Role of ventilatory drive in obstructive sleep apnea: An avenue for precision intervention - PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) is a highly prevalent disorder characterized by repetitive upper airway obstruction that has major deleterious effects on health. However, the leading treatment, continuous positive airway pressure (CPAP), is poorly tolerated by many individuals. Thus, new treatment strategies are needed. We recently discovered that neural ventilatory drive plays a far greater role in upper airway obstruction than previously appreciated: In a 60% majority of patients, ventilatory drive falls in tight synchrony with the loss of airflow during respiratory events; these patients—referred to as “drive-dependent”—no longer exhibit respiratory events when drive rises at some time during the night (<10% likelihood at 200% resting drive). By contrast, patients who exhibit “classic” events (reduced airflow despite rising drive), continue to exhibit events regardless of drive. The current proposal will address major clinically-relevant questions that emerged from this discovery: ● In Aim 1, we will show that the role for ventilatory drive in OSA is experimentally reversible (i.e. causal). Falling ventilatory drive during events will be mitigated with carefully-timed inspired carbon dioxide stimulation (2% for 3-4 breaths). We expect to show that events are prevented, and the characteristic loss of airflow and pharyngeal muscle activity (genioglossus EMG) is spared, when falling drive (per intraesophageal diaphragm EMG) is averted. Benefits are expected exclusively in patients with “drive-dependent OSA” (N=18) but not “classic OSA” (N=18). ● The discovery also has major implications for which patients may respond to the promising ventilatory drive stimulant acetazolamide. In Aim 2, in a randomized placebo-controlled mechanistic crossover trial, we will assess whether drive-dependent OSA (N=18) is more amenable to ventilatory drive stimulation with acetazolamide than classic OSA (N=18). Physiological measurements of ventilation and ventilatory drive will describe how acetazolamide, by mitigating dips in drive, raises airflow and prevents events exclusively in “drive- dependent OSA”. An open label extension will confirm subgroup differences over a longer period (4-weeks). ● In a translational aim (Aim 3), we will refine our clinically-applicable method to identify drive-dependent OSA from routine sleep studies, and thereby predict responders to acetazolamide therapy (precision medicine). Our preliminary model using five clinically-recognizable characteristics already demonstrates potential clinical utility. Further methods development will utilize non-invasive ventilatory drive surrogates to improve the preliminary model, which will be prospectively validated using the new physiological studies in Aims 1 and 2. Overall, our proposal will establish that mitigating ventilatory drive decline is a promising therapeutic strategy for a large recognizable subgroup of OSA patients. The work will also provide the necessary background knowledge for further trials of acetazolamide or other drive interventions in selected patients with drive-dependent OSA (precision medicine), and has great potential to improve OSA-related adverse health outcomes for those without a tolerable therapy for their untreated disorder.
