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(Stroke. 1999;30:2019-2024.)
© 1999 American Heart Association, Inc.
Original Contributions |
From the Departments of Medicine (M.R.D., R.R.S., S.H.), Neurology (R.L.S.), and Public Health (Epidemiology) (R.L.S.) in the Sergievsky Center, Columbia-Presbyterian Medical Center, New York, NY.
Correspondence and reprint requests to Marco R. Di Tullio, MD, Division of CardiologyPH 3-342, ColumbiaPresbyterian Medical Center, 630 West 168th St, New York, NY 10032. E-mail md42{at}columbia.edu
| Abstract |
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MethodsA population-based case-control study was conducted in 352 patients aged >39 years with first ischemic stroke and in 369 age-, gender-, and race-ethnicitymatched community controls. Left atrial diameter was measured by 2-dimensional transthoracic echocardiography and indexed by body surface area. Conditional logistic regression analysis was performed to assess the risk of stroke associated with left atrial index in the overall group and in the age, gender, and race-ethnic strata after adjustment for the presence of other stroke risk factors.
ResultsLeft atrial index was associated with ischemic stroke in the overall group (adjusted OR 1.47 per 10 mm/1.7 m2 of body surface area; 95% CI 1.03 to 2.11). The association was present in men (adjusted OR 2.81, 95% CI 1.42 to 5.57) but not in women (adjusted OR 1.08, 95% CI 0.70 to 1.66), and in patients aged <60 years (adjusted OR 3.78, 95% CI 1.36 to 10.54) but not >60 years (adjusted OR 1.23, 95% CI 0.84 to 1.81). Subgroup analyses showed the risk to be present in men across all age subgroups. In women, the lack of association between left atrial index and stroke was most strongly influenced by left ventricular hypertrophy. A trend toward an association between left atrial index and stroke was observed in whites (adjusted OR 1.81, 95% CI 0.81 to 4.09) and Hispanics (adjusted OR 1.61, 95% CI 0.98 to 2.65) but was less evident in blacks (adjusted OR 1.25, 95% CI 0.74 to 2.14).
ConclusionsLeft atrial enlargement is associated with an increased risk of ischemic stroke after adjustment for other stroke risk factors, including left ventricular hypertrophy. The association is observed in men of all ages, whereas in women it is attenuated by other factors, especially left ventricular hypertrophy. Interracial differences in the stroke risk may exist that need further investigation.
Key Words: cerebrovascular disorders cardioembolic stroke echocardiography
| Introduction |
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The aim of the present community-based case-control study was to evaluate the role of left atrial enlargement as an independent risk factor for ischemic stroke in the multiethnic population enrolled in the Northern Manhattan Stroke Study (NOMASS).
| Subjects and Methods |
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Prospective case surveillance consisted of daily screening of all admissions, discharges, and head CT scan logs at the Presbyterian Hospital in the city of New York, the only hospital in the community, where approximately 80% of all patients in Northern Manhattan with cerebral infarction are hospitalized.
Community controls were eligible if they (1) had never been diagnosed with a stroke, (2) were aged >39 years, and (3) had resided in Northern Manhattan for at least 3 months in a household with a telephone. Stroke-free subjects were identified by random-digit dialing, which used dual frame sampling to identify both published and unpublished telephone numbers. Control subjects were individually matched to stroke patients by age (within 5 years), gender, and race-ethnicity.
Data were collected through interview of the cases and controls by trained research assistants, review of the medical records, physical and neurological examination by the study physicians, in-person measurements, and fasting blood specimens for lipid and glucose measurements. Data were obtained directly from study subjects with the standardized data collection instruments. If the subject was unable to answer questions because of death, aphasia, coma, dementia, or other conditions, a proxy who was knowledgeable about the patient's history was interviewed. Stroke-free controls were interviewed in person and evaluated in the same manner as cases. Cases were interviewed as soon as possible after their stroke, within a median time of 4 days from stroke onset.
As a part of NOMASS, 384 patients with first ischemic stroke who were aged >39 years and 405 stroke-free control subjects underwent 2-dimensional transthoracic echocardiography from June 1993 through December 1996. Written informed consent to participate in the study was obtained from all subjects. The study was approved by the Institutional Review Board of ColumbiaPresbyterian Medical Center.
Diagnostic Evaluation
Stroke risk factors were collected by direct interview or
medical record review in all case patients and control subjects.
Routine laboratory tests included complete blood counts, coagulation
studies, serum electrolytes, liver function tests, and glucose and
cholesterol determination. Arterial
hypertension was defined as the presence of a positive history or
antihypertensive treatment, or blood pressure values >160 mm Hg
(systolic) or >95 mm Hg (diastolic) during
the interview. Hypercholesterolemia was defined
as a total serum cholesterol >200 mg/dL or the presence of
appropriate drug treatment. Diabetes mellitus was defined on the basis
of abnormal fasting blood sugar, positive history, or the presence of
oral or insulin treatment. Coronary artery disease included
history of myocardial infarction or typical angina, the presence of a
positive diagnostic test (stress test or coronary
angiography), or drug treatment. The presence of atrial fibrillation
had to be documented on a current or past ECG or Holter monitoring. A
diagnosis of congestive heart failure was made on the basis of clinical
signs, symptoms, and/or anti-failure treatment. The diagnosis of
ischemic stroke was confirmed in all cases by means of head CT
or MRI. The cardiac evaluation included 12-lead ECG and 2-dimensional
color-Doppler transthoracic
echocardiography.
Echocardiographic Evaluation
Transthoracic echocardiography
was performed in all study subjects with Hewlett-Packard Sonos 1000 and
2500 ultrasound equipment (Hewlett-Packard Imaging Systems
Division). Studies were performed and measurements taken
according to the guidelines of the American Society of
Echocardiography.20 In particular,
left atrial anteroposterior diameter was measured at the level of the
aortic valve according to a leading edgetoleading edge convention.
The diameter was then normalized by the subject's body surface area.
The left atrial index thus obtained was used in the data
analysis. Left ventricular hypertrophy
was considered to be present when the interventricular
septum or posterior wall thickness was
12 mm (75th percentile of
the control group). The interpretation of the
echocardiographic studies was blinded to case-control
status and other clinical characteristics.
Statistical Analysis
Data are reported as mean±SD for continuous variables and
as frequency for categorical variables. Differences between
proportions were assessed by the
2 test,
replaced by the Fisher exact test when the expected cell count was <5.
Differences between mean values were assessed by unpaired Student's
t test. A 2-tailed P value of
0.05 was
considered significant.
Univariate and multivariate conditional logistic regression analysis (PROC PHREG, SAS statistical package, version 6.12; SAS Inc) was used to test the association between left atrial index (independent variable) and ischemic stroke (dependent variable). Unadjusted ORs for the association between left atrial index and ischemic stroke were calculated for the entire study group and for age, gender and race-ethnic subgroups.
Multivariate analysis was used to determine the adjusted OR for left atrial index after other established stroke risk factors were entered as potential confounding factors in the model.21 Variables significantly associated with ischemic stroke by univariate analysis (arterial hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, congestive heart failure, and left ventricular hypertrophy) were entered as independent variables in the model. Mitral regurgitation was also added to the model because of its relevance to the size of the left atrium. Cigarette smoking was entered into the model even though not significantly associated with ischemic stroke in the entire group because of its biological relevance and because of a statistically significant association with stroke in some race-ethnic subgroups.
To assess the effect of age (40 to 59 years,
60 years), gender, and
race-ethnicity on the association between left atrial index and stroke,
separate variables were fit in the model to quantify the effect of
left atrial index independently for each strata. Differences between
strata were tested with Wald's
2. An
additional analysis was performed to assess the age-gender
interaction. Adjusted ORs and 95% CIs were calculated from the beta
coefficients and the standard errors.
| Results |
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Sixteen percent of strokes were considered to be atherosclerotic or atheroembolic in origin, 19% were considered cardioembolic, 23% small vessel lacunar, and 5% from other causes. The remaining 37% of strokes were considered cryptogenic.
Left Atrial Dimension and Risk of Ischemic Stroke
Mean left atrial anteroposterior diameter was 40.5±6.3 mm in
stroke patients and 38.4±4.9 mm in control subjects
(P<0.001). Mean left atrial index (left atrial
diameter/body surface area) was 23.1±4.0 and 21.8±3.3
mm/m2 (P<0.001), respectively.
An increased left atrial index was found to be associated with
ischemic stroke in the entire study group, both at
univariate analysis and after adjusting for other
stroke risk factors (Table 3
). The
unadjusted odds ratio was 1.97 (95% CI 1.48 to 2.62) per each 10-mm
increase in left atrial index. Of note, an increased risk was
present after adjustment for the presence of left
ventricular hypertrophy and atrial
fibrillation. The adjusted OR in the multivariate
analysis was 1.47 (95% CI 1.03 to 2.11) per each 10-mm
increase in left atrial index. To assess the linearity of the effect of
left atrial index, quartiles were determined for the index. The
Figure
shows the results of univariate and
multivariate analyses in which ORs for stroke
relative to the first quartile of left atrial index were calculated for
the second, third, and fourth quartiles. A reasonably linear trend was
observed, with both unadjusted and adjusted ORs largest for the fourth
quartile.
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Effect of Age, Gender, and Race-Ethnicity
Table 3
also summarizes the stroke risk associated with an
increased left atrial index in gender, age, and race-ethnic subgroups.
A significant association was observed in men and in patients between
the ages of 40 and 59, but not in women or in the older age subgroup.
The difference in effect between age groups was statistically
significant (P<0.05), as was the difference between genders
(P<0.05). Among different race-ethnic subgroups, a trend
toward an association between left atrial index and stroke was observed
in whites and Hispanics, although it did not achieve independent
statistical significance in the multivariate
analysis, possibly due to the smaller number of subjects in
each subgroup. No definite association appeared to exist between left
atrial index and stroke risk in blacks.
Given the presence of significant age and gender differences in the
association between left atrial index and ischemic stroke,
additional analyses were performed in age and gender subgroups,
the results of which are summarized in Table 4
. A significant association between left
atrial size and stroke was observed in men in both the younger and the
older subgroups. In women, no significant association was observed
between left atrial index and stroke risk after adjustment for other
stroke risk factors. An age-related difference appeared to exist, with
a trend toward an association observed in the younger subgroup but not
in the older one. The gender difference in the older age group was
statistically significant (P<0.05).
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To assess which variable in the multivariate analysis most influenced the differences in the relationship between left atrial index and stroke observed between the age and gender subgroups, a series of exploratory analyses were performed with left atrial index and only a single stroke risk factor in the model at a time. The difference in the effect of left atrial index on stroke risk was largest for the model that included left ventricular hypertrophy, in which the strength of association decreased in older women (OR decrease from 1.53 to 1.11) and, to a much lesser extent, in younger women (OR decrease from 4.11 to 3.56). Left ventricular hypertrophy did not attenuate the strength of the association between left atrial size and stroke in men, with ORs slightly increasing in both the younger (from 2.62 to 3.51) and the older (from 2.38 to 3.16) subgroups.
| Discussion |
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Effect of Gender, Age, and Race-Ethnicity
Considerable gender differences in the association between left
atrial size and stroke risk were observed in our study, with a
significant risk excess observed in men but not in women. This confirms
the observations of the Framingham Study,19 which detected
an increased risk of stroke associated with left atrial enlargement in
men only. In that study, the association with ischemic stroke
was largely mediated by left ventricular mass. In our
study, the association between left atrial size and stroke did not
appear to be mediated by the presence of left ventricular
hypertrophy in the overall group, because it persisted
after adjustment for the presence of
echocardiographically determined
hypertrophy. However, a separate analysis in women
revealed that left ventricular hypertrophy was
the most important variable in explaining the attenuation of the
stroke risk observed in the multivariate
analysis, whereas its effect on risk estimates was modest in
men. This observation suggests that the stroke risk associated with
left atrial enlargement may be mediated by left ventricular
mass to a greater extent in women than in men. Gender differences in
the role of left ventricular hypertrophy as a
cardiovascular risk factor have been reported in the
past, with a greater impact on total and cardiac death observed in
women than in men.26
Age differences in the stroke risk associated with an increased left atrial size were also observed in our study, with the younger group being at higher risk than the older group. The weaker role played by left atrial enlargement in the older subgroup may be a reflection of the relatively greater contribution of other conventional stroke risk factors. This appeared to be especially true for left ventricular hypertrophy in women, the effect of which erased any association between left atrial size and stroke risk in the older subgroup.
Left atrial enlargement tended to be associated with ischemic stroke in whites and Hispanics, although the relatively small number of subjects in each subgroup did not allow for the achievement of independent statistical significance. The weaker association observed in blacks may be explained at least in part by the greater proportion of women in that race-ethnic subgroup. The consistency of the OR observed in whites and Hispanics despite differences in the distribution of stroke risk factors appears to further support the existence of an independent effect of left atrial size on the risk of stroke.
Comparison With Previous Studies
The results of the present study are related to similar
observations from the Framingham study,19 which described
a significant association between left atrial size and the risk of
stroke in men and the risk of death in both genders. Such association
was attenuated by adjustment for ECG-derived left
ventricular mass/height. Although differences in the study
design (case-control versus prospective) and subject characteristics
prevent a direct comparison of the results, the present study
suggests a stronger independent effect of left atrial size on the
stroke risk even after adjustment for
echocardiographically derived left
ventricular hypertrophy. This is possibly due
the presence in our study group of a larger number of younger subjects
(the lower age limit was 40 years instead of 50), in whom the stroke
risk associated with left atrial enlargement was found to be greater.
Also, the adjustment for echocardiographically
determined left ventricular hypertrophy in our
study, with its higher sensitivity,27 may have allowed for
a better assessment of the effect of left ventricular
hypertrophy on the risk estimates. Our study included
subjects from 3 different race-ethnic groups, which provided an
opportunity for insight into possible race-ethnic differences in the
stroke risk that was not obtainable from the exclusively white
population of the Framingham study. Finally,
echocardiographic variables were obtained from
2-dimensional instead of M-mode echocardiography,
with potential differences in the measurement of left atrial size and
in the determination of left ventricular
hypertrophy.
Strengths and Limitations
The present study is the first to address the possible
independent effect of left atrial size on the risk of ischemic
stroke in a community-based multiethnic population. The
sociodemographic distribution allowed for the assessment of the risk in
age, gender, and race-ethnic subgroups after adjustment for other
stroke risk factors.
Case-control design has some limitations, including potential bias in the selection of subjects. This was minimized in our study by the recruitment of cases and controls from the same community (to reduce the possibility of differences in socioeconomic variables, including access to medical care); the randomized procedure for control selection; and the individual matching of cases and controls by age, gender, and race-ethnicity. The possibility that differences between cases and controls may have existed in variables that were not measured cannot be excluded. Moreover, the study did not have the power to address the association between left atrial size and different stroke subtypes, and its power for detecting interracial differences in the stroke risk was also suboptimal.
The application of left atrial size measurement for assessing stroke
risk in individual patients must be done with caution, because its
accuracy is affected by measurement variability. In our study, the
average left atrial index in controls was 21.8
mm/m2. Given our quartiles distribution
(Figure
[fgc+]), a measurement variability of 10% (or 2.18
mm/m2) would correspond to half the difference
between the top of the first quartile and the bottom of the fourth
quartile. This suggests that, assuming a measurement variability of
10%, our data can be used in individual patients only to discriminate
between subjects at high and low risk.
Clinical Implications
The demonstration of a significant association between left atrial
size and stroke has potential preventive implications. Left atrial
enlargement is a known potential consequence of arterial
hypertension. Recently, different antihypertensive treatments have been
shown to have differential effects in decreasing the left atrial size,
partially independent of their effects on left ventricular
hypertrophy.28 Our data seem to indicate that
the size of the left atrium should be taken into consideration in the
global assessment of the individual stroke risk, and possibly in the
decision of the type of preventive treatment. The use of drugs that
more effectively decrease left atrial size might be considered for the
treatment of patients with arterial hypertension and left
atrial enlargement, similar to the way in which antihypertensive drugs
that promote reduction in left ventricular mass are chosen
in patients with hypertension and left ventricular
hypertrophy. All other factors being equal, an increased
atrial size could be an additional factor to consider when deciding on
the need for prophylactic anticoagulation. Also, different
stroke-prevention strategies could be envisioned for men and women,
given the different impact of left atrial size and left
ventricular hypertrophy on their respective
risks. Additional studies are needed to evaluate the efficacy of
decreasing the size of the left atrium in reducing the risk of
stroke.
| Acknowledgments |
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Received June 11, 1999; revision received July 16, 1999; accepted July 16, 1999.
| References |
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