PPIs Block hERG-Potassium Channels and Increase the Risk of QTc Prolongation
abstract
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Access this abstract nowBackground
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.
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Additional Info
Proton Pump Inhibitors Directly Block hERG-Potassium Channel and Independently Increase the Risk of QTc Prolongation in a Large Cohort of US Veterans
Circ Arrhythm Electrophysiol 2021 Jun 18;[EPub Ahead of Print], PE Lazzerini, A Cartocci, YS Qu, S Saponara, S Furini, F Fusi, F Fabris, A Gamberucci, N El-Sherif, G Cevenini, F Pettini, F Laghi-Pasini, M Acampa, I Bertolozzi, PL Capecchi, D Lazaro, M BoutjdirFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
To investigate the electrophysiologic role of proton pump inhibitors (PPIs) such as esomeprazole (Nexium), the investigators embarked on a translational study using combinations of electrophysiology, molecular dynamics simulations, and population data.
They found that clinically relevant concentrations of different PPIs induced a concentration-dependent 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. The hERG channel is a critical regulator of potassium egress required for ventricular repolarization. Blockade of this channel leads to prolonged ventricular repolarization, noted as an increase in the QT interval.
In a US veterans cohort, the investigators found that PPI treatment was independently associated with about a 20% to 40% increased risk of QTc prolongation. That finding has previously been explained by development of hypomagnesemia, but the investigators noted it occurred regardless of hypomagnesemia. Moreover, they noted a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors.
The take-home message for clinicians is that PPIs can promote QTc prolongation by directly inhibiting hERG function, independently of magnesium concentrations. Large population studies have shown that PPI treatment has been independently associated with increased risk of death, possibly due to an increased incidence of life-threatening ventricular arrhythmias, particularly torsades de pointes.
Therefore, avoiding other QT-prolonging risk factors and drugs, even in the absence of hypomagnesemia, is strongly suggested when treating with PPIs.