Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction

Background-Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. Methods and Results-Participants were patients with ST-segment-elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (beta=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P = 6.4x10(-4)) and ISZ (beta=-0.41 [95% CI, -0.60 to -0.21]; P = 3.2x10(-5)). In addition, 24 hours post-MI measurements of medium HDL-TG (beta=-0.40 [95% CI, -0.60 to -0.20]; P = 6.4x2x10(-5)), small HDL-TG (beta=-0.34 [95% CI, -0.53 to -0.14]; P = 7.3x10(-4)), and the triglyceride content of very large HDL (beta=-0.38 [95% CI, -0.58 to -0.18]; P = 2.7x10(-4)) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P = 7.5x10(-5)); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P = 2.4x10(-4)). Conclusions-HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles.