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Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study

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Abstract

Background

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor, which has been associated with total and cardiovascular mortality in various clinical settings. Studies on its structural isomer, symmetric dimethylarginine (SDMA), are scarce. This study aimed to determine the associations of both ADMA and SDMA levels with secondary cardiovascular disease events and all-cause mortality in patients with stable coronary heart disease (CHD).

Methods

In the observational prospective cohort study KAROLA, 1,148 CHD patients were followed for a median of 8.1 years. ADMA and SDMA were determined by liquid chromatography–tandem mass spectrometry. Baseline ADMA and SDMA levels were categorized in quartiles or standardized by their respective standard deviation, and appropriate hazard ratios and 95 % confidence intervals (HR [95 % CI]) were estimated in Cox proportional hazards models.

Results

150 patients experienced secondary cardiovascular disease events (CVD) and 121 patients died. After adjustment for confounders, ADMA was not associated with the risk of secondary CVD events (HR per standard deviation increase: 1.02 [95 %CI: 0.86–1.21]), whereas an association was suggested for SDMA (HR 1.17 [1.00–1.37]). Higher hazard ratios were observed in all-cause mortality models (ADMA: HR 1.15 [0.95–1.37]; SDMA: HR 1.29 [1.09–1.52]).

Conclusions

Our results suggest that especially SDMA might possibly have potential as a risk marker for all-cause mortality and to a lesser extent for secondary cardiovascular events. Future studies are needed to quantify these associations more precisely and should, in particular, further address the possibility of residual confounding by impaired kidney function.

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Acknowledgments

The authors wish to thank the participating patients and doctors. Our special thanks go out to Claudia El Idrissi-Lamghari, Data Manager of the KAROLA study, Mariola Kastner and Anna Steenpaß for the technical assistance with the ADMA measurements and Prof. Dr. F. M. Helmerhorst for the sparkling discussions on the subject. Funding: The work reflected in this article was in part funded by the German Ministry of Education and Research (Grant 01GD9820/0), the Association of German Pension Fund Agencies (Grant 02708), Willy-Robert-Pitzer Foundation, the Leducq Foundation, Paris, France for the development of Transatlantic Networks of Excellence in Cardiovascular Research (grant 04 CVD 02) and the Erasmus Life Learning Programme.

Conflict of interest

Renke Maas, Edzard Schwedhelm, and Rainer Böger are co-inventors of a method to determine methylarginines. All other authors have no conflicts to report.

Author information

Authors and Affiliations

  1. German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research C070, Heidelberg, Germany

    Bob Siegerink, Dietrich Rothenbacher, Hermann Brenner & Lutz P. Breitling

  2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    Bob Siegerink & Carla Y. Vossen

  3. Friedrich-Alexander Universität Erlangen-Nürnberg, Institute of Experimental and Clinical Pharmacology and Toxicology, Erlangen, Germany

    Renke Maas

  4. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    Carla Y. Vossen

  5. Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Edzard Schwedhelm & Rainer Böger

  6. Department of Internal Medicine II-Cardiology, Ulm University, Ulm, Germany

    Wolfgang Koenig

  7. Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany

    Dietrich Rothenbacher

  8. Clinic for Gastroenterology, Hepatology and Infectiology, University Hospital Düsseldorf, Düsseldorf, Germany

    Lutz P. Breitling

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  1. Bob Siegerink
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Corresponding author

Correspondence to Wolfgang Koenig.

Additional information

Bob Siegerink and Renke Maas contributed equally to this manuscript.

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Siegerink, B., Maas, R., Vossen, C.Y. et al. Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study. Clin Res Cardiol 102, 193–202 (2013). https://doi.org/10.1007/s00392-012-0515-4

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  • DOI: https://doi.org/10.1007/s00392-012-0515-4

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