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Proton Pump Inhibitor Exposure and Acute Myocardial Infarction Risk: A Nested Cohort Study

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Abstract

Background: Association of proton pump inhibitor (PPI) exposure with acute myocardial infarction (AMI) risk in the Caucasian population remains under debate. Here, we clarified whether PPI exposure might be related to an increased new-onset AMI risk in an Asian population. Method: Data of 27,624 patients with PPI exposure followed by new-onset AMI development were extracted from Taiwan National Health Insurance Research Database and age- and sex-matched with 27,624 controls with PPIs exposure, but without subsequent AMI and ischemic heart disease development. The amount of PPI exposure was calculated based on the cumulative defined daily dose (cDDD) during the follow-up period. Subsequent AMI risk was measured after adjustments of demographic data and indication of PPI use. Results: AMI risk increased with an increase in PPI exposure: with cDDD ≤ 30 as the reference, the odds ratios (95% confidence intervals) for cDDDs of > 365 was 1.56 (1.45–1.69). All five PPI categories, including pantoprazole, lansoprazole, omeprazole, esomeprazole, and rabeprazole, increased AMI risk. Conclusions: Our study demonstrated long-term or high-dose PPI exposure associated with increased new-onset AMI risk in patients without a history of any ischemic heart disease. The underlying mechanisms of PPI-related cardiovascular effects deserve more investigation.

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References

  1. Aso, S., Imamura, H., et al. (2011). Incidence and mortality of acute myocardial infarction. A population-based study including patients with out-of-hospital cardiac arrest. International Heart Journal, 52(4), 197–202.

    Article  Google Scholar 

  2. Yeh, R. W., Sidney, S., et al. (2010). Population trends in the incidence and outcomes of acute myocardial infarction. New England Journal of Medicine, 362(23), 2155–2165.

    Article  CAS  Google Scholar 

  3. Reed, G. W., Rossi, J. E., et al. (2017). Acute myocardial infarction. Lancet, 389(10065), 197–210.

    Article  Google Scholar 

  4. Rathore, V., Singh, N., et al. (2018). Risk factors for acute myocardial infarction: A review. Eurasian Journal of Medical Investigation, 2, 1–7.

    Google Scholar 

  5. Batchelor, R., Kumar, R., et al. (2018). Systematic review with meta-analysis: Risk of adverse cardiovascular events with proton pump inhibitors independent of clopidogrel. Alimentary Pharmacology & Therapeutics, 48(8), 780–796.

    Article  CAS  Google Scholar 

  6. US Food and Drug Administration. (2013). Update of safety review-follow-up to the august 9, 2007, communication about the ongoing safety review of omeprazole and esomeprazole.

  7. Lundell, L., Miettinen, P., et al. (2009). Comparison of outcomes twelve years after antireflux surgery or omeprazole maintenance therapy for reflux esophagitis. Clinical Gastroenterology and Hepatology, 7(12), 1292–1298.

    Article  Google Scholar 

  8. Manolis, A. A., Manolis, T. A., et al. (2020). Proton pump inhibitors and cardiovascular adverse effects: Real or surreal worries? European Journal of Internal Medicine, 72, 15–26.

    Article  CAS  Google Scholar 

  9. Shah, N. H., LePendu, P., et al. (2015). Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS One, 10(6), e0124653.

    Article  Google Scholar 

  10. Shih, C. J., Chen, Y. T., et al. (2014). Proton pump inhibitor use represents an independent risk factor for myocardial infarction. International Journal of Cardiology, 177(1), 292–297.

    Article  Google Scholar 

  11. Sun, S., Cui, Z., et al. (2017). Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: A meta-analysis. Neurogastroenterology & Motility, 29(2), e12926.

    Article  Google Scholar 

  12. Zhu, W., & Hong, K. (2017). Potential cardiovascular risks of proton pump inhibitors in the general population. International Heart Journal, 58(2), 163–166.

    Article  CAS  Google Scholar 

  13. Turkiewicz, A., Vicente, R. P., et al. (2015). Revising the link between proton-pump inhibitors and risk of acute myocardial infarction-a case-crossover analysis. European Journal of Clinical Pharmacology, 71(1), 125–129.

    Article  CAS  Google Scholar 

  14. Chen, M. H., Hsu, J. W., et al. (2018). Sexually transmitted infection among adolescents and young adults with attention-deficit/hyperactivity disorder: A nationwide longitudinal study. Journal of the American Academy of Child and Adolescent Psychiatry, 57(1), 48–53.

    Article  Google Scholar 

  15. Chen, M. H., Lan, W. H., et al. (2016). Risk of developing type 2 diabetes in adolescents and young adults with autism spectrum disorder: A nationwide longitudinal study. Diabetes Care, 39(5), 788–793.

    Article  CAS  Google Scholar 

  16. Chen, M. H., Pan, T. L., et al. (2015). Risk of stroke among patients with post-traumatic stress disorder: Nationwide longitudinal study. British Journal of Psychiatry, 206(4), 302–307.

    Article  Google Scholar 

  17. Cheng, C. M., Chang, W. H., et al. (2017). Co-aggregation of major psychiatric disorders in individuals with first-degree relatives with schizophrenia: a nationwide population-based study. Molecular Psychiatry, 23(8), 1756–1763.

    Article  Google Scholar 

  18. Cheng, C. L., Lee, C. H., et al. (2014). Validation of acute myocardial infarction cases in the national health insurance research database in taiwan. Journal of Epidemiology, 24(6), 500–507.

    Article  Google Scholar 

  19. Charlson, M. E., Pompei, P., et al. (1987). A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. Journal of Chronic Diseases, 40(5), 373–383.

    Article  CAS  Google Scholar 

  20. Schillinger, W., Teucher, N., et al. (2007). Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits: Evaluation of mechanisms. Circulation, 116(1), 57–66.

    Article  CAS  Google Scholar 

  21. Yenisehirli, A., & Naseri, E. (2008). Omeprazole, lansoprazole and pantoprazole had no effect on blood pressure and electrocardiogram of anesthetized rat. Pharmacological Research, 58(1), 65–71.

    Article  CAS  Google Scholar 

  22. Yenisehirli, A., & Onur, R. (2005). Positive inotropic and negative chronotropic effects of proton pump inhibitors in isolated rat atrium. European Journal of Pharmacology, 519(3), 259–266.

    Article  CAS  Google Scholar 

  23. Cooke, J. P. (2004). Asymmetrical dimethylarginine: The Uber marker? Circulation, 109(15), 1813–1818.

    Article  Google Scholar 

  24. Cooke, J. P. (2010). DDAH: A target for vascular therapy? Vascular Medicine, 15(3), 235–238.

    Article  Google Scholar 

  25. Ghebremariam, Y. T., LePendu, P., et al. (2013). Unexpected effect of proton pump inhibitors: Elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation, 128(8), 845–853.

    Article  CAS  Google Scholar 

  26. Lu, T. M., Chung, M. Y., et al. (2011). Plasma asymmetric dimethylarginine predicts death and major adverse cardiovascular events in individuals referred for coronary angiography. International Journal of Cardiology, 153(2), 135–140.

    Article  Google Scholar 

  27. Mittermayer, F., Krzyzanowska, K., et al. (2006). Asymmetric dimethylarginine predicts major adverse cardiovascular events in patients with advanced peripheral artery disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(11), 2536–2540.

    Article  CAS  Google Scholar 

  28. Wilson, A. M., Shin, D. S., et al. (2010). Asymmetric dimethylarginine correlates with measures of disease severity, major adverse cardiovascular events and all-cause mortality in patients with peripheral arterial disease. Vascular Medicine, 15(4), 267–274.

    Article  Google Scholar 

  29. Clooney, A. G., Bernstein, C. N., et al. (2016). A comparison of the gut microbiome between long-term users and non-users of proton pump inhibitors. Alimentary Pharmacology & Therapeutics, 43(9), 974–984.

    Article  CAS  Google Scholar 

  30. Imhann, F., Bonder, M. J., et al. (2016). Proton pump inhibitors affect the gut microbiome. Gut, 65(5), 740–748.

    Article  CAS  Google Scholar 

  31. Leonard, J., Marshall, J. K., et al. (2007). Systematic review of the risk of enteric infection in patients taking acid suppression. The American Journal of Gastroenterology, 102(9), 2047–2056.

    Article  Google Scholar 

  32. Seldin, M. M., Meng, Y., et al. (2016). Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear Factor-kappaB. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.115.002767.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sun, X., Jiao, X., et al. (2016). Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochemical and Biophysical Research Communications, 481(1–2), 63–70.

    Article  CAS  Google Scholar 

  34. Tang, W. H., & Hazen, S. L. (2014). The contributory role of gut microbiota in cardiovascular disease. Journal of Clinical Investigation, 124(10), 4204–4211.

    Article  CAS  Google Scholar 

  35. Zhu, W., Gregory, J. C., et al. (2016). Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell, 165(1), 111–124.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Mr I-Fan Hu for his friendship and support.

Funding

The study was supported by a grant from Taipei Veterans General Hospital (V106B-020, V107B-010, V107C-181, V108B-012), Yen Tjing Ling Medical Foundation (CI-110-30), and Ministry of Science and Technology, Taiwan (107-2314-B-075-063-MY3, 108-2314-B-075-037). The funding source had no role in any process of our study. None of the aforementioned funding organizations had any role in the study design, data collection, analysis, interpretation of the result, writing of the report, and the ultimate decision to submit the paper for publication.

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Author notes

  1. Hsiang-Jung Tseng and Chih-Ming Cheng have contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan

    Hsiang-Jung Tseng, Chih-Ming Cheng, Shih-Jen Tsai, Wei-Chen Lin, Ya-Mei Bai, Chia-Fen Tsai, Tung-Ping Su, Cheng-Ta Li & Mu-Hong Chen

  2. Division of Psychiatry, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Chih-Ming Cheng, Shih-Jen Tsai, Wei-Chen Lin, Ya-Mei Bai, Chia-Fen Tsai, Tung-Ping Su, Cheng-Ta Li & Mu-Hong Chen

  3. Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Tzeng-Ji Chen

  4. Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Tzeng-Ji Chen

  5. Department of Psychiatry, General Cheng Hsin Hospital, Taipei, Taiwan

    Tung-Ping Su

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  1. Hsiang-Jung Tseng
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Contributions

Drs MHC, SJT, WCL, and YMB designed the study and wrote the protocol. Drs MHC and HJT drafted the manuscript. Dr CMC prepared the rebuttal letter and revised the manuscript. Drs CFT, TPS, SJT, WCL, YMB, and CTL reviewed and revised the manuscript paper. Drs MHC and TJC performed the statistical analysis. All authors reviewed the final manuscript and approved for publication.

Corresponding author

Correspondence to Mu-Hong Chen.

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Tseng, HJ., Cheng, CM., Tsai, SJ. et al. Proton Pump Inhibitor Exposure and Acute Myocardial Infarction Risk: A Nested Cohort Study. Cardiovasc Toxicol 21, 444–450 (2021). https://doi.org/10.1007/s12012-021-09637-2

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  • DOI: https://doi.org/10.1007/s12012-021-09637-2

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