Abstract 458: Obesity-related Alterations in Cardiac Lipid Profile During the Transition to Diastolic Dysfunction

Abstract

Myocardial accumulation of fatty acids and lipid intermediates may contribute to cardiac dysfunction, but the interrelationship between different lipid species to diastolic dysfunction is not clearly understood. Herein, we examined changes in levels and composition of different lipid species during the progression to diastolic dysfunction in a clinically relevant model of obese insulin-resistant db/db mice at 12 and 15 wks of age. Obese db/db mice manifested loss of circadian BP dipping and diastolic dysfunction at 15 wks. Myocardial lipidomic analysis demonstrated elevated ceramides and fatty acids in db/db at 12 wks, but their levels were decreased at 15 wk and this was accompanied by increased fatty acid oxidation and enhanced production of reactive oxygen species. Triacylglyceride and diacylglyceride levels remained elevated at both 12 and 15 wk, but their composition changed to consist of more saturated and less unsaturated fatty acyl at 15 wks of age compared to 12 wk. Dysregulation of phospholipid metabolism persisted at 15 wk in db/db. Changes in triacylglyceride and diacylglyceride composition, phospholipid metabolism, β-oxidation, and oxidative stress that are temporally related to non-dipping of BP and diastolic dysfunction suggest a switch in metabolism of lipid intermediates contributes to the development of diastolic dysfunction in over-nutrition.