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Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion

Item Type:Article
Title:Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion
Creators Name:Lisewski, U. and Köhncke, C. and Schleussner, L. and Purfürst, B. and Lee, S.M. and De Silva, A. and Manville, R.W. and Abbott, G.W. and Roepke, T.K.
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.
Keywords:Dilated Cardiomyopathy, Heart Failure, KCNE, Microbiome, Potassium Channel, Animals, Mice
Source:FASEB Journal
Publisher:Federation of American Societies for Experimental Biology
Page Range:10699-10719
Date:August 2020
Additional Information:Copyright © 2020 Federation of American Societies for Experimental Biology
Official Publication:https://doi.org/10.1096/fj.202000013RR
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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