Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion

Ulrike Lisewski, Clemens Köhncke, Leonhard Schleussner, Bettina Purfürst, Soo Min Lee, Angele De Silva, Rian Manville, Geoffrey Abbott, Torsten Roepke

Research output: Contribution to journalArticle

Abstract

Heart failure (HF) is an increasing global health crisis, affecting 40 million people and causing 50% mortality within 5 years of diagnosis. A fuller understanding of the genetic and environmental factors underlying HF, and novel therapeutic approaches to address it, are urgently warranted. Here, we discovered that cardiac-specific germline deletion in mice of potassium channel β subunit-encoding Kcne2 (Kcne2 CS−/−) causes dilated cardiomyopathy and terminal HF (median longevity, 28 weeks). Mice with global Kcne2 deletion (Kcne2 Glo−/−) exhibit multiple HF risk factors, yet, paradoxically survived over twice as long as Kcne2 CS−/− mice. Global Kcne2 deletion, which inhibits gastric acid secretion, reduced the relative abundance of species within Bacteroidales, a bacterial order that positively correlates with increased lifetime risk of human cardiovascular disease. Strikingly, the proton-pump inhibitor omeprazole similarly altered the microbiome and delayed terminal HF in Kcne2 CS−/− mice, increasing survival 10-fold at 44 weeks. Thus, genetic or pharmacologic induction of hypochlorhydria and decreased gut Bacteroidales species are associated with lifespan extension in a novel HF model.

Original languageEnglish
Pages (from-to)10699-10719
Number of pages21
JournalThe FASEB Journal
Volume34
Issue number8
DOIs
Publication statusPublished - 25 Jun 2020

Keywords

  • dilated cardiomyopathy
  • heart failure
  • KCNE
  • microbiome
  • potassium channel

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    Lisewski, U., Köhncke, C., Schleussner, L., Purfürst, B., Lee, S. M., De Silva, A., Manville, R., Abbott, G., & Roepke, T. (2020). Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion. The FASEB Journal, 34(8), 10699-10719. https://doi.org/10.1096/fj.202000013RR