Cyrus Desouza

Drugs affecting homocysteine metabolism: impact on cardiovascular risk.

Elevated total plasma homocysteine has been established as an independent risk factor for thrombosis and cardiovascular disease. A strong relationship between plasma homocysteine levels and mortality has been reported in patients with angiographically confirmed coronary artery disease.Homocysteine is a thiol containing amino acid. It can be metabolised by different pathways, requiring various enzymes such as cystathionine β-synthase and methylenetetrahydrofolate reductase. These reactions also require several co-factors such as vitamin B6 and folate. Medications may interfere with these pathways leading to an alteration of plasma homocysteine levels.Several drugs have been shown to effect homocysteine levels. Some drugs frequently used in patients at risk of cardiovascular disease, such as the fibric acid derivatives used in certain dyslipidaemias and metformin in type 2 (non-insulin-dependent) diabetes mellitus, also raise plasma homocysteine levels. This elevation poses a theoretical risk of negating some of the benefits of these drugs.The mechanisms by which drugs alter plasma homocysteine levels vary. Drugs such as cholestyramine and metformin interfere with vitamin absorption from the gut. Interference with folate and homocysteine metabolism by methotrexate, nicotinic acid (niacin) and fibric acid derivatives, may lead to increased plasma homocysteine levels.Treatment with folate or vitamins B6 and B12 lowers plasma homocysteine levels effectively and is relatively inexpensive. Although it still remains to be demonstrated that lowering plasma homocysteine levels reduces cardiovascular morbidity, surrogate markers for cardiovascular disease have been shown to improve with treatment of hyperhomocystenaemia. Would drugs like metformin, fibric acid derivatives and nicotinic acid be more effective in lowering cardiovascular morbidity and mortality, if the accompanying hyperhomocysteinaemia is treated? The purpose of this review is to highlight the importance of homocysteine as a risk factor, and examine the role and implications of drug induced modulation of homocysteine metabolism.

Role of Inflammation and Insulin Resistance in Endothelial Progenitor Cell Dysfunction

OBJECTIVE Endothelial progenitor cells (EPCs) are decreased in number and function in type 2 diabetes. Mechanisms by which this dysfunction occurs are largely unknown. We tested the hypothesis that a chronic inflammatory environment leads to insulin signaling defects in EPCs and thereby reduces their survival. Modifying EPCs by a knockdown of nuclear factor-κB (NF-κB) can reverse the insulin signaling defects, improve EPC survival, and decrease neointimal hyperplasia in Zucker fatty rats postangioplasty. RESEARCH DESIGN AND METHODS EPCs from Zucker fatty insulin-resistant rats were cultured and exposed to tumor necrosis factor-α (TNF-α). Insulin signaling defects and apoptosis were measured in the presence and absence of an NF-κB inhibitor, BAY11. Then, EPCs were modified by a knockdown of NF-κB (RelA) and exposed to TNF-α. For in vivo experiments, Zucker fatty rats were given modified EPCs post–carotid angioplasty. Tracking of EPCs was done at various time points, and neointimal hyperplasia was measured 3 weeks later. RESULTS Insulin signaling as measured by the phosphorylated–to–total AKT ratio was reduced by 56% in EPCs exposed to TNF-α. Apoptosis was increased by 71%. These defects were reversed by pretreatment with an NF-κB inhibitor, BAY11. Modified EPCs exposed to TNF-α showed a lesser reduction (RelA 20%) in insulin-stimulated AKT phosphorylation versus a 55% reduction in unmodified EPCs. Apoptosis was 41% decreased for RelA knockdown EPCs. Noeintimal hyperplasia postangioplasty was significantly less in rats receiving modified EPCs than in controls (intima-to-media ratio 0.58 vs. 1.62). CONCLUSIONS In conclusion, we have shown that insulin signaling and EPC survival is impaired in Zucker fatty insulin resistant rats. For the first time, we have shown that this defect can be significantly ameliorated by a knockdown of NF-κB and that these EPCs given to Zucker fatty rats decrease neointimal hyperplasia post–carotid angioplasty.

Therapeutic targets to reduce cardiovascular disease in type 2 diabetes

The potential cardiovascular risks that are associated with drugs for type 2 diabetes have recently raised considerable clinical and regulatory concerns. As some risk factors for cardiovascular disease and type 2 diabetes are related, identifying agents that target shared underlying pathways and processes is an attractive therapeutic strategy. In this article, we review the background to and the implications of recent regulatory guidance on the development of new drugs for diabetes, and discuss the potential cardiovascular effects of selected classes of diabetes drugs that are currently being investigated.

Is weight loss possible in patients treated with thiazolidinediones? Experience with a low-calorie diet

SUMMARY Background: Weight gain is a frequent side-effect of thiazolidinediones, possibly related to fluid retention and stimulation of pre-adipocyte differentiation. Methods: We report our experience with a low-calorie diet (800cal, sodium content 1500 mmol day−1) combined with behavior modification on eight patients treated with thiazolidinediones (six pioglitazone and two rosiglitazone). Results: All patients had reported previous weight gain following treatment with thiazolidinediones. All patients lost weight over 12 weeks in the program with their mean ± SD body weight falling from 270 ± 54 lbs (123 ± 25 kg) to 244 ± 61 lbs (111 ± 28 kg) (p < 0.01). The weight loss observed was no different from that observed in 16 age- and gender-matched patients with type 2 diabetes not treated with thiazolidinediones (from 263 ± 54 lbs (120 ± 25 kg) to 239 ± 52 lbs (109 ± 24 kg); p < 0.01). Glycemic control improved while reducing insulin treatment. Blood pressure control also improved and antihypertensive medications were decreased. The degree and time course of weight loss is no different from that in patients treated with other diabetic therapies and is associated with improved glycemic and blood pressure control. Conclusions: We conclude that a program of caloric restriction and behavior modification is effective in leading to weight loss in patients treated with thiazolidinediones. This effect is reassuring, since thiazolidinediones stimulate adipogenesis.

Effects of the Thiazolidinediones on Cardiovascular Risk Factors

Rosiglitazone and pioglitazone are medications from the thiazolidinedione class of compounds currently available for the treatment of type 2 diabetes mellitus. Traditionally used to enhance insulin sensitivity and decrease plasma insulin levels, added applications have emerged beyond those involving glycemic control. Cardiovascular risk factors associated with insulin resistance such as elevated blood pressure, dyslipidemia, abnormal fibrinolysis, and endothelial and vascular dysfunction have been shown to improve after thiazolidinedione treatment. Therapy with rosiglitazone or pioglitazone has been found to modify vascular reactivity and other processes involved in atherosclerosis. There may be differences between the agents in their effects on plasma lipid characteristics and particle size. These agents serve as excellent adjuncts to oral and insulin therapy for patients with type 2 diabetes mellitus and hold promise for the prevention of cardiovascular disease associated with the insulin resistance syndrome. Clinical trials are in progress to determine whether such therapy will lead to a reduction in cardiovascular events.

Effects of Salsalate Therapy on Recovery From Vascular Injury in Female Zucker Fatty Rats

OBJECTIVE Salsalate is a dimeric form of salicylic acid that has been shown to have anti-inflammatory activity and to reduce glucose levels, insulin resistance, and cytokine expression. However, the effect of salsalate on vascular injury has not been determined. The objective of this study is to investigate the effect of salsalate on vascular injury and repair in a rat model of carotid artery balloon catheter injury. RESEARCH DESIGN AND METHODS Salsalate treatment was started in female Zucker fatty rats (insulin resistant) 1 week before carotid artery balloon catheter injury and continued for 21 days, at which time the animals were killed and studied. RESULTS Treatment with salsalate significantly decreased the intima-to-media ratio and upregulated the expression of aortic endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) (ser 1177), and manganese superoxide dismutase (MnSOD) and reduced serum interleukin (IL)-6 with concomitant downregulation of nuclear factor (NF) κB subunit p65 and vascular endothelial growth factor (VEGF) expression in the balloon-injured carotid artery of female Zucker fatty rats. CONCLUSIONS The present study shows that salsalate treatment decreases vascular damage caused by balloon catheter injury in female Zucker fatty rats. The beneficial effect of salsalate on vascular injury was associated with upregulation of eNOS, p-eNOS, and MnSOD, which reduce oxidative stress and have anti-inflammatory properties, as evidenced by reduction in serum IL-6 and the downregulation of VEGF and NFκB, which promote inflammation without changing glucose levels. These results suggest that salsalate may be useful in reducing vascular injury and restenosis following interventional revascularization procedures.

Animal models of catheter-induced intimal hyperplasia in type 1 and type 2 diabetes and the effects of pharmacologic intervention

Diabetes is a complex disorder characterized by impaired insulin formation, release or action (insulin resistance), elevated blood glucose, and multiple long-term complications. It is a common endocrine disorder of humans and is associated with abnormalities of carbohydrate and lipid metabolism. There are two forms of diabetes, classified as type 1 and type 2. In type 1 diabetes, hyperglycemia is due to an absolute lack of insulin, whereas in type 2 diabetes, hyperglycemia is due to a relative lack of insulin and insulin resistance. More than 90% of people with diabetes have type 2 with varied degrees of insulin resistance. Insulin resistance is often associated with impaired insulin secretion, and hyperglycemia is a common feature in both types of diabetes, but failure to make a distinction between the types of diabetes in different animal models has led to confusion in the literature. This is particularly true in relation to cardiovascular disease in the presence of diabetes and especially the response to vascular injury, in which there are major differences between the two types of diabetes. Animal models do not completely mimic the clinical disease seen in humans. Animal models are at best analogies of the pathologic process they are designed to represent. The focus of this review is an analysis of intimal hyperplasia following catheter-induced vascular injury, including factors that may complicate comparisons between different animal models or between in vitro and in vivo studies. We examine the variables, pitfalls, and caveats that follow from the manner of induction of the injury and the diabetic state of the animal. The efficacy of selected antidiabetic drugs in inhibiting the development of the hyperplastic response is also discussed.

Peroxisome proliferator-activated receptors as stimulants of angiogenesis in cardiovascular disease and diabetes

The incidence of diabetes is directly related to the incidence of obesity, which is at epidemic proportions in the US. Cardiovascular disease is a common complication of diabetes, which results in high morbidity and mortality. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear hormone receptors that regulate lipid and glucose metabolism. PPAR-α agonists such as fenofibrate and PPAR-γ agonists such as the thiozolidinediones have been used to treat dyslipidemia and insulin resistance in diabetes. Over the past few years research has discovered the role of PPARs in the regulation of inflammation, proliferation, and angiogenesis. Clinical trials looking at the effect of PPAR agonists on cardiovascular outcomes have produced controversial results. Studies looking at angiogenesis and proliferation in various animal models and cell lines have shown a wide variation in results. This may be due to the differential effects of PPARs on proliferation and angiogenesis in various tissues and pathologic states. This review discusses the role of PPARs in stimulating angiogenesis. It also reviews the settings in which stimulation of angiogenesis may be either beneficial or harmful.

The enigma of glucose and cardiovascular disease

Vivian A Fonseca Vasudevan A Raghavan Cyrus Desouza Strong epidemiological evidence indicates that diabetes is a major risk factor for cardiovascular disease (CVD), and despite advances in the treatment of CVD, outcomes in patients with diabetes mellitus (DM) remain suboptimal. In the European prospective investigation into cancer in Norfolk (EPIC–NORFOLK) study,1 the risk of CVD and total mortality associated with haemoglobin A1c (HbA1c) concentrations increased continuously through the sample distribution. An increase in HbA1c of 1 percentage point was associated with a relative risk of death from any cause of 1.24 (95% CI 1.14 to 1.34; p<0.001) in men and with a relative risk of 1.28 (95% CI 1.06 to 1.32; p<0.001) in women. Several meta-analyses2–4 arrived at similar conclusions, setting the stage for the conduct of randomised controlled trials exploring the effect of glycaemic control on CVD outcomes. Several plausible mechanisms underlie the relationship of DM and CVD, all of which lend themselves to the development of specific treatment targets, although the lowering of glucose per se appears to be an appropriate and potentially beneficial intervention. Obesity is characterised by an expanding adipose tissue mass and the development of an inflammatory state caused by the increased secretion of cytokines and adipokines from adipose tissue.5 The hyperglycaemic state causes oxidative stress and increased glycation of proteins in the body, leading to the formation of advanced glycation end products.6 These in turn contribute to exacerbation of the proinflammatory state, activation of macrophages and vascular smooth muscle cells, low-density lipoprotein oxidation and accelerated atherogenesis. It thus seems logical that a reduction in blood glucose to near normal would result in a reduction in CVD events. Although clinical trials have shown that intensive glucose control reduces the risk of microvascular complications among patients with type 2 DM, its effect …