Abstract 11973: Proton Pump Inhibitors (PPIs) Increase Risk of MACE: Role of DDAH
Background: Proton pump inhibitors (PPIs) are commonly used for gastric acid suppression. Emerging evidence in patients with acute coronary syndromes suggests that PPIs may be associated with increased major adverse cardiovascular events (MACE). We now provide a mechanism by which PPIs may increase MACE, and provide evidence that PPIs increase MACE in the general patient population.
Methods and Results: In a high throughput screen of the Stanford small molecule library (130,000 compounds) we discovered that PPIs inhibit the enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH), an active-site cysteine enzyme that metabolizes asymmetric dimethylarginine (ADMA); an endogenous inhibitor of nitric oxide (NO) synthase (NOS). This is of interest, as multiple clinical studies have indicated that elevated ADMA is a risk factor for MACE. We confirmed this finding in orthogonal biochemical and cellular assays, which showed that each member of the class of PPIs inhibit DDAH activity and prototype PPIs increase cellular ADMA. In mice administered with a PPI, plasma ADMA levels increased by 20-30%. Subsequently, using a novel data mining approach of unstructured clinical notes (of roughly a million patients over a decade) we discovered that the use of PPIs in a general patient population significantly increases the risk of stroke, myocardial infarction (MI) or cardiovascular (CV) death by 20-50% depending upon the individual PPI used.
Conclusion: To conclude, a high throughput enzymatic screen, confirmed by an orthogonal biochemical assay, as well as cell biological and animal studies, suggests that PPIs may increase MACE by inhibiting DDAH and increasing plasma ADMA. A data mining effort provides further level of concern that PPIs may substantially increase cardiovascular risk in the general patient population. • Cardiovascular Core = Vascular Disease: Biology and Clinical Science
- © 2012 by American Heart Association, Inc.