(Circulation. 1995;92:2178-2182.)
© 1995 American Heart Association, Inc.
Articles |
Silent Cerebral Infarction in Patients With Nonrheumatic Atrial Fibrillation
From the VA Medical Center, West Haven, Conn, and Department of Medicine, Yale University (M.D.E.); the VA Medical Center, Portland, Ore, and Department of Public Health and Preventive Medicine, Oregon Health Sciences University (K.E.J.); the VA Medical Center, Little Rock, Ark, and Department of Neurology, University of Arkansas (S.M.N.); the VA Medical Center, Minneapolis, Minn, and Department of Neurology, University of Minnesota (J.D.); the Department of Neurology, University of Cincinnati, Cincinnati, Ohio (J.P.B.); the VA Medical Center, Hines, Ill, and Department of Neurology, Loyola University (S.R.G.); the Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH (V.T.); Yale University, New Haven, Conn (M.L.M.); and Yale–New Haven Medical Center, New Haven, Conn (S.L.B.).
Correspondence to Kenneth E. James, PhD, Health Services Research and Development (152), VA Medical Center, 3710 SW US Veterans Hospital Rd, Portland, OR 97201. E-mail james@hsrd.gov
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion Appendix References |
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Background Cerebral infarction in patients with atrial fibrillation may vary from being clinically silent to catastrophic. The prevalence of silent cerebral infarction and its effect as a risk factor for symptomatic stroke are important considerations for the evaluation of patients with atrial fibrillation.
Methods and Results This Veterans Affairs cooperative study was a double-blind controlled trial designed primarily to determine the efficacy of warfarin for the prevention of stroke in neurologically normal patients with nonrheumatic atrial fibrillation. It also was designed to evaluate patients with silent cerebral infarction. Computed tomography scans of the head were performed at entry, at the time of any subsequent stroke, and at termination of follow-up on all patients who completed the study without a neurological event. Of 516 evaluable scans performed at entry, 76 (14.7%) had evidence of one or more silent cerebral infarcts. Age (P=.011), a history of hypertension (P=.003), active angina (P=.012), and elevated mean systolic blood pressure (P<.001) were associated with the presence of this finding. Silent cerebral infarction occurred during the study at rates of 1.01% and 1.57% per year for the placebo and warfarin treatment groups, respectively (NS). Silent cerebral infarction at entry was not an independent predictor of later symptomatic stroke, but active angina was a significant predictor; 15% of the placebo-assigned patients with angina developed a stroke compared with 5% of the placebo-assigned patients without angina.
Conclusions Silent cerebral infarction is frequently seen in asymptomatic patients with atrial fibrillation. Age, history of hypertension, active angina, and elevated mean systolic blood pressure were associated with silent infarction at entry. The sample size was too small to determine whether warfarin had an effect on the incidence of silent infarction during the trial. Active angina at baseline was the only significant independent predictor for the later development of symptomatic stroke.
Key Words: cerebral infarction • atrial fibrillation • tomography
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Introduction |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Since the advent of brain imaging with computed tomography (CT), it has been recognized that lesions typical of cerebral infarction appear in patients who have no history or other clinical evidence of stroke. Silent cerebral infarcts have been found in a variety of clinical contexts including patients with asymptomatic carotid stenosis,1 atrial fibrillation,2 3 4 5 6 7 8 and symptomatic cerebrovascular disease.5 6 7 9 Although ubiquitous, their reported prevalence is variable, their pathogenesis is uncertain, and their clinical significance has not been defined. Several studies involving small numbers of patients, which included three studies in asymptomatic populations,2 3 4 have addressed the relationship of atrial fibrillation to silent cerebral infarction. These studies evaluated patients at a particular point in time but did not follow the asymptomatic events longitudinally. The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF) study provided a unique opportunity to prospectively evaluate silent cerebral infarction in patients with atrial fibrillation.10 The SPINAF study was a prospective, randomized, double-blind, placebo-controlled trial designed primarily to evaluate low-dose warfarin therapy for the prevention of stroke in patients without prior clinical stroke. The protocol included the acquisition of noncontrast CT scans of the head of all patients at entry into the study, at the time of any suspected stroke, and on completion of the study. Thus, it was possible to determine the prevalence of silent cerebral infarction in neurologically normal patients with atrial fibrillation, to identify the risk factors associated with silent infarction, to evaluate the effect of warfarin therapy, and to assess the relationship of silent infarction to the later development of clinically apparent stroke during the course of the study.
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Methods |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Design of the SPINAF Study
The SPINAF study was conducted in 16 Veterans Affairs medical centers. The protocol was approved by the institutional review board at each participating center, and informed consent was obtained from each patient. Men of any age were candidates for the study if they had atrial fibrillation documented by two ECGs at least 4 weeks apart and had no echocardiographic evidence of rheumatic heart disease. Baseline prothrombin times had to be within the normal range. For this report we evaluated only patients free of previous stroke or a transient ischemic attack within the 5 years before entry into the study. The neurological examination taken at entry had to be normal with no focal deficit. The examination was performed by a board-certified or board-eligible neurologist and included evaluation of the retina. All subsequent examinations were performed at scheduled intervals and at study end points by the same neurologist, using the same data format. Nonstandard cerebral investigations, such as neuropsychological testing, was not performed.
Patients were randomly assigned to receive warfarin or placebo. The goal of warfarin therapy was the maintenance of the patient's prothrombin time ratio within the range of 1.2 to 1.5, corresponding to an International Normalized Ratio of approximately 1.4 to 2.8. All patients were followed for 3 years or until termination of the study. Patients who had a stroke during the study were followed for survival.
The primary end point of the SPINAF study was clinically evident cerebral infarction, defined as a new neurological deficit not attributable to dysfunction of a single cranial nerve, the spinal cord, or the peripheral nervous system. The deficit or some portion thereof had to persist for longer than 12 hours. The first cranial CT scan obtained after onset of the deficit had to have no evidence of intracerebral hemorrhage or tumor.
CT Scan Acquisition and Analysis
Noncontrast CT scans were
obtained from patients at entry to and
termination from the study. A scan was also performed when a patient
had a stroke. All available scans were evaluated after the conclusion
of the study by a committee of six neurologists. Each scan was read by
two neurologists who had no knowledge of the physical condition or
clinical course of the patient, and their consensus interpretation was
recorded. Reading pairs were rotated after every 50 scans to
minimize bias. When a consensus was not reached by the two primary
readers, the scan in question was reviewed and classified by the entire
six-member committee.
Silent cerebral infarction was defined as a defect on the CT scan consistent with a cerebral infarct in a neurologically normal patient. Silent cerebral infarcts were divided into large and small; superficial and deep; and into three vascular territories: anterior (anterior and middle cerebral, and anterior choroidal arteries), posterior (posterior cerebral artery and other branches of the vertebrobasilar system), and watershed (in the border zone vascular distributions between the anterior-middle and middle-posterior cerebral arteries). Assignment of vascular territories was based on previously published CT templates.11 Lucencies of 4.2 cm3 (corresponding to the volume of a sphere of 2.0 cm in diameter) or greater were considered to be large infarcts. This choice was based on the commonly accepted upper limit of diameter for lacunar infarcts, as formulated by Fisher.12 Deep infarcts were defined as involving central cerebral white and gray matter; superficial infarcts as involving cortical and/or adjacent subcortical areas. Enlarged cortical sulci alone were not interpreted as infarcts.
The size of an infarct was estimated from the maximal lesion dimension in centimeters (x axis) times the axis perpendicular to the x axis (y axis) times the number of 1-cm slices (n) in which the infarct appeared. The volume was calculated by the formula
 | (1) |
which is based on the formula for the volume of an ellipsoid of principal diameters a, b, and c:
 | (2) |
Carotid Ultrasound
Carotid duplex ultrasound studies were
performed on patients
entering the SPINAF trial at 12 of the 16 hospitals. The local hospital
interpretations of these studies were used in this analysis.
Ultrasound equipment and technical procedures were not standardized and
interpretations were not reviewed centrally.
Data Analysis
The data were analyzed by the Veterans Affairs
Cooperative Studies Program Coordinating Center in Palo Alto, Calif.
All analyses were performed on an intent-to-treat
basis. Baseline characteristics of patients with and without silent
cerebral infarction were compared with use of the Student's
t test for continuous variables and
2 for noncontinuous variables.
Ninety-five percent confidence intervals were calculated for
relative risk of silent cerebral infarction using the Taylor series
approximation for the variance of the risk ratio.13
Multivariate logistic regression14 was
used to assess the effect of silent cerebral infarction at entry on the
later occurrence of symptomatic cerebral infarction in the
presence of baseline age, systolic blood pressure, history of
hypertension, history of diabetes, and angina. Entry scans, used to
measure the prevalence of silent cerebral infarction, were excluded
from analysis if acquired more than 30 days after
randomization. Termination scans, for assessing the incidence of silent
cerebral infarction, were excluded if they were obtained more than 90
days after termination or if the matching entry scans were acquired
more than 90 days before randomization.
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Results |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Prevalence of Silent Infarction
A total of 525 patients without previous stroke participated in the SPINAF study (Table 1
). Of these, 6 patients had
missing initial scans and 3 patients had scans not meeting the window
criteria, giving 516 evaluable patients. Among the scans from these 516
patients, 76 (14.7%) had evidence of one or more silent cerebral
infarcts at entry to the study. Fifty-nine scans (78%) had a
single infarct. Of the remaining 17 scans, 12 had 2 infarcts, 3 scans
had 3 infarcts, and 2 scans had 4 infarcts, giving a total of 100
infarcts.
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Location, Size, and Distribution of Silent Infarcts
The
majority, 46 of the 76 abnormal entry scans, had silent
cerebral infarcts that were both small and deeply located, while 40 of
the 76 scans had large or superficial lesions consistent with
an embolic etiology (Table 2). Note that both of these
groups include scans from 10 patients who had multiple lesions that
were both small and deep as well as large and superficial. Among the
patients who suffered a symptomatic stroke during the
course of the study, 7 of the 9 poststroke scans with visible lesions
showed large, superficial lesions ranging from 6 to 141
cm3.
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Most of the 100 silent infarcts (n=70) from the 76 patients (scans) were in the territory of the middle cerebral artery; 14 were in the cerebral watershed areas, and 11 were in the posterior cerebral artery territory. Four were in the cerebellum, and only one was in the anterior cerebral artery territory.
Risk Factors for Silent Cerebral Infarction at Entry
A
univariate comparison of the baseline
characteristics for patients with and without silent cerebral
infarction at entry was performed (Table 3). Age
(P=.011), a history of hypertension (P=.003),
active angina (P=.012), and elevated systolic blood
pressure (P<.001) were associated with silent cerebral
infarction. The remainder of the characteristics in Table 3
were not
significantly associated with silent infarction.
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Carotid Doppler Studies
Among the 516 patients with
analyzable scans, 323 patients also
had carotid duplex ultrasound studies performed at entry. Two hundred
eighty of these had normal CT scans, with 10 (4%) having
stenosis of the internal carotid artery measuring greater than
75%. Two (5%) of the 43 patients with silent cerebral infarction had
stenosis of more than 75%. Thus, silent cerebral infarction at
entry did not appear to be associated with the presence of carotid
stenosis.
Incidence of Silent Infarction During the Course of the
Study
Of the 525 patients randomized in SPINAF, 307 had both an
initial
and termination scan available for analysis (Table 1
). There
were 8 new silent cerebral infarcts during the course of the study, 3
in the placebo and 5 in the warfarin treatment groups (1.01% per year
versus 1.57% per year; relative risk, 1.55; 95% confidence interval,
0.40 to 6.11). In five scans, the lesions were small and deep, in two
they were small and superficial, and the lesion in the remaining scan
was small, but its location was not recorded.
Silent Cerebral Infarction as a Risk Factor for Subsequent
Symptomatic Stroke
During the course of the SPINAF study, 23 patients
(19 in the
placebo group and 4 in the warfarin group) had a
symptomatic stroke. Univariate analysis
of the data from the original 525 patients showed that active angina
was associated with the occurrence of symptomatic stroke
(P=.047). A multivariate logistic regression
analysis was performed on the data from the 260 patients with
evaluable scans randomized to placebo using age, systolic blood
pressure, history of hypertension, history of diabetes, active angina,
and silent cerebral infarction as possible predictors of
symptomatic stroke. Active angina was considered as stable
and symptomatic angina present at entry to the study.
Angina was the most significant predictor (P=.017; odds
ratio, 3.34; 95% confidence interval, 1.25 to 8.92). With angina in
the regression model, silent cerebral infarction contributed very
little (P=.472; odds ratio, 1.52; 95% confidence interval,
0.49 to 4.73), as did the other tested variables. Of the 59 placebo
patients with angina, 9 (15.3%) experienced a stroke compared with 10
(5.0%) of the 201 placebo patients without angina
(P=.017).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Silent Cerebral Infarction in Patients With Atrial Fibrillation
The 14.7% prevalence of silent cerebral infarction reported here is the lowest figure found in the literature for asymptomatic patients with atrial fibrillation. In the three other reports of asymptomatic patients with atrial fibrillation, the prevalence ranged from 26% to 48%.2 3 4 This may relate in part to differences in definition of silent cerebral infarction. The definition used in the Copenhagen AFASAK study was broad and probably included patients with cerebral atrophy.2 It is likely that there were differences in the patient populations studied. The Stroke Prevention Atrial Fibrillation (SPAF) study included patients with 6 clinical strokes occurring greater than 2 years before the study.4 Some patients in our study may have had previous mild symptomatic strokes with deficits that had resolved by the time of study entry. A review of the clinical information, however, failed to identify symptoms or signs that might be correlated with the CT lesions.
A limitation of this study is the absence of a comparison group matched for baseline characteristics but lacking atrial fibrillation. Thus, while there is some circumstantial evidence that atrial fibrillation is a factor in the occurrence of silent cerebral infarction, a direct link is not conclusively demonstrated by this study.
We found that 46 of 76 patients with silent cerebral infarction (61%) had lesions that were small and located in the deep hemispheric areas and are typically classified as lacunar infarcts. These data are consistent with the distribution of silent infarcts found in other studies.3 4 5 6 7 9 Two of eight studies of atrial fibrillation have reported a predominance of larger and more superficial lesions.2 8 In our study, 40 of 76 patients had lesions that were either large or superficial, which is commonly associated with a cardioembolic pathophysiology. Note, again, that there were 10 patients who had multiple lesions that were both small and deep as well as larger or more superficial. It is important to recognize that the cause of these silent cerebral lesions remains undetermined and that several stroke mechanisms may be present in a particular patient.
Risk Factors Associated With Silent Cerebral
Infarction
In our study we found that increasing age, history of
hypertension, active angina, and elevated systolic blood
pressure were associated with silent cerebral infarction. Evidence of
heart failure and echocardiographically determined left
atrial size were not associated with increasing risk. The SPAF
study4 reported that enlarged left atrial diameter was a
risk factor for silent cerebral infarction, an observation found in one
other study.9 This latter report also included patients
without atrial fibrillation. The associations we found are similar to
those in two other studies.2 6 Our study is the only
one
to identify active angina as a risk factor for silent cerebral
infarction. Other risk factors reported in single studies, including
diabetes7 and claudication,6 may relate to
differences in the populations investigated.
Development of Silent Cerebral Infarction During the
Study
The low incidence of silent cerebral infarction during this
study
is of substantial interest, since this is the first large prospectively
studied cohort under continuous observation. In the warfarin- and
placebo-treated groups combined, 8 patients had silent infarctions
in 616 patient-years of follow-up, for a mean incidence rate of
1.3% per year. Since patients in our study had regular neurological
interviews and examinations, we expect that the possibility of missing
a symptomatic stroke was minimized and that our figures
accurately reflect the true incidence in a patient population under
close scrutiny. Failure to identify minor strokes is likely to be
higher when patients self-report.
Silent Cerebral Infarction as a Marker of Subsequent
Stroke
From a clinical standpoint, we expected cerebral infarction to
be
a predictor for the occurrence of symptomatic stroke.
Indeed, others have found that patients with atrial fibrillation and a
previous minor stroke are at a higher risk for the development of a
second stroke.15 16 In our study, only active angina
was
predictive of symptomatic stroke. The presence of silent cerebral
infarction did not significantly increase the probability of such an
event. Thus, CT scans appear to be of questionable value in defining a
group of patients who are at higher risk for developing a subsequent
symptomatic event.
Summary
A specific association of silent cerebral infarction
with
diabetes, peripheral vascular disease, and carotid disease
was not observed in this study. Silent cerebral infarction appears to
have no independent benefit as a predictor of symptomatic
stroke in a population of patients with atrial fibrillation. This study
does not support the use of cerebral CT scanning in the evaluation of
neurologically asymptomatic patients with atrial
fibrillation.
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Appendix |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Study Participants
Study Cochairmen: S.L. Bridgers, MD; M.D. Ezekowitz, MD, PhD. Study Biostatistician: K.E. James, PhD. Participating VA Centers: Baltimore: N.H. Carliner, MD; H.S. Panitch, MD; C. Baker, PharmD; G.L. Hershey, RN; M. James; B. Shelton, RN. Boston: E. Ascher, MD; V.L. Babikian, MD; K. Crane-Spier, RN; L. Fiore, MD; A. Koufos; V. Blaustein, MD; H. Kleinman, MD. Cincinnati: L. Wexler, MD; J. Broderick, MD; S. Allmyer, RN; E.E. Lower, MD; T. Brott, MD; T. Herold. Hines: S.R. Gupta, MD; L. Edwards, MD; M. Ryan, RN; N. Bhoopalam, MD; D. McCall. Little Rock: S.M. Nazarian, MD; M.L. Murphy, MD; S. Thomas, RN; A. Mansouri, MD; C. Arnold. Long Beach: A. Alzarka, MD; J. Feuer, MD; J.R. Hyde, MD; S. Forbes, RN; R.I. Sato, PharmD. Minneapolis: C.C. Gornick, MD; J. Davenport, MD; L. Kvernen, RNC, ANP; W.R. Swaim, MD; N. Carsberg; D. Ripley; S. Wilker. Newington: M.J. Radford, MD; S. Patel, MD; M. Giarniero, RN; R. Edwards, MD; O. Hubenko. Northport: G. Mallis, MD; G. Kaplan, MD; J. Gustavson, RN; M. Zarrabi, MD; S. Zucker. Palo Alto: E. Atwood, MD; G. Albers, MD; S. Quaglietti, RN; F. Yee, PharmD; E. Bushnell, RN. Roseburg: C. Carter, MD; H. Lundh, MD; A. Sedlacek, RN; S. Gibson, MD; B. Iwata; C. Huang, MD. San Diego: R. Shabetai, MD; P. Lyden, MD; C. Nielsen, RN; A.P. Gass, MD; V. Tihanyi. Seattle: J. Stratton, MD; T. Bird, MD; A. Leavell, RN; G. Roth, MD; J. Kousbaugh; J. Ritchie, MD; T. Glickman, RN. Tampa: S. Zachariah, MD; C. Taylor, MD; M.M. Branch, MD; H. Saba, MD, PhD; M. Morgan; W.P. Nelson, MD. Washington, DC: P. Carson, MD; S.A. Houff, MD; V. Papademetriou, MD; M. Metcalfe, RN; J. Zeller, MD; L. Roman; C. Smith, RN; J. Swankhaus, MD. West Haven: E. Winter, MD; V. Thadani, MD; B. Cessionee, RN; M. Drickamer, MD; P. Alberg; L. Brass, MD; A.H. Gradman, MD.
Chairman's Office, West Haven
S.L. Bridgers, MD; M.D.
Ezekowitz, MD, PhD; E. Hanahan; E.S.
Teeple; S. Klepper; M.L. Meyer, BS.
Clinical Research Pharmacy, Albuquerque
C.L. Colling, RPh,
MS; J. Boren; M.R. Sather, RPh, MS.
Statistical Coordinating Center, Palo Alto
K.E. James, PhD;
H. Krause-Steinrauf, MS; B. Watanaubi, MS; R.
Yen, MS; R. Yezzi; R. Fischer; P. Lavori, PhD.
Executive Committee
S.L. Bridgers, MD; C.L. Colling, RPh, MS;
M.D. Ezekowitz, MD,
PhD; C.C. Gornick, MD; K.E. James, PhD; J.F. Kurtzke, MD (ad hoc); S.M.
Nazarian, MD; F.R. Rickles, MD; R. Shabetai, MD.
Data Monitoring Board
M. Dunn, MD (Chair); L.R. Caplan, MD;
W.M. O'Fallon, PhD; D.A.
Triplett, MD.
End Points Committee
S. Jonas, MD (Chair); L. Reik, Jr, MD;
B. Duckrow, MD; J.
Sacco, MD; J. Rutherford, MD.
CT Scan Committee
S.M. Nazarian, MD (Chair); S.L. Bridgers,
MD; J.P.
Broderick, MD; J. Davenport, MD; S.R. Gupta, MD; V. Thadani, MD.
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Acknowledgments |
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This study was supported by the Department of Veterans Affairs Cooperative Studies Program, Washington, DC.
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Footnotes |
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A complete list of investigators and institutions participating in the study appears in the "Appendix." This material has been presented in part at the 19th International Joint Conference on Stroke and Cerebral Circulation, American Heart Association, February 1994, San Diego, Calif.
Received February 14, 1995; revision received May 15, 1995; accepted May 22, 1995.
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B. Freestone, G. Y.H. Lip, S. E. Vermeer, A. Hofman, M. M.B. Breteler, and P. J. Koudstaal Prevalence and Risk Factors of Silent Brain Infarcts in the Population Stroke, May 1, 2002; 33(5): 1179 - 1180. [Full Text] [PDF]
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N.M. Al-Saady and M. Sopher Prothrombotic markers in atrial fibrillation: what is new? Eur. Heart J., September 2, 2001; 22(18): 1635 - 1639. [PDF]
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S. S. Chugh, J. L. Blackshear, W.-K. Shen, S. C. Hammill, and B. J. Gersh Epidemiology and natural history of atrial fibrillation: clinical implications J. Am. Coll. Cardiol., February 1, 2001; 37(2): 371 - 378. [Abstract] [Full Text] [PDF]
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G. W. Albers, J. E. Dalen, A. Laupacis, W. J. Manning, P. Petersen, and D. E. Singer Antithrombotic Therapy in Atrial Fibrillation Chest, January 1, 2001; 119 (2009): 194S - 206S. [Full Text] [PDF]
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C. DeCarli, T. Reed, B. L. Miller, P. A. Wolf, G. E. Swan, and D. Carmelli Impact of Apolipoprotein E {epsilon}4 and Vascular Disease on Brain Morphology in Men From the NHLBI Twin Study Stroke, August 1, 1999; 30(8): 1548 - 1553. [Abstract] [Full Text] [PDF]
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C. DeCarli, B. L. Miller, G. E. Swan, T. Reed, P. A. Wolf, J. Garner, L. Jack, and D. Carmelli Predictors of Brain Morphology for the Men of the NHLBI Twin Study Stroke, March 1, 1999; 30(3): 529 - 536. [Abstract] [Full Text] [PDF]
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R. A. Bhadelia, M. Anderson, J. F. Polak, T. A. Manolio, N. Beauchamp, L. Knepper, and D. H. O'Leary Prevalence and Associations of MRI-Demonstrated Brain Infarcts in Elderly Subjects With a History of Transient Ischemic Attack : The Cardiovascular Health Study Stroke, February 1, 1999; 30(2): 383 - 388. [Abstract] [Full Text] [PDF]
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 T. Minamino, M. Kitakaze, S. Sanada, H. Asanuama, T. Kurotobi, Y. Koretsune, M. Fukunami, T. Kuzuya, N. Hoki, and M. Hori Increased Expression of P-Selectin on Platelets Is a Risk Factor for Silent Cerebral Infarction in Patients With Atrial Fibrillation : Role of Nitric Oxide Circulation, October 27, 1998; 98(17): 1721 - 1727. [Abstract] [Full Text] [PDF]
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D. I. Silverman and W. J. Manning Role of Echocardiography in Patients Undergoing Elective Cardioversion of Atrial Fibrillation Circulation, August 4, 1998; 98(5): 479 - 486. [Abstract] [Full Text] [PDF]
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 Y.-G. Li and S. H. Hohnloser Clinical Review : Update on Atrial Fibrillation: Restoration of Sinus Rhythm or Ventricular Rate Control? Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1998; 3(2): 185 - 194. [Abstract] [PDF]
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T. R. Price, T. A. Manolio, R. A. Kronmal, S. J. Kittner, N. C. Yue, J. Robbins, H. Anton-Culver, and D. H. O'Leary Silent Brain Infarction on Magnetic Resonance Imaging and Neurological Abnormalities in Community-Dwelling Older Adults : The Cardiovascular Health Study Stroke, June 1, 1997; 28(6): 1158 - 1164. [Abstract] [Full Text]
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A. Ott, M. M.B. Breteler, M. C. de Bruyne, F. van Harskamp, D. E. Grobbee, and A. Hofman Atrial Fibrillation and Dementia in a Population-Based Study: The Rotterdam Study Stroke, February 1, 1997; 28(2): 316 - 321. [Abstract] [Full Text]
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 SILENT STROKE IS COMMON IN ATRIAL FIBRILLATION Journal Watch (General), October 31, 1995; 1995(1031): 6 - 6. [Full Text]
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