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Migraine and CVD: A call for greater awareness
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Migraine affects almost 20% of the population, and 4.4% of persons have migraine with aura, according to the Guidelines for the Prevention of Stroke in Women released by the American Heart Association and American Stroke Association. Migraine is especially common in women, who are four times more likely to have migraine episodes compared with men.
Various studies have demonstrated a link between migraine and increased risk for CVD, especially in women. In a BMJ study published in 2016 looking at data from the Nurses’ Health Study II, researchers found a strong link between migraine and CVD events, including CV mortality.
“Given the high prevalence of migraine in the general population, an urgent need exists to understand the biological processes involved and to provide preventive solutions for patients,” Tobias Kurth, MD, ScD, professor of public health and epidemiology and director of the Institute of Public Health at Charité – Universitätsmedizin Berlin, and colleagues wrote in BMJ.
The disparity in migraine between sexes also extends to migraine with aura, which is also more common in women than men (see Sidebar). A BMJ study from 2008 concluded that vascular risk status should be assessed in women with migraine with aura to determine who is at increased risk for CVD events, particularly ischemic stroke and MI. Age may also play a factor. In the study, the association between migraine with aura and stroke was more common among women younger than 55 years.
Even with evidence to support that women with migraines have increased risk for CVD events, the mechanism behind this association remains unknown.
“We know that migraine is four to five times more common in women, but we don’t know why that is,” Gina Lundberg, MD, FACC, clinical director of Emory Women’s Heart Center and associate professor of medicine at Emory University School of Medicine in Atlanta, told Cardiology Today. “There are certainly factors that are more common in women than men that we don’t understand. It always comes back to, ‘It must be our ovaries because that’s the only thing different about us.’ Except no, men have a Y chromosome and we have two X’s. There’s a lot more than just the ovaries and hormones going on.”
Migraine and CVD risk, mechanisms
Endothelial dysfunction may underlie the association between migraine and stroke or MI, Gretchen E. Tietjen, MD, professor and chair of neurology and director of the headache treatment and research program at University of Toledo Medical Center in Ohio, said in an interview, adding that inflammation, as demonstrated by increased C-reactive protein, and hypercoagulability are consequences of this.
It is unknown whether migraine causes inflammation and hypercoagulability, or the other way around, but it is likely that the risk for stroke associated with migraine may be, at least in some cases, related to endothelial dysfunction, experts told Cardiology Today. Ischemia can lead to a slowly propagating wave of depolarization of neurons and glia that spreads across cerebral cortex, Tietjen said, noting this physiological phenomenon is referred to as cortical spreading depression and is thought to be the cause of migraine aura.
Compounding this, stroke can sometimes mimic migraine, and migraine can sometimes mimic stroke, which makes it difficult to study the mechanism connecting the two, experts told Cardiology Today.
Patients with patent foramen ovale are also predisposed to elevated risk for migraine and stroke. If a patient has a PFO between the left and right atria, it can be a pathway for a clot in the venous circulation to enter the arterial circulation, which can go into the brain and cause ischemia-related cortical spreading depression or a stroke, Tietjen said. It may also allow serotonin or other soluble substances to bypass filtration from the lung, which can increase the risk for migraine.
“The most compelling explanation is that the proportion of people with PFO-mediated migraine are responsible for the connection,” Bernhard Meier, MD, professor of cardiology at University Hospital of Bern in Switzerland, told Cardiology Today. “These people are also prone to PFO-mediated paradoxical cerebral and coronary emboli, causing strokes and myocardial infarctions.”
Jonathan M. Tobis, MD, clinical professor of medicine in cardiology and director of interventional cardiology research at UCLA David Geffen School of Medicine, agreed.
“The connection is due to the presence of a patent foramen ovale, which is more prevalent in people with migraine and aura. This creates the pathway by which they have paradoxical embolism either to the brain or heart later on in life,” he said in an interview. “The increase in cardiovascular ‘disease’ is not due to an increase in atherosclerosis, which has never been proven, but is due to embolic phenomenon through the PFO.”
Although stroke risk is increased in patients with migraine, common migraine is not associated with stroke, Lundberg said. Migraine with aura is linked to an increased risk for stroke, as different senses or functions of the brain are affected during migraines with aura.
“It’s different things for different people,” Lundberg said. “Sometimes it’s floaters in the eyes, sometimes it’s blurred vision, sometimes it’s wavy lines, sometimes it’s halos around light or halos around things. It can also be weakness, numbness, trouble with speech or a strange smell. Our vision is coming from our brain, so it’s affecting different parts of your brain on your perception and your vision. It could be that it’s a more intense vasoconstriction. It could just be that the arteries involved have to do with vision.”
Studying the different risks associated with migraine with or without aura can sometimes be difficult because in patients who have migraine with aura, an aura is not present during every migraine event, experts said.
The association between migraine and stroke has been studied more than the risk with MI, as the risk for MI with migraines may not be as high as the risk for stroke.
Migraine may also be associated with spontaneous coronary artery dissection. At the American Heart Association Scientific Sessions in November, Marysia S. Tweet, MD, assistant professor of medicine and senior associate consultant in the department of cardiovascular medicine at Mayo Clinic, and colleagues presented data showing that 40% of patients with spontaneous coronary artery dissection (SCAD) also had migraines. Those who had migraines and SCAD were more likely to be younger, report a history of anxiety and depression and have more chest pain after SCAD.
“Further investigation into this association is necessary to develop safe, effective methods both for headache, chest pain, depression, anxiety after SCAD, but you can extrapolate some of these recommendations to any young woman who has a myocardial infarction, whether it be from SCAD or atherosclerosis. These are important considerations,” Tweet, a Cardiology Today Next Gen Innovator, said during her presentation.
Medications to alleviate migraines may also increase risk for stroke and MI, particularly NSAIDs.
Strategies to reduce CV risk
The optimal treatment to reduce CV risk among patients with migraines with and without aura remains unknown because the relationship between CVD and migraines still must be defined. Research has suggested that reducing the number of migraine headaches with aura may reduce the risk for CVD, especially in women.
If the increase in CVD risk related to migraines is due to atherosclerosis, the patient should be treated with statins, Tobis told Cardiology Today. In a study published in the Annals of Neurology in 2015, patients with episodic migraines who were treated with 20 mg simvastatin and 1,000 IU vitamin D3 twice per day had greater headache prevention and repaired endothelial dysfunction compared with patients treated with placebo.
CVD risk reduction should be approached in patients with migraine in the same way as patients without migraine. This includes a healthy diet, regular exercise, increased water intake and preferably 8 hours of sleep.
“Those types of things probably do lower your risk of stroke and heart disease if you have migraine as it would if you don’t have migraine,” Tietjen said.
Patients with migraine, particularly younger patients, should also be evaluated for CVD risk factors including high BP, high cholesterol and diabetes, experts said.
Some recommendations from the Guidelines for the Prevention of Stroke in Women for women with migraine with aura include treatments to reduce the frequency of migraine and smoking cessation. A major focus should be placed on smoking cessation to prevent any injury to the arteries or an increase in blood viscosity, experts said.
Patients with migraine should also avoid chiropractic manipulation on the neck, as it may increase risk for cervical artery dissection, experts said.
It is also important to assess a patient’s current medications. For example, sumatriptan succinate, a migraine medication, has been associated with a slight increased risk for MI.
“You don’t want the treatment to be worse than the disease,” Lundberg said.
Among patients with migraine with aura, PFO closure may be more effective to reduce stroke risk vs. medical therapy, especially if the risk is associated with paradoxical embolism, Tobis said. Currently, there is no indication for closing PFO in patients with migraine. Results from two separate trials have shown mixed outcomes regarding this treatment option. In the PRIMA trial, published in the European Heart Journal in 2016, in patients with migraine with aura who underwent PFO closure, reduction in overall monthly migraine days was present, but failed statistical significance. In the PREMIUM trial of patients with migraine and PFO, published in the Journal of the American College of Cardiology in 2017 by Tobis and colleagues, the PFO closure group had a significantly greater reduction in headache days and a higher rate of complete migraine remission for 1 year compared with the control group. However, the reduction in migraine and adverse events between those who underwent PFO closure with the Amplatzer device (Abbott/St. Jude Medical) and those who did not was not statistically significant.
“Ten years ago, when the PREMIUM trial was initially queued, there were a lot of case reports of people who had migraine without aura with a PFO who responded to PFO closure clinically, but it turns out that there’s a very high placebo effect,” Tobis said in an interview. “About 35% of people who did not get a PFO closure and were just treated with medical therapy had a clinical response, so that’s why observational studies can be misleading.”
Although the primary endpoints in both trials were not met, there remains a benefit of PFO closure in these patients.
“[In] all of the patients who got PFO closure for migraine, you have the collateral benefit that they will never have a paradoxical embolism in their life,” Meier said. “That’s even more important for me than migraine status. In those publications, we cannot mention that because that was not one of the outcomes. I’m sure that if you follow all those migraine trials up for 20 years, you’ll have more strokes in those who were in the control arm and never had the PFO closed than in those who had the PFO closed. I don’t need another trial to show that.”
Future research
Experts interviewed by Cardiology Today called for further research into the exact mechanisms behind migraine and elevated CVD risk, in addition to treatment options to reduce risk.
“Migraine probably falls under the category of endothelial dysfunction or abnormal vasoreactivity of the arteries,” Lundberg said. “They’re not dilating and contracting the way they should. When that happens in the brain, that can be a migraine. When that happens in the heart, that can be what we call small vessel or microvascular disease.”
It is important to include more women in these research studies. Some studies in this area include fewer than 20% women.
PFO closure is another area that requires more research. To date, no study has been conducted focusing on patients who never had a stroke and underwent PFO closure.
“The difficulty is that the risk of developing stroke is small,” Tobis said. “It’s approximately 1 in 1,000 people per year, so you would have to have 30,000 people studied for 10 years prospectively to show a difference. The number needed to treat would be enormous, and it’s probably not justified. That’s why it’s going to be difficult to show prospectively in a randomized trial that closing the PFO is the right thing to do.”
A trial on PFO closure in patients with migraine is currently under development and being discussed with the FDA. This study aims to isolate a patient population that benefits from PFO closure, Tobis said. If the study is approved, experts are hoping for its initiation by the end of 2018.
Use of aspirin as a treatment option for migraine with aura also warrants investigation. Aspirin in this group was looked at in a subgroup analysis of the Women’s Health Study, published in Cephalalgia in 2011, which found that aspirin had similar protective effects on ischemic stroke in women with and without migraine, although risk for MI was increased.
“Rather than just trying to prevent the migraine with some of the other kinds of medications, maybe [we should be] trying to prevent the aura with something like an aspirin-like product and see what the long-term effect of that is,” Tietjen said.
The cardiologist’s role
Migraine is predominantly treated by neurologists, but cardiologists can also play a critical role in treating these patients.
“We’re starting to realize that cardiovascular disease is a head-to-toe problem, that it’s affecting the whole body and that we’re slowly embracing treating it that way,” Lundberg said.
Although it is not the role of the cardiologist to prescribe migraine medication, it is important to discuss with patients — especially women — their migraine history and triggers and how to reduce risk for CVD. In patients with a history of migraine with aura, it is warranted to closely monitor for stroke and MI.
The relationship between migraine and CVD risk is known by many, but there is room for increased awareness and education of all cardiologists.
Patients with migraine may warrant a multidisciplinary treatment approach that involves not only neurologists, who may refer their patients with migraine to the cardiologist, but also the cardiology team to monitor CVD risk. There is a need for improved collaboration, especially for patients with migraine with aura who should be referred for PFO screening and closure, if needed, which does not happen as much as it should, Meier said.
“Neurologists are generally not interested in myocardial infarction, but they are interested in preventing stroke,” Meier said. “They should really be proactive now and send the patient with migraine, at least those with aura, for PFO screening and also for closure if they find one, but unfortunately they are still not doing that.” – by Darlene Dobkowski
- References:
- Buettner C, et al. Ann Neurol. 2015;doi:10.1002/ana.24534.
- Bushnell C, et al. Stroke. 2014;doi:10.1161/01.str.0000442009.06663.48.
- Kurth T, et al. BMJ. 2008;doi:10.1136/bmj.a636.
- Kurth T, et al. BMJ. 2016;doi:10.1136/bmj.i2610.
- Kurth T, et al. Cephalalgia. 2011;doi:10.1177/0333102411412628.
- Mattle HP, et al. Eur Heart J. 2016;doi:10.1093/eurheartj/ehw027.
- Tobis JM, et al. J Am Coll Cardiol. 2017;doi:10.1016/j.jacc.2017.09.1105.
- Tweet M, et al. Outcomes and prevalence of migraines in patients with spontaneous coronary artery dissections: A cohort study. Presented at: American Heart Association Scientific Sessions; Nov. 11-15, 2017; Anaheim, Calif.
- For more information:
- Gina Lundberg, MD, FACC, can be reached at Emory Heart and Vascular, 137 Johnston Ferry Road, Suite 1200, Marietta, GA 30068; email: gina.lundberg@emory.edu.
- Bernhard Meier, MD, can be reached at University Hospital (Inselspital), Freiburgstrasse 18, 3010 Bern, Switzerland; email: bernhard.meier@insel.ch.
- Gretchen E. Tietjen, MD, can be reached at Promedica/UT Neurosciences Center, 2130 Central Ave., Toledo, OH 43606; email: gretchen.tietjen@utoledo.edu.
- Jonathan M. Tobis, MD, can be reached at Cardiovascular Center, 100 Medical Plaza, 100 UCLA Medical Plaza, Suite 630, Los Angeles, CA 90095; email: jtobis@mednet.ucla.edu.
- Marysia S. Tweet, MD, can be reached at Mayo Clinic, 200 First St. Southwest, Rochester, MN 55905; email: tweet.marysia@mayo.edu.
Disclosures: Lundberg, Tietjen, Tobis and Tweet report no relevant financial disclosures. Meier reports he received honoraria from Abbott.