Cardiovascular disease risk in women with migraine

Migraine is a chronic disorder that affects a large proportion of the population, with a female-to-male ratio ranging from 2:1 to 3:1. This condition predominantly affects middle-aged women and has a complex pathophysiology involving both neuronal and vascular mechanisms [1‐4]. Migraine is often characterized by recurrent attacks of moderate to severe pulsating headache, which may be localised in the frontotemporal, unilateral or bilateral areas. The attacks are usually accompanied by nausea, vomiting, and photo-, phono- or osmophobia, lasting 4 to 72 hours, whether or not preceded by focal neurological phenomena known as the migraine aura [5].

Relationships between migraine and classical cardiovascular (CV) risk factors have been suggested in previous studies [3, 6, 7], but controversy remains [8, 9]. Furthermore, no universally accepted mechanism to explain this connection has been put forward so far [10]. In Brazil, there are scarce data on the prevalence of risk factors for cardiovascular disease (CVD) among female migraineurs, especially middle-aged women [10]. The prevalence of obesity among migraineurs is high [11], but little is known about whether this could be a determining factor. Recent data have suggested that normal weight migraineurs exhibit an atherogenic lipid profile, which shares several features with obesity-related lipid alterations [12].

In addition to research into traditional CV risk factors, such as blood pressure (BP), lipid profile, diabetes, and physical inactivity, the study of newly recognized CV risk factors, in particular those related to inflammation [13], oxidative stress [12], and proposed surrogate predictors of CV risk [14‐16], could help clarify these unsolved questions. Therefore, hypothesising that migraine would be associated with worse CV risk regardless of nutritional status, the aim of this study was to investigate traditional and newly recognized risk factors as well as other surrogate markers of CV risk in obese and normal weight women with migraine compared to obese and normal weight controls.

A total of 59 probands were included in the study. Fifteen normal weight (mean BMI 22.8±1.8 kg/m²) and 15 obese (mean BMI 33.3±3.0 kg/m²) migraineurs were investigated. The control groups included 15 normal weight (mean BMI 22.2±1.7 kg/m²) and 14 obese (mean BMI 34.7±4.6 kg/m²) subjects. The socio-demographic characteristics of the sample are given in Table 1. Migraine with aura was diagnosed in six patients; other migraine characteristics are described in Table 2.

Anthropometric data and CV risk factors are shown in Table 3, stratified by headache status.

There were no significant between-group differences in PA, nor in the following traditional CV risk factors: total cholesterol, LDL-c, triglycerides, and glucose. However, obese migraineurs had lower HDL-c compared to normal weight groups (controls and migraineurs), although no difference was found compared to obese controls. Insulin resistance (measured by HOMA-IR) and insulinaemia were associated with obesity. When compared to normal weight migraineurs, obese migraineurs had significantly higher mean systolic BP values. Diastolic BP was lower in normal weight migraineurs than in obese controls and obese migraineurs. Although the difference was not significant, obese migraineurs tended to have higher levels of oxidized LDL. Most of the study subjects were non-smokers (n=52; 88.1%), and this risk factor was not associated with any group. All migraineurs were sedentary irrespective of nutritional status, whereas normal weight controls were physically active. A history of CVD in first-degree relatives was reported with equal frequency by all groups.

Framingham risk score was higher in obese migraineurs, whereas normal weight controls had lower scores.

Levels of CRP, a newly recognized CV risk factor related to inflammation, followed a broadly similar pattern across all groups.

Regarding depression, migraineurs had higher BDI scores irrespective of nutritional status, consistent with mild/moderate depression in normal weight migraineurs and severe depression in obese migraineurs. In controls, normal weight was associated with absence of depression.

In the present study, we investigated traditional CV risk factors (lipid profile, abnormalities in serum glucose and insulin levels, oxidative stress, BP, physical activity, and smoking), a newly recognized CV risk marker (CRP), and a series of surrogate factors (sleep quality and duration, depression, and bioelectrical PA) in obese and normal weight migraineurs and age- and BMI-matched controls, hypothesising that migraine would be associated with worse CV risk, regardless of nutritional status. Our main findings were that (a) obese migraineurs had lower HDL-c than normal weight controls and migraineurs, (b) insulin resistance and insulinaemia were associated with obesity, (c) all migraineurs were sedentary irrespective of nutritional status, (d) Framingham risk scores were higher in obese migraineurs, (e) migraineurs had higher depression scores and shorter sleep duration, and (f) migraineurs, both obese and overall, had worse sleep quality scores.

In this study, obese migraineurs exhibited higher CV risk (as measured by Framingham 10-year risk for general CVD scores) than normal weight migraineurs or controls (the latter regardless of nutritional status), whereas normal weight controls seemed to be protected against an unfavourable risk profile. Nevertheless, there seems to be an overlap of migraine and obesity in terms of CV risk profile in migraineurs. Some recent studies have reported on CV risk profiles in this population [6, 8, 31, 32]. Winsvold et al. [33] suggest that a possible mechanism linking headache to CV risk profile is that headache, especially if frequent, may lead to lifestyle changes such as decreased physical activity, altered smoking habit, or unhealthy diet. Stam et al. [34] quantified atherosclerosis by intima media thickness, pulse wave velocity, and ankle-brachial index and found no differences between migraineurs and controls, concluding that enhanced atherosclerosis is an unlikely explanation for CV risk in migraine patients.

It bears noting that none of the migraineurs in our sample reported physical activity, whereas normal weight controls clearly led an active life. It is well known that higher levels of physical activity are associated with fewer CV events. Although the precise mechanisms underlying this inverse association are unclear, differences in several CV risk factors may mediate these effects, particularly inflammatory/haemostatic factors and BP [35]. It is also widely established that exercise is reported by migraineurs as a trigger of attacks, which may explain why some patients with migraine avoid physical activity [36]. In our study, underlying factors associated with physical activity, such as insulinaemia, insulin resistance, and HDL-c, were only related to obesity, and BP values remained within the reference range in all groups [35]. Therefore, headache status and the associated physical inactivity do not appear to be the link that connects these factors. Nevertheless, our findings corroborate those of an earlier study showing that migraineurs engage in less physical activity than individuals without headache [37].

Conversely, considering the component items of the Framingham score, there was an insignificant number of smokers among obese migraineurs and control groups, and cholesterol profile and diabetes status did not differ either by headache status or by nutritional status. However, HDL-c was lower in obese migraineurs than in all other groups and systolic BP was higher compared to normal weight migraineurs, although remaining, as mentioned above, within the clinically normal range. Furthermore, other traditional CV risk factors, such as triglycerides, glucose, HOMA-IR index, LDL-c, and insulinaemia, did not differ among groups. Differences in systolic and diastolic BP values, despite being statistically significant, were not clinically relevant. These data suggest that isolated factors do not play a significant role in determining risk, but combinations of risk factors may have been decisive determinants of CV risk in obese migraineurs as evaluated by the Framingham score. It bears noting that a previous longitudinal Brazilian study also failed to find any differences in BP, diabetes prevalence, and total serum cholesterol levels between elderly migraineurs and controls, differing from our data with regard to HDL-c and Framingham risk scores. Overall, the authors did not find a worse CV profile among migraineurs using the Framingham 10-year risk of myocardial infarction or coronary heart disease death scores [10]. It is also important to note that we evaluated general CV risk by Framingham score, while several previous studies have examined risk of stroke [38, 39], coronary heart disease [7, 9], myocardial infarction [33] or first coronary events [32], limiting the strength of comparisons.

De Luis et al. [14] reported differences in fat mass, glucose, HOMA-IR and inflammatory markers such as leptin and IL-6 levels in different bioelectrical PAs in obese women, suggesting that a low tertile of PA could be a surrogate CV factor. However, the biological meaning of PA has yet to be fully understood. A lower PA suggests cell death or decreased cell integrity, whereas a higher PA suggests large quantities of intact cell membranes [40]. Despite its association with worse prognosis in established chronic heart failure [31], the role of PA as a predictor of CV risk in subjects without baseline CVD is virtually nonexistent, except for the above-cited study. In our investigation, neither headache nor nutritional status showed any relation to PA. We also found no difference among groups in the factors mentioned by De Luis et al. [14] as associated with variation in PA, such as glucose, HOMA index, and CRP levels. To our knowledge, the present study was the first to attempt to quantify PA in migraineurs. Further studies are required to ascertain whether PA is affected by migraine and whether the hypothesised use of PA as a surrogate marker of CV risk in obese women [14] also applies to non-obese women.

CRP is a sensitive indicator of active systemic inflammation and an independent risk marker for CV morbidity, including ischaemic stroke [41]. A small, uncontrolled retrospective review found abnormal CRP levels in migraineurs with complex clinical features [42]. Although no significant differences have been seen in obese or normal weight migraineurs compared with controls [12], several studies support the role of inflammation in migraine [43, 44]. It is also noteworthy that, although the difference was not significant, obese migraineurs tended to have higher levels of oxidized LDL. Our results, derived from a small sample, need confirmation in larger controlled studies. Furthermore, prospective studies may establish whether measurements of CRP and oxidative parameters can identify patients with migraine at risk of CV events.

Few observational studies have reported a positive association between depression and incidence of coronary heart disease [45]. In a large prospective community-based cohort, depressive symptoms at baseline were consistently associated with fatal coronary heart disease and stroke events [46]. In another cohort of middle-aged women without baseline coronary heart disease, depressive symptoms were associated with higher risks of cardiac events [15]. Part of this association could be explained by increased risk of fatal ventricular arrhythmias [15]. Additionally, a relationship between migraine and depression has been proved by several studies [47‐49], and is reported to be bidirectional [47, 50]. Our data corroborate these associations, with migraineurs exhibiting mild/moderate and severe depression. Recurrently, obese migraineurs showed the worst profile, suggesting overlapping effects of obesity and headache.

There is emerging evidence that sleep parameters, specifically sleep duration [30] and quality of sleep [16], are associated with CV outcomes. Studies point to a U-shaped association between sleep duration and coronary heart disease and stroke [30]. The prevalence of sleep abnormalities has been reported as being much higher in migraineurs as compared with controls [51, 52]. In our study, even though no between-group differences in sleep quality were found, we detected shorter sleep duration in migraineurs compared to controls, regardless of nutritional status. This could affect migraine severity [53] and headache threshold [54] and be associated with worse CV outcomes, such as greater risk of developing or dying of coronary heart disease and stroke, as described by Cappuccio et al. [30] in a meta-analysis of prospective studies. Nevertheless, the known CV outcomes correlated with sleep disorders, such as hypertension [55], diabetes [56], dyslipidaemia, and hypercholesterolaemia [57], were not detected in our study. Obesity itself did not show any influence on these parameters. Likewise, sleep quality was not associated with any of the study groups.

Although Bigal et al. [32] described, in a large population-based study, that both migraine with and without aura were associated with risk factors for CVD, several studies point to a much stronger association for migraine with aura [9, 58, 59]. Stratification by migraine subtype could shed some light on this relationship, but this was not possible in our sample, because only six patients were diagnosed with migraine with aura.

Further studies with larger sample sizes as well as prospective controlled studies investigating additional recognized biomarkers, such as oxidized LDL-c, lipoprotein A, other inflammatory markers, and eating behaviours, may help ascertain whether migraine is associated with unfavourable CV risk and whether these features are independent of obesity acting as a potentiating factor.

Some strengths of this study are that diagnosis of migraine was made by a headache specialist, interviews were conducted and anthropometric parameters were measured by a trained nutritionist, and several surrogate markers were evaluated in addition to conventional parameters. A limitation is the small sample size and the convenience sampling strategy employed, which precluded further or more robust statistical analyses; therefore, we cannot make assumptions about the directionality of the relationship between migraine and CV risk factors or extrapolate results to the overall population of migraineurs.

Our findings point to marked inactivity, depression, and some sleep disturbances in female migraineurs, and that the effects of obesity and migraine on HDL-c levels and Framingham 10-year general CV risk probably overlap. Therefore, we believe that clinicians should maintain heightened vigilance for these modifiable CV risk factors in migraineurs. This additional attention is justified by well established benefits of modifying these factors. Also, monitoring BMI and other risk factors for CVD is accepted as good practice in patients with migraine.