Obesity and the metabolic syndrome are occuring at epidemic rates in the United States and worldwide, and contribute to the development of coronary heart disease (CHD), the leading cause of death and disabilty in our society. Recent studies demonstrate chronic subacute inflammation is associated with obesity- and dietinduced insulin resistance and may well be involved in the pathogenesis of CHD. Diets rich in calories, animal fats, and sugars have been shown to induce fatty livers, insulin resistance, dyslipidemia, increase activity of the inflammatory NF-KB pathway, and increase levels of inflammatory markers such as C reactive protein (CRP), serum amyloid A (SAA), and fibrinogen in both animals and humans. This pattern has also been associated with increased CHD risk. Our lab has identified anti-inflammatory salicylates as a potential new class of drugs for the treatment of these disorders and the IKKp/NF-KB pathway as the molecular target of this therapy. We hypothesize activation of IKKP/NF-KB signaling pathways contributes to the development of atherosclerosis. Moreover this process can be inhibited or prevented by administration of high dose salicylates which inhibit NF-KB activity. The effect of NF-KB on the vasculature may occur directly, through regulation of adipokines and cytokines that lead to vascular injury, or indirectly through metabolic changes in insulin sensitivity as intervention studies which have improved insulin resistance using metformin or thiazolidendiones have been shown to decrease CHD risk or effect on vascular remodeling in humans. Remodeling of CHD, especially of soft, vulnerable, non-calcified plague, can now be assessed with a minimally invasive technique by multi-detector computed tornographic angiography (MD-CTA) after injection of intravenous contrast material. This modality can also be used to assess visceral and liver fat content. This project will specifically assess inhibition of NF-KB using the salicylate, salsalate (DisalsidTM), to reduce inflammation and insulin resistance and promote vascuar remodeling in 400 patients with CHD and the metabolic syndrome in a double masked placebo controlled trial design. This project will test the hypothesis that aggressive treatment of inflammation and insulin resistance with salsalate can have significant favorable effects on coronary vascular remodeling as assessed by change in non-calcified plaque volume, cardiac endpoints, visceral and liver fat, lipid and circulating markers and mediatiors of inflammation.
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