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The recent development of highly active antiretroviral therapy (HAART) has drastically improved the life expectancy of AIDS patients, by reducing infection-related mortality. However, the prolongation of the lives of HIV-1-infected patients and/or the long-term use of novel, potent antiviral agents have generated a score of new problems and complications. Among them is the AIDS-related insulin resistance and lipodystrophy syndrome, which is observed in 30-80% of AIDS patients who are well controlled by HAART. This syndrome is associated with severe metabolic disturbances, such as carbohydrate intolerance/diabetes mellitus and dyslipidemia, which cause atherosclerotic cardiovascular disease. The etiology of this syndrome appears to be multi-factorial; other than the anti-viral drugs, hypercytokinemia and the HIV-1 infection itself, including the virally encoded molecules Vpr and Tat, could contribute to the development of these pathologic changes or increase the vulnerability of patients to the adverse effect of the therapeutic compounds. In this article, we review our current understanding of the pathogenesis and therapeutic approach of this newly emerging AIDS-associated metabolic syndrome.
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PMID:AIDS-related insulin resistance and lipodystrophy syndrome. 1276 83

Antibodies to heat shock protein (hsp) are strongly associated with atherosclerotic cardiovascular disease in the non-diabetic population as well as in patients with type 2 diabetes mellitus. In type 1 diabetes increased antibody titers to hsp were found to be a symptom of the autoimmune disease leading to beta-cell damage. We asked whether hsp antibody titers are related to metabolic control and late complications in type 1 diabetic patients. Serum neopterin, also an indicator of chronic inflammation, was also evaluated. The hsp65 antibody titer was determined in 138 patients with type 1 diabetes, 47 women and 91 men, aged 35.5 +/- 12 years with a mean diabetes duration of 16.6 +/- 10.5 years. A history of diabetic late complications and cardiovascular disease was taken. A fundoscopy and a neurological examination were performed, nephropathy was assessed by measurement of the urinary albumin excretion rate. For the measurement of the hsp antibody titer an enzyme-linked immunosorbent assay (ELISA) was applied, for neopterin a radio-immuno assay (RIA) was used. The hsp65 antibody titer was found to be positively related to the patients' age (r = 0.237; p < 0.035). Patients with retinopathy revealed significantly higher hsp65 antibody titers (307.2 +/- 38.6) than those without retinopathy (150.0 +/- 18.5;p < 0.003). No correlation was found between hsp antibody titer and metabolic control. Serum neopterin levels revealed a trend towards a positive relationship with diabetes duration (r = 0.205; p < 0.0539) and a significant correlation with serum cholesterol levels (r = 0.436; p < 0.001), but not with HbA1 c values. Our data add further information to the role of inflammatory markers in the development of diabetic microangiopathy.
Exp Clin Endocrinol Diabetes 2003 May
PMID:Antibodies to heat-shock protein 65 and neopterin levels in patients with type 1 diabetes mellitus. 1278 85

The Adult Treatment Panel III report reemphasized the importance of reducing elevated levels of low-density lipoprotein cholesterol as the most efficacious treatment target to reducing coronary heart disease morbidity and mortality, which is the leading cause of disability and death in the United States. Although the etiologic role of elevated levels of low-density lipoprotein cholesterol in atherosclerosis is well established, treatment with statins still leaves a large proportion of patients vulnerable to cardiovascular events. The role of high-density lipoprotein cholesterol in atherosclerosis is increasingly recognized because of its strong inverse association with coronary heart disease in epidemiologic studies, and the observed high prevalence of low high-density lipoprotein cholesterol that occurs in populations with coronary heart disease, with or without elevated low-density lipoprotein cholesterol, especially among patients with diabetes and metabolic syndrome. This report highlights some of the therapeutic implications of the Adult Treatment Panel III report and various therapeutic approaches to both lowering elevated low-density lipoprotein cholesterol and triglycerides as well as increasing low levels of high-density lipoprotein cholesterol to optimize clinical event rate reduction in patients with coronary heart disease. Among available dyslipidemic therapies, although statins remain the mainstay for lowering low-density lipoprotein cholesterol and clinical events, niacin is currently the most effective agent for increasing low high-density lipoprotein cholesterol levels. The importance of combination dyslipidemic therapy, such as a statin plus niacin, in treating more optimally the entire lipid profile has been demonstrated not only to decrease progression and increase regression of atherosclerotic lesions, but to enhance event-free survival compared with statin monotherapy. Combination dyslipidemic therapy affords the most efficacious approach to controlling the multiple lipid abnormalities associated with atherosclerotic cardiovascular disease and optimizing cardiovascular event rate reduction in patients with coronary heart disease.
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PMID:Therapeutic implications of recent ATP III guidelines and the important role of combination therapy in total dyslipidemia management. 1285 26

Atherosclerotic cardiovascular disease is the leading cause of premature death in patients with diabetes. Atherosclerosis is a chronic immune-mediated disease, the initiation, progression, and destabilization of which is driven and regulated by inflammatory cells. One critical event in the initiation of this vascular inflammatory disease is the adhesion of leukocytes to the activated endothelium and their migration into the vessel wall. These processes are mediated by the upregulation of adhesion molecules on endothelial cells (ECs) and an increased expression in the vascular wall of chemotactic factors to leukocytes. Monocyte binding to ECs is increased in diabetes. One major determinant of this alteration could be oxidative stress. Given the free-radical scavenging activity of gliclazide, we determined the ex vivo and in vitro effects of this drug on human monocyte binding to ECs and the molecular mechanisms involved in this effect. Our results demonstrate that short-term administration of gliclazide to patients with type 2 diabetes normalizes the levels of plasma lipid peroxides and monocyte adhesion in these subjects. Gliclazide (10 microg/mL) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to ECs in vitro. The inhibitory effect of this drug on AGE-induced monocyte adhesion involves a reduction in EC adhesion molecule expression and inhibition of nuclear factor kappaB (NF-kappaB) activation. In addition, gliclazide inhibits oxLDL-induced monocyte adhesion to cultured human aortic vascular smooth muscle cells (HASMCs) in vitro and reduces the production of monocyte chemotactic protein-1 (MCP-1) by these cells. Taken collectively, these results show that gliclazide, at concentrations in the therapeutic range, inhibits ex vivo and in vitro monocyte adhesiveness to vascular cells. By doing so, this drug could reduce monocyte recruitment into the vessel wall and thereby contribute to attenuating the sustained inflammatory process that occurs in the atherosclerotic plaque. These findings suggest that treatment of diabetic patients with this drug may prevent or retard the development of vasculopathies associated with diabetes.
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PMID:Benefits of gliclazide in the atherosclerotic process: decrease in monocyte adhesion to endothelial cells. 1293 34

Type 2 diabetes is a disease of insulin deficiency along with insulin resistance, and the natural history is a progressive worsening of insulin secretion over time. The obvious conclusion supported by clinical experience is most patients will eventually need insulin therapy. However, there is often a reluctance on the part of many care providers to prescribe insulin because of fears of weight gain, hypoglycemia, or cardiovascular consequences, or because the patient is unwilling. Another problem is many practitioners are uncertain how to use insulin in type 2 diabetes. This review discusses the benefits of insulin therapy in patients with type 2 diabetes when it is required for optimal glycemia control. It also debunks the fears over unwanted consequences such as severe hypoglycemia and worsening of atherosclerotic cardiovascular disease. Finally, it provides a "hands on" approach on how to start basal insulin therapy and multishot insulin therapy in type 2 diabetes.
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PMID:Insulin therapy for type 2 diabetes. 1297 27

The ATP III report represents an important advance from previous ATP reports dating back to the late 1980s. The guidelines are more tightly evidence-based than previous reports, partly because of evolution of the guideline process, requiring clearly delineated links between evidence and recommendations and also because of the robust evidence base published over the last decade. An important change in ATP III is the expansion of the high-risk category to include patients without evident vascular disease, but with a level of risk equivalent to those patients with established CHD. This group termed "coronary heart disease equivalents" now includes patients with diabetes, and those with a 10-year absolute risk of over 20 percent for CHD events. With the ATP III report, the Framingham risk score is formally introduced into the guideline process. The scoring system allows for easy calculation of the absolute risk for an individual of having a "hard" CHD event (myocardial infarction, or CHD death). The report also discusses in detail concepts of lifetime or long-term risk. ATP III has broadened recommendations for lifestyle change termed "therapeutic lifestyle change (TLC)," and eliminated the step 1 and step 2 diet approach. Finally, the report details established approaches to improve adherence and provides patients and clinicians with a set of implementation tools to enhance use of the guidelines and compliance with the guidelines' recommendations. It is hoped that by improved understanding, recognition of a firm evidence base, and education through multiple channels, that adherence with the new ATP III guidelines will improve the care of our population by more effectively targeting lipid factors that lead to the development and progression of atherosclerotic cardiovascular disease.
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PMID:Report of the Adult Treatment Panel III: the 2001 National Cholesterol Education Program guidelines on the detection, evaluation and treatment of elevated cholesterol in adults. 1462 53

Type 2 diabetes is increasing in epidemic proportions worldwide, and is strongly associated with atherosclerotic cardiovascular disease (CVD). Hyperglycaemia increases risk of CVD, but glycaemic control does not substantially reduce CVD risk. There are several potential explanations for this apparent paradox, including the roles of the metabolic syndrome and post-load hyperglycaemia in the association of type 2 diabetes and CVD.
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PMID:Epidemiology of cardiovascular complications in type 2 diabetes mellitus. 1470 69

Our genetic make-up, shaped through millions of years of evolution, determines our nutritional and activity needs. Although the human genome has remained primarily unchanged since the agricultural revolution 10,000 years ago, our diet and lifestyle have become progressively more divergent from those of our ancient ancestors. Accumulating evidence suggests that this mismatch between our modern diet and lifestyle and our Paleolithic genome is playing a substantial role in the ongoing epidemics of obesity, hypertension, diabetes, and atherosclerotic cardiovascular disease. Until 500 generations ago, all humans consumed only wild and unprocessed food foraged and hunted from their environment. These circumstances provided a diet high in lean protein, polyunsaturated fats (especially omega-3 [omega-3] fatty acids), monounsaturated fats, fiber, vitamins, minerals, antioxidants, and other beneficial phytochemicals. Historical and anthropological studies show hunter-gatherers generally to be healthy, fit, and largely free of the degenerative cardiovascular diseases common in modern societies. This review outlines the essence of our hunter-gatherer genetic legacy and suggests practical steps to re-align our modern milieu with our ancient genome in an effort to improve cardiovascular health.
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PMID:Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. 1513 22

Plasma levels of high-density lipoprotein-cholesterol (HDL-C) are a powerful independent cardiovascular risk factor, bearing an inverse relationship with atherosclerotic cardiovascular disease (with risk rising sharply when levels are <1.04 mmol/L). Apart from its protective role in atherosclerosis, HDL-C increases fibrinolysis, is an antioxidant to low density lipoprotein-cholesterol (LDL-C), and decreases platelet aggregability. Up to a third of patients with atherosclerotic cardiovascular disease have 'desirable' plasma levels of total cholesterol but low HDL-C levels. Benefits of treating low plasma HDL-C levels were clearly demonstrated in the Veterans Affairs HDL Intervention Trial (VA-HIT) where gemfibrozil reduced nonfatal infarcts and coronary deaths by 22%. This was achieved by a 6% increase in plasma HDL-C levels, and a 24.5% decrease in plasma levels of triglycerides, without any significant decrease in LDL-C levels. Multivariate analyses revealed the rise in plasma HDL-C levels after treatment, but not decreases in plasma levels of triglycerides or LDL-C, predicted coronary artery disease events. The typical patient under consideration in this article is one with plasma levels of HDL-C <1 mmol/L, LDL-C <3.37 mmol/L [either receiving therapeutic lifestyle changes or or LDL-C-lowering therapy comprising a hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor or bile acid sequestrant] and fasting triglycerides <2.26 mmol/L. We propose this dyslipidemia be classified as Type VI phenotype following the Frederickson and Lees classification. High-risk patients (with >/=2 risk factors for atherosclerotic cardiovascular disease, or 10-year cardiovascular risk >20%), patients with established atherosclerotic cardiovascular disease, or type 2 diabetes mellitus, or metabolic syndrome should receive pharmacotherapy. Plasma HDL-C levels >1.16 mmol/L may be considered optimal and between 1 and 1.16 mmol/L as desirable. Fibric acid derivatives, nicotinic acid, HMG-CoA reductase inhibitors, estrogens, and ethanol (not recommended as therapy) increase plasma HDL-C levels. Nicotinic acid is the most potent agent and recent reports indicate that, in contrast to gemfibrozil, it selectively increases antiatherogenic HDL subfraction, lipoprotein (Lp) AI (without apolipoprotein AII), in patients with low plasma HDL-C levels. An extended-release formulation, administered once daily, has improved the tolerability of nicotinic acid. Recent evidence also indicates that nicotinic acid may effectively correct dyslipidemia in patients with diabetes mellitus without significantly compromising glycemic control. Fibric acid derivatives and estrogen raise plasma HDL-C levels by different mechanisms of action, and these agents may be used with nicotinic acid. Combination therapy (especially HMG-CoA reductase inhibitor and nicotinic acid) should be considered in patients with atherosclerotic cardiovascular disease and low plasma HDL-C levels.
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PMID:Optimal therapy of low levels of high density lipoprotein-cholesterol. 1472 46

Results from clinical trials suggest that antiarrhythmic drugs (AD) can facilitate electrical cardioversion (EC) for persistent atrial fibrillation (AF) (duration >48 hours, no spontaneous termination) by suppression of immediate reinitiation of AF following the procedure. Class IC agents may increase the atrial defibrillation threshold (DFT) by significantly reducing the availability of Na+-channel for depolarization. In contrast, class III agents may decrease the atrial DFT by markedly prolonging atrial refractoriness. Among all AD, ibutilide and amoidarone have been shown to be most effective in enhancing the acute outcome of EC. In patients who are over 65 years of age at high risks of stroke (e.g., atherosclerotic cardiovascular disease, diabetes, hypertension, previous thromboembolism, etc.), the rhythm control strategy offers no survival advantage over the rate control strategy and frequently subjects patients to serious adverse effects of AD therapy. It can not be overemphasized that adequate anticoagulation (INR 2.0-3.0) with warfarin is needed regardless of whichever strategy is chosen unless there are contraindications. On the other hand, in patients who are under 65 years of age without structural heart disease or other risk factors of stroke, rhythm control can be the treatment of choice. Specifically, if a patient has failed EC alone or if the patient has characteristics (e.g., duration of AF >6 months, left atrium >50 mm, etc.) that EC could fail, AD may be given before the procedure to facilitate EC. In the subgroup of patients who are symptomatic with hypertrophic cardiomyopathy and severe diastolic dysfunction requiring maintenance of sinus rhythm to have sufficient ventricular function for optimization of cardiac output, an aggressive approach for rhythm control with amiodarone along with adequate anticoagulation with warfarin should be encouraged.
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PMID:Facilitating electrical cardioversion of persistant atrial fibrillation by antiarrhythmic drugs: update on clinical trial results. 1473 33


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