Migraine and severe headache affect an estimated 15% of the US population, with prevalence rates twice as high in women as in men.1 These patients often face significant disability and debilitating symptoms; common comorbidities such as insomnia and psychiatric disorders may further add to this burden. A substantial body of research demonstrates consistent associations between migraine headaches and cardiovascular disease (CVD).2

Although associations between migraine headaches and CVD have been known for more than 40 years, the underlying pathobiology of this connection has not been appreciated until recently.

A range of studies have revealed a link between migraine – especially migraine with aura – and stroke, including a case-control study showing higher rates of migraine with aura among patients with ischemic stroke vs those with no history of stroke (18.3% vs 4.4%, P =.0001).2 The increased stroke risk associated with migraine with aura was observed in women but not in male participants.

In a meta-analysis of 21 studies composed of 622,381 participants, migraine was independently associated with ischemic stroke, with a pooled adjusted odds ratio (OR) of 2.04 (95% CI, 1.72–2.43).3 An earlier investigation, which surveyed US male physicians with migraine, found a relative risk of 1.84 (95% CI, 1.06-3.20) for total stroke and 2.00 (95% CI, 1.10-3.64) for ischemic stroke compared with the physicians with no migraine history.2


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In a large population-based cohort study published in 2018 in BMJ, researchers investigated the risk of various cardiovascular disorders in 51,032 patients with migraine compared with 510,320 individuals from the general population during a period of 19 years.4 Migraine was shown to be positively associated with ischemic stroke (HR, 2.26; 95% CI, 2.11-2.41), hemorrhagic stroke (HR, 1.94; 95% CI, 1.68-2.23), venous thromboembolism (HR, 1.59; 95% CI, 1.45-1.74), myocardial infarction (adjusted HR, 1.49; 95% CI, 1.36-1.64), and atrial fibrillation or atrial flutter (HR, 1.25; 95% CI, 1.16-1.36). 

The association between migraine and stroke was especially pronounced in women who had been diagnosed with migraine with aura within the previous 12 months.2 Other studies further support this relationship between migraine and CVD in women, most often in those who have migraine with aura, as well as those who were younger than 45 years, smoked cigarettes, or took oral contraceptives.

Despite consistent evidence illuminating the connection between migraine and CVD, a survey of 80 physicians demonstrated that more than one-third of responding neurologists and cardiologists were not aware that migraine is a risk factor for CVD, compared with more than 85% of obstetricians/gynecologists –likely due to the high prevalence of migraine in women of childbearing age.2

Such findings indicate that “academic curriculum needs to include [migraine] as a CVD risk factor to improve physician awareness and improve overall CVD risk assessment,” wrote the authors of a review published in Trends in Cardiovascular Medicine. 2 “Evaluation of [migraine], especially migraine with aura, should be implemented into the risk stratification of CVD for women during primary care, neurology and cardiology evaluations.”

In women with migraine with aura who use combined hormonal contraceptives, studies have noted a 6-fold increase in the risk for ischemic stroke, which could be “due to the deleterious effects of estrogen on changes in coagulation factors, lipid levels, and blood pressure.”5,2   

In selecting contraceptives for these patients, providers should consider that some products are associated with a higher risk for stroke occurrence (combined oral contraceptives containing >35 μg ethinyl estradiol), others with a medium risk (such as combined oral hormonal contraceptives containing ≤35 μg ethinyl estradiol and the combined contraceptive patch), and some with no risk (progestogen-only contraceptives in various forms), as well as nonhormonal contraception including copper-bearing intrauterine devices.

Additional evidence points to endothelial dysfunction, a well-defined risk factor for CVD, as a potential mechanism underlying the connection between migraine with aura and stroke in female patients. Elevated levels of endothelial microparticles (EMPs) have been observed in women with migraine with aura and were associated with increased arterial stiffness.

“EMPs may decrease nitric-oxide-dependent vasodilation, thereby increasing arterial stiffness, promoting inflammation, and initiating thrombosis,” as explained in the 2019 article.2 These changes are also confirmed by the increased plasma inflammatory biomarkers, such as fibrinogen, C-reactive protein, and erythrocyte sedimentation rate.”

Accumulating research also highlights the potential role of genetic factors in the connection between migraine and CVD, including various studies identifying higher risk of CVD events and death in migraine patients with certain single nucleotide polymorphisms. Further research is warranted to clarify these associations and their clinical implications.

Neurology Advisor interviewed the following experts to learn more about the migraine-CVD link: Nada Hindiyeh, MD, headache specialist and clinical assistant professor in the Department of Neurology and Neurological Sciences at Stanford Health Care in Stanford, California, and Gina P. Lundberg, MD, FACC, FAHA, associate professor of medicine in the Division of Cardiology at Emory University School of Medicine, clinical director of the Emory Women’s Heart Center, and co-author of the 2019 review described here.

Neurology Advisor: What is known thus far about associations between migraine and cardiovascular disease?

Dr Hindiyeh: Several studies have established a link between migraine and CVD, particularly stroke and ischemic heart disease. 

A recent review by Saeed et al6 discussed various studies suggesting that migraine is a risk factor for CVD, and this risk may be further increased in young women who have migraine with aura. Migraine is also thought to be associated with myocardial infarction, angina, arrhythmia, patent foramen ovale, atrial septal defect, and mitral valve prolapse.

…one of the problems with migraine as a risk factor [for CVD] is that very few physicians know about it   Dr Lundberg

There is a well-established association between migraine and stroke, with the relationship found to be more robust in people with migraine with aura. There also seems to be a higher risk in all people under the age of 45 and in women, especially those using estrogen-containing contraceptives. 

Dr Lundberg: Heart disease is the number 1 killer of men and women in the United States and across the world.7 We have established only a few of the cardiovascular risk factors for coronary disease and atherosclerotic CVD. By determining more of these risk factors, we can help protect more people by identifying them early and getting them started on risk reduction and preventive therapy. 

However, one of the problems with migraine as a risk factor is that very few physicians know about it. Neurologists generally treat the worst cases of headache and gynecologists treat most of the female patients. More women have migraine headaches, and many seek treatment with their gynecologists, who are generally not going to discuss CVD risks or treatments. Unfortunately, many cardiologists have not heard about this association, so it is not being picked up by them either. 

Increasing awareness of this important risk factor may help to identify more people at risk and help save lives in the long term. Women with traditional risk factors are still undertreated and undertested for CVD compared with men, so looking for migraine headache in these women may help to alert them to their long-term risks for CVD. 

Patients with migraine, especially women, should be screened for cardiovascular risk factors Dr Hindiyeh

Neurology Advisor: What are believed to be the mechanisms underlying these links?

Dr Hindiyeh: The exact mechanisms linking migraine and ischemic heart disease are still not fully known, but some studies suggest a multifactorial etiology that includes genetics, environmental factors, and biological factors such as endothelial dysfunction, as well as hormonal fluctuations.  

Neurology Advisor: What are the relevant recommendations for clinicians in terms of screening and treatment?

Dr Hindiyeh: Patients with migraine, especially women, should be screened for cardiovascular risk factors. Women, particularly those with migraine with aura who are receiving birth control, should be counseled on stroke risk. Those women taking estrogen-containing birth control pills should try to maintain estrogen levels of less than 20 μg.

Dr Lundberg: Patients who have migraine headache with aura should also be asked about known cardiovascular risk factors such as family history, smoking, high blood pressure, high cholesterol, diabetes, inactivity, and excessive stress. They should be encouraged to make healthy lifestyle modifications. And, when appropriate, medical treatment for high blood pressure, high cholesterol, or diabetes may be indicated.

Neurology Advisor: What are some of important remaining needs pertaining to this topic?

I hope that practitioners…will start to inquire about migraine headaches (with and without aura) and their frequency, and educate patients on known CVD risk factors so more people can take advantage of prevention through lifestyle and medical therapy  Dr Lundberg

Dr Hindiyeh: The pathophysiology of migraine and its association to CVD remains to be fully elucidated, and research should focus on genetic and biological mechanisms as well as prevention of migraine and CVD. Education on these risk factors and the link between migraine and CVD are important not only for patients but also for clinicians.

Dr Lundberg: Research is becoming more sex specific as well as gender specific. Large studies have been forced to create sex-specific data and attempt to enroll at least 50% women in each study, but this is still greatly lacking. Many studies have included of 85% white men, and this cannot provide accurate information for women or African Americans and other nonwhites. We need diverse research studies to give us better information about individual people. 

I hope that practitioners in family practice, internal medicine, obstetrics/gynecology, neurology, and cardiology will start to inquire about migraine headaches (with and without aura) and their frequency, and educate patients on known CVD risk factors so more people can take advantage of prevention through lifestyle and medical therapy. We believe that 80% of all cases of CVD could be prevented through early identification and aggressive risk reduction.8

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References

  1. Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies. Headache. 2018;58(4):496-505.
  2. Chen D, Willis-Parker M, Lundberg GP. Migraine headache: is it only a neurological disorder? Links between migraine and cardiovascular disorders. [Published online October 24, 2019.] Trends Cardiovasc Med. doi: 10.1016/j.tcm.2019.10.005
  3. Spector JT, Kahn SR, Jones MR, Jayakumar M, Dalal D, Nazarian S. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med. 2010;123(7):612–624.
  4. Adelborg K, Szépligeti SK, Holland-Bill L, et al. Migraine and risk of cardiovascular diseases: Danish population based matched cohort study. BMJ. 2018;360:k96.
  5. Champaloux SW, Tepper NK, Monsour M, et al. Use of combined hormonal contraceptives among women with migraines and risk of ischemic stroke. Am J Obstet Gynecol. 2017;216(5):489.e1-489.e7.
  6. Saeed A, Rana KF, Warriach ZI, Tariq MA, Malik BH. Association of migraine and ischemic heart disease: a review. Cureus. 2019;11(9):e5719.
  7. American Heart Association. CDC prevention programs. https://www.heart.org/en/get-involved/advocate/federal-priorities/cdc-prevention-programs. Accessed December 16, 2019.
  8. Mehta LS, Watson KE, Barac A, et al. Cardiovascular disease and breast cancer: where these entities intersect. Circulation. 2018;137:e30-e66.

This article originally appeared on Neurology Advisor