Increased TNF Levels Found to Be Mechanism Behind Apnea‐Stroke Link

Neurology Today
1 July 2010; Volume 10(13); p 13

HURLEY, DAN

In a small study involving ischemic stroke patients, those with obstructive sleep apnea (OSA), as measured by a cardiorespiratory polygraphy, had significantly higher plasma concentrations of TNF receptor 1 and 2 than did those without OSA, the investigators reported.

TORONTO—A team of German and Austrian investigators searching for a mechanism to explain the association between obstructive sleep apnea and increased risk of stroke told neurologists here at the AAN annual meeting that they have found a possible culprit: receptors to the inflammatory protein tumor necrosis factor (TNF).

Among 76 ischemic stroke patients admitted to a hospital, those with obstructive sleep apnea (OSA), as measured by a cardiorespiratory polygraphy, had significantly higher plasma concentrations of TNF receptor 1 and 2 than did those without OSA, the investigators reported.

Although the associational study offered no proof of direct causation, the researchers said they suspect that the OSA causes inflammation, which in turn raises the risk of stroke.

“According to our data, we think that this inflammation is the origin of the vessel damage that results in stroke,” said Jörg Kraus, MD, associate professor of neurology at Paracelsus Medical University in Salzburg, Austria.

The investigators, led by Rainer Dziewas, MD, of the University Hospital of Münster, Germany, measured plasma concentration of TNF-R1 and TNF-R2, as well as other biomarkers of inflammation and endothelial dysfunction: TNF-beta, soluble intercellular cell adhesion molecule, and soluble vascular cell adhesion molecule.

Among 76 patients who had had an ischemic stroke, they identified 37 (48.7 percent) who met a standard measure of OSA, having more than 10 apneic incidents per hour. TNF-R1 and TNF-R2 levels were significantly higher in patients with OSA than in patients without it, they found. Other biomarkers, however, showed no significant difference between the groups.

Figure. OBSTRUCTIVE SLEEP APNEA occurs when the airway is occluded due to collapse of the hypopharynx. Normally the airway remains open during sleep.Carol R. Taylor, Carol Lillis, RN, et al. Fundamentals of Nursing, The Art And Science Of Nursing Care, Sixth Edition. Philadelphia: Lippincott Williams & Wilkins 2008.

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Prior studies have shown that biomarkers of inflammation, including TNF-alpha, are raised in patients with apnea. Last year, Greek researchers published a study in the journal Sleep showing that levels of TNF-alpha and other inflammatory biomarkers are significantly reduced in apnea patients after six months of treatment with continuous positive airway pressure (CPAP).

But the study presented by Dr. Kraus and Alexander Kunz, MD, a neurology resident at Paracelsus Medical University, is the first to examine the apnea-TNF link in stroke patients, said the principal investigator of last year's study in Sleep. “This scientific team moved one step further than all previous studies with TNF and apnea,” said Paschalis Steiropoulos, MD, PhD, a pulmonologist at the medical school at Democritus University of Thrace in Alexandroupolis. “I believe this is a good study and I expect to see it published.”

He pointed out, however, that because the cardiorespiratory polygraphies establishing the presence of OSA were all performed following ischemic stroke, “It is possible that a significant number of the recorded apneas are actually central apneas, due to cerebral ischemia, and the AHI [apnea-hypopnea index] may not reflect the pre-stroke apneic condition of the patients.”

Other neurologists who specialize in the study of sleep disorders described the paper as a modest but important step forward in understanding the risks associated with obstructive sleep apnea.

Several recent observational cohort studies have shown that the presence of obstructive sleep apnea increases the risk for stroke and death, however, the mechanisms linking apnea and stroke are incompletely understood, said Kanika Bagai, MD, an associate professor of neurology at Vanderbilt University School of Medicine and associate director of its sleep medicine fellowship program. The researchers involved in the new study, she said, “are looking at the underlying pathophysiologic links. In that sense this is a very important study.”

Bradley V. Vaughn, MD, vice chair of the department of neurology and chief of the division of sleep and epilepsy at the University of North Carolina School of Medicine called the paper “interesting” but said it focused on only a “small piece of a very large puzzle.”

“TNF receptors may be one of many pathways linking sleep apnea and stroke,” Dr. Vaughn said. “They're picking one pathway out of a substantial list of issues that occur with sleep apnea.”

Added David Gozal, MD, the Herbert T. Abelson Distinguished Professor and chair of pediatrics at the University of Chicago's Comer Children's Hospital: “Systemic inflammation is a rather universal characteristic of apnea. As such, increased plasma concentrations of this or that inflammatory marker in patients with stroke and sleep apnea compared to stroke alone is not surprising.”

Dr. Gozal published a paper in the journal Sleep in March showing that TNF-alpha levels are increased in pediatric OSA, driven primarily by sleep fragmentation and body mass index, and are closely associated with the degree of sleepiness. The study also showed that surgical treatment of OSA (a standard treatment for the disorder in children) resulted in significant reductions in TNF-alpha levels with reciprocal prolongations in sleep.

In addition to TNF-alpha, more than a dozen other biomarkers of inflammation and endothelial dysfunction have been linked in prior studies to sleep apnea, said Karin Johnson, MD, a neurologist and sleep medicine specialist at Baystate Medical Center and assistant professor of neurology at the Tufts University School of Medicine.

The important clinical point for neurologists, she and others emphasized, is the need to inquire about the presence of OSA in their patients, and to refer them for treatment if necessary.

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Steiropoulos P, Kotsianidis I, Nena E, et al. Long-term effect of continuous positive airway pressure therapy on inflammation markers of patients with obstructive sleep apnea syndrome. 2009;32(4):537–543.

Gozal D, Serpero LD, Kheirandish-Gozal L, et al. Sleep measures and morning plasma TNF-alpha levels in children with sleep-disordered breathing. 2010;33 (3):319–25.

Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: A meta-analysis. 2010;6(2):131–137.