Research ArticleHeart Failure

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

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Science Translational Medicine  17 May 2017:
Vol. 9, Issue 390, eaag1303
DOI: 10.1126/scitranslmed.aag1303

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A brainy treatment for heart failure

Respiratory difficulty and diaphragm weakness are known symptoms of heart failure, but they are usually attributed to pulmonary edema damaging the diaphragm through physical stress. Now, Foster et al. have determined that this is not the only contributing factor, using mouse models to demonstrate that diaphragm weakness develops even in heart failure without pulmonary edema. The authors linked this observation to changes in angiotensin II and β-adrenergic signaling, which result in centrally controlled ventilatory overdrive. As a result, the researchers found that drugs targeting β-adrenergic signaling were effective in preventing ventilatory overdrive and subsequent diaphragmatic injury but only if they penetrated the blood-brain barrier.


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 diaphragm strength, Perk expression, EIF2α phosphorylation, and diaphragmatic cross-sectional area. Only drugs that were able to penetrate the blood-brain barrier were effective in treating ventilatory overdrive and preventing diaphragmatic atrophy. These data provide insight into why similar drugs have different benefits on mortality and symptomatology, despite comparable cardiovascular effects.

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