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

Idiopathic hyperventilation syndrome (HVS) is a poorly understood condition with potential mechanisms involving altered CO₂ chemosensitivity, CO₂ store depletion, and reduced plant gain (PG). 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 and DRT), extrapolated apneic and chemoreflex thresholds (AT and CT), CO₂ stores, PG, and peripheral sensitivity range (PSR = VRT-AT). Compared to HVS-, patients with HVS+ showed elevated baseline ventilation, ventilatory variability, drive-to-breathe, and dyspnea (all <i>P</i> ≤ 0.048). During HHCT, despite a similar β-slope, HVS+ exhibited a leftward-shifted ventilatory response curve, with lower AT and CT, expanded PSR, and reduced PG (all <i>P</i> ≤ 0.021), suggesting reduced CO₂ buffering and heightened peripheral chemosensitivity. While in HVS- baseline breathing patterns correlated closely with end-tidal CO₂ pressure and VRT, in HVS+ the ventilation magnitude and variability were associated with PG, PSR, and CO₂ stores (all <i>P</i> ≤ 0.048). Multivariate regression showed that PG was predicted by PSR, CO₂ stores, and their interaction. PG and ventilatory variability emerged as strong predictors of HVS+. These findings reveal a distinct ventilatory phenotype in HVS+ marked by increased reliance on peripheral chemoreflex inputs and disrupted CO₂ 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.<b>NEW & NOTEWORTHY</b> Patients with idiopathic hyperventilation syndrome (HVS) displayed preserved central chemosensitivity but altered ventilatory control at rest, characterized by elevated ventilation, increased variability, and a leftward-shifted hypercapnic response. These features were strongly associated with peripheral chemosensitivity, CO₂ stores, and reduced plant gain, patterns not observed in controls. These findings support a novel integrative model in which altered CO₂ buffering and peripheral afferent inputs, rather than central mechanisms alone, contribute to ventilatory instability in HVS.