Current Hypertension Reviews - Volume 2, Issue 4, 2006

The prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) are steadily increasing. This phenomenon is in part linked to the aging of the US population, in part to the increasing prevalence of obesity, diabetes and related renal diseases. Some believe that renal ischemia may be a frequent cause of CKD and ESRD, but the prevalence of this condition is difficult to ascertain due to limitations of available diagnostic tools. The current definition of renal ischemia is also ground for confusion. Renal ischemia as a cause of progressive renal disease is commonly defined as a progressive decrease in glomerular filtration rate due to atherosclerosis of the main renal arteries. This definition however, is too restrictive and it does not take into account that functional and anatomical alterations of the renal microcirculation may also lead to progressive renal failure. In this review, we evaluate the clinical and pathophysiological aspects of ischemia-related progressive kidney disease.

Myocardial fibrosis has drawn an attention as the pathogenesis of impaired diastolic function in hypertensive hearts. However, the mechanisms whereby hypertension provokes myocardial fibrosis are not fully understood. Recently, we have demonstrated that Wistar rat with a suprarenal aortic constriction is a model of cardiac hypertrophy associated with preserved systolic, but impaired diastolic function. In this model, a rapid blood pressure rise provokes transient upregulations of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant factor-1 (MCP-1) in the intramyocardial arteries, which in turn trigger perivascular macrophage infiltration. Following the inflammatory changes, myocardial fibrosis extends from perivascular to intermuscular interstitial spaces, which resulting in typical feature of reactive fibrosis. MCP-1 function blocking not only inhibits macrophage infiltration but also prevents reactive fibrosis and diastolic dysfunction, while not affecting blood pressure, myocyte hypertrophy, and systolic function. Tissue angiotensin system is a possible activator of perivascular inflammation. Accordingly, a substantial role of inflammation is suggested in myocardial fibrosis and diastolic dysfunction in hypertensive hearts. Targeting inflammation may be a new strategy for prevention and treatment of myocardial fibrosis and diastolic dysfunction in hypertensive hearts.

Isolated systolic hypertension (ISHTN) is rapidly rising in prevalence, largely due to the advancing age of the population and it will soon become the most common type of hypertension. Untreated patients with merely borderline ISHTN already have a 50% grater risk for cardiovascular complications. Several studies demonstrated that treating ISHTN is beneficial. However, such treatment could cause a potential harm by further reducing the non-elevated diastolic blood pressure; a theory that underlies the controversial “J curve”. In this review, we summarize the epidemiology and pathogenesis of this disorder according to the latest studies, with special emphasis on when, and to what goal, blood pressure should be lowered, and with which medications.

Hypertension is a chronic age-related disorder, affecting nearly 20% of all adult Europeans. This disease entails debilitating cardiovascular complications and is the leading cause for drug prescriptions in Europeans older then 50 years. Intensive research over the past two decades failed so far to identify common genetic polymorphisms with major impact on blood pressure or associated cardiovascular phenotypes, suggesting that multiple genes each with a minor impact, along with gene-gene and gene-environment interactions play a role. The European Project on Genes in Hypertension (EPOGH) is a large-scale family-based study, in which participants from 7 different populations were phenotyped and genotyped according to standardised procedures. This review article summarizes the initial 5-year findings and puts these observations into perspective against other published studies. EPOGH demonstrated that phenotype-genotype relations strongly depend on host factors, such as gender and lifestyle, in particular salt intake as reflected by the 24-hour urinary excretion of sodium. EPOGH therefore highlights the concept that phenotype-genotype relations can only be studied within a defined ecogenetic context.

Adrenomedullin (AM) is a bioactive peptide having a wide range of biological actions such as vasodilatation, natriuresis, diuresis and inhibition of aldosterone secretion. Various organs and tissues, including the myocardium, vascular wall and kidneys, produce AM, and AM is also present in the bloodstream. Plasma levels of AM were elevated in patients with essential or secondary hypertension as compared with normotensive controls. When infused in a relatively short period of time, AM reduced blood pressure in humans and experimental animals largely through vasodilatation. The blood pressure of transgenic mice overexpressing AM was lower than that of their wild-type littermates; while heterozygotes of AM knockout mice showed higher blood pressure, suggesting a role for endogenous AM in the regulation of blood pressure. Studies with cultured cardiac cells suggest a role for AM in inhibiting hypertrophy or fibrosis of the heart as an autocrine or paracrine factor. Animal experiment studies showed that either prolonged infusion or virally mediated overexpression of AM ameliorated the cardiovascular and renal damage associated with hypertension. Thus, a body of evidence accumulated in this field suggests that AM functions to counteract the elevation in blood pressure and progression of hypertensive organ damage.

Tonic activation of the sympathetic nervous system is a major factor contributing to hypertension in patients with chronic renal failure. Besides its role in blood pressure regulation, sympathetic overactivity causes structural and functional alterations of the myocardium and large artery walls. Altogether, these factors contribute substantially to the increased cardiovascular morbidity and mortality in patients with chronic renal disease. Moreover, increased sympathetic outflow in conjunction with increased oxidative stress causes progression of renal disease thereby accelerating the course towards the need of renal replacement therapy. The origin of increased sympathetic outflow in patients with renal disease still has not been fully elucidated. There is sound evidence that signals arising from the diseased kidneys - mediated via renal afferent nerves - cause tonic activation of efferent sympathetic nerve fibres. Renal ischemia with release of adenosine and renal chemoreceptor activation, accumulation of angiotensin II and fibroproliferative scarring with renal mechanoreceptor dysfunction may be involved in the activation of renal afferences. Sympathetic overactivity in renal disease can be diminished by blockers of the renin angiotensin aldosterone system, by adrenoreceptor blockers and by substances inhibiting central sympathetic outflow such as imidazolines. These drugs not only reduce sympathetic nerve activity, they attenuate cardiovascular pathology and they slow the progression of renal disease. A combination of these drugs in patients with chronic renal failure seems promising and warrants randomized large-scale studies.

The metabolic syndrome is a common generator of diseases in countries with western civilization lifestyles. Type 2 diabetes, atherosclerotic disease manifestations, hypertension, obesity, dyslipidaemia, hyperuricaemia, hyperinsulinaemia, dysfibrinolysis and microalbuminuria are considered to be established components of the metabolic syndrome. A clinical observation that obese and/or diabetic men appeared to have a greater prostate gland than men without these conditions generated a series of scientific investigations. An important finding was that benign prostatic hyperplasia (BPH), as measured by the total prostate gland volume or the annual BPH growth rate, was statistically associated with 17 out of 19 components of the metabolic syndrome. Another important finding was that clinical prostate cancer, as measured by stage, grade and PSA-value, was linked to seven of nine components of the metabolic syndrome. Furthermore, it was found that lethal clinical prostate cancer was associated with six (and two more with borderline statistical significance) of ten components of the metabolic syndrome. Still another important finding was that fasting plasma insulin was independently associated with both BPH and clinical prostate cancer. In conclusion, the results of these studies indicate that there is an association between the metabolic syndrome and two important urological tumors, namely BPH and clinical prostate cancer. The results also indicate that BPH and clinical prostate cancer may be regarded as two new components of the metabolic syndrome besides Type 2 diabetes, hypertension, atherosclerotic disease manifestations, obesity, dyslipidaemia and others. The studies also suggest that fasting plasma insulin is a promoter of both BPH and clinical prostate cancer. The results have generated the hypothesis that hyperinsulinaemia is a primary event in the development of both BPH and clinical prostate cancer. If the results can be confirmed in future studies, they would give rise to very significant practical implications in the medical care sector. This article is essentially a review of the findings of our research group over the last 15 years on the link between hyperinsulinaemia and related metabolic perturbations.

During pregnancy, the renin-angiotensin system (RAS) plays an important role in regulating the markedly expanded circulating blood volume in the uteroplacental circulation. RAS is activated during normal pregnancy; however, blood pressure decreases from the 1st trimester to the 2nd trimester. Vascular responsiveness to angiotensin II (AngII) decreases early in pregnancy; on the other hand, pregnant women who subsequently develop PIH are exquisitely sensitive to the pressor effect of AngII. Interestingly. the maternal circulating RAS and the placental concentration of AngII receptor (ATR) are stable or reduced in PIH. The balance of expression between ATR subtype 1 (AT1) and 2 (AT2) is potentially important in the regulation of vascular tone during pregnancy. Increased AT1/AT2 may explain the loss of vascular refractoriness to AngII in the pathogenesis of PIH. Recently, endothelial progenitor cell (EPC) has been found in the peripheral blood of pregnant women. Although AngII stimulates EPC proliferation, the mobilization is inhibited in PIH. Impairment of EPC mobilization may contribute to insufficient regeneration of endothelium in the impaired utero-placental circulation of PIH. This review focuses on vascular endothelial dysfunction and the effect of RAS in the pathophysiology of PIH.

Pre-eclampsia (PE), a hypertensive disorder of human pregnancy, shares some similarities with atherosclerosis and some studies support the theory that PE may work as a marker of increased cardiovascular risk later in life. Atherosclerosis is an inflammatory disease and raised C-reactive protein (CRP) levels have emerged as a powerful marker in predicting cardiovascular events. PE may represent an exacerbated form of inflammation compared with normal pregnancies; actually, a large number of studies have reported higher CRP levels in women with established PE. This paper reviews the association of elevated CRP levels with the development of PE and with the development of cardiovascular disease later in life. The need of studies evaluating CRP, as well as other novel cardiovascular risk factors, in non-pregnant women with a history of PE is highlighted, and attention is given to the potential preventive strategies to reduce cardiovascular risk in such women.

The renin-angiotensin system (RAS) has been known to exert various actions on diverse target tissues such as kidney, heart, vascular system, and brain as well as blood pressure regulation and fluid homeostasis. In addition, various animal experiments and clinical studies suggested a role of RAS on the erythropoiesis. In RAS activated clinical situations such as posttransplant erythrocytosis, renin secreting tumors, and renal artery stenosis, positive erythropoiesis has been suggested. In contrast, by use of anti-RAS drugs such as angiotensin converting enzyme inhibitors or angiotensin II type 1 receptor blockers, negative erythropoiesis has been also reported in RAS inhibited situations. In this era of genetically engineered mice available, transgenic and knockout mice of RAS components have been conspicuously analyzed and these animals definitely revealed positive and negative regulation of erythropoiesis by RAS in vivo. The primary mechanism of enhanced erythropoiesis by RAS activation is increased erythropoietin production via angiotensin II type 1 receptor. A mechanism of progression of anemia by RAS inhibition is less clear. While a slight decrease of hemoglobin is observed in association with the use anti-RAS drugs in clinical situations, other beneficial effects of these reagents apparently validate application of these reagents to patients.