Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes
Jessica A. Regan, Robert J. Mentz, Maggie Nguyen, Jennifer B. Green, Lauren K. Truby, Olga Ilkayeva, Christopher B. Newgard, John B. Buse, Harald Sourij, C. David Sjöström, Naveed Sattar, Robert W. McGarrah, Yinggan Zheng, Darren K. McGuire, Eberhard Standl, Paul Armstrong, Eric D. Peterson, Adrian F. Hernandez, Rury R. Holman, Svati H. Shah
Jessica A. Regan, Robert J. Mentz, Maggie Nguyen, Jennifer B. Green, Lauren K. Truby, Olga Ilkayeva, Christopher B. Newgard, John B. Buse, Harald Sourij, C. David Sjöström, Naveed Sattar, Robert W. McGarrah, Yinggan Zheng, Darren K. McGuire, Eberhard Standl, Paul Armstrong, Eric D. Peterson, Adrian F. Hernandez, Rury R. Holman, Svati H. Shah
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Research Article Cardiology Metabolism

Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes

Abstract

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Authors

Jessica A. Regan, Robert J. Mentz, Maggie Nguyen, Jennifer B. Green, Lauren K. Truby, Olga Ilkayeva, Christopher B. Newgard, John B. Buse, Harald Sourij, C. David Sjöström, Naveed Sattar, Robert W. McGarrah, Yinggan Zheng, Darren K. McGuire, Eberhard Standl, Paul Armstrong, Eric D. Peterson, Adrian F. Hernandez, Rury R. Holman, Svati H. Shah

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Figure 5

Mitochondrial markers of dysregulated fatty acid oxidation associate with MACE in T2D.

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Mitochondrial markers of dysregulated fatty acid oxidation associate wit...
Medium- and long-chain fatty acids are transported across the plasma membrane by fatty acid transporters and then converted into their acyl-CoA and cross the outer mitochondrial membranes. The inner mitochondrial membrane is impermeable to acyl-CoAs and carnitine palmitoyl transferase I is required to esterify the acyl-CoA plus carnitine into acylcarnitines. Inside the inner mitochondrial membrane, carnitine acyltransferase is reverse esterified back to an acyl-CoA to undergo β oxidation with carbon chain removal until an acetyl-CoA remains to enter the TCA cycle and, ultimately, the electron transport chain for ATP energy production. In states of impaired mitochondrial fatty acid β oxidation and metabolic inflexibility, plasma levels of MCACs and LCACs levels may increase. Based on the present analyses in T2D, increased levels of MCACs and LCACs associate with incident MACE. The working hypothesis for the data presented here is that inefficient fatty acid oxidation in the mitochondria contribute to the bottle neck of substrate utilization and buildup of circulating levels of acylcarnitines. However, the tissue source is not clear and, alternatively, accumulations in these metabolites could also reflect increased mitochondrial fatty acid flux with incomplete fatty acid oxidation. CPT I, carnitine palmitoyltransferase I; CPT II, carnitine palmitoyltransferase II.