OBJECTIVE: Red wine (RW) consumption has been associated with a reduction of cardiovascular events, but limited data are available on potential mediating mechanisms. This study tested the hypothesis that intake of RW may promote circulating endothelial progenitor cell (EPC) level and function through enhancement of nitric oxide bioavailability. METHODS AND RESULTS: Eighty healthy, young subjects were randomized and assigned to consume water (100 mL), RW (100 mL), beer (250 mL), or vodka (30 mL) daily for 3 weeks. Flow cytometry was used to quantify circulating EPC numbers, and in vitro assays were used to evaluate EPC functions. After RW ingestion, endothelial function determined by flow-mediated vasodilation was significantly enhanced; however, it remained unchanged after water, beer, or vodka intake. There were significantly increased numbers of circulating EPC (defined as KDR(+)CD133(+), CD34(+)CD133(+), CD34(+)KDR(+)) and EPC colony-forming units only in the RW group (all P<0.05). Only RW ingestion significantly enhanced plasma levels of nitric oxide and decreased asymmetrical dimethylarginine (both P<0.01). Incubation of EPC with RW (but not beer or ethanol) and resveratrol in vitro attenuated tumor necrosis factor-alpha-induced EPC senescence and improved tumor necrosis factor-alpha-suppressed EPC functions and tube formation. Incubation with nitric oxide donor sodium nitroprusside significantly ameliorated the inhibition of tumor necrosis factor-alpha on EPC proliferation, but incubation with endothelial nitric oxide synthase inhibitor L-NAME and PI3K inhibitor markedly attenuated the effect of RW on EPC proliferation. CONCLUSIONS: The intake of RW significantly enhanced circulating EPC levels and improved EPC functions by modifying nitric oxide bioavailability. These findings may help explain the beneficial effects of RW on the cardiovascular system. This study demonstrated that a moderate intake of RW can enhance circulating levels of EPC in healthy subjects by increasing nitric oxide availability. Direct incubation of EPC with RW and resveratrol can modify the functions of EPC, including attenuation of senescence and promotion of EPC adhesion, migration, and tube formation. These data suggest that RW ingestion may alter the biology of EPC, and these alterations may contribute to its unique cardiovascular-protective effect.

Background: Baseline fasting plasma glucose (FPG) level predicts the onset of type 2 diabetes mellitus (DM). Other predictors have been less investigated. This study aimed to investigate non-glucose predictors together with FPG for future onset of type 2 DM in fresh essential hypertensives. Methods: Consecutive nondiabetic patients with newly diagnosed essential hypertension were prospectively evaluated for diurnal blood pressure (BP) change by ambulatory BP monitoring, vascular endothelial function by plethysmography, and biomarkers by blood biochemistry. They were then given guideline-based treatment and followed-up regularly for more than 5 years. Results: During a mean follow-up period of 5.9 years, 6 of the 106 study patients developed DM. Baseline FPG, alanine aminotransferase (ALT) level, and day-night difference in diastolic BP were related to future onset of DM. FPG > 5.8 mmol/L (p = 0.034) and ALT > 31 U/L (p = 0.048) independently and day-night difference in diastolic BP </= 2.9% potentially predicted new-onset DM (p = 0.089). Simultaneously having at least 2 of the indicators mentioned above at baseline is predictive of new-onset DM. Parameters of reactive hyperemia by plethysmography were not relevant. Conclusion: In addition to FPG, baseline serum ALT level independently and diurnal diastolic BP changes potentially predicted future onset of type 2 DM in newly diagnosed hypertensives. Both glucose and non-glucose indicators could be examined together for early risk stratification of future DM.

Background: Antihypertensive agents differentially influence the plasma adiponectin concentration and the effects of fixed-dose combination regimens remain unclear. The influence of a combination of an angiotensin-converting enzyme inhibitor (ACEI) and a thiazide-type diuretic or an ACEI alone on plasma adiponectin concentrations in patients with essential hypertension was evaluated in the present study. Methods and Results: After a 2-week placebo run-in phase, 30 patients with essential hypertension were randomized to receive preterax (2 mg perindopril/0.625 mg indapamide) or cilazapril (2.5 mg) once daily for 12 weeks. Plasma adiponectin and insulin concentrations were measured before and after treatment. Insulin resistance was measured by homeostasis assessment index (HOMA-IR). Treatment with preterax (P=0.003) and cilazapril (P=0.031) significantly reduced systolic blood pressure (BP), but only preterax reduced diastolic BP (P=0.024). Cilazapril treatment significantly increased the plasma adiponectin concentration (P=0.025) and reduced plasma triglycerides (P=0.041), whereas preterax treatment increased the plasma insulin concentration (P=0.041) and tended to increase HOMA-IR. Conclusions: The combination of an ACEI and indapamide improved BP control, but attenuated the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension. Such a combination may be best reserved for improved BP control rather than for metabolic protection in clinical hypertension.

OBJECTIVE: Both matrix metalloproteinases (MMPs) and endothelial progenitor cells (EPCs) have been implicated in the process of neovascularization. Here we show that the impaired neovascularization in mice lacking MMP-9 is related to a defect in EPC functions in vasculogenesis. METHODS AND RESULTS: Hindlimb ischemia surgery was conducted in MMP-9(-/-) mice and wild-type (MMP-9(+/+)) mice. Blood flow recovery was markedly impaired in MMP-9(-/-) mice when compared with that in wild-type mice as determined by laser Doppler imaging. Flow cytometry demonstrated that the number of EPC-like cells (Sca-1(+)/Flk-1(+)) in peripheral blood increased in wild-type mice after hindlimb ischemia surgery and exogenous vascular endothelial growth factor stimulation, but not in MMP-9(-/-) mice. Plasma levels and bone marrow concentrations of soluble Kit-ligand (sKitL) were significantly elevated in wild-type mice in response to tissue ischemia, but not in MMP-9(-/-) mice. C-kit positive bone marrow cells of MMP-9(-/-) mice have attenuated adhesion and migration than those isolated from wild-type mice. In in vitro studies, incubation with selective MMP-9 inhibitor suppressed the colony formation, migration, and tube formation capacities of EPC. Transplantation of bone marrow cells from wild-type mice restored collateral flow formation in MMP-9(-/-) mice. CONCLUSIONS: These findings suggest that MMP-9 deficiency impairs ischemia-induced neovascularization, and these effects may occur through a reduction in releasing the stem cell-active cytokine, and EPC mobilization, migration, and vasculogenesis functions.

OBJECTIVES: We sought to test the hypothesis that decreased plasma soluble receptor for advanced glycation end products (sRAGE) levels were associated with endothelial dysfunction in nondiabetic patients. BACKGROUND: sRAGE, a C-truncated secretary isoform of the receptor protein, has been shown to neutralize vascular damage mediated by advanced glycation end products, and has been implicated in atherogenesis. However, the relation between plasma sRAGE level and endothelial function remains unclear. METHODS: Plasma levels of sRAGE were examined in 180 nondiabetic participants with suspected coronary artery disease. Endothelial function was evaluated by endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery. The primary end point was the combined occurrence of major adverse cardiovascular events, including nonfatal myocardial infarction, revascularization with percutaneous coronary intervention or coronary artery bypass grafting, ischemic stroke, and cardiovascular death. RESULTS: All participants were divided into three groups according to the magnitude of FMD: group 1 (FMD <3%), group 2 (FMD >or=3 and <6%), group 3 (FMD >or=6%). The plasma levels of sRAGE were significantly decreased in group 1 compared with groups 2 and 3 (676+/-270, 820+/-357, and 1140+/-451 pg/ml; P<0.001). By multivariate analysis, it was shown that the plasma sRAGE level was an independent predictor of endothelium-dependent FMD (R = 0.46; P<0.001). After a 48-month follow-up period, there were 23 events (26%) in the lower sRAGE group(<or=median, 809 pg/ml) and 11 events (12%) in the higher sRAGE group (>809 pg/ml; P<0.05). By the Kaplan-Meier analysis, it was shown that enhanced plasma levels of sRAGE were associated with better major adverse cardiovascular event-free survival (P = 0.032). CONCLUSION: The results indicate that plasma sRAGE levels are positively associated with endothelial function and predict cardiovascular events in nondiabetic participants with suspected coronary artery disease, suggesting its pivotal role in atherothrombosis.

Objective This study was conducted to investigate the potential role of intravascular oxidative stress in inexplicable episodes of coronary artery spasm (CAS) during coronary angiography (CAG). Design and Methods Serial patients with stable angina scheduled for routine CAG were prospectively evaluated. Patients with clinical evidence of variant angina were excluded. Blood sampling was done immediately before CAG. Results Inexplicable episodes of CAS were identified during CAG in 7 patients with and 8 patients without significant coronary artery disease (CAD). Compared to those without CAS (n=220), the 15 patients with CAS had significantly increased plasma triglyceride level, white blood cell (WBC) count and superoxide production in whole blood, and reduced plasma high-density lipoprotein (HDL) level. In multivariate analysis, CAS episodes were associated with an elevated baseline WBC count (relative risk, RR, of increasing one tertile, 2.49) and peak whole blood superoxide production (RR, 2.36), and a reduced plasma HDL level (RR, 0.37). Conclusions Both an increased WBC count and superoxide production in whole blood preceded and predicted the inexplicable development of CAS during CAG irrespective of the presence of CAD, suggesting that intravascular oxidative stress might be the major mediator. Antioxidants given before CAG may be warranted to prevent CAS episodes.

OBJECTIVES: This study tested the hypothesis that plasma heparin cofactor II (HCII) activity independently predicts cardiovascular events in patients after acute myocardial infarction (AMI) and attempted to elucidate the role of HCII in atherothrombosis. BACKGROUND: HCII inhibits thrombin activity by binding to dermatan sulfate and has been shown to be a novel and independent risk factor for atherosclerosis. However, there is limited data on the relation between plasma levels of HCII after AMI and future cardiovascular events. METHODS: A total of 110 consecutive patients (aged 63+/-11 years) with AMI were followed up for 42+/-12 months. Plasma HCII activity was determined from blood samples collected immediately after hospitalization. The primary end point was the combined occurrence of major adverse cardiovascular events (MACE), including rehospitalization because of unstable angina, nonfatal MI, revascularization with either percutaneous coronary intervention or coronary artery bypass grafting, ischemic stroke, and cardiovascular death. RESULTS: All patients were divided into three groups: a high-HCII group (>122%, n=35), a normal-HCII group (>98% and </=122%, n=41), and a low-HCII group (</=98%, n=34). The high-HCII group had reduced MACE compared with the other groups, although the difference was not significant (P=0.150). Enhanced plasma HCII activity was, however, significantly associated with decreased MACE in the nondiabetic patients (P=0.034). In a Cox multivariate regression analysis that included all patients, plasma HCII activity was an independent predictor of future MACE (P=0.029). CONCLUSION: The results indicate a potential association between plasma HCII activity and future cardiovascular events after AMI. Moreover, HCII activity seems to play a pivotal role in atherothrombosis.

OBJECTIVE: We examined whether the combined use of high-sensitive C-reactive protein (hsCRP) and N-terminal-probrain natriuretic peptide (NT-proBNP) could increase the predictive value for future cardiovascular events. BACKGROUND: hsCRP and NT-proBNP both have been shown to be strong predictors of cardiovascular events in patients with coronary artery disease. Few data are, however, available to assess whether combined use of these two distinct biomarkers improves the risk stratification in predicting cardiovascular events. METHODS: A total of 205 participants with suspected coronary artery disease referred for coronary angiography were enrolled in the study. Plasma levels of hsCRP and NT-proBNP were measured before coronary angiography. Cox regression analyses were conducted for the 205 participants, with cardiovascular events being defined as nonfatal myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, and ischemic stroke. RESULTS: All patients were divided into four groups by using median values of hsCRP (1.1 mg/l) and NT-proBNP (472.6 fmol/ml): group 1, low hsCRP/low NT-proBNP (n=60); group 2, high hsCRP/low NT-proBNP (n=42); group 3, low hsCRP/high NT-proBNP (n=42); and group 4, high hsCRP/high NT-proBNP (n=61). During a median follow-up of 4 years, there were 84 cardiovascular events (41%): 11 events (18%) in group 1, 13 events (31%) in group 2, 20 events (48%) in group 3, and 40 events (66%) in group 4 (P<0.001). Patients with cardiovascular event had significantly attenuated flow-mediated vasodilation (3.6+/-3.4 vs. 5.3+/-3.5%, P=0.001) and increased plasma levels of NT-proBNP (627+/-330 vs. 458+/-196 fmol/ml, P<0.001). Simple linear regression analysis on all studied participants demonstrated significant associations between levels of hsCRP and NT-proBNP (hsCRP vs. NT-proBNP: r=0.354, P<0.001). Cox regression hazards model showed that combined use of NT-proBNP and hsCRP significantly increased predictive value for future cardiovascular events [hazard ratio (HR) 4.922, 95% confidence interval (CI), 2.519-9.617; P<0.0001 for high hsCRP/high NT-proBNP vs. low hsCRP/low NT-proBNP]. CONCLUSION: These findings demonstrated that a simple combination of distinct biomarkers of hsCRP and NT-proBNP might provide additional information for predicting cardiovascular events.

OBJECTIVES:: This study aimed to investigate whether baseline serum levels of matrix metalloproteinases (MMPs) could predict long-term prognosis of coronary revascularizations. DESIGNS AND METHODS:: Ninety-one consecutive patients receiving coronary revascularizations (58 percutaneous coronary interventions and 33 coronary artery bypass graft surgeries) for stable coronary artery disease (CAD) were studied. Baseline serum levels of high-sensitive C-reactive protein (hsCRP), MMP-2,-3 and -9 drawn before revascularization were correlated to the clinical adverse events within >12 months after revascularizations. RESULTS:: Baseline characteristics were similar between the two groups. There were total 22 major adverse cardiovascular events during a mean period of 27 months. Only baseline serum MMP-9 level independently predicted future cardiovascular events after coronary revascularization either by multivariate analysis (relative risk 3.18, p=0.028) or by Kaplan-Meier analysis (p=0.021). CONCLUSIONS:: Baseline serum MMP-9 level predicted the prognosis after coronary revascularizations, suggesting its potential role in risk stratification before revascularization strategies for stable CAD.

Matrix metalloproteinase (MMP) is critical to the progression of atherosclerosis and neointima hyperplasia after vascular injury. We investigated the effects of carvedilol, a pharmacological antioxidant with alpha- and beta-adrenergic blocking activity, on MMP-2 and MMP-9 expression. Vascular injury was induced with the balloon catheters on abdominal aortas of high-cholesterol-fed rabbits. On Day 21, there was significant aortic neointima formation with increased oxidative DNA damage by immunostaining with 8-hydroxy-2'-deoxyguanosine and enhanced MMP-2 and MMP-9 expressions by Western blotting, which were significantly reduced by oral administration of carvedilol (20 mg/kg/day) or probucol (100 mg/kg/day). Vascular expression (by Western blot), activity (by gelatin zymography), and mRNA levels of MMP-2 and MMP-9 were also reduced by carvedilol or probucol. Besides, pretreatment with carvedilol or probucol but not propranolol, a beta-blocker, or prazocin, an alpha-blocker, inhibited tumor necrosis factor-alpha-stimulated expressions and activities of MMP-2 and MMP-9 in human aortic smooth muscle cells. On electrophoretic mobility-shift assay, carvedilol inhibited the binding activities of activator protein-1 and specific protein-1, two major transcription factors for MMP promoter regions. Accordingly, carvedilol, a pharmacological antioxidant, inhibited in vivo and in vitro expression of MMP-2 and MMP-9 properly by modulating the redox-related pathways, suggesting its potential clinical implications.

BACKGROUND: Beta-blockers are one of the more commonly prescribed classes of anti-hypertensive drugs, both as first-line and second-line. OBJECTIVES: To quantify the effect on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and withdrawals due to adverse effects of beta-blocker therapy when given as a second-line drug in adult patients with primary hypertension. SEARCH STRATEGY: CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1966-Aug 2009), EMBASE (1988-Aug 2009) and bibliographic citations of articles and reviews were searched. SELECTION CRITERIA: Double-blind, randomized controlled trials comparing a beta-blocker in combination with a drug from another class of anti-hypertensive drugs compared with that drug alone for a duration of 3 to 12 weeks in patients with primary hypertension were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted the data and assessed trial quality of each included study. MAIN RESULTS: 20 double-blind RCTs evaluated the BP lowering efficacy of beta-blockers as second-line drug in 3744 hypertensive patients (baseline BP of 158/102 mmHg; mean duration of 7 weeks). The BP reduction from adding a beta-blocker as the second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. A reduction in BP was seen with adding a beta-blocker to thiazide diuretics or calcium channel blockers at doses as low as 0.25 times the manufacturer's recommended starting dose. The BP lowering efficacy of beta-blockers as a second drug was 6/4 mmHg at 1 times the starting dose and 8/6 mmHg at 2 times the starting dose. Beta-blockers reduced heart rate by 10 beats/min at 1 to 2 times the starting dose. Beta-blockers did not statistically significantly increase withdrawals due to adverse effects but this was likely due to the lack of reporting of this outcome in 35% of the included RCTs. AUTHORS' CONCLUSIONS: Addition of a beta-blocker to diuretics or calcium-channel blockers reduces BP by 6/4mmHg at 1 times the starting dose and by 8/6 mmHg at 2 times the starting dose. When the blood pressure lowering effect of beta-blockers from this review was compared to that of thiazide diuretics from our previous review (Chen 2009), second-line beta-blockers reduce systolic BP to the same extent as second-line thiazide diuretics, but reduce diastolic BP to a greater degree. The different effect on diastolic BP means that beta-blockers have little or no effect on pulse pressure whereas thiazides cause a significant dose-related decrease in pulse pressure. This difference in the pattern of BP lowering with beta-blockers as compared to thiazides might be the explanation for the fact that beta-blockers appear to be less effective at reducing adverse cardiovascular outcomes than thiazide diuretics, particularly in older individuals.

BackgroundOxidized lipoproteins and antioxidized low-density lipoprotein (anti-oxLDL) antibodies (Abs) have been detected in plasma in response to blood pressure (BP) elevation, suggesting the participation of the adaptive immune system. Therefore, treatment of hypertension may act on the immune response by decreasing oxidation stimuli. However, this issue has not been addressed. Thus, we have here analyzed anti-oxLDL Abs in untreated (naive) hypertensive patients shortly after initiation of antihypertensive therapeutic regimens.MethodsTiters of anti-oxLDL Abs were measured in subjects with recently diagnosed hypertension on stage 1 (n = 94), in primary prevention of coronary disease, with no other risk factors, and naive of antihypertensive medication at entry. Subjects were randomly assigned to receive perindopril, hydrochlorothiazide (HCTZ), or indapamide (INDA) for 12 weeks, with additional perindopril if necessary to achieve BP control. Abs against copper-oxidized LDL were measured by enzyme-linked immunosorbent assay.ResultsTwelve-week antihypertensive treatment reduced both office-based and 24-h ambulatory BP measurements (P < 0.0005). The decrease in BP was accompanied by reduction in thiobarbituric acid-reactive substances (TBARS)(P < 0.05), increase in anti-oxLDL Ab titers (P < 0.005), and improvement in flow-mediated dilation (FMD)(P < 0.0005), independently of treatment. Although BP was reduced, we observed favorable changes in anti-oxLDL titers and FMD.ConclusionsWe observed that anti-oxLDL Ab titers increase after antihypertensive therapy in primary prevention when achieving BP targets. Our results are in agreement with the concept that propensity to oxidation is increased by essential hypertension and anti-oxLDL Abs may be protective and potential biomarkers for the follow-up of hypertension treatment.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.214.

Optimal control of hypertension reduces the risk of long-term cardiovascular complications, and current guidelines recommend blood pressure (BP) targets of <140/90 mmHg for patients. Despite this, the BP of many patients with hypertension in primary health care remains poorly controlled. The ACE inhibitor perindopril has proven BP-lowering efficacy as well as protective effects against cardiovascular events among patients with additional cardiovascular risk factors. The PREFER study assessed the antihypertensive efficacy and safety of perindopril 5-10 mg/day among hypertensive patients who were unresponsive to treatment with other ACE-inhibitor-based regimens. The PREFER study was an open-label, prospective, observational study conducted in primary health-care centres throughout Romania. Patients selected for the study (n = 824; mean +/- SD age 60.3 +/- 9.8 years) had uncontrolled hypertension (i.e. seated BP >/=140/90 mmHg, or >/=130/80 mmHg in patients with diabetes mellitus or at high cardiovascular risk) despite receiving ACE inhibitors either alone or in free combination with other antihypertensive classes. At study entry, current ACE inhibitor treatment was replaced by perindopril 5 mg/day. Patients were followed up monthly for 3 months and the dosage of perindopril could be increased to 10 mg/day in cases of failure to achieve BP control. No other change in antihypertensive therapy was permitted. Replacing the previous ACE inhibitor with perindopril 5-10 mg/day resulted in decreases of 26.2 mmHg (from 162.6 +/- 15.6 to 136.4 +/- 14.6 mmHg [p < 0.001]) in systolic BP and of 12.6 mmHg (from 96.9 +/- 17.2 to 84.3 +/- 12.8 mmHg [p < 0.001]) in diastolic BP. Mean pulse pressure (PP) was reduced by 13.6 mmHg (from 65.7 to 52.1 mmHg) with greater decreases seen in patients aged >70 years or with isolated systolic hypertension. BP control was achieved in 48.1% of the previously uncontrolled population. Antihypertensive efficacy was observed across patient subgroups regardless of the severity of hypertension at baseline and number of cardiovascular risk factors. Patient compliance with treatment was high throughout the study. Perindopril 5-10 mg/day lowers BP and PP and improves BP control among hypertensive patients who were previously unresponsive to other ACE inhibitor-based regimens.

Many guidelines recommended strict blood pressure (BP) control to prevent cardiovascular events. However, BP control in a substantial majority of hypertensives remains to be insufficient. We have determined the trends of BP control of the same patients during 15 years in a hypertension clinic. One hundred three patients (age 32-91, mean 68 +/- 11 years in 2006), who were followed at our hypertension clinic between 1991-2006, were retrospectively investigated. We compared the clinical characteristics of the patients in 2006 to those in 1991, 1996, and 2001, using the averaged BP determined at two occasions of each year for our analysis. The average BP decreased from 144 +/- 17/87 +/- 10 mmHg to 132 +/- 12/75 +/- 10 mmHg (p < 0.01) during the 15 years between 1991 and 2006. When good BP control was defined as < 140/90 mmHg, the rate of patients with good BP control increased from 35% in 1991 to 45% in 1996, to 54% in 2001 (p < 0.01 vs. 1991), and to 72% in 2006 (p < 0.01 vs. 1991). The number of anti-hypertensive drugs used in 2006 significantly increased compared to those in 1991, 1996, and 2001. More specifically, the use of diuretics and alpha-blockers increased significantly during this period. Results suggest that BP control improved in the 15 years studied, and the increased use of the anti-hypertensive drugs, as well as the increased awareness of the importance of strict BP control, seems to have contributed to improve the BP control.

The anti-hypertensive effect of GABA-rich Chlorella was studied after oral administration for 12 weeks in the subjects with high-normal blood pressure and borderline hypertension in the placebo-controlled, double-blind manner in order to investigate if GABA-rich Chlorella, a dietary supplement, is useful in control of blood pressure. Eighty subjects with Systolic blood pressure (SBP) 130-159 mmHg or diastolic blood pressure (DBP) 85-99 mmHg (40 subjects/group) took the blinded substance of GABA-rich Chlorella (20 mg as gamma-aminobutyric acid) or placebo twice daily for 12 weeks, and had follow-up observation for an additional 4 weeks. Systolic blood pressure in the subjects given GABA-rich Chlorella significantly decreased compared with placebo (p < 0.01). Diastolic blood pressure had the tendency to decrease after intake of GABA-rich Chlorella. Neither adverse events nor abnormal laboratory findings were reported throughout the study period. Reduction of SBP in the subjects with borderline hypertension was higher than those in the subjects with high-normal blood pressure. These results suggest that GABA-rich Chlorella significantly decreased high-normal blood pressure and borderline hypertension, and is a beneficial dietary supplement for prevention of the development of hypertension.

OBJECTIVE: The blood pressure (BP)-lowering response to renin-angiotensin-aldosterone system blockade in hypertensive African-Americans is typically less than in whites. To determine whether higher than conventional doses of renin-angiotensin-aldosterone system blockade can improve BP reduction in African-American patients. METHODS: Hypertensive patients with type 2 diabetes and albuminuria were enrolled: 110 African-Americans (BP = 150/87 mmHg, aged 57.5 +/- 11 years) and 281 non-African-Americans (BP = 151/89 mmHg, aged 57.7 +/- 11 years). All patients received valsartan 160 mg once daily in the morning for 4 weeks, following which patients were randomized to receive one of three valsartan doses: 160, 320 or 640 mg/day (2x, maximal recommended dose) for 26 weeks. If at week 6, target BP (<130/80 mmHg) was not achieved, then other add-on antihypertensives were allowed. RESULTS: The predominant BP (DeltaSBP/DeltaDBP) reduction was observed within 4 weeks and was lesser in African-Americans (7.8 +/- 15/4.5 +/- 9 mmHg) than non-African-Americans (8.9 +/- 14/6.6 +/- 1 mmHg, P < 0.05). Greater reduction in urinary albumin excretion was observed with higher doses (320 or 640 mg); however, the responses were similar between African-Americans and non-African-Americans. Use of add-on antihypertensives was higher in African-American (56%) vs. non-African-American patients (36%) with a similar rate across the three valsartan doses. From week 4-26, reduction in BP was lesser (P < 0.05) for African-American than non-African-American patients at the160-mg dose but not with 320 and 640-mg doses. CONCLUSION: In African-American patients, a lower BP reduction response was observed to conventional doses of valsartan than non-African-American patients, but at 640 mg, a higher response was observed in African-American patients than in non-African-American patients.

Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy.

Background: Antihypertensive agents differentially influence the plasma adiponectin concentration and the effects of fixed-dose combination regimens remain unclear. The influence of a combination of an angiotensin-converting enzyme inhibitor (ACEI) and a thiazide-type diuretic or an ACEI alone on plasma adiponectin concentrations in patients with essential hypertension was evaluated in the present study. Methods and Results: After a 2-week placebo run-in phase, 30 patients with essential hypertension were randomized to receive preterax (2 mg perindopril/0.625 mg indapamide) or cilazapril (2.5 mg) once daily for 12 weeks. Plasma adiponectin and insulin concentrations were measured before and after treatment. Insulin resistance was measured by homeostasis assessment index (HOMA-IR). Treatment with preterax (P=0.003) and cilazapril (P=0.031) significantly reduced systolic blood pressure (BP), but only preterax reduced diastolic BP (P=0.024). Cilazapril treatment significantly increased the plasma adiponectin concentration (P=0.025) and reduced plasma triglycerides (P=0.041), whereas preterax treatment increased the plasma insulin concentration (P=0.041) and tended to increase HOMA-IR. Conclusions: The combination of an ACEI and indapamide improved BP control, but attenuated the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension. Such a combination may be best reserved for improved BP control rather than for metabolic protection in clinical hypertension.

Abstract Objective: This study was designed to explore antihypertensive efficacy and safety of a combination of amlodipine (CCB) and valsartan (ARB), in essential hypertensive patients not adequately controlled by amlodipine monotherapy. Methods: This was a multi-centre, randomised, double-blind, active-controlled study in patients with essential hypertension. After a washout period followed by a single-blind amlodipine 10 mg run-in period, patients with mean sitting diastolic blood pressure (msDBP)>/=90 mmHg and <110 mmHg were randomised to receive amlodipine/valsartan (10/160 mg o.d.) or amlodipine (10 mg o.d.) for 8 weeks. Trial registration number: NCT00171002. Main outcome measures: The primary efficacy variable was change from baseline in msDBP at study endpoint. Secondary efficacy variables were change from baseline in mean sitting systolic blood pressure (msSBP), responder rate (msDBP <90 mmHg or >/=10 mmHg reduction from baseline) and DBP control rate (msDBP <90 mmHg). Results: Of the 1283 patients enrolled in single-blind period, 944 were randomised to receive amlodipine/valsartan 10/160 mg (n = 473) and amlodipine 10 mg (n = 471). Statistically significant greater reductions (p < 0.0001) from baseline in msSBP/msDBP were observed with combination therapy (12.9/11.4 mmHg) compared to monotherapy (10.0/9.3 mmHg). Responder rate was significantly greater (p = 0.0011) with combination therapy (79.0%) compared to monotherapy (70.1%). The percentage of patients with controlled DBP was also significantly (p < 0.0001) higher with combination therapy (77.8%) compared to monotherapy (66.5%). Incidence of peripheral oedema was slightly higher with amlodipine monotherapy (9.4%) compared to combination therapy (7.6%). Conclusion: The combination of amlodipine/valsartan in this 8-week double-blind study provided additional BP control and was well tolerated in patients inadequately controlled with amlodipine monotherapy. Results should be interpreted with the knowledge that study entry criteria may limit application to a wider population.

black triangle Nebivolol is a beta-adrenergic receptor antagonist with a dual mechanism of action. It shows high selectivity for beta(1)-adrenergic receptors and appears to have nitric oxide-mediated vasodilatory activity. black triangle Once-daily nebivolol effectively lowered BP in patients with mild to moderate hypertension in four randomized, double-blind, placebo-controlled, 12-week trials. Trough sitting DBP and SBP were reduced to a significantly greater extent in nebivolol than in placebo recipients in trials in demographically heterogenous hypertensive patient groups, as well as in trials involving only Black patients and in patients continuing previous stable antihypertensive drug therapies. black triangle Treatment response (defined as a mean sitting DBP <90 mmHg or a >/=10 mmHg reduction from baseline) rates were significantly higher in nebivolol versus placebo recipients in trials enrolling patient groups considered representative of the US hypertensive population (46-65% vs 25%), in Black patients (57-64% vs 27%), and in patients concurrently treated with other antihypertensive drugs (53-65% vs 41%). black triangle Nebivolol was generally well tolerated in the treatment of hypertension, with the majority of adverse events described as being mild or moderate in severity. The incidences of fatigue, bradycardia, dyspnea, depression, and erectile dysfunction (events commonly associated with beta-adrenergic receptor antagonist use) did not significantly differ between nebivolol and placebo recipients in the 12-week trials.