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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
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
27
28 Circulation January 4/11, 2000
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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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
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-
class, tended to be slightly older, and had a lower enrollment farction ventricular septal rupture: the importance of location of infarction
and right ventricular function in determining survival. Circulation. 1986;
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with mortality.23 It is worth noting that the 30-day mortality 5. Feneley MP, Chang VP, ORourke MF. Myocardial rupture after acute
of patients not having surgical repair was 94%. myocardial infarction: ten year review. Br Heart J. 1983;49:550 556.
The relation of cardiac rupture to timing of thrombolytic admin- 6. Skehan JD, Carey C, Norrell MS, DeBelder M, Balcon R, Mills PG.
Patterns of coronary artery disease in post-infarction ventricular septal
istration is controversial. Some studies have shown an increased risk rupture. Br Heart J. 1989;62:268 272.
with late therapy (ie, .12 hours after symptom onset),18 but more 7. Pohjola-Sintonen S, Muller JE, Stone PH, Willich SN, Antman EM,
recent evidence does not support this finding.21 We did not find a Davis VG, Parker CB, Braunwald E, for the MILIS Study Group. Ven-
significant difference in the timing of thrombolytic administration tricular septal and free wall rupture complicating acute myocardial
infarction: experience in the multicenter investigation of limitation of
between those who developed VSD and those who did not (3.1
infarct size. Am Heart J. 1989;117:809 816.
versus 2.8 hours). However, enrollment criteria for GUSTO-I 8. Radford MJ, Johnson RA, Daggett WM, Fallon JT, Buckley MJ, Gold HK,
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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Quantitative analysis of right and left ventricular infarction in the presence of
The number of patients in the present study, although 1 of postinfarction ventricular septal defect. Circulation. 1988;77:3342.
the largest series reported, is still relatively small with limited 10. Cheriex EC, de Swart H, Dijkman LW, Havenith MG, Maessen JG,
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Circulation. 2000;101:27-32
doi: 10.1161/01.CIR.101.1.27
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Copyright 2000 American Heart Association, Inc. All rights reserved.
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