Introduction

The World Health Organization (WHO) stated in 2016 that headache has been underestimated, underrecognized, and undertreated throughout the world. Migraine affects at least 1 billion people worldwide and results in a large global socioeconomic burden. According to the Global Burden of Disease Study 2019 (GBD2019), migraine persists as the second most disabling cause worldwide (after low back pain) and remains number one in women <50 years of age. The GBD2019 showed once more that migraine is more prevalent in women compared with men.

The 2021 European Society of Cardiology (ESC) guidelines on cardiovascular disease (CVD) prevention recommend that migraine with aura should be considered in CVD risk assessment. The QRISK3 score, a tool to assess the 10-year risk of CVD, has incorporated migraine in the score. There is a growing interest in the link between migraine and CVD. Basic background information on the pathophysiology of migraine is presented in this paper. Associations between migraine and different types of CVD have been established, such as stroke, obstructive coronary artery disease (CAD), including myocardial infarction (MI), atrial fibrillation (AF), and cardiovascular death. Knowledge on migraine and ischaemia with non-obstructive coronary arteries (INOCA), patent foramen ovale (PFO), or atrial septal defects (ASD) is still the focus of new research. Acute and preventative medications for patients with migraine and CVD are discussed, and data on possible contraindications for their use are presented in this review.

This state-of-the-art review aims to provide background information on the disorder migraine and its associations with CVD based on current data, summarize treatment dilemmas in patients with migraine and CVD, and present knowledge gaps on this topic.

Migraine

Definition and prevalence

Migraine is a primary headache disorder characterized by recurrent moderate to severe headache attacks with a duration between 4 and 72 h. Migraine can occur with and without aura, and ∼30% of people with migraine have migraine with aura. Migraine without aura is defined by the Headache Classification Committee of the International Headache Society as headache commonly unilateral, pulsating, moderate to severe, aggravated by movement, and ≥1 from the following: nausea and/or vomiting, photophobia, and phonophobia. In addition, migraine with aura usually starts with unilateral, fully reversible aura symptoms of visual, sensory, or other central nervous system symptoms that develop gradually and are usually followed by headache and associated migraine symptoms (Table 1).

Table 1
Migraine definition according to ICHD-3

• Migraine without aura

1. At least five attacks that fulfil criteria 2–5
2. Headache attacks that last 4–72 h when untreated or unsuccessfully treated
3. Headache has at least two of the following four characteristics:
   • Unilateral location
   • Pulsating quality
   • Moderate or severe pain intensity
   • Aggravation by, or causing avoidance of, routine physical activity (e.g. walking or climbing stairs)
4. At least one of the following during the headache: nausea and/or vomiting, photophobia, and phonophobia
5. Not better accounted for by another ICHD-3 diagnosis

• Migraine with aura

1. At least two attacks that fulfil criteria 2 and 3
2. One or more of the following fully reversible aura symptoms:
   • Visual
   • Sensory
   • Speech and/or language
   • Motor
   • Brainstem
   • Retinal
3. At least three of the following six characteristics:
   • At least one aura symptom spreads gradually over ≥5 min
   • Two or more aura symptoms occur in succession
   • Each individual aura symptom lasts 5–60 min
   • At least one aura symptom is unilateral
   • At least one aura symptom is positive
   • The aura is accompanied with or followed by headache within 60 min
4. Not better accounted for by another ICHD-3 diagnosis

ICHD-3, International Classification of Headache Disorders, 3rd edition.

Migraine prevalence seems stable, and ∼15% of the general population is affected. However, prevalence numbers may be underestimated due to migraine patients not seeking medical help. A 15 000-household questionnaire in the USA showed that 17.6% of women and 5.6% of men reported at least one migraine attack in the previous year. Prevalence is two to three times higher in women compared with men and is highest in people aged 35–45 years old and is higher in people with lower income.

Episodic migraine is defined as that type of migraine with migraine days and headache days of <15 days per month. Chronic migraine is defined as headache for ≥15 days/month for ≥3 months, of which at least 8 migraine days/month for ≥3 months. It affects 1%–2% of the global population, and 2.5% of persons with episodic migraine progress to chronic migraine each year.

Pathophysiology

Genetic

Migraine has been associated with 123 loci in a recent large genome-wide association study (GWAS). For migraine without aura, two risk variants have been identified, for migraine with aura three risk variants, and for all types of migraine nine risk variants. In the phosphatase and actin regulator 1 gene (PHACTR1), an intronic variant has been located that is involved in migraine as well as fibromuscular dysplasia (FMD) and CAD.

Familial hemiplegic migraine (FHM) is a subtype of migraine with aura and is an autosomal dominant disorder, in which in two-thirds of cases, it can be linked to chromosome 19p3. Genetic testing has found that this can be caused by 9 different missense mutations in the CACNA1A gene in FHM type 1. Chromosome 1q21–23 altered by another mutation in the ATP1A2 gene seems also to be causal to migraine in FHM type 2. The SCN1A gene is also known to be involved in FHM type 3.

Neurovascular

Cortical spreading depression (CSD) is thought to induce migraine aura by a short-term depolarization wave that runs with a constant speed towards the frontal from the occipital area. Noxious stimulation occurs through shifts in the cortical steady-state potential, such as an increase in potassium, nitric oxide, and glutamate. Cortical blood flow increases (hyperaemia) at first and decreases thereafter for a sustained period (hypoperfusion), varying from 30 min to 6 h, then slowly returning to baseline. Headache results from trigeminal sensory neuron activation by neuropeptides like calcitonin gene-related peptide (CGRP) from sensory C-fibre terminals, resulting in vasodilatation, plasma protein extravasation, and platelet activation and possibly neurogenic inflammation. Sterile inflammation of the dura leads to increased plasma and cerebrospinal fluid pro-inflammatory cytokines and chemokines and is associated with migraine attacks. The relation between autonomic dysfunction and migraine remains unclear. Conflicting results have been reported on sympathetic and parasympathetic function in migraine patients, with studies reporting increased, normal, and reduced sympathetic function and increased, normal, and decreased parasympathetic function in patients with migraine.

Hormonal

Fluctuating oestrogen and progesterone may lower the threshold for migraine attacks (Figure 1). These hormones might increase susceptibility for CSD but could also affect the pathophysiology of migraine on a neurovascular, peripheral level. Prior to puberty, migraine is uncommon, with an increase in prevalence in both sexes during puberty. Migraine can also be triggered by the menstrual cycle. It can be classified accordingly: pure menstrual, menstrually related, and non-menstrual, though pure menstrual migraine is uncommon. Migraine generally improves during pregnancy due to stable high oestrogen levels. Around menopause, it peaks, and after menopause, the amount of migraine attacks seems to decrease.

Figure 1

Hormonal levels and migraine incidence in women. Adapted from Sacco et al. (J Headache Pain 2012;13:177–89) and Ibrahimi et al. (Maturitas 2014;78:277–80).

There is a link between ovarian steroid hormones and CGRP. It seems that oestrogens especially modulate CGRP in the trigeminovascular system. This is of relevance because CGRP induces trigeminal nerve hypersensitivity and photosensitivity and is the target of novel migraine therapies.

One of the proposed mechanisms of the role of oestrogen in migraine is that oestrogen can also influence tryptophan. Tryptophan hydroxylase (TPH) is an enzyme that synthesizes 5-hydroxytryptamine (5-HT, serotonin) from tryptophan into 5-hydroxytryptophan (5-HTP). Low 5-HT levels have been associated with migraine. In a study including men with and without migraine, elevated oestradiol levels, both absolute and relative to free testosterone, were observed in men with migraine. In a study evaluating male-to-female transsexuals, a similar prevalence of migraine was observed in male-to-female transsexuals as in the genetic female population (25%) compared with 7.5% in men. Testosterone therapy has been investigated in small pilot studies. It seemed effective in reducing the prevalence and severity of migraine headaches in both pre- and post-menopausal women with periodic hormonally related migraine.

Trigger factors

External factors might trigger migraine. Triggers can individually differ, but commonly reported triggers include bright (sun)light, stress, physical exercise and/or sexual activity, mild head trauma, skipping a meal, certain food or non-alcoholic beverages, alcoholic beverages, sleep deprivation, high altitudes, weather changes, and menstruation. However, the exact role of each of these trigger factors remains unclear.

Socioeconomic burden

The GBD2019 showed that migraine remains the second most disabling cause of disease worldwide and number one cause in women <50 years of age. Not only does migraine cause pain, but it also results in secondary disability. This secondary disability consists of reduced function ability, which results in the inability to work (absenteeism) or reduced effectiveness and productivity at work (presenteeism). The high prevalence of migraine in people in their productive years results in a financial burden for society due to people with migraine not working or not working to their full career potential. Surprisingly, these data have not resulted in global health policy debates. Data from the Genetic Epidemiology of Migraine (GEM) study showed that health-related quality of life (HRQOL) is lower in people with migraine, compared with people without migraine, and consistently lower in all eight domains (physical functioning, social functioning, physical role limitations, emotional role limitations, mental health, pain, vitality, and general health perception).

Moreover, the consequence of recurrent migraine attacks results not only in work and therefore financial losses but also in losses in social life. Not only people with migraine are affected, but also their family, friends, and work colleagues can be affected by changed social roles during migraine attacks.