Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets

Abstract

Rationale: The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized.

Objectives: To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA.

Methods: Seventy-five men and women with and without OSA aged 20-65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA.

Measurements and main results: Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold, and 36% had high loop gain. A total of 28% had multiple nonanatomic features. Although overall the upper airway was more collapsible in patients with OSA (Pcrit, 0.3 [-1.5 to 1.9] vs. -6.2 [-12.4 to -3.6] cm H2O; P <0.01), 19% had a relatively noncollapsible upper airway similar to many of the control subjects (Pcrit, -2 to -5 cm H2O). In these patients, loop gain was almost twice as high as patients with a Pcrit greater than -2 cm H2O (-5.9 [-8.8 to -4.5] vs. -3.2 [-4.8 to -2.4] dimensionless; P = 0.01). A three-point scale for weighting the relative contribution of the traits is proposed. It suggests that nonanatomic features play an important role in 56% of patients with OSA.

Conclusions: This study confirms that OSA is a heterogeneous disorder. Although Pcrit-anatomy is an important determinant, abnormalities in nonanatomic traits are also present in most patients with OSA.

Figure 1.

(A) Example of a continuous positive airway pressure (CPAP) drop highlighting the variables of interest for calculation of Pcrit, genioglossus muscle responsiveness, and the respiratory arousal threshold. (B) Determination of loop gain from a CPAP drop. (1) Before the drop, the patient’s airway is open and ventilation is at eupnea. (2) When CPAP is dropped, the upper airway narrows and limits ventilation. (3) As a result, CO₂ increases and, in many individuals, activates and stiffens the pharyngeal muscles and increases ventilation slightly (although it typically remains below eupnea). In this schematic example, the disturbance is a change in ventilation of −1.4 L/min. (4) The response to this disturbance is determined by reopening the airway with CPAP and measuring the ventilatory overshoot, which is 4.2 L/min. Therefore, the loop gain is 4.2 ÷ −1.4 = −3 (i.e., for every liter per minute reduction in ventilation, there is a threefold increase in ventilatory drive). (5) After the airway is reopened and the excess CO₂ is blown off, ventilation returns back to eupnea. Refer to the text and reference (27) for further detail. GG = genioglossus; MTA = 100 millisecond moving-time-average of the rectified raw electromyographic activity; Pepi = epiglottic pressure; Pcrit = critical closing pressure of the upper airway; Pmask = mask pressure.

Figure 2.

Critical closing pressure of the upper airway (Pcrit) versus the apnea-hypopnea index (AHI). Grey circles represent individuals with an AHI less than 10 events per hour of sleep.

Figure 3.

Phenotypic trait scatter plots for (A) slope of genioglossus muscle responsiveness versus negative epiglottic pressure, (B) the respiratory arousal threshold, and (C) loop gain. Note the large degree of between-subject variability within patients with OSA and control subjects and considerable between-group overlap for each of the pathophysiologic parameters. Horizontal black lines represent median values. Values above the dashed grey lines in A (more positive) and B (more positive) indicate poor muscle responsiveness and a low arousal threshold, respectively. Values below the dashed grey line in C (more negative) indicate a high loop gain. Refer to text and Tables 2 and 3 for further detail. *Significant difference between groups (P < 0.05). OSA = obstructive sleep apnea; Pepi = epiglottic pressure.

Figure 4.

Phenotypic traits according to upper airway collapsibility (critical closing pressure of the upper airway [Pcrit]) category. Control subjects with a Pcrit less than −5 cm H₂O (n = 11; 65%) had a median apnea-hypopnea index (AHI) of 2 (1–3) events per hour of sleep. Control subjects with a Pcrit between −5 and −2 cm H₂O (n = 6; 35%) had a median AHI of 5 (3–9) events per hour of sleep. Patients with obstructive sleep apnea (OSA) with a Pcrit between −5 and −2 cm H₂O (n = 11; 19%) had a median AHI of 19 (12–39) events per hour of sleep. Patients with OSA with a Pcrit between −2 and +2 cm H₂O (n = 33; 58%) had a median AHI of 32 (19–56) events per hour of sleep. Patients with OSA with a Pcrit greater than +2 cm H₂O (n = 13; 23%) had a median AHI of 76 (48–100) events per hour of sleep. (A) The dots indicate the median arousal threshold, which is higher in the OSA groups. The two control groups have a relatively low arousal threshold, but note how they can achieve a high level of genioglossus (GG) muscle activity because of their steep slope and high starting point. Thus, combined with a relatively noncollapsible upper airway, these individuals probably do not need a higher arousal threshold to prevent OSA. The patients with OSA with a Pcrit greater than +2 have a steep muscle responsiveness slope and a high arousal threshold and thus can achieve the greatest amount of muscle activity. However, they are limited by their highly collapsible upper airway. The OSA group with a relatively uncollapsible upper airway (Pcrit between −5 and −2 cm H₂O) has the poorest muscle activation response, which is likely to be an issue for this group. (B) Loop gain is substantially higher in the patients with OSA with a Pcrit between −5 and −2 cm H₂O, in which ventilatory motor output increases sixfold for every liter per minute reduction in ventilation. The other groups exhibit only a threefold to fourfold increase and thus are much more stable. Horizontal white lines indicate median values and the grey portions of the box plot represent the 25th and 75th centiles. *Significant difference between groups (P < 0.05).