Julia Walker recently published an article entitled "Commentary: Central-acting therapeutics alleviate respiratory weakness caused by heart failure–induced ventilatory overdrive" in Frontiers in Physiology. Co-authors include Amy Pastava.

Abstract

Heart failure (HF) is a chronic, progressive condition that manifests not only in cardiac dysfunction but also in respiratory dysfunction. Diaphragmatic myopathy is common and contributes to dyspnea and exercise intolerance in advancing stages of HF (reviewed in Cahalin and Arena, 2015; Dubé et al., 2016). The potential pathophysiological mechanisms driving diaphragmatic myopathy over the evolution of HF have remained elusive. Long-held views suggest that a HF-induced increase in lung mechanical load (either from pulmonary edema or lung fibrosis) is the primary cause of progressive diaphragmatic myopathy (Mahdyoon et al., 1989; Chomsky et al., 1997; Gheorghiade et al., 2010; Cahalin and Arena, 2015; Dubé et al., 2016). However, Foster et al. provide compelling evidence for an additional explanation (Foster et al., 2017). In the article “Central-acting therapeutics alleviates inspiratory weakness caused by HF-induced ventilatory overdrive” they elegantly demonstrate that initiation of diaphragmatic myopathy is mediated by a hormonal mechanism independent of lung mechanical load. They used two mouse models of pressure-overload-induced HF to show that activation of functionally codependent angiotensin type-1 (AT1) receptors and beta-adrenergic receptors (β-ARs) triggers an excessive central drive to breathe that underlies the development of diaphragm myopathy. This ventilatory (AbdAlla et al., 2005) overdrive was associated with increased mRNA expression of PERK (protein kinase R–like endoplasmic reticulum kinase), hyperphosphorylation-mediated inhibition of EIF2a (eukaryotic translation initiation factor 2α) and consequent reduction in protein translation and cross-sectional area of the diaphragm. Given that only blood-brain-barrier (BBB)-permeant antagonists of the AT1 receptors and β-ARs were able to diminish diaphragmatic myopathy, Foster et al. concluded that receptors behind the BBB were responsible for ventilatory overdrive. These atrophic changes preceded detectible evidence of diaphragm force changes and weakness. Thus, ventilatory overdrive associated with HF may now be thought of, and perhaps treated, as an early hormonal complication of the disease.

In our opinion, the important therapeutic impact of the Foster et al., findings is twofold. First, their study provides rationale for early initiation of treatment to prevent ventilatory overdrive—perhaps upon diagnosis of HF, but certainly well before lung structural or mechanical changes occur. Second, this work highlights the therapeutic importance of considering the BBB-permeant and other characteristics of AT1 receptor and βAR blockers used to treat HF. Before commenting on the pharmacological aspects of the Foster manuscript it may be instructive to provide clarification of some of the complex terminology and concepts used in the manuscript.