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.