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Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion
Ulrike Lisewski1, Clemens Köhncke1,2, Leonhard Schleussner1
1Experimental and Clinical Research Center, Berlin, Germany.
Insights
Genetic deletion of Kcne2 in mice causes heart failure. Inhibiting stomach acid and reducing gut Bacteroidales bacteria extended lifespan in this heart failure model, offering new therapeutic insights.
Area of Science:
- Cardiovascular Biology
- Microbiome Research
- Genetics
Background:
- Heart failure (HF) is a global health crisis with high mortality.
- Understanding genetic and environmental factors in HF is crucial for novel therapies.
Purpose of the Study:
- To investigate the role of Kcne2 in heart failure pathogenesis.
- To explore the impact of gut microbiome alterations on HF progression and lifespan.
Main Methods:
- Generated cardiac-specific (Kcne2CS-/-) and global (Kcne2Glo-/-) Kcne2 knockout mice.
- Analyzed HF phenotypes, longevity, and gut microbiome composition.
- Administered omeprazole, a proton-pump inhibitor, to assess its effect on HF and survival.
Main Results:
- Cardiac-specific Kcne2 deletion induced dilated cardiomyopathy and premature death.
- Global Kcne2 deletion paradoxically increased lifespan despite HF risk factors.
- Reduced gastric acid secretion and decreased gut Bacteroidales abundance correlated with extended survival.
- Omeprazole treatment mimicked these effects, significantly prolonging survival in Kcne2CS-/- mice.
Conclusions:
- Kcne2 plays a critical role in cardiac function and HF development.
- Modulating gastric acid and gut microbiome composition, specifically reducing Bacteroidales, offers a novel therapeutic strategy for extending lifespan in HF models.
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 (Kcne2CS-/- ) causes dilated cardiomyopathy and terminal HF (median longevity, 28 weeks). Mice with global Kcne2 deletion (Kcne2Glo-/- ) exhibit multiple HF risk factors, yet, paradoxically survived over twice as long as Kcne2CS-/- 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 Kcne2CS-/- 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.
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