Metabolic syndrome and obesity are reaching epidemic proportions and increase the risk of coronary heartdisease (CHD), the leading cause of death and disability in our society. The Western diet, which is rich incalories, saturated fat, trans fat, cholesterol and glycemic load, and central obesity increase risk of CHD byactivating the NF-KB cascade and increasing plasma levels of proinflammatory cytokines, TNF-alpha and IL-6,and levels of inflammatory markers as C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen.Activation of NF-KB leads to insulin resistance, increased triglyceride levels, low HDL-C levels and fatty liver,all characteristics of the metabolic syndrome. The third Adult Treatment Panel has recommended that firstline therapy for metabolic syndrome be lifestyle changes geared toward weight reduction (especially centraladiposity) through diet and increased physical activity. In this project, 'Weight Loss, Inflammation andVascular Remodeling', subjects with metabolic syndrome and CHD (all on statin) will be randomized to alifestyle modification program (30 minutes of daily exercise, 1500-2000 calories/day, < 7% saturated fat,<200 mg cholesterol/day, low trans fat, low glycemic load diet, along with a nutritional supplement rich in co-3fatty acids, folate, and vitamins B 6 and B12) or usual care. Coronary plaque will be assessed bymultidetector computed tomographic angiography (MDCTA) at baseline and 30-month follow-up. Liver andabdominal fat will also be assessed with MDCT. Since the Western diet and obesity activate the NF-KBcascade and lead to inflammation, we hypothesize that weight loss achieved through dietary and exerciseintervention will suppress the subacute inflammatory process to promote vascular remodeling and regressionof soft plaque assessed by MDCTA in patients with established CHD. The hypotheses to be tested are that:1) those in the lifestyle arm will have regression of soft plaque (approximately 5%) compared to progression(approximately 5%) in the usual care arm and also reduction in hepatic and abdominal fat and significantlylower levels of CRP, TNF-alpha, MMP 9, SAA, fibrinogen, PAI-1, IL-6 and a measure of oxidative stress,nitrotyrosine; 2) the amount of regression will be directly correlated with the % decrease in hepatic fat, bodyweight and abdominal fat; 3) the % reduction in inflammatory markers will be correlated with the % change insoft plaque and % reduction in hepatic and abdominal fat and body weight. These studies will allow us totest the hypothesis that aggressive lifestyle modification with weight loss and nutritionalsupplements will have favorable effects on vascular remodeling and inflammatory markers of CHDrisk versus usual care alone in CHD patients with the metabolic syndrome.
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