Haemorheological, platelet and endothelial indices in relation to global measures of cardiovascular risk in hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial.

INTRODUCTION AND METHODS: We tested the hypothesis that there was a significant relationship between haemorheological markers [white blood cell count (WCC), plasma viscosity (PV), haematocrit (HCT) and fibrinogen], as well as plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation), to five global measures of cardiovascular risk [i.e. Framingham coronary heart disease (CHD), stroke and cardiovascular death score, the Pocock cardiovascular risk score and the sum of individual risk factors]. RESULTS: Men with a high (> or = median, n = 156) Framingham 10-year CHD risk score had higher levels of WBC (P = 0.027), fibrinogen (P = 0.012) and vWF (P = 0.002) than 153 men with results < median. Men with a high 10-year stroke risk score had significantly higher levels of fibrinogen (P = 0.01) and vWF (P < 0.0001). In stepwise linear regression analysis in men, vWF and fibrinogen were independent predictors of the number of risk factors (P < 0.0001), whilst WCC, vWF and fibrinogen emerged as independent predictors of Framingham CHD risk (P < 0.0001), and fibrinogen and vWF predicted Framingham stroke risk (R(2) = 0.089, P < 0.0001). vWF, PV and fibrinogen were predictors of Pocock cardiovascular death risk (P < 0.0001) but vWF was the only independent predictor of Framingham cardiovascular death risk (P = 0.001). CONCLUSIONS: Abnormal haemorheological factors (particularly high plasma fibrinogen levels) and endothelial damage/dysfunction (high vWF), but not platelet activation (sP-sel), are related to established cardiovascular and death risk scores. This relationship was most evident amongst male 'high-risk' hypertensive subjects.

Antithrombotic therapy in hypertension: a Cochrane Systematic review.

Although elevated systemic blood pressure (BP) results in high intravascular pressure, the main complications of hypertension are related to thrombosis rather than haemorrhage. It therefore seemed plausible that use of antithrombotic therapy may be useful in preventing thrombosis-related complications of elevated BP. The objectives were to conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with BP, to address the following hypotheses: (i) antiplatelet agents reduce total deaths and/or major thrombotic events when compared to placebo or other active treatment; and (ii) oral anticoagulants reduce total deaths and/or major thromboembolic events when compared to placebo or other active treatment. A systematic review of randomised studies in patients with elevated BP was performed. Studies were included if they were >3 months in duration and compared antithrombotic therapy with control or other active treatment. One meta-analysis of antiplatelet therapy for secondary prevention in patients with elevated BP reported an absolute reduction in vascular events of 4.1% as compared to placebo. Acetylsalicylic acid (ASA) did not reduce stroke or 'all cardiovascular events' compared to placebo in primary prevention patients with elevated BP and no prior cardiovascular disease. Based on one large trial, ASA taken for 5 years reduced myocardial infarction (ARR, 0.5%, NNT 200 for 5 years), increased major haemorrhage (ARI, 0.7%, NNT 154), and did not reduce all cause mortality or cardiovascular mortality. In two small trials, warfarin alone or in combination with ASA did not reduce stroke or coronary events. Glycoprotein IIb/IIIa inhibitors as well as ticlopidine and clopidogrel have not been sufficiently evaluated in patients with elevated BP. To conclude for primary prevention in patients with elevated BP, antiplatelet therapy with ASA cannot be recommended since the magnitude of benefit, a reduction in myocardial infarction, is negated by a harm of similar magnitude, an increase in major haemorrhage. For secondary prevention in patients with elevated BP, antiplatelet therapy is recommended because the magnitude of the absolute benefit is many times greater. Warfarin therapy alone or in combination with aspirin in patients with elevated BP cannot be recommended because of lack of demonstrated benefit. Further trials of antithrombotic therapy are required in patients with elevated BP.

Antiplatelet agents and anticoagulants for hypertension.

BACKGROUND: Although elevated systemic blood pressure results in high intravascular pressure, the main complications, coronary heart disease (CHD), ischaemic strokes and peripheral vascular disease (PVD), are related to thrombosis rather than haemorrhage. Some complications related to elevated blood pressure, heart failure or atrial fibrillation, are themselves associated with stroke and thromboembolism. It therefore seemed plausible that use of antithrombotic therapy may be particularly useful in preventing thrombosis-related complications of elevated blood pressure. OBJECTIVES: To conduct a systematic review of the role of antiplatelet therapy and anticoagulation in patients with blood pressure, including those with elevations in both systolic and diastolic blood pressure, isolated elevations of either systolic or diastolic blood pressure, to address the following hypotheses: (i) antiplatelet agents reduce total deaths and/or major thrombotic events when compared to placebo or other active treatment; and (ii) oral anticoagulants reduce total deaths and/or major thromboembolic events when compared to placebo or other active treatment. SEARCH STRATEGY: Reference lists of papers resulting from this search, electronic database searching (MEDLINE, EMBASE, DARE), and abstracts from national and international cardiovascular meetings were studied to identify unpublished studies. Relevant authors of these studies were contacted to obtain further data. SELECTION CRITERIA: Randomised controlled trials (RCTs) in patients with elevated blood pressure were included if they were of at least 3 months in duration and compared antithrombotic therapy with control or other active treatment. DATA COLLECTION AND ANALYSIS: Data were independently collected and verified by two reviewers. Data from different trials were pooled where appropriate. MAIN RESULTS: The ATC meta-analysis of antiplatelet therapy for secondary prevention in patients with elevated blood pressure reported an absolute reduction in vascular events of 4.1% as compared to placebo. Data on the patients with elevated blood pressure from the 29 individual trials included in this meta-analysis was requested but could not be obtained. Three additional trials met the inclusion criteria and are reported on here. Acetylsalicylic acid (ASA) did not reduce stroke or 'all cardiovascular events' compared to placebo in primary prevention patients with elevated blood pressure and no prior cardiovascular disease. Based on one large trial (HOT trial), ASA taken for 5 years reduced myocardial infarction (ARR, 0.5%, NNT 200 for 5 years), increased major haemorrhage (ARI, 0.7%, NNT 154), and did not reduce all cause mortality or cardiovascular mortality. There was no significant difference between ASA and clopidogrel for the composite endpoint of stroke, myocardial infarction or vascular death in one trial (CAPRIE 1996). In two small trials warfarin alone or in combination with ASA did not reduce stroke or coronary events. REVIEWERS' CONCLUSIONS: For primary prevention in patients with elevated blood pressure, anti-platelet therapy with ASA cannot be recommended since the magnitude of benefit, a reduction in myocardial infarction, is negated by a harm of similar magnitude, an increase in major haemorrhage. For secondary prevention in patients with elevated blood pressure (ATC meta-analysis: APTC 1994) antiplatelet therapy is recommended because the magnitude of the absolute benefit is many times greater. Warfarin therapy alone or in combination with aspirin in patients with elevated blood pressure cannot be recommended because of lack of demonstrated benefit. Glycoprotein IIb/IIIa inhibitors as well as ticlopidine and clopidogrel have not been sufficiently evaluated in patients with elevated blood pressure. Further trials of antithrombotic therapy with complete documentation of all benefits and harms are required in patients with elevated blood pressure.

Platelet and haemorheological markers in 'high risk' hypertensives are improved by tighter blood pressure control and cardiovascular risk management: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

OBJECTIVE: To investigate the impact of intensified cardiovascular risk management on soluble markers of platelet, endothelial and rheological function in a population of middle-aged hypertensive patients at high risk of cardiovascular complications. DESIGN: Prospective follow-up study. SUBJECTS AND METHODS: A total of 159 hypertensive patients [138 male, mean age 64 (+/-8) years] and 80 healthy controls were studied. Plasma levels of soluble P-selectin (sP-sel, a marker of platelet function), von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and rheological indices [fibrinogen (Fib), plasma viscosity (PV), haematocrit (HCT), white blood count (WBC) and platelet count] were measured at baseline and again (in the patients) after 6 months' treatment. RESULTS: As expected, 6 months of intensified cardiovascular risk management resulted in a significant fall in mean blood pressure (BP) and total cholesterol. It also resulted in reduced haematocrit, vWF, sP-sel, WBC and PV levels (all P < 0.001), but not plasma fibrinogen. There were no correlations between the fall in BP and the improvement in any of the research indices. CONCLUSIONS: Intensified cardiovascular risk management results in significant improvements in indices of endothelial, platelet and rheological function in a population of hypertensives at high risk of cardiovascular events. These improvements appear to be independent of the degree of change in BP. Given the fundamental role of interactions between the endothelium and circulating blood components in the pathogenesis of hypertensive complications this may be of importance in preventing adverse cardiovascular outcomes.

A comparison of flow-mediated dilatation and von Willebrand factor as markers of endothelial cell function in health and in hypertension: relationship to cardiovascular risk and effects of treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial.

Loss of adequate endothelial cell function (associated with various cardiovascular syndromes such as hypertension) is most widely quantified by assessing flow-mediated dilatation (FMD) or measuring plasma markers such as von Willebrand factor (vWF). However, the relationship between these two methods is unclear, as is their relationship to 10-year cardiovascular risk (defined by the Framingham equation) and their response to intensive cardiovascular risk factor management. We tested the hypothesis that there is an inverse relationship between vWF and FMD by measuring both in 132 subjects, of whom 89 were hypertensive (mean blood pressure, 167/91 mmHg) and 43 were healthy normotensive (mean blood pressure, 133/80 mmHg). High-resolution ultrasound assessed endothelium-dependent brachial artery FMD following reactive hyperaemia after occlusion. Plasma vWF was defined by enzyme-linked immunosorbent assay. These measurements were repeated in the patients after 6 months of intensive cardiovascular risk factor management. vWF and FMD correlated significantly (r = -0.517, P < 0.001), and both correlated with 10-year cardiovascular risk using the Framingham equation (vWF, r = 0.48, P < 0.001; FMD, r = -0.624, P < 0.001). Following 6 months intensive cardiovascular risk factor management, plasma vWF was significantly reduced whereas FMD significantly increased (both P < 0.002). We conclude that two fundamentally different methods for assessing endothelial function correlate well with each other, as well as with 10-year cardiovascular risk. Six months of intensive risk factor management is beneficial to the endothelium, as defined by improved vWF and FMD. These methods might therefore be useful indices to identify patients at risk of future cardiovascular events, and may also assist in the understanding of early developments in the pathogenesis of vascular risk in hypertension.

Physical activity in relation to indices of endothelial function and angiogenesis factors in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

BACKGROUND: Hypertension is an important risk factor for cardiovascular disease. The latest guidelines recommend regular physical exercise as initial step or adjunct in the treatment of hypertension. We investigated the association between physical activity and the degree of hypertension, as well as the relation to indices of endothelial damage/dysfunction and angiogenesis. METHODS: We studied 234 patients with hypertension (198 males; mean age 64 years; mean blood pressure 166/90 mmHg), who were compared with 60 age and sex-matched healthy normotensive controls. We assessed the patient's physical activity using the validated Baecke physical activity questionnaire and measured flow-mediated dilatation (FMD) of the brachial artery and von Willebrand factor (vWf) as indices of endothelial damage/dysfunction, whilst angiogenesis was assessed by measurement of plasma vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) both by ELISA. RESULTS: When hypertensive patients were compared with the controls, there was no statistically significant difference in total physical activity score using the Baecke questionnaire although plasma VEGF and vWf levels were higher, but sFlt-1 levels and FMD lower (all P < 0.001). Patients with high physical activity were younger, and had lower mean diastolic blood pressure and 10-year Framingham stroke risk, when compared with those with low physical activity; but indices of endothelial damage/dysfunction and angiogenesis were not significantly different. CONCLUSION: Physical activity scores in hypertensive patients are not significantly different from healthy normotensive controls, and there appears to be no relation to the abnormal processes of endothelial damage/dysfunction and angiogenesis seen in hypertensives.

Plasma vascular endothelial growth factor, soluble VEGF receptor FLT-1, and von Willebrand factor in glaucoma.

AIM: To investigate plasma indices of vascular permeability (vascular endothelial growth factor, VEGF-also an index of angiogenesis, as well as the soluble receptor for VEGF, sFlt-1) and endothelial damage/dysfunction (von Willebrand factor, vWf) in glaucoma. METHODS: Citrated plasma was assayed for VEGF, sFlt-1, and vWf (all ELISA) in a cross sectional study of 50 patients (20 male; mean age 63.9 years, SD 10.5) with glaucoma: 26 had normal tension glaucoma (NTG) and 24 had primary open angle glaucoma (POAG), who were compared with 26 healthy controls (mean age 73.4 years, SD 9.2). RESULTS: Median (interquartile range, IQR) levels of VEGF were significantly elevated in patients with NTG and POAG compared to healthy controls (Kruskal-Wallis test, p<0.001). Similarly, mean (SD) vWF levels were abnormal in NTG and POAG compared to healthy controls (one way ANOVA, p<0.001). Median levels of sFlt-1 were significantly lower in patients with NTG and POAG, when compared to healthy controls (Kruskal-Wallis test, p<0.001; p<0.05 with Tukey's post hoc test for controls v POAG). There were no significant differences in VEGF, sFlt-1 or vWf levels between the NTG and POAG groups (Tukey's test, all p=NS). In both NTG and POAG groups, there was a significant correlation between VEGF and sFlt-1 (Spearman, NTG: r=0.6517, p=0.001; POAG: r=0.6017, p=0.008). There were no significant correlations between VEGF and sFlt-1, or with vWf among the controls. CONCLUSIONS: The pathogenesis of optic nerve damage in both NTG and POAG may be associated with abnormal vascular permeability and endothelial damage/dysfunction, as indicated by abnormal plasma VEGF and vWf levels in these patients.

Antihypertensive therapy and cancer risk.

The aim of this article is to provide an overview of the available data linking antihypertensive drug therapy to cancer risk. In recent years, a number of mainly retrospective studies have reached different conclusions on the risk of cancer in patients with hypertension being treated with different antihypertensive drugs. At some point or another nearly all antihypertensive drugs have been suggested to increase the risk of cancer. Some studies have even found an association between hypertension itself and increased carcinogenesis. For calcium channel antagonists, beta-blockers and alpha-blockers, the available evidence seems to favour a neutral effect on cancer development and death rate. For ACE inhibitors, the overall data suggest a similar neutral effect on cancer or, possibly, a small protective effect. Perhaps the strongest evidence in favour of a link, although probably weak, between cancer and antihypertensive drugs is with the diuretics. Until further solid data are available from prospective clinical trials, we suggest that the management of hypertension should continue according to current treatment guidelines with little fear of any substantial cancer risk.

Resistant hypertension and the Birmingham Hypertension Square.

Recent guidelines for the treatment of hypertension place great emphasis on tighter blood pressure control, especially in the presence of hypertensive target organ damage and diabetes. In order to achieve these treatment targets, more patients will require a combination of antihypertensive medications. However, resistant hypertension may have many possible underlying causes, and clinicians should appreciate how to detect and tackle these potential problems. Effective and synergistic combinations are therefore of vital importance, especially in patients with resistant hypertension. The choice of rational first- and second-line drugs that act in synergy could lead to better blood pressure management as well as significant financial savings for health care resources. The use of the Birmingham Hypertension Square for the optimum choice of add-in drugs for the treatment of resistant hypertension may aid management.

Anomalous coronary arteries of aortic origin.

Anomalous coronary arteries cause only uncharacteristic symptoms and are therefore often an incidental finding during conventional coronary angiography, with an incidence of 0.3-0.8%. The commonest anomaly is an aberrant origin of the main left or right coronary artery from the wrong sinus of Valsalva. Rarely there is a fistula draining into one of the cardiac cavities (right ventricle, right atrium, left ventricle or, rarely, superior vena cava) or displaced connection, as seen in anomalous origin of coronary artery from the pulmonary artery, resulting in a left-to-right shunt. In congenital heart disease, especially Fallot's tetralogy, the incidence of abnormal coronary arteries may be 2% or more. The proximal course in the former category may be misdiagnosed in up to 50% of cases. Aortic root injection with subtraction angiography, further detailed investigation with transoesophageal echocardiography or magnetic resonance angiography are therefore required as these have potential implications on subsequent surgery. Because of the abnormal course between aorta and pulmonary artery/outflow tract of the right ventricle and acute angulation there is a risk of angina, acute myocardial infarction or sudden death during or after exercise. It is therefore important to identify the exact cardiac anatomy, particularly in patients undergoing angioplasty, stenting or cardiac surgery.

The renin-angiotensin-aldosterone system and fibrinolysis.

Activation of the RAAS has been linked with an increased risk of myocardial infarction and stroke,(1,2,37,38) and recently these beneficial effects have, in part, been attributed to the effects of the RAAS on the fibrinolytic system. Indeed, ACE seems to occupy a central position in modulating the fibrinolytic balance, where an angiotensin II-mediated increase of PAI-1 plays a major role. By contrast, the effect on bradykinin stimulated t-PA release may be of lesser importance, although the data are conflicting. Importantly, the impact of the RAAS on the fibrinolytic balance may also contribute to the favourable effects of ACE inhibition and AT1-receptor antagonists on cardiovascular events, particularly when considering the activation of the RAAS in hypertension and heart failure. More work is clearly required in this area to elucidate potential therapeutic targets.

The placebo effect and white coat effect in isolated systolic hypertension and systo-diastolic hypertension.

It is well recognised from many clinical trials that there is a blood pressure lowering effect when placebo is administered to patients with essential hypertension ("placebo effect"). The reduction in blood pressure, however, may also be partly due to loss of the alerting response ("white coat effect") as a result of familiarisation with the clinical environment. To investigate the hypothesis that there may be a more marked placebo effect and white coat effect in isolated systolic hypertension (ISH) compared with systo-diastolic hypertension (SDH), we studied 78 patients with hypertension: 34 had ISH and 44 patients had SDH. The 34 patients with ISH were older (68.7 vs 54.9 years), had a higher SBP (192.2 vs 169.6 mmHfg) and lower DBP (85.5 vs 102.0 mmHg) when compared to patients with SDH. Amongst the patients with ISH, there were no significant changes in mean blood pressures pre-placebo (paired t-test, p = NS). In the placebo period, there was a significant reduction in systolic blood pressures at all three points, and a significant reduction in diastolic blood pressures after 2 and 3 months placebo (paired t-test, p < 0.05). There was a mean reduction in mean systolic blood pressure at visit 1 by 5.2%, visit 2 by 5.1% and visit 3 by 4.6%, when compared to mean pre-placebo systolic blood pressures (p < 0.05). The mean reduction in diastolic blood pressure was 5.8% at visit 2 and 3.5% at visit 3, when compared to mean pre-placebo diastolic blood pressure (p < 0.05). At the 4-week visit after receiving placebo, the mean systolic blood pressure decreased by 9.4 mmHg (p = 0.003) and mean diastolic blood pressure by 2.7 mmHg (p = NS) in the patients with ISH. In patients with SDH, there were no statistically significant changes in recorded BP readings following the introduction of placebo. We suggest blood pressures in some patients with ISH may settle with careful follow up and initiation of treatment in these patients could potentially be delayed for at least 3 months, as therapy may not prove necessary.

Myocardial bridging.

We present a case of myocardial bridging, which was seen following urgent cardiac catherisation for post-infarction unstable angina in a 55-year-old man who was initially admitted with an acute inferior myocardial infarction.