Asymmetric Dimethylarginine versus Proton Pump Inhibitors Usage in Patients with Stable Coronary Artery Disease: A Cross-Sectional Study.

Olga Kruszelnicka,Jolanta Świerszcz,Andrzej Surdacki,Jacek Bednarek,Bernadeta Chyrchel,Jadwiga Nessler

doi:10.3390/ijms17040454

Olga Kruszelnicka, Jolanta Świerszcz + Show 4 more

Open Access

https://doi.org/10.3390/ijms17040454

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Abstract

A recent experimental study suggested that proton pump inhibitors (PPI), widely used to prevent gastroduodenal complications of dual antiplatelet therapy, may increase the accumulation of the endogenous nitric oxide synthesis antagonist asymmetric dimethylarginine (ADMA), an adverse outcome predictor. Our aim was to assess the effect of PPI usage on circulating ADMA in coronary artery disease (CAD). Plasma ADMA levels were compared according to PPI use for ≥1 month prior to admission in 128 previously described non-diabetic men with stable CAD who were free of heart failure or other coexistent diseases. Patients on PPI tended to be older and with insignificantly lower estimated glomerular filtration rate (GFR). PPI use was not associated with any effect on plasma ADMA (0.51 ± 0.11 (SD) vs. 0.50 ± 0.10 µmol/L for those with PPI (n = 53) and without PPI (n = 75), respectively; p = 0.7). Additionally, plasma ADMA did not differ between PPI users and non-users stratified by a history of current smoking, CAD severity or extent. The adjustment for patients’ age and GFR did not substantially change the results. Thus, PPI usage does not appear to affect circulating ADMA in non-diabetic men with stable CAD. Whether novel mechanisms of adverse PPI effects on the vasculature can be translated into clinical conditions, requires further studies.

Highlights

Proton pump inhibitors (PPI)—widely used to prevent gastroduodenal complications of dual antiplatelet therapy—have recently been demonstrated to raise intracellular levels of asymmetric dimethylargininie (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, which was accompanied by a lower NO formation, depressed endothelium-mediated vasorelaxation in vitro and increased circulating ADMA by about 20% in mice
Because ADMA is a recognized adverse outcome predictor in coronary artery disease (CAD) patients [2,3,4], the PPI-ADMA interaction might contribute to an excessive cardiovascular risk in patients on PPI irrespective of the use of antiplatelet agents including clopidogrel, or a prior history of myocardial infarction [5,6,7,8,9,10,11]
ADMA concentrations in our patients were only slightly lower than ADMA levels measured by the same enzyme-linked immunosorbent assay (ELISA) in control groups of largely untreated subjects of similar age from European populations and without evidence of atherosclerotic vascular disease [23,24,25], which argues against the proposed explanation and strengthens our findings

Summary

Introduction

Proton pump inhibitors (PPI)—widely used to prevent gastroduodenal complications of dual antiplatelet therapy—have recently been demonstrated to raise intracellular levels of asymmetric dimethylargininie (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, which was accompanied by a lower NO formation, depressed endothelium-mediated vasorelaxation in vitro and increased circulating ADMA by about 20% in mice. These effects were ascribed to a PPI-dependent direct inhibition of the activity of the major ADMA-degrading enzyme type 1 dimethylarginine dimethylaminohydrolase (DDAH-1) [1]. The proposed mechanistic concept [1] was not confirmed in a recent placebo-controlled, open-label, cross-over study where PPI administration for four weeks was not associated with significant effects on plasma ADMA or flow-dependent vasodilation in adults [15]

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