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Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.

Ghebremariam, YT, LePendu, P, Lee, JC, Erlanson, DA, Slaviero, A, Shah, NH, Leiper, J and Cooke, JP (2013) Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation, 128 (8). pp. 845-853.

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BACKGROUND: Proton pump inhibitors (PPIs) are gastric acid-suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed. METHODS AND RESULTS: Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA. CONCLUSIONS: We present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Ghebremariam, YT
LePendu, P
Lee, JC
Erlanson, DA
Shah, NH
Leiper, J
Cooke, JP
Date : 20 August 2013
DOI : 10.1161/CIRCULATIONAHA.113.003602
Uncontrolled Keywords : N,N dimethylarginine, dimethylarginine dimethylaminohydrolase, endothelium, nitric oxide, proton pump inhibitors, Amidohydrolases, Animals, Arginine, Biomarkers, Cardiovascular Diseases, Cells, Cultured, Disease Models, Animal, Endothelium, Vascular, Esomeprazole, Gastroesophageal Reflux, Humans, Lansoprazole, Male, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type III, Proton Pump Inhibitors, Risk Factors, Vasodilation
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:29
Last Modified : 24 Jan 2020 19:26

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