Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
Department of Pharmacology, Dalhousie Medicine, Saint John, New Brunswick E2L 4L5, Canada.
Sci Transl Med. 2017 May 17;9(390). doi: 10.1126/scitranslmed.aag1303.
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, 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.
膈肌无力是心力衰竭（HF）的一个特征，与呼吸困难和运动性疲劳有关。大多数研究都集中在 HF 的晚期，而导致这种情况的原因仍未得到解决。长期以来的理论认为肺水肿会造成机械压力，导致膈肌重塑，但稳定的 HF 患者很少出现肺水肿。我们研究了两种压力超负荷诱导的 HF 小鼠模型中膈肌无力的发展机制。与 HF 患者一样，这两种模型的安静呼吸呼吸压力和通气驱动都增加了。尽管没有肺水肿，但在压力超负荷期间，膈肌强度逐渐下降；这种下降与膈肌横截面积减少有关，并且早于肌肉无力的证据。我们发现血管紧张素 II 和 β-肾上腺素能（β-ADR）信号之间存在功能上的相互依存关系，这种关系增加了通气驱动。慢性超负荷与 PERK（双链 RNA 激活蛋白激酶 R 样内质网激酶）表达和 EIF2α（真核翻译起始因子 2α）磷酸化的增加有关，EIF2α 磷酸化抑制蛋白质合成。在施加压力超负荷后抑制 β-ADR 信号可以使膈肌强度、表达、EIF2α 磷酸化和膈肌横截面积正常化。只有能够穿透血脑屏障的药物才能有效治疗通气过度和预防膈肌萎缩。这些数据提供了一些见解，说明为什么尽管心血管效应相当，但类似的药物对死亡率和症状学有不同的益处。
