Obesity and the metabolic syndrome are occuring at epidemic rates in the United States and worldwide, andcontribute to the development of coronary heart disease (CHD), the leading cause of death and disabilty inour society. Recent studies demonstrate chronic subacute inflammation is associated with obesity- and dietinducedinsulin 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, increaseactivity of the inflammatory NF-KB pathway, and increase levels of inflammatory markers such as C reactiveprotein (CRP), serum amyloid A (SAA), and fibrinogen in both animals and humans. This pattern has alsobeen associated with increased CHD risk. Our lab has identified anti-inflammatory salicylates as a potentialnew class of drugs for the treatment of these disorders and the IKKp/NF-KB pathway as the molecular targetof this therapy. We hypothesize activation of IKKP/NF-KB signaling pathways contributes to the developmentof atherosclerosis. Moreover this process can be inhibited or prevented by administration of high dosesalicylates which inhibit NF-KB activity. The effect of NF-KB on the vasculature may occur directly, throughregulation of adipokines and cytokines that lead to vascular injury, or indirectly through metabolic changes ininsulin sensitivity as intervention studies which have improved insulin resistance using metformin orthiazolidendiones 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 aminimally invasive technique by multi-detector computed tornographic angiography (MD-CTA) after injectionof intravenous contrast material. This modality can also be used to assess visceral and liver fat content. Thisproject will specifically assess inhibition of NF-KB using the salicylate, salsalate (DisalsidTM), toreduce inflammation and insulin resistance and promote vascuar remodeling in 400 patients with CHD andthe metabolic syndrome in a double masked placebo controlled trial design. This project will test thehypothesis that aggressive treatment of inflammation and insulin resistance with salsalate can havesignificant favorable effects on coronary vascular remodeling as assessed by change in non-calcified plaquevolume, cardiac endpoints, visceral and liver fat, lipid and circulating markers and mediatiors of inflammation.
Showing the most recent 10 out of 67 publications
