e428 Article Type Correspondence We thank the authors for their positive comments and amplifying remarks in response to our article in Circulation. 1 We agree with the authors that the proton pump inhibitors (PPIs) may adversely influ- ence cardiovascular physiology in multiple ways. We found that PPIs reduce the enzymatic activity of dimethylarginine dimethylamino- hydrolase. In this way, PPIs increase plasma levels of asymmetrical dimethylarginine (ADMA). 1 Because it inhibits the generation of vascular nitric oxide (NO), ADMA would be expected to increase platelet interaction with the vessel wall. Chyrchel and colleagues cor- rectly point out that our findings may explain why PPIs attenuate the benefit of clopidogrel, as well as other P2Y 12 antiplatelet agents not dependent on CYP2C19 for their activity. We thank Montenegro and Lundberg for pointing out that NO may be generated in the stomach by the reduction of ingested nitrite, an effect that depends on low gastric pH. Dietary nitrate and nitrite are absorbed in the gastrointestinal tract, concentrated in the saliva as nitrite by the action of oral bacteria, and then converted to nitrous acid in the stom- ach. The spontaneous decomposition of nitrous acid generates NO. Gastric NO is known to increase blood flow, protect the gastric mucosa, and provide defense against pathogenic microorganisms. Accordingly, Montenegro and Lundberg raise the concern that PPIs could impair this exogenous nitrate/nitrite/NO cycle. Pinheiro and coworkers echo this concern and point out that the PPI esomeprazole has been observed to reduce the antihypertensive benefit of oral nitrates. The adverse effect of PPIs on this pathway may be of equal or greater importance to what we described. The ingestion of nitrate and nitrite may be critical to the cardiovascular benefits of diets rich in leafy greens and root vegetables as in the Dietary Approaches to Stop Hypertension study. 2 In addition, PPIs could influence circulating ADMA through their interference with the absorption of vitamin B 12 . 3 This vitamin is required for the conversion of homocysteine to cysteine. Elevated plasma homocysteine levels increase plasma levels of ADMA and may increase the susceptibility to coronary artery disease. 4 We have observed previously that an acute increase in homocysteine level acutely increases plasma ADMA and impairs endothelium-dependent vasodilation. 4 To conclude, we and the other respondents agree that the PPIs may dysregulate interdependent pathways that regulate vascular NO generation. As a result, chronic exposure to PPIs might be expected to impair vascular homeostasis and potentially expose consumers to an increased risk of major adverse cardiovascular events. We plan to publish pharmacovigilance data regarding this question. The accumu- lating data raise a concern for the medical community and regulatory bodies regarding the cardiovascular safety of these agents. Sources of Funding This work was supported in part by grants to JPC from the NI (RC2HL103400, 1U01HL100397, and K12HL087746), American Heart Association (AHA) (11IRG5180026), Stanford SPARK Translational Research Program, Stanford Translational Research and Applied Medicine (TRAM) Program and by the Tobacco-Related Disease Research Program of the University of California (18XT- 0098). YTG was a recipient of the Stanford School of Medicine Dean’s fellowship (1049528-149- KAVFB) and the Tobacco-Related Disease Research Program (TRDRP) of the University of California (20FT- 0090). He is currently supported by the National Institutes of Health National Heart, Lung, and Blood Institute (7K01HL118683-02). NHS and PL acknowledge support in part by NIH grant U54HG004028 from the National Center for Biomedical Ontology, seed funding by the Department of Medicine at Stanford University and the Stanford Center for Biomedical Informatics Research. NHS also acknowledges support from U54LM008748 for Informatics for Integrating Biology and the Bedside, and Research Gift Support from Apixio, Inc. Disclosures Drs Ghebremariam and Cooke are inventors on patents owned by Stanford University that protect the use of agents that modulate the nitric oxide synthase–dimethylarginine dimethylaminohydrolase pathway therapeutically. They are also cofounders of Altitude Pharma, a biotechnology company that is developing a product to therapeuti- cally regulate the nitric oxide synthase–dimethylarginine dimethyl- aminohydrolase pathway. The other authors report no conflicts. Yohannes T. Ghebremariam, PhD Department of Cardiovascular Sciences Texas Methodist Hospital Research Institute Houston, Texas Paea LePendu, PhD Jerry C. Lee, MSc Department of Medicine Stanford University Stanford, California Daniel A. Erlanson, PhD SPARK Translational Research Program Stanford University Stanford, California Anna Slaviero, PhD Nitric Oxide Signaling Group Medical Research Council Clinical Sciences Center Imperial College London London, United Kingdom Nigam H. Shah, MBBS, PhD Department of Medicine Stanford University Stanford, California James M. Leiper, PhD Nitric Oxide Signaling Group Medical Research Council Clinical Sciences Center Imperial College London London, United Kingdom John P. Cooke, MD, PhD Department of Cardiovascular Sciences Texas Methodist Hospital Research Institute Houston, Texas References 1. Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, Cooke JP. An unexpected effect of proton pump inhibitors: eleva- tion of the cardiovascular risk factor ADMA. Circulation. 2013; 128:845–53. 2. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM, Cutler JA, Windhauser MM, Lin PH, Karanja N. A clinical trial of the effects of dietary patterns on blood pressure: DASH Collaborative Research Group. N Engl J Med. 1997;336:1117–1124. 3. Howden CW. Vitamin b12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol. 2000;30:29–33. 4. Stühlinger MC, Oka RK, Graf EE, Schmölzer I, Upson BM, Kapoor O, Szuba A, Malinow MR, Wascher TC, Pachinger O, Cooke JP. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation. 2003;108:933–938. (Circulation. 2014;129:e428.) © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.114.009343 Response to Letters Regarding Article, “Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine” Downloaded from http://ahajournals.org by on August 4, 2022