Current Hypertension Reviews - Volume 1, Issue 3, 2005

Correction of cardiovascular risk factors is a mainstay of the treatment of hypertensive patients that have developed or might develop target organ damage. In addition to traditional risk factors, such as smoking, diabetes, obesity, and dyslipidemia, clinical research has identified additional conditions that put patients at a greater risk of developing cardiovascular disease and that might achieve particular relevance in the hypertensive state. Over the last decades, effective intervention in the treatment of traditional risk factors has reduced remarkably cardiovascular morbidity and mortality, but the incidence of coronary artery disease, stroke, and renal failure remains unacceptably high. Emerging cardiovascular risk factors are likely to contribute substantially to this picture and it could be anticipated that their contribution will become increasingly evident in the future. Physicians involved in the field of hypertension and dealing with problems concerning cardiovascular prevention should be aware of these new risk factors, give them an appropriate consideration, and correct them whenever possible. This review will consider the literature supporting the role of lipoprotein(a), homocysteine, and fibrinogen as contributors to cardiovascular risk in the general population and, more specifically, to the development and progression of target organ damage in hypertensive patients. The impact of early impairment of renal function on these factors will be analyzed in relation to the progression of renal disease as found in patients with hypertensive nephrosclerosis.

Endothelial dysfunction, a hallmark of many vascular diseases such as diabetes mellitus, atherosclerosis and essential hypertension, refers to significant impairment of a majority of endothelial activities e.g. modulation of vasomotor tone and inhibition of smooth muscle cell proliferation and/or migration. Several factors including increased synthesis of vasoconstrictor agents through the cyclooxygenase pathway and dysregulation of the gene encoding endothelial type of nitric oxide synthase in endothelium have been proposed to account for this defect in hypertensive subjects. However, a growing body of evidence has recently implicated diminished bio-availability of nitric oxide (NO), the most important endogenous vasodilator agent, due to excessive synthesis or reduced destruction of reactive oxygen species (ROS) in the pathogenesis of hypertensive endothelial dysfunction. Hence, this review aims to summarize the mechanisms by which vascular cells produce NO and ROS, to highlight the molecular mechanisms underlying the pathogenesis of hypertensive endothelial dysfunction with particular reference to interactions between ROS and NO, and finally to discuss the reversal of hypertensive endothelial dysfunction.

Left Ventricular Hypertrophy (LVH) is a risk factor for major cardiovascular diseases as stroke, myocardial infarction and sudden death, and is sustained by several hemodynamic and non-hemodynamic mechanisms. A wide spectrum of alterations in left ventricular hypertrophy geometric pattern can take the form of normal left ventricle, concentric left ventricular remodeling, concentric left ventricular hypertrophy, eccentric LVH. Hemodynamic and anatomic characteristics of LVH are represented by the alteration of coronary blood flow, endothelial dysfunction, extracellular collagen deposition and ventricular fibrosis. However, other biological phenomena such as genotype, gender, body size, environmental factors can influence left ventricular mass. The most important mechanism remains the activation of neurohormonal systems (first of all, renin-angiotensin system, secondarily catecolamines, insulin and leptin). Actual data cannot explain some LVH characteristics (LVH pattern development, LVH regression), so several open questions remain to be clarified through further investigations.

Atherosclerotic cardiovascular disease is a leading cause of death in most developed countries. Cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia initiate structural and functional abnormalities in the arterial wall, leading to the development of atherosclerosis. Atherosclerosis is characterized by the stiffening and/or thickening of the arterial wall. Aortic pulse wave velocity as evaluated by carotid and femoral arterial waves is the most established measure for arterial stiffness. Recently, a new arterial stiffness measure using brachial and tibial arterial waves has been developed. The measurement of the brachial-ankle wave velocity is fully automatic, needs no skill and is reproducible. Age and blood pressure are robust independent predictors for the brachial-ankle pulse wave velocity. Recent studies have shown that higher brachial ankle pulse wave velocity is associated with more advanced atherosclerotic changes of the arterial wall not only in the clinical patients but also in subclinical individuals. Thus, brachial-ankle pulse wave velocity may be a useful measure of vascular damage, which predisposes individuals to cardiovascular events. A multicenter trial examining the prognostic significance of the brachial-ankle pulse wave velocity is presently in progress.

Nephropathy developing from hypertension and/or non-insulin dependent diabetes mellitus (NIDDM) is becoming increasingly prevalent in the world population. Although there is a significant amount of research being conducted in this area, the etiologies of nephropathy are not known. It has been proposed that hemodynamic and metabolic alterations in the kidney contribute to the development and progression of nephropathy. More interesting however, is the identification of an inflammatory component to nephropathy that is characterized by increased expression of nuclear transcription factors, increased cytokine expression and interstitial cell infiltration. Cytochrome P450 epoxygenase metabolites have recently been reported to regulate sodium excretion as well as renal blood flow and blood pressure. In addition, the epoxyeicosatrienoic acids (EETs) have been identified as anti-inflammatory mediators. We propose that EETs can prevent the development and progression of nephropathy associated with NIDDM and hypertension, by inhibiting the expression of pro-inflammatory genes.

Vascular remodeling and hypertrophy/hyperplasia of the heart and kidney are known to be major servomechanisms of long-term maintenance of elevated blood pressure and the development of cardiovascular and renal complications seen in hypertension. Several lines of evidence suggest that these abnormalities are genetically determined and evoke an imbalance between cell proliferation and death. During the last 2 decades, it was shown that the level of cardiotonic steroids (CTS), i.e. potent and selective Na+,K+-ATPase inhibitors, is increased in several forms of volumeexpanded hypertension. We focus our review on recent data implicating CTS in the regulation of cell proliferation and death. At low concentrations, CTS augment proliferation of vascular smooth muscle cells (VSMC) as well as renal epithelial and vascular endothelial cells without significant inhibition of Na+,K+-ATPase-mediated ion fluxes. In contrast to cell proliferation, effect of CTS on cell survival is tissue-specific. In VSMC, CTS inhibit programmed cell death via a novel Na+ i-mediated, Ca2+ i-independent mechanism of expression of antiapoptotic genes including mortalin, whereas in vascular endothelial and renal epithelial cells, long-term exposure to CTS leads to cell death showing combined markers of apoptosis and necrosis. This mode of cell death is caused by interaction of CTS with Na+,K+-ATPase but is independent of inhibition of the Na+,K+-ATPase-mediated ion fluxes and inversion of the [Na+]i/[K+]i ratio. We propose that these novel signaling pathways triggered by enhanced production of endogenous CTS and/or abnormal Na+ handling contribute to cardiovascular and renal complications seen in hypertension.

Primary aldosteronism (PA) is a common form of endocrine hypertension in which aldosterone production is inappropriate and at least partially autonomous of the renin-angiotensin system. Recent studies using the plasma aldosterone/plasma renin activity (PRA) ratio (ARR) as a screening test for both hypokalaemic and normokalaemic hypertensives have reported a high prevalence of this disease, with PA accounting for up to 12% of hypertensive patients. Therefore, PA is considered the most common identifiable, specifically treatable and potentially curable form of hypertension. Of particular interest is the identification of the different subtypes of PA, since some of them benefit from surgical treatment, whereas others require medical treatment with mineralocorticoid receptor antagonists. Herein, we review the diagnostic strategies used to identify surgically-treatable forms of PA, i.e. those forms that display unilateral secretion of aldosterone and benefit from unilateral adrenalectomy. In particular, we compare the different imaging strategies, the role of hormonal tests and the indication and interpretation of adrenal venous sampling.

The four SDH genes encode succinate dehydrogenase (SDHA and SDHB) and its anchoring subunits (SDHC and SDHD), which constitute complex II of the mitochondrial membrane, involved both in the respiratory chain and the Krebs cycle. Mutations of SDHD and less frequently SDHB and SDHC are at the origin of rare hereditary forms of head and neck paraganglioma. Interestingly, SDHB mutations are also a major cause of sporadic and familial pheochromocytomas, which have the same embryonic origin as head and neck paragangliomas. Patients with SDHB mutations are at higher risk of developing malignant and recurrent forms of pheochromocytoma. SDHB mutations have also been found in pedigrees harbouring both paragangliomas and renal cell carcinomas. This association reminds us of the Von Hippel-Lindau syndrome caused by mutations in the VHL gene. It should be pointed out that several angiogenic factors (HIFa, VEGF) are overexpressed both in tumours associated with paraganglioma and Von Hippel-Lindau syndrome. Though the different steps leading from SDH mutations to paraganglioma remain obscure, it is tempting to hypothesise that SDH gene products, VHL and angiogenic factors belong to the same functional pathway. The story of SDH genes is an impressive example of how the unravelling of the genetic basis of a rare disease i.e. familial head and neck paraganglioma can provide new insights into mechanisms involved in more frequent conditions such as endocrine hypertension, tumourigenesis, angiogenesis and adaptation to hypoxia.

Hypertension affects an estimated thirty percent of all Americans, a number expected to climb as the population ages. At some point in their life, approximately one percent of these patients will experience a hypertensive crisis-either a hypertensive urgency or emergency. These rapid and worrisome elevations in blood pressure account for many visits to emergency departments and urgent treatment in primary care settings. Patients with hypertensive crises may be asymptomatic, or may present with encephalopathy, chest pain, heart failure, headache, epistaxis, and a number of other clinical disorders. The approach to treating these patients varies widely throughout the world, primarily because of the lack of quality clinical trial data that guides the treatment of this fairly large population of patients with hypertensive crises. In this paper, the categorization of hypertensive urgencies and emergencies will be reviewed. While the majority of the patients have longstanding primary hypertension with sometimes erratic and inadequate treatment, the hypertensive crisis may also be an indicator of another underlying clinical process. The pathophysiology and epidemiology of these conditions will be discussed. The current guidelines for treatment will be summarized. Additionally, the use and indications for various parenteral and intravenous drugs will be described.