Central Apnea in Heart Failure: Physiological Mechanisms to Inform Treatment

Our objective is to test mechanistic pathways to inform future clinical studies investigating the potential treatment of central sleep apnea (CSA) in veterans with heart failure and reduced ejection fraction (HF). The long-term goal is to transform the care of veterans living with these two conditions. We will test two key determinants of recurrent CSA in veterans with HF: augmented peripheral chemoreceptor activity and respiratory arousals. Specifically, the project will utilize a novel PAP plus approach, combining PAP therapy to alleviate upper airway obstruction with a specific intervention to target the mechanistic underpinnings of CSA. Our experiments will capitalize on the plasticity of the CO2 reserve as the gateway to the resolution of CSA. We will suppress arousals or dampen augmented PCR activity while maintaining upper airway patency with PAP. The long-term goal is to inform future multi-modality intervention studies. To this end, the following Specific Aims will be addressed in veterans with HF and CSA. Specific Aim 1: To determine the effect of decreasing respiratory arousals on the propensity to CSA. Hypothesis 1: Four weeks of combined PAP and trazodone therapy will be superior to PAP alone in elevating the arousal threshold, widening the CO2 reserve (primary outcome), and decreasing CSA indices. Specific Aim 2: To determine the effect of decreased peripheral chemoreceptor sensitivity on the propensity to CSA. Hypothesis 2: Four weeks of combined PAP and supplemental O2 (targeting peripheral chemoreceptor sensitivity) will be superior to PAP alone in widening the CO2 reserve (primary outcome), reducing controller gain, and decreasing CSA indices. The proposed studies are innovative, testing mechanistic “PAP Plus” approach targeting underlying causes of CSA and alleviating upper airway obstruction with PAP. These studies will inform future clinical trials to transform central apnea care in patients with heart failure. Project Number: 2I01RD001576-07A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: M.Safwan Badr | Institution: JOHN D DINGELL VA MEDICAL CENTER, DETROIT, MI | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURR-H (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11299757