Diabetes is associated with serious cardiovascular complications that include atherosclerotic coronary artery disease and myocardial dysfunction even in the absence of underlying coronary artery disease, a disorder termed diabetic cardiomyopathy (DCM). Data from studies of animal models and human subjects provide evidence that alterations in myocardial lipid metabolism is central to the pathogenesis of DCM, which early on can be asymptomatic, but which can progress to symptomatic heart failure. The ability to identify new disease markers to facilitate early detection and intervention is limited b inadequacies of existing measures of systemic and myocardial lipid metabolism in humans. In our Preliminary Studies, we have addressed this problem by using sensitive mass spectrometry-based metabolomics to identify two plasma very long-chain ceramides, Cer(22:0) and Cer(24:0), that are highly correlated with asymptomatic systolic dysfunction in obese and type 2 diabetic humans. Cell biological and mouse model studies suggest these species arise from the unique intersection of ectopic lipid accumulation and activation of innate immune signaling pathways. We hypothesize that plasma Cer(22:0) and Cer(24:0) reflect systemic alterations in lipid metabolism that can be exploited as novel biomarkers for DCM. While the diagnosis of cardiac dysfunction can be readily made noninvasively by echocardiogram, Cer(22:0) and Cer(24:0) track with pathophysiological consequences of ectopic lipid accumulation and thus have potential to predict individuals at risk, to further our understanding of disease mechanism, and to identify new treatment targets. We have assembled a multidisciplinary team to extend these findings by 1) Developing a robust high-throughput clinical assay for Cer(22:0) and Cer(24:0);2) Validating and extending these findings in two existing cohorts of human subjects;3) Exploring the mechanistic links between very long-chain ceramides and cardiac dysfunction in relevant mouse models of DCM;and 4) Defining the direction of causality in the relationships among lipid exposure, plasma ceramides, and cardiac function in humans with type 2 diabetes. Our approach has the potential to define an integrated measure of pathophysiologically relevant lipid exposure that can be used to track intervention success, data linking phenotype to a modifiable risk factor that is currently undertreated in the target population (dyslipidemia), and marker for future disease risk that can be acted upon to prevent clinically apparent morbidity and mortality.
Diabetes is associated with serious cardiovascular complications including heart failure that is unrelated to coronary artery disease. Scientific evidence suggests that blood fat levels play a major role in this complication. Our study will investigate the link between blood fat levels and heart function in adults with type 2 diabetes. Our goal is to develop new blood-based biomarkers of heart disease in diabetics and to provide insight into mechanisms underlying this disorder that will inform new therapeutic strategies.
|Airhart, Sophia; Cade, W Todd; Jiang, Hui et al. (2016) A Diet Rich in Medium-Chain Fatty Acids Improves Systolic Function and Alters the Lipidomic Profile in Patients With Type 2 Diabetes: A Pilot Study. J Clin Endocrinol Metab 101:504-12|
|Bowler, Russell P; Jacobson, Sean; Cruickshank, Charmion et al. (2015) Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes. Am J Respir Crit Care Med 191:275-84|
|Peterson, Linda R (2015) To Lose Weight or Not to Lose Weight, That Is the Big Question--in Obesity-Related Heart Failure. Diabetes 64:1509-10|
|Elezaby, Aly; Sverdlov, Aaron L; Tu, Vivian H et al. (2015) Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload. J Mol Cell Cardiol 79:275-83|
|Diani-Moore, Silvia; Ma, Yuliang; Gross, Steven S et al. (2014) Increases in levels of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EETs and DHETs) in liver and heart in vivo by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in hepatic EET:DHET ratios by cotreatment with TCDD and the soluble epoxide hydrolas Drug Metab Dispos 42:294-300|
|Crawford, Peter A; Schaffer, Jean E (2013) Metabolic stress in the myocardium: adaptations of gene expression. J Mol Cell Cardiol 55:130-8|
|Schilling, Joel D; Machkovech, Heather M; He, Li et al. (2013) Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. J Biol Chem 288:2923-32|
|Kadkhodayan, Ana; Coggan, Andrew R; Peterson, Linda R (2013) A "PET" area of interest: myocardial metabolism in human systolic heart failure. Heart Fail Rev 18:567-74|
|Jiang, Hui; Hsu, Fong-Fu; Farmer, Marsha S et al. (2013) Development and validation of LC-MS/MS method for determination of very long acyl chain (C22:0 and C24:0) ceramides in human plasma. Anal Bioanal Chem 405:7357-65|
|Schilling, Joel D; Machkovech, Heather M; Kim, Alfred H J et al. (2012) Macrophages modulate cardiac function in lipotoxic cardiomyopathy. Am J Physiol Heart Circ Physiol 303:H1366-73|