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Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease

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Abstract

Introduction

In chronic obstructive pulmonary disease (COPD), there is an activation of the l-arginine nitric oxide pathway. Pulmonary obstruction causes to elevated nitric oxide (NO) levels, which lead to higher production of the NO-inhibiting metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA).

Methods

We investigated the association of l-arginine, ADMA, and SDMA with clinical outcomes in a well-defined observational cohort of 150 patients with acute exacerbation of COPD. We measured l-arginine, ADMA, and SDMA by mass spectrometry in patients with pneumonic or non-pneumonic exacerbation of COPD included in a Swiss multicenter trial. We used Cox regression models to investigate the associations between blood marker levels and disease severity as well as all-cause mortality over a follow-up of 6.1 years.

Results

Six-year all-cause mortality was 54%. Admission levels of ADMA and SDMA (μmol L−1) were increased in 6-year non-survivors compared to survivors’ median (0.60 vs. 0.46, p = 0.004; and 1.05 vs. 0.85, p = 0.012). In a multivariate Cox regression analysis, ADMA was associated with long-term mortality resulting in an age- and comorbidity-adjusted hazard ratio (HR) of 4.55 (95% confidence interval 1.02–20.43, p = 0.048). SDMA was only associated in univariate models and no association of l-arginine with outcome was found.

Conclusion

ADMA was found to be an independent risk factor for long-term all-cause mortality in patients with acute exacerbation of COPD. Whether therapeutic modification of the l-arginine–nitric oxide pathway has the potential to improve outcome should be evaluated in future interventional trials.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

AUC:

Area under the receiver operating characteristic curve

BMI:

Body mass index

CAD:

Coronary artery disease

CAP:

Community-acquired pneumonia

CHF:

Congestive heart failure

CI:

Confidence interval

COPD:

Chronic obstructive pulmonary disease

CRF:

Chronic renal failure

DDAH:

Dimethylarginine dimethylaminohydrolase

DM:

Diabetes mellitus

ED:

Emergency department

eNOS:

Endothelial nitric oxide synthase

HR:

Hazard ratio

IQR:

Interquartile range

iNOS:

Inducible nitric oxide synthase

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

MRM:

Multiple reaction monitoring

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PCT:

Procalcitonin

PRMT:

Protein arginine methyl transferase

SDMA:

Symmetric dimethylarginine

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Acknowledgements

We are thankful to the ED, medical clinic, and central laboratory staff of the University Hospital Basel and the Cantonal Hospitals of Aarau, Liestal, Lucerne, and Muensterlingen, and the ‘Buergerspital’ Solothurn for their assistance and technical support. In particular, we thank all the patients, patients’ relatives, and all local general practitioners who participated in this study. Finally, we would like to acknowledge the ProHOSP Study Group for their important support.

Funding

This study was supported in part by the Swiss National Science Foundation (SNSF Professorship, PP00P3_150531/1) and the Research Council of the Kantonsspital Aarau (1410.000.044). The initial trial was funded by the Swiss National Science Foundation (Grant SNF 3200BO-116177/1), Santé Suisse, the Gottfried and Julia Bangerter-Rhyner Foundation, and BRAHMS Biomarkers.

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Authors and Affiliations

  1. University Department of Internal Medicine, Kantonsspital Aarau, Tellstrasse, Aarau, CH-5001, Switzerland

    Alaadin Vögeli, Manuel Ottiger, Marc A. Meier, Beat Mueller & Philipp Schuetz

  2. Department of Laboratory Medicine, Kantonsspital, Aarau, Switzerland

    Christian Steuer, Luca Bernasconi & Andreas Huber

  3. Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland

    Mirjam Christ-Crain

  4. Department of Internal Medicine, Kantonsspital, Luzern, Switzerland

    Christoph Henzen

  5. Department of Internal Medicine, Kantonsspital, Münsterlingen, Switzerland

    Claus Hoess

  6. Department of Internal Medicine, Bürgerspital, Solothurn, Switzerland

    Robert Thomann

  7. University Department of Internal Medicine, Kantonsspital, Baselland, Switzerland

    Werner Zimmerli

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  1. Alaadin Vögeli
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  2. Manuel Ottiger
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Contributions

PS, MC-C, and BM created the concept and design, wrote the protocol, and initiated the initial ProHOSP study. PS, MO, MM, and AV drafted the manuscript and performed statistical analyses. CS, LB, and AH performed laboratory measurements of the p180 Kit. All authors contributed to data acquisition, interpretation and drafting of the analyses, critical review of important content, and final approval of the manuscript. PS had full access to all data in the study and takes responsibility for the integrity of the work and the accuracy of data analysis. The ProHOSP Study Group included U. Schild, K. Regez, R. Bossart, C. Blum, M. Wolbers, S. Neidert, I. Suter, H.C. Bucher, F. Mueller, A. Chaudry, J. Haeuptle, R. Zarbosky, R. Fiumefreddo, M. Wieland, C. Nussbaumer, A. Christ, R. Bingisser, and K. Schneider (University Hospital Basel, Basel, Switzerland); T. Bregenzer, D. Conen, A. Huber, and J. Staehelin (Kantonsspital Aarau, Aarau, Switzerland); W. Zimmerli, C. Falconnier, and C. Bruehlhardt (Kantonsspital Liestal, Liestal, Switzerland); C. Henzen and V. Briner (Kantonsspital Luzern, Luzern, Switzerland); T. Fricker, C. Hoess, M. Krause, I. Lambinon, and M. Zueger (Kantonsspital Muensterlingen, Muensterlingen, Switzerland); and R. Thomann, R. Schoenenberger, and R. Luginbuehl (Buergerspital Solothurn, Solothurn, Switzerland).

Corresponding author

Correspondence to Philipp Schuetz.

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All authors confirm that they do not have any conflict of interest associated with this manuscript.

Ethical Approval

The ethics committee of the University of Basel approved the initial study protocol. 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.

Informed Consent

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

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Vögeli, A., Ottiger, M., Meier, M.A. et al. Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Lung 195, 717–727 (2017). https://doi.org/10.1007/s00408-017-0047-9

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