An altered balance of plasma arginine metabolites is associated with increased thickness of the coronary intima-media complex in the adjacent to the culprit segment of an infarct-related artery

Abstract

Abstract Background The biomarkers of atherosclerosis remain insufficiently understood. Purpose We sought to investigate whether an altered balance of arginine metabolites in patients following myocardial infarction (MI) is associated with remodeling of the adjacent to the culprit segments of an infarct-related artery (IRA) and with clinical outcomes. Methods Arginine and its metabolites including ornithine, citrulline, proline and asymmetric dimethylarginine were measured using liquid chromatography and tandem mass spectrometry in 85 consecutive ST-segment elevation MI patients upon admission and at 6-month follow-up and were compared with morphology of the adjacent to the culprit proximal and distal 10-mm segments of IRA assessed with optical coherence tomography. A composite ischemic event was defined as death, recurrent MI, stroke, or unplanned percutaneous coronary intervention. Results The ratios of citrulline/ornithine and citrulline/arginine decreased 5.22 and 2.20 times (both P<0.001) respectively, while the ornithine/arginine index (I_O/A) increased 2.96 times (P<0.001) following ischemia compared with stable follow-up, indicating the enhanced arginase activity over nitric oxide synthase (NOS) in acute phase of STEMI. Follow-up I_O/A correlated with the mean intima-media (R=0.34, P=0.003, Figure 1A) and intima (R=0.30, P=0.008) diameter of an adjacent to the culprit IRA segment. By multivariate analysis, apart from male gender (P<0.001) and diabetes mellitus (P=0.02), a higher follow-up I_O/A was associated with the larger mean intima-media diameter of an adjacent to the culprit IRA segments (coefficient 0.218, 95% confidence interval 0.040–0.397, P=0.017, per 0.01). Within the median follow-up of 25 (19–35) months, ischemic composite endpoint was found in 13 (15.3%) patients. The follow-up I_O/A reached the area under the ROC curve of 0.78 (95% confidence interval 0.66–0.91, P=0.005) for prediction of composite ischemic endpoint with a cut-off value of ≥0.57, and a sensitivity of 72.3% and specificity of 80.0% (Figure !B). Conclusions Our findings provide arguments that during the acute phase of MI, arginine metabolism is shifted from NOS towards arginase, as compared to 6-month stable conditions. Simultaneously, the enhanced residual arginase activity over NOS in chronic phase was correlated with a higher thickness of intima or intima-media in the adjacent to the culprit segment within the IRA, and was also associated with unfavorable clinical outcomes. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant of the National Science Center of Poland (Number 2016/21/B/NZ5/01378 to J.Z.)