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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac allograft vasculopathy (CAV) remains a troublesome long-term complication of heart transplantation. It is manifested by a unique and unusually accelerated form of coronary disease affecting both intramural and epicardial coronary arteries and veins.CAV is characterized by vascular injury induced by a variety of noxious stimuli, including the immune system response to the allograft, ischemia-reperfusion injury, viral infection, immunosuppressive drugs, and classic risk factors such as hyperlipidemia, insulin resistance, and hypertension. The obstructive vascular lesions are thought to progress through repetitive endothelial injury followed by repair response. The role of major histocompatibility complex donor-recipient differences in the pathogenesis of CAV has not yet been completely elucidated. Intracoronary ultrasound studies reveal a dual morphology with donor-transmitted or de novo focal, noncircumferential plaques in proximal segments and/or a diffuse, concentric pattern observed in distal segments. A lack of correlation between microvascular and epicardial vessel disease suggests discordant manifestations and progression of CAV. Apoptosis and loss of functional vascular remodeling have to be considered as important mediators of clinically relevant CAV. Strategies for blocking T-cell costimulation and expression of adhesion molecules may help prevent chronic rejection in clinical transplantation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and antiproliferative drugs may slow progression of CAV by various effects. Methods to augment endogenous nitric oxide bioavailability as well as newer immunosuppressive regimens may be protective. Balloon angioplasty has a limited role in the treatment of focal lesions. Experiences with coronary stenting, coronary artery bypass grafting, and transmyocardial laser revascularization are limited. Retransplantation has a worse outcome than initial transplantation.
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PMID:Cardiac allograft vasculopathy: a review. 932

The generation of nitric oxide by the vascular endothelium maintains a continuous vasodilator tone that is essential for the regulation of blood flow and blood pressure. Nitric oxide also contributes to the control of platelet aggregation and has important antiatherogenic effects. These properties are mediated by the action of constitutive nitric oxide synthase and subsequent activation by nitric oxide of soluble guanylate cyclase. Impaired release of nitric oxide occurs in most animal and human models of hypertension, contributing to the increased peripheral resistance and most likely to the development of cardiovascular complications. Antihypertensive medications (angiotensin-converting enzyme [ACE] inhibitors and calcium channel blockers) appear to prevent the impairment of nitric oxide-mediated vasodilation in experimental hypertension, though in humans the data are not as clear. Reduced nitric oxide release appears therefore to be a consequence rather than a cause of high blood pressure, and the reduction in blood pressure per se is most important. In hyperlipidaemia, endothelium-dependent relaxations are reduced probably due to the inhibitory action of oxidized low-density lipoproteins on endothelium-dependent relaxations. Lipid-lowering strategies and, more recently, ACE inhibition have been demonstrated to improve nitric oxide dependent coronary vasodilation in hypercholesterolaemic patients with and without atheromatous coronary disease. Nitric oxide dependent vasodilation is also impaired in insulin- and non-insulin-dependent diabetes as well as in healthy aging. Endothelial dysfunction may be improved in non-insulin-dependent diabetes by administration of the antioxidants, supporting the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes.
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PMID:Impairment and restoration of nitric oxide-dependent vasodilation in cardiovascular disease. 948 1

In order to investigate the effect of fenofibrate on microcirculation, 16 patients (5 female, 11 male, age 58 +/- 8 years) were studied with the aid of nailfold capillaroscopy before and after treatment with 200 mg fenofibrate per day over six weeks. Fenofibrate resulted in a significant decrease in triglycerides, total and LDL-cholesterol and apolipoprotein B and an increase in apolipoprotein A. As a parameter of an improved microcirculation the time to peak capillary blood cell velocity during postreactive hyperemia (occlusion of the lower arm for 2 minutes, 200 mmHg) decreased markedly from 45 +/- 5 to 16 +/- 3 s, p < 0.0001). Fibrinogen levels were significantly decreased (p < 0.04) in contrast to other parameters with a possible impact on microvascular perfusion (hemoglobin, hematocrit, mean platelet volume, total protein) and to blood pressure and heart rate. These findings suggest that fenofibrate treatment improves microcirculation in patients with hyperlipidemia. This beneficial effect of fenofibrate may arise from two leading mechanisms. One of these might be the decrease in fibrinogen levels reducing plasma viscosity, the other mechanism might be an indirect effect on functional abnormalities of the vascular endothelium arising from hyperlipdidemia. By lowering plasma lipids fenofibrate is likely to restore the impaired formation or efficacy of the endothelium derived relaxing factor (nitric oxide, NO).
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PMID:Fenofibrate improves microcirculation in patients with hyperlipidemia. 951 68

1. There is accumulating evidence for a range of abnormalities in the nitric oxide (NO) signalling cascade in human cardiovascular disorders. 2. In the present review we assess the literature detailing such evidence in early (hyperlipidaemia) and end-stage (heart failure) disease, with emphasis on the mechanisms by which the disturbances are thought to occur. 3. Strategies for the correction of disturbed NO signalling in these states are reviewed and include both prescribed pharmacological interventions, such as lipid-lowering therapy and novel uses of angiotensin-converting enzyme inhibitors, as well as non-pharmacological interventions, such as exercise and dietary supplementation with L-arginine and n-3 polyunsaturated fatty acids. 4. In addition to a decreased production/function of NO, the possible detrimental effects of a chronic elevation in NO production in patients with liver cirrhosis, together with a novel use of antibiotics to correct this perturbation, is outlined.
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PMID:Restoration of nitric oxide function in human hyperlipidaemia, congestive heart failure and liver cirrhosis. 975 Sep 51

Noninsulin-dependent diabetes mellitus (NIDDM), a major health care problem in the Western world, is a disease typified by a relative deficiency of insulin, leading to vast derangements in glucose and lipid homeostasis with disastrous vascular complications. Despite immense research efforts aimed at a clear understanding of the etiology of this complex disease, the molecular mechanisms causing the disorder still remain elusive. This article reviews extant data from recent publications implicating novel signal transduction pathways as important regulators of the insulin stimulus-secretion coupling in the pancreatic beta-cell. The significance of nitric oxide and serine/threonine protein phosphatases, and their inactivation by insulin secretagogues, glucose metabolites, ATP, GTP, glutamate, and inositol hexaphosphate in this arena is scrutinized. Additionally, also presented is the growing concept that an important signal for insulin secretion may reside in the inextricable interplay between glucose and lipid metabolism, specifically the generation of malonyl-CoA, which inhibits carnitine palmitoyltransferase 1 with the attendant accumulation of long-chain acyl CoA esters. Moreover, attention is directed towards novel intracellular actions of hypoglycemic sulfonylureas in the beta-cell. Finally, the importance of "lipotoxicity" and aberrations in glucose uptake and metabolism in beta-cell dysfunction is given consideration. Future research efforts should aim at further characterization of effects of second messengers on protein phosphorylation elements in beta-cells. Additionally, long-term regulation by glucose and the diabetic state (e.g., fatty acids and ketones) on beta-cell protein phosphatases, pyruvate dehydrogenase, and carnitine palmitoyltransferase 1 needs to be explored in greater depth. Clearly, the detrimental impact of diabetic hyperlipidemia on beta-cell function has been a relatively neglected area, but futu re pharmacological approaches directed at preventing lipotoxicity may prove beneficial in the treatment of diabetes.
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PMID:Aspects of novel sites of regulation of the insulin stimulus-secretion coupling in normal and diabetic pancreatic islets. 979 25

Metabolism in man is regulated by complex hormonal signals and substrate interactions, and for many years the clinical focus has centred on the metabolic and hormonal picture after an overnight fast. More recently, the postprandial state, i.e. 'the period that comprises and follows a meal', has received more attention. The oral glucose tolerance test (OGTT), although highly non-physiological, has been used largely as a model of the postprandial state. Epidemiological studies have shown that, when 'impaired', oral glucose tolerance is associated with an increased risk of cardiovascular disease. Postprandial hyperlipidaemia has been investigated more recently in epidemiological, mechanistical and intervention studies, most of which indicate that high postprandial triglyceride levels, and particularly postprandial rich triglyceride remnants, constitute an increased risk for cardiovascular disease. Recent studies have shown that excessive postprandial glucose excursions are accompanied by oxidative stress and, less well known, activation of blood coagulation (increase in circulating D-dimers and prothrombin fragments). The mechanisms through which increased postprandial glucose levels and lipid concentrations may damage endothelial cells on blood vessel walls appear to be complex. These mechanisms include the activation of protein kinase C, increased expression of adhesion molecules, increased adhesion and uptake of leucocytes, increased production of proliferative substances such as endothelin, increased proliferation of endothelial cells, increased synthesis of collagen IV and fibronectin, and decreased production of nitric oxide (NO). In conclusion, the 'postprandial state' cumulatively covers almost half of the nycthemeral period, and its physiology involves numerous finely regulated motor, secretory, hormonal and metabolic events. Epidemiological and mechanistical studies have suggested that perturbations of the postprandial state are involved in cardiovascular disease. Correcting the abnormalities of the postprandial state must form part of the strategy for the prevention and management of cardiovascular diseases, particularly those that are associated with diabetes mellitus.
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PMID:The postprandial state and risk of cardiovascular disease. 986 96

Hyperlipidemia has been associated with an increase in the incidence of atherosclerosis. The oxidation of low density lipoprotein (LDL) plays an important role in the initiation and progression of atherosclerosis, one of its effects being the inhibition of endothelium dependent relaxation (EDR). The elevated level of lysophosphatidylcholine (LPC) in oxidatively modified LDL has been shown to be a biochemical factor responsible for the impairment of EDR in vascular ring preparations. Several endothelium-derived modulators are thought to control vascular responsiveness. The present work examined whether acetylcholine (ACh)-induced EDR in rat aorta (pre-contracted with phenylephrine, PE) involved both endothelium-derived nitric oxide (EDNO) and endothelium-dependent hyperpolarizing factor (EDHF) and whether LPC inhibited either of these selectively. Indomethacin (10(-5) M), had no significant effect on EDR, indicating that products of cyclooxygenase, including prostacyclin, are not involved. Treatment with either N(W)-nitro-L-arginine methyl ester (L-NAME, 6.8 microM) to inhibit the production of EDNO or with elevated K+ (15 mM), to block the hyperpolarizing effect of EDHF impaired EDR considerably (each of these shifting the inhibitory dose-response relationship to ACh by almost one log unit); in muscles treated with both of these agents EDR was completely inhibited. In each of L-NAME- and K-treated muscles, the addition of LPC (20 microM) further impaired EDR. LPC did not independently raise the tone of resting- or PE-contracted aorta. We conclude that the inhibition of EDR of rat aorta by LPC involves the actions of both EDNO and EDHF.
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PMID:Inhibition of endothelium-dependent vascular relaxation by lysophosphatidylcholine: impact of lysophosphatidylcholine on mechanisms involving endothelium-derived nitric oxide and endothelium derived hyperpolarizing factor. 1048 17

Coronary hypersensitivity to serotonin promotes platelet aggregation and, therefore, the progression of the atherosclerotic process. This abnormality occurs in the early stages of coronary atherosclerosis when the responses to bradykinin are still preserved. To determine whether such changes also occur early after cardiac transplantation, intracoronary injections of bradykinin and serotonin were performed in 7 control patients, in 19 patients with dyslipidemia, and in 15 cardiac transplant recipients (1 year after operation). Coronary angiography was normal in the 3 groups. In the segments where serotonin effects were the most pronounced, the diameter changes were measured by quantitative angiography. Bradykinin (60, 200, and 600 ng) increased in the same way as the coronary diameters in the 3 groups; in contrast, serotonin elicited vasodilation only in the control group (7+/-3%, percentage of baseline) and vasoconstriction in the hyperlipidemic group (-9+/-2%) and in transplant recipients (-15+/-3%). After intracoronary infusion of L-arginine (40 mg/min for 14 minutes), serotonin-induced constriction was attenuated in the hyperlipidemic group but not in transplant recipients. Thus, the response to bradykinin is preserved in the early stages of graft vasculopathy. However, in contrast to patients with hyperlipidemia, the absence of an L-arginine effect on the responses to serotonin suggests the involvement of mechanisms other than a decrease in endothelium-derived nitric oxide availability. Immune processes promoting the release of endothelium-derived contracting factors such as endothelin and/or superoxide anion may play a role.
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PMID:Absence of L-arginine effect on coronary hypersensitivity to serotonin in cardiac transplant recipients. 1056 27

Acute myocardial ischemia, which results from a significant imbalance between myocardial oxygen demands and myocardial oxygen supply, occurs in as many as six million persons with atherosclerotic coronary artery disease in the United States. Accordingly, a clear understanding of the physiologic and pathophysiologic factors that influence coronary artery blood flow is important to the clinician and provides the basis for the judicious use of medications for the treatment of patients with atherosclerotic coronary artery disease. This review discusses the endothelial, metabolic, myogenic, and neurohumoral mechanisms of coronary blood flow regulation and the interaction of the different mechanisms in the regulation of coronary blood flow. The importance of nitric oxide in coronary blood flow regulation is emphasized. We also discuss the common clinical problems of hyperlipidemia and coronary atherosclerosis, coronary artery spasm, and systemic arterial hypertension that result in coronary artery endothelial dysfunction, the impaired production and increased inactivation of nitric oxide, and impairment in coronary blood flow regulation. This information is important to clinicians because more than forty million people in the United States have atherosclerotic or hypertensive heart disease and therefore are at risk for significant myocardial complications due to impairment of coronary blood flow regulation.
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PMID:Coronary artery blood flow: physiologic and pathophysiologic regulation. 1062 79

Vitamin E, the major lipid soluble plasma antioxidant, has been reported to be reduced in patients with coronary atherosclerosis. We have measured the levels of plasma alpha-tocopherol (the predominant form of plasma vitamin E) in 128 patients with different reported degrees of angina. Patients with mild to moderate angina (grades I or II (CSS score)) (n = 64), and patients with severe angina (grades III and IV) (n = 64) were recruited from Cardiology Clinics in the U. K. Healthy controls (n = 33) and patients with hyperlipidaemia (n = 28) were also recruited. The groups of patients with angina did not differ significantly for mean age (58 +/- 1.0 years vs. 59 +/- 1.0 years, respectively); sex distribution (the M:F ratio was 48 : 16 and 46 : 18 for the respective groups); or prevalence of smoking (12% vs. 9%), or hypertension (19% vs. 33%). Total cholesterol levels were higher in the group with severe angina (5.9 +/- 0.16 mmol/l vs. 5.3 +/- 0.13 mmol/l P < 0.05). Absolute levels of plasma vitamin E were not significantly different between the angina subgroups (12.9 +/- 0.40 mg/l for the mild-moderate angina group vs. 12.5 +/- 0.51 mg/l for the severely affected group), but were positively correlated with plasma cholesterol concentrations in each case (P < 0.001). The ratio between plasma vitamin E: total cholesterol was significantly lower in the patients with severe angina (mean 2.20 +/- 0.09 mg/mmol) vs. a mean value of 2.46 +/- 0. 08 mg/m mol in the mildly affected group (P < 0.05). The plasma vitamin E: total cholesterol ratio in patients with severe angina was also significantly lower (P < 0.05) compared to either healthy controls with comparable total cholesterol levels (n = 33), or hypercholesterolaemic subjects (n = 28) without symptomatic coronary disease (mean ratios were 2.69 +/- 0.40 mg/mmol and 2.74 +/- 0.68 mg/mmol, respectively). Vitamin E has previously been demonstrated to protect endothelial function in the presence of hypercholesterolaemia, possibly by preserving nitric oxide bio-activity. It also inhibits LDL oxidation. Hence, a high plasma vitamin E: total cholesterol ratio may be associated with an amelioration of angina.
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PMID:Cholesterol standardized plasma vitamin E levels are reduced in patients with severe angina pectoris. 1071 65


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