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      Increased symmetric dimethylarginine, but not asymmetric dimethylarginine, concentrations are associated with transient myocardial ischemia and predict outcome

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          Abstract

          Objective

          Asymmetric and symmetric dimethylarginines (ADMA and SDMA) are endothelial dysfunction markers. ADMA inhibits synthesis of nitric oxide. We aimed to analyze both markers in patients with coronary artery disease (CAD) who were referred for stress/rest myocardial perfusion scintigraphy (MPS).

          Methods

          All patients underwent a 2-day dipyridamole (DP) stress/rest protocol. Thereafter, patients with transient myocardial perfusion abnormality were followed up and their coronary blood flow was quantitatively assessed. Venous blood was taken before and after DP stress to measure markers.

          Results

          Baseline ADMA and SDMA concentrations were significantly higher in patients with CAD compared with healthy subjects. Pre- and post-stress SDMA concentrations were significantly higher in patients with transient myocardial perfusion abnormality compared with those with negative MPS results. However, ADMA and L-arginine concentrations were not significantly different between the two groups. None of the markers were significantly different between patients with angiographically proven low coronary flow and those with normal coronary flow. Pre-stress SDMA concentrations were an independent predictor of cardiovascular mortality during a 8-year follow-up.

          Conclusions

          Elevated serum SDMA concentrations may be helpful for selecting high-risk patients with CAD if there is any doubt in interpreting MPS. SDMA concentrations may also predict cardiovascular outcome.

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          Most cited references24

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          TIMI frame count: a quantitative method of assessing coronary artery flow.

          C Gibson, C Cannon, W Daley … (1996)
          Although the Thrombolysis in Myocardial Infarction (TIMI) flow grade is valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature. In normal patients and patients with acute myocardial infarction (MI) (TIMI 4), the number of cineframes needed for dye to reach standardized distal landmarks was counted to objectively assess an index of coronary blood flow as a continuous variable. The TIMI frame-counting method was reproducible (mean absolute difference between two injections, 4.7 +/- 3.9 frames, n=85). In 78 consecutive normal arteries, the left anterior descending coronary artery (LAD) TIMI frame count (36.2 +/- 2.6 frames) was 1.7 times longer than the mean of the right coronary artery (20.4 +/- 3.0) and circumflex counts (22.2 +/- 4.1, P < .001 for either versus LAD). Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC). The mean CTFC in culprit arteries 90 minutes after thrombolytic administration followed a continuous unimodal distribution (there were not subpopulations of slow and fast flow) with a mean value of 39.2 +/- 20.0 frames, which improved to 31.7 +/- 12.9 frames by 18 to 36 hours (P < .001). No correlation existed between improvements in CTFCs and changes in minimum lumen diameter (r=-.05, P=.59). The mean 90-minute CTFC among nonculprit arteries (25.5 +/- 9.8) was significantly higher (flow was slower) compared with arteries with normal flow in the absence of acute MI (21.0 +/- 3.1, P < .001) but improved to that of normal arteries by 1 day after thrombolysis (21.7 +/- 7.1, P=NS). The CTFC is a simple, reproducible, objective and quantitative index of coronary flow that allows standardization of TIMI flow grades and facilitates comparisons of angiographic end points between trials. Disordered resistance vessel function may account in part for reductions in flow in the early hours after thrombolysis.
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            Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease.

            Manfred Fobker, Jan Kielstein, Jens Martens-Lobenhoffer … (2006)
            Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine. Whereas the major route of asymmetric dimethylarginine elimination is the hydrolytic degradation by dimethylarginine dimethylaminohydrolase, SDMA is eliminated by renal excretion. SDMA does not directly inhibit NOS but is a competitor of arginine transport. This study showed for the first time that measurement of SDMA can be a marker of estimated GFR and extent of coronary artery disease (CAD). In 97 patients with CAD, SDMA was a marker of estimated GFR. On multiple regression analysis of the CAD parameter stenosis score, SDMA was the only parameter retained. In addition, endothelial cells from the third passage were cultured in medium that contained 70 micromol/L arginine and was incubated for 24 h in the presence of various concentration of SDMA (0, 2, 5, 10, and 100 micromol/L). The levels of nitrate and nitrite in conditioned media, the protein expression of NOS, and the content of reactive oxygen species in endothelial cells were determined. SDMA inhibited dose dependently the NO synthesis in intact endothelial cells, whereas it had no effect on protein expression of NOS. This effect was associated with an increase in reactive oxygen species. Co-incubation with L-arginine but not D-arginine reversed the effect of SDMA on NOS pathway. Our data suggest that SDMA reduced the endothelial NO synthesis, probably by limiting L-arginine supply to NOS. It is concluded that SDMA might be a useful parameter for detecting patients in very early stages of chronic kidney disease and for determining their risk for developing cardiovascular disease.
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              Symmetrical and asymmetrical dimethylarginine as predictors for mortality in patients referred for coronary angiography: the Ludwigshafen Risk and Cardiovascular Health study.

              Stefan Pilz, Bernhard R. Winkelmann, Andreas Meinitzer … (2010)
              Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been linked to cardiovascular risk. The clinical role of its structural isomer symmetrical dimethylarginine (SDMA) remains largely unclear. We measured SDMA and ADMA in 3229 patients undergoing coronary angiography at baseline (1997-2000) and recorded total and cardiovascular mortality during a median follow-up time of 7.7 years. We investigated associations of SDMA with cardiovascular risk factors and mortality and compared its role as a cardiovascular risk factor with ADMA, which predicted mortality in previous analyses of our study. In linear regression analyses including common cardiovascular risk factors as covariates, SDMA and ADMA were significantly associated with cystatin C, N-terminal pro-B-type natriuretic peptide, New York Heart Association classification, and homocysteine. The regression coefficients were higher for SDMA than for ADMA. In Cox proportional-hazards models adjusted for cardiovascular risk factors, the hazard ratios (HRs) (with 95% CI) in the second, third, and fourth SDMA quartile compared to the lowest quartile were 0.77 (0.60-0.99), 0.99 (0.78-1.25), and 1.51 (1.20-1.91) for total mortality and 0.92 (0.68-1.25), 0.93 (0.68-1.26), and 1.54 (1.14-2.01) for cardiovascular mortality. The same calculations for ADMA quartiles revealed HRs of 1.05 (0.83-1.32), 1.19 (0.95-1.50), and 1.61 (1.30-1.99) for total mortality and HR of 1.00 (0.74-1.34), 1.26 (0.95-1.68), and 1.54 (1.18-2.02) for cardiovascular mortality. Serum concentrations of SDMA are independently associated with increased cardiovascular and all-cause mortality in patients undergoing coronary angiography. The pattern of risk linked to SDMA is different from that linked to ADMA, suggesting different pathophysiological roles of these 2 methylarginine metabolites.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Int Med Res
                Journal ID (iso-abbrev): J. Int. Med. Res
                Journal ID (publisher-id): IMR
                Journal ID (hwp): spimr
                Title: The Journal of International Medical Research
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 0300-0605
                ISSN (Electronic): 1473-2300
                Publication date (Electronic): 12 June 2020
                Publication date Collection: June 2020
                Volume: 48
                Issue: 6
                Electronic Location Identifier: 0300060520920439
                Affiliations
                [1 ]Department of Nuclear Medicine, Medical School, University of Pecs, Pecs, Hungary
                [2 ]First Department of Medicine, Medical School, University of Pecs, Pecs, Hungary
                [3 ]Department of Applied Chemistry, University of Debrecen, Debrecen, Hungary
                [4 ]Department of Anesthesiology and Intensive Care, Medical School, University of Pecs, Pecs, Hungary
                Author notes
                [*]Tihamer Molnar, Department of Anesthesiology and Intensive Care, University of Pecs, Medical School, Pecs, Ifjusag u. 13., Pecs, 7623 Hungary. Email: tihamermolnar@ 123456yahoo.com
                Author information
                https://orcid.org/0000-0002-6149-9787
                Article
                Publisher ID: 10.1177_0300060520920439
                DOI: 10.1177/0300060520920439
                PMC ID: 7294388
                PubMed ID: 32529878
                SO-VID: f0244017-2323-47b4-83fe-e738cb0c5348
                Copyright © © The Author(s) 2020
                License:

                Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 11 October 2019
                Date accepted : 23 March 2020
                Categories
                Subject: Prospective Clinical Research Report
                Custom metadata
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                typesetter ts2

                Keywords: dipyridamole,coronary artery disease,asymmetric dimethylarginine,myocardial perfusion scintigraphy,l-arginine,cardiovascular mortality
                Data availability:
                Keywords: dipyridamole, coronary artery disease, asymmetric dimethylarginine, myocardial perfusion scintigraphy, l-arginine, cardiovascular mortality

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