Phenotyping Using Polysomnography Attributes Reduced Respiratory Events after Continuous Positive Airway Pressure Therapy to Improved Upper Airway Collapsibility

<b>Rationale:</b> In patients with obstructive sleep apnea (OSA) treated with continuous positive airway pressure (CPAP), the apnea-hypopnea index (AHI) measured <i>off</i> CPAP may be decreased relative to baseline AHI preceding CPAP treatment. Semiinvasive "endophenotyping" sleep studies attribute this fall in AHI primarily to improved ventilatory control stability. Phenotyping Using Polysomnography (PUP) attempts to reproduce these studies using routine polysomnography (PSG). <b>Objectives:</b> To determine whether changes in AHI after CPAP associate primarily with changes in PUP-estimated ventilatory control stability (loop gain with a 1-minute cycle time [LG₁]) or with changes in other PUP-estimated pathophysiologic mechanisms. <b>Methods:</b> PUP analyses were performed on existing PSGs in research participants who underwent baseline PSG, 4.4 ± 2.2 months of CPAP therapy, and CPAP withdrawal with repeat PSG on Night 2 of withdrawal. Pre-CPAP PUP-estimated LG₁, arousal threshold, and upper airway collapsibility (Vpassive) and muscular compensation (Vcomp) were compared with corresponding values during CPAP withdrawal. Mixed-effects models were constructed to determine which PUP estimate best explained changes in AHI. <b>Results:</b> PSG data were available for 35 participants (mean age, 47 ± 10.8 yr; 12 women; mean body mass index, 38.5 ± 8.6 kg/m²; mean AHI with hypopneas defined according to 3% oxygen desaturation and/or arousal, 58.8 ± 33.1 events/h; 9 participants with mild/moderate OSA and 26 with severe OSA). After CPAP, AHI decreased, but the change was not statistically significant. However, a significant decrease was observed in those with severe OSA (pre-CPAP 68.2 [32.6-86.3] vs. CPAP withdrawal 49.0 [36.1-74.4] events/h). Across all participants, changes in PUP estimates did not exceed test-retest agreement limits. For those with severe OSA, decrease in LG₁ (0.86 [0.61-1.13] before CPAP vs. 0.71 [0.61-0.99] on CPAP withdrawal) and increase in Vpassive (fraction of eupneic ventilation 64.8% [5.4-88.4%] before CPAP vs. 76.4% [20.7-92.7%] on CPAP withdrawal) exceeded test-retest agreement limits. Increased Vpassive, decreased LG₁, and decreased arousal threshold were predictors of decreased AHI in mixed-effects models. Vpassive had the greatest estimated effect on AHI. After accounting for Vpassive, additional estimates did not improve model performance. However, Vpassive and LG₁ were correlated, and <i>post hoc</i> analyses suggest that these estimates may be influenced by both upper airway collapsibility and ventilatory control. <b>Conclusions:</b> According to PUP physiologic estimates, decreases in AHI after several months of CPAP therapy are attributable primarily to improved upper airway collapsibility.