The risk for cardiovascular disease (CVD) and left ventricular dysfunction (LVD) is greater in HIV-infected people than in the general population, but the pathogenesis is unclear. Many HIV-infected people develop metabolic syndromes (HIV+MS) that include traditional CVD and LVD risk factors (dyslipidemia, insulin resistance, visceral adiposity) that are commonly observed in HIV-seronegative people and referred to as The Metabolic Syndrome.' We have reported that HIV+MS is characterized by an elevated free fatty acid rate of appearance (FFA Ra) in the circulation (ie, increased whole-body lipolytic rate), and lipid accumulation in skeletal muscle and liver. In HIV+MS, we hypothesize that the elevated FFA Ra increases FFA delivery, uptake and oxidation by the myocardium, but that myocardial FFA uptake eventually exceeds the ability of the heart to oxidize FFAs; intramyocardial lipid accumulation may result. We hypothesize that increased myocardial FFA uptake and oxidation are associated with structural changes in the left ventricle, and ventricular diastolic and systolic contractile dysfunction in HIV+MS. We propose to quantify whole-body FFA Ra (using 13C-palmitate and mass spectrometry), myocardial FFA delivery, uptake and oxidation (using radio-labeled palmitate and cardiac positron emission tomography (PET) imaging), and left ventricular (LV) structure, diastolic and systolic contractile function (using 2-D and tissue Doppler echocardiography) in 30 HIV+MS and 30 HIV-infected people without MS. We will compare these parameters between these 2 groups, and to exactly the same parameters quantified in HIV-seronegative people with and without The Metabolic Syndrome' who are currently being studied by co-investigators on this proposal at our Institution. For this project, HIV+MS is defined as HIV-infected women and men receiving stable anti-retroviral therapy and experiencing hypertriglyceridemia, low HDL-cholesterol levels, insulin resistance and visceral adiposity. The findings will identify similarities/differences in myocardial metabolism and LV contractile function between HIV+MS and The Metabolic Syndrome'. The findings may provide a mechanistic link between dysregulated whole-body and myocardial FFA metabolism that contributes to alterations in LV structure, contractile function and CVD. If so, treatments designed to reduce circulating FFA levels in HIV+MS, might effectively reduce CVD and LVD in HIV-infected people.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059531-07
Application #
7119012
Study Section
Special Emphasis Panel (ZRG1-AARR-A (06))
Program Officer
Laughlin, Maren R
Project Start
2000-09-15
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
7
Fiscal Year
2006
Total Cost
$511,742
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Cade, W Todd; Reeds, Dominic N; Overton, E Turner et al. (2013) Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications. HIV Clin Trials 14:303-12
Cade, W Todd; Reeds, Dominic N; Overton, E Turner et al. (2011) Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis. Cardiovasc Diabetol 10:111
Yarasheski, Kevin E; Scherzer, Rebecca; Kotler, Donald P et al. (2011) Age-related skeletal muscle decline is similar in HIV-infected and uninfected individuals. J Gerontol A Biol Sci Med Sci 66:332-40
Chen, Fabian; Lam, Raymond; Shaywitz, David et al. (2011) Evaluation of early biomarkers of muscle anabolic response to testosterone. J Cachexia Sarcopenia Muscle 2:45-56
Yarasheski, Kevin E; Cade, W Todd; Overton, E Turner et al. (2011) Exercise training augments the peripheral insulin-sensitizing effects of pioglitazone in HIV-infected adults with insulin resistance and central adiposity. Am J Physiol Endocrinol Metab 300:E243-51
Richmond, Scott R; Carper, Michael J; Lei, Xiaoyong et al. (2010) HIV-protease inhibitors suppress skeletal muscle fatty acid oxidation by reducing CD36 and CPT1 fatty acid transporters. Biochim Biophys Acta 1801:559-66
Cade, W T; Reeds, D N; Mondy, K E et al. (2010) Yoga lifestyle intervention reduces blood pressure in HIV-infected adults with cardiovascular disease risk factors. HIV Med 11:379-88
Flint, Oliver P; Noor, Mustafa A; Hruz, Paul W et al. (2009) The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular mechanisms and clinical implications. Toxicol Pathol 37:65-77
O'Connor, Robert D; Bashir, Adil; Todd Cade, W et al. (2009) 1H-magnetic resonance spectroscopy for quantifying myocardial lipid content in humans with the cardiometabolic syndrome. J Clin Hypertens (Greenwich) 11:528-32

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