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© Blackwell Publishing Ltd

Cephalalgia

, 2007, 27, 988–990

Headache Currents

CURRENT LITERATURE: CLINICAL SCIENCE

Migraine and ischaemic heart disease and stroke: potential mechanisms and treatment options

INTRODUCTION

ultiple epidemiological studies cited in this issue of

Headache Currents

support the link of migraine and ahigher risk for vascular disease, especially ischaemic

stroke in women with migraine with aura before age 45 years.The precise mechanism by which migraine predisposes to strokehas not been clearly delineated, although studies show that therisk of stroke in women with migraine is increased with oralcontraceptive use and smoking. Other potential factors increas-ing the risk of stroke in migraineurs include endothelial dysfunc-tion, prothrombotic factors, vasospasm, hyperhomocysteinaemiaand possible embolic mechanisms such as paradoxical embolusvia a patent foramen ovale (PFO) or related to mitral valveprolapse. Migraine has also been associated with an increased riskof cervicocephalic dissection, which may lead to ischaemicstroke, and migraine frequently occurs years before clinicalischaemic brain disease in individuals with

Notch 3

gene muta-tions associated with cerebral autosomal dominant arteriopathywith subcortical infarcts and leukoencephalopathy (CADASIL).If these potential mechanisms were not complex enough, thereis concern that medications such as triptans and ergots, used totreat migraine headaches, may potentially cause ischaemic brainor heart disease (angina and myocardial infarction).

Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ, Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 2005; 64:614–20.

Background:

Migraine, particularly with aura, is a risk factor for early-onset ischaemic stroke. The underlying mechanisms are unknown, but may in part be due to migraineurs having an increased risk profile for cardiovas-cular disease. In this study, the authors compare the car-diovascular risk profile of adult migraineurs with that of non-migraineurs.

Methods:

Participants (

n

=

5755, 48% men, age 20–65 years) were from the Genetic Epidemiology of Migraine (GEM) study, a population-based study in the Nether-lands. A total of 620 current migraineurs were identified: 31% with aura (MA), 64% without aura (MoA) and 5% unclassified. Controls were 5135 individuals without life-time migraine. Measured cardiovascular risk factors included blood pressure (BP), serum total and high-density lipoprotein cholesterol (TC, HDL), smoking, oral contra-ceptive use and the Framingham risk score for myocardial infarction or coronary heart disease (CHD) death.

M

Results:

Compared with controls, migraineurs were more likely to smoke [odds ratio (OR) 1.43; 1.1, 1.8}, less likely to consume alcohol (OR 0.58; 0.5, 0.7) and more likely to report a parental history of early myocardial infarction. Migraineurs with aura were more likely to have an unfavourable cholesterol profile [TC

≥

240 mg/dl (OR 1.43; 0.97, 2.1), TC:HDL ratio

>

5.0 (OR 1.64; 1.1, 2.4)], have elevated BP [systolic BP

>

140 mmHg or diastolic BP

>

90 mmHg (OR 1.76; 1.04, 3.0)] and report a history of early-onset CHD or stroke (OR 3.96; 1.1, 14.3); female migraineurs with aura were more likely to be using oral contraceptives (OR 2.06; 1.05, 4.0). The odds of having an elevated Framingham risk score for CHD were approx-imately doubled for the migraineurs with aura.

Conclusions:

Migraineurs, particularly with aura, have a higher cardiovascular risk profile than individuals without migraine.

COMMENTARY

This population-based case–control study from the Netherlandsexamines the cardiovascular risk profile of individuals with MA,MoA and control subjects. Its findings are that migraineurs,especially those with aura, are more likely to have a higher-riskcardiovascular risk profile than individuals who do not havemigraine. This includes a higher likelihood of smoking, reportedfamily history (parents) of early myocardial infarction, unfavour-able cholesterol profile, elevated BP and a history of early-onsetCHD or stroke. In addition, women with aura were more likelyto be using oral contraceptives than women with no history ofmigraine. The latter have been associated with hypercoagulabil-ity. This study also shows that individuals with MA were approx-imately twice as likely to have an elevated risk of coronary arterydisease using the Framingham coronary heart disease risk score.Women with migraine were more likely to have received a diag-nosis of gestational hypertension, and there is evidence to linkthis with hypertension later in life. As the authors point out, itis not possible to determine if migraine modifies cardiovascularrisk factors or if cardiovascular risk factors modify the clinicalexpression of migraine. Nevertheless, this study does show thatindividuals with migraine (especially MA) are more likely to haverisk factors that have been associated with cardiovascular disease.It will be important for the findings in this Dutch population beconfirmed in other populations. Meanwhile, those who care forpatients with migraine, especially those in primary care, shouldbe aware that there is a likelihood of cardiovascular risk factorsbeing higher than in those individuals without migraine andshould appropriately screen these patients for modifiable risk

© Blackwell Publishing Ltd

Cephalalgia

, 2007, 27, 988–990

989

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Headache Currents

Although these results suggest that significant right-to-leftshunts contribute to the increased stroke risk in individuals withmigraine, there are shortcomings in this study. Clearly, periph-erally located large vessel cerebral infarctions are more likely tobe of embolic origin, but deep small infarctions are often due tosmall vessel disease. The authors provide no information regard-ing localization and, indeed, it is not clear whether the patientsunderwent neuroimaging. The authors do not detail other riskfactors for ischaemic stroke such as diabetes mellitus, hypercho-lesterolaemia and hypertension which might predispose toischaemic strokes via other mechanisms. In addition, the authorsincluded patients who were

>

50 years old, when atheroscleroticmechanisms play a larger role in symptomatic cerebrovasculardisease than at younger ages. All of these shortcomings may haveled to misattribution of strokes to a paradoxical embolism.

Despite the shortcomings, the study lends credence to thehypothesis that paradoxical embolism is likely to account forsome of the excess stroke risk in patients with migraine.

Anzola GP, Morandi E, Casilli F, Onorato E. Different degrees of right-to-left shunting predict migraine and stroke: data from 420 patients. Neurology 2006; 66:765–7.

The authors analyse the extent of right-to-left shunting in patients with migraine, patients with cryptogenic stroke and controls. Patients with both migraine and stroke had larger shunts than those with migraine without stroke (

P

=

0.038), patients with no migraine with stroke (

P

=

0.007) and control patients (

P

<

0.0001). Patients with migraine have overall larger shunts than non-migraineurs, particularly if they have had a stroke. Right-to-left shunting may be causally related to migraine and to the increased stroke risk of migraine.

COMMENTARY

The authors of this retrospective study used contrast-enhancedtranscranial Doppler studies to identify evidence of right-to-leftshunts in patients and, as in the study by Wilmshurst et al.,found that patients with migraine had larger shunts than non-migraineurs, particularly if they had suffered a stroke. They alsoconclude that large right-to-left shunts are more likely to beassociated with stroke in patients with migraine. However, justas in the Wilmshurst study, the study can be criticized for lackof characterization of strokes and lack of control for other strokerisk factors. Nevertheless, the overall findings suggest that someof the excess stroke risk in migraineurs is attributable to largerright-to-left shunts. Even though this study and that of Wilm-shurst et al. suggest that right-to-left shunts may contribute toincreased stroke risk in migraine, there have been no randomizedcontrolled trials that have demonstrated that closure of a PFOprevents ischaemic stroke in patients with migraine or is aneffective treatment for migraine attacks.

factors. When hypertension, elevated cholesterol and smokingare present, intervention should be undertaken to modify themto reduce the future risk of vascular events.

Wilmshurst P, Nightingale S, Pearson M, Morrison L, Walsh K. Relation of atrial shunts to migraine in patients with ischemic stroke and peripheral emboli. Am J Cardiol 2006; 98:831–3.

This study investigated whether the increased incidence of stroke in young subjects with migraine is because they have an increased prevalence of atrial right-to-left shunts. The investigators report the prevalence of clinically relevant atrial shunts in those with stroke and migraine compared with those with stroke but without migraine, and also in historic control groups of subjects who had MA but no stroke and in population controls. Of 60 consecutive stroke patients, 42 (70%) had large- or medium-sized atrial shunts. Transcatheter shunt closure was performed in 39 patients, of whom 35 had a PFO (mean diameter 9.8

±

4.1 mm) and four had atrial septal defects. If atrial shunts were unrelated to stroke in patients with migraines, shunt prevalence in those with migraine and stroke would be the same as in those with migraine but without stroke. However, a much greater shunt prevalence was found in those with stroke and MA (84%) than in those with MA but no stroke (38.1%,

P

<

0.001), population controls (12.2%,

P

<

0.001) and those with stroke but no migraine (55.6%,

P

<

0.05). Shunt prevalence was also significantly greater in patients who had stroke and MoA (75%) than in population controls (

P

<

0.001) and in those with MA but no stroke (

P

<

0.05). In conclusion, the increased inci-dence of stroke in subjects with migraine compared with the general population is because they have a higher prev-alence of large atrial shunts and hence an increased risk for paradoxic embolism.

COMMENTARY

Several studies have demonstrated a higher occurrence of PFOin patients with MA. This study included 60 consecutive patientswho presented with ischaemic stroke and underwent contrastechocardiography to seek evidence of possible paradoxic embo-lism. All patients were

<

66 years old at the time of presentationor, for those with more than one stroke, the first stroke was at

<

66 years (mean age 42.7

±

13.3 years and an age range of 11–65). Patients were excluded if carotid Doppler showed significantcarotid artery disease, if transthoracic echocardiography showeda left-sided cardiac source of emboli, or 24-h ambulatory elec-trocardiography showed atrial fibrillation or flutter. As outlinedabove, shunt prevalence was greater in patients with stroke whohad migraine, both MA and MoA, compared with populationcontrols.

© Blackwell Publishing Ltd

Cephalalgia

, 2007, 27, 988–990

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Headache Currents

Velentgas P, Cole JA, Mo J, Sikes CR, Walker AM. Severe vascular events in migraine patients. Headache 2004; 44:642–51.

Objective:

To estimate rates of vascular events in relation to dispensing of triptans and ergot alkaloids among migraineurs, and to compare these rates with those of non-migraineurs.

Context:

It has been speculated that the use of triptans or ergot alkaloid drugs might increase risk of ischaemic events through vasoconstriction.

Design:

A retrospective cohort study of 130 411 migraineurs and 130 411 age-, sex- and health plan-matched non-migraineurs who were members of United-Healthcare during 1995–1999. The data source for this study was Ingenix’s research database containing pharmacy and medical claims for UnitedHealthcare members, and the National Death Index.

Main outcome measures:

Incidence of cardiovascular and cerebrovascular events and mortality. Migraineurs and non-migraineurs had identical rates of myocardial infarc-tion: 1.4 per 1000 person-years. Migraineurs were 67% more likely to suffer a stroke than non-migraineurs [adjusted relative risk (RR) 1.67, 95% confidence interval (CI) 1.31, 2.13] and had higher rates of unstable angina and transient ischaemic attacks. There was no increase in risk of myocardial infarction with current (adjusted RR 0.80, 95% CI 0.58, 1.11) or recent (adjusted RR 1.15, 95% CI 0.71, 1.87) triptan use. Neither current (adjusted RR 0.90, 95% CI 0.64, 1.26) nor recent (adjusted RR 0.84, 95% CI 0.46, 1.55) triptan use was associated with risk of stroke. Current users of ergot alkaloids were some-what more likely to have a stroke than other migraineurs (adjusted RR 1.49, 95% CI 0.93, 2.41), but there was no dose–response relationship.

Conclusions:

Use of triptans is not associated with increased risk of any ischaemic events, including myocar-

dial infarction and stroke, or mortality. Consistent with previous studies, migraineurs in general have an elevated risk of stroke, but not myocardial infarction, compared with non-migraineurs.

COMMENTARY

This large retrospective study of members of a healthcare com-pany in USA assessed whether migraine was associated withstroke or myocardial infarction and found, as in other studies,that migraine is a stroke risk, but no association was found withmyocardial infarction. It did not control for independent strokeor cardiovascular risk factors. Importantly, it did show that trip-tan use was not associated with stroke or myocardial infarction.On the other hand, use of ergots was associated with stroke risk.As clinicians, we are frequently faced with treatment of acutemigraine headaches. Triptans, as a group, are the most usefulgroup of agents yet developed for this purpose. The appropriateconcern that triptans have been rarely associated with cardiac orcerebral ischaemia often causes hesitation in providing theseagents. This study is reassuring that there is no significant asso-ciation of these agents with vascular events. This suggests that,in general, triptans can be prescribed safely. This should reassureclinicians regarding the safety of this class so that they willprescribe these agents, which have been shown to decreasemigraine-related disability. Nevertheless, they are contraindi-cated in individuals with coronary artery disease, ischaemic cere-brovascular disease, uncontrolled hypertension, and those at highrisk for such disorders.

JW Swanson

Mayo Clinic, Department of Neurology, Rochester,MN 55905, USA

swanson.jerry@mayo.edu