Dizziness in Astronauts Leads NASA Researchers to Find Genetic Cause for Orthostatic Intolerance


Studies of astronauts before, during, and after spaceflight not only will help stop the dizziness that occurs after returning to gravity but, may also help many people on Earth who get dizzy simply when standing up.

Orthostatic intolerance manifests itself as a drop in blood pressure and flow to the brain when a person stands from a sitting or lying down position. (Pressure is measured in mmHg, or millimeters of mercury.)

It is a regular occurrence in families - the inheritance of a trait from grandparent to parent to child. Often it's something easily recognized, like red hair or blue eyes. Occasionally it's something more serious, like a medical condition. The trait can be the result of a genetic defect that happened generations ago and has been passed down through the family ever since. Diabetes, sickle-cell anemia, and color blindness are conditions caused by genetic defects that frequently run in families. Most families don't realize that their medical trait is the result of a genetic defect, and they wouldn't expect the link between their trait and a genetic defect to be discovered through NASA research. But such was the case with the disorder orthostatic intolerance (OI), which causes individuals to feel lightheaded when they stand up from sitting or lying down.

Now why, you might ask, does studying people with OI help the space program? It helps because many astronauts experience OI for the first few days after they return from spaceflight, and NASA scientists want to find out why. David Robertson, director of the Center for Space Physiology and Medicine at Vanderbilt University, had been studying OI in ground-based patients for many years. Along with his colleagues, Robertson designed several experiments for the Neurolab space mission in April 1998 to try and find the cause of OI in astronauts. They hope that this research will uncover the cause or causes of OI and thus protect both astronauts and the many people who are chronic sufferers of OI from experiencing this disorder.

What Is Orthostatic Intolerance?

Orthostatic intolerance is a dysfunction of the autonomic (involuntary) nervous system that affects, in addition to the astro-nauts, an estimated 500,000 people in the United States, according to the National Dysautonomia Research Foundation. Normally, when a person stands up, the autonomic nervous system automatically adjusts the cardiovascular system to main-tain the necessary blood pressure and flow, especially to the brain. When a person with OI stands up from a sitting or lying position, the autonomic nervous system malfunctions, blood flow and pressure are not properly maintained, the brain does not get the blood flow it needs, and the person experiences symptoms ranging from dizziness and nausea to blurred vision and heart palpitations.

Robertson explains why the simple act of standing up can be so stressful on the body: "I think the answer to that lies in the fact that standing up is relatively new from an evolutionary standpoint. You've got to pump blood all the way up to the top of a 5-foot or 6-foot person to get the brain plenty of blood. It's a lot easier to pump the blood when there's no gravity between the heart and the brain than it is the other way around. Moreover, you've got those legs down there where blood can pool, and if it pools down there in the legs, not as much comes back to fill the heart, and so the heart has to pump more often in order to do the same thing." In people with OI, these effects can range in severity from annoying to severely disabling, preventing some sufferers from holding down jobs and living regular lives.

Prior to the early 1990s, doctors frequently misdiagnosed OI. "I'm sorry to say that 20 years ago I probably told young women who came to see me about this problem . . . [that] they were deconditioned and they needed to get more exercise," says Robertson. "What changed my view was a finding in the early 1990s that cerebral blood flow, blood flow to the brain, fell more in these patients than in normal subjects. Even though the blood pressure was just as high when they stood, their brain blood flow fell when they stood, more than it should. And that's what keyed me in. We used to think if the pressure was okay when you were standing, your brain would do fine. In this group of patients [ones with OI], that proved not to be the case."

Expected Results

When Robertson and his colleagues set up the experiments for the Neurolab space mission, they thought they knew what they would find. "We were focused on the disease being caused by a partial damage or dysfunction of the auto-nomic nervous system, and when those nerves in the lower part of the body are not doing their job, blood pools there," says Robertson.

From previous ground-based experi-ments, Robertson thought the expected dysfunction of the autonomic nervous system would manifest itself as a below-normal level of neurotransmitters in the blood. Neurotransmitters, such as norepinephrine and epinephrine, are chemicals that help the sympathetic nerves constrict blood vessels. Sympathetic nerves are part of the autonomic nervous system. It is this constriction that maintains a sufficient pressure and flow, especially in blood vessels that run up the body and against the pull of gravity. A low level of these chemicals would account for lower activity in the autonomic nervous system. The blood vessels would not constrict enough to keep the pressure sufficiently high to move the blood up the body and into the brain. This would cause blood to pool in the legs and reduce the total blood volume available to the brain. As the body's priority is to supply blood to the heart first, the brain does not get enough and the body experiences orthostatic intolerance.

Robertson's results, however, revealed that OI was primarily caused by elevated levels of neurotransmitters, specifically norepinephrine, in the blood. Robertson explains what these increased levels do to the body: "First it raises the heart rate and causes constriction of all blood vessels; [then as a result,] there is a secondary loss of blood volume [to the brain], and this creates a vicious cycle." The higher levels cause the blood vessels to constrict too much, with the same results of retarded flow to the brain. The effects of this cycle are what cause orthostatic intolerance.

For astronauts, this increased level appeared to be caused by the decrease in blood volume that normally occurs when they are in space. "Low blood volume can make the sympathetic nervous system work harder," explained Robertson, ". . . and when the sympathetic nervous system works harder, the plasma [blood] norepinephrine level goes up because sympathetic nerves release norepinephrine." Astronauts do not experience the symptoms of orthostatic intoler-ance until they return to gravity. Once on Earth, OI symptoms only last until the astronauts' blood levels return to normal. When this happens, the cycle is broken and they no longer experience orthostatic intolerance.

For ground-based patients, the causes and effects were not as obvious. Armed with the results from the Neurolab space mission experiments, Robertson and his colleagues revisited the data from their regular patients. They discovered that some patients being studied had several family members who also had OI. "We saw that some patients resembled the astro-nauts in the way their bodies operated, and some looked very different. Those that looked very different seemed to have a hereditary component, and it was through that com-parison that we nailed down the fact that a particular gene was abnormal," says Robertson.

Common Factor Found

From the Neurolab results, Robertson knew that the common factor among astro-nauts and Earth-based subjects was an elevated level of norepinephrine in the blood. This could only have two causes: one, that the body released more norepinephrine than is normal; or two, that the body did not remove the excess norepinephrine at the normal rate. The first cause seemed to be what happened with the astronauts and appeared to be related, at least in part, to the reduction in blood volume during space-flight. The second cause appeared to have its roots in a defect of the norepinephrine transporter (NET) function. The NET is a protein, a coiled string of amino acids arranged in a specific sequence that is determined by an individual's DNA. A mutation in the code can cause the resulting NET protein to malfunction. The NET's job is to remove excess norepinephrine from the blood, and the malfunction results in an above-normal level of the neurotransmitter.

Once Robertson realized that the NET malfunction was caused by an abnormal gene, the next step was to locate the gene. He worked with Randy Blakely, director of the Center for Molecular Neuroscience at Vanderbilt, to find and characterize the mutation in the gene that codes for the NET. Nancy Flattem, a medical student from Blakely's group, found the defect — one "letter" of the DNA code that determines the sequence of amino acids in the NET was different from the normal gene. This mutation causes the amino acid in position 457 to be the amino acid proline instead of the amino acid alanine, resulting in a 98 percent failure of function for the NET. This failure prevents the NET from doing its job, too much norepinephrine stays in the blood stream, and the patient experiences orthostatic intolerance.

These findings mark the first time a genetic defect has been linked to a disorder of the autonomic nervous system. This discovery could help scientists design drugs and treatments that might significantly improve the quality of life for sufferers of OI, both temporary, like the astronauts, and chronic, like the ground-based patients.

Moving toward this goal will take time, however. While much has been learned about orthostatic intolerance due to the NASA research, Robertson and his colleagues still have a lot of work ahead of them. "We're looking for other genetic causes," he says. "We're looking for problems in the body's handling of blood volume. And we're looking for problems in how the brain controls the heart and the cardiovascular system."

As to how to stop the symptoms that the astronauts were experiencing, Robertson says, "I think better ways to maintain hydration and normal autonomic control in the microgravity environment will be the critical factor." How this can be done will, of course, be the goal of future research. There are a lot of questions still to be answered. With the opportunities soon to be available on the International Space Station, Robertson and his colleagues will have the chance to find those answers.

Robertson's research team included Italo Biaggioni, Rose Marie Robertson, Andre Diedrich, F. Andrew Gaffney, Andrew Ertl, and graduate students Sachin Paranjape and Robert Carson.

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