Incidence of All-Cause and Cardiovascular Mortality Predicted by Symmetric Dimethylarginine in the Population-Based Study of Health in Pomerania

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Abstract

Background

L-Arginine and its dimethylated derivatives asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been associated with cardiovascular (CV) and all-cause mortality in populations at risk. The present study aimed to investigate the prognostic value of L-arginine and its derivatives in the general population.

Methods and Results

We evaluated 3,952 individuals (1,936 men and 2,016 women) aged 20–81 (median (IQR) 51 (37; 64) years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous [per standard deviation (SD) increase] and categorized (age- and sex-specific tertiles) serum L-arginine, ADMA, and SDMA concentrations with all-cause and cause-specific mortality were analysed. During a median (IQR) follow-up period of 10.1 (9.3; 10.8) years (38,476 person-years), 426 deaths (10.8%) were observed, including 139 CV deaths (3.5%), and 150 cancer deaths (3.8%). After multivariable adjustment, we revealed a positive association of SDMA with all-cause [hazard ratio (HR) per SD increase: 1.16, 95% confidence interval (CI): 1.07–1.25] and CV mortality [HR: 1.19, 95% CI: 1.05–1.35]. In contrast, we did not observe any association of SDMA with cancer mortality. Neither L-arginine nor ADMA were associated with all-cause or CV mortality.

Conclusion

SDMA, but not ADMA, is an independent predictor of all-cause and CV mortality in a large population-based cohort of European ancestry.

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Most cited references 19

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Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.

Timothy Collier, A Calver, Peter A. Leone … (1992)

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.

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The role of nitric oxide on endothelial function.

Dimitris Tousoulis, Christodoulos Stefanadis, Anna-Maria Kampoli … (2011)

The vascular endothelium is a monolayer of cells between the vessel lumen and the vascular smooth muscle cells. Nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme nitric oxide synthase (NOS). This substance has a wide range of biological properties that maintain vascular homeostasis, including modulation of vascular dilator tone, regulation of local cell growth, and protection of the vessel from injurious consequences of platelets and cells circulating in blood, playing in this way a crucial role in the normal endothelial function. A growing list of conditions, including those commonly associated as risk factors for atherosclerosis such as hypertension, hypercholesterolemia, smoking, diabetes mellitus and heart failure are associated with diminished release of nitric oxide into the arterial wall either because of impaired synthesis or excessive oxidative degradation. The decreased production of NO in these pathological states causes serious problems in endothelial equilibrium and that is the reason why numerous therapies have been investigated to assess the possibility of reversing endothelial dysfunction by enhancing the release of nitric oxide from the endothelium. In the present review we will discuss the important role of nitric oxide in physiological endothelium and we will pinpoint the significance of this molecule in pathological states altering the endothelial function.

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Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community.

Rainer H. Böger, Lisa M. Sullivan, Edzard Schwedhelm … (2009)

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated. We related plasma ADMA, l-arginine (Arg), and the ratio of Arg to ADMA to the incidence of cardiovascular disease (fatal or nonfatal myocardial infarction, coronary insufficiency, angina pectoris, stroke or transient ischemic attack, intermittent claudication, or heart failure) and death in 3320 Framingham Offspring Study participants (1769 women; mean age, 59 years). Over a follow-up period of 10.9 years, 281 individuals of 2956 free of cardiovascular disease at baseline developed incident cardiovascular disease, and 285 participants died. In multivariable models adjusting for established risk factors and other biomarkers (B-type natriuretic peptide, renin, homocysteine, urine albumin excretion, and C-reactive protein), ADMA and the ratio of Arg to ADMA were significantly associated with all-cause mortality (adjusted-hazard ratio [HR] per 1-SD increment, 1.21; 95% CI, 1.07 to 1.37; and HR per 1-SD increment, 0.80; 95% CI, 0.69 to 0.93, respectively), whereas Arg was not (HR per 1-SD increment, 0.89; 95% CI, 0.77 to 1.02). We noted effect modification by diabetes status; ADMA was associated with death in individuals without diabetes (adjusted HR per 1-SD increment, 1.30; 95% CI, 1.13 to 1.50) but not in individuals with diabetes (adjusted HR per 1-SD increment, 0.85; 95% CI, 0.62 to 1.16). ADMA, Arg, and the ratio of Arg to ADMA were not associated with cardiovascular disease incidence (P>0.10). In our large community-based sample, ADMA was significantly associated with all-cause mortality, particularly in nondiabetic individuals.

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Author and article information

Contributors

Suminori Akiba: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 12 May 2014

Volume: 9

Issue: 5

Electronic Location Identifier: e96875

Affiliations

[1 ]Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

[2 ]Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

[3 ]DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Hamburg, Germany

[4 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany

[5 ]DZHK (German Centre for Cardiovascular Research), Partner Site, Greifswald, Germany

[6 ]Department of Internal Medicine B/Cardiology, University Medicine Greifswald, Greifswald, Germany

[7 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

[8 ]DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany

[9 ]Institute of Community Medicine, Department SHIP/Clinical Epidemiology, University Medicine Greifswald, Greifswald, Germany

Kagoshima University Graduate School of Medical and Dental Sciences, Japan

Author notes

* E-mail: schwedhelm@ 123456uke.de (ES); nele.friedrich@ 123456uni-greifswald.de (NF)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: ES HW RHB NF. Analyzed the data: NF. Wrote the paper: ES DA NF. Interpretion of data and revision of manuscript: ES NF RHB HW MD MN UV HKK HV.

Article

Publisher ID: PONE-D-14-05930

DOI: 10.1371/journal.pone.0096875

PMC ID: 4018357

PubMed ID: 24819070

SO-VID: b00c8453-a3c1-44e4-bfc0-8aaeb2d647d1

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 10 February 2014

Date accepted : 13 April 2014

Page count

Pages: 8

Funding

SHIP is part of the Community Medicine Net ( http://www.medizin.uni-greifswald.de/icm) of the University of Greifswald, which is funded by grants from the German Federal Ministry of Education and Research (BMBF, grant 01ZZ96030, 01ZZ0701); the Ministry for Education, Research, and Cultural Affairs; and the Ministry for Social Affairs of the Federal State of Mecklenburg–West Pomerania as well by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Incidence of All-Cause and Cardiovascular Mortality Predicted by Symmetric Dimethylarginine in the Population-Based Study of Health in Pomerania

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Abstract

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Methods and Results

Conclusion

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Most cited references 19

Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.

The role of nitric oxide on endothelial function.

Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community.

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