Atheroma Reduction With Chloroquine in Patients With the Metabolic Syndrome (ARCH-MS)

Metabolic syndrome is one of the most common disorders in industrialized countries. It consists of abnormal serum lipids, glucose intolerance, elevated blood pressure, and central obesity in the setting of insulin resistance. The syndrome substantially increases the risk of developing diabetes and vascular disease, but there is no clear unifying approach to treat this disorder. In animals, activation of the protein ataxia telangiectasia mutated (ATM) using the antimalarial drug chloroquine improves features of metabolic syndrome and decreases atherosclerosis, a build-up of fatty plaque within arteries. The purpose of this study is to examine the effect of long-term treatment with low doses of chloroquine on atherosclerosis in people with metabolic syndrome. At a baseline study visit, participants will undergo an ultrasound of the neck to evaluate carotid artery intima-media thickness (IMT) and MRI to evaluate plaque composition. In addition, blood will be collected for laboratory testing and blood pressure will be measured. Participants will then be randomly assigned to receive either placebo or chloroquine. Study visits will occur every 3 months for 1 year. At each visit, blood pressure will be measured and blood will be collected. At Months 6 and 12, a repeat ultrasound will be performed. At month 12 a repeat carotid MRI is performed. Participants will attend one follow-up visit at Month 24 and will undergo a final ultrasound. Sub-Study: VEGF and Cardiometabolic Risk, (This is an observational, case-study of existing baseline plasma and carotid intimal-medial thickness measurements) VEGF is also closely linked to vascular disease. From cell culture and animal models it is known that VEGF is increased in atherosclerotic lesions. It is controversial whether that relationship is causative or reparative. Both pro- and anti-VEGF therapies have been proposed for atherosclerosis. However, the association of VEGF with atherosclerosis indicates that it should be a marker of the disorder, which is the hypothesis we wish to test. No previous studies of circulating VEGF have been published. Other markers may be related to vascular disease or VEGF in this dataset. Tumor necrosis factor (TNF)-alpha results in increased expression of VEGF and may be correlated positively with VEGF. By Erenna Technology testing, cardiac troponin I can be measured at levels much lower than current clinical assays and is expected to be elevated in ischemia but not necessarily in the stable vascular disease anticipated in our subjects. High sensitivity C-reactive protein (hsCRP)has been proposed as a marker for vascular disease that merits drug treatment in its own right and may also be correlated with VEGF and vascular disease. However, currently the relationship between hsCRP and vascular disease is not completely clear. For this preliminary VEGF study observational data from the baseline only will be studied. Baseline testing includes carotid artery intimal-medial thickness, carotid MRI, lipid panel, complete blood count, comprehensive metabolic chemistry panel, Thyroid-stimulating hormone (TSH) and glucose tolerance test with plasma insulin and glucose responses. Plasma collected at baseline (approximately 1 ml) will be transferred to Singulex on dry ice. Samples will be coded but will not contain patient identifiers. Erenna Technology assays will be done for VEGF-A, cardiac troponin I,TNF-alpha, interleukin-6, interleukin-17A, and other cytokines at Singulex. This method utilizes single-photon counting of visible light to improve assay sensitivity. Separately, Washington University's Core Lab for Clinical Studies (CLCS) will determine hsCRP.