The association between migraine and cardiovascular events has been explored in several studies. For TIA, ischemic stroke, and subclinical lesions in the brain, the association with MA has been demonstrated in case-control and cross-sectional studies, summarized in meta-analyses,25–27
and demonstrated in large longitudinal studies.3,4,28
Due to the association between migraine (mostly MA) and ischemic stroke, it is of interest whether migraine is similarly associated with coronary heart disease as well. Although some studies yielded negative results,29
and cohort studies9
found an association between migraine and chest pain, and with ischemic electrocardiographic changes.31
Furthermore, 3 recent population studies supported the relationship between MA and coronary disease.3,7–9
Finally, subclinical markers of vascular disease have also been suggested to be altered in patients with migraine.10
Some of our findings confirm the results of prior population studies, while some of them add information to what has been largely seen as controversial. Among the confirmatory components, we found that MA is a risk factor for not only stroke, but also for heart attack and claudication, as well as for CVD risk factors (especially diabetes, hypertension, and high cholesterol). Our study clearly suggests that MO is also associated with heart attack (but not stroke), and with risk factors for cardiovascular events. For established events, the magnitude of risk was inferior to MA, but existent. For risk factors for cardiovascular events, the difference between MO and MA was smaller. Individuals with MO, as individuals with MA, had elevated cardiovascular risk, as assessed by the modified Framingham score, when compared to controls.
The mechanisms that link migraine to ischemic vascular disease remain unclear and are likely to be complex, and the topic was reviewed elsewhere.32
For example, cortical spreading depression, the presumed substrate of aura, may directly predispose to brain lesions, and that would explain why MA is consistently demonstrated as a risk factor for cerebral ischemia. For heart attack and claudication, other factors should play a role (e.g., migraine being associated with overall atherosclerosis,10
or being comorbid with risk factors for CVD11
). Understanding the causal nature and the pathophysiology of the association is fundamental. Nonetheless, although our knowledge of the mechanisms of the association is limited, when put in the context of the available evidence, our findings suggest that a change in the conceptual paradigm of migraine may be of importance. It had been suggested that only patients with MA were at increased risk for CVD and therefore, the vast majority of patients (especially those with MO) should be reassured.33
We agree that most migraineurs (with or without aura) should be reassured. Nonetheless, the risk is existent. Future studies should focus on defining migraineurs at especially higher risk. Examples include assessing the importance of headache frequency and severity, frequency of auras, as well as the cumulative importance of multiple risk factors and the relative risk of migraine vs other risk factors. Second, it is important to assess how migraine treatment modifies the risk. For example, if frequency of auras and of headaches increases the risk of CVD, migraine prophylaxis should be associated with a decreased risk. Alternatively, the relevance of acute treatment in either reducing or increasing the risk should be estimated, especially considering that some antiinflammatory medications are associated with increased cardiovascular risk,34
and that compounds with ergotamine are vasoconstrictive.35
Furthermore, the importance of cardioprotective medications in the context of migraine treatment should be assessed.36
Finally, based on the findings, clinicians should have heightened vigilance for modifiable cardiovascular risk factors in migraineurs, such as obesity, hypertension, hyperlipidemia, and diabetes. Furthermore, components of the metabolic syndrome are comorbid with migraine.37
Our study has limitations. First, headache diagnoses were based on questionnaires and not on in-person clinical assessment. Though our questionnaires were well-validated and have great sensitivity and specificity,38
some degree of diagnostic error is likely. However, these errors would unlikely account for our strikingly positive findings. Second, assessment of cardiovascular events and risk factors were also based on self-report of medical diagnosis. Again, these methods have been validated through adjudication of events and are widely accepted.3,22
Nonetheless, as a preparation for future steps of our study, we are also conducting adjudication of cardiovascular events, in order to revalidate the method. While this step is not finished, caution is suggested. In addition, many factors that could add to the risk of CVD were not collected, mostly due to limitations in the length of the questionnaire survey. Most notably, we have not modeled the influence of using contraceptive pills or hormone replacement therapy in our findings. Nonetheless, since our results remained strikingly positive for men, and unless a differential use of contraceptive medications or hormone replacement therapy between migraineurs and controls exists, the potential for bias should not be high. Also, some of the comparisons made, particularly the subgroup comparisons, involved a small number of events and therefore some findings for these subgroup analyses may not be reliable. Furthermore, since our sample size is large, some of the statistically significant differences may not be clinically relevant. Finally, we acknowledge the limitation that individuals with risk factors for CVD may visit a physician more frequently than those without, with a correspondent higher chance of being diagnosed with migraine.
Strengths of our study include the meticulous assessment of headache features, the use of very well-validated instruments, the good characterization of the cohort, the confidence about lack of headaches in controls (since they were surveyed twice: in 2004 and again for this study), and the robustness of our sample size.
Both MA and MO are associated with CVD and with risk factors for CVD. Providers should be aware of this association in order to properly identify individuals at particularly high risk, as well as in order to plan treatment that targets not only migraine, but the complications potentially associated with migraine.