High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction

PLOS ONE, Dec 2019

Objectives Low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of acute myocardial infarction possibly through impaired endothelial atheroprotection and decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) mediates endothelial function by inhibiting nitric oxide synthase activity. In patients with acute myocardial infarction, we investigated the relationship between serum levels of HDL and ADMA. Approach and Results Blood samples from 612 consecutive patients hospitalized for acute MI <24 hours after symptom onset were taken on admission. Serum levels of ADMA, its stereoisomer, symmetric dimethylarginine (SDMA) and L-arginine were determined using high-performance liquid chromatography. Patients with low HDL (<40 mg/dL for men and <50 mg/dL for women) were compared with patients with higher HDL. Most patients (59%) had low HDL levels. Median ADMA levels were markedly higher in the low HDL group (0.69 vs. 0.50 µmole/L, p<0.001). In contrast, SDMA and L-arginine levels were similar for the two groups (p = 0.120 and p = 0.064). Notably, ADMA, but not SDMA or L-arginine, was inversely correlated with HDL (r = −0.311, p<0.001). In stratified analysis, this relationship was only found for low HDL levels (r = −0.265, p<0.001), but not when HDL levels were higher (r = −0.077, p = 0.225). By multivariate logistic regression analysis, ADMA level was strongly associated with low HDL levels (OR(95%CI):6.06(3.48–10.53), p<0.001), beyond traditional confounding factors. Conclusions Our large population-based study showed for the first time a strong inverse relationship between HDL and ADMA in myocardial infarction patients, suggesting a functional interaction between HDL and endothelium, beyond metabolic conditions associated with low HDL levels.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064796&type=printable

High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction

et al. (2013) High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction. PLoS ONE 8(6): e64796. doi:10.1371/journal.pone.0064796 High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction Julie Lorin 0 Jean-Claude Guilland 0 Claudia Korandji 0 Claude Touzery 0 Florence Bichat 0 Aline Chagnon 0 Yves Cottin 0 Luc Rochette 0 Catherine Vergely 0 Marianne Zeller 0 Alexander A. Mongin, Albany Medical College, United States of America 0 1 INSERM UMR866- Laboratory of Cardiometabolic Physiopathology and Pharmacology, University of Burgundy, Dijon, France, 2 Cardiology Department, University Hospital , Dijon , France Objectives: Low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of acute myocardial infarction possibly through impaired endothelial atheroprotection and decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) mediates endothelial function by inhibiting nitric oxide synthase activity. In patients with acute myocardial infarction, we investigated the relationship between serum levels of HDL and ADMA. Approach and Results: Blood samples from 612 consecutive patients hospitalized for acute MI ,24 hours after symptom onset were taken on admission. Serum levels of ADMA, its stereoisomer, symmetric dimethylarginine (SDMA) and L-arginine were determined using high-performance liquid chromatography. Patients with low HDL (,40 mg/dL for men and ,50 mg/dL for women) were compared with patients with higher HDL. Most patients (59%) had low HDL levels. Median ADMA levels were markedly higher in the low HDL group (0.69 vs. 0.50 mmole/L, p,0.001). In contrast, SDMA and L-arginine levels were similar for the two groups (p = 0.120 and p = 0.064). Notably, ADMA, but not SDMA or L-arginine, was inversely correlated with HDL (r = 20.311, p,0.001). In stratified analysis, this relationship was only found for low HDL levels (r = 20.265, p,0.001), but not when HDL levels were higher (r = 20.077, p = 0.225). By multivariate logistic regression analysis, ADMA level was strongly associated with low HDL levels (OR(95%CI):6.06(3.48-10.53), p,0.001), beyond traditional confounding factors. Conclusions: Our large population-based study showed for the first time a strong inverse relationship between HDL and ADMA in myocardial infarction patients, suggesting a functional interaction between HDL and endothelium, beyond metabolic conditions associated with low HDL levels. - Funding: This work was supported by the University Hospital of Dijon, the Association de Cardiologie de Bourgogne, and by grants from the Agence Regionale de Sante (ARS) de Bourgogne, the French Ministry of Research from the Institut National de la Sante et de la Recherche Medicale (INSERM) and from the Regional Council of Burgundy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Reduced endothelial nitric oxide (NO) bioavailability contributes to the development and progression of atherosclerosis, leading to coronary artery disease (CAD). Asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of all isoforms of nitric oxide synthases (NOS), may compete with L-arginine as the substrate for the enzyme or inhibit NOS phosphorylation and thus decrease NO bioavailability [1,2]. ADMA and its stereoisomer, symmetric dimethylarginine (SDMA) are endogenously produced by the methylation of arginine residues from nuclear proteins and are released after proteolysis. Unlike ADMA, which is a primary factor in the control of NOS activity, SDMA has insignificant inhibitory effects on the enzyme. High ADMA concentrations have been associated with most cardiovascular risk factors, including dyslipidemia [3,4]. Moreover, several lines of evidence have demonstrated that elevated ADMA levels are associated with endothelial dysfunction in healthy subjects and in patients with CAD or hypercholesterolemia, [3,5]. Epidemiological studies and randomized clinical trials have showed that low plasma levels of high-density lipoprotein (HDL) are associated with an increased risk of cardiovascular events in CAD patients, suggesting that HDL-C (HDL cholesterol) has cardioprotective effects [6]. This strong relationship has stimulated interest in determining mechanisms and optimal management of low levels of HDL-C. Beyond reverse cholesterol transport, the molecular mechanisms underlying the anti-atherogenic properties of HDL-C include antioxidant, anti-inflammatory and vasculoprotective effects [7]. Moreover, experimental studies have identified various direct endothelial protective effects of HDL-C, including the stimulation of endothelial NO production [8]. HDLC restores endothelial function by increasing NO bioavailabi (...truncated)


This is a preview of a remote PDF: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0064796&type=printable

Julie Lorin, Jean-Claude Guilland, Claudia Korandji, Claude Touzery, Florence Bichat, Aline Chagnon, Yves Cottin, Luc Rochette, Catherine Vergely, Marianne Zeller. High Levels of Asymmetric Dimethylarginine Are Strongly Associated with Low HDL in Patients with Acute Myocardial Infarction, PLOS ONE, 2013, Volume 8, Issue 6, DOI: 10.1371/journal.pone.0064796