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443
Cerebral Ischemia and Mitral Valve Prolapse:
Case-Control Study of Associated Factors
Roger E. Kelley, MD, Ileana Pina, MD, and Shih-Chang Lee, PhD
We evaluated 36 patients with cerebral ischemia and mitral valve prolapse and compared them with
36 age-matched controls with cerebral ischemia who had similar attributes but who did not have mitral
valve prolapse. Stepwise logistic regression analysis revealed an inverse relation between cerebral
ischemia in the presence of mitral valve prolapse and hypertension, diabetes mellitus, occlusive
cerebrovascular disease, and completed stroke at p<0.01. We also found, by correlation analysis, a
negative correlation between both hypertension and diabetes mellitus versus mitral valve prolapse at
p<0.05. Overall, 10 study patients compared with two control patients had no risk factors for
cerebrovascular disease detected (x2 = 4.9, p<0.05). These data indicate that the association of mitral
valve prolapse and cerebral ischemia is of special importance in patients who do not have other detected
risk factors for cerebrovascular disease. (Stroke 1988; 19:443—446)
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T
here continues to be considerable controversy
about the exact role of mitral valve prolapse
(MVP) in cerebral ischemia (CI). The numerous reports suggesting an association1"4 have been
influenced by patient selection and possible referral
bias. One would expect, for example, that with a
2.5-7% prevalence of MVP in the general population5"7
a significantly higher percentage of patients in prospective stroke series would be detected with MVP.
This has not been found to be the case. In one large
stroke series,8 no patient with MVP was detected
despite 55% of those with presumptive cerebral embolus having echocardiography performed. In a recent
series of 144 young patients with ischemic stroke,9
eight patients (5.6%) had MVP, and only three of these
eight were believed to have MVP as the primary
etiologic factor after intensive investigation. This has
led to speculation that, although MVP has the potential
to promote cerebral embolus, its relative importance is
quite small, and that published reports to the contrary
are artifactual.10
The purpose of our study was to assess the frequency
of risk factors for stroke in a group of patients with CI
plus MVP (study patients) and to compare the results
with those from a group of patients with CI who had
similar characteristics but who did not have MVP
(control patients). The primary objective, therefore,
was to assess possible differences in the stroke-prone
profile between the two groups.
Subjects and Methods
From July 1983 through June 1987, 36 patients with
acute CI who were found to have MVP were compared
with 36 patients with CI seen over the same time period
who did not have evidence of MVP by echocardiogFrom the Departments of Neurology (R.E.K.) and Cardiology
(I.P.), University of Miami School of Medicine and the Department
of Statistics (S-C.L.), Florida International University, Miami,
Florida.
Address for reprints: Dr. Kelley, Department of Neurology
(D4-5), 1501 NW Ninth Avenue, Miami, FL 33136.
Received September 17, 1987; accepted November 25, 1987.
raphy; neither group had other possible anatomic
sources of cerebral embolus by this study. Patients were
pair-matched on the basis of age ( ± 5 years), sex, race,
and type of ischemia (transient ischemic attack [TIA],
large artery embolus/thrombus, or lacuna). The patients were assessed in a prospective, standardized
fashion on coded forms. This format hopefully served
to avoid selection bias in terms of associated factors
when matching patients with and without MVP.
All patients were personally evaluated and a detailed
medical history, physical examination, and review of
pertinent diagnostic studies were obtained. Particular
attention was paid to the presence of risk factors for
cerebrovascular disease, history compatible with migraine, results of cardiac evaluation, and results of
neurologic evaluation including computed tomographic (CT) brain scan, magnetic resonance imaging
(MRI) brain scan, carotid noninvasive battery (consisting of B-mode ultrasonography, direct Doppler
ultrasonography, periorbital Doppler ultrasonography, and oculopneumoplethysmography), and cerebral
angiography. All but one study patient had a CT brain
scan, and that patient had a MRI brain scan. All control
patients had a CT brain scan. A total of 25 study
patients had either carotid noninvasive battery (n = 18)
or cerebral angiography (n = 7), while 20 control
patients had either carotid noninvasive battery (n = 11)
or cerebral angiography (n = 9). Twenty-nine study
patients (81%) had 24-hour cardiac monitoring compared with 26 control patients (72%). All patients
underwent routine blood laboratory screening including complete blood count, platelet count, prothrombin
time, partial thromboplastin time, and syphilis serology as well as fasting serum glucose, cholesterol, and
triglyceride.
Each patient underwent M-mode and twodimensional (2-D) echocardiography. Standard views
for the latter were obtained from the parasternal and
apical windows. A diagnosis of MVP in each patient
was made on the basis of published criteria for
M-mode" and 2-D'2 images. The echocardiograms
were all independently read by a board-certified car-
444
Stroke
Vol 19, No 4, April 1988
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diologist. Two study patients had corroboration of
MVP by angiocardiography. All patients with MVP
were believed to have a midsystolic click on cardiac
auscultation. One control patient was believed to have
a possible midsystolic click, but she did not have
evidence of MVP by echocardiography performed
twice.
Risk factors for stroke that were analyzed by
correlation analysis13 and stepwise multiple logistic
regression14 included age, sex, race, hypertension,
diabetes mellitus, coronary artery disease, atrial fibrillation, congestive heart failure, ventricular ectopy
( a 10 ventricular premature contractions/min or those
occurring in couplets or runs), previous stroke, oral
contraceptive use, hyperlipidemia, hypercoagulable
state, occlusive cerebrovascular disease, and cigarette
smoking. Occlusive cerebrovascular disease was
judged to be significant on the basis of carotid
noninvasive examination or cerebral angiography, and
we included those patients with extracranial or intracranial stenoses of £ 30%. Cigarette smoking was
defined as significant if the patient smoked an average
of a 1 pack/day over a 1-year consecutive time period.
We also included in the analysis whether there was
completed stroke or TIA and whether there was
migraine. The presence of factors such as hypertension, ischemic heart disease, diabetes mellitus, and
migraine was based on history and the need for specific
ongoing therapy for these disorders.
Results
There were 36 patients, 17 men and 19 women, 23
white and 13 black, in each group. The mean ± SD
age was 47.2 ± 17.4 years in the study group and 46.7
± 1 5 . 3 years in the control group. The age distribution
is shown in Table 1. There were 25 patients with
completed infarction and 11 patients with TIA in each
group. Of the patients with completed stroke, there
were three matched pairs with capsular lacunae.
The most obvious difference in the frequency of risk
factors between the two groups was hypertension (14%
in study patients vs. 47% in controls) and diabetes
mellitus (0% in study patients vs. 3 1 % in controls).
Although the numbers were small, we found previous
TABLE 1. Age Distribution in Age-Matched Patients With
and Without Mitral Valve Prolapse
Age
group
(yr)
10-19
20-29
30-39
40-49
50-59
60-69
70-79
Total
Mitral valve prolapse
No mitral valve prolapse
Com- Transient
pleted ischemic
Total
attack
stroke
1
1
0
3
3
6
8
4
4
4
1
5
6
6
0
4
2
6
1
4
3
11
25
36
Com- Transient
pleted ischemic
stroke attack Total
1
0
1
3
2
5
4
3
7
5
3
8
6
0
6
4
3
7
0
2
2
11
25
36
stroke (8% vs. 19%) and occlusive cerebrovascular
disease (6% vs. 28%) also to be more common in the
control group. No patient with hyperlipidemia was
detected. One study patient was believed to be hypercoagulable on the basis of protein S deficiency. This
patient had deep venous thrombosis (DVT) and pulmonary embolus. A control patient had DVT and the
lupus anticoagulant. Two study patients versus one
control patient were using oral contraceptives at the
time of their CI.
By stepwise logistic regression analysis, factors
negatively associated with CI in the presence of MVP
at p<0.01 were diabetes mellitus, hypertension,
occlusive cerebrovascular disease, and completed
stroke. Two other factors that were negatively correlated with each other at p< 0.01 were hypertension
and migraine.
Table 2 summarizes the results of the correlation
analysis using Kendall t correlation coefficients of all
risk factors. The correlations at p < 0 . 0 5 , whether
positive or negative, are recorded. Age was positively
correlated with hypertension, diabetes mellitus, and
coronary artery disease while it was negatively correlated with migraine. Migraine was also negatively
correlated with hypertension but was found more
frequently in women. Hypertension was positively
correlated with completed stroke but, as in the logistic
regression analysis, negatively correlated with MVP.
Diabetes mellitus was also negatively correlated with
MVP. The positive correlation of cigarette smoking
and oral contraceptive use in patients with CI is not
unexpected, and neither is the correlation between atrial
fibrillation and congestive heart failure or the correlation between ventricular ectopy and occlusive cerebrovascular disease. Completed stroke was negatively
correlated with migraine.
Discussion
Our data indicate that the association of MVP with
CI is of primary importance in patients who do not have
major risk factors for stroke. We found no difference
in the frequency of risk factors between TIA patients
(mean age 42 years) and those with completed stroke
(mean age 48 years). Overall, there were 10 study
patients, six with TIA and four with completed stroke,
compared with two control patients (x2 = 4.9, p< 0.05)
who had no detectable risk factors. The mean age of
the study patients without risk factors was 43 years,
while that of the study patients with risk factors was 48
years.
Age was not found to be a significant factor in the
relation between CI and MVP in the logistic model. A
positive correlation between age $nd hypertension as
well as between age and diabetes mellitus was noted
(p<0.05), but no additional correlations were detected, and age was systematically eliminated with the
use of a step-down procedure.15 Presumably, however,
one would expect MVP-related CI to be of greatest
significance in younger stroke patients in whom atherosclerosis is less likely to play a role in cerebral
thromboembolic disease.
Kelley et al
Cerebral Ischemia and Mitral Prolapse
445
TABLE 2. Kendall's x Correlation Coefficients for Factors Possibly Related to Cerebral Iscbemla in Patients
With and Without Mitral Valve Prolapse
Mitral
Coronary Congestive Com- Occlusive
Hyper- Diabetes Cigarette
heart
artery
pleted cerebrovasvalve
tension mellitus smoking
failure
disease
stroke cular disease Migraine prolapse
—
0.24
—
—
—
-0.32
—
Age
0.32
0.25
—
—
—
—
—
—
—
Sex
—
0.32*
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Hypertension
—
—
Diabetes
mellitus
—
—
Oral contraceptives
—
—
Completed
stroke
—
—
Atrial fibrillation
—
—
Ventricular
ectopy
—
—
p<0.05 for reported values.
•Women only.
—
—
—
0.31
—
-0.27
-0.36
—
—
—
—
—
—
-0.42
0.29
—
—
—
—
—
—
—
—
—
—
—
-0.25
—
—
—
0.39
—
—
—
—
—
—
—
—
0.26
—
—
There are a number of theoretical reasons to expect
a higher frequency of CI in patients with MVP. These
include an increased risk of infective endocarditis,16-17
the relatively high frequency of MVP in severe
coronary artery disease18 with the attendant risk of acute
myocardial infarction for cerebral embolus," the association of atrial fibrillation with MVP,20 which may
be of special importance in the promotion of cerebral
embolus,21-22 and thrombus formation in the region of
MVP.23 In addition, migraine is seen in association with
MVP,24 and symptoms of migraine can mimic TIA or
there can actually be migrainous infarction.25 Also, CI
in association with MVP may be related to platelet
hyperaggregability.26"28 Thus, it is not unexpected that
Sandok and Giuliani29 reported that the prevalence rate
for stroke in persons with MVP was four times greater
than that for the normal population.
What remains unexplained is the relatively low
detection rate for MVP in large prospective series of
stroke patients. Such series of stroke and TIA patients
studied by echocardiography give a rather consistent
prevalence of MVP of between 0% and 5%. 8 ' 9 ' a ^ 3 7 On
the other hand, Barnett et al1 reported that 24 of 60
patients younger than 45 (40%) with TIA or partial
stroke had MVP compared with 8 of 141 patients older
than 45 years of age (5.7%). Myxomatous degeneration
of the chorda tendinea may be the more common
mechanism of prolapse of the mitral valve in older
patients,38 whereas primary degeneration of the valve
leaflets is the primary factor in younger individuals.39
This might have implications for stroke risk in the two
age groups. Two additional studies of stroke in younger
individuals found MVP in 34.8%40 and 32%. 41 These
studies are not in agreement, however, with a study of
30 consecutive young stroke patients that found no
significant difference in the prevalence of MVP compared with matched control patients.42
Hart and Easton43 emphasize the importance of
differentiating studies of CI in groups of unselected
patients versus those in whom the ischemia is unexplained. They feel that the discrepancy in the prevalence of MVP between the two types of studies reflects
a low absolute risk for MVP-associated stroke overall
but a relatively high prevalence in young adults with
unexplained CI. A recent survey of the literature44
cogently points out that even if MVP accounts for one
third of stroke in persons younger than 40, the incidence
of stroke in this age group (approximately 3/100,000/
yr) results in an overall stroke risk for MVP of
approximately 1/100,000/yr. This is approximately the
same risk for MVP-associated stroke in older patients.
Furthermore, assuming a prevalence of 6% for MVP
in younger individuals, the incidence of stroke in young
individuals with MVP is relatively low, approximately
1/6,000/yr (0.2%).
The complexity of the association of MVP and CI
was underscored by one study patient who had a
hypercoagulable state that was not discovered until 4
weeks after his stroke. This 23-year-old man presented
with a moderate-sized, right middle cerebral artery
distribution stroke and was found to have a midsystolic
click on cardiac auscultation, with MVP documented
by echocardiography. Despite progressive recovery
with increasingly independent walking, he developed
DVT with secondary pulmonary embolus. Extensive
hematologic investigation revealed protein S deficiency, which has recently been observed in association
with ischemic stroke.45 This patient illustrates that,
despite the potential of MVP to be associated with CI,
other possible mechanisms require evaluation.
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1988
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KEY
WORDS
• risk factors
•
cerebral ischemia
•
mitral valve prolapse
Cerebral ischemia and mitral valve prolapse: case-control study of associated factors.
R E Kelley, I Pina and S C Lee
Stroke. 1988;19:443-446
doi: 10.1161/01.STR.19.4.443
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