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Cardiovascular disease is the major cause of death in patients with end-stage renal disease (ESRD). ESRD patients are almost invariably hypertensive. They all have acquired combined hyperlipidemia and increased Lp(a), hyperhomocysteinemia, decreased physical activity, psychosocial stress, insulin resistance, procoagulant factors, left ventricular hypertrophy, and increased oxidative stress. Diabetes mellitus, a major risk factor for both cardiovascular disease and ESRD, has become the commonest cause of ESRD. If ESRD patients choose to smoke, the additive risk is profound. Moreover, ESRD patients are becoming older and are often menopausal if female. Finally, ESRD patients have a dramatic tendency for vascular and cardiac calcification, probably related to hyperphosphatemia and hyperparathyroidism. Cardiovascular disease is also a major risk in patients with decreased renal function of nearly any degree. Data from the HDFP study showed that patients with a serum creatinine concentration > 1.5 mg/dl had a profoundly higher risk of cardiovascular disease than patients with creatinine values below this value. These data were recently corroborated in the HOPE study. Microalbuminuria (MAU), with or without diabetes mellitus, indicates increased cardiovascular disease risk even without decreases in glomerular filtration rate. We found earlier that nondiabetic hypertensive patients with MAU had much higher rates of myocardial infarction, stroke, and peripheral vascular disease, than similar hypertensive patients without MAU. In conclusion, the presence of decreased renal function or MAU is a major cardiovascular risk factor. ESRD can be regarded as a catastrophic risk factor. Prophylactic measures known to be effective in reducing the risk from cardiovascular disease are grossly underused. Unfortunately, they are less effective in patients with renal disease, and new strategies are needed.
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PMID:Renal disease as a risk factor for cardiovascular disease. 1119 57

Over a 4.5 year follow-up period, the HOPE (Heart Outcomes Prevention Evaluation) trial, and the MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) and SECURE (Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E) substudies have all demonstrated a large benefit of ramipril versus placebo in patients over 55 years at high risk (by reason of a prior vascular event), or by being diabetic subjects with one additional risk factor. The baseline blood pressure on average was normal, at 139/79 mmHg, and was modestly reduced by 3.3/1.4 mmHg. Patients with known left ventricular dysfunction were excluded, as were those with uncontrolled hypertension. The incidence of stroke was reduced by 32%, myocardial infarction by 20% and cardiovascular death by 25%. The benefits conferred were in addition to, and largely independent of, other conventional treatments such as aspirin, lipid-lowering agents, beta-blockers, diuretics and calcium channel blockers. The relative risk reduction was very similar whether or not the patient was a known hypertensive at baseline. High dose ACE inhibition with ramipril is applicable to a far wider population of patients at high risk of cardiovascular events than the current indications of hypertension and left ventricular dysfunction.
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PMID:Future perspectives and implications. 1171 55

Diabetes is a major risk factor for cardiovascular events. Indeed, people with diabetes are 2-4 times more likely to die from cardiovascular causes than individuals without diabetes. Despite evidence to suggest that the burden of cardiovascular disease may be decreasing in Western populations, this trend has not been repeated in diabetic populations. Diabetes is also the most common cause of new-onset end-stage renal disease, blindness and amputations. The growing incidence of diabetes throughout the world, particularly in developing nations, suggests that diabetes-related cardiovascular disease and other chronic cardiovascular diseases will constitute a serious global threat to health and well-being. The HOPE (Heart Outcomes Prevention Evaluation) study was designed to determine if the angiotensin converting enzyme (ACE) inhibitor, ramipril, prevents cardiovascular events in high risk patients. As people with diabetes have a high risk of such events, this group was specified for inclusion and analysis in the HOPE study. The HOPE study was designed to include up to 4,000 people with diabetes and was designed with high power to detect an 18% risk reduction in the diabetic sub group alone. A total of 3,577 individuals with diabetes were randomised to receive either 10 mg of ramipril or placebo. After a period of 4.5 years of follow-up, the group of patients receiving ramipril had a statistically and clinically significant risk reduction of 25% in the primary outcome of myocardial infarction (MI), stroke or cardiovascular (CV) death. This comprises a 37% risk reduction in CV death, a 22% risk reduction in MI, a 33% reduction in stroke and a 24% reduction in all-cause mortality. The MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) sub study assessed the effect of ramipril on diabetic nephropathy. This was detected by a centrally measured urine albumin:creatinine ratio and confirmed by timed urine collection. Ramipril significantly reduced the risk of overt nephropathy by 22% (P = 0.045), and overt nephropathy, laser therapy or dialysis by 15% (P = 0.05). ACE inhibition with ramipril represents a new macrovascular and microvascular preventive therapy for people with diabetes.
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PMID:Diabetes and the HOPE study: implications for macrovascular and microvascular disease. 1171 57

Clinical data have established microalbuminuria/proteinuria as an independent risk factor for the development and progression of renal disease in patients with either diabetes or essential hypertension. Decreased kidney function is associated with increased cardiovascular risk, even at modest reductions in estimated creatinine clearance (to approximately 60 mL/min/1.73 m(2)) or modest elevations in serum creatinine (>1.4 mg/dL). Treatment with angiotensin-converting enzyme inhibitors has been shown in clinical trials to delay or stabilize the rate of progression of renal disease. Reduction in cardiovascular events, such as stroke and myocardial infarction, also has been shown in these high-risk individuals. These effects are dependent and independent of blood pressure control, suggesting a nonhemodynamic effect in blockade of the renin-angiotensin system. In conjunction with other therapeutic interventions, such as dietary modification and control of serum lipids, it appears that for at least a subgroup of patients it is possible to delay or prevent progression of kidney failure. There frequently is a clustering of risk factors in these individuals, including insulin resistance, salt sensitivity, hypertension, and dyslipidemia. The mechanism of the relationship between albuminuria and cardiovascular disease is unclear but may be related to endothelial cell dysfunction. Nonetheless, the presence of microalbuminuria/proteinuria as a marker for cardiovascular disease has important implications for the identification and treatment of individuals at risk.
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PMID:Metabolic pathogenesis of cardiorenal disease. 1172 77

Microalbuminuria is more prevalent in patients with risk factors for cardiovascular diseases and reflects the widespread vascular damage predisposing to atherosclerosis. It is also found in acute clinical conditions, e.g. myocardial infarction, pancreatitis and stroke, and predicts poor outcome. The mechanism leading to increased albuminuria in these conditions is unknown, therefore we designed the study to investigate the relationship between increased urinary albumin excretion in acute stroke and biochemical markers of stress and inflammatory reaction as well as markers of endothelial damage. Sixty patients with first-time ischemic stroke, admitted within 24 hours to the stroke unit took part in the study. We excluded patients with diabetes, infection, nephropathy and abnormal urinalysis. Neurological deficit was assessed on admission and after 24 hours by Scandinavian Stroke Scale. Daily urinary albumin excretion on Day 2 was measured using the immunonephelometric method. The serum cortisol concentration was measured on Day 1 at 6.00 AM, 10.00 AM, 6.00 PM and 10.00 PM. Daily urinary excretion of epinephrine and norepinephrine was measured on Day 1 and on Day 3. We assessed also hematocrit, ESR, serum glucose and fibrinogen, leukocytosis, thrombocytosis and von Willebrand factor activity. Microalbuminuria was found in 46.7% of patients. There was no difference between patients with micro-albuminuria and those without it regarding sex, age and the prevalence of risk factors for stroke. Patients with micro-albuminuria had greater urinary excretion of epinephrine on Day 1. We did not find any differences regarding von Willebrand factor activity, serum cortisol concentration or other assessed variables. In logistic regression analysis the urinary excretion of epinephrine on Day 1 was the only independent variable predicting the occurrence of microalbuminuria in patients with acute ischemic stroke.
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PMID:[Mechanisms determining the occurrence of microalbuminuria in patients with acute ischemic stroke]. 1195 14

The Heart Outcomes Prevention Evaluation (HOPE) study was designed to test the hypotheses that two preventive intervention strategies, namely angiotensin-converting enzyme (ACE) inhibition or vitamin E, would improve morbidity and mortality in patients at high risk of cardiovascular events compared with placebo. This review addresses the ACE inhibitor (ACE-I) (ramipril) arm of the study, both on the trial population as a whole, and on the large diabetic subgroup. Patients were included in the study who were considered to be at high risk of future fatal or non-fatal cardiovascular events, by virtue of their age (>55 years), existing or previous cardiovascular disease, or diabetes. Diabetics had at least one other risk factor, either known vascular disease or other factors such as cigarette smoking, high cholesterol or hypertension. Ramipril or placebo was added to concomitant medication, which included, in a substantial proportion of patients, antihypertensive drugs (excluding ACE-I), lipid-lowering agents or aspirin. As a result, despite a history of hypertension in nearly 50% of patients, blood pressure (BP) at baseline was normal and the reduction in BP attributable to ramipril modest (a fall of 3-4 mmHg systolic BP and 1-2 mmHg diastolic). The trial was stopped early on the advice of the Data Monitoring Committee because of convincing evidence of the benefit of ramipril treatment on the combined primary endpoint of cardiovascular death, non-fatal myocardial infarct (MI) and non-fatal stroke (14% vs. 17.8% on ramipril and placebo, respectively; relative risk reduction 22%, p<0.001). This comprised a risk reduction of 32% for stroke, 20% for MI, 26% for cardiovascular death and 16% for all-cause mortality, as well as a reduction in the risk of several other endpoints including heart failure and revascularisation procedures. The results among the 3577 diabetic subjects were even more striking, with a reduction of 25% in the combined primary endpoint. This reduction in the combined endpoint and in particular the reduction in MI far exceeded that which would be expected from the modest fall in BP. Furthermore, a multiple regression analysis of the diabetic subgroup showed similar relative risk reductions even after allowing for the effects of the fall in BP. Possible explanations for the non BP-mediated benefits of ramipril include reduction of angiotensin II-induced intimal and vascular smooth muscle proliferation and possible plaque stabilisation. The HOPE study results show that it is both safe and beneficial to lower BP that is already within the 'normal' range, particularly in patients with known vascular risk factors. This should greatly extend the use of ACE-I to a wider group of patients - not only those with left ventricular dysfunction, hypertension or diabetic microalbuminuria, but to the sort of high-risk patients who are currently given prophylactic treatment with aspirin.
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PMID:The HOPE Study (Heart Outcomes Prevention Evaluation). 1196 89

Diabetes mellitus (DM) is strongly associated with cardiomyopathy and hypertension. This study focuses on early hemodynamic impairment and DM exposure time amplified by atherosclerosis before the onset of associated cardiomyopathy and hypertension in central Africans. Prospectively, demographic, hemodynamic, lipid, anthropometric, and urinary data of 48 atheromatous diabetics, 39 uncomplicated diabetics, and 27 normal subjects before incidence of cardiomyopathy, hypertension, stroke, and peripheral vascular disease (PVD) were analysed. Age, waist-hip ratio (WHR), DM duration, blood pressures (BPs), pulse pressure (PP), mean arterial pressure (MAP), lipidic profile, and microalbuminuria were more elevated in atheromatous diabetics than in uncomplicated diabetes and normal subjects. PP, MAP, BP of atheromatous diabetics were significantly (P<.01) correlated with age, DM duration, and microalbuminuria, but stroke volume was negatively (P<.001) correlated with diastolic blood pressure (DBP) and microalbuminuria. The evolution of atheromatous diabetes was characterized by the onset of the highest rates of hypertension (86.2%), cardiomyopathy and congestive failure (69%), stroke (46%), and PVD (42%). Atheromatous diabetes of central Africans is associated with early and age-induced significant changes of PP, BP, the highest rates of hypertension, cardiomyopathy, stroke, and PVD. Impaired left ventricular function, as stroke volume decreases with increasing DBP, C-peptide, and microalbuminuria, precedes cardiomyopathy and congestive failure in African diabetics.
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PMID:The role of early hemodynamic impairment and disease duration on diabetic cardiomyopathy and hypertension in central Africans with atherosclerosis. 1203 97

Microalbuminuria is a frequent finding in several acute clinical conditions and predicts poor outcome; its role in acute ischemic stroke, however, is unknown. This study was designed to investigate the prevalence and predictive power of microalbuminuria in acute stroke patients and to establish the relationship between microalbuminuria and the patients' clinical status. We studied 60 patients admitted within 24 h of their first ischemic stroke, 50 patients with a history of ischemic stroke, and 30 control subjects without known cerebrovascular diseases. Neurological deficit was assessed by the Scandinavian Stroke Scale (SSS) on admission and on days 1, 7, 14, and 30. Urinary albumin excretion was measured using immunonephelometric method, with 24-hour collections performed on day 2. Outcome was assessed by 30-day, 90-day and 1-year mortality. Microalbuminuria was found in 46.7% of patients with acute stroke, 16% of subjects with a history of stroke, and 16.7% of controls. On admission, acute stroke patients with microalbuminuria had more severe neurological deficit (median of SSS score on admission was 28 vs. 40, and on day 1, 22 vs. 39, both p < 0.05; Mann-Whitney U test) and more often had a decreased level of consciousness (32 vs. 10%, p < 0.05; Fisher exact test). Mortality was higher in the group of patients with microalbuminuria in acute stroke (21 vs. 3% after 30 days, 39 vs. 6% after 90 days and 50 vs. 9% after 1 year, p < 0.05 for all differences; Fisher exact test). In logistic regression analysis, microalbuminuria was found to be an independent predictor of 1-year mortality after ischemic stroke (OR = 6.0; p = 0.022; 95% CI = 1.3-27.7).
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PMID:Microalbuminuria in nondiabetic patients with acute ischemic stroke: prevalence, clinical correlates, and prognostic significance. 1209 46

The Heart Outcomes Prevention Evaluation (HOPE) study, an international randomized trial, was designed to evaluate the effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril and vitamin E in patients at high risk for cardiovascular events. The study did not detect any cardiovascular benefit or harm using vitamin E. Results for the vitamin E arm are not discussed here. Of 9541 patients, 3577 with diabetes received either ramipril (10 mg) or placebo. Among these patients, ramipril use was associated with a significant 25% reduction in risk for the composite endpoint of myocardial infarction (MI), stroke, or cardiovascular death after a median follow-up period of 4.5 years. This benefit was independent of any blood pressure-lowering effect. The Microalbuminuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO-HOPE) substudy in this patient population showed that ramipril treatment was associated with a decreased risk of development of overt nephropathy. Use of a composite measure of microvascular complications also suggested a protective effect of ramipril treatment. An interesting finding in the HOPE study is that ramipril treatment was associated with a significant 34% reduction in new diagnoses of diabetes. The possibility that ACE inhibitor treatment with ramipril may prevent new diabetes in non-diabetic patients at high risk of the disease is to be examined prospectively in the Diabetes Reduction Assessment with ramipril and rosiglitazone (DREAM) trial.
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PMID:Reduction of cardiovascular events and microvascular complications in diabetes with ACE inhibitor treatment: HOPE and MICRO-HOPE. 1232 91

The Multi-Ethnic Study of Atherosclerosis was initiated in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD) in a population-based sample of 6,500 men and women aged 45-84 years. The cohort will be selected from six US field centers. Approximately 38% of the cohort will be White, 28% African-American, 23% Hispanic, and 11% Asian (of Chinese descent). Baseline measurements will include measurement of coronary calcium using computed tomography; measurement of ventricular mass and function using cardiac magnetic resonance imaging; measurement of flow-mediated brachial artery endothelial vasodilation, carotid intimal-medial wall thickness, and distensibility of the carotid arteries using ultrasonography; measurement of peripheral vascular disease using ankle and brachial blood pressures; electrocardiography; and assessments of microalbuminuria, standard CVD risk factors, sociodemographic factors, life habits, and psychosocial factors. Blood samples will be assayed for putative biochemical risk factors and stored for use in nested case-control studies. DNA will be extracted and lymphocytes will be immortalized for genetic studies. Measurement of selected subclinical disease indicators and risk factors will be repeated for the study of progression over 7 years. Participants will be followed through 2008 for identification and characterization of CVD events, including acute myocardial infarction and other coronary heart disease, stroke, peripheral vascular disease, and congestive heart failure; therapeutic interventions for CVD; and mortality.
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PMID:Multi-Ethnic Study of Atherosclerosis: objectives and design. 1239 6

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