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Content 965

Headache Currents
David W. Dodick, M.D., UCLA
Department of Neurology,
Mayo Clinic, Arizona
13400 E. Shea Blvd.,
Scottsdale, Arizona 85259
Chief Editor
David W. Dodick, Scottsdale, AZ
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Address correspondence to Tobias Kurth, Division of Aging, Brigham and Womens Hospital,
1620 Tremont Street, 3rd Floor, Boston, MA 021201613, USA. Tel.

+

1 617 732 8355, fax

+

1 617 525 7739, e-mail tkurth@rics.bwh.harvard.edu

CURRENT REVIEW: BASIC SCIENCE

Migraine and ischaemic vascular
events

T Kurth, MD, ScD

An association between migraine and ischaemic vascular
events, particularly ischaemic stroke, has been debated for
many years. The pathophysiology of migraine has been
explored in detail, and it is known that a dysfunction of brain
cells and arteries is a major component of this disorder. The
involvement of cerebral arteries during the migraine attack
as well as the high prevalence of migraine among young
individuals with ischaemic stroke has led to the hypothesis
that migraine may be a risk factor for ischaemic stroke.
Furthermore, there is evidence that the vascular nature of
migraine is not limited to meningeal blood vessels and that
migraine and overall cardiovascular disease may share
aetiological pathways. The aim of this review is to summarize
the epidemiological evidence that links migraine with
ischaemic stroke and ischaemic heart disease and to discuss
potential biological mechanisms.
Key words:

ischaemic heart disease, ischaemic stroke, migraine

MIGRAINE AND RISK OF ISCHAEMIC STROKE

Migraine is a very common neurovascular disorder (1,2). Over
the last decades, an increasing body of publications has linked
migraine, specically migraine with aura, with ischaemic stroke.
Several retrospective case-control (312), three prospective (13
15), as well as one cross-sectional cohort study (16), and some
studies using data from stroke registries (17,18), have been pub-
lished on the association between migraine and stroke risk. Three
of the case-control studies found increased risk of ischaemic
stroke among women

<

45 years of age who reported a history
of migraine with aura (6,7,10), with risk estimates ranging from
3.8 (7) to 8.4 (10), and two additional case-control studies (3,5)
found increased risk for migraineurs with aura among both gen-
ders. In one case-control study, migraine without aura was asso-
ciated with increased risk of ischaemic stroke (6).
A meta-analysis of 11 case-control and three cohort studies
published before 2004 indicated that the risk of stroke is
increased in people with migraine (pooled relative risk 2.16, 95%
condence interval (CI), 1.892.48). This risk was consistent in
people who had migraine with aura (relative risk, 2.27; 95% CI,
1.613.19) and migraine without aura (relative risk, 1.83; 95%
CI, 1.063.15) (19).
Since the publication of the meta-analysis, two large-scale
prospective cohort studies (14,15) and one population-based
case-control study (12) were published. The rst prospective
cohort study used data from the Womens Health Study, which
included over 39 000 apparently healthy women 45 years of age
or older who were followed for an average of 9 years (14). This
study found a 1.7-fold increased risk for ischaemic stroke (rela-
tive risk, 1.71; 95% CI, 1.112.66) for women who reported
migraine with aura when compared with women without
migraine. This risk was stronger in those who were 4555 years
of age (relative risk, 2.25; 95% CI, 1.303.91) and was not seen
in older women. Migraine without aura was not associated with
an increased risk of ischaemic stroke (relative risk, 1.01; 95% CI,
0.631.62 14).
The second prospective study used data from the Atheroscle-
rosis Risk in Communities Study and included over 12 000 men
and women aged 55 and older (15). Compared with participants
without migraine or other headache, migraineurs had a 1.8-fold
increased risk of ischaemic stroke (relative risk, 1.84; 95% CI,
0.893.82). The fact that the risk estimates did not reach statis-
tical signicance may be due to the headache and aura classi-
cation. Specically, the category of other headache with aura,
which showed a signicant increased risk of ischaemic stroke
(relative risk, 2.91, 95% CI, 1.396.11), probably contains par-
ticipants with migraine with aura because the only other head-
ache form that has an aura, i.e. cluster headache, is rare in
population-based studies (20). Again, migraine or headache
without aura was not associated with increased risk. This study
also had a retrospective component, which showed in general
higher risk estimates and also found increased risk for
migraineurs without aura. As both prospective studies found an
association between migraine and ischaemic stroke in partici-
pants older then 45 and 55, respectively, the migrainestroke
association may not be limited to younger individuals.
The Stroke Prevention in Young Women Study matched 386
women aged 1549 years with rst ischaemic stroke with 614
age- and ethnicity-matched controls (12). Subjects were classied
as having no headache, probable migraine without visual symp-
toms, and probable migraine with visual symptoms. Compared
with women without headache, those who reported probable
migraine with visual symptoms had a 1.5-fold increased risk of
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ischaemic stroke (odds ratio, 1.5; 95 CI, 1.12.0), which slightly
attenuated after control for stroke risk factors. This risk further
increased for women who reported a probable migraine fre-
quency of at least 12 per year (odds ratio, 2.3; 95% CI, 1.53.5)
and for those who had begun having migraines during the prior
year (odds ratio, 6.7; 95% CI, 2.319.2). Women with probable
migraine without visual symptoms were not at increased risk for
ischaemic stroke.
In the existing literature, when the interaction between
migraine and other risk factors for stroke was evaluated, the risk
was more than tripled by smoking (odds ratio

=

10) (6), and
quadrupled by oral contraceptive use (odds ratios

=

13.916.9)
(6,7). The combination of migraine, oral contraceptives and
smoking further increased the risk (7,12).
In several studies, migraine has been associated with clinically
silent brain lesions, mostly in the white matter (2124). In a
meta-analysis of neuroimaging studies, the odds ratio between
migraine and white-matter lesions was 3.9 (95% CI, 2.36.7)
(25). A large nested case-control study randomly selected
patients with migraine with aura, with migraine without aura,
and controls, who were frequency matched to cases for age, sex
and place of residence and were studied by MRI (26). The
authors found no signicant difference between patients with
migraine and controls in overall infarct prevalence (8.1%

vs

5.0%). However, in the cerebellar region of the posterior circu-
lation territory, patients with migraine had a higher prevalence
of silent infarcts than controls (5.4%

vs

0.7%;

P



=

0.02; adjusted
odds ratio, 7.1; 95% CI, 0.955). The adjusted odds ratio was
13.7 (95% CI, 1.7112) for patients with migraine with aura
when compared with controls. In patients with migraine with a
frequency of attacks of one or more per month, the adjusted odds
ratio was 9.3 (95% CI, 1.176). The highest risk was in patients
with migraine with aura with one attack or more per month
(odds ratio, 15.8; 95% CI, 1.8140).
The association between migraine and ischaemic stroke
from retrospective and prospective studies is summarized in
Table 1.

MIGRAINE AND RISK OF ISCHAEMIC HEART DISEASE

The association between migraine and increased prevalence of
cardiovascular risk factors and the observation that the vascular
dysfunction of migraine may also extend to coronary arteries
(27,28), has led to speculation that migraine may not only be
associated with increased risk of stroke but also with ischaemic
coronary events. Case reports and clinical data suggest an asso-
ciation between migraine and angina (2729), especially the
variant type and migraine. However, although several case
reports (2729) and large-scale cohort studies (30,31) found an
association between migraine and chest pain that in some cases
was associated with documented ischaemic electrocardiographic
changes (28,29), an association between migraine and subse-
quent coronary events could not be rmly established (32).
Some studies have suggested a link between migraine and
prevalent coronary heart disease. In a Spanish case-control study
of 40 patients with acute myocardial infarction and matched
controls, patients with myocardial infarction had a higher prev-
alence of migraine (25%

vs

18.5%) (33). Two larger studies
found associations between migraine and existing cardiovascular
disease (34,35). The rst was a community-based study of 3654
men and women from Australia aged 49 or older, which showed
an approximately two-fold increased risk of prevalent myocar-
dial infarction, stroke and angina for migraineurs (34). The
second was a population-based study from the Netherlands,
which identied 620 patients with migraine and 5135 controls
without migraine. Migraineurs with aura had a four-fold
increased risk of self-reported history of coronary heart disease
prior to age 46 (35). In a large prospective matched cohort
study, patients with migraine were at increased risk of subse-
quent non-myocardial infarction ischaemic heart disease (rela-
tive risk, 1.29; 95% CI, 1.151.44). The association between
migraine and myocardial infarction demonstrated slight
increased risk, which was not statistically signicant (relative
risk, 1.15; 95% CI, 0.961.38 36). In addition, one large study
found an association between migraine and coronary events
only in the subgroup of women with a family history of myo-
cardial infarction (30).
In contrast, results from large cohort studies did not nd an
association between overall migraine (37) or migraine with aura
(31) and coronary events. In another study of 905 women who
were referred for coronary angioplasty, 24% reported a history
of migraine (38). Compared with women without migraine,
migraineurs had lower angiographic coronary severity scores and
less severe coronary artery disease. After a mean of 4.4 years of
follow-up of 873 of the participants, women with a history of
migraine were not statistically signicantly more likely to expe-
rience subsequent vascular events, although the relative risk esti-
mate for any cardiovascular event was increased (relative risk,
1.21; 95% CI, 0.931.58). Information about migraine aura was
not recorded in this study.
Recently, however, two large-scale prospective cohort studies
found associations between migraine and ischaemic heart disease.
Data from the Womens Health Study indicated an association
between overall migraine and major ischaemic cardiovascular
disease, including coronary heart disease, after a mean of 10 years
of follow-up (39), which was not apparent with shorter follow-
up (40). In this prospective cohort of 27 840 apparently healthy
women, overall migraine was associated with a signicantly
increased risk of ischaemic major cardiovascular disease (non-
fatal myocardial infarction, non-fatal ischaemic stroke, ischaemic
cardiovascular disease death), myocardial infarction, coronary
revascularizations, angina and cardiovascular disease death when
compared with women with no history of migraine (39). More
specically, the results of the Womens Health Study indicate that
the increased risk for any ischaemic vascular event is only appar-
ent for women with migraine with aura (Table 2). Compared
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with women who did not report any history of migraine and
after adjustment for traditional cardiovascular disease risk factors,
women who reported migraine with aura had a signicantly
approximately two-fold increased risk of major cardiovascular
disease, myocardial infarction, coronary revascularization, angina
and cardiovascular disease death. Women who reported migraine
without aura did not have increased risk for any ischaemic vas-
cular events (39). The shape of the cumulative incidence curves
for major cardiovascular disease showed a striking increased risk
after approximately 6 years of follow-up (Fig. 1). Potential expla-
nations for this interesting observation, however, are speculative
and would have to involve a differential effect for migraineurs
with aura. Besides chance, such explanations may include the
design of the Womens Health Study, underlying biological
mechanisms that increase the risk of CVD only after some time
period, or a change in environmental factors during the 10-year
follow-up of the study. The shapes of the association between
migraine and aura status and risk of specic vascular events were
similar (39).
With regard to men, recent data from the Physicians Health
Study indicate an association between overall migraine and major
cardiovascular disease, which was driven by a signicant 42%
increase in the risk of myocardial infarction (41). In this study,
20 084 apparently healthy US male physicians were followed
for a mean of 15.7 years, during which a total of 1449
major cardiovascular disease events occurred. Compared with

Table 1.Multivariable-adjusted* relative risks of ischaemic stroke according to migraine status

Study (reference)
Migraine status Age range of study
participants at study
entry (years) Gender
Overall
RR (95% CI)
With aura
RR (95% CI)
Without aura
RR (95% CI)
Prospective studies
Buring, 1995 (13) 2.00 (1.103.64) 4084 Men
Nightingale, 2004 (78) 2.33 (1.045.21) 1549 Women
Hall, 2004 (36) 1.52 (1.291.78) Any Men and women
Velentgas, 2004 (37) 1.67 (1.312.13) Any Men and women
Kurth, 2005 (14) 1.36 (0.971.92) 1.73 (1.102.71) 1.11 (0.691.78)


45 Women
Stang, 2005 (15) 2.07 (0.964.44) 0.86 (0.372.00) 4564 Men and women
Retrospective studies
Collaborative Group, 1975 (79) 2.00 Women
Heinrich, 1989 (3) 1.8 (0.93.6) 2.6 (1.16.6) 1.3 (0.53.6) 1565 Men and women
Marini, 1993 (80) 1.91 (1.053.5) 14.85 (1.8124) 1.6 (0.93.0)
Tzourio, 1993 (4) 1.3 (0.82.3) 1.3 (0.53.8) 0.8 (0.41.5) 1880 Men and women
Tzourio, 1995 (6) 3.5 (1.86.4) 6.2 (2.118.0) 3.0 (1.55.8) 1844 Women
Lindegaard, 1995 (8) 2.8 (2.118) 1544 Women
Carolei, 1996 (5) 1.3 (0.72.4) 8.6 (1.075.0) 1.0 (0.52.0) 1544 Men and women
Haapaniemi, 1997 (81) 2.12 (1.052.95) 1660 Women
Chang, 1999 (7) 3.54 (1.309.61) 3.81 (1.2611.5) 2.97 (0.6613.5) 2044 Women
Donaghy, 2002 (10) 8.37 (2.3330.1) 2.21 (0.4910.1) 2044 Women
Schwaag, 2003 (11) 2.11 (1.163.82) 1545 Men and women
Stang, 2005 (15) 5.46 (3.648.18) 2.45 (1.663.60) 4564 Men and women
MacClellan, 2007 (12) 1.3 (0.91.8) 1.0 (0.61.5) 1549 Women
RR denotes relative risk. CI denotes condence interval.
*Presented are the relative risks of the fully adjusted multivariable model in cases when several multivariable models were presented.
Prospective indicates migraine assessment prior to the occurrence of a stroke event.
Retrospective indicates that migraine was assessed after a stroke event occurred.
Study included also men but a relative risk for the entire study and men was not shown.
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non-migraineurs, men who reported migraine had an adjusted
relative risk (95% CI) of 1.24 (1.061.46;

P



=

0.008) for major
CVD, 1.12 (0.841.50;

P



=

0.43) for ischaemic stroke, 1.42
(1.151.77;

P



<

0.001) for myocardial infarction, 1.05 (0.89
1.24;

P



=

0.54) for coronary revascularization, 1.15 (0.991.33;

P



=

0.068) for angina, and 1.07 (0.801.43;

P



=

0.65) for
ischaemic cardiovascular death. The cumulative incidence curves
for major CVD are shown in Fig. 2. With regard to stroke, there
was a signicant modication by age, indicating that the men
who were younger than 55 years of age had increased risk of
stroke (relative risk, 1.84; 95% CI, 1.103.08), which was not
apparent in the older age group.

Table 2.Adjusted* relative risks for ischaemic vascular events according to migraine status in the Womens Health Study (

n

=== =

27 840)

No migraine
history
Any history
of migraine
Relative risk
(95% CI)

P

Active migraine
with aura
Relative risk
(95% CI)

P

Active migraine
without aura
Relative risk
(95% CI)

P

Number of participants 22 715 5125 1434 2176
Major vascular event 1.00 1.42 (1.161.74) 0.001 2.15 (1.582.92)

<

0.001 1.23 (0.881.73)
0.23
Ischaemic stroke 1.00 1.22 (0.881.68) 0.23 1.91 (1.173.10) 0.01 1.27 (0.772.09)
0.36
Myocardial infarction 1.00 1.41 (1.031.91) 0.03 2.08 (1.303.31) 0.002 1.22 (0.732.05)
0.45
Coronary revascularization 1.00 1.35 (1.091.67) 0.006 1.74 (1.232.46) 0.002 0.98 (0.671.42)
0.90
Cardiovascular disease death 1.00 1.63 (1.072.50) 0.02 2.33 (1.214.51) 0.01 1.06 (0.462.45)
0.89
Modied from (39).
CI denotes condence interval.
*Adjusted for age, systolic blood pressure, antihypertensive medication use, history of diabetes, body mass index, smoking, alcohol consumption,
exercise, postmenopausal status, postmenopausal hormone use, history of oral contraceptive use, family history of myocardial infarction before age
60, low-density and high-density lipoprotein, cholesterol lowering medication use, and randomized treatment assignments.
Sum of women with active migraine with aura, active migraine without aura, and prior migraine (history of migraine but no active migraine in the
previous year, data not shown).
A major cardiovascular event was dened as the rst of any of these events: non-fatal ischaemic stroke, non-fatal myocardial infarction, or death from
ischaemic cardiovascular cause.
Includes reports of bypass surgery or percutaneous coronary angioplasty.

Fig 1.Association between migraine status and major
cardiovascular disease in women. Reprinted with
permission from Kurth T, Gaziano JM, Cook NR et al.
Migraine and risk of cardiovascular disease in women.
JAMA 2006; 296:28391.
0.030
0.025
0.020
0.015
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e
*

o
f

m
a
j
o
r

c
a
r
d
i
o
v
a
s
c
u
l
a
r

e
v
e
n
t
s

0.010
Active migraine with aura
Active migraine without aura
No migraine history
0.005
0.0
0 2 4
Follow-up (years)
6 8 10
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POTENTIAL BIOLOGICAL MECHANISMS

The precise mechanisms by which migraine may lead to
ischaemic vascular events are currently unknown and likely to be
complex. Several hypotheses can be envisioned: (i) migraine may
directly cause an ischaemic event (i.e. a migrainous infarct); (ii)
migraine pathophysiology may affect the endothelial function
and by this alone or in combination with existing local vascular
pathologies increase the risk of stroke outside of a migraine
attack; (iii) migraine is associated with an increased prevalence
of risk factors for ischaemic vascular events; (iv) the link is caused
by migraine-specic drugs; and (v) migraine and ischaemic vas-
cular events are linked via a genetic component. With regard to
ischaemic stroke, congenital heart defects, in particular patent
foramen ovale, have also been discussed as potential biological
mechanisms.
A migrainous infarct is a rare event since the International
Headache Society introduced strict criteria in 1988 (42,43) and
2004 (44). The denition includes one or more aura symptoms
associated with ischaemic brain lesion in an appropriate territory
demonstrated by neuroimaging. This ischaemic brain lesion
must occur in conjunction with a migraine attack in a patient
with migraine with aura, which is typical of previous attacks
except that one or more aura symptoms persists for

>

60 min.
Other causes for ischaemia have to be ruled out (44). Migrainous
infarcts that are caused by severe hypoperfusion during a
migraine attack with aura, however, are rare and likely to be over-
diagnosed (45). In addition, most ischaemic strokes among
migraine patients occur between attacks and not during or
shortly after a migraine attack with aura (4,6); therefore, a
migrainous stroke is unlikely to explain the overall migraine
stroke association.
There is increasing evidence that migraine effects the vascular
system not just in the brain but outside as well (4648). For
example, in a cross-sectional study of 50 patients with migraine
and an equal number of matched controls without migraine,
brachial artery diameter as well as brachial artery and femoral
artery compliance were decreased in migraine patients. Further-
more, aortic augmentation index was increased in migraine
patients (46). Recent results from the Atherosclerosis Risk in
Communities Study indicate that middle-aged persons with
migraine and other headaches were more likely to have retinop-
athy signs (48). At this point, however, it remains unclear
whether endothelial dysfunction is a cause or a consequence of
migraine or whether they coexist for other reasons.
Recently, migraine has been associated with a more unfavour-
able cardiovascular risk prole. The Genetic Epidemiology of
Migraine (GEM) study found that compared with controls,
migraineurs are more likely to smoke and are more likely to have
a parental history of early myocardial infarction (35). The study
also found that migraineurs with aura are more likely to have an
unfavourable cholesterol prole, elevated blood pressure, report
a history of early onset coronary heart disease or stroke, and have
a two-fold increased risk of a high Framingham risk score-pre-
dicted 10-year risk of coronary heart disease even after adjusting
for age (35,49). Furthermore, a recent study linked migraine
frequency and severity with increased body mass index (50).
However, in most studies that evaluated the migraine
ischaemic vascular event association, the estimated relative risks
were not attenuated after controlling for traditional cardiovascu-
lar risk factors (6,1416,39,41). In addition, several studies indi-
cated that the migrainestroke association was particularly
present in the absence of traditional cardiovascular risk factors
(3,12,14,18). This may also explain why the association between
migraine and stroke diminishes with increasing age in most
studies: other major risk factors for ischaemic stroke, such as
hypertension and diabetes, acquire greater importance with
increasing age or interact with the mechanism by which migraine
may lead to stroke. This would result in a relatively lesser

Fig 2.Association between migraine status and
major cardiovascular disease in men. Reprinted
with permission from Kurth T, Gaziano JM, Cook
N et al

.

Migraine and risk of cardiovascular disease
in men. Arch Intern Med 2007; 167:795801.
0.12
Migraine
No migraine
0.10
0.08
0.06
0.04
C
u
m
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l
a
t
i
v
e

i
n
c
i
d
e
n
c
e
*
0.02
0.0
0 4 8 10 12
Follow-up (years)
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inuence of migraine as a risk factor for ischaemic stroke in the
elderly. Furthermore, these data may suggest that migraine can
increase the risk of ischaemic stroke only among those with intact
vasculature.
Concerns have been raised regarding the cardiovascular safety
of the use of migraine medications, especially the triptans, due
to their vasoconstrictive ability and the occurrence of sensations
that include chest pressure and tightness shortly after their use.
Indeed, the use of ergots has been associated with white-matter
lesions (26). However, recent reviews of the clinical, pharmaco-
logical and post-marketing cardiovascular safety data of triptans
currently do not support a direct association of these drugs and
ischaemic vascular events (36,37,5155). It is important to
note, however, that most of the data from clinical trials and
clinical practice regarding the safety of triptans have been
derived from patients without known cardiovascular disease
(53). Contraindications for triptans already include existing cor-
onary artery and cardiovascular disease and uncontrolled hyper-
tension. With regard to an increased risk of ischaemic events
due to triptan therapy, two large-scale studies from a health-care
provider in the USA (37) and from the General Practice
Research Database in the United Kingdom (36) found no
association between triptans and ischaemic vascular events.
Recently, a large claims-based study from the Netherlands eval-
uated whether overuse of triptans or ergotamin was associated
with increased risk of ischaemic vascular events (56). The results
of this study indicate that overuse of triptans even among
patients concomitantly using cardiovascular drugs did not
increase the risk of vascular events. In contrast, overuse of ergo-
tamin was associated with an increased risk (odds ratio 2.55;
95% CI, 1.225.36) that was further increased for those
patients who concomitantly used cardiovascular drugs. Thera-
peutic doses of either triptans or ergotamins were not associated
with increased risk of vascular events (56). In addition to these
data, all migraine patients are utilizing migraine-specic drugs
and thus, unless there is a biological interaction between these
drugs and migraine aura, use of these medications is an unlikely
explanation for the association between migraine with aura and
ischaemic vascular events.
In some patients, migraine and ischaemic stroke occur com-
monly as part of a distinct disorder, including, for example,
cerebral autosomal dominant arteriopathy with subcortical inf-
arcts and leukoencephalopathy (CADASIL) (57,58) and mito-
chondrial myopathy, encephalopathy, lactacidosis and stroke
(MELAS) (59). These, however, are distinct diseases only affect-
ing very few migraine patients. These disorders are autosomal
dominant diseases, pointing to a potential genetic component of
the migrainestroke association. Furthermore, the familiar hemi-
plegic form of migraine is also an autosomal dominant disorder
(6062). However, genetic aspects underlying the common
forms of migraine have not been established. Because of the
broad clinical spectrum of migraine, the interaction of several
polymorphisms is likely to determine the manifestation and
severity of migraine, and the effect of a single genetic mutation
is expected to be small.
Migraine, in particular migraine with aura, has been associated
with MTHFR C677T genotype (63,64), which is associated
with increased homocysteine levels, a risk factor for vascular
events. In recent years, a large number of studies have investi-
gated the genetic basis underlying cerebro- and cardiovascular
diseases, and numerous polymorphisms have been detected that
show a rm association. For example, the following physiological
systems are involved: beta-adreno-receptors (65), G-protein-
coupled intracellular signal transduction cascades (66), the renin-
angiotensin-aldosterone system (67), lipoprotein metabolism
(68), coagulation cascades (69), and inammatory cascades (70).
Some of the prophylactic treatments for migraine, such as beta-
blockers and calcium channel blockers, involve the cardiac sys-
tem and thus a potential link between genetic markers of cardio-
vascular disease and migraine is possible, however, currently
speculative.
There is increasing evidence that migraine, and particularly
migraine with aura, is associated with increased prevalence of
patent foramen ovale (PFO) (71). This link may be a potential
explanation for the migraineischaemic stroke association but
does not explain the association between migraine and coronary
heart disease. In small case-control studies, PFO was about three
times more frequent in migraine patients with aura compared
with controls without migraine (7274). In addition, migraine
was associated with large PFO (75). However, these studies
should be interpreted carefully because potential biases such as
selection and detection bias are plausible and prospective popu-
lation-based data are still lacking. It has also been reported from
observational studies that closure of a PFO is associated with
reduced migraine frequency (72,76). However, the only random-
ized and controlled trial of PFO closure in migraineurs does
not support a causal link (77). The primary endpoint,

cure

of
migraine, was not signicantly different between PFO closure
and control groups. There was a trend towards reduction of
migraine frequency in the active-treatment group, which, how-
ever, was not signicant after adjustment for the imbalance in
migraine frequency at baseline. In addition, the procedure was
associated with some serious adverse events.
In summary, there is good epidemiological evidence that
migraine with aura is associated with an increased risk of
ischaemic stroke, which appears to be stronger among the young
but may persist in the elderly. There is recent evidence that
migraine, and again migraine with aura, is associated with
increased risk of any ischaemic vascular event, including coro-
nary heart disease. This may lead to the hypothesis that migraine
with aura is associated with a systemic vascular disorder. How-
ever, the precise mechanisms by which migraine with aura may
lead to ischaemic vascular events are currently unknown and
likely to be complex. At least from prospective data, there is no
evidence that migraine without aura is associated with increased
risk of any ischaemic vascular events. As the absolute risk of
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increase in ischaemic vascular events for patients with migraine
with aura is considerably low, it is currently impossible to iden-
tify those at particular increased risk. Until there is further evi-
dence unveiling the association between migraine and ischaemic
vascular events, physicians should screen for and modify tradi-
tional major cardiovascular risk factors.

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