Qamar A Khan

Irbesartan, an angiotensin type 1 receptor inhibitor, regulates the vascular oxidative state in patients with coronary artery disease ☆

OBJECTIVES The aim of this study was to determine the effect of angiotensin II type 1 (AT(1)) receptor antagonists on pro-oxidant species observed in the pathogenesis of atherosclerosis. Parameters such as low-density lipoprotein (LDL) susceptibility, monocyte binding capacity, superoxide generation and lipid peroxidation were examined in the presence of the AT(1) receptor antagonist irbesartan. BACKGROUND Low-density lipoprotein oxidation is a key component in the process of atherogenesis. This modification may involve various mechanisms, including changes in nitric oxide levels and superoxide levels. Additionally, compounds that suppress these mechanisms may retard or inhibit the pathogenesis of atherosclerosis. METHODS Forty-seven patients with documented coronary artery disease were treated with irbesartan for a 12-week period. Patients were randomized to receive irbesartan or placebo. Lipid peroxidation, superoxide levels, monocyte binding and LDL oxidation were measured at 0, 4 and 12 weeks. Findings were statistically evaluated by two-way repeated measures analysis of variance with p < 0.05 being significant. RESULTS Treatment with irbesartan significantly decreased the pro-oxidative environment seen in our study population. Lag time for LDL oxidation increased 32% at 12 weeks, suggesting an increased resistance of LDL modification in the serum. Thiobarbituric acid reactive substances activity indicated that lipid peroxidation decreased by 36% in comparison to placebo. In addition, superoxide levels and monocyte-binding capacity were also significantly reduced in coronary artery disease patients receiving irbesartan. CONCLUSIONS Our results indicate that irbesartan may suppress the atherosclerotic process by inhibiting the intravascular oxidative state and the production of reactive oxygen species, compounds that may cause damage to the vasculature.

Effects of Eprosartan Versus Hydrochlorothiazide on Markers of Vascular Oxidation and Inflammation and Blood Pressure (Renin-Angiotensin System Antagonists, Oxidation, and Inflammation)

Antagonists of the renin-angiotensin system, such as angiotensin type 1 (AT(1)) receptor inhibitors and angiotensin-converting enzyme inhibitors, are becoming increasingly popular agents in treating patients with systemic hypertension and minimizing organ damage. In the present study, we compared the effects of eprosartan, an AT(1) receptor inhibitor, with the diuretic hydrochlorothiazide in a group of newly diagnosed hypertensive patients with multiple risk factors for atherosclerosis. The subjects were monitored and tested at 0 and 4 weeks to determine their individual effects on vascular and inflammatory markers. Although blood pressure reduction was comparable between the 2 agents, there were notable differences in their effects on markers of inflammation and oxidation. We observed a 28% reduction in neutrophil superoxide anion generating capacity, a 34% reduction in soluble monocyte chemotactic protein-1, and a 35% reduction in soluble vascular cell adhesion molecule with eprosartan therapy (all p <0.05 from the start of therapy). In addition, eprosartan showed further benefit in its ability to increase low-density lipoprotein oxidation lag time, suggesting an increased resistance to oxidation and/or modification of low-density lipoprotein. Although hydrochlorothiazide was effective in blood pressure reduction, there were no significant changes in any of the above parameters after 4 weeks of treatment. These findings suggest that eprosartan, an AT(1) receptor inhibitor, effectively reduces systemic blood pressure and, compared with hydrochlorothiazide, suggests additional benefits in the vasculature by inhibiting mechanisms of inflammation and oxidation.

Usefulness of quinapril and irbesartan to improve the anti-inflammatory response of atorvastatin and aspirin in patients with coronary heart disease

A that inhibit the renin-angiotensin system (RAS), such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers, have considerable benefit in hypertension and heart failure.1–3 These compounds decrease hemodynamic stress, increase nitric oxide bioactivity, and reduce pulse pressure.4–6 Recent longterm clinical studies have indicated that the addition of an ACE inhibitor decreases morbidity and mortality in patients with stable coronary artery disease.7,8 Furthermore, we have previously demonstrated that treatment with irbesartan in patients with early atherosclerosis decreases markers of inflammation that may be sensitive to the oxidative state in the vasculature.9,10 In the present study, we examine the potential mechanisms by which the addition of either quinapril or irbesartan can regulate vascular function in patients already on a regimen of aspirin and atorvastatin therapy. • • • One hundred twelve subjects (64 men and 48 women) with coronary artery disease and with a systolic blood pressure of 140 mm Hg were enrolled into the study from several medical facilities in metropolitan Atlanta, Georgia. All patients had been on antianginal therapy, had undergone coronary artery bypass graft surgery, and/or had undergone percutaneous transluminal coronary angioplasty 6 months before the start of the study. All patients were considered stable on their medical regimen and free of any acute coronary syndrome or subjective symptoms of chest pain for 6 months. Patients were started on atorvastatin (10 to 40 mg/day) to obtain a target lowdensity lipoprotein cholesterol of 100 mg/dl. Serum was collected and stored at the initiation of atorvastatin therapy. All subjects were on aspirin (81 to 325 mg/day), and an equal number of subjects in each group were on nitrates and blockers. No patient had taken ACE inhibitors or AT1 receptor inhibitors for 6 months before the beginning of the study. A survey was performed of each potential subject, and the following were excluded: those with a medical necessity for ACE inhibitor therapy, current smokers, and subjects with acute or previous myocardial infarction, an ejection fraction 35% by echocardiography or ventriculography, diabetes with a glycosylated hemoglobin 8.5%, systolic blood pressure 140 mm Hg, serum creatinine 2.2 mg/dl, or active malignancy. The study protocol was approved by the research committee at Emory University, and all subjects provided written, informed consent. The subjects were placed on atorvastatin for an average of 3.7 months (range 1.9 to 5.3) to reach a target low-density lipoprotein cholesterol of 100 mg/dl. Using a randomized, open-label, crossover protocol, subjects received quinapril 20 mg/day (Pfizer Inc., New York, New York) (n 39), irbesartan 150 mg/day (Bristol-Myers Squibb and Sanofi-Synthelabo, Princeton, New Jersey) (n 37), or placebo (n 36) for 24 weeks. Serum samples were collected at 5 time intervals: (1) the start of atorvastatin; (2) start of quinapril, irbesartan, or placebo; (3) 4 weeks of quinapril, irbesartan, or placebo; (4) 12 weeks of quinapril, irbesartan, or placebo; and (5) 24 weeks of quinapril, irbesartan, or placebo. Whole blood immunotyping was performed in blood samples by fluorescence-activated cell sorting analysis using a monoclonal antibody to the human CD11b receptor, a protein with human binding sites and a very high binding affinity to human monocytes. The monoclonal antibody to the CD11b receptor was obtained through Pharmingen/BD Biosciences (Lexington, Kentucky). Using flow cytometry analysis, the changes in monocyte CD11b expression were determined as previously described.5,10 The plasma samples were centrifuged and stored at 20°C. Enzyme-linked immunosorbent assays (ELISA) for soluble interleukin-6 (sIL-6) were performed on each sample in triplicate (ELISA kits, Biosource International, Camarillo, California). Two hundred microliters of serum was used for analyses, and ELISA was performed as previously described.9 The levels of sIL-6 were read using an ELISA plate reader at an optical density of 450 nm. All data are presented as the mean value SEM. Comparisons were determined within the quinapril and irbesartan groups and between the quinapril and irbesartan groups with 2-way analysis of variance. A p value of 0.05 was considered statistically significant. (Bonferroni correction was applied; p values were related to analysis of variance.) From the Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; and University of Michigan, Division of Cardiology, Ann Arbor, Michigan. Dr. B. Khan was supported by the Emory Medical Care Foundation, Atlanta, Georgia, and Dr. Parthasarathy was supported by grant R01-HL34453 from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland. Dr. B. Khan’s address is: Emory University School of Medicine, Division of Cardiology, 69 Jesse Hill Drive SE, C233, Atlanta, Georgia 30303. E-mail: bkhan@emory.edu. Manuscript received July 8, 2002; revised manuscript received and accepted January 20, 2003.

Growing Cardiovascular and Metabolic Diseases in the Developing Countries: Is there a Role for Small Dense LDL Particles as an Inclusion Criteria for Individuals at Risk for the Metabolic Syndrome?

The prevalence of the metabolic syndrome is significant in nations with developed economies and is growing in countries with rapidly growing economies. The reasons for this are complex but include increased availability to cheaper (and less nutritious) food and increased mechanization. This results in reduced physical activity and an increase in total body fat and weight. Current inclusion criteria for the metabolic syndrome include parameters of obesity, elevated blood glucose, elevated triglycerides, and low HDL cholesterol. However, with the increased information regarding LDL (and specifically the small dense LDL particle) as a major risk factor for cardiovascular disease, no present consideration for LDL cholesterol as inclusion criteria for the metabolic syndrome is made. This article explores the role of LDL cholesterol as a cause and effect of complications with the metabolic syndrome in patients of these countries that are developing cardiovascular and metabolic diseases at an accelerated rate. Furthermore, as measurement of small dense LDL and apoprotein components becomes more widely available and cost effective, it may be that evaluation of these parameters and markers will assist the clinician and high-risk patient in the management and treatment of conditions that are associated with the metabolic syndrome.

Atorvastatin: beyond lipid-lowering effects in the diabetic population

Statins are the mainstay of therapy in coronary artery disease and hypercholesterolemia. Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor that is taken once daily. It has been shown to considerably reduce cardiovascular mortality events. Recently, several trials have demonstrated that atorvastatin has pleiotropic effects beyond its lipid-lowering capacities. Atorvastatin is especially beneficial in diabetics for stroke prevention and improving cardiovascular mortality risk.

Potential role of statin therapy in heart failure, atrial fibrillation and aortic stenosis

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are widely prescribed throughout the world, and considerable evidence has indicated their powerful effects in ischemic forms of cardiovascular disease. Recently, several trials have demonstrated that statins have pleiotropic effects beyond their lipid-lowering capacities. These findings may play a role in the use of statins to manage forms of cardiovascular disease that may or may not have an ischemic etiology: congestive heart failure, atrial fibrillation and aortic stenosis.