(Circulation. 2000;102:211.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Independent Prognostic Value of Cardiac Troponin T in Patients With Confirmed Pulmonary Embolism
From Medizinische Klinik II, Medizinische Universität zu Lübeck, Germany.
Correspondence to Prof Hugo A Katus, Medizinische Klinik II, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. E-mail giannits{at}medinf.mu-luebeck.de
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Abstract |
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Background—Cardiac troponin T (cTnT) is a sensitive and specific marker, allowing the detection of even minor myocardial cell injury. In patients with severe pulmonary embolism (PE), myocardial ischemia may lead to progressive right ventricular dysfunction. It was therefore the purpose of this study to test the presence of cTnT and its prognostic implications in patients with confirmed PE.
Methods and Results—Fifty-six consecutive patients with confirmed
PE were enrolled in this prospective study. PE was confirmed by
pulmonary angiography, lung scan, or
echocardiography and subsidiary analyses.
Severity of PE was assessed by a clinical scoring system, and cTnT was
measured within 12 hours after admission. cTnT was elevated (
0.1
µg/L) in 18 (32%) patients with massive and moderate PE but not in
patients with small PE. In-hospital death (odds ratio 29.6, 95% CI 3.3
to 265.3), prolonged hypotension and cardiogenic shock (odds ratio
11.4, 95% CI 2.1 to 63.4), and need for resuscitation (odds ratio
18.0, 95% CI 2.6 to 124.3) were more prevalent in patients with
elevated cTnT. cTnT-positive patients more often needed inotropic
support (odds ratio 37.6, 95% CI 5.8 to 245.6) and mechanical
ventilation (odds ratio 78.8, 95% CI 9.5 to 653.2). After adjustment,
cTnT remained an independent predictor of 30-day mortality (odds ratio
15.2, 95% CI 1.22 to 190.4).
Conclusions—cTnT may improve risk stratification in patients with PE and may aid in the identification of patients in whom a more aggressive therapy may be warranted.
Key Words: embolism • pulmonary heart disease • coronary disease
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Introduction |
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Right ventricular (RV) dysfunction is a frequent consequence of severe pulmonary embolism (PE) and correlates with increased risk of death.1 2 3 4 5 Experimental and clinical evidence suggests that myocardial ischemia and even RV infarction may result from an acute rise in pulmonary artery pressures and may then cause RV failure and eventually death.6 7 8 9 Risk stratification is particularly important because more aggressive therapies such as thrombolytics and inotropic vasoactive drugs may improve outcome.1 3 9 Detection of severe myocardial ischemia leading to minor myocardial damage or acute myocardial infarction (AMI) may improve risk stratification.
Cardiac troponin T (cTnT) is a highly sensitive and specific marker of myocardial cell injury,10 11 and its role for risk stratification in acute coronary syndromes is well established.12 13 14 15 The aim of the present study was to determine the incidence of minor myocardial damage and AMI in patients with PE and to elucidate the prognostic value of cTnT in these patients.
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Methods |
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Study Population
A cohort of 56 consecutive patients with confirmed diagnosis of acute PE were enrolled. Patients examined beyond 14 days after onset of symptoms were not included because potential benefits of more aggressive therapy, particularly thrombolytic therapy, have not been established in these patients.16 Diagnosis of PE was confirmed by pulmonary angiography or high probability ventilation-perfusion lung scan. A combination of abnormal echocardiography with clinical presentation (acute onset of dyspnea, tachypnea, chest pain, syncope, hypotension, or shock) in the absence of preexisting chronic pulmonary disease was regarded diagnostic as well. Diagnosis was further strengthened by objective evidence of deep-vein thrombosis, a positive plasma D-dimer–ELISA (
500 µg/L), a blood gas analysis revealing otherwise
unexplainable hypoxemia and hypocapnia, or an abnormal ECG
(tachycardia, large S wave in lead I or Q wave in lead III,
complete or incomplete right bundle-branch block, inverted T waves in
right precordial chest leads). The severity of PE was classified clinically into (1) massive, (2) moderate to large, and (3) small PE according to the grading system of Goldhaber.17 Patients were classified as having massive PE in the presence of persistent systemic hypotension or cardiogenic shock and signs of RV dysfunction. Moderate PE was defined as RV dysfunction in the presence of normal systemic arterial blood pressure, and small PE in the absence of both systemic arterial hypotension, and RV dysfunction.
RV function was assessed by transthoracic
echocardiography. Diagnosis of RV dysfunction was
made in the presence of any of the following: (1) abnormal motion of
the interventricular septum, (2) dilation of the right
ventricle (diastolic diameter 30 mm), (3)
hypokinesis of the RV, or (4) tricuspid valve
regurgitation (jet velocity >2.5
m/s).18
Data were collected on (1) clinical symptoms and signs on admission, (2) presence of underlying diseases or predisposing factors for PE, (3) history of coronary artery disease (CAD), (3) findings of diagnostic procedures including blood gas analysis, ECG, echocardiography, pulmonary angiography, right and left heart cardiac catheterization, and coronary angiography, ventilation-perfusion scans. Laboratory tests included measurements of D-dimers (ELISA, Asserachrom, upper limit of normal 400 µg/L), cTnT, creatine kinase (CK) (upper limit of normal 80 IU/L for men and 70 IU/L for women), and MB-isoenzyme activities (upper limit of normal 9 IU/L).
Blood samples for cTnT were obtained on admission. Patients with a negative test received a second measurement within 12 hours of presentation by means of a qualitative immunological assay (TropT, Roche Diagnostics) or a quantitative ELISA (ES 300 system, Roche Diagnostics). The qualitative assay with a detection limit of 0.1 µg/L19 was used in 41 (73.2%) of 56 patients. For practical reasons, qualitative and quantitative cTnT values exceeding the discriminator value are reported as positive.
All patients were followed up prospectively for in-hospital death related to PE.
Statistical Analysis
Mean values were calculated for continuous variables and
absolute and relative frequencies for discrete variables.
Univariate comparison of continuous data were performed
with the use of the unpaired Student’s t test or
Wilcoxon test. For comparison of discrete variables, a
2 test or Fisher’s exact test was used.
Multiple logistic regression analysis was performed for
prediction of in-hospital death. Only variables with significant
univariate association were included in different models.
Many variables were highly correlated. We therefore adjusted for
those variables that were most strongly associated with in-hospital
death, were less likely to be intercorrelated, and appeared to address
different issues. The variables included in the final model are
listed in Table 4
. A 2-tailed probability value of <0.05 was
considered significant. The cumulative survival curves were constructed
with the use of the Kaplan-Meier method, with death from PE as an end
point. Statistical analysis was performed with the use of a
commercially available statistical package (SPSS for Windows, Version
5.0.2).
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Results |
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Study Group
From April 1996 to November 1998, 56 consecutive patients with confirmed diagnosis of PE were included. PE was confirmed by pulmonary angiography in 18 (32%) and high-probability lung scintigraphy in 22 (39%) patients. In 16 (28.6%) patients, diagnosis of PE was based on echocardiography in combination with clinical presentation in the absence of a preexisting chronic pulmonary disease. Diagnosis of PE was strongly supported by elevated pulmonary artery pressures, which were measured invasively in 14 (25%) or by Doppler echocardiography in 32 (57%), objective evidence of deep-vein thrombosis in 22 (39.3%), or the result of a D-dimer test, which was performed in 21 patients and was positive in 17 (80.9%) cases. Absolute and relative frequencies of diagnostic subsidiary analyses in different diagnostic categories, that is, confirmed PE by pulmonary angiography (n=18), ventilation-perfusion lung scan (n=22), either angiography or lung scan (n=40), and neither angiography or lung scan (n=16) are displayed in Table 1
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Diagnosis of PE was confirmed after a median of 2 hours (range 0.5 to 22) after admission. Median time from onset of symptoms suggestive of acute PE or symptomatic recurrence of silent PE was 3 days (range 1 to 12).
Baseline clinical variables of the entire group and of cTnT groups
are displayed in Table 2. A positive cTnT
was detected in 18 (32%) patients and only among those with moderate
and severe PE. No significant differences were observed between cTnT
groups.
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According to the predefined criteria adapted from Goldhaber et
al,17 17 (30%) were diagnosed as having massive PE, 26
(46%) patients moderate to large PE, and 13 (23%) patients small PE
(Table 3). Sixteen patients received
thrombolytic therapy for massive or moderate to large
PE. All but 1 patient who had previously undergone a major surgical
intervention received intravenous heparin therapy adjusted
to a 2-fold increase of activated partial thromboplastin
time.
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Diagnostic Findings According to Levels of
cTnT
RV dysfunction was more often found in patients with elevated
cTnT. These patients also revealed more often a right bundle-branch
block and abnormal right precordial repolarization. Mean
pulmonary artery pressures as measured invasively and
systolic RV pressures were comparable.
Activities of CK and CK-MB were higher in cTnT-positive patients. In 4
(7.1%) patients, the profile of cardiac enzymes (CK activity >2 times
the upper limit of normal in combination with a CK-MB/CK ratio 0.06)
was suggestive of AMI without characteristic ECG changes. Details are
given in Table 3
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In-Hospital Course According to Levels of cTnT
Total in-hospital mortality rate was 16%. Marked
differences in mortality rates were observed in patients with massive
versus moderate PE (41.1% versus 7.7%, P=0.002) (Figure 1).
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TnT was highly discriminative with respect to mortality, being 44% in
cTnT-positive versus 3% in cTnT-negative patients
(P<0.001) (Figure 2).
Indicators of a more severe PE such as prolonged hypotension and shock,
severe hypoxemia, need for resuscitation, inotropic therapy, or
mechanical ventilation were also more frequently present in the
cTnT-positive patients. Moreover, cTnT-positive patients had a
significantly longer stay in the intensive care unit than did
cTnT-negative patients (P=0.003). It is tempting to
speculate that CAD may be more prevalent in cTnT-positive patients.
However, coronary angiography disclosed significant CAD in an
equal distribution between cTnT positive-and cTnT-negative
patients.
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Of the 16 patients treated with thrombolytic agents, 8
were cTnT positive and another 8 were cTnT negative. Details on
in-hospital outcomes are given in Table 4.
Predictors of In-Hospital Death
The clinical severity of PE proved valuable for prediction of
in-hospital death (massive versus moderate PE, [OR 8.4; 95% CI 1.5 to
47.7]). Moreover, cTnT indicated an increased hazard for in-hospital
death (cTnT 0.1 versus cTnT <0.1 µg/L, [OR 29.6; 95% CI 3.3 to
265.3]). Univariate analysis revealed an
association of death with syncope at presentation (OR 7.1;
95% CI 1.5 to 33.3), prolonged hypotension and cardiogenic shock (OR
11.4; 95% CI 2.1 to 63.4), need for mechanical ventilation (OR 78.8;
95% CI 9.5 to 653.2), resuscitation (OR 18; 95% CI 2.6 to 124.3) or
need for inotropic support (OR 37.6; 95% CI 5.8 to 245.6), severe
hypoxemia as suggested by
pO2/FIO2
ratio <250 mm Hg (OR 9.9; 95% CI 1.1 to 85.6), and evidence of
concomitant AMI (OR 18.3; 95% CI 3.2 to 106.5). In logistic regression
analysis, cTnT remained the only independent predictor of
in-hospital death (adjusted OR 15.2; 95% CI 1.22 to 190.37) and was
superior to CK activity, which was not independently predictive (Table 5).
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Discussion |
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In the present study, cTnT levels
0.1 µg/L were
frequently found in patients with moderate and severe PE. Along with
rises in total CK and CK-MB activities, circulating cTnT indicates
irreversible myocardial cell damage. Since elevations of cTnT were
observed even in patients without CAD, it is likely that release of
cTnT from myocardium results from acute RV pressure
overload, impaired coronary blood flow, and severe hypoxemia
caused by PE. Moreover, our data demonstrate that patients with
elevated cTnT are at considerably higher risk for subsequent
in-hospital death. Thus, this study not only confirms previous
experimental and clinical studies showing an association between
myocardial ischemia and RV dysfunction but also provides strong
evidence that myocardial cell injury is a major risk factor in patients
with PE.
Myocardial Ischemia in RV Dysfunction
That PE may cause myocardial ischemia and AMI has been
recognized for >50 years.20 Acute pressure overload in
acute PE may result in regional myocardial ischemia as the
result of increased wall tension and oxygen demand and reduced
coronary perfusion and oxygen supply.6 7 8
Limitation of pericardial expansion in the presence of a dilated right
ventricle together with leftward shift of the
interventricular septum appear to contribute to the
diminished left ventricular preload and resultant decreased
cardiac output.21 22 Hypoxemia, systemic
arterial hypotension, and cardiogenic shock may further
increase the propensity to ischemic damage, and preexisting
cardiopulmonary abnormalities may contribute to both the
hemodynamic alteration and the risk of ischemia
and infarction induced by PE.9 Accordingly, RV failure has
been reported to develop more likely in patients with
coexistent CAD.23 On the other hand, RV
infarction has been reported to occur with either normal or mildly to
moderately diseased coronary
vasculature.8 24 25 26
The role of the highly cardiospecific troponins for identification of AMI and minor myocardial damage is well established.10 11 12 The incidence, however, of elevated cTnT in the setting of acute PE remains largely undetermined. Recently, a small French prospective cohort that enrolled 29 patients with acute PE found elevated levels of troponin I in 2 patients.27 Both patients had submassive PE and survived. In our cohort, elevated cTnT levels were found in 18 (32%) of 56 consecutive patients and exclusively among patients with moderate and severe PE.
Some of these patients had concomitant significant CAD, increasing the propensity for myocardial ischemia. However, a considerable proportion developed elevated cTnT in the absence of CAD, which underscores the hypothesis that cTnT is being released as a consequence of ischemic injury to the right ventricle.6 7 8
Role of cTnT for Risk Assessment
Risk stratification in PE is paramount because prognosis strongly
influences selection of appropriate management strategies.
Hemodynamic instability and cardiogenic shock are
regarded as indications for thrombolytic
therapy,9 whereas the optimal therapy for normotensive
patients with RV dysfunction is still controversial. More recently,
there is accumulating evidence that RV dysfunction indicates a
high-risk subgroup and that improved outcome and lower rates of
recurrent PE are achieved with thrombolytic therapy in
these patients.1 3 9 RV dysfunction may be identified by
echocardiography even in critically ill patients,
demonstrating evidence of RV dysfunction in 46% to 81% of cases with
acute PE.1 4 28
In addition to RV dysfunction, there are some other indicators of increased risk for early death such as hemodynamic instability, prolonged arterial hypotension, older age, syncope at presentation, need of cardiopulmonary resuscitation, chronic pulmonary disease, and cardiovascular disease.3 19 29
The present study identifies a subgroup of patients with cTnT 0.1
µg/L at increased risk of subsequent death. In-hospital mortality
rate was 44% in patients with elevated cTnT compared with only 3% in
patients with normal cTnT. The predictive value of cTnT persisted even
after adjustment for severity of PE, thus correcting for
hemodynamic instability and presence of RV dysfunction.
An even less favorable outcome was found for those patients with cTnT
and a concomitant >2-fold increase of CK activity reflecting more
severe myocardial ischemia. All 4 patients with cTnT and
positive cardiac enzymes had massive PE requiring mechanical
ventilation and catecholamines and died subsequently from
progressive right heart failure and cardiogenic shock. In 3 of these
patients, an underlying CAD was ruled out by coronary
angiography.
In this study, diagnosis of PE was confirmed by pulmonary angiography in 32% and lung scan in 39% of all patients. Thus, the diagnostic workup in this study is comparable to that of 2 recent large-scaled registries reporting use of pulmonary angiography in 17% to 19% and lung scan in 47% to 55% of cases.5 18 In both registries and in the present study, PE was more frequently diagnosed by bedside echocardiography in combination with high clinical suspicion. Conversely, a diagnostic strategy seeking more definite confirmation of PE by use of pulmonary angiography and lung scan may lead to selection of a patient cohort with a more benign clinical outcome because transportation from the intensive care unit to the diagnostic facilities is possible only in the less critically ill patients.18
Interestingly, the total in-hospital mortality rate of our cohort was 16% and similar to the 17% to 22% mortality rates found in both large-scaled multicenter registries.5 18 Moreover, mortality rates in particular subgroups were comparable to earlier reports ranging from 4.1% for stable patients without RV dysfunction3 to 32% for massive PE presenting with hemodynamic instability.18 30
Limitations
The present study is limited by 2 shortcomings. First, sample
size is not sufficiently large to allow detailed statistical
investigation of all competing prognostic risk factors. However,
prognostic risk factors that usually contribute to patient risk
stratification were taken into account in the multiple regression
model. In particular, RV dysfunction and hemodynamic
instability were partially controlled because these variables
represented defining criteria for massive and large PE.
Second, the prevalence of CAD (42%) is higher than commonly reported
in unselected cohorts. However, the present study sought to
determine the cause of cTnT elevation in patients with PE. Therefore,
all patients except those who refused or died underwent
coronary angiography during early diagnostic workup
or at least before discharge, which may explain some discrepancies to
other registries with respect to the prevalence of CAD. Although there
were patients in whom significant CAD may have contributed to
myocardial ischemia during acute PE, our data clearly
demonstrate that cTnT elevations occur even in absence of CAD.
Conclusions
Increased cTnT levels are not uncommon during moderate and severe
PE. Although the exact pathomechanism remains unclear, the association
between cTnT and RV dysfunction in the absence of significant CAD
suggests a link between acute increase of RV afterload and severe and
possible irreversible myocardial ischemia. Moreover, cTnT was
an independent predictor of in-hospital death and thus may aid risk
stratification and guidance of the appropriate therapeutic management
of acute PE.
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Acknowledgments |
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The authors thank Dr Clara Schlaich for statistical advice.
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Footnotes |
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Prof Katus developed and patented the troponin T assay in cooperation with Roche-Boehringer, Mannheim, Germany. He is Medical Advisor of Roche-Boehringer-Mannheim.
Received December 3, 1999; revision received February 1, 2000; accepted February 9, 2000.
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