Abstract 452: A Unique Acylcarnitine Profile is Independently Associated with Diabetic Heart Failure and Associates with Adverse Clinical Outcomes: Insights from the FIGHT Trial

Abstract

Introduction: Heart failure with reduced ejection fraction (HFrEF) may be associated with unique metabolic derangements in patients with type 2 diabetes (T2DM). However, whether such derangements are associated with clinical outcomes remains unclear. Purpose: 1) To determine metabolic pathways that are dysregulated in high-risk HFrEF with and without T2DM. 2) To identify metabolomic signatures which may be differentially associated with clinical outcomes in HFrEF patients with T2DM. Methods: The FIGHT trial studied the effect of liraglutide on clinical stability in individuals with advanced HFrEF. Forty-five metabolites were quantified in 254 baseline plasma samples from the trial (T2DM: n=147, non-T2DM: n=107) using tandem flow injection mass spectrometry. Principal component analysis (PCA) was used to reduce the high number of correlated metabolites into uncorrelated factors. Linear regression was used to evaluate the association of T2DM with PCA-derived factor levels. Cox proportional hazards models, stratified by T2DM status, were used to test for time to mortality or HF hospitalization. Results: Patients with T2DM were older, had higher BMI, and were more likely to have CAD, but had similar gender composition and severity of HF, as compared with non-T2DM patients. PCA identified 13 metabolite factors grouping in biologically consistent pathways. T2DM status was associated with two factors, one composed of the short chain dicarboxyl-acylcarnitine, C6-DC, and the long-chain acylcarnitine C22 (β= -0.325, p=0.016), and one composed of aspartic acid/asparagine (β= -0.373, p=0.008), in fully adjusted models. The same C6-DC, C22 factor was associated with time to mortality or HF hospitalization beyond adjustment for sex, race, liraglutide exposure, baseline age, systolic blood pressure, creatinine, BMI, NT-pro-BNP, and liver function (T2DM: HR 1.573, p=0.007; Non-T2DM: HR 1.302, p=0.103). Conclusions: Amongst patients with high-risk HFrEF, those with T2DM had differential levels of a short chain dicarboxyl- and long-chain acylcarnitine, which were associated with adverse clinical outcomes. Such metabolites might serve as potential targets for diagnostic or therapeutic interventions in diabetic HFrEF.