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.
Hypoxia is both a consequence and cause of many acute and chronic diseases. Severe hypoxia causes hypertension with cardiovascular sequelae; however, the rare studies using moderate severities of hypoxia indicate that it can be beneficial, suggesting that hypoxia may not always be detrimental. Comparisons between studies are difficult because of the varied classifications of hypoxic severities, methods of delivery and use of anaesthetics. Thus, to investigate the long-term effects of moderate hypoxia on cardiovascular health, radiotelemetry was used to obtain in vivo physiological measurements in unanaesthetized mice during 24 h of either moderate or severe hypoxia, followed by 72 h of normoxic recovery. Systolic blood pressure was decreased during recovery following moderate hypoxia but increased following severe hypoxia. Moderate and severe hypoxia increased haeme oxygenase-1 expression during recovery, suggesting parity in hypoxic stress at the level of the artery. Severe but not moderate hypoxia increased the low/high frequency ratio of heart rate variability 72 h post-hypoxia, indicating a shift in sympathovagal balance. Moderate hypoxia dampened the amplitude of circadian rhythm, whereas severe disrupted rhythm during the entire insult, with perturbations persisting throughout normoxic recovery. Thus, hypoxic severity differentially regulates circadian blood pressure.
The discussions, processes, and procedural decisions documented in regulatory decisions can offer unique insight into a pharmaceutical's strengths, weaknesses, or residual knowledge gaps; yet these resources are often overlooked. From a research perspective, the disclosure of regulatory agency reviews, procedures and evidence holds significant value as the information contained within such documents is often more extensive than what is reported in the primary medical literature or continuing medical education. [1][2][3][4][5] As a result,
Limited data exist regarding the impact of an acute bout of exercise with varying intensities on irisin levels in the youth of different obesity statuses. The objectives were to (1) compare an acute bout of moderate continuous intensity (MCI) exercise and an acute bout of high‐intensity interval training (HIIT) on irisin response in youth with different obesity statuses and, (2) investigate whether changes in irisin levels are correlated with exploratory outcomes. A randomized crossover design study was conducted on 25 youth aged 12–18 years old. Participants were classified as either healthy weight (BMI percentile <85; n = 14) or overweight/obese (BMI percentile ≥85; n = 11). Participants performed an MCI exercise session at 50% of heart rate reserve for 35 min and a HIIT exercise session for 35 min, with intervals every 5 min increasing from 50% heart rate reserve to 85–90% for 2 min. Irisin was measured using an enzyme‐linked immunoabsorbent assay from plasma sampling obtained throughout the exercise (at times 0, 7, 14, 21, 28, and 35 min). A time effect was observed throughout the HIIT session [F(1,5) = 6.478, p < 0.001]. Bonferonni post‐hoc analysis revealed significant differences in irisin levels post‐exercise (35 min) compared to times 7, 14, 21, and 28 min. Irisin increased during HIIT (81.0% ± 71.3; p = 0.012) in youth with a healthy weight. No differences were observed for youth living as overweight or with obesity. Overall, HIIT elicits a higher peak irisin response compared to MCI exercise training in youth.
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