Proton Pump Inhibitors Directly Block hERG-Potassium Channel and Independently Increase the Risk of QTc Prolongation in a Large Cohort of US Veterans

Abstract

Background - Worldwide, there are millions of chronic proton pump inhibitors (PPIs) users, often without a compelling indication. Evidence indicates that PPI treatment can increase mortality, in part due to a higher risk of QTc-related malignant arrhythmias. Drug-induced hypomagnesemia is currently believed to be the underlying mechanism, and therefore serum magnesium monitoring is recommended to minimize arrhythmic risk. However, recent data suggest that PPIs might also directly interfere with cardiac electrophysiology. To test this hypothesis, a translational study was performed using a combination of electrophysiology, molecular dynamics simulations, and population data. Methods - First, the effect of different PPIs on the ether-a-go-go -related-gene potassium channel (hERG) current was evaluated in HEK293-cells expressing hERG. Then, free energy calculations were performed to investigate the binding of these drugs to hERG. Finally, the impact of PPIs on the risk of QTc prolongation was assessed in a retrospective observational cohort of 3867 US Veterans, including 1289 PPI-treated subjects. Results - Clinically-relevant concentrations of different PPIs induced a significant inhibition of the hERG-current in-vitro , pantoprazole and lansoprazole being the most potent compounds. Atomic simulations demonstrated that such a blocking class-effect is likely due to direct PPIs binding to hERG-channel pore cavity. Accordingly, in a US Veterans cohort, PPI treatment was independently associated with a ~20-40% increased risk of QTc prolongation, also regardless of hypomagnesemia. Moreover, a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors was demonstrated. Conclusions - Altogether, this study provides, for the first time, strong evidence that PPIs can per se promote QTc prolongation, by directly inhibiting hERG function. A careful evaluation of the benefit/risk ratio is recommended whenever PPIs are administered in subjects with other QT-prolonging risk factors, even in the absence of hypomagnesemia.

The association between proton pump inhibitor prescription and QT interval prolongation in intensive care unit patients

“…Our results indicated that pantoprazole increased the highest risk of QT prolongation among three PPIs, which may be attributed to the varying inhibition capacity of the Ikr among the three PPIs. Pantoprazole induced a higher inhibitory effect (82.8%) on the Ikr at a concentration of 100 µmol/L than lansoprazole (51.2%) and omeprazole (32.3%) [10]. Pantoprazole is the most frequent PPI related to TdP.…”

Severe Hypokalemia Causing Ventricular Tachycardia: A Case Report

“…However, he had two medications that could have contributed to prolonged QTc. Haloperidol can cause QTc prolongation [ 9 ], and recent studies have reported that proton pump inhibitors (PPIs) such as omeprazole may also cause QTc prolongation through inhibition of the hERG-K channel [ 10 ]. The unidentified pills, empty haloperidol bottles, and prescribed omeprazole may presumptively be associated with the patient’s prolonged QTc.…”

Ceftriaxone and the Risk of Ventricular Arrhythmia, Cardiac Arrest, and Death Among Patients Receiving Lansoprazole

“…The comparison of lansoprazole with other PPIs instead of no PPI addresses this confounding by indication, at least in part, because patients receiving lansoprazole and other PPIs were more likely to share similar comorbidities and concomitant medications. Proton pump inhibitors as a class may also prolong the QTc interval . Therefore, the comparison group of other PPIs was also useful to confirm that the drug interaction was specific to lansoprazole and excluded a PPI class effect by itself or with ceftriaxone.…”