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.

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.

Vascular endothelial growth factor and its receptor, Flt-1, in the plasma of patients with coronary or peripheral atherosclerosis, or Type II diabetes.

Since atherosclerosis is characterized by endothelial damage, re-growth seems likely to be occurring in order to repair or replace injured cells. Angiogenic vascular endothelial growth factor (VEGF), a likely mediator of these events, acts on the endothelium via a specific receptor, Flt-1. We hypothesized that patients with different manifestations of atherosclerosis, and others with diabetes, would have altered plasma levels of VEGF and Flt-1 compared with healthy individuals. Accordingly, 70 patients with peripheral artery disease (PAD), 70 patients with coronary artery disease (CAD), and 70 age- and sex-matched healthy controls were recruited. We also recruited 14 patients with diabetes asymptomatic for atherosclerosis, 14 patients with diabetes and atherosclerosis, and 14 age- and sex-matched controls. VEGF and soluble Flt-1 (sFlt-1) were measured by ELISA. In the main study of PAD and CAD, VEGF was raised in both patient groups (P<0.05) compared with the controls, but was not different between the patient groups. sFlt-1 was lower in patients with PAD (P<0.05), but not in those with CAD, compared with the controls. VEGF was raised in the patients with diabetes plus atherosclerosis (P<0.05), but not in the group with diabetes alone; levels of sFlt-1 were unaltered in both diabetes groups. Our data point to changes in plasma levels of VEGF and its receptor sFlt-1 in diabetes and atherosclerosis that may have relevance for therapy and angiogenesis in these conditions.