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. Author manuscript; available in PMC: 2014 Jul 21.
Published in final edited form as: Circulation. 2014 Apr 1;129(13):e428. doi: 10.1161/CIRCULATIONAHA.114.009343

Proton Pump Inhibitors and Cardiovascular Risk

Yohannes T Ghebremariam 1, Paea LePendu 2, Jerry C Lee 2, Daniel A Erlanson 3, Anna Slaviero 4, Nigam H Shah 2, James M Leiper 4, John P Cooke 1
PMCID: PMC4105215  NIHMSID: NIHMS612274  PMID: 24687654

To the Editor,

We thank the authors for their positive comments and amplifying remarks 1-3 in response to our paper in Circulation 4. We agree with the authors that the proton pump inhibitors (PPIs) may adversely influence cardiovascular physiology in multiple ways. We found that PPIs reduce the enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH). In this way, PPIs increase plasma levels of asymmetric dimethylarginine (ADMA) 4. Because it inhibits the generation of vascular nitric oxide, ADMA would be expected to increase platelet interaction with the vessel wall. Chyrchel and colleagues 1 correctly point out that our findings may explain why PPIs attenuate the benefit of clopidogrel as well as other P2Y12 anti-platelet agents not dependent upon CYP2C19 for their activity.

We thank Montenegro and Lunberg 2 for pointing out that NO may be generated in the stomach by the reduction of ingested nitrite, an effect that is dependent upon low gastric pH. Dietary nitrate (NO3-) and nitrite (NO2-) are absorbed in the gastrointestinal tract, concentrated in the saliva as NO2- by the action of oral bacteria and then converted to nitrous acid (HNO2) in the stomach. The spontaneous decomposition of HNO2 generates NO. Gastric NO is known to increase blood flow, protect the gastric mucosa and provide defense against pathogenic microorganisms. Accordingly, Montenegro and Lunberg raise the concern that PPIs could impair this exogenous nitrate/nitrite/NO cycle. Pinheiro and co-workers 3 echo this concern and point out that the PPI esomeprazole has been observed to reduce the anti-hypertensive benefit of oral nitrates. The adverse effect of PPIs on this pathway may be of equal or greater importance to that which 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 (DASH) study 5.

In addition, PPIs could influence circulating ADMA through their interference with the absorption of vitamin B12 6. 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 7. We have previously observed that acute increase in homocysteine level acutely increases plasma ADMA and impairs endothelium dependent vasodilation 7.

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 will soon publish pharmacovigilance data regarding this question. The accumulating data raises a concern for the medical community and regulatory bodies regarding the cardiovascular safety of these agents.

Footnotes

Disclosures:

YTG and JPC are inventors on patents owned by Stanford University that protect the use of agents that modulate the NOS/DDAH pathway therapeutically. They are also co-founders of Altitude Pharma; a biotechnology company that is developing a product to therapeutically regulate the NOS/DDAH pathway. LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH and Leiper JM have no disclosures to declare.

References

  • 1.Chyrchel B, Chyrchel M, Surdacki A. Proton Pump Inhibitors, Asymmetric Dimethylarginine and P2Y12 Antagonists. Circulation. 2014 doi: 10.1161/CIRCULATIONAHA.113.006284. this issue. [DOI] [PubMed] [Google Scholar]
  • 2.Montenegro MF, Lundberg JO. Impairments of vascular nitric oxide homeostasis by proton pump inhibitors. Circulation. 2014 this issue. [Google Scholar]
  • 3.Pinheiro LC, Amaral JH, Tanus-Santos JE. Mounting evidence for impaired nitric oxide mediated mechanisms possibly leading to cardiovascular events associated with proton pump inhibitors. Circulation. 2014 this issue. [Google Scholar]
  • 4.Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, Cooke JP. An unexpected effect of proton pump inhibitors: Elevation of the cardiovascular risk factor ADMA. Circulation. 2013;128:845–53. doi: 10.1161/CIRCULATIONAHA.113.003602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.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 Apr 17;336(16):1117–24. doi: 10.1056/NEJM199704173361601. [DOI] [PubMed] [Google Scholar]
  • 6.Howden CW. Vitamin b12 levels during prolonged treatment with proton pump inhibitors. Journal of clinical gastroenterology. 2000;30:29–33. doi: 10.1097/00004836-200001000-00006. [DOI] [PubMed] [Google Scholar]
  • 7.Stuhlinger MC, Oka RK, Graf EE, Schmolzer 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. doi: 10.1161/01.CIR.0000085067.55901.89. [DOI] [PubMed] [Google Scholar]

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