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Higher serum asymmetric dimethylarginine is related to higher risk of heart failure in the EPIC-Potsdam study

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Abstract

l-Arginine is the substrate of endothelial nitric oxide (NO) synthase forming NO which inherits various biological cardio-protective functions. The dimethylarginines asymmetric (ADMA) and symmetric dimethylarginine (SDMA) can impair the synthesis of NO and are elevated in patients with cardiovascular disease, including heart failure (HF). We investigated the association between dimethylarginines and HF risk in a case-cohort study of the European Prospective Investigation into Cancer and Nutrition (n = 27,548), comprising a random subcohort (n = 2224 including 19 HF cases), and all remaining HF cases (n = 176) that occurred within 8.3 years of follow-up. Serum concentrations of dimethylarginines were measured using liquid chromatography-tandem mass spectrometry. Hazards ratios (HRs) and 95% confidence intervals (CI) were estimated across quartiles and per doubling of ADMA and SDMA concentrations using Cox’s proportional hazards regression. After multivariable adjustment, each doubling of ADMA was associated with a 60% higher HF risk (HR [95% CI] 1.60 [1.10–2.31]). Between SDMA and HF risk a U-shaped association was observed (HR [95% CI] for the second, third and fourth quartile compared to the first: 0.52 [0.33–0.82], 0.63 [0.40–0.99], and 0.71 [0.46–1.10], p for nonlinearity <0.01). We provide substantiated evidence for a relationship between ADMA and cardiovascular endpoints. In addition to the established relation between ADMA and myocardial infarction, our findings indicate a positive association between ADMA and HF incidence in persons without apparent myocardial infarction. Targeting the ADMA metabolism might open up new therapeutic perspective for HF prevention and treatment. Further investigations are needed to shed more light on mechanisms involved in the pathogenesis of HF related to elevated ADMA levels.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

CAT:

Cationic amino acid transporter

CI:

Confidence interval

CVD:

Cardiovascular disease

eNOS:

Endothelial nitric oxide synthase

EPIC:

European Prospective Investigation into Cancer and Nutrition

hArg:

Homoarginine

HF:

Heart failure

HR:

Hazards ratio

ICD-10:

International Classification of Diseases, 10th revision

iNOS:

Inducible NOS

IQR:

Interquartile range

MI:

Myocardial infarction

NMMA:

N-Monomethylarginine

NO:

Nitric oxide

PRMT:

Protein arginine methyltransferase

SD:

Standard deviation

SDMA:

Symmetric dimethylarginine

SE:

Standard error

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Acknowledgements

We thank the Human Study Centre (HSC) of the German Institute of Human Nutrition Potsdam-Rehbruecke, namely the trustee and the data hub for the processing, and the participants for the provision of the data, the biobank for the processing of the biological samples and the head of the HSC, Manuela Bergmann, for the contribution to the study design and leading the underlying processes of data generation. We gratefully thank Mariola Kastner and Anna Steenpaß for their excellent technical assistance. This study was funded by a research Grant provided by the DZHK to CW, DA, and ES (Grant number 81X2710108). DA acknowledges the support of the European Union under a Marie Curie Intra-European Fellowship for Career Development.

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Authors and Affiliations

  1. Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA

    Janine Wirth

  2. German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany

    Janine Wirth, Romina di Giuseppe, Juliane Menzel, Heiner Boeing & Cornelia Weikert

  3. DZHK, Partner Site Berlin/Potsdam, Potsdam, Germany

    Janine Wirth, Romina di Giuseppe & Cornelia Weikert

  4. Department of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

    Dorothee Atzler, Kathrin Cordts, Rainer H. Böger & Edzard Schwedhelm

  5. DZHK, Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany

    Dorothee Atzler, Kathrin Cordts, Rainer H. Böger & Edzard Schwedhelm

  6. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK

    Dorothee Atzler

  7. Institute of Epidemiology, Christian-Albrechts University Kiel, Kiel, Germany

    Romina di Giuseppe

  8. Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, Berlin, Germany

    Juliane Menzel & Cornelia Weikert

  9. Federal Institute of Risk Assessment, Department of Food Safety, Berlin, Germany

    Cornelia Weikert

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  1. Janine Wirth
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  2. Dorothee Atzler
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  3. Romina di Giuseppe
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  4. Kathrin Cordts
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  5. Juliane Menzel
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  6. Rainer H. Böger
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  7. Heiner Boeing
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  8. Cornelia Weikert
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  9. Edzard Schwedhelm
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Correspondence to Janine Wirth.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Handling Editor: C.-A. A. Hu.

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Wirth, J., Atzler, D., di Giuseppe, R. et al. Higher serum asymmetric dimethylarginine is related to higher risk of heart failure in the EPIC-Potsdam study. Amino Acids 49, 173–182 (2017). https://doi.org/10.1007/s00726-016-2348-3

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  • DOI: https://doi.org/10.1007/s00726-016-2348-3

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