Current Pharmaceutical Design - Volume 9, Issue 29, 2003

Available data indicate that blood pressure (BP) is reduced below 140-90 mmHg in less than 30% of hypertensive patients. This poor control of BP derives from lack of diagnosis (unawareness of hypertension), lack of treatment of aware hypertensive patients and lack of efficacy of treatment. Systolic BP (SBP) is now considered as the most important parameter for diagnosis and stadiation of hypertension, above all in elderly patients, and the most frequent cause of unsatisfactory control of BP in the population. Lack of SBP control is caused both by physicians' attitude and difficulty in reducing SBP. Physicians are more prone to consider diastolic BP as the most important parameter for diagnosis and stadiation of hypertension, decision to treat and intensification of treatment and therefore SBP is often forgotten and-or misinterpreted in this decision making process. On the other hand, since current antihypertensive drugs are equally effective in lowering SBP and DBP and-or less effective in lowering SBP more than DBP, SBP is often uncontrolled in treated patients with isolated systolic hypertension or prevalent increase in SBP. The possibility of obtaining better control of SBP in the future is linked to better education of physicians, who need to pay greater attention to SBP as a parameter for diagnosing, treating and intensifying treatment, and to the development of new drugs more active in reducing SBP.

Endothelium-derived NO is not only a potent vasodilator but also inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis. Cardiovascular risk factors are associated with an imbalance of the redox equilibrium towards oxidative stress and, therefore, impair the integrity of the endothelium, leading to endothelial activation which involves blunted endothelium-dependent vasodilation (vasodilator dysfunction) as well as inflammatory processes extending to the milieu within the whole vasculature, making plaques prone to rupture. In prospective studies endothelial dysfunction is associated with increased incidence of cardiovascular events. Thus, the prevention of endothelial dysfunction can determine a strong advantage in the clinical outcome of patients with cardiovascular risk factors. Several non-pharmacological interventions can prevent endothelial dysfunction or improve impaired endotheliumdependent vasodilation. Probably the most effective non-pharmacological measure is represented by aerobic physical activity, which can reduce production of oxidative stress associated to increasing age. Moreover, physical activity can improve endothelial dysfunction even in patients with cardiovascular risk factors such as essential hypertension. In addition several other approaches, including vitamin and fish oil supplementation, or tea and red wine consumption, can lead to an improvement of endothelium-dependent vasodilation, possibly by a restoration of NO availability. It is worth noting that most of non-pharmacological measures act by preventing or reducing oxidative stress.

Direct visualization of the composition of the atherosclerotic plaque during its natural history and after therapeutic intervention may be helpful in detecting lesions with high risk of acute events and in understanding progression and regression of the disease. A wide variety of invasive and non-invasive imaging techniques is available to detect clue aspects of atherosclerosis from the early stage to the clinical evidence appearance. We will firstly review the ongoing technological and clinical research on both invasive and noninvasive techniques. Afterward, we will discuss in detail the use of high-resolution, multicontrast magnetic resonance imaging for non-invasive imaging of the plaque and its characterization in terms of its various components (i.e., thickness, lipid, fibrous, calcium, or thrombus). Finally, we will describe the potential of quantitative analysis in describing of plaque constituents with improved reproducibility.

Among the major Coronary Risk Factors (CRF) cigarette smoking has shown undoubtedly harmful effects on the heart and blood vessels either as active smoking (smoking a cigarette) or passive smoking (exposure to environmental tobacco smoke -ETS). The strong relationship between cigarette smoking and cardiovascular disease has been seen independent of the other CRF in a number of well-designated epidemiologic studies. However, a strong increase in the excess of cardiovascular risk has been defined along with the interaction of cigarette smoking and other major CRF. Thousands of pharmacologically active substances are present in tobacco smoke, and a large number of direct and indirect effects have been demonstrated. Different responses are also related to these types of exposure: active exposure or passive exposure. The cardiovascular risk increases with increasing levels of blood pressure and / or serum cholesterol and diabetes mellitus, and at each level of these three risk factors, distributed with different rates according to age and gender in individuals, the risk in active smokers or passive smokers is greater than the risk in nonsmokers. Further analytical and methodological observations are needed for better understanding of the chemical and biological synergism. Nevertheless, evidence is clear that cigarette smoking greatly increases the risk of cardiovascular diseases in individuals already at increased risk because of other CRF. Preventive measures must be absolutely conducted to prevent the CRF interaction. These are the changes in lifestyle (i.e. to give up smoking and make physical activity), drug administration, diet supplementation especially by those substances with antioxidant effects.

There is growing evidence that the components of the haemostatic system play a significant role in the development and progression of atherosclerosis and its complications. Lipidlowering interventions have been associated with a significant reduction of morbidity and mortality. However, the improvement in cardiovascular risk seen in several clinical trials is incompletely explained by cholesterol reduction. Therefore, the benefit from lipid lowering drugs may involve non-lipid mechanisms. These include beneficial effects on the arterial wall, improved endothelial function and a favourable influence on blood rheology and thrombogenesis. In this review, we consider the influence of lipid-lowering interventions on rheological and haemostatic parameters as well as the potential clinical relevance of these effects.

There is extensive trial-based evidence showing that antihypertensive drugs reduce the risk of vascular events (e.g. stroke and myocardial infarction) as well as target organ damage (e.g. left ventricular hypertrophy and microalbuminuria). However, some of these benefits appear to be, at least partially, independent of the extent of blood pressure (BP) lowering. It is also evident that in certain clinical situations some antihypertensive drugs are more effective than others. In this review we discuss the effects of antihypertensive drugs on the endothelium, platelets, fibrinolysis and coagulation. These properties may account for the observed BP-independent actions. Antihypertensive drugs exert multiple effects on the vascular endothelium. These include effects on nitric oxide (NO) and angiotensin II-mediated actions. Many BP lowering drugs can inhibit platelet activity, although the relevance of this property is unknown, especially if patients are also taking platelet inhibitors (e.g. aspirin). Antihypertensive drugs also influence fibrinolysis and coagulation. These effects may be mediated by a variety of mechanisms, including altering insulin sensitivity. The haemostatic actions of antihypertensive drugs deserve greater recognition and further investigation.

Coronary disease is currently a major cause of disability and mortality in older populations. Due to several factors - including increased noncardiovascular mortality, atypical presentation of coronary events, selective survival, and, possibly, clustering of protective genetic traits - the relative risk associated with almost all risk factors decreases with advancing age. Nonetheless, all available evidences from both observational studies and randomized trials indicate that, due to the higher event rates, the absolute risk reduction yielded by preventive interventions is much greater in the older age segments of populations. Another implication of the complex relationships between risk factors and comorbid conditions in the pathogenesis of coronary-related events and mortality, typical of the elderly subjects, is represented by the multiple effects of treatment for single risk factors, such as the decrease in LDL-cholesterol levels and inflammation markers yielded by statins. Taken together, these factors account for the more favorable cost-effectiveness ratios of preventive interventions in the older, as compared with the middle-aged subjects. On the other hand, the high level of interaction between coexistent risk factors and comorbidity renders a global approach to the prevention of coronary events in older subjects mandatory for physicians, as well as for decision-makers. In fact, a multidimensional assessment - including the evaluation of cognitive, affective and social disturbances- driving a multidisciplinary treatment of risk factors -encompassing behavioral counseling and social support - is essential to improve patients' compliance and to effectively reduce the burden of coronary-related morbidity and mortality in older populations.