Anchoring Metabolomic Changes to Phenotype P20 Project

Washington University School of Medicine

• Jean Schaffer, MD

• Linda R. Peterson, MD

• Daniel S. Ory, MD


Washington University BJCIH BuildingDiabetes 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. Data from studies of animal models and human subjects provide evidence that alterations in myocardial lipid metabolism are central to the pathogenesis of diabetic cardiomyopathy, 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 by 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 plasma lipids that are correlated with asymptomatic cardiac 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 these lipids reflect systemic alterations in lipid metabolism that can be exploited as novel biomarkers for diabetic cardiomyopathy. While the diagnosis of cardiac dysfunction can be readily made noninvasively by echocardiogram, blood measures that track with pathophysiological consequences of ectopic lipid accumulation have potential to predict individuals at risk, to further our understanding of disease mechanisms, and to identify new treatment targets.

We have assembled a multidisciplinary team to extend these findings by 1) Developing robust high-throughput clinical assays for lipid species of interest; 2) Validating and extending our preliminary findings in existing cohorts of human subjects at Washington University and in collaboration with the Framingham Heart Study; 3) Exploring the mechanistic links between plasma lipids and cardiac dysfunction in relevant mouse models of diabetic cardiomyopathy; and 4) Defining the direction of causality in the relationships among lipid exposure, plasma lipids, 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 a marker for future disease risk that can be acted upon to prevent morbidity and mortality.