Sleep Apnea May Affect the Heart Via Vessels

BUFFALO, N.Y., June 1 -- Endothelial injury may explain in part how obstructive sleep apnea raises cardiovascular risk, according to researchers here.

In a small study, moderate apnea was associated with significantly elevated levels of circulating apoptotic endothelial cells, which in turn were correlated with impaired vasodilation, found Ali A. El Solh, M.D., M.P.H., of the Erie County Medical Center and University at Buffalo here, and colleagues.

However, eight weeks of continuous positive airway pressure (CPAP) treatment improved these measures of vascular function, they reported in the first June issue of the American Journal of Respiratory and Critical Care Medicine.

Obstructive sleep apnea is known to cause vascular dysfunction and increase risk of coronary artery disease more than fourfold and risk of stroke more than eightfold, the researchers noted.

Many mechanisms have been proposed, such as hypoxia reoxygenation, oxidative stress, and release of proinflammatory markers, they wrote, "all of which have been described to cause endothelial cell apoptosis."

"These findings provide an additional mechanism for the predisposition of patients with obstructive sleep apnea to premature vascular disease," they said.

The study included 14 consecutive male patients who had an apnea-hypopnea index of more than five episodes per hour (average 23.7 per hour) verified by polysomnography at a single center.

Also, 10 men without sleep-disordered breathing were recruited from the center's wellness clinic as controls.

All participants were healthy nonsmokers not taking any medications. Baseline characteristics were similar between groups though body mass index tended to be higher in the apnea group (30.6 versus 27.8 kg/m³, P=0.11).

To detect apoptotic endothelial cells, the researchers performed flow cytometry on blood samples from subjects measuring for cells that were positive for expression of both CD146, which "is exclusively expressed on mature endothelial cells," and Annexin V, an early marker of apoptotic cell death.

Baseline flow cytometry showed that apnea patients had twice as many of these cells circulating as controls (39.2 versus 17.8 cells/mL, P<0.001).

Apoptotic endothelial cells in the circulation were correlated significantly with some aspects of sleep apnea. The associations were:

• Significant for the apnea-hypopnea index (P=0.004).
• Significant for time spent with less than 90% oxygen saturation (P=0.01).
• Not significant for the arousal index (P=0.15).

In a univariate analysis, higher levels of apoptotic endothelial cells was moderately associated with impaired vascular function as measured by endothelial-dependent brachial artery dilation (P=0.001).

This impairment is "a precursor of atherosclerosis related events," the investigators said.

After these baseline measurements, the sleep apnea group received nasal CPAP treatment for eight weeks with an average pressure setting of 9.7 mm Hg for an average of 5.2 hours per night.

After treatment, the sleep apnea group had significantly fewer circulating apoptotic endothelial cells (22.3 versus 39.2 cells/mL, P<0.001). All but two apnea patients had a reduction in this marker of vascular damage.

This change was associated with a trend toward improvement in endothelium-dependent vasodilation (P=0.07).

"The profound decrease in circulating apoptotic endothelial cells in patients after CPAP therapy underlines the role of obstructive sleep apnea in the initiation of apoptotic machinery," Dr. El Solh and colleagues wrote.

The mechanism for this effect is not clear, they said.

But, in vitro evidence suggests that endothelial injury or apoptosis causes elevated circulating levels of apoptotic endothelial cells rather than being a result of it, they noted.

Also, more circulating apoptotic endothelial cells would mean less nitric oxide production crucial to artery vasodilatation, they noted, potentially raising the risk of hypertension and acute heart attack.

CPAP likely restores the physiologic function of the lining of the blood vessels, reducing those risks, Dr. El Solh said.

Further research is needed before the results could be used clinically, he added.

Future applications could include using circulating apoptotic endothelial cells could be used "as a novel marker of vascular dysfunction, allowing risk stratification and monitoring of athero-modifying regimens," the researchers wrote.

They cautioned, though, that the findings were limited by lack of thorough assessment to exclude coronary artery disease in study participants.

Excluding women to keep the study population homogeneous means "further investigation is needed to determine whether sex exhibits differential endothelial apoptosis," they added.

They also noted that while the addition of a control group consisting of a parallel group of patients matched for age, sex, and severity of disease who would be denied CPAP treatment. would strengthen the results, it was not feasible. "Given what we know about the increased morbidity and mortality of untreated obstructive sleep apnea, such a design would be problematic."

But the findings likely would be generalizable to women because "it is well known that women, particularly those of reproductive age, have far better flow-mediated dilation responses," Dr. El Solh and colleagues concluded.