Studies of patients with obstructive sleep apnea suggest that high CPAP pressures may be the reason CPAP machines do not lower patients’ risk of heart disease, which is about two to three times higher than average.
“CPAP machines are very effective in treating obstructive sleep apnea, improving sleep and reducing daytime fatigue, but we haven’t seen the reduction in heart disease we hoped for, and we don’t know why,” says Sanja Jeric, MD, a critical care medicine specialist and sleep researcher at Columbia University Vagelos College of Medicine.
CPAP and Inflammation
Obstructive sleep apnea affects around 25% of adults in Western societies and occurs when muscles in the upper airway relax during sleep, causing the airway to close. The resulting drop in oxygen levels often causes people to wake up suddenly, sometimes every two minutes, leading to daytime fatigue.
“Oxygen levels go up and down throughout the night and can stay this way indefinitely,” says Jerrick. Repeated drops in oxygen levels are thought to worsen inflammation and increase the risk of heart disease associated with obstructive sleep apnea.
Because CPAP machines restore normal breathing while you sleep (using positive pressure to keep your upper airway open), researchers believed that CPAP also reduced patients’ risk of heart disease.
But a few years ago, research conducted by Jelick and collaborator Daniel Gottlieb, M.D., of Brigham and Women’s Hospital, began to suggest that this assumption was flawed. Designed to understand how CPAP affects the body, the study found that levels of the pro-inflammatory factor angiopoietin 2 do not decrease with CPAP use. Previous studies have linked high levels of Ang2 to a higher risk of stroke, coronary artery disease, vascular disease, and mortality.
“We were surprised because we would have naturally expected that removing the intermittent hypoxia with CPAP would stop the release of Ang2, but it actually got worse,” Jelic said.
Around the same time, results from three randomized trials of CPAP were published, all of which found no cardiovascular benefits from the device.
Jerrick found that the patterns of Ang2 and other biomarkers in CPAP users were similar to those in patients on high-pressure ventilators and hypothesized that the high pressure of CPAP could be the reason the expected reduction in heart disease did not materialize.
New Analysis
To dig deeper, Jerrick and Gottlieb looked more closely at participants in RICCADSA, the first study of 189 patients with obstructive sleep apnea in Sweden. The researchers analyzed stored blood samples for Ang2 and other inflammatory markers and compared those levels with CPAP adherence, median CPAP pressure, and patients’ cardiac health a year later.
Their analysis showed that Ang2 levels remained elevated in CPAP users, confirming previous findings from Jerrick’s smaller study, which showed that higher Ang2 levels were associated with an increased risk of cardiovascular disease 12 months after the start of the study.
The researchers found that patients with the highest Ang2 levels were those using higher CPAP pressures. A standard CPAP prescription uses pressures between 4 and 20 cm H2O, with median pressures varying within that range. In this study, participants with a median CPAP pressure of 4 to 7 had a lower incidence of cardiovascular events compared to those using a pressure of 8 or higher. No relationship was found between Ang2 levels and the number of hours of nighttime CPAP use.
“This suggests that there’s something in the lungs that responds to CPAP pressure that perpetuates, rather than reduces, the inflammation associated with obstructive sleep apnea,” Jerrick says.
Effect of pressure
CPAP is known to expand the lungs, although not as dramatically as a ventilator, so Jerrick thinks that the stretched endothelial cells in the lungs release the extra Ang2. While it is not possible to directly measure the release of Ang2 from human lungs, when other tissues are stretched in laboratory tests, the release of Ang2 from endothelial cells increases sharply.
Already, Dr. Jerrick is changing the way CPAP is used for patients with sleep apnea.
“I prescribe low pressure,” she says, “carefully titrating to what pressure will eliminate most of the obstructive events, and it’s worked well.”
Currently, most doctors adjust CPAP pressure to eliminate all obstructive episodes during sleep, but Jerrick says that even if some obstructive episodes do occur, lowering the pressure could reduce Ang2 and improve sleep and fatigue alike.
“That needs to be tested in a randomized trial,” she says.
