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Risk Factors, Angiographic Patterns, and Outcomes in

Patients With Ventricular Septal Defect Complicating


Acute Myocardial Infarction
Brian S. Crenshaw, MD; Christopher B. Granger, MD; Yochai Birnbaum, MD; Karen S. Pieper, MS;
Douglas C. Morris, MD; Neal S. Kleiman, MD; Alec Vahanian, MD;
Robert M. Califf, MD; Eric J. Topol, MD;
for the GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) Trial Investigators
BackgroundVentricular septal defect (VSD) complicating acute myocardial infarction has been studied primarily in
small, prethrombolytic-era trials. Our goal was to determine clinical predictors and angiographic and clinical outcomes
of this complication in the thrombolytic era.
Methods and ResultsWe compared enrollment characteristics, angiographic patterns, and outcomes (30-day and 1-year
mortality) of patients enrolled in the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries
(GUSTO-I) trial with and without a confirmed diagnosis of VSD. Univariable and multivariable analyses were used to
assess relations between enrollment factors and the development of VSD. In all, 84 of the 41 021 patients (0.2%)
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developed VSD, a smaller percentage than reported in the prethrombolytic era. The median time from symptom onset
to VSD diagnosis was 1 day. Enrollment factors most associated with this complication were advanced age, anterior
infarction, female sex, and no previous smoking. The infarct artery was more often the left anterior descending and more
likely to be totally occluded in patients who developed VSD. Mortality at 30 days was higher in patients with VSDs than
in those without this complication (73.8% versus 6.8%, P,0.001). Patients with VSDs selected for surgical repair
(n534) had better outcomes than patients treated medically (n535; 30-day mortality, 47% versus 94%).
ConclusionsCompared with historical control subjects, patients who undergo thrombolysis within 6 hours of infarction
onset may have a reduced risk of later VSD. If patients develop this mechanical complication, however, it typically
occurs sooner than described in the prethrombolytic era. Despite improvements in medical therapy and percutaneous and
surgical techniques, mortality with this complication remains extremely high. (Circulation. 2000;101:27-32.)
Key Words: defects n thrombolysis n myocardial infarction n prognosis n mortality

V entricular septal defect (VSD) complicating acute myo-


cardial infarction (MI) is uncommon with a reported
incidence in the prethrombolytic era of '1% to 2%.1,2 It
patient population from the Global Utilization of Streptokinase and
TPA for Occluded Coronary Arteries (GUSTO-I) trial41 021
patients enrolled at 1081 institutions in 15 countriesprovides a
typically occurs in the first week after infarction, with a mean unique opportunity to explore this topic more fully.16,17 The goals of
time from symptom onset of 3 to 5 days.1,3,4 Previous the present study were to establish the incidence of VSD after acute
investigations have found age and female sex to be risk MI in patients treated with thrombolytic therapy and to identify the
factors for its development5,6; such patients also commonly enrollment characteristics and angiographic patterns associated with
have no prior angina or MI.1,7,8 Angiographically, patients its occurrence. The association of this complication with patient
with VSD have been noted to have total occlusion of the outcomes also was to be evaluated. Finally, we wanted to identify
infarct-related artery with minimal collaterals.6,9,10 enrollment characteristics associated with increased mortality in
In the prethrombolytic era, outcomes after the development of
patients who develop VSD.
VSD were extremely poor, with an in-hospital mortality of
'45% in surgically treated patients and '90% in those man- Methods
aged medically.1,2,1113 Poor prognostic factors in this patient
Patient Population
population included the development of cardiogenic shock, right As described,16 enrollment criteria for the GUSTO-I trial included
ventricular dysfunction, and inferior infarct location.4,5,14,15 presentation to a participating hospital within 6 hours after the onset
Postinfarction VSD has not been well studied in the thrombolytic of symptoms, with chest pain lasting $20 minutes and accompanied
era, and most prior studies have been relatively small. The large by $0.1-mV ST-segment elevation in $2 limb leads or $0.2 mV in

Received May 27, 1999; revision received August 3, 1999; accepted August 5, 1999.
From the Duke Clinical Research Institute, Durham, NC (B.S.C., K.S.P., C.B.G., R.M.C.); Rabin Medical Center, Petah-Tiqva, Israel (Y.B.); Emory
University, Atlanta, Ga (D.C.M.); Baylor College of Medicine, Houston, Tex (N.S.K.); Hospital Tenon, Paris, France (A.V.); and the Cleveland Clinic
Foundation, Cleveland, Ohio (E.J.T.).
Correspondence to Christopher B. Granger, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail grang001@mc.duke.edu
2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

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28 Circulation January 4/11, 2000

TABLE 1. Methods Used to Diagnose VSD TABLE 2. Enrollment Characteristics


n VSD (n584) No VSD (n540 937)
Echocardiography alone 21 Median age, y 72 (67, 76) 61 (52, 70)
Cardiac and Swan-Ganz catheterization, echocardiography, and 10 Male sex, n (%) 36 (43) 30,617 (75)
bypass surgery Weight, kg 70 (63, 79) 78 (70, 88)
No method indicated 8 Height, cm 158 (165, 172) 172 (165, 178)
Cardiac and Swan-Ganz catheterization and echocardiography 8 Race, n (%)
Echocardiography and Swan-Ganz catheterization 7 White 71 (92) 36 288 (92)
Cardiac catheterization alone 5 Black 1 (1) 1156 (3)
Cardiac catheterization and bypass surgery 4 Other 5 (7) 2163 (5)
Cardiac and Swan-Ganz catheterization 4 Hypertension, n (%) 48 (57) 15 496 (38)
Echocardiography and bypass surgery 4 Diabetes, n (%) 18 (21) 5993 (15)
Swan-Ganz catheter alone 3 Smoking history, n (%)
Autopsy alone 3 Current 11 (13) 17 496 (43)
Cardiac catheterization, bypass surgery, and echocardiography 2 Ever 30 (37) 28 179 (70)
Bypass surgery alone 1 Previous infarction, n (%) 10 (12) 6697 (16)
Cardiac catheterization and echocardiography 1
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Previous bypass surgery, n (%) 4 (5) 1780 (4)


Cardiac catheterization, bypass surgery, and Swan-Ganz 1 Heart rate, bpm 81 (72, 92) 74 (62, 86)
catheterization
Systolic blood pressure, mm Hg 127 (109, 150) 130 (112, 144)
Cardiac and Swan-Ganz catheterization, echocardiography, and 1
Diastolic blood pressure, mm Hg 80 (64, 90) 80 (70, 90)
autopsy
Location of infarction, n (%)
Echocardiography and autopsy 1
Anterior 59 (70) 15 899 (39)
Total n584.
Inferior 24 (29) 23 467 (58)
Other 1 (1) 1350 (3)
$2 contiguous precordial leads. Exclusion criteria included previous
stroke, active bleeding, and recent trauma or major surgery. In- Killip class, n (%)
formed consent was obtained before enrollment. I 61 (74) 34 742 (85)
Patients were randomized to receive streptokinase with subcuta-
II 13 (16) 5107 (13)
neous heparin, streptokinase with intravenous heparin, accelerated
alteplase with intravenous heparin, or the combination of alteplase III 6 (7) 542 (1)
and streptokinase with intravenous heparin.16 Subcutaneous heparin IV 2 (2) 313 (,1)
(12 500 U twice daily) was continued for 7 days or until discharge; Time from symptom onset to 3.1 (2.1, 4.3) 2.8 (2.0, 3.9)
intravenous heparin (5000-U bolus, 1000 U/h, adjusted to maintain thrombolysis, h
an activated partial thromboplastin time of 60 to 85 seconds) was
given for 48 hours or longer at the investigators discretion. Chew- Values are medians (25th, 75th percentiles) when appropriate.
able aspirin ($160 mg) was given as soon as possible and daily
thereafter (160 to 325 mg/d). Patients without contraindication to
Angiography
b-blockers were treated with atenolol (10 mg IV given in 2 doses),
In patients not randomized to the angiographic substudy, angiogra-
followed by 50 to 100 mg orally daily. All other medications
phy was performed per institutional protocols. Patients enrolled in
(including calcium channel antagonists, nitrates, ACE inhibitors, and
the angiographic substudy underwent angiography as described.17
antiarrhythmics) and procedures (including coronary angiography, Ejection fractions were calculated by the area-length method.18
angioplasty, and bypass surgery) were at the discretion of the
attending physician.
End Points
The primary end point of this study was diagnosis of VSD as defined
Identification of Patients With VSD earlier. Of primary interest were the relations of enrollment clinical
Patients with VSDs were first identified by review of case report factors to the occurrence of this outcome. Also considered were the
form data (check box for VSD). Ancillary questionnaires were then relations between angiographic factors and VSD. Second, we inves-
distributed to sites with potential VSD patients to obtain further tigated the effect of VSD on other prospectively defined, in-hospital
information on their diagnosis and treatment. These forms, along clinical outcomes: reinfarction, shock, stroke, ischemia, and conges-
with all available source documents, were then reviewed. VSD tive heart failure or pulmonary edema. Mortality 30 days and 1 year
typically was diagnosed by echocardiography (disrupted ventricular after randomization also was assessed.
septum with evidence of left-to-right shunt by color Doppler),
cardiac catheterization (evidence of left-to-right shunt by ventricu- Statistical Analyses
lography), and/or pulmonary artery catheterization (increase in Each categorical factor is described as the number and percentage of
oxygen saturation from the right atrium to the right ventricle, patients with that characteristic. Continuous factors are described as
quantification of which was unavailable for most patients). Patients medians with 25th and 75th percentiles. With only 84 events, it was
thought to possibly have VSDs on the basis of cardiac arrest or necessary to diminish as much as possible the chance of finding
pulseless electrical activity were excluded. Data for the development spurious results. All formal statistical analyses were therefore re-
of VSD were complete for all 41 021 patients. For the purposes of served for the prospectively specified analysis of baseline (enroll-
this article, patients were divided into 2 groups: those with confirmed ment) predictors of VSD. The enrollment factors identified as having
VSDs and those without VSD confirmation. potential prognostic significance were age, sex, infarct location,
Crenshaw et al VSD in Myocardial Infarction 29

TABLE 3. Table of Angiographic Characteristics degrees of freedom. A reduced model was determined by use of
stepwise variable-reduction techniques. This model contains factors
VSD (n550) No VSD (n522 419) that are all multivariably significant at P,0.05. The predictive
Time from symptom onset to 21 (7, 76) 95 (45, 148) ability of the model was expressed by inclusion of a C index, the area
angiography, h under the receiver-operator characteristic curve.
The 1-year event rates for patients with and without VSDs and for
Infarct-related artery, n (%)
VSD patients who did and did not undergo surgical repair were
Left anterior descending 32 (64) 8148 (36) calculated by use of Kaplan-Meier survival estimates. Log-rank
Left circumflex 1 (2) 2626 (12) statistics were computed to determine the significance of the differ-
ences in the 1-year curves.
Right coronary 14 (28) 10 169 (45)
Left main 0 93 (,1) Results
Other 3 (6) 1382 (6)
Clinical Characteristics
TIMI flow grade, n (%) A total of 84 patients were identified as having confirmed
0 or 1 19 (61) 3922 (29) VSDs (0.2% of the total GUSTO-I population). In 43 of 50
2 or 3 12 (39) 9422 (71) patients (86%), VSD was suspected by physical examination.
Diseased vessels, n (%) The methods of diagnosis are shown in Table 1. VSD was
0 0 1698 (9) diagnosed most often by echocardiography alone (21 pa-
1 19 (50) 8735 (46) tients). The median time from MI symptom onset to VSD
2 15 (40) 5261 (28)
diagnosis was 1 day (range, 0 to 47 days); 94% of the cases
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were diagnosed within 1 week.


3 4 (11) 3354 (18)
Patients who developed VSDs were more likely to be older,
Stenosis of infarct-related 100 (95, 100) 90 (80, 99)
female, and hypertensive; have no history of smoking; and have
artery, %
anterior infarction, an increased heart rate, and a worse Killip
Total occlusion of infarct 25 (57) 3949 (18)
class at admission (Table 2). The relations between enrollment
artery, n (%)
systolic and diastolic blood pressures and VSD also was signif-
Left ventricular ejection 40 (30, 50) 51 (43, 60)
icant but not linear. The likelihood of VSD decreased with
fraction, %
increasing systolic pressure up to '130 mm Hg. Beyond
Values are medians (25th, 75th percentiles) when appropriate.
130 mm Hg, the likelihood of VSD increased with increasing
systolic pressure. Similarly, the likelihood of VSD decreased
smoking history, previous MI, heart rate, current smoking, hyper- with increasing diastolic blood pressure to '75 mm Hg and then
tension, systolic and diastolic blood pressures, Killip class, previous increased with increasing diastolic pressure .75 mm Hg. The
bypass surgery, and time from symptom onset to treatment. Other
factors, including the angiographic results, are presented for descrip- time from symptom onset to thrombolytic administration did not
tive purposes only. differ between groups.
Logistic regression modeling was used for the predictive analysis.
Spline transformations of each continuous factor versus outcome were Angiographic Characteristics
evaluated to determine the appropriateness of the linearity assumption. Angiographic data were available for 50 of 84 patients (60%)
Linear splines were applied to systolic and diastolic blood pressures.
A full model containing all the potential predictors was first fitted. diagnosed with VSDs (Table 3). These patients underwent
Then, the relative significance of each factor in the full model was first angiography at a median of 21 hours after onset of the
plotted as the Wald x2 for each factor minus the corresponding index infarction, in contrast to the median of 95 hours for

Relative importance of multivariable enroll-


ment predictors of VSD in GUSTO-I. All fac-
tors from age to prior infarction have corre-
sponding P,0.05. BP indicates blood
pressure; tx, treatment.
30 Circulation January 4/11, 2000

TABLE 4. Univariable and Multivariable Modeling


Univariable Models Multivariable Model

df Wald x2 P Wald x2 P
Age 1 66.5 ,0.001 18.70 ,0.001
Anterior infarction 2 29.9 ,0.001 11.53 0.003
Smoking status 2 37.1 ,0.001 10.15 0.006
Sex 1 39.1 ,0.001 7.33 0.007
Previous MI 1 1.1 0.286 3.98 0.046
Heart rate 1 10.1 0.001 3.40 0.065
Systolic blood pressure 2 13.2 0.002 3.56 0.169
Hypertension 1 12.4 ,0.001 1.91 0.167
Killip class 1 16.7 ,0.001 1.27 0.26
Previous bypass surgery 1 ,0.1 0.856 0.69 0.406
Diastolic blood pressure 2 11.1 0.004 1.43 0.489
Time, symptom onset to thrombolysis 1 0.8 0.357 0.06 0.803
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GUSTO-I patients who did not develop VSDs. Patients with Patients who underwent surgical repair had lower mortality at
VSDs were more likely to have TIMI grade 0 or 1 flow at first 30 days and 1 year than the 35 patients who were treated
angiography, and 57% had total occlusion of the infarct medically: 47% versus 94% at 30 days (P,0.001) and 53%
artery. The infarct-related artery was more often the left versus 97% at 1 year (P,0.001).
anterior descending in patients with VSDs than in patients Patients who developed VSDs and died within 30 days
with no VSDs. More than 50% of the patients with VSDs had were more likely to be female and to have an inferior
2- or 3-vessel coronary disease. The median ejection fraction infarction than those who survived (Table 7). All VSD
was lower in patients with VSDs. patients who had pulmonary congestion (Killip class III or
IV) at admission died within 30 days; the mortality rate was
Univariable and Multivariable Modeling 27% among VSD patients who were in Killip class I or II.
The complete set of variables included in the model to predict
VSD and their relative importance are shown in Table 4 and Discussion
the Figure. Increasing age, anterior infarction, and female sex VSD remains an infrequent but devastating complication of
were the most important multivariable predictors of VSD. acute MI. Its incidence in GUSTO-I was lower than in previous
Current smoking and prior MI also were significant in being
associated with not developing this complication. A reduced TABLE 6. In-Hospital Procedures and In-Hospital, 30-Day, and
version of the model (containing only the significant multi- 1-Year Outcomes
variable predictors) is shown in Table 5. The reduced model
VSD No VSD
performed well with a C index of 0.774.
(n584) (n540 937) P

In-Hospital Procedures and 30-Day and In-hospital procedures, n (%)


1-Year Outcomes Pacemaker 22 (27) 2849 (7)
Patients who developed VSDs showed a much greater use of Swan-Ganz catheter 56 (68) 5006 (12)
in-hospital procedures than those who did not; they also were Ventilator 49 (59) 4626 (11)
more likely to develop shock and congestive heart failure Bypass surgery 28 (33) 3498 (9)
(Table 6). Patients with VSDs also had significantly higher
Intra-aortic balloon pump 48 (57) 1439 (4)
mortality at 30 days and 1 year. Data regarding treatment of
Cardioversion 23 (28) 3822 (9)
VSD were available for 69 of the 84 patients. In all, 34
underwent surgical repair a median of 3.5 days (95% CI, 1 to In-hospital outcomes, n (%)
7) after MI symptom onset, including 3 (10%) who under- Reinfarction 5 (6.0) 1623 (4.0) 0.388
went repair between 30 days and 1 year after enrollment. Shock 56 (67) 2390 (5.9) ,0.001
Stroke 2 (2.4) 597 (1.5) 0.521
TABLE 5. Reduced Multivariable Model for the Prediction CHF or pulmonary edema 49 (59) 6583 (16) ,0.001
of VSD
Ischemia 21 (26) 8110 (20) 0.189
x2 P OR (95% CI) Death at 30 d (all patients), n (%) 62 (74) 2791 (6.8) ,0.001
Age 27 ,0.001 2.05 (1.622.58) Death at 1 y* (all patients), % 77.5 9.7 ,0.001
Anterior infarction 23 ,0.001 3.15 (1.965.06) CHF indicates congestive heart failure.
Female sex 16 ,0.001 2.54 (1.614.00) *One-year mortality rates are Kaplan-Meier survival estimates, and the
probability value is from log-rank statistic. All others are actual rates and
Current smoking 6 0.015 0.43 (0.220.85)
frequencies of events with probability values from log-likelihood x2 tests.
Crenshaw et al VSD in Myocardial Infarction 31

TABLE 7. Enrollment Characteristics for Patients With VSD by cause myocardial hemorrhage during the lytic state, so that
Survival at 30 Days if VSD occurs, its time course would be accelerated.
Lived 30 d Died Within 30 d Advanced age, anterior infarct location, female sex, and no
(n522) (n562) current smoking were found to be the most important predic-
Median age, y 71 (67, 74) 73 (68, 77)
tors of VSD. Unlike previous studies, hypertension21 and no
previous MI or angina7 were found to be less helpful when all
Male sex, n (%) 12 (55) 24 (39)
other variables were considered. There was a bidirectional
Weight, kg 71 (64, 79) 70 (61, 79)
association of systolic and diastolic blood pressures at enroll-
Height, cm 168 (157, 172) 165 (158, 172) ment with the incidence of VSD. The positive correlations
Race, n (%) (increase in the incidence of VSD as systolic blood pressure
White 20 (95) 51 (91) increased to .130 mm Hg and the diastolic blood pressure to
Black 0 1 (2) .75 mm Hg) reflect the association between hypertension
Other 1 (5) 4 (7) and VSD. Extensive MI and right ventricular involvement,
Smoking history, n (%)
both known risk factors for VSD, may cause hypotension and
cardiogenic shock on admission. The negative correlations
Current 4 (18) 7 (12)
between enrollment systolic (#130 mm Hg) and diastolic
Ever 8 (38) 22 (37) (#75 mm Hg) blood pressures with the incidence of VSD
Hypertension, n (%) 15 (68) 33 (53) probably reflect the incidence of hemodynamic compromise
Diabetes, n (%) 3 (14) 15 (24) associated with extensive MI or right ventricular infarction.
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Previous MI, n (%) 3 (14) 7 (11) Our angiographic data, consistent with previous studies,
Previous bypass surgery, n (%) 2 (9) 2 (3) show that patients who develop VSDs after acute MI are more
Heart rate, bpm 82 (75, 91) 80 (66, 93) likely to have total occlusion of the infarct artery.6,10,22 This
Systolic blood pressure, mm Hg 140 (118, 161) 120 (106, 142)
suggests that the pathophysiology of acute VSD involves
sudden, severe ischemia, leading to extensive myocardial
Diastolic blood pressure, mm Hg 87 (70, 99) 70 (60, 90)
necrosis, and that patients who do not reperfuse with
Killip class, n (%) thrombolysis are at increased risk of mechanical complica-
I 20 (95) 41 (67) tions. We also found that this patient population had exten-
II 1 (5) 12 (20) sive coronary artery disease (51% with 2- or 3-vessel disease)
III 0 (0) 6 (10) and poor left ventricular function.
IV 0 (0) 2 (3) Mortality with this complication remains extremely high in
Location of infarction, n (%) the thrombolytic era, despite improvements in medical ther-
apy and percutaneous and surgical techniques. However, the
Anterior 20 (91) 39 (63)
mortality rates for all patients with VSDs were similar at 30
Inferior 2 (9) 22 (36)
days and 1 year (74% and 78%). This suggests that if the
Other 0 (0) 1 (2) patient survives the initial admission, the long-term prognosis
Time from symptom onset to 2.7 (2.0, 3.3) 3.4 (2.2, 4.5) is relatively good.
thrombolysis, h Although this is the largest study of VSD in a prospective
Values are medians (25th, 75th percentiles) when appropriate. trial of thrombolysis, the number of patients with VSDs was
insufficient to fully determine enrollment characteristics as-
reports, which may reflect 2 factors. First, all patients in this trial sociated with survival. However, it appeared that patients
were treated with thrombolytics within 6 hours of symptom with inferior infarcts and VSDs tended to have a worse
onset. Reperfusion therapy, particularly if begun early, may outcome than those with anterior infarcts. This is most likely
prevent the extensive myocardial necrosis typically associated related to factors previously noted by Edwards and col-
with mechanical complications.19 Second, we included only leagues.3 In their necropsy study, inferior infarcts were more
patients with confirmed diagnoses of VSD to better define likely to be associated with complex VSDs (multiple, irreg-
enrollment characteristics and overall outcomes associated with ular, and/or variable interventricular connections) located in
this complication. Although this may have caused an underesti- the inferobasal portion of the septum and therefore were more
mation of the incidence of VSD (by excluding patients who died difficult to approach surgically. Anterior infarcts were more
before the diagnosis could be confirmed), it may be more useful commonly associated with simple, through-and-through de-
clinically because it provides information on outcomes once the fects in the apical septum, which tend to be more easily
diagnosis has been made. repaired. Right ventricular infarction and dysfunction, more
The mean time from infarction to development of VSD commonly associated with inferior infarcts, also have been
was found to be 1 day, shorter than the 3 to 5 days reported shown to be poor prognostic factors in patients with
from the prethrombolytic era.1,3,4 Becker and colleagues,20,21 VSD.4,9,14,15 All patients in our study with Killip class III or
who reported a time similar to that of the present study, IV at presentation died. Nonsurvivors also were older and
postulated that this may be due to different pathophysiolog- more likely to have reduced blood pressure at enrollment.
ical mechanisms. Thrombolytic therapy may prevent exten- Patients with VSDs in GUSTO-I selected for surgical
sive transmural necrosis, a prerequisite for cardiac rupture in repair had better outcomes than those treated medically.
the prethrombolytic era. However, thrombolysis also may However, those who did not undergo surgical repair may
32 Circulation January 4/11, 2000

have been more critically ill; these patients had a worse Killip 4. Moore CA, Nygaard TW, Kaiser DL, Cooper AA, Gibson RS. Postin-
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included a 6-hour limit from symptom onset; therefore, we cannot Leinbach RC. Ventricular septal rupture: a review of clinical and physiologic
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Circulation. 2000;101:27-32
doi: 10.1161/01.CIR.101.1.27
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