The SERIOUS-study: Sex, gEnder and caRdIOvascUlar riSk in migraine taken seriously

Migraine is a chronic neurovascular disease that has been ranked by the World Health Organization (WHO) as the second most disabling disease worldwide, leading to a reduced quality of life as well as significant health and economic costs on society (1-4). Compared with men, migraine affects women three times more often. With a one-year prevalence of 6% in men versus 17% in women and a lifetime incidence of 18% versus 43%, respectively, migraine has classically been labeled as "woman's disease" (5, 6). This discrepancy between men and women develops strongly after the menarche and is influenced by the menstrual cycle, pregnancy, menopause, as well as the use of hormone therapy (7, 8). This association between women-specific events and migraine suggests that fluctuations in sex steroids, especially estrogens, play a critical role in the underlying pathophysiological mechanism (9-12). 
Besides the direct burden caused by its disabling attacks, migraine is also an important cardiovascular risk factor, of which the pathophysiology is yet not well understood (13). Indeed, the incidence rate of major cardiovascular disease for women with migraine with aura has been shown to be significantly higher than the adjusted incidence rate among women with obesity (2.29 [95% CI, 2.02-2.56]), high triglycerides (2.67 [95% CI, 2.38-2.95]), or low high-density lipoprotein cholesterol (2.63 [95% CI, 2.33-2.94]) (14). Migraine is slowly being recognized as a cardiovascular risk factor, and recently, migraine has been included in a cardiovascular prediction score, the QRISK3 risk prediction (15). A traditional sex-specific cardiovascular risk score that includes age, total cholesterol, smoking, High-Density Lipoprotein (HDL), and systolic blood pressure is the Framingham Risk Score (FRS) (16). Besides, the Systematic COronary Risk Evaluation (SCORE) risk estimation system is currently recommended from the European guidelines for cardiovascular disease and requires similar variables as the FRS (17). 
In collaboration with the research group under the supervision of professor T. Kurth (Charité, Berlin), co-applicant of this grant, we recently demonstrated in a well-known and large women's cohort, the Women's Health Study, that women with a history of migraine, but who did not experience any migraine attacks in the year before inclusion in the Women's Health Study, have a FRS ≥10 at baseline (OR = 1.74, 95% CI 1.38 to 2.18) compared to women without migraine. Remarkably, women with active migraine at baseline (OR = 0.55, 95% CI 0.44 to 0.68), and women with newly reported migraine during follow-up (OR = 0.42, 95% CI 0.25 to 0.69) had a decreased risk of having a FRS ≥10 (18). 
These findings are in line with our recent study in which women who met the criteria for lifetime history of migraine had less arterial calcification in the intracranial carotid artery than women without migraine (no distinction was made based on the onset or disappearance of migraine), despite their higher cardiovascular risk (13, 19). These studies suggest that migraine directly affects cardiovascular risk. 
Whereas our prior work found an association between migraine and traditional cardiovascular risk, as measured by traditional cardiovascular risk factor levels (FRS), in an international, women-specific and large cohort – with sufficient power to detect this clinically relevant difference – insight of the presence of such a pattern in males is lacking. However, this knowledge is crucial for an enhanced understanding of the biological and pathophysiological differences between both sexes in the relationship between migraine and cardiovascular outcomes. More insight into this pathophysiology leads to possibilities for personalized preventive treatments, in which sex and gender aspects are given a prominent role. The Sex, gEnder and caRdIOvascUlar riSk (SERIOUS) study takes these aspects seriously, and its primary aim is to contribute to an enhanced understanding of the increased cardiovascular risk in both female and male migraine sufferers. Based on the advice of the national funding organization, ZonMw, we will also look at the associations with the SCORE risk estimation system, more appropriate for European populations. 
In addition to sex differences, we believe it is important that gender aspects be taken into account as well, since these fields largely overlap in medical research. Since the FRS mainly consists of risk factors that are associated with lifestyle (including the day and night rhythm, nutrition, and exercise), which may be linked to gender roles, we aim to include these gender aspects as much as possible. Additional gender aspects relate to habits such as smoking and alcohol consumption. Therefore, we will account for these gender aspects in studying the relationship between migraine and cardiovascular risk by sex. Given the complex interaction of migraine with various covariates and diversity aspects, namely age and socioeconomic status, we will also take these factors into account. 
Relevance 
Research on cardiovascular outcomes in men has dominated science for a long time. Consequently, the cardiovascular risk in women has been wrongly underestimated due to the misconception that women are given "hormonal protection" (20). Nevertheless, in recent years there has been increasing knowledge about the difference in the epidemiology, manifestation, pathophysiology, treatment, and outcomes of cardiovascular diseases between men and women (21). 
Migraine, on the other hand, is described in the literature, particularly in women. This is not only based on the sex aspect (the previously described fluctuations in hormones), but also an essential gender aspect. After all, previous studies have shown that men with migraine and other severe headache complaints are significantly less likely to use prescription medication than women (22). The male gender is a barrier to getting the right migraine diagnosis, and thus, access to healthcare (23). 
The aforementioned representation of our current knowledge shows that both diseases, migraine and cardiovascular diseases, which are the focus of the SERIOUS-study, are subject to various sex and gender differences as well as misconceptions. This increases health differences between men and women. The SERIOUS-study aims to change this and draws attention to these sex and gender aspects, which in turn will help to clarify the migraine pathophysiology. 
The association between migraine and the increased risk of cardiovascular diseases has been consistently described in the medical literature (24). It is still unclear whether this increased cardiovascular risk in migraine patients can be attributed simply to an association with elevated "traditional" cardiovascular risk profile reflected by the FRS or may be caused by other migraine-related cardiovascular risk factors not reflected in the FRS, such as an increased vascular reactivity or endothelial dysfunction. After all, migraine is associated with an unfavorable vascular risk profile, including the FRS for coronary heart disease (25, 26). However, other studies showed no increased cardiovascular risk factors, such as atherosclerosis, in migraine patients (27, 28). It is, therefore, essential to investigate how this increased cardiovascular risk exactly relates to migraine. 
In addition, various studies describe the lifetime prevalence of migraine. In contrast, the relationship between migraine and cardiovascular diseases across the life course has yet to be sufficiently described. This is due in part to a lack of studies with longitudinal information on migraine trajectories over time. Such data are urgently needed to better understand the well-described heterogeneity of the manifestation of migraine, as migraine attacks can disappear in later age, or newly develop during, for example, pregnancy or menopause ('new-onset') (22, 29-31). Given these known changes in the disease presentation over time, it is feasible that biological sex modifies the effect of migraine on cardiovascular risk and warrants further investigation. 
To improve our understanding of these sex differences in the effect of migraine on cardiovascular risk, it is essential to put them into context, and account for gender aspects such as diet and lifestyle that known to lead to epigenetic modifications during different phases of life (in both (young) adults and elderly) (21). In this proposed work, we also consider age (one of the population heterogeneity aspects) in the SERIOUS study, which will allow for unique insights into  potentially relevant differences in younger age groups (aged 18-45 years).