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

Salman Oday^1*, Khayat Omar^1*, Ahmad Kashif¹, Azzo Joe David², Dov Vachss¹, El-Sayegh Suzanne³

¹Department of Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, NY
²Department of Internal Medicine, Cooper University Hospital, Camden, NJ

³Division of Nephrology, Department of Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, NY

*Oday Salman and Omar Khayat contributed equally to this work

*Corresponding author: El-Sayegh Suzanne, Division of Nephrology, Department of Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, NY

Received: 30 April 2026; Accepted: 05 May 2026; Published: 11 June 2026

Introduction

Proton pump inhibitors (PPIs) represent one of the most widely prescribed classes of medications worldwide [1]. Over the past two decades, their use has expanded significantly, partly due to the availability of generic formulations, over-the-counter accessibility, and the perception of a favorable safety profile [2]. Interestingly, while the prevalence of conditions for which PPIs are formally indicated, such as gastroesophageal reflux disease, peptic ulcer disease, and Helicobacter pylori infection, has remained relatively stable, the overall consumption of PPIs has continued to rise. This trend has raised concerns regarding potential misuse, as clinical guidelines generally recommend short-term therapy, often limited to 8 to 12 weeks, yet many patients remain on these agents indefinitely without ongoing indication, especially the elderly [3]. Although PPIs are effective in controlling gastric acid secretion, long-term and widespread use has prompted growing scrutiny of their adverse effects. In addition to established associations with renal dysfunction, bone health, micronutrient deficiencies, Clostridioides difficile infection, enteric colonisation with multidrug-resistant organisms, and gastric cancer, increasing attention has been directed toward possible cardiovascular implications [4]. Emerging data suggest that PPIs may contribute to adverse cardiovascular outcomes, including ischemic events, heart failure progression, and disturbances of cardiac electrophysiology. Among these, the potential for PPIs to predispose patients to arrhythmias through mechanisms such as electrolyte imbalances, impaired ion channel regulation, and interactions with concomitant cardiovascular therapies remains under-explored [4]. The rising incidence of atherosclerotic cardiovascular disease (ASCVD) and arrhythmias represents a growing public health challenge, particularly in the context of an ageing population. While traditional risk factors have long been recognized, emerging evidence suggests that commonly prescribed medications such as PPIs may also contribute to cardiovascular risk [4]. Highlighting this overlooked association is important, as it may inform prevention strategies, guide risk stratification, and support de-prescription initiatives aimed at minimizing unnecessary long-term PPI use [2,3]. Unlike prior reviews that primarily emphasize ischemic or atherosclerotic outcomes, this review focuses specifically on arrhythmic endpoints and integrates electrophysiologic and autonomic mechanisms with population-level data. This arrhythmia-centered synthesis represents a distinct and underexplored dimension of PPI-associated cardiovascular risk. Importantly, the majority of data linking PPI use to cardiovascular and arrhythmic outcomes remains observational, and causality cannot be definitively inferred. While emerging mechanistic studies provide biological plausibility, these findings should be interpreted as hypothesis-generating rather than confirmatory. Accordingly, this review aims to synthesize epidemiologic signals and mechanistic insights while explicitly acknowledging the current limitations of causal inference. Moreover, this review does not constitute a systematic review or meta-analysis but rather a narrative synthesis focusing on arrhythmic outcomes and mechanistic plausibility.

PPIs and Cardiovascular Disease (CVD) - Current Evidence

ARIC Cohort Studies

Among the first studies to suggest potential cardiovascular risk associated with chronic PPI use was the analysis by Shah et al [5], which used electronic health record data from large clinical databases and identified an excess risk of myocardial infarction among PPI users, a signal not observed with H2-receptor antagonists. While exploratory and limited by the nature of retrospective data mining, this study raised the possibility of a cardiovascular safety concern and laid the groundwork for subsequent investigations in large, prospective cohorts discussed below.

Table 1 as seen below, provides an overview of the major cohort studies that have investigated the association between long-term PPI use and cardiovascular outcomes, highlighting differences in study design, populations, exposure definitions, and primary endpoints. In the ARIC population cohort, Rooney et al. showed that PPI use was significantly associated with an elevated risk of cardiovascular disease. Over a median follow-up of 5.6 years, PPI users had a 31% higher risk of incident composite CVD, which remained significant after multivariable adjustment for demographics, lifestyle factors, and traditional cardiovascular risk factors (HR 1.31, 95% CI 1.10-1.57).

Table 1: Summary of Key Epidemiological Studies Evaluating the Association Between Proton Pump Inhibitor Use and Cardiovascular Outcomes. AF, atrial fibrillation; ASCVD, atherosclerotic cardiovascular disease; ARIC, Atherosclerosis Risk in Communities; CAD, coronary artery disease; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; EMR, electronic medical record; GERD, gastroesophageal reflux disease; H2B, histamine-2 receptor blocker; HF, heart failure; HR, hazard ratio; ICD, International Classification of Diseases; MI, myocardial infarction; OR, odds ratio; PAD, peripheral artery disease; PPI, proton pump inhibitor; RCT, randomized controlled trial; RR, risk ratio; T2D, type 2 diabetes.

Interestingly, H2-receptor blockers, used as a negative control, showed no association with cardiovascular risk, indicating that the observed relationship may not be attributable to acid suppression alone but rather to a PPI-specific association. Also, a mediation analysis tested whether hypomagnesemia explained the association between PPI use and composite cardiovascular outcomes, but the effect was not statistically significant [6]. In a complementary analysis of the same ARIC cohort, Bell et al. evaluated the impact of cumulative PPI exposure and found that individuals with over five years of regular use had nearly double the risk of cardiovascular disease and heart failure compared to non-users, even after comprehensive adjustment for demographic, clinical, and socioeconomic variables. These findings underscore the importance of exposure duration, suggesting that long-term use may carry more pronounced cardiovascular consequences, particularly for heart failure [7].

UK Biobank cohort

A similar study was conducted by Li et al. in the UK Biobank cohort, PPI use was also significantly associated with increased cardiovascular risk across multiple outcomes over a median follow-up of 8 years. In fully adjusted models controlling for demographic, lifestyle, and clinical covariates, PPI use was associated with a 44% higher risk of composite cardiovascular disease (HR 1.44, 95% CI 1.39-1.50). Associations were consistently observed across individual endpoints, including coronary heart disease (HR 1.65, 95% CI 1.57-1.74), stroke (HR 1.21, 95% CI 1.09-1.33), heart failure (HR 1.61, 95% CI 1.37-1.89), and venous thromboembolism (HR 1.36, 95% CI 1.24-1.50). Importantly, the associations persisted even when the analysis was restricted to participants with clear clinical indications for PPI therapy, suggesting that the observed relationships were not solely attributable to indication bias. Subgroup analyses suggested that the adverse associations were more pronounced in participants <60 years of age and in current smokers. Intriguingly, to further address residual confounding, the investigators reported an E-value of 2.17, indicating that only an unmeasured confounder with a very strong association with both PPI use and cardiovascular disease could fully account for the observed relationship, making the findings more robust [8].

Another UK Biobank-based study by Ma et al. conducted on participants without prior cardiovascular disease or antihypertensive treatment, regular PPI use was again associated with elevated risk of ASCVD during a median follow-up of 12.5 years. In fully adjusted models accounting for demographics, socioeconomic status, lifestyle behaviors, cardiometabolic risk factors, comorbidities, and gastrointestinal indications, PPI use remained significantly associated with incident ASCVD (HR 1.16, 95% CI 1.09-1.23), including coronary artery disease (HR 1.12, 95% CI 1.04-1.21), myocardial infarction (HR 1.11, 95% CI 1.02-1.20), peripheral artery disease (HR 1.25, 95% CI 1.09-1.43), and ischemic stroke (HR 1.17, 95% CI 1.03-1.35). Consistent with the findings of Rooney et al., H2-receptor antagonists showed no significant associations with ASCVD or its components, further suggesting a result specific to PPIs rather than an effect of acid suppression. Notably, in drug-specific analyses, omeprazole, lansoprazole, and pantoprazole were associated with elevated ASCVD risk, where pantoprazole had the strongest association, whereas esomeprazole and rabeprazole were not. As discussed in the following section, these same agents (omeprazole, lansoprazole, and pantoprazole) have also demonstrated pro-arrhythmic effects in basic science models, including altered ion channel function and impaired myocardial repolarization, raising the possibility of shared electrophysiologic mechanisms contributing to both atherosclerotic and arrhythmogenic risk [9]. Similarly to Li et al.’s study, Ma et al. also found that younger participants (age <65) carried a greater excess risk with PPI use. However, in contrast to Li’s findings, Ma et al. observed that the association was limited to individuals without a documented indication for acid suppression, whereas Lee et al. demonstrated that the risk remained significant even after adjusting for clinical indications [9].

Complementing these findings, Yang et al. conducted a focused analysis of stroke outcomes in nearly 500,000 UK Biobank participants without baseline cerebrovascular disease and similarly found that regular PPI use was associated with a significantly increased risk of incident stroke (HR 1.16, 95% CI 1.06-1.27) [10]. The absolute risk difference was particularly notable among individuals at higher baseline stroke risk, where excess event rates were more than fourfold higher compared to those in the lowest-risk strata. Additionally, Yang et al performed a meta-analysis of nine randomized controlled trials and reported a comparable yet modestly elevated risk (pooled RR 1.22, 95% CI 1.00-1.50), reinforcing the consistency of this association across observational and experimental settings. These findings extend prior work by highlighting stroke as a distinct cardiovascular endpoint that may be influenced by chronic PPI exposure [10]. In contrast to Ma et al.’s focus on ASCVD in a general population sample, Geng et al. examined PPI use in a UK Biobank cohort restricted to individuals with type 2 diabetes and found similar statistically significant elevated risks of coronary artery disease, myocardial infarction, and heart failure. Unlike Ma et al., however, Geng et al. did not observe a significant association with stroke, but did report a 30% higher risk of all-cause mortality, underscoring potential vulnerability in this high-risk subgroup [11].

Danish National Registries

In a nationwide Danish registry cohort of 214,998 individuals undergoing upper gastrointestinal endoscopy and free of prior stroke or MI, Sehested et al. found that current PPI use was associated with increased risk of both ischemic stroke (HR 1.13, 95% CI 1.08-1.19) and myocardial infarction (HR 1.31, 95% CI 1.23-1.39) during a median 5.8-year follow-up. A dose-dependent and cumulative exposure relationship was observed, with increased risks at higher doses, reaching a hazard ratio of 1.31 (95% CI 1.21–1.42) for stroke and 1.43 (95% CI 1.30–1.57) for myocardial infarction. Importantly, only long-term PPI use was significantly associated with increased cardiovascular risk, conferring a 29% increase in absolute risk of ischemic stroke and a 36% increase in risk of myocardial infarction within six months compared with non-users. Importantly, H2-receptor antagonists again showed no significant association with either outcome, further suggesting the effect may be specific to PPIs [12]. In another Danish nationwide cohort, Charlot et al. evaluated over 56,000 patients discharged after myocardial infarction and found that PPI use was independently associated with a significantly elevated risk of cardiovascular death and rehospitalization for MI or stroke, even after adjusting for age, comorbidities, and concurrent clopidogrel use [13]. Notably, the observed excess risk persisted regardless of clopidogrel exposure, challenging the assumption that cardiovascular harm is solely driven by pharmacodynamic interference with antiplatelet therapies and instead pointing toward a broader vascular liability associated with chronic PPI use.

U.S. Women’s Health Initiative

In yet another study by Soliman et al. who studied a prospective cohort of 85,000 older post menopausal women, PPI use was associated with a significantly higher risk of incident cardiovascular disease, with the fully adjusted model showing a 21% increased risk (HR 1.21, 95% CI 1.02-1.43). Importantly, a cumulative exposure effect was observed, with progressively higher risks among those using PPIs for <1 year, 1-3 years, and >3 years (HRs 1.11, 1.27, and 1.33, respectively; p for trend = 0.02) [14].. This mirrors the findings of Sehested et al., who also reported elevated risk confined to long-term PPI use [12]. Stratified analyses suggested stronger associations in women aged 60–69 and in NSAID users, though other subgroup effects were less consistent. Taken together, the above studies provide converging evidence from multiple large-scale, prospective cohorts and national registries that long-term PPI use is associated with increased cardiovascular risk. While the magnitude of association varies across populations and endpoints, consistent patterns emerge: risk appears to rise with longer duration of use, is not replicated with H2-receptor antagonists, and persists across diverse settings including general, diabetic, and post-MI populations. Moreover, findings from high-quality studies in Denmark, the UK, Sweden, and the U.S. collectively reinforce the robustness of this association. These insights underscore the need for careful risk-benefit evaluation in prolonged PPI therapy, especially in individuals with elevated baseline cardiovascular risk or without a clear indication for continued acid suppression.

PPI and Arrhythmogenesis

Although epidemiologic studies have reported associations between proton pump inhibitor use and increased arrhythmic risk, direct causal evidence remains limited. Mechanistic studies to date largely consist of preclinical, translational, and pharmacologic investigations that support biological plausibility rather than definitive causation. The following section synthesizes these mechanistic signals to contextualize observed epidemiologic associations.

Experimental and Translational Evidence

Hypomagnesemia

Hypomagnesemia promotes QT prolongation and TdP by disturbing ion channel homeostasis. Magnesium normally stabilizes cardiac repolarization by enhancing potassium outward currents and inhibiting L-type calcium currents. Depletion removes these stabilizing effects, prolonging action potential duration [15,16]. Figure 1 summarizes the proposed mechanistic pathways through which chronic proton pump inhibitor use may contribute to arrhythmogenesis, integrating experimental, translational, and epidemiologic evidence.

Figure 1: Proposed mechanisms linking chronic proton pump inhibitor use to arrhythmic risk. Chronic proton pump inhibitor (PPI) use may increase arrhythmic risk through three converging pathways: hypomagnesemia-mediated ion channel instability, direct hERG/IKr potassium channel inhibition with delayed repolarization, and oxidative stress–mediated myocardial and endothelial remodeling. These mechanisms may contribute to QT prolongation, torsades de pointes susceptibility, malignant ventricular arrhythmias, atrial fibrillation, and sudden cardiac death. ADMA, asymmetric dimethylarginine; hERG, human ether-à-go-go–related gene; IKr, rapid delayed rectifier potassium current; TRPM, transient receptor potential melastatin.

hERG Potassium Channel Blockade

While electrolyte imbalances play a central role, PPIs may also exert direct electrophysiologic effects on cardiac ion channels. In a Clinical Cardiology study utilizing the MIMIC-III ICU database, Liu et al. demonstrated that ICU patients treated with PPIs had a significantly greater prevalence of QT prolongation, even after controlling for confounding medications and serum electrolytes [17]. Complementary experimental data by Lorberbaum et al [18]. demonstrated that lansoprazole reduced human ether-à-go-go–related gene (hERG) potassium channel, responsible for the rapid delayed rectifier current, by up to 14% alone and by 58% when combined with ceftriaxone, suggesting additive or synergistic channel blockade. This was corroborated by Lazzerini et al., who provided compelling translational data by combining patch-clamp experiments with clinical observations [19]. The authors demonstrated that commonly prescribed PPIs, particularly pantoprazole and lansoprazole, directly inhibited the hERG potassium channel in a concentration-dependent manner, leading to prolonged cardiac repolarization at clinically relevant levels. This electrophysiologic effect translated to a significantly higher incidence of QT prolongation among PPI users in a large veteran population, even after controlling for magnesium levels and other confounders. These findings underscore that PPIs may provoke arrhythmogenesis through direct interference with cardiac ion currents independent of electrolyte status. Collectively, these findings support a potential electrophysiologic mechanism, but are derived primarily from experimental and retrospective clinical data, limiting causal inference.

Oxidative stress

Beyond ion channel blockade and magnesium depletion, PPIs may promote arrhythmias through oxidative stress-induced cardiac remodelling. In a rat myocardial infarction model, Lee et al. found that chronic omeprazole administration exacerbated ventricular arrhythmias by inducing superoxide-mediated nerve growth factor upregulation and sympathetic hyperinnervation in the infarct border zone. These effects were reversible with magnesium supplementation or antioxidant therapy (Tiron), confirming the mechanistic link between magnesium deficiency, reactive oxide generation, and sympathetic sprouting. The resultant autonomic imbalance increases ventricular excitability and arrhythmogenic potential [20]. Similarly, Chen et al. demonstrated nearly parallel findings using a rat myocardial infarction model, where prolonged omeprazole exposure triggered oxidative cardiac remodeling through a distinct but complementary pathway [21]. Specifically, omeprazole reduced gastric vitamin C absorption and impaired nitric oxide signaling by suppressing endothelial nitric oxide synthase (eNOS) activity while increasing levels of asymmetric dimethylarginine, an endogenous eNOS inhibitor. This redox imbalance led to enhanced myocardial fibrosis and structural remodeling, changes known to promote arrhythmogenesis. Notably, these effects were mitigated by either vitamin C supplementation or angiotensin receptor blockade, further supporting the involvement of redox-sensitive mechanisms.

Extending these findings beyond animal models, Yepuri et al. demonstrated that PPIs also induce oxidative and structural dysfunction at the vascular level [22]. In cultured human endothelial cells, esomeprazole was shown to accelerate endothelial aging, characterized by telomere shortening, increased oxidative stress, and disruption of lysosomal pH homeostasis. These alterations were accompanied by blunted nitric oxide signaling. This mirrors the redox-related mechanisms observed in cardiac models. Importantly, these effects were not seen with H2-receptor antagonists, further crystallizing the notion of a PPI-specific effect. This indicates that endothelial dysfunction might provide a unifying biological link between the arrhythmogenic and atherogenic potential of PPIs through shared redox-sensitive pathways. Translation of these experimental findings to clinical arrhythmic risk in humans remains incompletely defined.

Observational and Epidemiologic Evidence

Consistent with experimental observations, few large scale cohort studies have demonstrated a significant association between PPI use and increased arrythmic burden. A nationwide Danish registry study by Eroglu et al. identified a significantly increased risk of out-of-hospital cardiac arrest among current PPI users [23]. Among more than 46,000 cases, PPI use was associated with a 32% higher odds of sudden arrhythmic death, independent of cardiovascular comorbidities or other medications (OR 1.32, 95% CI 1.28-1.37). Individual analyses revealed that omeprazole, esomeprazole, lansoprazole, and pantoprazole were each significantly associated with increased odds of out-of-hospital cardiac arrest. Risk was most pronounced with pantoprazole (OR 1.52, 95% CI 1.45-1.60), aligning with in vitro studies showing the strongest hERG inhibition with this agent [19]. These findings provide real-world support for a consistent signal that PPIs may be associated with an increased risk of malignant arrhythmias and sudden death, potentially through both ion channel blockade and additive interactions with other QT-prolonging therapies. Moreover, in the ARIC cohort, Rooney et al. reported that PPI use was independently and significantly associated with a 37% increased risk of incident AF, even after controlling for demographic factors, comorbidities, cardiovascular medications, and serum magnesium levels (HR 1.37, 95% CI 1.07-1.77) [6]. This association was reinforced in the UK Biobank by Li et al., who observed a statistically significant 17% elevated risk of AF among regular PPI users over a median follow-up of 8 years (HR 1.17, 95% CI 1.08-1.28) [8]. Notably, drug-specific analyses from the UK Biobank identified omeprazole, lansoprazole, and pantoprazole as the agents most strongly associated with increased cardiovascular risk, including arrhythmic outcomes, whereas esomeprazole and rabeprazole did not show significant associations [9].

Collectively, mechanistic data from translational models and real-world population studies point in the same direction: proton pump inhibitors may contribute to arrhythmogenesis through multiple interrelated pathways. These include hypomagnesemia-induced repolarization instability, direct blockade of hERG potassium channels, and oxidative stress driven cardiac and vascular remodeling. Among the various agents, pantoprazole, lansoprazole, and omeprazole have emerged as the most consistently implicated compounds, with evidence demonstrating both molecular effects and corresponding clinical risk signals. Importantly, these arrhythmogenic effects appear independent of acid suppression and distinct from H2-receptor antagonists, suggesting a potential class effect.

GERD, AF, and Confounding by Indication

AF represents both a major independent cardiovascular risk factor [24-26] and a potential downstream consequence of GERD [27-30], so it is important to distinguish whether PPI-associated CV risks arise from the drug itself or from the underlying condition for which it is prescribed. Atrial fibrillation itself is an established, independent risk factor for adverse cardiovascular outcomes. Longitudinal studies (e.g., the Framingham Heart Study) have shown that AF confers a markedly elevated risk of stroke (around 5-fold) and doubles all-cause mortality even after adjustment for other risk factors [24,25]. Likewise, a large meta-analysis of 104 cohorts (around 9.7 million participants) confirmed that AF is associated with significantly higher risks of stroke, heart failure, and cardiovascular death [26]. These observations underscore that any intervention or comorbidity influencing AF incidence can substantially impact downstream cardiovascular risk. Emerging evidence suggests that GERD, the primary indication for chronic PPI therapy, may itself predispose patients to AF. Multiple observational studies link GERD to modestly increased AF incidence (HRs around 1.3 in population-based cohorts) [27]., although findings are mixed and not all analyses reach significance [28,29]. Notably, recent Mendelian randomization analyses support a causal relationship, reporting that genetically predetermined predisposition to to GERD increases AF risk by approximately 17-34% [28,30]. This interrelationship creates potential for confounding by indication: the apparent association between PPI use and AF or CVD events may reflect the presence of underlying GERD (and its arrhythmogenic or inflammatory consequences) rather than a direct pharmacologic and class specific effect of PPIs. Accordingly, future studies of PPI-associated cardiovascular or arrhythmic risk should rigorously adjust for GERD diagnosis and severity to delineate drug effects from the risk conferred by the underlying esophageal disease.

Limitations and Interpretation

The current evidence linking PPI exposure to cardiovascular and arrhythmic outcomes is predominantly observational, and therefore susceptible to residual confounding and confounding by indication. Mechanistic studies largely remain preclinical or translational, supporting biological plausibility rather than establishing causality in humans. Furthermore, GERD itself may contribute to arrhythmic risk, complicating attribution of observed associations solely to PPIs. Accordingly, the available data are best interpreted as a consistent risk signal that warrants cautious clinical awareness and prospective validation.

Conclusion

Taken together, the totality of evidence from experimental, translational, and population-based studies suggests a consistent association between chronic PPI use, arrhythmic outcomes, and adverse cardiovascular events. Across diverse cohorts, including ARIC, UK Biobank, and Danish national registries, PPI exposure has been reproducibly linked to increased risk of atherosclerotic events, heart failure, and arrhythmias, with signals of duration and dose dependent patterns. Importantly, these associations are not mirrored with H2-receptor antagonists, suggesting an effect that may be specific to PPIs rather than to acid suppression. Mechanistic studies support biological plausibility, demonstrating that PPIs may influence multiple pathways critical to myocardial and vascular stability, including impaired magnesium homeostasis via TRPM6/7 channel inhibition, direct blockade of the hERG potassium current, and oxidative stress-mediated endothelial and myocardial remodeling. However, because most human evidence is observational, causality cannot be definitively inferred, and residual confounding remains possible. The convergence of findings across molecular, electrophysiologic, and epidemiologic domains strengthens concern for a clinically relevant risk signal, but does not establish a causal relationship. At the same time, the interplay between GERD, AF, and cardiovascular risk introduces an additional layer of complexity that warrants careful consideration. GERD, the primary indication for chronic PPI therapy, appears to possibly increase AF risk through inflammatory, autonomic, and possibly mechanical mechanisms. This creates potential for confounding by indication, where part of the cardiovascular signal attributed to PPIs may in fact reflect the arrhythmogenic effect conferred by the underlying reflux disease. Nonetheless, the observation that PPIs most strongly associated with adverse cardiovascular outcomes in cohort studies are the same agents shown to disrupt cardiac repolarization in basic models suggests that a portion of the observed risk may reflect drug-specific electrophysiologic effects in susceptible individuals. Collectively, these patterns support the need for prospective studies and mechanistic human investigations that can delineate drug-related effects from disease-related risk, identify susceptible patient subgroups, and clarify whether modification of PPI therapy, magnesium status, or reflux control can mitigate downstream cardiovascular and arrhythmic events. Until such data are available, long-term PPI therapy should be periodically re-evaluated to ensure an ongoing indication, particularly in patients at elevated arrhythmic risk or exposed to other QT-prolonging therapies.

References

1. Freedberg DE, Kim LS, Yang YX. The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association. Gastroenterology. 152 (2017): 706-715.
2. Jaynes M, Kumar AB. The risks of long-term use of proton pump inhibitors: a critical review. Ther Adv Drug Saf 10 (2019): 2042098618809927.
3. Targownik LE, Fisher DA, Saini SD. AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review. Gastroenterology 162 (2022): 1334-1342.
4. Andrawes M, Andrawes W, Das A, et al. Proton Pump Inhibitors (PPIs)—An Evidence-Based Review of Indications, Efficacy, Harms, and Deprescribing. Medicina 61 (2025): 1569.
5. Shah NH, LePendu P, Bauer-Mehren A, et al. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. PLoS One 10 (2015): e0124653.
6. Rooney MR, Bell EJ, Alonso A, et al. Proton Pump Inhibitor Use, Hypomagnesemia and Risk of Cardiovascular Diseases: The Atherosclerosis Risk in Communities (ARIC) Study. J Clin Gastroenterol 55 (2021): 677-683.
7. Bell EJ, Bielinski SJ, St Sauver JL, et al. Association of Proton Pump Inhibitors With Higher Risk of Cardiovascular Disease and Heart Failure. Mayo Clin Proc 96 (2021): 2540-2549.
8. Li Z-H, Zhong W-F, Qiu C-S, et al. Association between regular proton pump inhibitors use and cardiovascular outcomes: A large prospective cohort study. International Journal of Cardiology (2024): 395.
9. Ma Y, Li S, Yang H, et al. Acid suppressants use and risk of atherosclerotic cardiovascular disease in middle-aged and older adults. Atherosclerosis 358 (2022): 47-54.
10. Yang M, He Q, Gao F, et al. Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials. BMC Med 19 (2021): 316.
11. Geng T, Chen J-X, Zhou Y-F, et al. Proton Pump Inhibitor Use and Risks of Cardiovascular Disease and Mortality in Patients With Type 2 Diabetes. The Journal of Clinical Endocrinology & Metabolism 108 (2022): e216-e222.
12. Sehested TSG, Gerds TA, Fosbøl EL, et al. Long-term use of proton pump inhibitors, dose–response relationship and associated risk of ischemic stroke and myocardial infarction. Journal of Internal Medicine 283 (2018): 268-281.
13. Charlot M, Ahlehoff O, Norgaard ML, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med 153 (2010): 378-386.
14. Soliman AI, Wactawski-Wende J, Millen AE, et al. Proton Pump Inhibitor Use and Incident Cardiovascular Disease in Older Postmenopausal Women. J Am Geriatr Soc 73 (2025): 411-421.
15. Zhao M, Feng R, Shao D, et al. Mg2+-dependent facilitation and inactivation of L-type Ca2+ channels in guinea pig ventricular myocytes. Journal of Pharmacological Sciences 129 (2015): 143-149.
16. Kelepouris E, Kasama R, Agus ZS. Effects of intracellular magnesium on calcium, potassium and chloride channels. Miner Electrolyte Metab 19 (1993): 277-281.
17. Fan W, Liu H, Shen Y, et al. The Association of Proton Pump Inhibitors and QT Interval Prolongation in Critically Ill Patients. Cardiovasc Drugs Ther 38 (2024): 517-525.
18. Lorberbaum T, Sampson KJ, Chang JB, et al. Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation. J Am Coll Cardiol 68 (2016): 1756-1764.
19. Lazzerini PE, Cartocci A, Qu YS, et al. Proton Pump Inhibitors Directly Block hERG-Potassium Channel and Independently Increase the Risk of QTc Prolongation in a Large Cohort of US Veterans. Circulation: Arrhythmia and Electrophysiology 14 (2021): e010042.
20. Lee TM, Chang NC, Lin SZ. Effect of proton pump inhibitors on sympathetic hyperinnervation in infarcted rats: Role of magnesium. PLoS One 13 (2018): e0202979.
21. Chen WT, Shie CB, Yang CC, et al. Blockade of Cardiac Proton Pump Impairs Ventricular Remodeling Through a Superoxide-DDAH-Dependent Pathway in Infarcted Rats. Acta Cardiol Sin 35 (2019): 165-178.
22. Yepuri G, Sukhovershin R, Nazari-Shafti TZ, et al. Proton Pump Inhibitors Accelerate Endothelial Senescence. Circ Res 118 (2016): e36-42.
23. Eroglu TE, Coronel R, Gislason GH. Use of proton pump inhibitors is associated with increased risk of out-of-hospital cardiac arrest in the general population: a nested case-control study. Eur Heart J Cardiovasc Pharmacother. 2024;10:413-419. doi: 10.1093/ehjcvp/pvae020
24. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22 (1991): 983-988.
25. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98 (1998): 946-952.
26. Odutayo A, Wong CX, Hsiao AJ, et al. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. Bmj 354 (2016): i4482.
27. Huang C-C, Chan W-L, Luo J-C, et al. Gastroesophageal Reflux Disease and Atrial Fibrillation: A Nationwide Population-Based Study. PLOS ONE 7 (2012): e47575.
28. Wang L, Lu YW. Gastroesophageal reflux disease may causally associate with the increased atrial fibrillation risk: evidence from two-sample Mendelian randomization analyses. Frontiers in Cardiovascular Medicine 11 (2024).
29. Bunch TJ, Packer DL, Jahangir A, et al. Long-term risk of atrial fibrillation with symptomatic gastroesophageal reflux disease and esophagitis. Am J Cardiol 102 (2008): 1207-1211.
30. Chen X, Li A, Kuang Y, Ma Q. Gastroesophageal reflux disease and atrial fibrillation: a bidirectional Mendelian randomization study. Int J Med Sci 21 (2024): 1321-1328.