Consequences of a bad night's sleep

Illustration of woman in bed with window behind her showing Emory clock tower

Micah Fisher will always remember the patient who planted the seeds for his career.

The summer before he started medical school, he was working at a Pennsylvania hospital where a woman was admitted with pulmonary hypertension, a condition in which the right side of the heart has trouble pumping blood into the lungs.

"She was afraid. I remember the look on her and her family's faces," Fisher says. "She coded and died right in front of me. It was the first time I'd seen that."

Now medical director of Emory University Hospital's Medical Intensive Care Unit, Fisher organizes Emory's participation in clinical trials testing new treatments for pulmonary hypertension. 

Pulmonary hypertension has many causes, including chronic obstructive pulmonary disease and congenital heart defects. It can occur as the result of another disease that burdens the circulatory system, such as kidney problems associated with autoimmunity or sickle cell anemia. Or its cause can originate in obstructive sleep apnea (periodic interruptions in breathing throughout the night).

Its symptoms—swelling of the legs, dizziness, and difficulty in breathing or walking—can be attributable to a variety of conditions, Fisher says. An accurate diagnosis usually involves an electrocardiogram or invasive imaging of the heart such as catheterization.


Hart's laboratory has found that depriving mice of oxygen

(either chronically or in cycles that resemble the periodic gasping

of sleep apnea) leads to pulmonary hypertension. 


Although several types of medications are available to treat pulmonary hypertension, many of these have drawbacks, according to Fisher. Some, for example, require the implantation of a pump for intravenous administration of drugs, and others need careful monitoring because of their potential to damage the liver.

Among other research, Fisher is overseeing a trial in which the drug sildenafil, sold commercially as Viagra, is used with a liver-sensitive drug to allow medication dosage for patients with pulmonary hypertension to be reduced. Sildenafil (known to relax blood vessels) was originally discovered by scientists working on blood pressure regulation.

"Even though some of these drugs work pretty well, there is still a significant need for better options because of the mortality surrounding pulmonary hypertension," says Emory pulmonologist Mike Hart, who serves as acting associate chief of staff for research at the Atlanta VA Medical Center. 

Hart's laboratory has found that depriving mice of oxygen (either chronically or in cycles that resemble the periodic gasping of sleep apnea) leads to pulmonary hypertension. The work—published in the May 1, 2009 issue of the American Journal of Respiratory Cell and Molecular Biology—builds on research showing that pulmonary hypertension develops because blood vessels in the lungs thicken and present the heart with too much resistance. 

In the Emory study, the cells surrounding blood vessels in the lungs produced more of an enzyme called NADPH oxidase in response to low oxygen levels. Some forms of NADPH oxidase are helpful, even essential, because they are responsible for making superoxide. Superoxide is a reactive free radical that the immune system uses to kill bacteria. But increased superoxide also interferes with signals that allow blood vessels to relax and can lead to thickening of blood vessels.

Hart's team also has shown that a class of drugs already used to treat diabetes can push back against increases in NADPH oxidase and superoxide. Treating mice with this class of drugs, called thiazolidinediones, prevents exposure to low oxygen from triggering pulmonary hypertension. It may even be able to reverse the process.

Thiazolidinediones, however, have their own history of harmful side effects, so Hart is not celebrating yet. 

Still, the finding is useful, he says, because it provides insight into how the molecules involved in regulating blood vessel function are regulated and will help scientists hone in on the specific effects of this class of drugs. 

Thanks to this research, there may be several more options available in the coming years to effectively treat patients like the woman Micah Fisher remembers so well. —Quinn Eastman

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Emory Health - Winter 2010