To prepare for the grueling 2,200 miles of the Tour de France, cyclists train their muscles at both low and high altitudes. Riding at elevation does more than prepare them for the infamous mountain stages in the Alps, it has a biological effect, increasing the capacity of red blood cells to carry oxygen and improving how their muscles use energy. Though it may seem counter-intuitive, training in the low oxygen conditions found at high altitude is actually beneficial to an athlete’s muscular performance long-term. Could the same be said for another important muscle – the one located inside your skull?
That’s one implication of a new study from University of Chicago researchers on the relationship between the sleep disorder sleep apnea and strokes. Patients with sleep apnea suffer from repeated breathing “pauses” during the night, moments where their brain is briefly deprived of oxygen (known scientifically as “hypoxia”). One or two of these hypoxic episodes may not be dangerous by themselves, but cumulatively, they can be very harmful – sleep apnea has been associated with cognitive impairment, behavioral effects, and cardiovascular disease.
Indeed, sleep apnea increases the danger twice over for one especially serious vascular problem: stroke. Research indicates that patients with the disorder are more likely to suffer a stroke, and if a stroke occurs, it is more likely to cause severe brain damage than in people without sleep apnea. Both sides of this connection have been targeted by investigators from the Department of Pediatrics sleep research group at the University of Chicago Medical Center. In one recent study, led by David Gozal, chair and professor of pediatrics, and Richard Li, assistant professor of pediatrics, the researchers found a mechanism for why putting rats through “intermittent hypoxia” during sleep (an animal model of sleep apnea) can increase the risk of atherosclerosis, the hardening of the arteries involved in many cardiovascular conditions.
But another study, published last month in The Journal of Neuroscience, focused on stroke’s aftermath, testing whether the extra brain damage from a stroke in sleep apnea patients was due to the low-oxygen episodes or an associated risk factor such as obesity. A team led by Yang Wang, associate professor of pediatrics and director of basic research for the sleep medicine laboratory, again simulated sleep apnea in otherwise normal rats with intermittent hypoxia (IH), comparing them with rats that slept in normal oxygen conditions. When a controlled stroke was induced in each of these groups, the resulting damage was very different – the IH rats suffered more damage than controls, indicating a direct effect of hypoxic episodes upon recovery after stroke.
“It seems that something very bad is happening that affects the ability of the cells to survive or to recover after stroke,” Gozal said.
The researchers then focused on a possible mechanism for why intermittent hypoxia leads to more severe strokes, choosing energy metabolism as their primary suspect. When the brain is active – or trying to recover from damage – it needs a lot of fuel. As with the rest of the body, glucose is the first option for providing energy. But like muscles, a healthy brain can also use lactate as an alternative energy source in times of high demand. The gas pump for getting lactate into neurons is a protein called monocarboxylate transporter 2, or MCT2. Wang and colleagues looked at how intermittent hypoxia affected levels of MCT2 and how MCT2 levels affected the severity of stroke.
The pathway fell into place – exposing rats to IH decreased the expression of the MCT2 gene, while decreasing MCT2 activity through various methods increased brain damage after stroke. A transgenic mouse with elevated MCT2 was even created, and found to be protected against a stroke’s damaging effects. Thus, repeated hypoxia events during sleep could disrupt MCT2 and impair the brain’s ability to use lactate for energy – perhaps by “crying wolf” too many times. Gozal used the metaphor of a night watchman repeatedly running up the stairs for minor smoke alarms, only to be too tired to respond when the big fire starts.
“I think we have dissected in a very careful way, with a lot of work, the mechanisms that may explain why patients with sleep apnea are not only at increased risk of stroke, but also why when that stroke hits, they have a risk of not really recovering,” Gozal said.
The study also raised an intriguing idea about how to prevent this elevated sensitivity to stroke in sleep apnea patients.
Rats exposed to sustained hypoxia, constant low levels of oxygen similar to high altitudes, were also protected against stroke damage. That defense suggests that the brain, like the muscles of cyclists, may benefit from “training” in high-altitude, low-oxygen conditions to improve energy metabolism.
“The more efficient you are with lactate transport, the better off you are in sustained efforts,” Gozal said. “It’s the same with the brain. The brain is essentially another muscle, using a slightly different strategy but very, very similar.”
Protecting sleep apnea patients from severe strokes may not require them to book a vacation in Denver. A hypobaric chamber might be used instead, or drugs might be created that mimic a low oxygen state, Gozal said, activating some of the cellular responses to hypoxia without actually putting the patient in hypoxic conditions.
“It would be unthinkable many years ago to get patients with heart disease to go to high altitude. They already have compromised function, so why put more stress on them?,” Gozal said. “But if you could optimize their MCT2 availability in the period preceding a potential stroke, maybe that in itself could prevent a stroke from reaching a point of severity and ultimately allow for a better recovery.”
Wang Y, Guo SZ, Bonen A, Li RC, Kheirandish-Gozal L, Zhang SX, Brittian KR, & Gozal D (2011). Monocarboxylate transporter 2 and stroke severity in a rodent model of sleep apnea. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (28), 10241-8 PMID: 21753001
Li RC, Haribabu B, Mathis SP, Kim J, & Gozal D (2011). Leukotriene B4 Receptor-1 Mediates Intermittent Hypoxia-induced Atherogenesis. American journal of respiratory and critical care medicine, 184 (1), 124-31 PMID: 21493735