The shifted balance of arginine metabolites in acute myocardial infarction patients and its clinical relevance

Abstract

The arginine metabolism as a target for cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI) remains insufficiently understood. Arginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA) and proline plasma levels were measured using liquid chromatography and tandem mass spectrometry in 70 consecutive STEMI patients upon admission and at 6-month follow-up and were compared with left ventricular function, volumes, and infarct characteristics determined by cardiac magnetic resonance imaging, and with 5-year clinical outcomes. Baseline median concentration of arginine was higher by 49% (P = 0.002) when compared to 6-month measurements and was correlated with an ischemia risk area (R = 0.34, P = 0.004) and infarct size (R = 0.33, P = 0.006). Following ischemia median citrulline/arginine index decreased when compared with 6-month result (P = 0.002), while citrulline/ornithine and arginine/ADMA ratios maintained unchanged indicating a shift of arginine metabolism from nitric oxide synthase (NOS) towards arginase. The 6-month arginine concentration reached the area under the ROC curve of 0.67 (95% confidence interval 0.54–0.81) for prediction of death, myocardial infarction or heart failure hospitalization and its value of < 29 µM was associated with lower event free survival (P = 0.02). In STEMI patients, during ischemia conversion of elevated plasma arginine was shifted from NOS towards arginase. Decreased 6-month arginine concentrations were associated with worse long-term outcomes.

An Untargeted LC–MS based approach for identification of altered metabolites in blood plasma of rheumatic heart disease patients

“…Arginine is one of the most adaptable amino acid which acts as a precursor for protein, nitric oxide, polyamines, urea, glutamate, proline, agmatine and creatinine 21 . Lower arginine availability has been earlier reported to be associated with cardiovascular risk 22 . Proline and hydroxyproline are amino acids which help in maintaining cell structure and functions.…”

Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure

“…Many of these ‘adaptative immune response’ pathway members, and those involved in TCR signalling in particular, were negatively correlated ( Figure ) with both arginase gene transcripts (ARG1 and ARG2); which were 14%–16% more abundant in those that subsequently died (online supplementary Table ). Arginase degrades arginine and decreased arginine, preceded by a measurable increase in arginase activity, is associated with poorer 6‐month outcomes in patients with ST‐elevation myocardial infarction 19 . Arginase gene expression, induced by lactate production consequent to hypoxia, can limit T‐cell proliferation 20 .…”

“…Arginase degrades arginine and decreased arginine, preceded by a measurable increase in arginase activity, is associated with poorer 6-month outcomes in patients with ST-elevation myocardial infarction. 19 Arginase gene expression, induced by lactate production consequent to hypoxia, can limit T-cell proliferation. 20 A negative association between ARG2 and the pro-survival IL-7 receptor (IL7R/CD127) was observed in survivors (Figure 3A) potentially linking arginine metabolism and IL7R signalling role in T-cell survival and memory responses.…”

Identification of Potential Core Genes and Promising Compounds in STEMI Using Bioinformatics Analysis

“…A clinical investigation demonstrated that the expression level of arginase (ARG1) is elevated in individuals with STEMI and that it serves as an indicator of plaque susceptibility and has a correlation with infarction size in the clinical progression of this disease [50]. The underlying mechanism is that ARG1 lowers NO bioavailability and leads to atherosclerosis by depleting its common substrate (L-arginine) [51]. In acute MI, reduced NO bioavailability leads to endothelial impairment, plaque destabilization, and greater vulnerability to ischemia-reperfusion damage [52].…”