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

• DOI: 10.1126/scitranslmed.aag1303
• Publication Date: 2017-05-17T18:20:22Z
• Authors: Andrew J. Foster; Mathew J. Platt; Jason S. Huber; Ashley L. Eadie; Alicia M. Arkell; Nadya Romanova; David C. Wright; Todd E. Gillis; Coral L. Murrant; Keith R. Brunt; Jeremy A. Simpson
• Keywords: Investigational Drugs

Diaphragmatic weakness is a feature of heart failure (HF) associated with dyspnea and exertional fatigue. Most studies have focused on advanced stages HF, leaving the cause unresolved. The long-standing theory that pulmonary edema imposes mechanical stress, resulting in diaphragmatic remodeling, but stable HF patients rarely exhibit edema. We investigated how develops two mouse models pressure overload-induced HF. As patients, both had increased eupneic respiratory pressures ventilatory drive. Despite absence edema, strength progressively declined during overload; this decline correlated reduction diaphragm cross-sectional area preceded evidence muscle weakness. uncovered functional codependence between angiotensin II β-adrenergic (β-ADR) signaling, which Chronic overdrive was PERK (double-stranded RNA-activated protein kinase R-like ER kinase) expression phosphorylation EIF2α (eukaryotic translation initiation factor 2α), inhibits synthesis. Inhibition β-ADR signaling after application overload normalized strength, Perk expression, phosphorylation, area. Only drugs were able to penetrate blood-brain barrier effective treating preventing atrophy. These data provide insight into why similar different benefits mortality symptomatology, despite comparable cardiovascular effects.