Central Apnea in Heart Failure: Physiological Mechanisms to Inform Treatment

Central Apnea in Heart Failure: Physiological Mechanisms to Inform Treatment

Central sleep apnea (CSA) is common in patients with heart failure and those using opioid analgesics. Unfortunately, effective treatment of central apnea remains elusive, pressure therapy given the modest efficiency of positive airway pressure therapy. The focus of this proposal is to identify mechanistic pathways to guide future therapeutic interventions for central sleep apnea based on the strong premise that multi-modality therapy will normalize respiration and hence mitigate adverse long-term consequences of CSA. The investigators' proposed studies will test combination therapies, including positive airway pressure (PAP) plus a pharmacological agent who have heart failure or are using opioid analgesics. The investigators anticipate that findings will inform future clinical trials to improve care and quality of life among Veterans suffering from central sleep apnea, which remains difficult to treat using existing approaches.

The objective in this project 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. The investigators 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. The experiments will capitalize on the plasticity of the CO2 reserve as the gateway to the resolution of CSA. The investigators 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. The investigators hypothesize that 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. The investigators hypothesize that 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.

Inclusion Criteria:

• Men and Women Veterans with central sleep apnea, defined as Apnea Hypopnea Index (AHI)>15/hour with CAHI>5/hour, will be included with the experiments.
• Those with chronic, stable heart failure with reduced ejection fraction, receiving stable optimized guideline-based therapy and no hospitalizations or change in the medical regimen for the past 90 days before enrollment.

Exclusion Criteria:

• less than 18 years old
• pregnant or breastfeeding females
• moderate or severe obstructive or restrictive lung disease, including supplemental o2 use
• current treatment for CSA, including any form of PAP in the past three months, or phrenic nerve situation.
• too ill to engage in the study procedures, inability to provide consent for participation.
• a history of cardiac arrhythmia
• Alcohol or substance abuse (less than 90 days sobriety) or current participation in a treatment program
• depression or a history of suicidality
• severe insomnia (ISI>21) or reported short sleep duration (<6 hours)
• PAP-emergent central sleep apnea
• Lack of PAP acceptance/adherence after a one-week home PAP trial after enrollment.

Additional Trazodone Exclusions:

• Prolonged QT on baseline ECG, using medications that inhibit CYP3A4
• Patients with severe renal impairment (GFR < 20ml/min/1.73m2) or end-stage renal disease