PPI and ADMA

An Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor ADMA

1. Yohannes T. Ghebremariam1; 
2. Paea LePendu2; 
3. Jerry C. Lee2;
4. Daniel A. Erlanson2; 
5. Anna Slaviero3; 
6. Nigam H. Shah2; 
7. James Leiper3;
8. John P. Cooke1*

+Author Affiliations

1. ¹Texas Methodist Hospital Research Institute, Houston, TX
2. ²Stanford University, Stanford, CA
3. ³MRC Clinical Sciences Center, Imperial College London, London, UK

1. ↵* Department of Cardiovascular Sciences, Texas Methodist Research Institute, Houston TX, 77030 john.cooke@stanford.edu

Abstract

Background—Proton pump inhibitors (PPIs) are gastric acid suppressing agents widely prescribed for the treatment of gastro-esophageal reflux disease (GERD). Recently, several studies in patients with acute coronary syndrome (ACS) have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events (MACE). 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 ADMA is an endogenous inhibitor of nitric oxide synthase (NOS). Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely due to its attenuation of the vasoprotective effects of endothelial NOS. We find that PPIs elevate plasma asymmetric dimethylarginine (ADMA) level and reduce nitric oxide (NO) 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 (DDAH), the enzyme that degrades ADMA.

Conclusions—We present a plausible biological mechanism to explain the association of PPIs with increased MACE 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 use of the PPIs in the general population.