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12th May 2008 @ 2:34am |
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Volume 3, Number 2, June 2002PAPERAge-related increase of pulse pressure and gene polymorphisms in essential hypertension: a preliminary study Genes may modulate the changes of blood pressure (BP) with age; this possibility has never been studied for the age-related increase of pulse pressure (PP), although in older populations, PP is considered the stronger mechanical factor predicting cardiovascular mortality. In humans, the presence of the mutant allele C of the angiotensin II (Ang II) AT1-receptor or of the mutant allele T of the eNOS G298 T gene polymorphisms is associated with enhanced contractile properties of conduit arteries in response to vasoconstrictive agents. In this study, we evaluated, in subjects with untreated essential hypertension, whether the presence of these mutant alleles or their combination might influence the age-related increase of PP. Three main findings emerged from the study and were particularly observed in women: 1) the presence of the C and/or of the T mutant alleles or their combination were associated with a steeper slope of the age versus PP curve, compared with subjects without the mutant allele; 2) the slope was more significantly enhanced when the two mutant alleles were associated in the same genotype; and 3) no comparable age- and gender-related changes in systolic, diastolic or mean BP were found according to this genetic classification. In subjects with essential hypertension, genes may modulate the age-mediated increase of PP. This finding gives new insights in the interactions between genes, mechanical factors and cardiovascular risk. JRAAS 2002;3:109-115. POPULAR Several systemic factors have been shown to contribute to the acceleration of large vessel atheroma. Correction of these factors leads to a reduction in the progression of plaque formation and associated arterial wall thickness. Atheroma remains, however, a focal disease, developing at characteristic sites within the arterial tree. These sites are typically at areas of vessel branching or marked curvature, and correspond to regions of high tensile stress and low sheer stress, leading to the hypothesis that local haemodynamic factors and vessel wall mechanics potentiate the focal development of atheroma. JRAAS 2002;3:116-122. PAPERLack of rapid aldosterone effects on forearm resistance vasculature in health Objectives:
Systemic infusions of aldosterone cause an acute increase in systemic vascular resistance (SVR) in healthy subjects. It is not clear whether this is due to a direct effect on the vasculature or the result of increased sympathetic tone. We investigated the short-term effects of locally infused aldosterone on the forearm resistance bed. JRAAS 2002;3:123-125. PAPERHigh plasma adrenomedullin concentrations in patients with high-renin essential hypertension Adrenomedullin (AM) is a novel peptide, first isolated from human phaeochromocytoma, which elicits a long-lasting vasorelaxant activity. Recently, it has been reported that endothelial cells produce AM and that immunoreactive AM plasma levels may be elevated in human arterial hypertension, although the exact pathophysiological role of AM remains to be established. JRAAS 2002;3:126-129. PAPERNephrectomy and peritoneal dialysis eliminates circulating renin and controls uraemia in the rat Objective:
The aim of the present study was to develop a rat model for in vivo studies of the local effects of the renin-angiotensin system (RAS) following elimination of circulating renin. JRAAS 2002;3:130-134. POPULAR The Study on Cognition and Prognosis in the Elderly (SCOPE) was designed to provide outcome data on cardiovascular endpoints and cognitive function in 4500 elderly hypertensive patients randomised to the angiotensin receptor blocker, candesartan, or to placebo and followed up for 4.5 years. JRAAS 2002;3:61-62. POPULAR The effective treatment of hypertension still poses many problems. In the last decade it has become apparent that in many patients multi-drug regimens are needed to effect blood pressure control. How best to combine medications and what might be a preferred order of initiating drugs is still open to debate and has proven the substance of many of the published guidelines on this theme. Like most matters in the clinical sector the approach to a disease – in this case hypertension – should remain highly individualised and cognisant of what can be significant cost considerations. JRAAS 2002;3:63-65. EDITORIAL REVIEWThe practical aspects of combination therapy with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) are widely prescribed for the management of hypertension. ACE inhibitors (ACE-I) and, more recently, ARBs have an established track record of success in the treatment of congestive heart failure (CHF), proteinuric renal disease and most recently the hypertensive patient with a high cardiac-risk profile. The individual success of each of these drug classes has fuelled speculation that given together the overall effect of both would exceed that of either given alone. This premise, although biologically plausible, has yet to be proven in a convincing enough fashion to support the routine use of these two drug classes in combination. Additional clarifying studies are needed to establish whether specific patient subsets exist that might benefit from such combination therapy. JRAAS 2002;3:66-71. POPULAR The rationale for using angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARBs) in combination with thiazide diuretic therapy has centred formerly around antihypertensive synergy and counter-balancing adverse metabolic effects, particularly on potassium homeostasis. However, two recent landmark clinical trials that included high-risk hypertensive patients have now provided an evidence base for this form of combination therapy by demonstrating the efficacy of perindopril/indapamide and losartan/ hydrochlorothiazide in reducing vascular morbidity and mortality, a proportion of the benefit being unaccounted for by blood pressure reduction alone. Several unresolved issues remain concerning class effects versus specific drug effects, optimal dosing, potential differences in efficacy between ACE-I and ARBs, whether elderly mild hypertensives benefit from this form of combination therapy, and the possibility that the optimal regimen may be a triple combination of ACE-I, ARB and thiazide diuretic. These issues will be resolved by ongoing and future major endpoint trials in hypertension. JRAAS 2002;3:72-78. EDITORIAL REVIEWCalcium channel blockade in combination with angiotensin-converting enzyme inhibition or angiotensin II (AT1-receptor) antagonism in hypertensive diabetics and patients with renal disease and hypertension Effective reduction in blood pressure (BP) improves survival and morbidity in hypertensive patients. Combination therapy with multiple antihypertensive agents is frequently required in clinical practice and therapeutic trials to achieve target BP. Patients at elevated cardiovascular risk achieve the greatest benefit from equivalent reduction in BP and also require more stringent BP control. In patients with hypertension and diabetes mellitus or renal disease, BP control is of primary importance and blockade of the renin-angiotensin system (RAS) should be the initial therapeutic intervention. Choice of combination therapy has been insufficiently studied in major clinical cardiovascular endpoint trials. Diuretic therapy remains the logical addition to RAS blockade. Despite previous debate, the available evidence suggests long-acting calcium-channel blockers are also a safe and very effective addition to improve BP control further. The choice of antihypertensive combination therapy should not override the fundamental necessity of lowering BP to target levels. JRAAS 2002;3:79-89. POPULAR Vasopeptidase inhibitors are a new class of drugs that have dual inhibitory effects on two key enzymes involved in the metabolism of vasoactive peptides. Essentially, they inhibit angiotensin-converting enzyme (ACE), thereby blocking the generation of angiotensin II (Ang II); at the same time they prevent the breakdown of natriuretic peptides by the enzyme neutral endopeptidase. The combination of reduction of Ang II on a background of increased natriuretic peptide activity has several potential advantages for the treatment of cardiovascular and renal disease and in particular, hypertension and congestive heart failure (CHF). Several vasopeptidase inhibitors, such as sampatrilat, fasidotril, gemopatrilat and omapatrilat (VanlevTM, the most clinically developed vasopeptidase inhibitor to date) are under intensive clinical investigation. Recent clinical trials have demonstrated effective antihypertensive activity in hypertension, independent of age, renin and salt status or ethnic origin, and have also highlighted the potential for vasopeptidase inhibition as a new therapeutic modality for the treatment of CHF. Moreover, ongoing research suggests that this new class of drugs may be an important approach, not only for the treatment of hypertension and of conditions associated with overt volume overload but also for ischaemic heart disease. JRAAS 2002;3:90-95. EDITORIAL REVIEWRenin-angiotensin system antagonism and lipid-lowering therapy in cardiovascular risk management The renin-angiotensin system (RAS) and dyslipidaemia have been shown to be involved in the genesis and progression of atherosclerosis. Manipulation of the RAS has been effective in modifying human coronary artery disease progression. Similarly, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors or ‘statins’ have been shown to reduce cholesterol and lower cardiovascular events in primary and secondary prevention trials in coronary artery disease. In addition to their primary mode of action, statins and blockers of the RAS possess common additional properties that include restoration of endothelial activity and inhibition of cellular proliferation. This article reviews the current data on the common properties of these classes of drugs in which the beneficial effects extend beyond their antihypertensive and lipid-lowering properties. JRAAS 2002;3:96-102. POPULAR Treatment of high blood pressure (BP) reduces the risk of death and morbidity from stroke and coronary heart disease. There is accumulating evidence from large outcome studies that support a move towards lower treatment targets in hypertensives, particularly for those with concomitant risk factors or evidence of established target organ damage. At present, the achieved rates for BP control in the UK are very poor. Amongst the many possible reasons for poor BP control is the under utilisation of effective drug combinations. This article addresses the rationale for two and three drug combination therapy in hypertension and reviews the trial evidence for efficacy of combinations. JRAAS 2002;3:103-108. CASE STUDYRenal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor: unmasking of an unknown iliac artery stenosis Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report describes a case of acute renal graft dysfunction following the addition of an ARB to existing ACE inhibition. This unmasked an unknown iliac artery stenosis. The case indicates a possible important role of Ang II generated by non-ACE pathways in this situation. JRAAS 2002;3:135-137. CASE STUDYGrossly elevated serum angiotensin-converting enzyme activities are still suppressible with ACE inhibitor therapy JRAAS 2002;3:138. |
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