As we have became the fattest nation in the world, obesity is an increasingly important cause of myocardial morbidity and mortality in the United States. Obesity indirectly contributes to heart disease by increasing plasma lipids and predisposing to diabetes and hypertension (i.e. traditional cardiovascular risk factors). In addition, recent work from Roger Unger advances the novel hypothesis that obesity per se constitutes a direct cause of left systolic ventricular dysfunction and hypertrophy by promoting cardiac steatosis. Major Hypothesis: Cardiac steatosis is an integral feature of human obesity, contributing to decrease of LV systolic function. I further hypothesize that these functional abnormalities of the human heart are provoked by the development of non-insulin dependent diabetes mellitus (type 2 diabetes) and can be reversed by treatment with Thiazolidinediones.
Specific Aims : In human subjects without heart disease, I will measure lipid deposition in the ventricular septum using double gated localized proton nuclear magnetic resonance (1H NMR) as well as LV systolic function with magnetic resonance imaging (MRI) to accomplish the following specific aims:
Aim 1 : To document the intra-subject reproducibility of the 1H NMR measurement of intra-myocardial lipid content.
Aim 2 : To establish the relation between adiposity and myocardial lipid deposition over a wide range of BMI and determine the impact of gender, and ethnicity on these relations.
Aim 3 : To determine if intra-myocardial lipid deposition is greater in individuals with IGT and insulin resistance than in these with normal glucose tolerance matched for BMI, age, gender and ethnicity. I hypothesize that the greater myocardial lipid in diabetic and prediabetic individuals will be accompanied by decreased LV systolic function.
Aim 4 : To perform randomized prospective study to test the hypothesis that the elevated myocardial lipid content and decreased systolic LV function can be reversed or minimized by the treatment with Thiazolidinediones. In contrast, I predict that functional cardiac abnormalities will be unaffected when diabetic subjects are treated with sulfonylureases that have no effect on PPAR-gamma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25HL068736-04
Application #
6929347
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M2))
Program Officer
Scott, Jane
Project Start
2002-09-30
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$128,050
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lee, Y; Lingvay, I; Szczepaniak, L S et al. (2010) Pancreatic steatosis: harbinger of type 2 diabetes in obese rodents. Int J Obes (Lond) 34:396-400
Lingvay, Ildiko; Raskin, Philip; Szczepaniak, Lidia S (2007) Effect of insulin-metformin combination on hepatic steatosis in patients with type 2 diabetes. J Diabetes Complications 21:137-42
McGavock, Jonathan M; Lingvay, Ildiko; Zib, Ivana et al. (2007) Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116:1170-5
Szczepaniak, Lidia S; Victor, Ronald G; Orci, Lelio et al. (2007) Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ Res 101:759-67
Zib, Ivana; Jacob, Aris N; Lingvay, Ildiko et al. (2007) Effect of pioglitazone therapy on myocardial and hepatic steatosis in insulin-treated patients with type 2 diabetes. J Investig Med 55:230-6
McGavock, Jonathan M; Victor, Ronald G; Unger, Roger H et al. (2006) Adiposity of the heart, revisited. Ann Intern Med 144:517-24
Szczepaniak, Lidia S; Nurenberg, Pamela; Leonard, David et al. (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288:E462-8
Reingold, Jason S; McGavock, Jonathan M; Kaka, Shaheen et al. (2005) Determination of triglyceride in the human myocardium by magnetic resonance spectroscopy: reproducibility and sensitivity of the method. Am J Physiol Endocrinol Metab 289:E935-9