Proton Pump Inhibitors and Cardiac Safety: Emerging Evidence Linking Cardiovascular Disease, Arrhythmias, and Mechanistic Pathways

Proton pump inhibitors (PPIs) are globally prescribed medications long perceived as pharmacologically safe. However, emerging evidence challenges this, revealing a potential association between chronic PPI exposure and adverse cardiovascular outcomes, including arrhythmogenesis. This review synthesizes findings from large, robust epidemiologic cohorts (ARIC, UK Biobank, Danish registries, Women’s Health Initiative (WHI)), consistently demonstrating that long-term PPI use is associated with higher risks of myocardial infarction, stroke, heart failure, and malignant arrhythmias, including out-of-hospital cardiac arrest and atrial fibrillation. These associations exhibit clear duration and dose-response patterns and are not replicated with H2 -receptor antagonists, suggesting a PPI-specific pharmacologic effect. Arrhythmic outcomes, while clinically consequential, remain under-investigated. We place particular emphasis on their biological plausibility. Mechanistic evidence provides converging pathways, including TRPM6/7-mediated hypomagnesemia, direct blockade of the hERG potassium channel, oxidative stress-driven remodeling, sympathetic hyperinnervation, and nitric oxide signaling impairment. Collectively, these influence myocardial repolarization and autonomic tone, offering a cohesive framework linking PPIs to both arrhythmic and atherosclerotic risk. Agents such as pantoprazole, omeprazole, and lansoprazole are most consistently implicated. The potential role of confounding by indication is discussed, noting that cardiovascular associations often persist after adjusting for underlying reflux disease. By integrating large-scale data with mechanistic insights, this review underscores the need to reconsider the cardiovascular neutrality of PPIs, particularly with long-term use. Future studies must clarify causality, identify susceptible phenotypes, and determine if therapy modification can mitigate downstream cardiovascular and arrhythmic risk.