Effects of "newer" and "older" antihypertensive drugs on hemorrheological, platelet, and endothelial factors. A substudy of the Anglo-Scandinavian Cardiac Outcomes Trial.

BACKGROUND: Different antihypertensive therapies may exert benefits via not only a reduction in blood pressure but also in improving the risk of thrombosis. METHODS: We tested the hypothesis that a more modern antihypertensive drug regimen (ie, amlodipine +/- perindopril) would have a more beneficial effect on hemorheological markers (white blood-cell count [WCC], plasma viscosity [PV], hematocrit [HCT], and fibrinogen)--and on plasma von Willebrand factor (vWf, an index of endothelial damage and dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation), compared with an older antihypertensive drug regimen (ie, atenolol +/- bendroflumethiazide). RESULTS: After 6 months, PV, sP-sel, and HCT fell in both groups (P < .01), while fibrinogen was unchanged. However, those 74 patients randomized to amlodipine +/- perindopril had significant reductions in WCC (P = .005), with no significant changes in vWF or platelet count. Conversely, in those 85 patients randomized to atenolol +/- bendroflumethiazide, there were significant reductions in vWF (P = .001) and platelet count (P = .011) but no significant reductions in WCC. There were no significant differences in the levels of any of the variables between the two arms of the trial, nor a significant difference in the magnitude of reduction between the two treatment arms. CONCLUSIONS: Within the constraints of this substudy design, there was no differential effect apparent of the two antihypertensive treatment arms on hemorheological parameters or endothelial and platelet function (as assessed by vWF and sP-sel), suggesting that other pathophysiological mechanisms may be involved.

Relationship of homocysteine to markers of platelet and endothelial activation in "high risk" hypertensives: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial.

OBJECTIVE: To examine the relationship between plasma homocysteine (HCY) and rheological, endothelial and platelet markers in "high risk" hypertensive patients. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: A total of 165 consecutive hypertensive patients (136 male; mean age 63 years (S.D. 8)) at high risk of cardiovascular disease who screened for inclusion in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) were studied along with 38 population normotensive healthy controls. We measured levels of plasma homocysteine [high pressure liquid chromatography (HPLC)], soluble P-selectin, a marker of platelet function, von Willebrand factor (vWF), an index of endothelial damage/dysfunction [both by ELISA] and fibrinogen (CLAUSS). The Framingham cardiovascular and cerebrovascular risk scores were calculated. RESULTS: Hypertensives had significantly higher blood pressure (BP) [165/90(16/10) vs. 138/82(12/8) mm Hg, p<0.0001], sP-sel [54(44-67) vs. 45(35-57) ng/ml, p=0.002], vWF [133(34) vs. 110(28) IU/dl, p<0.0001], and fibrinogen [2.98(2.52-3.47) vs. 2.43(2.20-2.83)g/l, p=<0.0001]. Homocysteine were lower in our hypertensives compared with controls [8.7(6.9-11.2) vs. 10.5(8.5-13.1) micromol/l, p=0.005], but there were significant correlations between homocysteine levels and both calculated 10-year coronary heart disease risk (Spearman r=0.197, p=0.026) and stroke risk (r=0.210, p=0.018), using the Framingham equation. There was a positive correlation between plasma homocysteine and soluble P-selectin (r=0.180, p=0.025), which persisted in multiple linear regression analysis. There was no significant relationship between homocysteine and HCT, PV, or the endothelial marker, vWF. CONCLUSION: Hypertensives demonstrate abnormalities of endothelial, platelet and rheological function. Homocysteine is related to both 10-year coronary heart disease risk and stroke risk, and is significantly correlated with soluble P-selectin, a marker of platelet activation, in hypertensives but only weakly or not at all to other thrombotic markers. Increased platelet activation as reflected by soluble P-selectin may be one mechanism by which hyperhomocysteinaemia confers an increased thrombotic risk in hypertension.

Relation of thrombogenesis in systemic hypertension to angiogenesis and endothelial damage/dysfunction (a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT]).

Increasing evidence points toward a prothrombotic state in hypertension and atherosclerosis, conditions associated with thrombosis-related complications, such as myocardial infarction and stroke. We hypothesized that this increased risk of thrombogenesis may be related to endothelial damage/dysfunction and abnormal angiogenesis, and thus, an increased risk of future cardiovascular disease. Thrombogenesis, endothelial damage/dysfunction, and angiogenesis can be assessed by measurement of tissue factor (TF), von Willebrand Factor (vWF), flow-mediated dilatation (FMD), and vascular endothelial growth factor (VEGF), respectively. To test this hypothesis, we measured TF, vWF, FMD, and VEGF in 76 patients with systemic hypertension (71 men; mean age 64; mean blood pressure 167/72 mm Hg), considered additional risk factors such as diabetes, and related them to the patient's 10-year cardiovascular and cerebrovascular risk score using the Framingham equation. Patients were compared with 48 healthy normotensive controls. In these patients, the effects of 6 months of intensified blood pressure and (where appropriate) lipid-lowering treatment were investigated. In our patients, TF, VEGF, and vWF levels were higher, but FMD was lower (all p <0.001) compared with the controls. All markers correlated with each other and with both cardiovascular and cerebrovascular risk scores (all p <0.001). After intensified blood pressure and hypercholesterolemia treatment, total cholesterol, blood pressure, TF, VEGF, and vWF levels all decreased, whereas FMD increased (all p <0.001). Thus, in subjects with hypertension and other risk factors, endothelial damage/dysfunction (and thus, atherogenesis), thrombogenesis, and angiogenesis are abnormal, correlate with overall cardiovascular risk, and importantly, can be related to each other in a "Birmingham Vascular Triangle." Furthermore, these processes are beneficially affected by intensive blood pressure and lipid treatment.

Low-density lipoprotein subfractions and cardiovascular risk in hypertension: relationship to endothelial dysfunction and effects of treatment.

Although hypertensive patients are at particular risk of vascular complications, the possible contribution of an atherogenic lipoprotein profile and endothelial dysfunction to this risk is unclear. We investigated this by measuring LDL subfractions and flow-mediated dilation (FMD) (reflecting endothelial dysfunction) in a cohort of high-risk hypertensive patients. We studied 84 hypertensive patients (74 men; mean age, 64 years; SD 8). Chylomicron-free LDL subfractions were analyzed by disc polyacrylamide gel electrophoresis, producing an LDL score, with higher scores being equivalent to a greater proportion of the more atherogenic LDL subfractions. High-resolution ultrasound was used to assess endothelium-dependent brachial artery FMD after reactive hyperemia after vessel occlusion. Baseline levels were compared with 61 age- and gender-matched healthy normotensive control subjects. Mean LDL score was higher and FMD impaired in hypertensive subjects compared with control subjects. These indexes were significantly improved after 6 months of cardiovascular risk factor management. LDL score correlated significantly with the 10-year Framingham coronary heart disease risk score, with a negative correlation with FMD (both P<0.001). Abnormal atherogenesis and endothelial dysfunction are both present in hypertension and appear to be related to each other, potentially leading to vascular complications. The abnormal LDL scores also correlate with the 10-year cardiovascular risk and can be positively influenced by cardiovascular risk management.

Endothelial damage and angiogenesis in hypertensive patients: relationship to cardiovascular risk factors and risk factor management.

BACKGROUND: Hypertensive patients are at particular risk of cardiovascular complications, possibly related to endothelial damage or dysfunction, or to abnormal angiogenesis. These pathophysiologic processes are assessable by measurement of plasma levels of von Willebrand factor (vWf), and by vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1). We hypothesized that these markers would correlate with the Framingham cardiovascular risk score and would be responsive to treatment. METHODS: We measured these markers by enzyme-linked immunosorbent assay in 286 patients with hypertension (239 men; mean age 63 years; mean systolic blood pressure [BP]/diastolic BP 162/89 mm Hg) and additional risk factors, and related them to the patient's cardiovascular disease (CVD) and cerebrovascular accident (CVA) risk, using the Framingham equation. Patients were compared with 60 healthy normotensive controls. In 248 patients, the effects of 6 months of intensified cardiovascular risk factor management, including BP and (where appropriate) lipid-lowering treatment, were investigated. RESULTS: Plasma VEGF and vWf levels were higher, but sFlt-1 levels lower (all P <.001), in the hypertensive patients compared with the controls. The VEGF and vWf levels correlated significantly with age, systolic and diastolic BP, 10-year CVD risk, and CVA risk scores (all P <.01), whereas sFlt-1 was negatively correlated with these risk scores (P <.01). After intensified cardiovascular risk factor management, total cholesterol, BP, VEGF, and vWf levels were all reduced, yet sFlt-1 levels increased (all P <.05). CONCLUSIONS: In hypertension, the processes of endothelial damage and angiogenesis are abnormal, and correlate with overall cardiovascular risk. Indices of endothelial damage and angiogenesis are beneficially changed by intensive cardiovascular risk factor management.

Von Willebrand factor, soluble P-selectin, and target organ damage in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (P=0.002,) and a greater proportion of smokers, 31% versus 16% (P=0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all P<0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function.