Nancy A. Melville

October 29, 2014

BALTIMORE, Maryland — Patients with patent foramen ovale (PFO) show significant and sustained reductions of homocysteine, serotonin, and other vasoactive factors following endovascular procedures to close the PFO, new research suggests.

"Traditionally, it has been thought that PFO is just a 'back door to the brain,' allowing clots to travel to the brain through the heart," principal investigator MingMing Ning, MD, director of the Clinical Proteomics Research Center at Massachusetts General Hospital/Harvard Medical School in Boston, told Medscape Medical News.

"However, we report here that PFO does not just allow clots, but also changes the whole circulation — routing blood to short-cut from the venous to arterial circulation, bypassing the lungs. As a result, not just clots, but harmful substances normally filtered out by the lungs can go directly to the brain, potentially causing strokes and migraines."

The researchers presented their findings here at the American Neurological Association (ANA) 2014 Annual Meeting.

Plasma Samples

For the study, Dr Ning and her colleagues evaluated plasma samples from the left and right atria of 250 patients before and after PFO closure. Venous blood was also evaluated 3 months after closure.

They found that levels of homocysteine, which is itself independently associated with stroke, were similar in the right and left atrium before closure. However, left atrial blood significantly decreased immediately following PFO closure (4.56 ± 0.04), and the effect continued in peripheral venous circulation at 3 months following the procedure (4.57 ± 0.06; P = .001).

Significant reductions were also seen in bisphosphoglycerate after PFO closure (P = .002).

The findings, in combination with previous research Dr Ning and her colleagues conducted showing similar changes involving serotonin, were unexpected.

"The findings were very surprising — we are not aware of previous research that has demonstrated this," Dr Ning said. "We have found that PFO can also alter blood chemistry in detrimental ways by allowing harmful substances to remain in circulation at persistently elevated levels."

Among the numerous clinical implications is that PFO endovascular closure may accomplish much more than keeping clots away from the brain, and in fact alter the body's blood chemistry.

PFO stroke risk could meanwhile feasibly be identified with a simple blood test to evaluate levels of homocysteine and other PFO-related metabolic factors, Dr Ning added.

"Since PFO itself is very common, a blood test that could specifically identify and stratify PFO-related stroke risk would help clinicians to select the best treatment plan for each individual patient."

While elevated homocysteine is associated with atherosclerosis and an elevated oxidative/inflammatory state, it is, importantly, treatable.

"Homocysteine is a modifiable factor, and if our findings are confirmed, it can be easily treated by folate (folic acid), a vitamin in green vegetables," Dr Ning said.

Overall, the findings also may offer a key piece of the puzzle regarding PFO's role in stroke, which has been the subject of much debate in recent years.

"Very little is known about how PFO causes stroke, except for the obvious fact that it can allow clots to get to the brain," Dr Ning explained.

"But with more than 80% of PFO stroke patients having no genetic tendency for forming clots, a key question is where do the clots come from in the first place?" Dr Ning said.

The findings suggest an answer to that question.

"We describe here an innovative mechanism of PFO that can cause stroke — by allowing harmful atherogenic/procoagulant signals such as homocysteine to stay in circulation, possibly both affecting the brain and over time and propagating a condition that causes clots to form, leading to strokes."

Important Questions

Seemant Chaturvedi, MD, a professor of clinical neurology at the University of Miami's Miller School of Medicine in Florida, expressed some skepticism about the findings, noting important questions on such issues as the role of stroke in PFO.

"One, I think the significance of this research is still uncertain," he told Medscape Medical News. "The authors have not shown that these chemicals are harmful to the brain."

In addition, he notes, "the relationship between PFO and stroke is controversial. It has never been shown that closing a PFO prevents stroke."

Dr Chaturvedi, a member of the American Academy of Neurology, further questioned the possibility of a blood test for the condition.

"Since closing a PFO is of uncertain value, I have healthy skepticism about the value of the blood test."

The study received funding support from the National Institutes of Health/National Institute on Neurological Disorders and Stroke. Major contributors include Clinical Proteomics Research Center, Cardio-Neurology Clinic, BRIMS Center, University of Michigan and Neuroprotection Research Laboratory. Dr Chaturvedi has disclosed no relevant financial relationships.

American Neurological Association (ANA) 2014 Annual Meeting. Abstract M1216. Presented October 13, 2014.

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