Shinzo Kimura

HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells

BACKGROUND It has been demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HRIs) reduce the incidence of acute cardiovascular events in patients with hyperlipidemia. Recent reports have shown that the protective effects of these drugs against cardiovascular events are also observed in patients without hyperlipidemia, but the mechanism of this favorable effect still remains unclear. In this study, the effects of HRIs on the endothelial regulation of thrombus formation were elucidated. METHODS AND RESULTS The mRNA and protein expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by angiotensin II (Ang II) were evaluated in cultured rat aortic endothelial cells. Pretreatment with simvastatin (0.03-3 microg/ml) significantly inhibited TF and PAI-1 induction by Ang II in a dose- and time-dependent manner. These inhibitions were significantly attenuated by mevalonic acid or geranylgeranyl pyrophosphate. Both Rho inhibitor, C3 exoenzyme, and Rho kinase inhibitor, Y-27632, mimicked the inhibitory effects of simvastatin against TF and PAI-1 induced by Ang II. This result suggested that the Rho/Rho kinase pathway is related to the TF and PAI-1 induction by Ang II. CONCLUSION It was indicated that simvastatin maintains endothelial cells to be antithrombotic by inhibiting TF and PAI-1 expression via the Rho/Rho kinase pathways in which AngII induces TF and PAI-1 expression. These observations explain, at least partly, the mechanism of the favorable effects of simvastatin in reducing the thrombotic events.

Adrenomedullin Inhibits Angiotensin II–Induced Expression of Tissue Factor and Plasminogen Activator Inhibitor-1 in Cultured Rat Aortic Endothelial Cells

Abstract—Adrenomedullin (AM) is a potent vasodilating peptide having a variety of pharmacological properties mainly in respect to vascular pathophysiology. We have previously demonstrated that angiotensin II (Ang II) or natriuretic peptides have influence on the expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) in vascular endothelial cells. The aim of this study was to elucidate the effects of AM on TF and PAI-1 mRNA and protein expression in endothelial cells. As a result, AM inhibited Ang II-induced TF and PAI-1 mRNA expression in a dose- and time-dependent manner. Because the expression of TF and PAI-1 mRNA induced by Ang II was attenuated by the increase of intracellular concentrations of cAMP by forskolin and 8-bromo-cAMP and because AM increased the intracellular level of cAMP in rat aortic endothelial cells, it was indicated that the inhibitory effect of AM on the expressions of TF and PAI-1 was mainly mediated by the cAMP-dependent signal transduction. Furthermore, the inhibitory effect of AM on TF and PAI-1 expression was partly attenuated by an NO synthase inhibitor, NG-nitro-l-arginine methyl ester. In conclusion, AM is shown to contribute to the regulation of blood coagulation and fibrinolysis by vascular endothelial cells mainly via the cAMP pathway.

Clinical Outcome After Permanent Pacemaker Implantation in Patients With a High Percentage of Ventricular Pacing

Previous reports have suggested that right ventricular apical pacing may lead to cardiac dysfunction. Septal pacing is thought to be superior to apical pacing in the prevention of cardiac dyssynchrony, however, there have been no reports on the contribution of septal pacing to improving clinical outcome.We retrospectively evaluated factors associated with cardiac events in patients with right ventricular pacing.The study population consisted of 256 consecutive patients newly implanted with permanent pacemakers and followed-up for 29 ± 18 months. Cardiac events, consisting of cardiac death or heart failure requiring hospitalization, occurred in 22 patients. Kaplan-Meier curves revealed that patients with a high percentage of ventricular pacing (> 90%, n = 101, group H) had a higher incidence of cardiac events than patients with a low percentage of ventricular pacing (< 10%, n = 83, group L) (P = 0.002). In group H, multivariate analysis showed that age (HR: 1.174, 95%CI: 1.066-1.291, P = 0.001), ejection fraction (EF) (HR: 0.898, 95%CI: 0.836-0.964, P = 0.003), QRS duration during cardiac pacing (HR: 1.059, 95%CI: 1.017-1.103, P = 0.006), and existing basal cardiac diseases (HR: 13.080, 95%CI: 2.463-69.479, P = 0.003) were significant predictors of cardiac events, although pacing site had no significant association with prognosis (P = 0.56).Higher age, lower EF, longer QRS duration during cardiac pacing, and existing basal cardiac diseases are associated with poor prognosis in patients with a high percentage of ventricular pacing.

Effects of argatroban and heparin on thrombus formation and tissue plasminogen activator-induced thrombolysis in a microvascular thrombosis model

Effects of (2R,4R)-4-methyl-1-[N(2)-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidine-carboxylic acid monohydrate (argatroban) and unfractionated heparin (UFH) were compared with respect to thrombus formation and tissue-type plasminogen activator (t-PA)-induced thrombolysis in a microvasculature thrombosis model. The antithrombotic activities of anticoagulants were evaluated with respect to the time required for the initiation of thrombus formation (T(i)) and the time required for the thrombus to stop blood flow (T(s)). The effects of anticoagulants administered with t-PA were evaluated by percent stenosis of the vessel and percent area of the thrombus. Argatroban (1-3 mg/kg/bolus) significantly prolonged T(i) and T(s) in a dose-dependent fashion compared to control. Argatroban (3 mg/kg/bolus) significantly prolonged both the T(i) and T(s) more effectively than UFH (100 anti-XaU (a-XaU)/kg/bolus), despite equivalent prolongation of the activated partial thromboplastin time (aPTT). Higher doses of UFH (300-500 a-XaU/kg) were required to significantly prolong T(i) and T(s), but at these doses, UFH caused over-prolongation of aPTT (>180 s), which might consequently cause bleeding complications. Argatroban (0.1-0.3 mg/kg/h) significantly accelerated thrombolysis by t-PA in both a dose- and time-dependent fashion. Although argatroban (0.1-0.2 mg/kg/h) did not significantly prolong the aPTT and bleeding time (BT) as compared with control, it significantly accelerated thrombolysis by t-PA at these doses of lower bleeding risk. Argatroban (0.3 mg/kg/h) significantly enhanced thrombolysis by t-PA, while UFH (12.5 anti-XaU/kg/h) attenuated it again, despite equivalent prolongation of the aPTT and BT. We conclude that argatroban seems to be a more efficient and safer anticoagulant than UFH for the prevention of thrombus formation and acceleration of t-PA-induced thrombolysis.

Bradykinin enhances in vitro procoagulant and antifibrinolytic properties of rat vascular endothelial cells.

INTRODUCTION Bradykinin (BK) is a biologically active peptides that exerts a broad spectrum of pathophysiological effects mainly by producing nitric oxide (NO) and prostacyclin from vascular endothelial cells. A direct effect of BK on vascular endothelial cells regarding the expression of the regulatory proteins of coagulation and fibrinolysis has not been fully elucidated. MATERIALS AND METHODS The effects of BK on the expression of tissue factor (TF), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (TPA) in cultured rat aortic endothelial cells (RAECs) were respectively evaluated by Northern blot and chromogenic assay or enzyme-linked immunosorbent assay (ELISA). RESULTS BK significantly increased the expression of TF and PAI-1 in both mRNA and protein levels, but it did not affect the expression of TFPI. Although BK tended to increase TPA mRNA expression, the observed increase was not statistically significant. Those effects are considered to be mediated by B(2) receptor, because B(2) receptor antagonist (Hoe 140) suppressed those mRNA inductions by BK. Furthermore, since those mRNA inductions by BK were enhanced by nitro-L-arginine-methyl ester (L-NAME) and attenuated by L-arginine (L-Arg), NO was speculated to negatively contribute to the expressions of TF and PAI-1. CONCLUSION BK was indicated to modify the property of vascular endothelial cells to be procoagulant and antifibrinolytic. Those effects of BK were considered to be the net of its direct effect and the effect negatively mediated by NO.

Combination Effect of Calcium Channel Blocker and Valsartan on Cardiovascular Event Prevention in Patients with High-Risk Hypertension: Ancillary Results of the KYOTO HEART Study

The ancillary analysis of the KYOTO HEART Study (n = 3031) was designed to assess the combined treatment with calcium channel blocker (CCB) plus valsartan for high-risk hypertension. With-CCB (n = 1807) showed less primary events than without-CCB (n = 1224) (P = .037), in which acute myocardial infarction was significantly reduced. With-CCB plus valsartan (n = 773) showed lower incidence than with-CCB plus non-angiotensin receptor blocker (ARB) (n = 1034) (P = .0002), in which angina pectoris and heart failure were significantly reduced. Without-CCB plus valsartan (n = 744) was superior to without-CCB plus non-ARB (n = 480) (P = .0013), in which stroke was reduced. CCB-based therapy was useful, and CCB plus valsartan combination provided a more efficient prevention for high-risk hypertensive patients.

573 Antihypertensive efficacy and safety of Losartan/hydrochlorothiazide vs. high-dose angiotensin receptor blocker (ARB) in patients with uncontrolled hypertension: Kamanza Anti-Hypertensive Treatment Trial (KAHT-Trial)

Objectives: According to the current guidelines, archiving strict blood pressure control is essential to reduce cardiovascular events in patients with hypertension. The aim of this study was to evaluate antihypertensive efficacy and safety of losartan/hydrochlorothiazide (Los/HCTZ) combination drug vs. high-dose angiotensin receptor blocker (ARB) in patients with uncontrolled hypertension. Methods: This study was conducted at 11 centers for the KAHT-Trial group. A total of 65 hypertensive patients receiving regular-dose ARB therapy whose BP remained above 140/90 mmHg were prospectively enrolled. The patients were randomly assigned to receive Los/HCTZ combination drug (Los/HTCZ group, n = 67) or high-dose ARB (high-dose ARB group, n = 68) and followed for 1year. Results: After 3 months of treatment, BP significantly decreased from 157 ± 12/87 ± 9 mmHg to 137 ± 14/78 ± 8 mmHg in the Los/HCTZ group and from 158 ± 12 /91 ± 12 mmHg to 139 ± 12/80 ± 8 mmHg in the high-dose ARB group. Decreases in BP were well-maintained for 1year in the both groups. However, decreases in BP were not different between the two groups. After 1 year of treatment, levels of HbA1c, eGFR, plasma glucose, cholesterol and uric acid showed no significant changes in the both groups. Conclusions: Our results suggest that Los/HCTZ combined therapy was effective in reducing uncontrolled hypertension without deteriorating glucose, lipid and uric acid metabolism as well as high-dose ARB. Los/HCTZ combined therapy may have beneficial effect in terms of tolerability and medical economics.

Prognostic Value of Plasma Aldosterone Levels on the Future Risk of New-Onset Atrial Fibrillation

Background: Renin-angiotensin-aldosterone system has been reported as one of the risk factors of atrial fibrillation (Af). However, roles of aldosterone (ALD) and predictor of new-onset Af are still unclear. We therefore evaluated predictive value of plasma ALD levels on the incidence of Af. Methods: The levels of plasma ALD were quantified in a prospective cohort study of 796 consecutive outpatient clinic patients initially free from Af (age 68.5±12.6). The subjects were divided into two groups of elevated ALD group (group H) and non-elevated ALD group (group L) according to the median value of baseline plasma ALD. The end point of the study was new-onset Af. Results: The median value of baseline ALD was 89.0 pg/mL in all patients. During a median follow-up of 941 days, incidence of new-onset Af was 7.5%. Patients of group H had a significantly higher Af incidence rates, as compared to those of group L (12.5% vs. 2.5%, P<0.0001). Elevated ALD were independent predictor of increased future incident Af risk in Cox regression analyses adjusted for age, sex, body mass index, C-reactive protein and brain natriuretic peptide. The adjusted hazard ratio was 3.691 (95% CI, 1.962–6.942; P<0.0001). Conclusions: In Japanese patients without Af, higher ALD was independent predictor of developing Af.