Migraine and Cardiovascular Disease

The association between migraine and ischemic vascular events has been debated for many years.^{1 - 2} Migraine with aura is now well established as a risk factor for ischemic stroke, particularly among women.³ The relationship of migraine and ischemic cardiac disease has been less clear. Several reports have demonstrated an association between migraine, particularly migraine with aura, and angina,⁴ although convincing evidence linking migraine to ominous cardiovascular outcomes such as myocardial infarction or coronary revascularization has not been available.

The study by Kurth and colleagues in this issue of JAMA changes this landscape.⁵ The investigators examined the relationship between migraine and a range of prospectively determined cardiovascular end points using data from the Women's Health Study, a cohort study that followed nearly 28 000 women for an average of more than 10 years. Their primary composite end point, major cardiovascular disease (CVD), included nonfatal ischemic stroke, myocardial infarction, and death related to cardiovascular events. The study followed presumably healthy women aged 45 years or older to test the benefits of low doses of aspirin and vitamin E in the prevention of CVD and cancer. Migraine with aura was associated with about a 2-fold increased risk of major CVD, myocardial infarction, ischemic stroke, and ischemic cardiovascular death and a 1.7-fold increased risk of coronary revascularization. These associations remained significant after adjusting for cardiovascular risk factors and did not occur in the most common type of migraine, migraine without aura.

There are several potential explanations for this association. First, as with nearly any observational study, the association may be spurious, but that appears unlikely for several reasons. The cohort design, with its prospectively determined outcomes, protects against a number of sources of bias. Furthermore, the authors measured and adjusted for many but certainly not all risk factors for CVD. For example, patent foramen ovale may be a comorbid condition in patients with migraine with aura.⁶ Although it is unlikely that patent foramen ovale explains the risk of coronary disease, it may have contributed to the association between migraine and stroke.

The association of CVD was limited to migraine with aura and did not occur in migraine without aura. In theory, the stress of migraine attacks could unmask coronary artery disease acutely or could contribute to the development of vasculopathy over the course of multiple headache attacks. If that were true, an association also would be expected with migraine without aura, not just migraine with aura. This hypothesis is, therefore, inconsistent with the data. Similarly, an environmental exposure that would account for the association would have to have differential effects in migraine with and without aura. For example, medications that constrict coronary arteries, such as the triptans and compounds containing ergotamine, could increase the risk of CVD in treated migraine patients. Since migraine with and without aura are similarly treated, this hypothesis is unlikely. In addition, triptan use appears protective against coronary artery disease in large cohort studies, probably because of selective prescribing.⁷

An association between migraine and cardiovascular risk factors could account for the relationship between migraine with aura and CVD. In a Dutch population study, Scher et al⁸ showed that, in comparison with controls, migraine with aura was associated with a significantly increased risk for hyperlipidemia, hypertension, and elevated Framingham scores. In the larger group of migraine without aura, these associations were not significant. Even though the authors adjusted for many cardiovascular risk factors, adjustment may have been incomplete.

Why is there an association between migraine with aura and risk factors for CVD? One suggestion is that genetic polymorphisms may predispose to both cardiovascular risk factors and migraine with aura. A polymorphism in the methyltetrahydrofolate reductase gene (C677T) is associated with a moderately increased homocysteine level, which, in turn, is associated with risk of CVD. The same polymorphism is overexpressed in migraine with aura but not migraine without aura.⁹

From a clinical perspective, most migraine patients have migraine without aura and, therefore, are not at increased risk of CVD. They can be reassured. Kurth et al⁵ convincingly show that migraine with aura is a risk factor for CVD in women aged 45 years or older. These important observations need to be confirmed and assessed in men and in younger age groups of women. For patients with migraine with aura, clinicians should have heightened vigilance for modifiable cardiovascular risk factors, such as hypertension, hyperlipidemia, and smoking. Ultimately, it will be important to determine whether migraine with aura is itself a modifiable risk factor for CVD. Future studies should investigate the possibility that preventive medications for migraine or antiplatelet therapy might reduce the risk of CVD in patients with migraine with aura.