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Abstract

Epidemiological studies suggests that migraine is associated with disorders of the cerebral, coronary, retinal, dermal and peripheral vasculature. There is evidence that migraine is associated with endothelial dysfunction, both as a cause and a consequence. Endothelial dysfunction, a vascular risk factor, is characterized by endothelial activation and impaired vascular reactivity. Plasma and genetic biomarkers for these conditions have been identified. The clinical significance lies in the potential for the rapid identification of migraineurs at increased risk of ischaemic stroke and vascular disease through ascertainment of endothelial dysfunction biomarkers. It is uncertain whether stroke, myocardial infarction and other vasculopathies can be prevented by migraine prophylaxis, endothelial repair, platelet inhibition or a combination of these strategies.

Keywords

migraine vasculopathy endothelial dysfunction cardiovascular retinopathy

INTRODUCTION

T he widely accepted neurovascular theory of migraine integrates the phenomena of head pain and aura, defined as focal neurological symptoms that precede or accompany headache. Migraine pain has been ascribed to dural and meningeal vascular dilatation, perivascular inflammation and nociceptor activation (1). Trigeminal nerves emanate from the brainstem and innervate the extracerebral vasculature, although the exact nature of the coupling of aura and pain remains elusive. Migraine aura, once attributed to intracranial vasospasm, is now generally accepted as a consequence of cortical spreading depression (CSD) of Leao (2). Functional imaging data suggest CSD also occurs in migraine without aura (3). Cortical spreading depression is understood to be a short-lasting depolarization wave, which moves across the cortex at a rate of about 5 mm/min. In CSD, the brief phase of excitation of the neuronal and astroglial network is immediately followed by prolonged nerve cell depression. This process induces an efflux of excitatory amino acids from nerve cells, enhanced energy metabolism, changes in genes, growth factors, neurotransmitter, neuromodulators, and inflammatory mediators. CSD, which may be a consequence of ischaemia, also generates microvascular changes, which are marked by a brief cortical spreading hyperaemia (4), followed by a longer lasting cortical spreading oligaemia (5). PET and MRI imaging demonstrate that cerebral blood flow during the oligemic phase of CSD mostly remains above the range associated with ischaemic injury (3, 6). Interest in the role of the vasculature in persons with migraine is mounting because of growing evidence that migraine is a risk factor for clinical and subclinical brain ischaemia, as well as for more widespread vascular changes. The vasculopathy of migraine is thought to reflect endothelial dysfunction, a disorder of endothelial activation and impaired vascular reactivity, which is a risk factor for vascular events. This paper explores the epidemiological evidence of systemic vasculopathy in migraine, and describes the pathophysiology of endothelial dysfunction and evidence that it occurs in migraine.

MIGRAINE-ASSOCIATED VASCULOPATHY

Cerebral vasculature

Migraine and cerebral ischaemia have been linked for over 30 years, with reports of ischaemic stroke occurring during (migrainous infarction) and between migraine attacks, particularly in young women and in those with aura (7–16). This association is independent of other cardiovascular risk factors and furthers the hypothesis that there is a subgroup of persons with migraine and vasculopathy in the absence of atherosclerotic disease. The risk of stroke with migraine is, however, not restricted to women. The all-male prospective Physicians Health Study reported a doubling of the lifetime risk for stroke in persons with self-reported migraine (9). A large-scale epidemiologic study in the United States, the National Health and Nutrition Evaluation Survey (NHANES), reported the risk of stroke to be doubled in migraineurs, both male and female (12). The Atherosclerotic Risk in the Community Study (ARIC), a prospective cohort study of 12 750 men and women older than 55 years, found that migraine with aura carried a threefold risk of ischaemic stroke (14). In addition to clinical strokes, there have also been several radiological series that cite the presence of subclinical lesions (typically in the white matter) in patients with migraine (17, 18). A population-based study (19) of healthy persons 30–60 years of age showed that cerebellar lesions were more common in the patients with migraine, particularly in those with aura and with frequent attacks, than in people who did not have migraine. Among women, but not men, deep white-matter lesions were more prevalent in those with migraine, irrespective of migraine type. Risk increased with the frequency of attack. The question remains as to whether the lesions are caused by migraine or are a marker of ischaemic disease, which in turn induces symptoms (i.e. aura and headache) reminiscent of migraine.

Coronary vasculature

Migraine has been associated with ischaemic heart disease in both women (14, 18) and men (19). In the large, prospective cohort of women in the Women's Health Study (WHS), active migraine with aura was associated with an increased risk of myocardial infarction, ischaemic stroke, and death due to ischaemia, as well as with coronary revascularization and angina. Active migraine without aura was not associated with increased risk of any CVD event (14). In addition, the association between migraine with aura and cardiovascular disease in the WHS varies by vascular risk status (18). Compared with women without migraine, the age adjusted hazard ratios in women who reported migraine with aura in the highest Framingham risk score group were 3.34 (1.50–7.46) for myocardial infarction as opposed to 1.00 (0.24–4.14) for ischaemic stroke. In the lowest Framingham risk score group, the age adjusted hazard ratios in women who reported migraine with aura were 1.29 (0.40–4.21) for myocardial infarction, and 3.88 (1.87–8.08) for ischaemic stroke. The reason for these differences is intriguing but uncertain, and suggests that the underlying mechanism in the coronary bed is atherosclerotic, whereas in the brain, it is not. In the all-male Physicians Health Study with a 16 year follow-up, there was a 42% increase in the risk of myocardial infarction in those with migraine, and only a 12% increase in the risk of ischaemic stroke. In the youngest cohort of migraineurs (<55 years old) there was an 84% increase in ischaemic stroke. In the ARIC Study it was determined that Rose angina (variant angina) was associated with migraine, particularly migraine with aura, whereas coronary heart disease was not. This suggests a pathophysiological mechanism (i.e. vasospasm) different from atherosclerotic disease (20).

Retinal vasculature

Migraine has been associated with vascular retinopathy (21). In the population of middle-aged individuals in the Atherosclerosis Risk in the Community (ARIC) Study, it was determined that persons with migraine headache were more likely to have retinopathy than those without a history of headaches (odds ratio [OR]= 1.38, 95% CI = 0.96–1.99, for migraine/other headaches with aura; OR = 1.49, 95% CI = 1.05–2.12 for migraine without aura; and OR = 1.28, 95% CI = 0.99–1.65 for other headaches), after controlling for age, gender, race, study centre, and cardiovascular risk factors. Associations with migraine were actually stronger among the subset of participants without a history of diabetes or hypertension (21). The association of retinopathy with migraine in younger people independent of these factors suggests that other pathophysiologic processes, such as endothelial dysfunction, may play a role.

Dermal and peripheral vasculature

We identified in young women an association of migraine with livedo reticularis, a violaceous netlike dermatopathy resulting from stasis of blood in the superficial venous drainage systems of the skin due to hyperviscosity or obstruction of dermal arteries (22, 23). We also found that in migraineurs with livedo reticularis, stroke was more common (22). Interestingly, Sneddon's syndrome, an idiopathic condition linking stoke and livedo reticularis and most common in young women, is also associated with migraine headache (24). Raynauds disorder may also be associated with migraine (25), especially in those also having vasospastic angina (20), suggesting a shared pathogenetic defect of the vasculature. Pre-eclampsia, a condition characterized by gestational hypertension and proteinuria, predisposed women to ischaemic stroke. A number of studies, including the GEM Study (OR = 1.63; 95% CI = 1.2–2.1), have found an association between migraine and gestational hypertension and pre-eclampsia (26). It has been hypothesized that the aetiologic link is endothelial dysfunction, with systemic impairment of vascular reactivity and increased platelet aggregability.

VASCULAR BIOLOGY AND THE PATHOPHYSIOLOGY OF ENDOTHELIAL DYSFUNCTION

Arteries are composed of the inner intima (a monolayer of endothelial cells and the internal elastic lamina), the media (predominantly smooth muscle cells) and the outer adventitia (connective tissue). The vascular endothelium constitutes approximately 1% of body mass and has a surface area of approximately 5000 m², and is postulated to be the largest gland of the body (27). The endothelium serves as a mechanical and biological barrier between the blood and vacular wall. Endothelial cells are an active endocrine organ, producing substances important for maintaining vascular and neural homeostasis (e.g. prostacyclin, endothelin-1, angiotensin II and nitric oxide), while inactivating other vasoactive substances (e.g. serotonin and bradykinin). Endothelial dysfunction is mediated by oxidative stress and characterized by a reduction in the bioavailability of vasodilators and an increase in endothelium-derived contracting factors, leading to impairment of endothelium-dependent vasodilation. Vasodilators include endothelium derived hyperpolarizing factor, prostacyclin and nitric oxide, a substance also involved in pain transmission, hyperalgesia, chronic pain and central sensitization. Vasoconstrictors include endothelin-1 and angiotensin II. In addition to impaired cerebral reactivity, endothelial dysfunction also comprises endothelial activation, which is characterized by proinflammatory and procoagulatory milieu (Fig. 1) (28).

Figure 1

Upstream and downstream markers of endothelial dysfunction.

EVIDENCE FOR ENDOTHELIAL DYSFUNCTION IN MIGRAINE

Endothelial activation markers

Studies examining upstream (oxidative stress) and downstream (thrombosis and inflammation) markers of endothelial dysfunction strongly suggest that endothelial dysfunction occurs in migraine, although the nature of the association is speculative. In clinical studies, markers of oxidative stress, known as thiobarbituric acid reactive substances (TBARs), collected between migraine attacks, were elevated compared with a control group (29). Nitric oxide (NO) bioavailability decreases in the face of an oxidizing environment (30), and in a recent interictal study of premenopausal women, urinary nitrite/nitrate concentrations were decreased in those with migraine compared with controls, and the association was strongest in the group with migraine with aura. Although controversial (31), there is evidence that migraine is associated with hypercoagulability, including the interictal identification of elevated levels of the prothrombin fragment 1 and 2 (a marker of secondary hemostasis) in migraineurs with aura (32). Primary haemostasis related to platelet activation, which in turn activates coagulation factors, has been reported in migraine (33). Several studies in migraineurs have also demonstrated elevated levels of von Willebrand factor (vWF) in migraine (34). Our work comparing migraine with livedo reticularis with migraine without livedo reticularis and controls shows that those with livedo reticularis have platelet hypercoagulability and elevated vWF activity (35). Von Willebrand factor (vWF) is a large, multimeric glycoprotein produced, stored and released into the circulation from the vascular endothelium in response to oxidative stress. It is widely considered to be one of the most important plasma markers of endothelial dysfunction (36), and raised levels of vWF are associated with each major cardiovascular risk factor (37, 38). Von Willebrand factor has also been independently linked to stroke in clinic- and community-based longitudinal studies (39, 40). Reflecting reduced fibrinolysis, elevated plasma tPA antigen has been reported in migraine compared with controls (41). Although not previously studied in migraine, a population-based case-control study of young women demonstrated that elevated plasma tPA antigen was an independent marker of increased stroke risk (42). Vascular inflammation is another downstream result of endothelial dysfunction. The association of C-reactive protein, a marker of inflammation, with migraine has only previously been demonstrated in two case control studies (43, 44) and a large prospective cohort study of women aged 45 years or older (45). CRP is the best established biomarker of increased risk of ischaemic stroke and myocardial infarction (46). Circulating endothelial progenitor cells (EPC) are released from the bone marrow into the circulation to provide an endogenous repair mechanism to counteract endothelial cell injury and to replace dysfunctional endothelium. In normal subjects, higher Framingham risk scores are associated with diminished EPC counts. A recent study found circulating EPC numbers and functions are reduced in migraine patients, supporting a theory of a link between migraine and cardiovascular risk (47).

Impaired reactivity markers

Altered reactivity in the cerebral circulation has been demonstrated in migraine, with some studies showing increased and others decreased reactivity. For example, some transcranial Doppler (TCD) studies have demonstrated decreased vasodilatory responses to hypercapnia during headache-free intervals in migraineurs compared with non-headache control groups (48), although in one study the finding was restricted to the posterior circulation (49). Other TCD studies and CBF studies reported excessive cerebrovascular CO₂ responsiveness (50–52). Similarly, a small near-infrared spectroscopy study in migraine showed decreased cerebrovascular reactivity to hypercapnia (53), while another showed increased reactivity (54). With regards to the systemic circulation, three recent studies documented altered reactivity of the systemic vasculature, with increased peripheral arterial stiffness, and decreased flow-mediated (endothelial dependent) dilation of the brachial artery in migraineurs, a sign of endothelial dysfunction (55, 56). There is also evidence of increased peripheral vascular tone with decreased diameter and compliance of superficial muscular arteries, increased peripheral and central pressure, and increased aortic augmentation index (AIx). Increased aortic AIx, not previously reported in migraine studies, is likely to be caused by altered intensity of reflected pressure waves, which in turn is determined by the diameter and compliance of small arteries and arterioles. A study of retinal vasomotor reactivity in response to mean arterial pressure showed impairment in migraine (57). Cutaneous microvascular responses to endothelial and non-endothelial dependent dilators were tested using laser Doppler flowmetry in combination with iontophoresis in a small study. In this study, there was no change in the microvascular responsiveness of the subcutaneous microvasculature in migraine compared with controls (58).

Genetic markers

A number of genes associated with endothelial dysfunction appear to increase susceptibility to migraine. The endothelin type A receptor (ETA) gene-231 A/A polymorphism is associated with migraine in adults (59). Angiotensin I-converting enzyme (ACE) deletion/deletion (DD) polymorphism has been associated with endothelial dysfunction, possibly through effects on nitric oxide pathways (60–62). This polymorphism has also been tied to venous thrombophilia (63), hypercoagulability (64), decreased vasomotion, increased vascular smooth muscle tone, vascular wall thickening, and decreased bradykinin (61). The relationship of ACE DD genotype to ischaemic stroke and cardiovascular disease is controversial (64–67), but it has been independently linked to lacunar infarction (68) in the absence of carotid atheroma (69), and to leaukoariosis (70). It has also been linked to deep white matter hyperintesities in persons with vascular dementia (71). The ACE DD polymorphism has been associated with migraine, both with (72) and without aura (73). In the migraine without aura population, ACE DD was associated with increased frequency of attacks (73). Data from the large cohort of women in the Women's Health Study (WHS) did not suggest an association of the ACE DD polymorphism with migraine, migraine aura status, or cardiovascular disease. The increased risk for cardiovascular disease among migraineurs with aura was, however, only apparent for carriers of the DD/DI genotype (74). Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of homocysteine, an amino acid derived during the metabolism of methionine, and a risk factor for cerebral small vessel disease acting via endothelial dysfunction (75). The 677 TT polymorphism predisposes to hyperhomocysteinaemia, particularly in the setting of folate deficiency, and has been implicated as a genetic stroke risk factor (76). The TT polymorphism has been purported to be associated with an increased risk of migraine (77), particularly migraine with aura independent of other cardiovascular risk factors (78). In the WHS there was a suggestion of a modest protective effect of the MTHFR 677TT genotype on migraine with aura, yet the increased risk for cardiovascular disease (particularly ischaemic stroke) among migraineurs with aura was magnified for TT genotype carriers (79). The MTHFR 677 TT genotype and the ACE DD genotype have been shown in combination to increase migraine susceptibility, with the greatest effect being in the migraine with aura subgroup (OR=2.89, 95% CI = 1.47–5.72) (80). In a study of premenopausal women, we found that vWF activity is higher in ACE DD, than DI or II (81), and that it is highest in those with both the ACE DD and the MTHFR 677TT genotypes (82). Endothelial nitric oxide synthase (eNOS) gene Glu298Asp polymorphism has been demonstrated to decrease endothelial NOS activity. In a case control study, persons with migraine with aura were twice as likely to have eNOS AspAsp as non-headache controls (OR = 2.21, 95% CI: 1.00–5.04) (83). There are also data to suggest that the eNOS 894 T or eNOS 894 TT genotypes in combination with the MTHFR 677 TT or ACE DD genotype increase the risk of ischaemic stroke (84).

EVIDENCE SUGGESTING MIGRAINE ATTACKS LEAD TO ENDOTHELIAL DYSFUNCTION

Findings that episodes of migraine are associated with ictal changes in endothelial biomarkers suggest that migraine attacks may be causally related to the dysfunction. One can hypothesize that with recurrent migraine attacks, inflammation, hypoxia, shifts in vascular diameter and blood-brain barrier disruption cause perturbation and injury of the vascular endothelium. In clinical studies, thiobarbituric acid reactive substances (TBARs), markers of oxidative stress, were higher during, compared with between, migraine attacks (29). A small study of persons with migraine without aura demonstrated that vWF levels were also significantly higher ictally (85). Ictal studies in migraine have also documented increased endothelin-1 (migraine with and without aura) (86), soluble intercellular adhesion molecule, tissue necrosis factor (migraine without aura) (87), VEGF, TGF beta 1, and matrix metalloproteinase 9 (migraine with and without aura) (88). Matrix metalloproteases degrade laminin, collagen type-IV, a critical component of brain blood vessels. With the finding that circulating EPCs were reduced in number and function one can hypothesize that migraine attacks cause repeated endothelial damage, and exhaust the available supply of EPCs.

EVIDENCE SUGGESTING THAT ENDOTHELIAL DYSFUNCTION LEADS TO MIGRAINE

Endothelin-1, a vasconstrictor and potent inducer of cortical spreading depression (CSD) in an in vivo rat model, may link endothelial irritation to migraine aura (89). A recent study demonstrated endothelial dysfunction (increased vascular tone and decreased reactivity) in the systemic circulation of persons with migraine of recent onset (56). This infers that endothelial dysfunction may be causally related to migraine, rather than a consequence of longstanding migraine attacks or of triptan pharmacotherapy. The population-based Genetic Epidemiology in Migraine (GEM) study demonstrated that migraineurs, particularly those with aura, have a greater cardiovascular risk profile than individuals without migraine (90). Similarly, analysis of the Nationwide Inpatient Sample database in peripartum women demonstrated that diabetes, hypertension and smoking were associated with migraine (91). These findings suggest that conditions that cause endothelial dysfunction predispose to migraine. Other evidence is the finding that several genetic polymorphisms associated with endothelial dysfunction are also associated with migraine, as previously discussed. The finding that the endothelin type A receptor (ETA) gene-231 A/A polymorphism is associated with migraine in adults (59) but not in children, suggests that migraine may be a consequence of endothelial dysfunction, which increases with age, rather than being directly related to the genotype (92). There are also monogenic neurovascular syndromes (involving mutations in NOTCH3, COL4A1 or TREX1 genes) associated with a high prevalence of migraine and vasculopathy, suggesting that endothelial dysfunction may be an important mechanism leading to migraine. In cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), for example, there are alterations in cerebral and cutaneous vascular reactivity (93), with MRI lesions often preceding clinical symptoms. Migraine, a frequent presenting symptom, precedes TIAs and strokes by many years (94). Indirect evidence that endothelial dysfunction leads to migraine is the fact that medications such as calcium channel blockers, ACE inhibitors and angiotensin receptor blockers (ARBs), which improve endothelial dysfunction (95), have demonstrated efficacy in migraine prophylaxis, although the mechanism is uncertain (96–98).

CONCLUSION

Epidemiological evidence suggests that migraine affects the cerebral and systemic circulation. Endothelial dysfunction, which is more prevalent in migraineurs, may be the underlying pathophysiological process underlying this widespread vasculopathy. Plasma vWF and CRP appear to be particularly promising biomarkers for identification and monitoring of endothelial dysfunction. Evidence suggests that the migraine ictus is directly linked to endothelial dysfunction, and may discern differences between the effect of attacks with and without aura on the endothelium. Although indirect, there is also evidence that endothelial dysfunction is a risk factor for migraine, including (i) evidence of an association between migraine-susceptibility genetic polymorphisms and endothelial dysfunction in the migraine population, and (ii) evidence that pharmacotherapy that improves endothelial function also prevents migraine. This complex relationship may explain migraine progression to chronic headache (i.e. migraine causes endothelial dysfunction, which causes more migraine) and to ischaemic disease, including stroke. Without contradicting proposed genetic models of migraine and neuronal hypersensitivity, the model (Fig. 2) offers a framework for understanding how migraine begets migraine, is associated with other vascular risk factors, and is linked to stroke and systemic vascular outcomes. The clinical significance lies in the potential of increasing the armamentarium for preventing migraine progression (e.g. prophylaxing against migraine, improving endothelial function, and treating inflammation and coagulopathy). The findings may also allow for the rapid identification of migraineurs at increased risk of ischaemic stroke and vascular disease through ascertainment of plasma and genetic markers. Being able to identify those migraineurs at highest risk of developing endothelial dysfunction may allow for preventive strategies to avoid the cerebral and systemic consequences.

Figure 2

Model of relationship of migraine and endothelial dysfunction.

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Migraine as a Systemic Vasculopathy

Abstract

Keywords

INTRODUCTION

MIGRAINE-ASSOCIATED VASCULOPATHY

Cerebral vasculature

Coronary vasculature

Retinal vasculature

Dermal and peripheral vasculature

VASCULAR BIOLOGY AND THE PATHOPHYSIOLOGY OF ENDOTHELIAL DYSFUNCTION

EVIDENCE FOR ENDOTHELIAL DYSFUNCTION IN MIGRAINE

Endothelial activation markers

Impaired reactivity markers

Genetic markers

EVIDENCE SUGGESTING MIGRAINE ATTACKS LEAD TO ENDOTHELIAL DYSFUNCTION

EVIDENCE SUGGESTING THAT ENDOTHELIAL DYSFUNCTION LEADS TO MIGRAINE

CONCLUSION

References