Plasma metabolome reveals systemic oxidative stress and impaired mitochondrial energetics in coronary microvascular dysfunction
R Najjar, C Liu, Y Go, F Rashid, V Thaker, B Bogan, A Quyyumi, D Jones, P K MehtaAbstract
Background
Coronary microvascuar dysfunction (CMD) is a major mechanism of ischemia with non-obstructive coronary artery disease (CAD) and associated with poor physical function. CMD (coronary flow reserve <2.5) is linked to endothelial dysfunction and oxidative stress, but the pathobiological processes reflected in the plasma metabolome remain poorly characterized.
Purpose
The objective was to identify metabolites and pathway-level signatures that distinguish CMD from non-CMD using untargeted plasma metabolomics.
Methods
Plasma from CMD (n=22) and non-CMD (n=15) women (ages 56±11) was analyzed by untargeted high-resolution metabolomic profiling using standard liquid chromatography-mass spectrometry methods. Putative metabolite annotations used m/z and retention time (MS1 level). Data were filtered for low variance and missingness, imputed at the limit of detection, median-normalized, log2-transformed, and autoscaled. Group differences were assessed with univariate linear models (FDR-corrected q<0.05). Significant features were ranked by t-statistic for mummichog pathway analysis. For selected features, normalized intensities were compared using Welch’s t-tests (unadjusted p<0.05).
Results
Plasma metabolomic profiling identified statistically significant, distinct biochemical signatures in CMD indicative of increased oxidative stress, altered mitochondrial substrate utilization, and impaired energetics (Figure). A) Oxidative stress: Compared to non-CMD group, those with CMD had increased dehydroascorbic acid and α-tocotrienoxyl radical, products of vitamin C and E oxidation, respectively. L-xylonic acid, indicative of sustained oxidative stress, was also increased in CMD. B) Mitochondrial substrate handling: In CMD group, free fatty acids were reduced alongside increased long-chain acylcarnitines, indicating incomplete β-oxidation, acyl-CoA accumulation, and subsequent acylcarnitine overflow. C) Impaired energy metabolism: Non-oxidative pentose phosphate pathway intermediates (D-glucuronate, L-gulonate, 3-dehydro-gulonate, and sedoheptulose) were elevated in CMD group, indicating increased fuel to sustain glycolysis. Increased lactate accumulation in CMD group indicated impaired pyruvate oxidation and TCA-cycle bottlenecks (increased malate, decreased oxaloacetate). This was supported by increased propanoylcarnitine and 2-methylaconitate/methylisocitrate, which may reflect increased propionyl-CoA, and increased inhibitory methylcitrate-intermediates. Adenosine monophosphate levels were increased, consistent with reduced cellular energetics.
Conclusion
CMD is associated with metabolomic signatures of oxidative stress, mitochondrial substrate congestion, and impaired oxidative energy metabolism. These findings implicate mitochondrial dysfunction as a key component of CMD pathophysiology that may contribute to impaired physical function. Targeted MS/MS confirmation is needed to validate these findings.Mitochondrial dysfunction in CMD