224-OR: Cardiac Imaging and Metabolomics Studies Suggest Shared and Distinct Risk Factors for Atherosclerosis and Cardiomyopathy in Renoprotected, Long-Duration Type 1 Diabetes

Cardiovascular disease (CVD) is a major cause of mortality in long-duration type 1 diabetes (T1D) despite the absence of nephropathy (DN). However, its mechanisms are incompletely understood. Joslin 50-Year “Medalists”, with T1D≥50 years, are ideal for studying CVD in a renoprotected T1D cohort, as only 13% have DN, yet 40% have CVD. A Medalist subset underwent coronary artery calcification scans (CAC; n=75) and cardiac magnetic resonance (CMR; n=60) of left ventricular (LV) mass and volumes. In exploratory analyses, we studied the association of these imaging parameters with Medalists’ cardiometabolic profiles. Compared to males, females were less likely to have CAC>200 (p=0.02) and had lower (more favorable) values for CMR structure parameters such as LV mass index (MI) and end-systolic (ESV) and end-diastolic (EDV) volumes (all p<0.05). Higher HbA1C showed a trend towards association with CAC>200 and higher LV MI (both p=0.1). CAC>200 also associated with retinopathy (PDR; p=0.04) and lower superficial capillary density on retinal imaging (p=0.049), and a trend towards association with lower HDL and higher C-reactive protein (both p=0.09). LV MI and EDV were associated with DN (p=0.04 and p=0.05, respectively). In untargeted metabolomics, LV MI, EDV, and ESV were also associated with higher levels of short-medium chain acylcarnitines and histamine metabolites, and lower levels of tryptophan metabolites via the indole pathway (all FDR<0.1). These preliminary findings suggest that while sex and glycemic control are shared contributors to atherosclerosis and cardiomyopathy in T1D, PDR, lipids and inflammation appear distinctly tied to atherosclerosis; while DN and endogenous metabolites may play a role in cardiomyopathy. Our findings suggest the need for targeted therapeutic approaches for CVD in T1D, depending on whether manifestations are predominantly atherosclerotic or cardiomyopathic.