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(Circulation. 1995;92:835-841.)
© 1995 American Heart Association, Inc.

Articles

Left Atrial Size and the Risk of Stroke and Death

The Framingham Heart Study

Emelia J. Benjamin, MD, ScM; Ralph B. D'Agostino, PhD; Albert J. Belanger, MA; Philip A. Wolf, MD; Daniel Levy, MD

From The Framingham Heart Study, Framingham, Mass (E.J.B., R.B.D., A.J.B., P.A.W., D.L.); the Departments of Cardiology (E.J.B.), Neurology (P.A.W.), and Preventive Medicine (E.J.B., P.A.W., D.L.), Boston (Mass) University School of Medicine; the Department of Mathematics, Boston (Mass) University (R.B.D., A.J.B.); the Division of Cardiology and Clinical Epidemiology, Beth Israel Hospital, Boston, Mass (D.L.); and the NHLBI, Bethesda, Md (D.L.).

Correspondence and reprint requests to Emelia J. Benjamin, MD, ScM, The Framingham Heart Study, 5 Thurber St, Framingham, MA 01701.

	Abstract

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Background The medical literature contains conflicting reports on the association of left atrial (LA) enlargement with risk of stroke. The relation of LA size to risk of stroke and death in the general population remains largely unexplored.

Methods and Results Subjects 50 years of age and older from the Framingham Heart Study were studied to assess the relations between echocardiographic LA size and risk of stroke and death. During 8 years of follow-up, 64 of 1371 (4.7%) men and 73 of 1728 (4.2%) women sustained a stroke, and 296 (21.6%) men and 271 (15.7%) women died. Sex-specific Cox proportional-hazards models were adjusted for age, hypertension, diabetes, atrial fibrillation, smoking, ECG left ventricular (LV) hypertrophy, and congestive heart failure or myocardial infarction. After multivariable adjustment, for every 10-mm increase in LA size, the relative risk of stroke was 2.4 in men (95% CI, 1.6 to 3.7) and 1.4 in women (95% CI, 0.9 to 2.1); the relative risk of death was 1.3 in men (95% CI, 1.0 to 1.5) and 1.4 in women (95% CI, 1.1 to 1.7). Adjusting for ECG LV mass/height attenuated the relation of LA size to stroke and death.

Conclusions After multivariable adjustment, LA enlargement remained a significant predictor of stroke in men and death in both sexes. The relation of LA enlargement to stroke and death appears to be partially mediated by LV mass.

Key Words: echocardiography • cerebrovascular disorders • heart atrium • hypertrophy • risk factors • mortality

	Introduction

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In the United States, stroke is the third leading cause of death¹ and a leading cause of disability in the elderly. With the aging of the population,² stroke will likely result in an even greater burden of disability and death in the future. Whether left atrial enlargement promotes stroke remains controversial. Disagreement about the importance of left atrial enlargement first emerged regarding patients with mitral valve disease^{3 4 5 6 7 8 9 10} and has continued in the nonrheumatic atrial fibrillation literature.^{11 12 13 14 15 16 17 18 19 20 21 22 23} The impact of left atrial dilation on the risk of stroke and death in the general population has not been explored previously.

The introduction of echocardiography into the Framingham Heart Study in 1979 provided an opportunity to investigate noninvasively the contribution of alterations of cardiac structure to the risk of stroke and death. Echocardiographic examination may aid in the identification of subjects at increased risk for stroke and death and may provide insights into the pathogenesis of stroke. The purpose of this investigation was to evaluate the contribution of left atrial size to risk of stroke and death in a longitudinal, population-based cohort of subjects.

	Methods

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The Framingham Heart Study was initiated in 1948 to prospectively investigate risk factors for cardiovascular disease. A sample of 5209 residents of Framingham, Mass, was enrolled in the study and subsequently has received biennial examinations. The children (and their spouses) of the original cohort were recruited in the early 1970s and were examined 8, 12, and 16 years after their initial examinations. Previous reports detailed the study design.^{24 25} At each examination, a medical history, physical examination, and 12-lead ECG were routinely performed. Echocardiography became available at the Framingham Study at the 16th original cohort and second offspring examinations (1979 through 1983), the index examinations. At the index examinations, 3645 subjects 50 years of age and older were alive and attended the examinations; echocardiography was routinely performed on 3581 subjects. Subjects were excluded from analysis if they had prior stroke (n=91), mitral valve prosthesis, or mitral stenosis (by echocardiogram or physical examination, n=27) at or before the index examination; subjects also were excluded if they were lost to follow-up in the subsequent 8 years (n=50).

Two-dimensional guided M-mode echocardiograms were performed with subjects in the left lateral decubitus position from a parasternal window with a Hoffrel 201 ultrasound machine, an Aerotech 2.25-MHz transducer, and a Jason thermographic printer. M-mode measurements were made from paper strip charts by use of the American Society of Echocardiography leading-edge-to-leading-edge convention²⁶ at the time of the index examinations. Left atrial dimension was measured at end systole. Standardized assessment of mitral annular calcification was available on the original cohort subjects only; it was considered present if an echo-dense band behind the mitral valve leaflet was visualized throughout the cardiac cycle.²⁷ Left ventricular mass in grams was calculated with the Penn formula: {1.04[(LVID+VST+PWT)³-(LVID)³]}-13.6, where LVID is the left ventricular internal diameter, VST is the ventricular septal thickness, and PWT is the posterior wall thickness, corrected for height in meters.²⁸

Clinical parameters entered into the multivariable models were obtained from the index examinations unless otherwise specified. Hypertension was considered present if systolic pressure was 160 mm Hg or diastolic pressure was 95 mm Hg on each of two successive readings obtained by the clinic physician or if the subject was receiving antihypertensive medication. Diabetes was defined as a nonfasting blood glucose level of 11.11 mmol/L (200 mg/dL) or the use of insulin or an oral hypoglycemic agent. Cigarette smoking was ascertained at the 15th examination of the original cohort and the index offspring examination. Prevalent atrial fibrillation was diagnosed if transient or chronic atrial fibrillation or atrial flutter was documented at any examination up to and including the index examination or from any prior hospital or outside physician records. Interim atrial fibrillation was diagnosed if it was documented in the interval between the index examination and the occurrence of stroke. If atrial fibrillation was initially found by ECG on hospitalization for stroke, the rhythm was considered interim atrial fibrillation. ECG left ventricular hypertrophy was diagnosed when a subject had voltage criteria for left ventricular hypertrophy with lateral repolarization changes.²⁹ Prevalent congestive heart failure and myocardial infarction were determined by a panel of three physicians using previously published criteria.^{30 31}

Stroke events were detected by three means: review of interim Framingham Heart Study examinations, surveillance of all admissions to the local hospital, and scrutiny of outside hospital records. If stroke was suspected, the subject was referred to the Framingham Heart Study for a neurologist-administered, detailed examination. The diagnosis of a cerebrovascular event was made by a panel of three investigators (including a neurologist) after they reviewed all records from relevant hospitalizations and clinic visits. Stroke events were categorized with previously published criteria as atherothrombotic brain infarction, cerebral embolus, intraparenchymal hemorrhage, or subarachnoid hemorrhage.^{30 31}

Statistical Analyses
All analyses were age-adjusted because age is related to left atrial size, stroke, and death. For descriptive purposes, the data were analyzed according to tertiles of left atrial size. The analysis of tertiles divided the subjects into sex-specific thirds based on the distribution of left atrial size observed in the sample. The tertiles were slightly uneven because left atrial dimension was measured to the nearest millimeter. Logistic regression was used to calculate the age-adjusted prevalence of the dichotomous clinical risk factors within sex-specific tertiles of left atrial size and to test for trend across the tertiles of left atrial size. Linear regression was used to calculate the age-adjusted mean left ventricular mass/height for each tertile. The cumulative incidences of stroke and death were computed by the Kaplan-Meier³² technique and age-adjusted by the direct method. The sex-specific 8-year incidences of stroke and death for each tertile of left atrial size were computed and age-adjusted by the direct method. For the principal analyses, Cox³³ proportional-hazards models were used to explore the association of left atrial size with outcomes in sex-specific multivariable models, controlling for other known clinical risk factors for stroke and death (age, hypertension, diabetes, smoking, atrial fibrillation, ECG left ventricular hypertrophy, and myocardial infarction or congestive heart failure). Results from these regressions were expressed as relative risks with 95% CI per 10-mm increments of left atrial size. Analyses were performed with the SAS program.³⁴

	Results

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Characteristics of the Subjects
Of the 3413 eligible subjects, 314 (9.2%) were excluded because they had M-mode echocardiograms technically inadequate for measuring left atrial size, leaving 1371 men and 1728 women available for analysis. A sex-specific, age-adjusted comparison of subjects with and without measurable left atrial size disclosed no significant differences in the rates of stroke and death. The average age of the study population at the index examination of 63±9 years for men and 65±9 years for women (range, 50 to 90 years, both sexes). The mean left atrial size was 41±5 mm in men and 38±5 mm in women. The sample was divided into approximate sex-specific tertiles of left atrial size (Table 1). Table 1 also lists the sex-specific, age-adjusted characteristics of the sample by tertile of left atrial size. In both sexes, increasing left atrial size was associated with increasing age and echocardiographic left ventricular mass and a higher prevalence of hypertension, atrial fibrillation, congestive heart failure or myocardial infarction, and mitral annular calcification; cigarette smoking was less common as left atrial size increased. In women, diabetes was also more common with increasing left atrial size.

View this table: [in this window] [in a new window]   Table 1. Population Characteristics by Tertile of Left Atrial Size

Stroke
During 8 years of follow-up, 64 men (4.7%) and 73 women (4.2%) had strokes. Fig 1 displays the 8-year, age-adjusted cumulative incidence of stroke by tertile of left atrial size. Table 2 delineates the distribution of stroke events by tertile of left atrial size. Men in the lowest and highest tertiles of left atrial size had age-adjusted stroke rates of 3.1 and 9.4 per 1000 person-years, respectively. Corresponding rates in women were 3.0 and 5.9 strokes per 1000 person-years.

View larger version (13K): [in this window] [in a new window]   Figure 1. Line graphs showing age-adjusted cumulative incidence of stroke by tertile of left atrial (LA) size in men and women. Vertical axis gives the percent with strokes during follow-up; horizontal axis, years of follow-up. The figure gives the number of subjects at risk at every 2 years of follow-up.

View this table: [in this window] [in a new window]   Table 2. Strokes and Death by Tertile of Left Atrial Size in 8 Years of Follow-up

Table 3 gives the results of age-adjusted and multivariable analyses. For every 10-mm increment in left atrial size, the age-adjusted relative risk of stroke was 2.2 in men and 2.0 in women. After adjustment for traditional stroke risk factors (age, hypertension, diabetes, smoking, ECG left ventricular hypertrophy, prevalent atrial fibrillation, and prevalent congestive heart failure or myocardial infarction), the relative risk of stroke in men was 2.4 (95% CI, 1.6 to 3.7), whereas the risk of stroke was 1.4 in women (95% CI, 0.9 to 2.1). The variables most responsible for diminishing the relative risk of stroke in women from 2.0 in the age-adjusted model to 1.4 per 10 mm of left atrial size in the multivariable model were prevalent atrial fibrillation and prevalent congestive heart failure or myocardial infarction.

View this table: [in this window] [in a new window]   Table 3. Multivariable Models Examining the Relation Between Left Atrial Size and Stroke

Additional analyses were performed to clarify whether the stroke–left atrial size relation was restricted to particular subsets of subjects or altered by other stroke risk factors (Table 3). The risk associated with increasing left atrial size was not restricted to subjects with atrial fibrillation at baseline; eliminating subjects with prevalent atrial fibrillation did not alter the left atrial size–stroke relation. Adjusting for atrial fibrillation at any time before stroke (ie, both prevalent and interim atrial fibrillation) modestly diminished the stroke–left atrial size relation in both sexes, but left atrial size remained predictive of stroke in men (relative risk of stroke was 2.0 in men and 1.2 in women per 10-mm increment in left atrial size).

Mitral annular calcification assessment was available only in the original cohort subjects. After adjustment for mitral annular calcification²⁷ and the traditional stroke risk factors listed above, the stroke–left atrial size relation remained essentially unaltered (Table 3). To explore whether the deleterious impact of left atrial enlargement was limited to subjects with structural heart disease, the data were reanalyzed. After exclusion of subjects with congestive heart failure or myocardial infarction at baseline,³⁵ the relative risk of stroke per 10-mm increment in left atrial size was 2.8 in men and 1.6 in women. Finally, we examined whether left ventricular mass contributed to the risk of stroke with left atrial dilation. After adjustment for left ventricular mass/height, the multivariable relative risk of stroke was 1.8 in men and 0.9 in women per 10-mm increment in left atrial size (Table 3).

Death
During 8 years of follow-up, 296 (21.6%) men and 271 (15.7%) women died. Fig 2 shows the age-adjusted cumulative incidence of death by tertile of left atrial size. As opposed to the relation of left atrial size to stroke, which was graded across the tertiles, the excess risk for mortality appeared to reside largely in the highest tertile of left atrial size. It should be noted, however, that the narrow range of left atrial size in the second tertile (4 mm in both sexes) may have accounted for the lack of difference in mortality compared with the first tertile. The age-adjusted death rates for men in the lowest and highest tertiles of left atrial size were 23.3 and 30.8 per 1000 person-years, respectively. The corresponding death rates for women were 13.9 and 22.7 per 1000 person-years, respectively (Table 2). The age-adjusted relative risk of death for every 10-mm increment in left atrial size was 1.3 in men and 1.7 in women (Table 4). In the multivariable model adjusted for clinical risk factors (Table 4), left atrial size remained a significant predictor of death in both sexes, with a relative risk of 1.3 in men (95% CI, 1.0 to 1.5) and 1.4 in women (95% CI, 1.1 to 1.7) per 10-mm increment in left atrial size. When subjects with myocardial infarction or congestive heart failure at baseline were eliminated, left atrial size remained a significant predictor of death in men, with a relative risk of 1.4, and was marginally predictive of death in women, with a relative risk of 1.3. Adjusting for left ventricular mass/height diminished the left atrial size–mortality relation in the multivariable model (Table 4); the relative risk of death was 1.2 per 10-mm increment of left atrial size in both sexes.

View larger version (11K): [in this window] [in a new window]   Figure 2. Line graphs showing age-adjusted cumulative death rate by tertile of left atrial (LA) size in men and women. Vertical axis gives the percent with subjects dead during follow-up; horizontal axis, years of follow-up. The figure gives the number of subjects at risk at every 2 years of follow-up.

View this table: [in this window] [in a new window]   Table 4. Multivariable Models Examining Relation Between Left Atrial Size and Death

	Discussion

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In this population-based cohort, left atrial size was significantly associated with the age-adjusted risk for stroke and for death in both sexes. Left atrial size was associated with many risk factors for stroke and death, however, underscoring the need for multivariable analyses. After adjustment for age, hypertension, diabetes, smoking, ECG left ventricular hypertrophy, prevalent atrial fibrillation, and prevalent congestive heart failure or myocardial infarction, left atrial size remained a significant predictor of stroke in men (relative risk, 2.4 per 10-mm increment) and death in both sexes (relative risk, 1.3 in men and 1.4 in women).

Mechanisms of Risk
The mechanisms of the increased risk of stroke and death in subjects with left atrial enlargement are incompletely understood. Left atrial dilation promotes stasis of blood, which in turn predisposes to thrombus formation and the potential for embolization. The thrombogenicity of left atrial dilation is supported by transesophageal echocardiography studies that found that left atrial dilation was associated with spontaneous echocardiographic contrast, left atrial thrombus, and embolic events.^{36 37 38} It seems less likely that left atrial size predisposed to nonstroke death in a causal fashion.

Another possible mechanism is that left atrial dilation may serve as a marker for other risk factors for stroke and death such as atrial fibrillation, structural heart disease, hypertension, or increased left ventricular mass. Left atrial enlargement may function as an indicator for more severe cases of congestive heart failure or myocardial infarction. Nevertheless, it is noteworthy that the relation between left atrial enlargement and stroke and death persisted when subjects with congestive heart failure or myocardial infarction were excluded. In addition, left atrial enlargement is a powerful echocardiographic predictor of nonrheumatic atrial fibrillation risk³⁹ ; in turn, atrial fibrillation is a leading stroke risk factor⁴⁰ and is associated with a doubling of all-cause mortality.⁴¹ Eliminating subjects with prevalent atrial fibrillation at baseline, however, had little impact on the relation of left atrial size to stroke. The possibility remains that left atrial enlargement promoted the development of interim atrial fibrillation, which in turn predisposed to stroke. In the multivariable model adjusted for atrial fibrillation at anytime before stroke, the risk of stroke continued to double for every 10-mm increment in left atrial size in men. In women, in contrast, adjusting for atrial fibrillation at anytime before stroke further diminished the stroke–left atrial size relation, suggesting that the relation in women may be mediated in part by atrial fibrillation.

Left atrial enlargement and left ventricular hypertrophy are both manifestations of cardiac target organ damage in established hypertension.^{42 43 44} Left atrial enlargement also is significantly related to left ventricular mass.⁴⁴ Other Framingham Heart Study analyses have found that increased left ventricular mass predicts stroke⁴⁵ and death.⁴⁶ After adjustment for left ventricular mass and other stroke risk factors, the left atrial size–stroke relation remained marginally significant in men (P=.05), suggesting that the association is not totally accounted for by blood pressure and left ventricular mass. In contrast, adjusting for left ventricular mass eliminated the relation between left atrial size and stroke in women and attenuated the relation with death in both sexes, partially because left atrial size and left ventricular mass are collinear. Of note, the inclusion of left ventricular mass in the model diminished the number of subjects by 22% and the number of stroke and death end points by 33% and 36%, respectively. Even if left atrial size is merely a biological marker for hypertensive heart disease, given the greater difficulty of measuring left ventricular mass, left atrial size may serve as a useful clinical predictor. Finally, left atrial enlargement may serve as a surrogate for other unidentified risk factors for stroke and death.

Comparison With Previous Studies
Despite extensive literature, it remains uncertain whether^{3 4 8 9 11 12 13 14 15 16} or not^{5 6 7 10 17 18 19 20 21 22 23} left atrial enlargement is a risk factor for stroke. Most studies were restricted to subjects with mitral valve disease^{3 4 5 6 7 8 9 10} or atrial fibrillation.^{11 12 13 14 15 16 17 18 19 20 21 22 23} Subjects with mitral stenosis or prosthesis were excluded from the current study because we lacked sufficient power to explore the stroke–left atrial enlargement relation in this subset of subjects. The most thorough studies to examine the left atrial size–stroke relation were the randomized trials of anticoagulation in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Study supported an association between stroke and left atrial enlargement,¹⁶ while the other two cohort trials to examine the issue rejected such a relation.^{22 23} Many of the studies in subjects with atrial fibrillation were hampered by small sample size or small numbers of stroke,^{11 12 13 14 18 19 20 21 22} nonroutine or referral ascertainment of echocardiograms,^{11 15 17 18 20 21} and echocardiographic interpretations in which the patient's stroke status was not explicitly stated to be blinded to the readers.^{11 12 13 14 17 18 20 21} Furthermore, the majority of prior studies used a case-control design^{11 12 13 14 17 18 19 20} and retrospective or cross-sectional analyses.^{11 12 13 14 17 18 19 20 21} The majority of studies performed only univariate^{11 14 18 19 20 22} or partial multivariable analyses and failed to control for several important potential confounders.^{12 13 15 17 21} Finally, to the best of our knowledge, prior studies did not analyze men and women separately, did not examine subjects without atrial fibrillation or mitral valve disease, and did not investigate the relation of left atrial size to death.

Strengths and Limitations
The potential for bias was minimized by routine ascertainment of echocardiograms, which were read blinded to subject characteristics, and by the longitudinal population-based cohort design. In addition, the relatively large sample size and routine collection of antecedent risk factor information provided the opportunity to perform sex-specific and multivariable analyses. Additional study is required to determine whether the relation between left atrial size and death is continuous or whether there is a threshold of left atrial dilation above which excess mortality is observed. Further investigation is also necessary to determine whether the results are generalizable to other races or ages because the current sample was white and 50 years of age or older.

The echocardiographic examination was limited to M-mode technology, which may have resulted in some misclassification of left atrial size.⁴⁷ In addition, we and other investigators⁴⁸ have noted that subtypes of ischemic stroke are subject to misclassification because of clinical difficulties in distinguishing between atherothrombotic and cardioembolic stroke. Finally, the study lacked sufficient power to analyze the relation of left atrial size to specific stroke subtypes.

Clinical Implications
The current study demonstrated that left atrial size was significantly related to the risk of stroke in men and death in both sexes; this association was attenuated by adjustment for echocardiographic left ventricular mass. The mechanisms of the increased risk are not fully understood and may be multifactorial. However, our analyses suggest that left ventricular mass partially mediates the excess risk of stroke and death in the setting of left atrial dilation. Strategies for the prevention of stroke and death in the setting of left atrial enlargement remain to be determined. Nevertheless, echocardiographic left atrial enlargement has prognostic value in identifying a subset of persons at increased risk for stroke and death.

	Acknowledgments

 
The Framingham Study is supported in part through NIH/NHLBI contract NO1-HC-38038 and by NINDS grant 2-R01-NS-17950-11. We would like to thank David M. Pollak for editorial assistance; Jonathan Plehn, MD, for contributions to the preliminary analyses; Martin Larson, ScD, for assistance in analyzing the prior literature and reviewing the manuscript; and Sonya Vaziri, MD, for insights into the determinants of left atrial size.

Received December 12, 1994; revision received January 30, 1995; accepted February 10, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. American Heart Association. Heart and Stroke Facts Statistics: 1995 Statistical Supplement. Dallas, Tex: American Heart Association; 1994.
   
2. Schneider EL, Guralnik JM. The aging of America: impact on health care costs. JAMA. 1990;263:2335-2340. [Abstract]
   
3. Somerville W, Chambers RJ. Systemic embolism in mitral stenosis: relation to the size of the left atrial appendix. Br Med J. 1964;2:1167-1171.
   
4. Sherrid MV, Clark RD, Cohn K. Echocardiographic analysis of left atrial size before and after operation in mitral valve disease. Am J Cardiol. 1979;43:171-178. [Medline] [Order article via Infotrieve]
   
5. Casella L, Abelmann WH, Ellis LB. Patients with mitral stenosis and systemic emboli. Arch Intern Med. 1964;114:773-781.
   
6. Coulshed N, Epstein EJ, McKendrick CS, Galloway RW, Walker E. Systemic embolism in mitral valve disease. Br Heart J. 1970;32:26-34. [Free Full Text]
   
7. Fleming HA, Bailey SM. Mitral valve disease, systemic embolism and anticoagulants. Postgrad Med J. 1971;47:599-604. [Medline] [Order article via Infotrieve]
   
8. Nielson GH, Galea EG, Hossack KF. Thromboembolic complications of mitral valve disease. Aust N Z J Med. 1978;8:372-376. [Medline] [Order article via Infotrieve]
   
9. Dewar HA, Weightman D. A study of embolism in mitral valve disease and atrial fibrillation. Br Heart J. 1983;49:133-140. [Abstract/Free Full Text]
   
10. Burchfiel CM, Hammermeister KE, Krause-Steinrauf H, Sethi GK, Henderson WG, Crawford MH, Wong M, for the participants in the Department of Veterans Affairs Cooperative Study on Valvular Heart Disease. Left atrial dimension and risk of systemic embolism in patients with a prosthetic heart valve. J Am Coll Cardiol. 1990;15:32-41. [Abstract]
    
11. Caplan LR, D'Cruz I, Hier DB, Reddy H, Shah S. Atrial size, atrial fibrillation and stroke. Ann Neurol. 1986;19:158-161. [Medline] [Order article via Infotrieve]
    
12. Aronow WS, Gutstein H, Hsieh FY. Risk factors for thromboembolic stroke in elderly patients with chronic atrial fibrillation.Am J Cardiol. 1989;63:366-367. [Medline] [Order article via Infotrieve]
    
13. Corbalán R, Arriagada D, Braun S, Tapia J, Huete I, Kramer A, Chávez A. Risk factors for systemic embolism in patients with paroxysmal atrial fibrillation. Am Heart J. 1992;124:149-153. [Medline] [Order article via Infotrieve]
    
14. Seneviratne BI, Reimers J. Nonvalvular atrial fibrillation associated with cardioembolic stroke: the role of hypertensive heart disease. Aust N Z J Med. 1990;20:127-134. [Medline] [Order article via Infotrieve]
    
15. Cabin HS, Clubb S, Hall C, Perlmutter RA, Feinstein AR. Risk for systemic embolization of atrial fibrillation without mitral stenosis. Am J Cardiol. 1990;65:1112-1116. [Medline] [Order article via Infotrieve]
    
16. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation, II: echocardiographic features of patients at risk. Ann Intern Med. 1992;116:6-12.
    
17. Moulton AW, Singer DE, Haas JS. Risk factors for stroke in patients with nonrheumatic atrial fibrillation: a case-control study. Am J Med. 1991;91:156-160. [Medline] [Order article via Infotrieve]
    
18. Wiener I, Hafner R, Nicolai M, Lyons H. Clinical and echocardiographic correlates of systemic embolization in nonrheumatic atrial fibrillation. Am J Cardiol. 1987;59:177. [Medline] [Order article via Infotrieve]
    
19. Petersen P, Pedersen F, Madsen EB, Brun B, Glyldensted, Boysen G. Echocardiography and cerebral computed tomography in chronic atrial fibrillation. Eur Heart J. 1989;10:1101-1104. [Abstract/Free Full Text]
    
20. D'Olhaberriague L, Hernández-Vidal A, Molina L, Soler-Singla L, Marrugat J, Pons S, Moral A, Pou-Serradell A. A prospective study of atrial fibrillation and stroke. Stroke. 1989;20:1648-1652. [Abstract/Free Full Text]
    
21. Flegel KM, Hanley J. Risk factors for stroke and other embolic events in patients with nonrheumatic atrial fibrillation. Stroke. 1989;20:1000-1004. [Abstract/Free Full Text]
    
22. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med. 1990;323:1505-1511. [Abstract]
    
23. Petersen P, Kastrup J, Helweg-Larsen S, Boysen G, Godtfredsen J. Risk factors for thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Arch Intern Med. 1990;150:819-821. [Abstract]
    
24. Dawber TR, Kannel WB, Lyell LP. An approach to longitudinal studies in a community: the Framingham Study. Ann N Y Acad Sci. 1963;107:539-556.
    
25. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families: the Framingham Offspring Study. Am J Epidemiol. 1979;110:281-290. [Abstract/Free Full Text]
    
26. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58:1072-1083. [Abstract/Free Full Text]
    
27. Benjamin EJ, Plehn JF, D'Agostino RB, Belanger AJ, Comai K, Fuller DL, Wolf PA, Levy D. Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J Med. 1992;327:374-379. [Abstract]
    
28. Levy D, Savage DD, Garrison RJ, Anderson KM, Kannel WB, Castelli WP. Echocardiographic criteria for left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol. 1986;59:956-960.
    
29. Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram: prevalence, incidence, and mortality in the Framingham Study. Ann Intern Med. 1969;71:89-105.
    
30. Shurtleff D. Some characteristics related to the incidence of cardiovascular disease and death: Framingham Study, 18-year follow-up. In: Kannel WB, Gordon T, eds. The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Washington, DC: Government Printing Office; 1974. DHEW publication NIH 74-599, section 30.
    
31. Cupples LA, D'Agostino RB. Survival following initial cardiovascular events: 30 year follow-up. In: Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Bethesda, Md: NHLBI, NIH; 1988. NIH publication 88-204029, section 35.
    
32. Kaplan E, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481.
    
33. Cox DR. Regressions models and life tables. J R Stat Soc. 1972;34(series B):187-220.
    
34. SAS Institute Inc. SAS/STAT User's Guide, Version 6. 4th ed. Cary, NC: SAS Institute Inc; 1989.
    
35. Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to stroke: the Framingham Study. JAMA. 1983;250:2942-2946. [Abstract]
    
36. Lee RJ, Bartzokis T, Yeoh TK, Grogin HR, Choi D, Schnittger I. Enhanced detection of intracardiac sources of emboli by transesophageal echocardiography. Stroke. 1991;22:734-739. [Abstract/Free Full Text]
    
37. Daniel WG, Nellessen U, Schröder E, Nonnast-Daniel B, Bednarski P, Nikutta P, Lichtlen PR. Left atrial spontaneous echo contrast in mitral valve disease: an indicator for an increased thromboembolic risk. J Am Coll Cardiol. 1988;11:1204-1211. [Abstract]
    
38. Cujec B, Polasek P, Voll C, Shuaib A. Transesophageal echocardiography in the detection of potential cardiac source of embolism in stroke patients. Stroke. 1991;22:727-733. [Abstract/Free Full Text]
    
39. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation: the Framingham Heart Study. Circulation. 1994;89:724-730. [Abstract/Free Full Text]
    
40. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-988. [Abstract/Free Full Text]
    
41. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation: the Framingham Study. N Engl J Med. 1982;306:1018-1022. [Abstract]
    
42. Miller JT, O'Rourke RA, Crawford MH. Left atrial enlargement: an early sign of hypertensive heart disease. Am Heart J. 1988;116:1048-1051. [Medline] [Order article via Infotrieve]
    
43. Frolich ED, Apstein C, Chobanian AV, Devereux RB, Dustan HP, Dzau V, Faud-Tarazi F, Horan MJ, Marcus M, Massie B, Pfeffer MA, Re RN, Roccella EJ, Savage D, Shub C. The heart in hypertension. N Engl J Med. 1992;327:998-1008. [Medline] [Order article via Infotrieve]
    
44. Vaziri SM, Lauer MS, Larson MG, Benjamin EJ, Levy D. The influence of systolic blood pressure on left atrial size. Hypertension. 1995;26.
    
45. Bikkina M, Levy D, Evans JC, Larson MG, Benjamin EJ, Wolf PA, Levy D, Castelli WP. Left ventricular mass and risk of stroke in an elderly cohort: the Framingham Heart Study. JAMA. 1994;272:33-36. [Abstract]
    
46. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322:1561-1566. [Abstract]
    
47. Feigenbaum H. Echocardiography. 5th ed. Philadelphia, Pa: Lea & Febiger; 1994:167.
    
48. Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR, Wolf PA. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol. 1989;25:382-390.[Medline] [Order article via Infotrieve]
    

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