Peripheral chemoreceptors, plant gain & CO ₂ stores as drivers of resting ventilatory control in idiopathic hyperventilation: a prospective case-control study.

Introduction: Idiopathic Hyperventilation Syndrome (HVS) is a poorly understood condition with potential mechanisms involving altered CO 2 chemosensitivity, CO 2 stores depletion and reduced plant gain (PG). Methods: Twelve carefully selected patients with HVS (HVS+), diagnosed by symptoms, normal lung function, and a positive hyperventilation provocation test, were compared to 12 matched healthy controls (HVS-). All participants underwent a Hypercapnic-Hyperoxic Challenge Test (HHCT), assessing ventilatory and drive-to-breathe responses, and dyspnea. Parameters included controller gain (β-slope), ventilatory and drive recruitment thresholds (VRT, DRT), extrapolated apnoeic and chemoreflex thresholds (AT, CT), CO 2 stores, PG, and Peripheral Sensitivity Range (PSR=VRT-AT). Results: Compared to HVS-, patients with HVS+ showed elevated baseline ventilation, ventilatory variability, drive-to-breathe and dyspnea (all p≤0.048). During HHCT, despite similar β-slope, HVS+ exhibited a leftward-shifted ventilatory response curve, with lower AT and CT, expanded PSR, and reduced PG (all p≤0.021), suggesting reduced CO 2 buffering and heightened peripheral chemosensitivity. While in HVS-, baseline breathing patterns correlated closely with end-tidal CO 2 pressure and VRT, in HVS+ the ventilation magnitude and variability were associated with PG, PSR and CO 2 stores (all p≤0.048). Multivariate regression showed that PG was predicted by PSR, CO 2 stores, and their interaction. PG and ventilatory variability emerged as strong predictors of HVS+. Conclusion: These findings reveal a distinct ventilatory phenotype in HVS+ marked by increased reliance on peripheral chemoreflex inputs and disrupted CO 2 buffering capacity. PG and ventilatory variability emerged as strong predictors of HVS+ status, reinforcing their potential diagnostic value. These results support a novel pathophysiological model that warrants further investigation.