dalcetrapib and Aortic-Diseases

This study sought to longitudinally investigate the relationship between a broad spectrum of serum inflammatory biomarkers and plaque inflammation assessed by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).. Both plaque inflammation and serum biomarkers of inflammation are associated with atherothrombotic events; however, the relationship between them is unclear.. We conducted a post hoc analysis of the dal-PLAQUE (A Randomized Placebo-Controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors), a randomized, placebo-controlled study of dalcetrapib, a cholesteryl ester transfer protein inhibitor, in 130 patients with coronary heart disease, or coronary heart disease risk equivalents on stable lipid-lowering therapy. Baseline and change after 3-month follow-up in inflammatory biomarker levels and baseline and change after 3-month follow-up in aorta and carotid (18)F-FDG PET/CT (mean maximum target-to-background ratio of the most diseased segment [TBRmds]) were analyzed.. Baseline myeloperoxidase positively correlated with baseline carotid TBRmds (rho = 0.25, p = 0.02). This correlation remained at the 3-month follow-up and was independent of traditional cardiovascular disease risk factors. Baseline lipoprotein-associated phospholipase A2 mass correlated with aorta TBRmds (rho = 0.21, p = 0.03). However, this correlation disappeared at the 3-month follow-up and was not independent of cardiovascular disease risk factors. There was no association between change from baseline in myeloperoxidase or lipoprotein-associated phospholipase A2 mass and change from baseline in aorta and carotid TBRmds. Baseline and change from baseline in high sensitivity C-reactive protein, interleukin 6, soluble P-selectin, soluble E-selectin, soluble intracellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and matrix-metalloproteinase 3 and 9 did not correlate with baseline or change from baseline in carotid or aorta TBRmds.. Our data show that, in patients with coronary heart disease or at high risk of coronary heart disease on stable lipid-lowering therapy, circulating myeloperoxidase levels are associated with carotid plaque inflammation. (A Randomized, Placebo-controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease [CHD] Including Patients With Other CHD Risk Factors [dal-PLAQUE]; NCT00655473).

Topics: Amides; Aorta; Aortic Diseases; Biomarkers; Carotid Arteries; Carotid Artery Diseases; Double-Blind Method; Esters; Fluorodeoxyglucose F18; Humans; Hypolipidemic Agents; Inflammation Mediators; Longitudinal Studies; Multimodal Imaging; Peroxidase; Plaque, Atherosclerotic; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Sulfhydryl Compounds; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Cholesteryl ester transfer protein (CETP) is a major determinant of plasma levels of high-density lipoprotein-cholesterol (HDL-C) in humans. The anti-atherogenic effect of lowering CETP levels is dependent not only on HDL-C levels but also on a metabolic background of increased low-density lipoprotein or very-low-density lipoprotein. Here we investigated the effects of JTT-705, a chemical inhibitor of CETP, on the development of atherosclerosis in Japanese white rabbits fed on a high cholesterol diet. After 4 weeks on a diet of 0.25% cholesterol-containing chow, 100 mg/kg (low dose) or 300 mg/kg (high dose) JTT-705 was given, and the animals were monitored at weeks 0, 4, 8 and 12. Aortic atherosclerotic lesions were determined at the end of this period. JTT-705 induced a significant increase in HDL-C in the high-dose group [from 21+/-3 to 50+/-7 mg/dl (mean+/-S.E.M.); P <0.0001] compared with the control group (from 21+/-2 to 27+/-2 mg/dl). The atheromatous area was 60+/-9% in the high-dose group and 58+/-9% in the control group. Moreover, correlation analysis showed that triacylglycerol and non-HDL-C levels had a direct relationship with the development of atherosclerosis, but CETP activity and HDL-C levels did not. Thus the CETP inhibitor JTT-705 alone did not have an anti-atherogenic effect in our rabbit model, of severe hypercholesterolaemia suggesting a relatively minor effect of HDL-elevating therapy as compared with decreases in non-HDL-C (or triacylglycerol) levels in patients with severe hypercholesterolaemia, such as familial hypercholesterolaemia.

Topics: Amides; Animals; Aortic Diseases; Arteriosclerosis; Body Weight; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol, Dietary; Diet, Atherogenic; Esters; Glycoproteins; Hypercholesterolemia; Lipase; Lipids; Lipoprotein Lipase; Liver; Male; Rabbits; Statistics, Nonparametric; Sulfhydryl Compounds