Current Hypertension Reviews - Volume 3, Issue 2, 2007

Stroke is the third most-frequent cause of death after cancer and heart disease in developed countries, and is one of the most common reasons for developing cognitive impairment and vascular dementia. Hypertension is known to be the most important factor for developing stroke and vascular dementia. In addition, the presence of cerebral white matter lesions (WML) is an important prognostic factor for the development of stroke, cognitive impairment and dementia. Older age and hypertension are constantly reported to be the main risk factors for cerebral WML. Hypertensive patients have a higher rate and extent of areas of cerebral WML compared with normotensives and, among hypertensive patients, treated uncontrolled patients have higher rates of WML than those who are controlled. Recent evidence strongly supports the idea that the presence of cerebral WML in hypertensive patients should be considered a silent early marker of brain damage.

Classification of hypertensive subjects according to different blood pressure patterns : i.e sustained vs isolated clinic hypertension (ICH) , dipping vs non dipping is now regarded as a useful mean for a more precise individual risk stratification and therapeutic making decisions. However, this subdivision is routinely based on a single ambulatory blood pressure monitoring (ABPM), despite the well-known day-to-day variability in blood pressure due to variations in mental, physical and environmental stimuli. In this short review we have tried to answer the following question : how reliable is the classification of non-dipping and ICH pattern based on single 24-h ABPM recording? Data from the recent literature clearly indicate that these categorizations in non diabetic mild to moderate hypertensive patients on the basis of a single ABPM are highly unreliable , as a large fraction of subjects (20-50%) classified in these categories at the first ABPM, do not confirm the same BP pattern during a second ABPM. Thus, these findings support the idea that a more reliable classification of patients according to dipping/nondipping status or ICH vs sustained hypertension should be performed by repeating a second ABPM within a short-term period.

Clinical and autopsy studies have suggested that patients with hypothyroidism have more advanced coronary atherosclerosis. The accelerated atherosclerosis has been explained by increases in low density lipoprotein cholesterol, blood pressure and newer risk factors such as homocysteine, C-reactive protein and plasminogen activator inhibitor-1 in hypothyroid state. In addition, recent studies have suggested that thyroid hormone has a direct effect on blood vessel, which may attenuate the progression of atherosclerosis. In addition to a direct relaxation of blood vessel through nongenomic effect, thyroid hormone has been reported to induce production of adrenomedullin and adenosine in vascular smooth muscle cells, which may be involved in vasodilation. Thyroid hormone also inhibits angiotensin II type1 receptor expression and signal transduction, and attenuates neointimal formation after balloon injury. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modifying risk factors.

The primacy of angiotensin II (Ang II) as the critical component mediating the multiple biological actions of the renin angiotensin system is undergoing a critical revision given the growth of the biochemical and physiological evidence demonstrating the existence of other proteins that, within the system, lead to the formation of alternate forms of angiotensin peptides. The persistent notion that Ang II is at the center of the mechanisms of action by which the renin angiotensin system exerts complex and pleiotropic effects on cellular growth, metabolism, and contraction has been challenged by the emerging understanding of the biochemical pathways entailing expression and function of the vasodilator/antigrowth properties of angiotensin-(1-7) [Ang-(1-7)], the role of the mas receptor as its ligand, and the cloning of a homologue of angiotensin converting enzyme (ACE2), which may limit the actions of Ang II by converting the peptide into Ang-(1-7). We analyze in this article the biochemical processing pathways leading to the formation of Ang-(1-7) from both angiotensin I and Ang II within the context of a functional paradigm that suggests that a deficit in the functional activity of the arm of the renin angiotensin system [ACE2/Ang-(1-7)/mas receptor] may play a critical role in the pathogenesis of hypertension.

Cardiovascular reactivity, an abrupt increase in blood pressure and heart rate in response to negative emotional stress is a risk factor for hypertension and heart disease. Brain angiotensin II (Ang II) has been recognized as an important regulator of cardiovascular reactivity. Apart from threatening events, exposure to appetitive stimuli is capable of inducing a distinct, sympathetically mediated rise in blood pressure in both animals and humans. Recent animal studies employing microinjection of AT1 receptor antagonists directly into hypothalamic and brainstem nuclei indicate that locally released AngII acts to facilitate, through a superoxide-dependent mechanism, the pressor response to negative stress. Conversely, animal studies demonstrated that brain Ang II is less important in the regulation of cardiovascular arousal associated with positively motivated behavior, such as anticipation and consumption of palatable food. Thus, endogenous AngII in the brain appears to control the activation of central pathways primarily associated with the defense response, rather than nonspecifically modulating cardiovascular reactivity regardless of emotional valence (attraction or aversion) of stimuli. These findings may be of clinical importance as they suggest that targeted inhibition of Ang II -superoxide signaling in the brain may selectively reduce blood pressure reactivity to negative emotional stress, without affecting cardiovascular arousal associated with normal daily activities.

Heavy alcohol use causes or exacerbates a number of medical conditions. In particular, hypertension (HTN), the most common primary diagnosis in primary care, is particularly alcohol-sensitive. In patients with HTN, excessive alcohol use (3 or more drinks a day) can interfere with successful blood pressure control and facilitate disease complications. Excessive alcohol use is one of 6 major causes of treatment-resistant HTN. This article summarizes the literature on the relationship between excessive drinking and HTN as well as findings supporting a beneficial BP-lowering impact of routine alcohol screening and intervention with hypertensive adults. Screening specifically for alcohol-induced hypertension rather than an alcohol use disorder per se is emphasized. Recent health services investigations have also addressed the problemof practical implementation of HTN alcohol screening in busy medical settings. These findings have important implications for the successful management of HTN patients in general and treatment-resistant HTN patients in particular.

Bone metabolism is closely regulated by hormones and cytokines, which have effects on both bone resorption and deposition. Since renin-angiotensin system (RAS) has been known to play an important role to regulate remodeling in several tissues, we focused on the potential role of RAS in bone metabolism. It is known that the receptors of angiotensin II are expressed in culture osteoclasts and osteoblasts, and angiotensin II is postulated to be able to act upon the cells involved in bone metabolism: osteoblasts and osteoclasts; and to regulate blood flow in bone marrow capillaries. In in vitro system, angiotensin II induced the differentiation and activation of osteoclasts responsible for bone resorption and the proliferation of osteoblast-rich populations of cells. As it has been known that osteoclast differentiation is regulated by a variety of hormones, local factors and inflammatory cytokines, such as IL-1 and TNF-α, RAS might also be involved in this autocrine system. In another aspect of RAS, angiotensin II can also regulate blood flow in bone marrow capillaries. Since recent evidence suggests that blood flow can be important to the development of matured bone, the blockade of reninangiotensin system may improve blood flow in bone marrow capillaries, which consequently enhances bone formation. Of importance, sub-analysis of recent clinical study demonstrated that the usage of angiotensin-converting enzyme inhibitors significantly reduced the fracture risk. RAS might be a novel target to treat the subgroups of hypertensive patients with osteoporosis.

Many individuals do not appear to have matching chronological and biological age, as evaluated by their general outlook, physical examination, or clinical investigations. One aspect of this is the concept of early vascular ageing. This could be useful both in research and clinical practice to understand and treat the increased cardiovascular risk in many patients, e.g. with hypertension in poor control. New ways of measuring biological ageing have been introduced, for example telomere length (“mitotic senescence”) that has now been explored in observational studies, and is promising to use also to evaluate biological effects in intervention studies. If the process of vascular ageing could be better understood, as well as its genetic and environmental correlates, new and better ways of offering preventive strategies to risk individuals could be formed. Smoking cessation is one of the classical ways to counteract biological and vascular ageing, but a variety of drugs could also be of potential importance in this respect, e.g. statins, blockers of the renin-angiotensin system, metformin and glitazones. This has to be evaluated in prospective studies, but pravastatin has already been shown to attenuate the associate between short telomere length and risk of coronary heart disease in the WOSCOP study in high-risk Scottish men.

Hypertensive heart disease (HHD) encompasses a spectrum of abnormalities resulting from structural and functional adaptations to chronic pressure overload. The clinical manifestations of HHD range from asymptomatic left ventricular hypertrophy (LVH) to symptomatic heart failure. HHD has been associated with increased risk of cardiovascular morbidity and all cause mortality. However, regression of LVH by antihypertensive therapy has been associated with improved outcome. The pathogenesis of HHD involves various hemodynamic and nonhemodynamic factors including neurohormone, aldosterone. Aldosterone enhances myocardial fibrosis through its direct effect on mineralocorticoid and angiotensin II receptors leading to excessive collagen deposition within the myocardium. Increased myocardial fibrosis is a major determinant of hypertensive remodeling and the transition to heart failure. Aldosterone antagonists are effective antihypertensive agents. Additionally, they have been shown to improve LV structural remodeling, systolic and diastolic function in patients with HHD independent of its effect on blood pressure. Data on long-term benefit of these agents have thus far been limited to patients with advanced systolic heart failure and post-acute myocardial infarction LV systolic dysfunction. The potential benefit of aldosterone antagonists in patients with heart failure and preserved LV systolic function is currently being investigated in large scale clinical trials.

Refractory or resistant hypertension, defined as the failure to control systolic (<140 mmHg) and/or diastolic blood pressure (< 90 mmHg) despite the use of three or more different classes of antihypertensive agents, is a common problem in clinical practice. Several factors induce treatment resistance, especially secondary hypertension, such as primary aldosteronism. Some authors have argued for a direct role of aldosterone autonomy as a mechanism for drug resistance and have recommended the search for primary aldosteronism in cases of severe or resistant hypertension. This proposal is further supported by the demonstration of antihypertensive efficacy of aldosterone antagonists in patients with refractory hypertension. Recently, we have demonstrated a direct role of aldosterone excess as a mechanism for drug resistance, since patients with elevated aldosterone plasma levels develop resistant hypertension, even in the absence of clinically diagnosed primary aldosteronism. The mechanism of resistance may be ascribed to increased plasma volume, regardless of renal function, and cardiovascular remodeling. The present review highlights the role of aldosterone excess as a cause of treatment resistance beyond true primary aldosteronism and provides a conceptual framework for the use of aldosterone antagonists in patients with resistant hypertension.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has multiple effects on the vascular endothelium and many other cells. Many cancers utilize VEGF for proliferation, progression and metastasis, making it a logical target of anti-tumor therapy. Numerous clinical oncology trials have employed this therapeutic approach to effectively treat various malignancies. Hypertension has emerged as one of the most important adverse effects of anti-VEGF therapy. This is supported by multiple clinical trials, using either anti-VEGF antibody, or small molecules targeting VEGF receptor tyrosine kinases. The incidence of hypertension associated with anti-VEGF antibody therapy ranges from 11 to 32% in most phase III clinical trials, while the incidence is about 16 to 43% with therapy targeted at VEGF receptors. The mechanisms underlying anti-VEGF associated hypertension are not understood. Several potential mechanisms have been proposed including vascular rarefaction, endothelial dysfunction, altered nitric oxide metabolism and aberrant neurohormones. More importantly, anti-VEGF related hypertension may have significant clinical implications. Poorly controlled hypertension may be associated with worsening cardiac and renal function, and reversible posterior encephalopathy syndrome. Further studies should focus on uncovering the mechanisms of anti-VEGF induced hypertension, as well as guiding therapy for this adverse effect.