Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion


  • U. Lisewski
  • C. Köhncke
  • L. Schleussner
  • B. Purfürst
  • S.M. Lee
  • A. De Silva
  • R.W. Manville
  • G.W. Abbott
  • T.K. Roepke


  • FASEB Journal


  • FASEB J 34 (8): 10699-10719


  • 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.