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Review
. 2019 Jul-Sep;15(3):214-219.
doi: 10.14797/mdcj-15-3-214.

Cardiovascular Risk of Proton Pump Inhibitors

Hannah Ariel  1 , John P Cooke  1
Affiliations
Review

Cardiovascular Risk of Proton Pump Inhibitors

Hannah Ariel et al. Methodist Debakey Cardiovasc J. 2019 Jul-Sep.

Abstract

Proton pump inhibitors (PPIs) are effective agents for the treatment of gastroesophageal reflux (GERD). However, these drugs have not been approved for long-term use. Now sold over the counter, these agents are being used chronically for GERD without medical supervision. The long-term use of PPIs may have significant adverse effects, in part mediated by their effect of accelerating vascular aging. Physicians should assist patients in tapering off their use of PPIs and replacing them with lifestyle modifications and/or other agents that have better long-term safety profiles.

Keywords: GERD; H2 antagonists; gastroesophageal reflux disease; proton pump inhibitor.

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Conflict of interest statement

Conflict of Interest Disclosure: Dr. Cooke is a scientific advisor to HumanN Inc., Merand Pharmaceuticals, Inc., and Fibralign Corporation and receives research funding from Cook Biotech, Inc. and VGXI, Inc.

Figures

Figure 1.
Figure 1.
(A) Physicians have prescribed proton pump inhibitors (PPIs) with the perception that these agents have specificity for the parietal cells of the stomach. PPIs bind irreversibly to the proton pump in the parietal cell to reduce the secretion of hydrogen ions (H+) into the stomach, thereby reducing gastric acidity. (B) However, similar proton pumps are also found in cell lysosomes. PPIs also bind to proton pumps in the lysosomes of endothelial cells lining the vasculature. The chronic impairment of lysosomal acidity impairs the function of lysosomal enzymes. This impairment results in the accumulation of protein aggregates in the endothelial cell, triggering processes that accelerate senescence. Senescent endothelial cells manifest a global cellular dysfunction, including greater adhesiveness for immune cells. Vascular inflammation is known to accelerate atherosclerosis and the risk for coronary artery disease.
Figure 2.
Figure 2.
Proton pump inhibitors (PPIs) impair endothelial function by inhibiting the enzyme dimethylarginine dimethylamino-hydrolase (DDAH). This enzyme is present in all cells, degrading asymmetric dimethylarginine (ADMA). Because ADMA inhibits the endothelial enzyme nitric oxide synthase (eNOS), an increase in ADMA will reduce levels of vasodilator nitric oxide (NO). Vascular NO inhibits thrombosis and vascular inflammation. PPIs also block endothelial lysosomal proton pumps, thus impairing lysosomal enzyme activity and increasing protein aggregation, which leads to oxidative stress, telomere erosion, and endothelial senescence. This broad impairment in endothelial function would be expected to increase major adverse cardiovascular events (MACE), dementia, and renal failure. EMT: epithelial-to-mesenchymal transition
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References

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