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Title: Arginine and its metabolites in acute myocardial infarction
Abstract:
Introduction Arginine is a substrate for nitric oxide (NO) synthesis and depends on the competition of nitric oxide synthase (NOS) and arginase. Experimental models provide arguments that during acute phase of myocardial infarction (MI) arginase activity increases simultaneously with decreased NO synthesis. There is no sufficient data about alterations in arginine metabolism during MI in human and its association with myocardial injury, incidence of vulnerable coronary plaques and burden of stable coronary intima-media lesions. I hypothesize that i) during acute MI phase in human arginine metabolism is shifted from NOS towards arginase, ii) enhanced arginase activity expressed as an altered balance of arginine metabolites is associated with myocardial damage and with unfavorable morphology of a culprit lesion in the infarct-related artery (IRA), iii) persistent enhanced arginase activity during follow-up is associated with increased intima-media burden adjacent to culprit region and that iv) enhanced arginase activity potentially might be useful for prediction of adverse clinical events. Aims: 1. To measure arginine metabolites in acute phase of MI and during stable 6-month follow up and to estimate shifts in arginine metabolism in human. 2. To compare alterations in arginine metabolites balance with myocardial injury. 3. To compare alterations in a ; rginine metabolites balance with morphology of a culprit lesion and of an adjacent to the culprit region of IRA. 4. To evaluate association between arginine metabolites balance and clinical prognosis after MI. Methods Plasma concentrations of arginine, its metabolites and nitrite/nitrate (NOx) were measured in duplicates using ultraperformance liquid chromatography- tandem mass spectrometer (UPLC-MS/MS) with Waters ACQUITY UPLC (Waters Corporation, Milford, MA, USA) coupled to a Waters TQD mass spectrometer (electrospray ionizationmode ESItandem quadrupole). In the first study, seventy consecutive ST segment elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (pPCI) were enrolled and plasma concentrations of arginine metabolites were measured using at baseline and at 6 months. Arginine metabolites and their indices were compared with left ventricle (LV) function, volumes, mass, area at risk (AAR), infarct size (IS) and microvascular obstruction (MVO) in cardiac magnetic resonance and with incidence of composite endpoint (death, recurrent MI or hospitalization due to heart failure) during follow-up. In the second study one hundred consecutive STEMI patients who underwent pPCI were enrolled and plasma concentrations of arginine metabolites were measured at baseline and at 6 months. Again, arginine ; measurements were compared with morphology of culprit lesion, including presence of thin-cap fibroatheroma (TCFA) and of adjacent to the culprit proximal and distal 10 millimeters segments assessed with optical coherence tomography. The composite ischemic endpoint in this study was death, recurrent MI, stroke, or unplanned PCI due to unstable angina. As controls served 25 patients without atherosclerotic lesions in coronary angiography despite positive stress tests for ischemia, similar to the MI group in terms of demographics, cardiovascular risk factors and comorbidities. Results In the first study, following ischemia median citrulline/arginine index decreased when compared with 6-month result (P=0,002). Baseline median concentrations of arginine, citrulline, ornithine and asymmetric dimethylarginine (ADMA) were correlated with ratios of AAR/LV and IS/LV. The concentrations of arginine (P=0,021) and ADMA (P=0,009) were higher but NOx (P=0,003) was lower in patients with MVO when compared to subjects without MVO. By Cox regression, arginine concentration lower <29 μM as measured 6 months following MI adjusted to age, sex and IS was independently associated with 2,5 more frequent composite endpoint including death, recurrent MI or heart failure hospitalization during 5-year follow-up. The results of the second study showed that during acute ph ; ase of MI the ornithine/arginine index and the proline/arginine index increased, while the citrulline/arginine index and the citrulline/ornithine index decreased as compared to 6- month follow-up (P<0,001 for all). Patients with TCFA present in the IRA culprit lesion in an acute phase had higher plasma levels of ADMA (P=0,015), ornithine (P=0,003) and lower indices of citrulline/ornithine (P=0,003) and arginine/ADMA (P=0,040) when compared with patients without TFCA. A mean diameter of the intima or intima-media in the adjacent segment of the IRA correlated with the ornithine/arginine ratio measured at follow-up (R=0,337; P=0,003). By multivariable analysis, a higher citrulline/ornithine index as measured in acute MI phase was associated with a lower risk of TCFA presence (odds ratio 0,978; 95% confidence interval [CI] for odds ratio 0,962-0,994; P=0,006) whereas a higher follow-up ornithine/arginine index correlated with larger intima-media diameter of adjacent segments (beta-coefficient 0,227, 95% CI for beta-coefficient 0,045–0,409; P = 0,018). The third paper, a care report of three aortic valve stenosis patients who suffered from a periprocedural MI as a result of iatrogenic coronary artery dissection, showed extremely high risk of death associated with this rare complication. Conclusions In acute phase of MI, plasma arginine metabolism is shift ; ed from NOS towards arginase as compared with stable condition. Moreover, following acute ischemia plasma levels of arginine and its metabolites correlated with myocardial and microvascular injury while metabolic arginine shift from NOS towards arginase is associated with the presence of TCFA in the culprit region of IRA. In turn, similar persistent metabolic alterations in a stable chronic phase correlated with the thickness of intima or intima-media in the adjacent to the culprit segment of IRA. Decreased 6-month arginine concentration and increased ornithine/arginine index were associated with an unfavorable long-term outcome.
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Rada Dyscypliny Nauki medyczne
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Last modified:
Jul 9, 2024
In our library since:
Jun 5, 2024
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http://dl.cm-uj.krakow.pl:8080/publication/5133
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| Edition name | Date |
|---|---|
| ZB-140238 | Jul 9, 2024 |
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