PPIs – Proton Pump Inhibitors Impair Vascular Relaxation, May Increase Adverse CV Events

MedicalResearch.com Interview with:
John P. Cooke MD PhD Chair, Department of Cardiovascular Sciences Director, Center for Cardiovascular Regeneration Houston Methodist Research Institute 6670 Bertner St MS:  R6-414, Houston, TX 77030John P. Cooke MD PhD
Chair, Department of Cardiovascular Sciences
Director, Center for Cardiovascular Regeneration
Houston Methodist Research Institute
6670 Bertner St MS:  R6-414, Houston, TX 77030


MedicalResearch.com: What are the main findings of the study?

Answer: We discovered that the proton pump inhibitors PPIs), as a class, impair vascular relaxation.  The PPIs have this effect by suppressing the activity of a key enzyme required for cardiovascular health. The enzyme is known as DDAH (for dimethylarginine dimethylaminohydrolase).  This enzyme is critical in clearing ADMA (asymmetric dimethylarginine) from tissues and the circulation.  Because ADMA is an endogenous inhibitor of nitric oxide synthase, accumulation of ADMA impairs vascular relaxation and vascular homeostasis.   Previously, we and others have found that, by inhibiting endothelium-derived nitric oxide, ADMA accelerates vascular disease in preclinical models.  In humans, ADMA is linked to the severity of vascular disease, and is an independent risk factor for major adverse cardiovascular events (MACE).  Thus, the effect of PPIs to inhibit DDAH would be anticipated to impair cardiovascular health, and to increase the risk of MACE.

MedicalResearch.com: Were any of the findings unexpected?

Answer: The finding that PPIs impair the generation of endothelium derived nitric oxide in human endothelial cells and human blood vessels was surprising, and disturbing.  PPIs are widely used for gastroesophageal disease (GERD).  Whereas their short-term use appears to be safe, these drugs were never approved for long-term use.  Now that many of these agents are over-the-counter, they are being used by millions of people, and often for years.  These individuals may be a greater risk for cardiovascular disease.

MedicalResearch.com: What should clinicians and patients take away from your report?

Answer: Patients should discuss with their doctors the risks of long-term PPI use, which include low magnesium levels, tendency for irregular heartbeats, and an increased risk of bone fractures.  Our new data adds another potential risk of long-term use.  Patients that require long-term suppression of gastric acidity might be switched to H2-receptor antagonists like ranitidine, which does not have the adverse effect on the vasculature described in our report.

MedicalResearch.com: What recommendations do you have for future research as a result of this study? 

Answer: Pharmacovigilance studies, using electronic medical records from large databases, may be useful in confirming the risk of long-term use of PPIs.  Analysis of data from these pharmacovigilance studies are currently under review.  In addition, smaller mechanistic studies to provide further documentation that PPIs can impair vascular function in patients should be performed.    Subsequently, further regulatory review may be required.


Unexpected Effect of Proton Pump Inhibitors

Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginin
Ghebremariam YT, Lependu P, Lee JC, Erlanson DA, Slaviero A,
Shah NH, Leiper J, Cooke JP.
1Texas Methodist Hospital Research Institute,
Houston, TX.
Circulation. 2013 Jul 3. [Epub ahead of print]

Last Updated on August 20, 2013 by Marie Benz MD FAAD