Obesity (body mass index > 30 kg/m 2) affects more than 43 million Americans, and particularly when involving the abdomen or viscera (AO), is associated with increased cardiac morbidity and mortality. Based on the results of studies in experimental models of obesity and our preliminary studies in humans with AO, we hypothesize that in humans with AO, increased lipolysis leading to increased release of fatty acids into the plasma results in increased fatty acid delivery to the heart. Particularly when combined with insulin resistance this results in an increase in myocardial fatty acid metabolism. We further hypothesize that this shift in myocardial substrate metabolism is associated with abnormalities in ventricular systolic and diastolic function. Moreover, we believe that under conditions that further increase fatty acid delivery, myocardial accumulation of neutral lipids is increased, which in turn may be paralleled by a further decline in ventricular systolic and diastolic function. We will prove or disprove this hypothesis by performing a series of highly-complex experiments that utilize PET quantification of myocardial substrate metabolism, echocardiographic measurements of left ventricular systolic and diastolic function and stable isotopic measurements of whole-body fatty acid and glucose kinetics in a well-screened group of lean and Class-lI AO subjects. The measurements will be obtained under a variety of conditions designed to assess the influence of moderate weight loss, insulin availability, and plasma fatty acid levels on the relationship between myocardial substrate metabolism, mechanical function and whole-body substrate metabolism in AO. If successful, the results of the studies described in the grant application will provide confirmation that the abnormalities in myocardial fatty acid metabolism observed in experimental models of obesity are seen in humans with AO. Such information will form the basis for more targeted studies designed to elucidate the mechanisms responsible for these abnormalities and potentially result in significant clinical benefit for humans with AO.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-S (F1))
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Ershow, Abby
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Washington University
Schools of Medicine
Saint Louis
United States
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Peterson, Linda R; Herrero, Pilar; Coggan, Andrew R et al. (2015) Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the human heart. Am J Physiol Heart Circ Physiol 308:H1510-6
Cade, William Todd; Overton, Edgar Turner; Mondy, Kristin et al. (2013) Relationships among HIV infection, metabolic risk factors, and left ventricular structure and function. AIDS Res Hum Retroviruses 29:1151-60
Peterson, Linda R; Saeed, Ibrahim M; McGill, Janet B et al. (2012) Sex and type 2 diabetes: obesity-independent effects on left ventricular substrate metabolism and relaxation in humans. Obesity (Silver Spring) 20:802-10
Lin, C Huie; Kurup, Suraj; Herrero, Pilar et al. (2011) Myocardial oxygen consumption change predicts left ventricular relaxation improvement in obese humans after weight loss. Obesity (Silver Spring) 19:1804-12
Peterson, Linda R; Gropler, Robert J (2010) Radionuclide imaging of myocardial metabolism. Circ Cardiovasc Imaging 3:211-22
Peterson, Linda R; Herrero, Pilar; McGill, Janet et al. (2008) Fatty acids and insulin modulate myocardial substrate metabolism in humans with type 1 diabetes. Diabetes 57:32-40
Peterson, Linda R; Soto, Pablo F; Herrero, Pilar et al. (2008) Impact of gender on the myocardial metabolic response to obesity. JACC Cardiovasc Imaging 1:424-33
Mittendorfer, Bettina; Peterson, Linda R (2008) Cardiovascular Consequences of Obesity and Targets for Treatment. Drug Discov Today Ther Strateg 5:53-61
St Vrain, Jeanette; Bilhorn, Kyle; Kurup, Suraj et al. (2008) Strain imaging using speckle tracking in the cardiometabolic syndrome: method and utility. J Cardiometab Syndr 3:258-61
Peterson, Linda R; Soto, Pablo F; Herrero, Pilar et al. (2007) Sex differences in myocardial oxygen and glucose metabolism. J Nucl Cardiol 14:573-81

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