Current Pharmaceutical Design - Volume 17, Issue 28, 2011

Usually, many papers on the hypertension start with, approximately, the following words: hypertension is a major risk factor for developing coronary heart disease and stroke. This statement may seem, at first sight, a trite sentence of introductory type, but, on the contrary, it contains the basic assumption, which defines meaningfully what is and the role of hypertension. Whatever hypertension may be approached, and there are many approaches to assess hypertension: clinical, biological, metabolic, epidemiologic, statistic, pathologic and others, all these approaches able to investigate peculiar characteristics of changes in blood pressure values, there is evidence that severe pathological alterations characterize the outcome of the disease. Moreover, until very recent years there were no unanimous opinions about the definition of hypertension [1-3]. Different opinions came out from three sources: a lack of effective statistical methods able to identify the number of hypertensive individuals due to difficulty in analysing how many people worldwide had rise in blood pressure; the continuously variable distribution of blood pressure among different race and sex, and the value range of both systolic or diastolic hypertension. In a recent past, hypertension was assessed by systolic and diastolic values over respectively 160 mmHg and 95 mmHg [2], which are very far from the current concepts. However, borderline hypertension was established for those individuals who were consistent with blood pressure from 140/90 mmHg to 159/94 mm Hg. Above described values for blood pressure had to be almost stable, since whether they were assessed occasionally, blood pressure was defined unstable or absent hypertension. A dramatic change in establishing whether blood pressure is stably elevated currently exists. High blood pressure is a common disorder in which values remains abnormally high, reading of 140/90 mm Hg or greater. Such a statement is, however, valid for those individuals with no other diseases or cardiovascular risk factors associated [3]. Indeed, recommendations are suggested for special categories of individuals, particularly diabetics, patients with kidney diseases and patients receiving antihypertensive treatment often difficult to conduct since physicians may use a large variety of drugs [4]. The first step to keep in mind is the ability to measure carefully blood pressure because of evaluating elevated blood pressure permitted, in far-off times, to demonstrate that those individuals who were suffering from high blood pressure met a large variety of lethal events [5]. When this statement found its support, a debated question rose: are hypertension and vascular-related events manifestations of a common underlying alteration or, conversely, did hypertension cause vascular disease? A first response to this question seemed to derive by the analysis of a large-scale trial [6]. This study analyzed the diastolic pressure between 115 and 129 mm Hg in 143 men enrolled in a randomized, placebo-controlled trial. Seventy-three individuals received therapy by using hydrochlorothiazide, hydralazine and reserpine while other 70 patients received placebo. Treated men who displayed reduction in diastolic blood pressure had markedly diminished the occurrence of strokes, heart failure and accelerated hypertension without change in rate of coronary heart disease. Obtained results would need different comments. In our opinion, there would be evidence that some vascular events are preferably linked to vessel damage caused by hypertension whereas others, like ischaemic heart disease, which recognizes, pathogenetically, a multifactorial aetiology, have a common substrate with hypertension and, therefore, would follow the same steps that may determine the increase in blood pressure. From the analysis of previous results, there is evidence, however, that the risk linked to elevated blood pressure may be certainly modified with appropriate measures. In addition, always more large-scale clinical trials clearly demonstrated the above statement in every type of population or elevated blood pressure [7- 12]. Changes in lifestyle contribute to reinforce the observed positive results similarly to what happens for other major cardiovascular risk factors [13].....

Epidemiological surveys demonstrate undoubtedly that cardiovascular disorders caused or associated with hypertension are at a high risk of non-fatal or fatal events and occurring with a great rate. Ischaemic heart disease with effort angina and myocardial infarction, often unrecognized myocardial infarction, stroke and transient ischaemic attack may be observed more frequently than other cardiovascular disorders in hypertensive patients. Large-scale trials do not support the hypothesis that effective benefits are reached by current non-pharmacological or pharmacological prevention which need enormous costs to public health. Lowering blood pressure is the main target to reach in an attempt to reduce cardiovascular complications in hypertensive patients. Therefore, the costs-benefit ratio, which estimates public health costs, needs yet marked improvement since the public health expenses are heaviest with results that do not support the economic effort. Statistically, quantitative measures to modify the current regimen need to better evaluate both public health costs and reached benefits.

Hypertension is a complex, multifactorial disease; genetic factors represent one third to half of the inter-individual variability of blood pressure values. Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have revealed the pathogenesis of hypertension in many of these conditions. Remarkably, the mechanism in every case has proved to be upregulation of sodium Na reabsorption in the distal nephron, with accompanying expansion of extracellular volume. On the contrary in the essential hypertension the underlying pathogenetic mechanism is more complex because of interplay between several ‘risk’ genes and environmental factors. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models. This review summarizes the current findings for candidate genes associated with blood pressure and focuses on recent advances and future potential of pharmacogenetics of hypertension, with the intent to clarify what amount of these investments in basic science research will be delivered into benefits to patients.

Changes in clinical, biochemical and pathological variables characterize cardiovascular damage from smoking and hypertension when it acts independently. However, combined action of these major risk factors increases the rate of cardiovascular events. Ischaemic heart disease with stable effort angina, myocardial infarction and post-infarction arrhythmias may affect cardiovascular system because of smoking exposure. Among cerebrovascular disease, there is evidence that stroke would be related primarily to active smoking. Isolated hypertension plays significantly major action to cause cerebrovascular disease including stroke, recurrent stoke and transient ischaemic attack. Among cardiac events, heart failure is, often, the end-point of hypertensive disease, even if manifestations of ischaemic heart disease similar to those caused by smoking may be increased in rate. Combined action of smoking and hypertension usually increases the rate of cardiovascular complications and leads to a progression of atherosclerosis with narrowing and plaque primarily at the the level of coronary, carotid and cerebrovascular arteries. A pattern specific of both active and passive smoking exposure, but not hypertension, is the thromboangiitis obliterans that dramatically worsens in continuing smokers while it can be improved by stopping smoking.

Blood pressure within prehypertensive levels confers higher cardiovascular risk. As prehypertension is also an intermediate stage for full hypertension, a precocious intervention with lifestyle changes or drugs is therefore appealing. Endothelial injury and dysfunction are thought to contribute to cardiovascular risk in prehypertension. Endothelial progenitor cell impairment has been linked to endothelial dysfunction, atherosclerotic disease progression and cardiovascular events. A potential mechanism contributing to the heightened cardiovascular risk in prehypertension may be linked to abnormalities in endothelial progenitor cell number and/or function. Aim of this review is to be up to date about the recent work on the correlation between endothelial progenitor cells and prehypertension and the possible prevention, treatment, and control of this pathology. The effect of an approach based on dietary intervention on both blood pressure and endothelial progenitor cells will be also shown.

The progressive ageing of world population, and the increasing prevalence hypertension in elderly people are leading to the consideration that hypertension in the elderly is one of the main topic in hypertension treatment. Multiple mechanisms, including stiffening of large arteries, endothelial dysfunction, cardiac remodeling, autonomic dysregulation, renal aspects, contribute to the great prevalence of hypertension in the elderly and to increased cardiovascular morbidity and mortality. Treatment of hypertension can hardly put back older patients in a low risk category, especially if target organ damage is present. Nevertheless, blood pressure control can successfully prevent stroke, cognitive decline, coronary heart disease and heart failure, and reduce mortality in the elderly, and even in patients >80 years, as recently demonstrated. Blood pressure should be lowered below 140/90 mmHg also in older patients. However the HYVET study suggests that a goal of 150/90 mmHg can be reasonable in patients aged 80 years or more. Drug treatment should be titrated with particular caution to adverse responses and excessive blood pressure lowering.

Hypertension is a leading cardiovascular risk for cardiovascular morbidity and mortality. Age is the strongest risk factor for dementia and with the increasing life expectancy the number of patients living with dementia worldwide is estimated to progressively rise. A number of studies support an association between hypertension, particularly in midlife, and the development of cognitive disorders and dementia, including Alzheimer's disease. According to this, considering hypertension as a possible modifiable risk factor for the cognitive decline is of great clinical interest. Treatment of hypertension in midlife seems to promote considerable benefits with regard to cardiovascular outcomes. Longitudinal studies examining the possible benefit of anti-hypertensive treatments on cognitive decline have produced promising results. Nevertheless, the results from randomised controlled clinical trials on treatment of hypertension are not conclusive for the effect on cognitive decline and dementia. New randomized controlled trials are needed to definitively clarify clinical advantages and specifically elucidate the relationship between anti-hypertensive treatments and cognitive function or dementia.

Arterial hypertension is a very common disease and an important risk factor for cardiovascular disease. Patients with arterial hypertension are characterized by functional and structural vascular abnormalities. Vascular endothelium plays a fundamental role in modulating vascular tone and structure. The physiological production of the relaxing factors including nitric oxide, prostacyclin and hyperpolarizing relaxing factors protects the vessel wall by antagonizing the first pathogenetic steps of atherosclerosis and thrombosis. Endothelial cells may also produce endothelium-derived contracting factors. The principal component of these contracting factors is endothelin-1, which promotes the growth of the smooth muscle cells and has a vasoconstrictive and blood pressure raising effect. Defective nitric oxide production is already detectable in normotensive offspring of hypertensive patients and young essential hypertensives. A dysfunctional endothelium due to reduced nitric oxide availability associated with an increased production of oxidative stress and vasoconstricting factors is considered as an early indicator of atherothrombotic damage and of cardiovascular events also in patients with arterial hypertension. Moreover, patients with arterial hypertension are also characterized by increased arterial stiffness. This parameter, known as a sign of cardiovascular risk since the 19th century, has been shown to be a predictor of adverse cardiovascular outcome and its measurement in hypertensive patients is suggested by the European guidelines for the diagnosis and treatment of hypertension.

The long preclinical phase of atherosclerosis involves the interaction of genetic and environmental factors that modulate the progression of disease from early life. A variety of noninvasive tests have been used to study the arterial phenotype of childhood, allowing identification of arterial alterations long before clinical symptoms of cardiovascular (CV) disease become apparent. These techniques have improved our understanding of the evolution of atherosclerosis, indentifying three major developmental factors which influence the future risk of CV disease in childhood: prenatal growth, early postnatal growth and childhood obesity. Specific changes in arterial properties and increased values of blood pressure are detectable in children with low birth weight, suggesting that intrauterine growth retardation could programme the future risk of CV disease. However, an accelerated growth rate in infancy and early childhood is often associated with low birth weight and with specific vascular alterations, making it difficult to distinguish the contribution of prenatal and postnatal growth patterns to later cardiovascular disease risk. Relationships between growth patterns and CV disease risk are further complicated by the link between rapid postnatal growth and later development of childhood overweight and obesity, conditions associated with early changes in vascular physiology and that potentially affect future CV outcome. This article aims to provide an overview of evidence in support of fetal programming and growth acceleration hypotheses for adult CV disease. Specific attention is given to obesity-related vascular alterations and their effects on future CV disease risk. We also summarise current non-invasive approaches to investigate the precursors and early development of CV disease, emphasising their potential applications in childhood.

Hypertension is increasingly considered a strong and independent risk factor for supraventricular and ventricular arrhythmias. The presence and complexity of both supraventricular and ventricular arrhythmias influence morbidity, mortality, as well as the quality of life of patients. Diastolic dysfunction of the left ventricle, left atrial size and function, and left ventricular hypertrophy have been suggested as the foremost underlying risk factors for supraventricular and ventricular arrhythmias in hypertensive patients. In particular, the presence of hypertension is a risk for sudden death and this risk is higher in those with left ventricular hypertrophy. Moreover, arrhythmias in the hypertrophic heart are often facilitated and aggravated by electrolyte disturbances, sympatho-vagal unbalance, transient blood pressure peaks, and occurrence of myocardial ischaemia. Several noninvasive biohumoral, electrocardiographic and imaging parameters have been widely investigated to identify hypertensive patients at higher risk for the development of arrhythmias. These parameters include neurohormones, signal averaged analysis of P wave, QT interval dispersion, heart rate variability, ventricular late potentials and T wave morphology analysis, as well as echocardiographic and magnetic resonance indexes of atrial and ventricular shape and function. The aim of this review is to evaluate the relationship of high blood pressure with ventricular and supraventricular arrhythmias, to discuss the available biomarkers for arrhythmic risk assessment in hypertensive patients and the effects of a tailored tight blood pressure control on the occurrence of arrhythmias.

Obesity, insulin resistance, glucose intolerance/type 2 diabetes and hypertension are clustered in the metabolic syndrome representing critical risk factors for increased incidence cardio-cerebro-vascular diseases, kidney failure and cancer. Ectopic fat accumulation, i.e., accumulation in the mediastinum, liver and the abdomen, as well as generalized fat accumulation are associated with arterial hypertension, either systolic or diastolic. Several mechanisms including insulin resistance, sub-inflammatory state, increased Renin- Angiotensin-Aldosterone System (RAAS) system activity, oxidative stress, autonomic dysregulation as well as mechanical compression on the kidneys are all activated by obesity. Interestingly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (ATII) receptor blockers, while correcting arterial hypertension, also have a positive effect on glucose metabolism and diabetes prevention, in high risk patients. The implementation of dietary, medical and surgical strategies to prevent and treat obesity, are cornerstones for the primary prevention as well as treatment of arterial hypertension.

This article reviews the current imaging techniques and the methodologies used to derive quantitative markers of hypertension in the cardiovascular system. Firstly, simple but effective methods to assess regional and global function of large arteries are discussed. After, the role of echocardiography and high-resolution magnetic resonance imaging to assess geometric and mechanical indices of hypertension related cardiac diseases are summarized. In particular, quantitative indices of deformation and strain are derived from quantitative analysis of doppler tissue and tagged magnetic resonance images. Finally, the importance of high field magnetic resonance imaging to assess myocardial microcirculation is described.