Dirk C. Felmeden

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 patients 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.

Low-Density Lipoprotein Subfractions and Cardiovascular Risk in Hypertension: Relationship to Endothelial Dysfunction and Effects of Treatment

Abstract—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 function and its assessment

Endothelial dysfunction is a characteristic aspect of most of the conditions associated with atherosclerosis and is commonly found as an early feature in atherothrombotic vascular disease. An appreciation of the underlying mechanisms of endothelial function, as well as dysfunction, is essential as this has critical influence on the different methods in the assessment of endothelial function and effects of various treatments on its quantification. Furthermore, endothelial dysfunction is recognised as a type of ‘target organ damage’ in common cardiovascular conditions (e.g., hypertension) and the area is of increasing interest for new drug development, as therapies that modulate the endothelium will have added advantages; thus, for the development of new/experimental drugs, an awareness of ways to assess the endothelium is necessary. In this review, an overview of different methods including biochemical markers, and invasive and non-invasive tools, to determine endothelial function is presented as well as their clinical relevance. Furthermore, the effects of various treatments on endothelial dysfunction and their underlying mechanisms are elucidated.

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

Abstract.  Felmeden DC, Spencer CGC, Blann AD, Beevers DG, Lip GYH (University Department of Medicine, City Hospital, Birmingham, UK). Physical activity in relation to indices of endothelial function and angiogenesis factors in hypertension: a substudy of the Anglo‐Scandinavian Cardiac Outcomes Trial (ASCOT). J Intern Med 2003; 253: 81–91.

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, β-blockers and α-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.

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.

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].

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.

Hormone Replacement Therapy and Hypertension

For many years, Hormone Replacement Therapy (HRT) was considered to be contraindicated in postmenopausal women with hypertension and many such women were excluded from HRT because of concerns that HRT may have an adverse effect on blood pressure. This perception was mainly due to the effects of oral contraceptive drugs, especially the oestrogen component, in increasing blood pressure. Differences exist between the formulation and doses of oestrogen preparations used, either as oral contraceptives in premenopausal women (in whom high-dose synthetic oestrogens are used) or as HRT in postmenopausal women (in whom low ?replacement? doses of natural oestrogens are used). This is not inconsequential, as postmenopausal women represent the largest category of women at risk for hypertension. The aim of this review is to give a balanced view on the effects of HRT on blood pressure in postmenopausal women.

Statins and the assessment of endothelial function.

DEAR SIR We read with great interest the paper by Šebeštjen et al. [1], which showed that lipid-lowering with both cerivastatin and fenofibrate improved arterial vasoreactivity in patients with combined hyperlipidaemia, although the effects were greater in the patients receiving the statin. This small but welldesigned study adds to the existing literature [2] that the statins have beneficial effects beyond lipidlowering, such as improvement in peripheral endothelial function [as measured by flow-mediated dilation (FMD) of the brachial artery], antithrombotic or antiinflammatory effects and plaque stabilization, which may contribute to the beneficial effects in reducing cardiovascular events. Endothelial dysfunction has been regarded as an early event in atherosclerosis, preceding the formation of atherosclerotic plaques and evidence of endothelial damage/dysfunction has been clearly demonstrated in patients with vascular diseases, as well as in risk factors for coronary disease, such as hypertension, diabetes mellitus, hypercholesterolaemia and smoking [3]. However, the best way of assessing endothelial damage/dysfunction is still uncertain, and it is likely that a continuum exists between endothelial activation (likely to be related to early exposure to risk factors, such as smoking), endothelial dysfunction (leading to thrombogenesis and atherogenesis) and, finally, endothelial damage (leading to overt vascular damage and atherosclerosis) [4]. Noninvasive assessment of endothelial function usually relies on postischaemic dilation of forearm vessels, using plethysmography or by FMD of the brachial artery. However, these techniques have several disadvantages, as they are observer-dependent, require expensive specialized equipment, which require trained observer(s), and the possibility of interand intraobserver variability. Such techniques are also not practically possible to be used in large population-based epidemiological studies. Nevertheless, it is of note that almost all previous studies on the effect of statins on endothelial function have employed FMD of the brachial artery. An alternative assessment of endothelial damage/ dysfunction is by measurement or plasma markers that are related to the endothelium, such as von Willebrand factor (vWf), soluble thrombomodulin or E-selectin [3]. For example, vWf has been widely accepted and well-established as a marker of endothelial damage. Raised levels of vWf been found in patients with all the major risk factors for atherosclerotic vascular disease and that treatment of these risk factors lowers vWf levels [3]. Goldsmith et al. [5] also reported a scanning electron microscopy study, which related the severity of atrial endothelial/endocardial damage to increasing plasma levels of vWf. Furthermore, we have pilot data in 89 hypertensive patients (78 men; mean age 64 years, SD 8.4; mean BP 167/91 mmHg) where plasma vWf levels significantly correlated with FMD (Spearman, r 1⁄4 )0.517, P < 0.001). Plasma markers such as vWf also have prognostic value in cardiovascular disease [3]. Indeed, prospective epidemiological studies have repeatedly shown vWf as an independent predictor of subsequent myocardial infarction or sudden death from coronary artery disease in patients with or without established coronary artery disease. Assessment of plasma markers is also relatively cheaper, more easily measured and readily available, with good reproducibility and low interand intraobserver variability, when compared with observer-dependent techniques such as FMD measurements. Plasma markers of endothelial damage/ dysfunction can even be measured in thousands of patients – an essential feature for a potential screening tool in large population-based epidemiological studies. Journal of Internal Medicine 2002; 251: 452–454