Abstract
FROM EPIDEMIOLOGY TO BASIC MECHANISMS
Kurth T, Schürks M, Logroscino G, Gaziano JM, Buring JE. Migraine, vascular risk, and cardiovascular events in women: prospective cohort study. BMJ 2008; 337:a636
COMMENTARY
Several recent epidemiological studies have convincingly established a link between migraine and systemic vascular diseases.
Migraine has been linked to stroke in a complex bidirectional relation. Migraine can be the expression of a stroke, be a risk factor for stroke or directly cause a stroke (migrainous infarction). Migraine and stroke can also share a common cause such as CADASIL, be associated with subclinical stroke and mimic stroke, such as in certain forms of isolated de novo auras without headache (1).
Several studies using different protocols (prospective, retrospective, cross-sectional, case-control, meta-analysis) have addressed migraine as a potential risk factor for ischaemic cerebrovascular diseases. Convincing evidence for an increased incidence of stroke in migraine patients seems to be present only in cases of migraine with aura only (2).
The US Women's Health Prospective cohort study, which included 27 840 US women older than 45 years and without angina or cardiovascular disease at study entry, was followed for a mean of 10 years. Migraine with aura was associated with an increased risk of cardiovascular disease (3). In this cohort, the increased cardiovascular risk in women was also associated with an increase in ischaemic stroke.
In a similar prospective cohort of 20 084 men aged 40–84 years (the Physicians'Health Study) followed for a mean of 16 years, migraine with and without aura was associated with an increased risk of cardiovascular events strictly expressed in the form of myocardial infarction but no increase in the incidence of ischaemic stroke could be proven in the migraineurs.
Of note, no epidemiological study has proven a correlation between migraine and an increased incidence of peripheral vascular disease and no large studies have determined migraine as a risk factor for arterial hypertension (4). Migraine with aura, at our current state of knowledge, in the absence of vascular risk factors (excluding smoking and the use of oral contraceptives in women) seems to be for women an independent risk factor for systemic vascular diseases with a specific regional distribution (cerebrovascular and cardiovascular) (5). In men, an increased incidence of cardiovascular events has been documented.
Lee ST, Chu K, Jung KH et al. Decreased number and function of endothelial progenitor cells in patients with migraine. Neurology 2008; 70:1510–17
In their study, the authors evaluated whether circulating endothelial progenitor cells (EPC) had a modified level or function in migraine patients. Circulating EPC are considered as a surrogate biological marker of vascular function and a diminution in their count is associated with an increased risk of cardiovascular disease.
The authors thus compared the EPC colony-forming units in peripheral blood samples, their migratory capacity and their cellular senescence levels in 74 patients with tension-type headache, 67 patients with migraine without aura (MO) and 25 patients with migraine with aura (MA).
They found a significant reduction in EPC numbers in MO and MA, and in addition the reduction in the MA was statistically more significant when compared with the MO group.
COMMENTARY
Because traditional risk factors in migraine, particularly in MA, cannot explain the increased incidence of cardiovascular risk in migraine and because diminished EPC counts in patients seem to correlate with traditional vascular risk factors, these findings may suggest for cardiovascular disease in migraine a specific endothelial dysfunction. The endothelium is seen as an important centre of vascular control, participating in the regulation of vascular tone, nutrient delivery and waste removal, inflammation, thrombosis and coagulation. Endothelial modulation of vascular function results from the balance between, among others, vasodilators such as eNOS and potent vasoconstrictors such as angiotensin II and endothelin (6). Chronic neurogenic inflammation (7, 8) associated especially with migraine with aura with repeated episodes of cortical spreading depression may be the leading mechanism for endothelial dysfunction with reduced EPC numbers in migraine. Inflammation seems to play a central role in the pathogenesis of systemic vascular disease (9).
Dreier JP, Kleeberg J, Alasm M et al. Endothelin-1-induced spreading depression in rats is associated with a microarea of selective neuronal necrosis. Exp Biol Medical 2007; 232:204–13
The authors studied the effect of endothelin-1 applied locally on the exposed cerebral cortex of anaesthetisedrats, inducing cortical spreading depression (CSD) in 50% of their studied animals. In five other animals CSD was induced by topical application of KCl on the cortex. In all animals where CSD was induced, a microarea of neuronal necrosis, but no neuronal damage, could be found after the application of either substance if no CSD had been induced.
COMMENTARY
This basic science observation suggests that CSD may not be a benign phenomenon for the brain and in particular the cerebral cortex. More and more evidence suggests that migraine could be a risk factor for subclinical brain lesions (10) and brain grey matter changes (11).
Possible interpretation:
Much attention in these past two decades has been devoted to migraine as a primary cerebral disorder, possibly at least in part associated with a chronic hyposerotonergic state (12) Serotonin serum levels are decreased in the interictal phase of migraine and increased at the time of the attack (13). With a normal endothelium serotonin releases nitric oxide but it would contract blood vessels when the endothelium becomes dysfunctional (14). These new findings suggest that our interpretation of migraine pathogenesis should be modulated with the integration of the potential negative effects of repeated episodes of CSD on the cerebral parenchyma and on the endothelium of the cerebral and cardiovascular blood vessels, leading to a small but definite risk of increased ischaemic changes in those organs.
Tronvik E, Stovner LJ, Schrader H, Bovim G. Involvement of the renin-angiotensin system in migraine. J Hypertens 2006; 24 (Suppl. 1):S139–43
The authors report on the clinical evidence for involvement of the angiotensin system in migraine. An ACE inhibitor was first tested in an open study back in 1981 and found to have a positive preventive effect (reduction by 50% in migraine frequency) in a group of patients that had failed multiple other prophylactic agents. Subsequently, several double-blind, randomized, placebo-controlled studies, including, however, small numbers of study subjects, were completed using ACE inhibitors and several angiotensin receptor blocking agents (ARB). These studies were summarized in a meta-analysis in 2002, which showed a 30% reduction in the risk of headaches as compared with the placebo group.
Furthermore, the ACE-DD polymorphism occurs more frequently in patients with migraine, with an increased ACE activity in their serum and with that phenotype an increase in the frequency of their migraineattacks. Moreover, the methylenetetrahydrofolate reductase gene (MTHFR), which increases serum homocysteine, has been found to interact with the ACE (ID/DD) genotype and increase the susceptibility to migraine by a factor of 2.18. It appears in addition that the ACE circadian periodicity is lost in migraine.
It seems that the ACE inhibitors and ARB agents have a reducing effect on migraine activity that is independent of their effect on blood pressure. Although peripheral angiotensin may reach the angiotensin II receptors in the circumventricular organs, which are excluded from the blood brain barrier, it seems that a brain-specific renin-angiotensin system is independently regulated from the peripheral one.
COMMENTARY
Although the association of migraine and hypertension has not been proven, a recent large population study found higher systolic and diastolic blood pressures in patients with migraine (15). Other studies have confirmed these findings and it seems that migraine is positively correlated with the diastolic blood pressure. Angiotensin II receptors are present on the surface of the endothelial cells and in the current understanding of endothelial dysfunction in migraine where there may be a trend towards a predominance in the constrictive tone, angiotensin II receptors inhibition may be a valuable strategy in preventing the potential negative effects of endothelial dysfunction documented in migraine.