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Decreased Number of Endothelial Progenitor Cells Found in Migraine Patients
Suggests an Underlying Link with Cardiovascular Risk

ARTICLE IN BRIEF

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A new study found that migraineurs had lower levels of endothelial progenitor cells, possibly leading to cardiovascular problems. Patients who had migraines with aura had particularly low levels of the cells, almost a third lower than those with tension headache.

An increasing number of studies show that migraine, particularly attacks with an aura, is a harbinger of other problems, specifically stroke and heart attack. Now new research points to a possible reason.

In the April 22 Neurology, S. T. Lee, MD, and colleagues of the department of neurology at Seoul National University Hospital in South Korea reported that migraineurs had lower levels of endothelial progenitor cells (EPCs), possibly leading to cardiovascular problems. Patients who had migraines with aura had particularly low levels of the cells, almost a third lower than those with tension headache.

“This study is a step in the right direction,” said Gretchen Tietjen, MD, chair of neurology and director of the Medical University of Ohio Headache Treatment and Research Program at the University of Toledo. Dr. Tietjen, who was not involved with the current study, added: “Understanding the role of the blood vessel in migraine may be helpful in figuring out which migraine patients are at a higher risk of heart attack or stroke.”

STUDY METHODS, FINDINGS

The study included 166 patients — 74 had tension-type headaches; 25, migraine with aura; and 67, migraine without aura. Findings in headache and migraine subjects were compared to 67 healthy normal volunteers.

From sera, the investigators measured EPC cells, which are released into the circulation from bone marrow and help maintain endothelial cells lining the blood vessel walls. These cells create a smooth surface along the vessel, allowing blood to flow smoothly.

Patients with tension-type headaches had more cardiovascular risk factors and more headache days than other subjects, with mean numbers of EPC units of 47.8 ± 24.3; compared to patients who had migraine without aura (20.4 ±22.2), and migraine with aura (8.6 ± 10.1). EPC counts in 37 normal subjects, however, were not significantly different from those with tension-type headaches.

EPCs in all migraine patients also showed reduced migratory capacity and increased signs of cellular aging than apparent in normal subjects and those with tension-type headache.

THEORIES FOR THE MECHANISM

On an ongoing basis, there may be damage to the blood vessel lining by the deposition of plaque, perhaps caused by trauma or by migraine with aura, said Richard B. Lipton, MD, director of the Montefiore Headache Center and vice chair of neurology at the Albert Einstein School of Medicine, who was not involved with the current study.

“EPCs may migrate to the region of damage and repair the lining of the blood vessels,” he explained. “In many ways, it's akin to the body's response to a skin abrasion — if you cut yourself and the skin is abraded, after a while it heals and the skin surface becomes smooth again.”

It's unclear exactly how EPCs play a role in migraine. Investigators don't know whether people with low EPC counts are predisposed to have attacks, or if the headaches cause the lower numbers.

The inflammatory and vascular reactions associated with migraine could damage the lining of the blood vessels, and those with low EPC counts simply may not heal as well, leading to blood clots and narrowing of vessels.

Dr. Tietjen noted that there could be a “positive feedback” loop in migraine, “whereby damage to the endothelial layer causes inflammation, and this, in turn, leads to further damage.”

Study investigators also contend that migraine may simply go hand-in-hand with other risk factors, such as high blood pressure, which contribute to increased risk of vascular disease.

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Investigators of the current study believe migraine with aura causes damage to the blood vessel, causing it to constrict and dilate, triggering pain.

“Migraine patients are at higher risk for ischemic stroke and, in particular, women with active migraine aura are at higher risk of cardiovascular diseases,” they wrote. “This cannot be explained solely by traditional cardiovascular risk factors. EPCs provide a circulating pool of cells that are capable of patching sites of denuding injury, or they can be used as a cellular reservoir for the replacement of dysfunctional endothelium.”

The study did not show a link between the frequency of attacks and lower EPC counts. And migraine experts said that they don't think the heart of migraine problems come from a blood vessel disorder.

“Most researchers don't think that an abnormality of the endothelial layer causes migraine,” said Dr. Tietjen. “It's likely something neuronal, and not vascular, underlies the predisposition to have migraine.”

MIGRAINE WITH AURA AND STROKE RISK

The relationship of the aura and lower EPC counts is also unclear. About 15 percent of migraineurs have an aura before an attack; some have an aura without the headache itself.

“Dr. Lee's work suggests that having a migraine with aura causes damage to the blood vessel,” said Dr. Lipton. Because of the low EPC counts “that vessel is less able to repair the damage and that's a set up for stroke.”

A 2005 meta-analysis in the British Medical Journal found that people with migraine have 2.16 times the risk of stroke compared to those who do not have these headaches. Taking birth control pills increases the risk by as much as eight times.

However, Dr. Lipton pointed out that the absolute risk of stroke in most people with migraine is still small. Migraine is mainly a disease of younger women, he said, so while the risk of a stroke might double from 15 per 100,000 to 30 per 100,000 for those who have migraine with aura, the risk is still slight.

The study was small, and researchers said further work is needed to determine whether lowering the frequency of migraine bouts affects EPC counts, stroke risk, and heart attacks at all. There were also questions about whether acute treatment affects long-term risk, particularly since some migraine medications constrict blood vessels.

Eventually, Dr. Tietjen said, further study could help doctors determine what treatment would work best for an individual patient based on the kind of migraine and other existing risk factors.

And while there are no current drug therapies that specifically address EPC levels, doctors should look at migraines, particularly those with aura, as a risk factor for stroke and heart disease, said Dr. Lipton.

“The only action at the moment is to manage all the other risk factors for heart disease,” he said.

REFERENCES

• Lee ST, Chu K, Roh JK, et al. Decreased number and function of endothelial progenitor cells in patients with migraine. Neurology 2008;70:1510–1517.
    • Etminan M, Takkouche B, Samii A, et al. Risk of ischaemic [sic] stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005;330:633.