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Randomized Controlled Trial
. 2024 Mar:101:105015.
doi: 10.1016/j.ebiom.2024.105015. Epub 2024 Feb 24.

CPAP may promote an endothelial inflammatory milieu in sleep apnoea after coronary revascularization

Yuksel Peker  1 , Yeliz Celik  2 , Afrouz Behboudi  3 , Susan Redline  4 , Jing Lyu  5 , Ying Wei  5 , Daniel J Gottlieb  6 , Sanja Jelic  7
Affiliations
Randomized Controlled Trial

CPAP may promote an endothelial inflammatory milieu in sleep apnoea after coronary revascularization

Yuksel Peker et al. EBioMedicine. 2024 Mar.

Abstract

Background: Continuous positive airway pressure (CPAP) has failed to reduce cardiovascular risk in obstructive sleep apnoea (OSA) in randomized trials. CPAP increases angiopoietin-2, a lung distension-responsive endothelial proinflammatory marker associated with increased cardiovascular risk. We investigated whether CPAP has unanticipated proinflammatory effects in patients with OSA and cardiovascular disease.

Methods: Patients with OSA (apnoea-hypopnea index [AHI] ≥15 events/h without excessive sleepiness) in the Randomized Intervention with CPAP in Coronary Artery Disease and OSA study were randomized to CPAP or usual care following coronary revascularization. Changes in plasma levels of biomarkers of endothelial (angiopoietin-2, Tie-2, E-selectin, vascular endothelial growth factor [VEGF-A]) and lung epithelial (soluble receptor of advanced glycation end-products [sRAGE]) function from baseline to 12-month follow-up were compared across groups and associations with cardiovascular morbidity and mortality assessed.

Findings: Patients with OSA (n = 189; 84% men; age 66 ± 8 years, BMI 28 ± 3.5 kg/m2, AHI 41 ± 23 events/h) and 91 patients without OSA participated. Angiopoietin-2 remained elevated whereas VEGF-A declined significantly over 12 months in the CPAP group (n = 91). In contrast, angiopoietin-2 significantly declined whereas VEGF-A remained elevated in the usual care (n = 98) and OSA-free groups. The changes in angiopoietin-2 and VEGF-A were significantly different between CPAP and usual care, whereas Tie-2, sRAGE and E-selectin were similar. Greater 12-month levels of angiopoietin-2 were associated with greater mortality. Greater CPAP levels were associated with worse cardiovascular outcomes.

Interpretation: Greater CPAP levels increase proinflammatory, lung distension-responsive angiopoietin-2 and reduce cardioprotective angiogenic factor VEGF-A compared to usual care, which may counteract the expected cardiovascular benefits of treating OSA.

Funding: National Institutes of Health/National Heart, Lung, and Blood Institute; Swedish Research Council; Swedish Heart-Lung Foundation; ResMed Foundation.

Keywords: Cardiovascular risk; Continuous positive airway pressure; Inflammation; Sleep apnoea.

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Conflict of interest statement

Declaration of interests Y.P. received institutional grants from ResMed Foundation and ResMed Ltd. S.R. received consulting fees from Apnimed Inc., and consulting fees and support for travel from Eli Lilly Inc. S.R. is an unpaid Board member for the National Sleep Foundation and Alliance for Sleep Apnea Partners. D.J.G. received consulting fees from Powell–Mansfield, Inc., and fees for participation on Scientific Advisory Board from Signifier Medical Technologies and Wesper, Inc., and fees for participation on Data Monitoring Committee from Apnimed, Inc. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Flow diagram and study protocol.
Fig. 2
Fig. 2
Circulating levels of angiopoietin-2 are associated with median CPAP pressure in patients with obstructive sleep apnoea after coronary revascularization (linear regression slope 0.30, 95% CI 0.03, 0.57, p = 0.039). The shaded area represents 95% confidence band. CPAP, continuous positive airway pressure.
Fig. 3
Fig. 3
The association of the composite cardiovascular outcome with CPAP pressure. Cox regression analysis for the composite cardiovascular outcome stratified by the CPAP pressure below vs. above the median pressure, adjusted for age, sex, BMI and baseline AHI (HR 2.81; 95% CI 1.22, 6.44, p = 0.021). The shaded areas represent 95% confidence bands. CPAP, continuous positive airway pressure.
Fig. 4
Fig. 4
CPAP therapy alters the pattern of plasma biomarker expression after coronary revascularization in patients with obstructive sleep apnoea (OSA) in a direction that favors inflammatory over angiogenic processes. While CPAP therapy reduces OSA-associated hypoxemia, with expected beneficial effects on endothelial function and inflammation, increased lung volumes during CPAP therapy may promote persistent increase in circulating levels of a pro-inflammatory factor angiopoietin-2 while elimination of intermittent hypoxia reduces levels of a proangiogenic factor VEGF-A. The reduction in VEGF-A in the setting of persistent elevation in angiopoietin-2 observed after CPAP therapy is hypothesized to increase the risk of recurrent events after coronary revascularization. Greater levels of angiopoietin-2 and sRAGE, a marker of lung epithelial injury, after 12 months of CPAP therapy were associated with significantly greater mortality and an increased incidence of cardiovascular events in patients with OSA. CPAP, continuous positive airway pressure; VEGF-A, vascular endothelial growth factor; sRAGE, soluble receptor of advanced glycation end-products.
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