Impact of Continuous Positive Airway Pressure on Biomarkers of Inflammation in Patients with Obstructive Sleep Apnea: The RICCADSA Study
Authors List
DJ Gottlieb1,2, Y Çelik3,4, A Behboudi5, S Redline2, Y Peker2,3,6, S Jelic4,
1VA Boston Healthcare System
2Brigham & Women’s Hospital, Boston, MA;
3Koç Univ. School of Medicine, Istanbul, Turkey;
4Columbia Univ. Medical Center, New York, NY;
5Univ. of Skövde, Skövde, Sweden;
6Univ. of Gothenburg, Gothenburg, Sweden.
Rationale
We previously reported that treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) for 3 to 6 months is associated with increased serum angiopoietin-2 (Ang-2), a marker and mediator of vascular inflammation that is associated with cardiovascular and all-cause mortality, suggesting a potential adverse effect of CPAP therapy. We further explored this in the setting of a randomized clinical trial (RCT) of CPAP therapy for secondary prevention of cardiovascular events (NCT 00519597), extending this observation to 12 months of follow-up and to additional biomarkers of inflammation.
Methods
Participants in the RICCADSA study were screened for OSA following a coronary revascularization procedure and were randomized to CPAP versus usual care if they had apneahypopnea index ≥15 events/hr but no excessive sleepiness. Randomization occurred approximately 3 months following revascularization and blood samples were obtained at baseline and at 12-month follow-up visits. Serum levels of Ang-2, E-selectin, and receptor of
advanced glycation end-products (RAGE) were measured by immunoassay (Luminex, R&D Systems). Mann-Whitney U-test was used to compare change in biomarker level across groups.
Results
Participants were 160 men and 30 women, age 66 (SD 8) years, BMI 28.4 (SD 3.5) kg/m2, AHI 29.2 (SD 13.4) events/hr. Mean CPAP adherence was 3.2 (SD 2.9) hrs/night in the CPAP group. Change in biomarker concentrations from baseline to 12 months are shown in the table, with results shown as median (25%, 75%) change in each group.
Conclusions
Systemic markers of inflammation are elevated in acute coronary syndrome and fall over a period of months. However, we found that in patients with non-sleepy OSA requiring coronary revascularization, CPAP was associated with a smaller fall in serum Ang-2 following coronary revascularization than was usual care. Two additional markers of inflammation, Eselectin and RAGE, also fell more with usual care than with CPAP; although the differences for
these additional biomarkers were not statistically significant, they were each in the direction of less reduction in inflammation in the CPAP group. This extends our prior findings on Ang-2 to a sample of patients with recent coronary revascularization studied using a more robust RCT design and showing the durability of an adverse effect of CPAP on Ang-2 over 12 months, possibly extending to other biomarkers of inflammation. This raises the concern that lung inflation caused by CPAP might induce vascular inflammation, in a manner analogous to ventilator-induced lung injury, possibly counteracting the expected cardiovascular benefits of treating OSA and suggesting an explanation for the failure of CPAP to reduce cardiovascular risk in several recent cardiovascular secondary prevention trials.
Funding: The main RICCADSA trial was supported by the Swedish Research Council, the Swedish Heart and Lung Foundation, ResMed Foundation and ResMed Inc. The present study was supported by NIH grants R01HL137234 and R01 HL106041.
DJ Gottlieb1,2, Y Çelik3,4, A Behboudi5, S Redline2, Y Peker2,3,6, S Jelic4,
1VA Boston Healthcare System
2Brigham & Women’s Hospital, Boston, MA;
3Koç Univ. School of Medicine, Istanbul, Turkey;
4Columbia Univ. Medical Center, New York, NY;
5Univ. of Skövde, Skövde, Sweden;
6Univ. of Gothenburg, Gothenburg, Sweden.
Rationale
We previously reported that treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) for 3 to 6 months is associated with increased serum angiopoietin-2 (Ang-2), a marker and mediator of vascular inflammation that is associated with cardiovascular and all-cause mortality, suggesting a potential adverse effect of CPAP therapy. We further explored this in the setting of a randomized clinical trial (RCT) of CPAP therapy for secondary prevention of cardiovascular events (NCT 00519597), extending this observation to 12 months of follow-up and to additional biomarkers of inflammation.
Methods
Participants in the RICCADSA study were screened for OSA following a coronary revascularization procedure and were randomized to CPAP versus usual care if they had apneahypopnea index ≥15 events/hr but no excessive sleepiness. Randomization occurred approximately 3 months following revascularization and blood samples were obtained at baseline and at 12-month follow-up visits. Serum levels of Ang-2, E-selectin, and receptor of
advanced glycation end-products (RAGE) were measured by immunoassay (Luminex, R&D Systems). Mann-Whitney U-test was used to compare change in biomarker level across groups.
Results
Participants were 160 men and 30 women, age 66 (SD 8) years, BMI 28.4 (SD 3.5) kg/m2, AHI 29.2 (SD 13.4) events/hr. Mean CPAP adherence was 3.2 (SD 2.9) hrs/night in the CPAP group. Change in biomarker concentrations from baseline to 12 months are shown in the table, with results shown as median (25%, 75%) change in each group.
Conclusions
Systemic markers of inflammation are elevated in acute coronary syndrome and fall over a period of months. However, we found that in patients with non-sleepy OSA requiring coronary revascularization, CPAP was associated with a smaller fall in serum Ang-2 following coronary revascularization than was usual care. Two additional markers of inflammation, Eselectin and RAGE, also fell more with usual care than with CPAP; although the differences for
these additional biomarkers were not statistically significant, they were each in the direction of less reduction in inflammation in the CPAP group. This extends our prior findings on Ang-2 to a sample of patients with recent coronary revascularization studied using a more robust RCT design and showing the durability of an adverse effect of CPAP on Ang-2 over 12 months, possibly extending to other biomarkers of inflammation. This raises the concern that lung inflation caused by CPAP might induce vascular inflammation, in a manner analogous to ventilator-induced lung injury, possibly counteracting the expected cardiovascular benefits of treating OSA and suggesting an explanation for the failure of CPAP to reduce cardiovascular risk in several recent cardiovascular secondary prevention trials.
Funding: The main RICCADSA trial was supported by the Swedish Research Council, the Swedish Heart and Lung Foundation, ResMed Foundation and ResMed Inc. The present study was supported by NIH grants R01HL137234 and R01 HL106041.
