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

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 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.

Early myopathy in Duchenne muscular dystrophy is associated with elevated mitochondrial H2O2 emission during impaired oxidative phosphorylation

“…Oesophageal pressure measurements were performed as previously described . Briefly, mice were anesthetized with an isoflurane/oxygen mix (2%:100%), and body temperature was maintained at 37°C.…”

“…27 Oesophageal pressure transduction Oesophageal pressure measurements were performed as previously described. 28 Briefly, mice were anesthetized with an isoflurane/oxygen mix (2%:100%), and body temperature was maintained at 37°C. Mice were intubated using a 20gauge angiocatheter (Becton, Dickinson and Company) to maintain an open/unobstructed airway.…”

Moderate and severe hypoxia elicit divergent effects on cardiovascular function and physiological rhythms

“…Samples were homogenized in buffer with a phosphatase and protease inhibitor cocktail and total protein content was measured by the bicinchoninic acid assay as described previously (Foster et al 2017). Briefly, samples were loaded onto a 4-20% Criterion TGX precast gel (Bio-Rad) alongside 10 μL of Precision Plus Protein Standards Kaleidoscope ladder (Bio-Rad) and then separated by SDS-PAGE followed by immunoblotting.…”

Pathophysiological Mapping of Experimental Heart Failure: Left and Right Ventricular Remodeling in Transverse Aortic Constriction Is Temporally, Kinetically and Structurally Distinct

“…Alternatively, animal models are used to investigate the chronology of cardiac events to a particular stress over time. Temporal studies in animal models provide insight into the time course of remodeling patterns ( Mirsky et al, 1983 ; Inoko et al, 1994 ; Klotz et al, 2006 ), and are valuable in the search for disease mechanisms and treatment targets ( Foster et al, 2017 ).…”