Skeletal muscle metaboreflex control of ventilation and perception of dyspnoea is enhanced in pulmonary arterial hypertension

Background: Exertional dyspnoea limits exercise capacity and worsens quality of life in pulmonary arterial hypertension (PAH). Exercise in PAH is characterised by excess ventilation, leading to dyspnoea, however the underlying mechanisms are incompletely understood. In PAH, there is evidence for skeletal muscle myopathy, with defects in mitochondrial function and metabolism. Such skeletal muscle dysfunction can lead to an early and more pronounced accumulation of metabolites during exercise that activates metabolically responsive skeletal muscle afferents (metaboreflex), thereby driving ventilation and exertional dyspnoea. To investigate this, the cardiorespiratory responses and ratings of perceived dyspnoea during metaboreflex activation were characterised in PAH. Hypothesis: We hypothesise that the skeletal muscle metaboreflex is augmented in PAH, driving ventilation and the perception of dyspnoea. Methods: Twelve PAH patients (8 female, 50 ± 13 years; mean ± SD) and 12 healthy control subjects (7 female, 51 ± 16 years) completed a handgrip exercise involving a baseline (2 min), isometric handgrip at 35% maximum voluntary contraction (2 min), and recovery (4 min). During recovery, participants underwent post-exercise circulatory occlusion (PECO) to activate the metaboreflex (2 min) followed by free-flow recovery (2 min). Minute ventilation (V̇E), heart rate (HR), and mean arterial blood pressure (MAP) were measured. Dyspnoea was subjectively rated with the Borg dyspnoea scale (0-10). Results: Baseline V̇E was not significantly different between PAH patients and healthy controls (14.2 ± 2.1 vs. 12.9 ± 2.2 L/min, p=0.163), nor were baseline ratings of perceived dyspnoea, HR and MAP significantly different between groups. During handgrip (2nd min), V̇E response was greater in PAH versus healthy controls (Δ4.7 ± 4.3 vs. 2.5 ± 1.8 L/min, p=0.007). The V̇E response during PECO (2nd min) was greater in PAH (Δ2.2 ± 1.7 vs. 0.4 ± 1.4 L/min, p=0.028). Ratings of perceived dyspnoea during PECO were greater in PAH patients (Δ2.0 ± 1.2 vs. 0.8 ± 1.2 units, p=0.017). HR and MAP responses to handgrip and PECO were not different between PAH and healthy controls. Conclusions: These findings indicate that during handgrip exercise, skeletal muscle metaboreflex activation enhances both the ventilatory response and perception of dyspnoea in PAH relative to healthy participants, but does not augment the cardiovascular response suggesting differential reflex sensitisation. This study has received funding support from the Greenlane Research and Educational Fund (Ref# 21/01/4153. MP, SS, JFRP, JPF), Health Research Council of New Zealand (Ref# 19/687. JFRP, JPF), and the Sydney Taylor Trust (JFRP). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.