Central-acting therapeutics alleviate respiratory weakness caused by heart failure-induced ventilatory overdrive

Science Translational Medicine
Andrew J FosterJeremy A Simpson

Abstract

Diaphragmatic weakness is a feature of heart failure (HF) associated with dyspnea and exertional fatigue. Most studies have focused on advanced stages of HF, leaving the cause unresolved. The long-standing theory is that pulmonary edema imposes a mechanical stress, resulting in diaphragmatic remodeling, but stable HF patients rarely exhibit pulmonary edema. We investigated how diaphragmatic weakness develops in two mouse models of pressure overload-induced HF. As in HF patients, both models had increased eupneic respiratory pressures and ventilatory drive. Despite the absence of pulmonary edema, diaphragmatic strength progressively declined during pressure overload; this decline correlated with a reduction in diaphragm cross-sectional area and preceded evidence of muscle weakness. We uncovered a functional codependence between angiotensin II and β-adrenergic (β-ADR) signaling, which increased ventilatory drive. Chronic overdrive was associated with increased PERK (double-stranded RNA-activated protein kinase R-like ER kinase) expression and phosphorylation of EIF2α (eukaryotic translation initiation factor 2α), which inhibits protein synthesis. Inhibition of β-ADR signaling after application of pressure overload normalized diap...Continue Reading

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Citations

Apr 1, 2018·The Journal of Physiology·Melissa A AllwoodJeremy A Simpson
Jun 30, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Ashley L EadieKeith R Brunt
Mar 29, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Leslie M OgilvieJeremy A Simpson
Jun 2, 2017·Nature Reviews. Cardiology·Karina Huynh
Dec 20, 2020·The American Journal of Pathology·Utano TomaruMasanori Kasahara
Mar 13, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Merry L LindseyCrystal M Ripplinger

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