A Metabolomics Study of Cardiac Dysfunction in Hyperglycemia: Findings From the Atherosclerosis Risk in Communities (ARIC) Study and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

OBJECTIVE Hyperglycemic states (prediabetes and diabetes) are associated with heart failure (HF) risk. We aimed to identify distinct metabolites for subclinical cardiac dysfunction, a precursor of HF, in hyperglycemic or euglycemic individuals. RESEARCH DESIGN AND METHODS We conducted cross-sectional and prospective analyses of 2,492 HF-free participants from the Atherosclerosis Risk in Communities (ARIC) study visit 5, 2011–2013. A total of 1,297 participants were hyperglycemic (assessed on the basis of hemoglobin A_1c >5.7%, fasting glucose >100 mg/dL, use of diabetes medication, or diagnosis), and 1,195 were euglycemic. We used logistic regression for analysis of association between 790 metabolites and cardiac dysfunction, defined according to echocardiographic abnormalities (left ventricular hypertrophy, systolic or diastolic dysfunction) or elevated NT-proBNP or troponin T, in two glycemic groups separately. We used Cox regression for prospective association between cardiac dysfunction–related metabolites identified in the prior step and HF risk, adjusting for clinical risk factors. Analyses were replicated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n = 5,167). RESULTS Microvascular disease–related metabolites (e.g., pseudouridine, N6-carbamoylthreonyl adenosine, N6-acetyllysine, N2,N5-diacetylornithine) were associated with cardiac dysfunction in hyperglycemic individuals. Carbohydrate and cofactor-derived metabolites (e.g., gulonate, erythrocyte) were associated with cardiac dysfunction in euglycemic individuals. These cardiac dysfunction–related metabolites were prospectively associated with HF risk in the two glycemic groups (follow-up 7.5 years, 137 and 94 HF cases, per-SD increase hazard ratios range 1–1.9 and 1.1–2.9), respectively. HCHS/SOL results were consistent with those from ARIC. CONCLUSIONS Metabolites known for microvascular complications were associated with cardiac dysfunction in hyperglycemic individuals but not among their euglycemic counterparts, supporting the premise that microvascular dysfunction contributes to HF pathogenesis in diabetes.