Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Besides cyclooxygenase and NO-synthase, another distinct endothelial pathway, endothelium-dependent hyperpolarization (EDHF), is involved in the relaxation of the vascular smooth muscle cells. EDHF has been demonstrated unequivocally in various blood vessels from different species, including human, and is likely to play an important role in cardiovascular physiology. This alternative pathway involves the activation of two populations of endothelial potassium channels, the small conductance and intermediate conductance calcium-activated potassium channels (SK(Ca) and IK(Ca), respectively). EDHF-mediated responses are clearly altered in various pathological conditions (ageing, hypertension, atherosclerosis, hypercholesterolemia, heart failure, ischemia-reperfusion, angioplasty, eclampsia, diabetes, sepsis). Therapeutic or adjutant interventions (angiotensin converting enzyme inhibitors, antagonist of the angiotensin receptor, estrogen, omega-3 polyunsaturated fatty acids, polyphenol derivatives, potassium and/or calcium intake) can restore these responses, suggesting that the improvement of the EDHF pathway contributes to the observed beneficial effect of these various substances. However, the improvement or restoration of EDHF responses has not been, yet, the direct purpose of any pharmaceutical effort. Activating endothelial IK(Ca) and/or SK(Ca) or increasing their expression as well as improving myo-endothelial communication, for instance by increasing the expression of connexin(s), could become interesting therapeutic targets.
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PMID:EDHF: new therapeutic targets? 1502 34

The Annual Scientific Sessions of the American Heart Association is the leading scientific conference in the cardiovascular field, both for basic and clinical research in cardiology and related disclipines. This report covers the outcome of major clinical trials that were presented in the 'late-breaking' clinical trial sessions. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigated the angiotensin receptor blocker valsartan, the angiotensin-converting enzyme inhibitor captopril, and their combination in 14,703 survivors of an acute myocardial infarction with a reduced left ventricular ejection fraction on clinical outcome. The study demonstrated that valsartan and captopril where equally effective, whereas the combination was associated with an increased risk of side effects without further benefit. VALIANT is a landmark trial because it was the first large study that compared the combination of an angiotensin receptor blocker with an angiotensin-converting enzyme inhibitor in the setting of acute myocardial infarction. Other trials that will be summarised in this report are the Na + /H + Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions Trial (EXPEDITION; cariporide in coronary artery bypass graft surgery), the Reversal of Atherosclerosis with Aggressive Lipid Lowering Trial (REVERSAL; atorvastatin and pravastatin for atherosclerosis reversal), the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation V (SPORTIF V; ximelagatran and warfarin for stroke prevention in atrial fibrillation), the Prophylactic Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularisation (PAPABEAR; amiodarone for the prevention of postoperative atrial fibrillation), the Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF; vasopressin 2 antagonist tolvaptan in congestive heart failure) and Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT; fosinopril and pravastatin in microalbuminuric subjects without hypertension or hypercholesterolemia).
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PMID:American Heart Association scientific sessions. 1510 93

In humans, the incidence and severity of abdominal aortic aneurysms (AAA) are greater in males than in females. Chronic infusion of angiotensin II (AngII) into apolipoprotein E-deficient (apoE(-/-)) mice promotes atherosclerosis and causes the formation of AAAs. Just as human males are more susceptible to developing AAAs, male mice are more susceptible to AngII-induced AAAs. We hypothesized that sex steroid hormones mediate gender differences in AngII-induced AAA through regulation of the renin-angiotensin system. To define the role of ovarian hormones, female apoE(-/-) mice were subjected to ovariectomy or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Ovariectomy had no effect on AngII-induced atherosclerosis, nor did it influence the incidence or severity of AAA. To define the role of testicular hormones, male apoE(-/-) mice were subjected to orchidectomy (orx) or sham operation and infused with AngII (1000 ng/kg x min) for 28 d. Orx resulted in a profound reduction in AAA incidence (85% vs. 18%, sham vs. orx; P = 0.003) to the level observed in females (25%). However, orx had no effect on AngII-induced reductions in plasma renin concentration or spleen AngII receptor density. In contrast, orx resulted in an increase in atherosclerosis (0.46 +/- 0.07 vs. 1.20 +/- 0.21 mm(2), sham vs. orx; P = 0.002). These results suggest that estrogen does not mediate gender differences in AngII-induced AAA. In contrast, androgens mediate a higher incidence of AngII- induced AAA, through mechanisms that do not appear to involve circulating renin or angiotensin receptor density.
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PMID:Orchidectomy, but not ovariectomy, regulates angiotensin II-induced vascular diseases in apolipoprotein E-deficient mice. 1510 80

The renin-angiotensin system is the major contributor to development of hypertension, atherosclerosis, and many other cardiovascular diseases. Angiotensin II, one of the main effectors of this system, contributes to the pathogenesis of hypertension and plays an important role in monocyte, platelet, and endothelium interactions. The effects on platelet and endothelial function, either by angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, are still not well understood. A double-blind, randomized, prospective trial of either enalapril (10-20 mg daily) or eprosartan (400-800 mg daily) over a 10-week period was conducted in 42 patients (27 males, 15 females). Platelet activation was evaluated by measuring platelet factor 4 (PF-4), beta-thromboglobulin (beta-TG), the ratio of platelet factor 4 to beta-thromboglobulin, and endothelial function by measuring total plasma nitrate levels, von Willebrand factor (vWF) levels, and blood flow using venous occlusive plethysmography. After a 10-week treatment with enalapril or eprosartan, the sitting blood pressure in both the enalapril group (from 152.2 +/- 18.7 mmHg to 141.9 +/- 23.5 mmHg, P < 0.05) and eprosartan group (from 151 +/- 10.0 mmHg to 142.3 +/- 12.9 mmHg, P < 0.05) was significantly reduced. Significant diastolic blood pressure (DPB) reduction (from 94 +/- 8.7 to 84.5 +/- 9.6 mmHg, P < 0.05) and a greater DBP reduction response were found in the eprosartan group (63% in eprosartan versus 25% in enalapril). Additionally, dose-dependent reductions in the indices of platelet activation and endothelial dysfunction were observed in patients administered high dose treatments of eprosartan and enalapril, and the beneficial effects of these agents were not correlated with the reduction of blood pressure using both agents. Eprosartan is effective and well-tolerated in the treatment of mid-to-moderate hypertension, and the DBP response reduction to eprosartin was better than that to enalapril. A high dose of either eprosartan or enalapril significantly decreased the indices of platelet activation and endothelial dysfunction in hypertensive patients. The benefits of both agents cannot be explained solely by their antihypertensive effects and possibly may be mediated through their unique effect on angiotensin blockade.
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PMID:A double blind randomized trial to compare the effects of eprosartan and enalapril on blood pressure, platelets, and endothelium function in patients with essential hypertension. 1535 73

The prevalence of heart failure is increasing in modern societies. Hypertension is a major contributor to the development of heart failure, whether through the development of left ventricular hypertrophy and diastolic dysfunction or by promoting atherosclerosis and myocardial infarction, which eventually leads to systolic dysfunction and left ventricular dysfunction. Effective therapy for hypertension can prevent more than 50% of heart failure events. Most studies done in the last three decades have used b blockers with diuretics as the modality of therapy. These agents have been shown to effectively prevent the development of heart failure. More recent comparative studies have shown that use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are also effective in preventing heart failure. Calcium channel blockers, however, seem to be less effective in preventing development of heart failure in patients with hypertension. It needs to be emphasized that the most important variable in preventing heart failure is the appropriate treatment of hypertension.
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PMID:From hypertension to heart failure. 1547 Feb 94

The understanding of the pathophysiology governing atherosclerosis supports a prominent role for inflammation pathways in plaque initiation and progression that result in stroke and myocardial infarction. Elevated levels of inflammatory markers in the blood, such as C-reactive protein and CD40 ligand/CD40, in concert with increased expression of adhesion molecules, chemokines, cytokines, matrix metalloproteinases (MMP), and inflammatory cells in the plaque, characterize the symptomatic atherothrombotic state. Advances in predictive capabilities of vascular events using a number of these biomarkers are beginning to remodel our clinical practice in the use of medications such as statins and angiotensin receptor blockers for stroke prevention. Although the general inflammatory features of atherosclerosis are becoming widely recognized, factors resulting in individual variability in plaque formation and instability remain poorly defined. Emerging literature points toward several acquired and innate susceptibility factors in the immune pathways that may provide insight into why many plaques rapidly evolve from a "stable" to an "unstable" or symptomatic state. First, exposure of plaque memory T-lymphocytes to infectious or endogenous antigens may result in rapid clonal expansion of T-cell variable beta chain subtypes and stimulate macrophages to release MMPs, causing plaque destabilization. The effects of infectious agents can further be influenced by an individual's major histocompatibility complex class II molecule profiles, which can affect susceptibility to specific organisms. Second, functional polymorphisms of genes that regulate the immune pathway can predispose patients to a more robust inflammatory expression after risk factor exposure. Identification of a susceptibility gene profile and immunologic mediators that promote T-cell activation provides a unique opportunity for early identification of stroke risk and targets for future therapy.
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PMID:Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation. 1547 6

Clinical trials have demonstrated the benefit of blood pressure (BP) reduction in reducing the risk of cardiovascular and renal complications in patients with diabetes mellitus. Incorporation of agents that inhibit the renin-angiotensin-aldosterone system (RAAS) into antihypertensive regimens has been shown to provide reductions in renal and cardiovascular events that are mediated by both BP-dependent and -independent mechanisms. Recent studies exploring these potential mechanisms have demonstrated a direct role of angiotensin II (ATII) in the pathology of the vasculature and other sites of end-organ injury. In animal models of diabetes, inhibition of the RAAS with angiotensin-converting enzyme (ACE) inhibition or angiotensin type 1 (AT(1)) receptor blockade has been shown to prevent atherosclerosis, an effect that was independent of BP reduction. In addition to its direct effects on the vasculature, ATII also has direct detrimental effects on end organs, including the kidney and the heart, which lead to the development of proteinuria and left ventricular hypertrophy (LVH), respectively. Left ventricular hypertrophy has been shown to be predictive of cardiovascular and renal events, and the benefits of RAAS inhibition with angiotensin receptor blocker therapy are accompanied by a reduction in LVH. In addition to preventing the cardiovascular and renal complications of diabetes, the RAAS blockade has also been shown, in several large randomized clinical trials, to inhibit new onset of diabetes. Recent studies have revealed that many tissues, including pancreatic islets and adipose tissue, have a local RAAS. In the diabetic rat model (Zucker diabetic fatty rats), pancreatic islets exhibit an increased intraislet expression of ACE and AT(1) as well as increased intraislet fibrosis, apoptosis, and oxidative stress. The local RAAS also appears to play a role in the function of the adipocyte. Angiotensin II inhibits adipocyte differentiation, potentially decreasing the storage capacity of adipose tissue. The reduced capacity of adipose tissue to store fatty acids may cause their accumulation in other tissues, leading to insulin resistance and development of diabetes. Collectively, these studies demonstrate that ATII has direct effects on multiple tissues, and inhibition of ATII action in these tissues may be responsible for many of the clinical benefits observed with RAAS inhibition.
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PMID:The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications. 1553 6

Aortic pulse wave velocity (PWV) and augmentation index are independent predictors of adverse cardiovascular events, including mortality. In hypertension and aging, central elastic arteries become stiffer, diastolic pressure decreases, and central systolic and pulse pressures are augmented due to increased PWV and early return of reflected waves to the heart from the periphery. Valuable information on arterial properties such as stiffness can be obtained from both central (aortic) and peripheral (radial artery) pressure waveforms, but absolute values of wave reflection amplitude and wasted left ventricular (LV) pressure energy can only be obtained from the central arterial pressure waveform. As the arterial system becomes stiffer, there is a marked increase in central systolic and pulse pressures and wasted LV energy, along with a decrease in pulse pressure amplification. The increase in aortic systolic and pulse pressures are due primarily to increases in PWV and wave reflection amplitude with a small increase in incident wave amplitude. In individuals with very stiff elastic arteries (eg, in older persons with isolated systolic hypertension), there is a decrease in diastolic pressure. These changes in pressure components increase LV afterload and myocardial oxygen demand and therefore cause an undesirable mismatch between ventricle emptying and arterial pulse wave transmission, which promotes ventricular hypertrophy. High systolic and pulse pressures resulting from advanced age or hypertension increase circumferential arterial wall stress, which likely causes breakdown of medial elastin and increases the possibility of local fatigue, endothelial damage and development of atherosclerosis. Vasodilator drugs may have little direct effect on large central elastic arteries, but at the same time, their effects on peripheral muscular arteries reduce wave reflection amplitude and markedly lower systolic and pulse pressures and ventricular afterload. These beneficial effects on central arterial pressure can occur with or without a reduction in cuff blood pressure (BP) and may explain the apparent "pressure-independent" effects of drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Therefore, optimal treatment of high BP and its complications should include consideration of arterial stiffness, augmentation of aortic pressure, and LV wasted energy, all of which should be reduced to the lowest possible level.
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PMID:Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. 1568 25

By failing to recognize the heterogeneity of hypertension, the authors of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study used a faulty premise to conduct a poorly designed clinical trial. By failing to control blood pressures equally across study drug groups, ALLHAT cannot be considered to be a definitive comparative trial. Being neither a monotherapy trial nor a trial that initiated therapy for blood pressure control, ALLHAT provided no data to recommend first-line therapy for hypertension, making the conclusions invalid. Thiazide-type diuretics increase angiotensin II and consequently promote atherosclerosis and arteriolarsclerosis. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers retard atherosclerosis and are nephroprotective. Multiple randomized controlled trials show beneficial clinical outcomes, including cardioprotection and nephroprotection, with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents, and not thiazide-type diuretics, should be used as first-line agents to retard the process of atherosclerosis and its clinical outcomes in the setting of arterial hypertension.
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PMID:Hypertension and atherosclerosis: clinical implications from the ALLHAT Trial. 1572 29

The metabolic abnormalities associated with diabetes mellitus result in macrovascular and microvascular complications in multiple organ systems; it is the cardiovascular impact that accounts for the greatest morbidity and mortality associated with this disease. Heart failure, both with reduced and preserved systolic function, is a major complication, arising from the frequent associations with coronary atherosclerosis, hypertension, and a specific heart muscle dysfunction (cardiomyopathy) that occurs independently of coronary artery disease. Hyperglycemia, insulin resistance, and hypertension, together with activation of both circulating and tissue renin-angiotensin-aldosterone systems, contribute to structural fibrosis and autonomic neuropathy. Thus it becomes imperative to identify cardiac abnormalities early in the course of both type 1 and type 2 diabetes in order to allow early and aggressive intervention to control glucose and blood pressure and to normalize blood lipid profiles. Patients with diabetes should be treated to secondary prevention targets, including blood pressure less than 130/80 mm Hg and LDL less than 100 mg/dL. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, certain calcium channel blockers, statins, and aspirin have all been demonstrated to significantly reduce cardiovascular morbidity and mortality in patients with diabetes.
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PMID:Heart failure in diabetes mellitus: causal and treatment considerations. 1572 10


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