturnal hypertension with higher sleep blood pressure (BP) and its variability, both of which increase cardiovascular risk. In this crossover design study, the effect of nighttime single-dose administration of vasodilating (nifedipine 40mg) vs sympatholytic (carvedilol 20mg) antihypertensive agents on sleep BP in 11 hypertensive OSAS patients was evaluated. The authors recently developed a trigger sleep BP monitor with an oxygen-triggered function that initiates BP measurement when oxygen desaturation falls. The BP-lowering effects of nifedipine on the mean (P<.05) and minimum sleep systolic BPs (SBPs) (P<.01) were stronger than those of carvedilol. Sleep SBP surge (difference between the hypoxia-peak SBP measured by oxygen-triggered function and SBPs within 30minutes before and after the peak SBP) was only significantly reduced by carvedilol (P<.05). The nighttime dosing of both vasodilating and sympatholytic antihypertensive drugs is effective to reduce sleep BP but with different BP-lowering profiles.

Objective: Recently, visit-to-visit blood pressure (BP) variability has been shown to be associated with vascular remodeling and cognitive dysfunction. However, there have been no studies that focused on the relationship between visit-to-visit BP variability and cognitive dysfunction in relation to vascular remodeling. In this study, we investigated the relationships among visit-to-visit BP measures, carotid artery remodeling and cognitive function in the elderly at high risk of cardiovascular disease. Methods: The cognitive function was evaluated using a Mini-Mental State Examination (MMSE) and global deterioration scale (GDS) in 201 elderly subjects at high risk of cardiovascular disease (79.9 +/- 6.4 years old; female 75%). Based on 12 visits (once a month), visit-to-visit BP variability (expressed as the coefficient of variation [CV] and as delta [maximum - minimum] BP) were measured. Carotid ultrasound was performed to measure intima-media thickness (IMT) and the stiffness parameter beta. Results: The patients having both high delta systolic BP (SBP) and high IMT had significantly higher prevalence of low MMSE score than those with both low delta SBP and low IMT (p < 0.05), and the patients having both high delta SBP and high stiffness parameter beta also had significantly higher prevalence of low MMSE score than those with both low delta SBP and low stiffness parameter beta (p < 0.01). In the logistic regression analysis adjusted for age, calcium channel blocker use, low density lipoprotein, average heart rate, and average SBP level, a significant interaction was found between delta SBP and stiffness parameter beta for the low MMSE score (p < 0.05). Conclusions: In the high risk elderly, exaggerated visit-to-visit BP variability and advanced carotid artery remodeling have a synergetic association with cognitive dysfunction. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

After a major disaster, such as the East Japan Earthquake with ensuing tsunami and nuclear accident in March 2011, there is typically a spike in cardiovascular disease onset due to increased blood pressure and hypercoagulability. The risk of cardiovascular disease after an earthquake can be reduced by understanding the characteristics of these risks and taking appropriate preventive and remedial measures. During the East Japan Earthquake disaster, Disaster Cardiovascular Prevention (DCAP) Risk Scores (0-6 points; goala parts per thousand currency sign4 points)/Prevention Scores (0-8 points; goal a parts per thousand yen 6 points) were used to identify patients at risk at shelters and then safeguard their living conditions, chiefly by monitoring blood pressure and offering appropriate lifestyle guidance as well as treatment. By quickly reducing elevated blood pressures and then assuring stable control we could prevent the mortality and morbidity associated with disaster hypertension. This paper reviews the disaster-related mechanisms that induce cardiovascular disease and introduces the DCAP system and four typical cases in which it intervened.

High residual platelet aggregability during thienopyridine treatment occurs because of low levels of the active drug metabolite, and is associated with an increased rate of major adverse cardiovascular events. Recent findings suggest that paraoxonase-1 (PON1) is a major determinant for clopidogrel efficacy. The aim of this study was to assess the impact of serum PON1 activity on platelet aggregability in thienopyridine-treated patients. In 72 patients receiving treatment with aspirin and ticlopidine after acute coronary syndrome, various laboratory data including the formation of platelet aggregations induced by agonists were compared with serum PON1 activities, measured as paraoxonase and homocysteine thiolactone hydrolase (HTLase). Serum paraoxonase activity was significantly associated with HTLase activity (R=0.4487, P<0.0001). These PON1 activities were not correlated with any parameters for platelet aggregation, hypertension, sleep apnea, and diabetes mellitus. In contrast, serum PON1 activities seemed to be involved in cardiac function, with brain natriuretic peptide and ejection fraction being significantly correlated with serum HTLase activity (R=-0.2767, P=0.0214) and paraoxonase activity (R=0.2558, P=0.0339), respectively. Paraoxonase activity also demonstrated a significant association with increased levels of ankle-brachial index (R=0.267, P=0.0255). Serum PON1 activities did not influence platelet aggregability during treatment with thienopyridine. However, they might modulate cardiac function after acute coronary syndrome and progression of atherosclerosis. (C) 2011 Elsevier Ltd. All rights reserved.

A 52-year-old woman with Takayasu arteritis developed acute coronary syndrome and received percutaneous coronary intervention (PCI). The patient experienced restenosis three times even with drug-eluting stent (DES) implantation. We started steroid administration after the fourth PCI to reduce inflammation due to autoimmunity. With DES and a steroid combination, the patient remained free of chest pain, and a follow-up angiography demonstrated good patency of the stent site. Since in-stent restenosis may result from a complicated combination of neointimal proliferation and autoimmune mechanisms, physicians should consider a combination of DES and a steroid for the treatment of coronary artery disease in Takayasu arteritis.

Background Inflammation plays an important role in the pathogenesis of hypertension and hypertensive organ damage. Interleukin (IL)-10, a pleiotropic anti-inflammatory cytokine, exerts vasculoprotective effects in many animal models. In the present study, we examined the preventive effects of adeno-associated virus (AAV) vector-mediated sustained IL-10 expression against hypertensive heart disease and renal dysfunction in Dahl salt-sensitive rats. Methods We injected the rats intramuscularly with an AAV type I-based vector encoding rat IL-10 or enhanced green fluorescent protein (EGFP) at 5 weeks of age; subsequently, the rats were fed a high-sodium diet from 6 weeks of age. Results Sustained IL-10 expression significantly improved survival rate of Dahl salt-sensitive rats compared with EGFP expression (62.5% versus 0%, p < 0.001); it also caused 26.0% reduction in systolic blood pressure at 15 weeks (p < 0.0001). Echocardiography exhibited a 22.0% reduction in hypertrophy (p < 0.0001) and a 26.3% improvement in fractional shortening (p < 0.0001) of the rat left ventricle in the IL-10 group compared to the EGFP group. IL-10 expression also caused a 21.7% decrease in the heart weight/body weight index and cardiac atrial natriuretic peptide levels. Histopathological studies revealed that IL-10 decreased inflammatory cell infiltration, fibrosis, and transforming growth factor-P, levels in the failing heart. Furthermore, IL-10 expression significantly reduced urine protein excretion with increased glomerular filtration rates. Conclusions This is the first study to demonstrate that the anti-inflammatory cytokine IL-10 has a significant anti-hypertensive effect. AAV vector-mediated IL-10 expression potentially prevents the progression of refractory hypertension and hypertensive organ damage in humans. Copyright (c) 2008 John Wiley & Sons, Ltd.

Background-Mechanically overloaded cardiomyocytes secrete a soluble interleukin-1 receptor family member called ST2. Serum levels of ST2 are associated with prognosis in nonischemic heart failure, but the predictive value of ST2 in patients with acute myocardial infarction is unknown. Methods and Results-ST2 levels were measured in serum from 810 patients with acute myocardial infarction in the Thrombolysis In Myocardial Infarction (TIMI) 14 (362 patients) and Enoxaparin and TNK-tPA With or Without GPIIb/IIIa Inhibitor as Reperfusion Strategy in STEMI (ENTIRE)-TIMI 23 ( 448 patients) clinical trials. Baseline levels of ST2 were significantly higher in those patients who died (0.379 versus 0.233 ng/mL, P=0.0001) or developed new congestive heart failure (0.287 versus 0.233 ng/mL, P=0.009) by 30 days. In an analysis of outcomes at 30 days by ST2 quartiles, both death (P=0.001) and the combined death/heart failure end point (P=0.001) showed a significant graded association with levels of ST2; furthermore, in-hospital death (P=0.003) and death/heart failure (P=0.004) were also significantly associated with higher ST2 levels. In a logistic regression analysis that controlled for important clinical factors, increasing levels of ST2 remained associated with death at 30 days (P=0.047). ST2 levels rose during the first day after infarction and were maximal at 12 hours; ST2 levels at 12 hours were also independently associated with death at 30 days (P<0.001). Conclusions-Serum levels of the interleukin-1 receptor family member ST2 predict mortality and heart failure in patients with acute myocardial infarction. These data suggest that ST2 may be a useful biomarker and that this novel inflammatory receptor may play a role in cardiac pathophysiology.

Interleukin-10 (IL-10) is an immunosuppressive cytokine produced by T lymphocytes and drawing attention as an inhibitor of tumor angiogenesis. In this study, we investigated antiangiogenic and tumor suppressive effects of IL-10 in ovarian cancer cells. mIL-10-expressing phismid was transferred into two ovarian cancer cell lines, SHIN-3 [vascular endothelial growth factor (VEGF) producing] and KOC-2S (non-VEGF producing). After selection, mIL-10-expressing cells were obtained as SHIN-3/mIL-10 and KOC-2S/mIL-10. No significant differences were observed in in vitro growth properties between mIL-10-expressing cells and control (luciferase expressing) cells in either KOC-2S or SHIN-3. The angiogenic activities of mIL-10-expressing cells were measured by dorsal air sac assay, which detected the number of newly formed blood vessels within a chamber in vivo. In addition, tumor formation was evaluated by s.c. tumor transplantation, and survival was monitored after i.p. injection of ovarian cancer cells into BALB/c nude mice. Both in vivo angiogenic activity and tumor growth were significantly inhibited in SHIN-3/mIL-10 cells compared with the control. Moreover, peritoneal dissemination was inhibited, and the survival period was significantly prolonged (mean survival days >90 versus 36). In contrast, in the case of KOC-2S cells, no significant differences were observed in any of the parameters tested. These results indicate that IL-10 has suppressive effects on angiogenesis, tumor growth, and peritoneal dissemination of VEGF-producing ovarian cancer cells. Although the mechanisms of the antiangiogenic effect of IL-10 are still unclear, the potential usefulness of IL-10-mediated gene therapy of ovarian cancer was suggested.

Background-Using genomic technology, we previously identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes. The soluble receptor form of ST2 is secreted and detectable in human serum. This study tested the hypothesis that soluble ST2 levels in the serum of patients with severe chronic heart failure are increased in patients with neurohormonal activation. Methods and Results-Serum samples, clinical variables, and neurohormone levels from the PRAISE-2 heart failure trial (NYHA functional class III-IV; end point, mortality or transplantation) were analyzed. ST2 serum measurements were performed with ELISA on samples from 161 patients obtained at trial enrollment and from 139 of the same patients obtained 2 weeks after trial enrollment. Baseline ST2 levels were correlated with baseline B-type natriuretic peptide (BNP) levels (r=0.36, P<0.0001), baseline proatrial natriuretic peptide (ProANP) levels (r=0.36, P<0.0001), and baseline norepinephrine levels (r=0.39, P<0.0001). The change in ST2 was significant as a univariate predictor of subsequent mortality or transplantation (P=0.048), as was baseline BNP (P<0.0001) and baseline ProANP (P<0.0001). In multivariate models including BNP and ProANP, the change in ST2 remained significant as a predictor of mortality or transplantation independent of BNP and ProANP. Conclusions-Serum soluble ST2 is a novel biomarker for neurohormonal activation in patients with heart failure. In patients with severe chronic NYHA class III to IV heart failure, the change in ST2 levels is an independent predictor of subsequent mortality or transplantation.

Background-We identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes and hypothesized that ST2 participates in the acute myocardial response to stress and injury. Methods and Results-ST2 mRNA was induced in cardiac myocytes by mechanical strain (4.7 +/- 0.9-fold) and interleukin-1beta (2.0 +/- 0.2-fold). Promoter analysis revealed that the proximal and not the distal promoter of ST2 is responsible for transcriptional activation in cardiac myocytes by strain and interleukin-1beta. In mice subjected to coronary artery ligation, serum ST2 was transiently increased compared with unoperated controls (20.8 +/- 4.4 versus 0.8 +/- 0.8 ng/mL, P < 0.05). Soluble ST2 levels were increased in the serum of human patients (N = 69) 1 day after myocardial infarction and correlated positively with creatine kinase (r = 0.41, P < 0.001) and negatively with ejection fraction (P = 0.02). Conclusions-These data identify ST2 release in response to myocardial infarction and suggest a role for this innate immune receptor in myocardial injury.

beta-very low-density lipoprotein (beta-VLDL). a collective term for VLDL and chylomicron remnants. has recently shown to potently promote the development of atherosclerosis, However. the effects of beta-VLDL oil the accumulation of nitric oxide (NO) and the expression of inducible NO synthase (iNOS) in vascular smooth muscle cells (VSMC) have not been determined. In this study. we measured the accumulation of nitrite. stable metabolite of NO and examined the expression of iNOS protein and mRNA using Western blotting and RT-PCR, respectively, in VSMC, NF-kappaB activation in VSMC was examined by gel retardation assay. Incubation of cell cultures With interleukin-1beta (IL-1beta) for 24 It caused a significant increase in nitrite accumulation. Although beta-VLDL alone did not increase nitrite accumulation in unstimulated VSMC. beta-VLDL significantly enhanced nitrite accumulation in IL-1beta-stimulated VSMC in a time- and dose-dependent manner. beta-VLDL-induced nitrite accumulation in IL-1beta-stimulated VSMC was accompanied by an increase in iNOS protein and mRNA expression. In addition. IL-1beta induced NF-kappaB activation in VSMC an effect that us increased by the addition of beta-VLDL. Use of specific tyrosine kinase inhibitor herbimycin A. genistein. or PP2 (Src family kinase inhibitor) indicated that tyrosine kinases are required for IL-1beta-stimulated and beta-VLDL-enhanced nitrite accumulation, while specific inhibition of ERK1/2 or p38-MAP kinase had no effects. Our results suggest that beta-VLDL enhances iNOS expression and nitrite accumulation ill IL-1beta-stimulated VSMC through tyrosine kinase(s)-dependent mechanisms. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Objectives: Clinical trials on therapeutic angiogenesis using vascular endothelial growth factor (VEGF) are ongoing, however the benefits of these therapies are still controversial. To establish a more efficient gene transfer method for ischemic diseases, we investigated the therapeutic potential of adeno-associated virus (AAV)-mediated VEGF gene transfer. Methods: We produced VEGF(165)-express in AAV vectors (AAV-VEGF). HEK-293 cells were transduced with AAV-VEGF in vitro and VEGF expression and secretion were examined. We used a rat ischemic hindlimb model and AAV-VEGF was administered intramuscularly into the ischemic limb. Gene expression was evaluated by RT-PCR and ELISA. Six weeks after gene transfer, we measured the blood flow of limb vessels and the skin temperature of limbs. Histochemical examination was performed to illustrate capillary growth. Results: Western blotting and ELISA revealed VEGF protein expression and secretion from AAV-VEGF-transduced HEK-293 cells. VEGF mRNA and protein expression was consistently observed in the injected muscle at least 10 weeks after the injection, while no VEGF mRNA could be detected at remote organs. The mean blood flow in AAV-VEGF-transduced ischemic limbs was significantly higher than in AAV-LacZ-transduced limbs. Capillary density was significantly higher in AAV-VEGF-injected tissues than in AAV-LacZ-injected tissues. Conclusions: This study demonstrates that (1) AAV-mediated VEGF gene transfer into rat skeletal muscles is efficient and stable without ectopic expression, and (2) AAV-mediated VEGF gene transfer stimulates angiogenesis and thereby improves blood flow in a rat hindlimb ischemia model. These findings suggest that AAV-mediated VEGF gene transfer may be useful for treatment of ischemic diseases. (C) 2002 Elsevier Science BY All rights reserved.

Interleukin-6 (IL-6) is a key molecule in chronic inflammation and has been implicated in the progression of atherosclerosis. HMG-CoA reductase inhibitors (statins) may reduce the cardiovascular risk and vulnerability of atherosclerotic plaque through nonlipid as well as lipid-lowering mechanisms, but their anti-inflammatory effects on the vascular tissue have not been fully elucidated. We investigated the effects of fluvastatin on IL-6 synthesis in human vascular smooth muscle cells (VSMCs). Addition of fluvastatin decreased IL-6 synthesis in VSMCs in a time (0-24 hours)- and dose (10(-)8-10(-)5 mol/L)-dependent manner. Fluvastatin also decreased IL-6 mRNA expression in VSMCs. The effects of fluvastatin on IL-6 expression were completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not squalene. Inhibition of Rho by C3 exoenzyme or Rho kinase by Y-27632 significantly decreased IL-6 expression in VSMCs. In conclusion, fluvastatin decreases IL-6 synthesis in human VSMCs through inhibition of Rho pathway. These findings suggested that reduction of IL-6 expression by statins may partially explain their therapeutic effects in patients with coronary artery disease.