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the Department of Neurology (T.E., K.S., D.S.), and the Institute of Clinical Chemistry (H.B.), Technical University of Munich, Germany.
Abstract
Background and Purpose— The prognostic value of cardiac troponins and natriuretic peptide in acute ischemic stroke is uncertain. We measured cardiac troponin T (cTnT), cardiac troponin I (cTnI), and N-terminal pro-brain natriuretic peptide (NT-proBNP) at admission in acute ischemic stroke patients without evident myocardial damage.
Methods— In 174 consecutive patients with MRI-confirmed ischemic stroke, serial measurements of cTnT, cTnI, and NT-proBNP were performed at 3 different time points in the hyperacute phase (at admission, on days 1 and 2). Relation of laboratory values to risk factors, stroke subtype classification, and clinical outcome after 3 months was analyzed.
Results— The highest proportion of raised parameters was found at day 2 for cTnI in 8 of 103 (7.8%), at day 3 for cTnT in 8 of 174 (4.6%), and NT-proBNP in 114 of 174 (65.5%) patients. Proportion of patients with good outcome was significantly reduced in the group with highest NT-proBNP quartile. However, using multivariate regression analysis, no significant relation to morbidity and mortality was found for cTnT, cTnI, or NT-proBNP. Significant impact on the outcome was detected for lesion size, insular involvement, sex, age, and stroke severity.
Conclusions— NT-proBNP is raised in nearly two thirds of acute stroke patients, whereas elevated cardiac troponins are found only in a small number of acute ischemic stroke patients. Neither NT-proBNP nor cardiac troponins influence clinical outcome if other risk factors are considered.
Key Words: natriuretic peptide stroke troponin
Introduction
Stroke is a major cause of mortality and morbidity in industrialized countries. In 20% to 30% of all strokes, a cardiac cause is detected; however, in up to 20% of all strokes, the etiology remains unclear and specific treatment cannot be initiated.1 Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are new biochemical markers of myocardial damage with high specificity and sensitivity. However, there are discordant results of the possible role of cTnT in acute stroke: according to a recent observational study, a raised serum concentration of cTnT among patients with acute ischemic stroke is related to a 3-fold increase in mortality.2 In contrast, another report on a small group of 32 patients could not detect any raised cTnT concentration within the first 5 days of stroke.3 Troponin I has been detected in 27% to 34% of patients with stroke.4,5 Several mechanisms may be responsible for raised concentrations of cardiac troponins during the early phase of stroke: primary myocardial damage with secondary cardioembolic cerebral ischemia, primary cerebral ischemia with secondary myocardial injury attributable to central activation of the sympathetic nervous system,6,7 or coexisting heart failure.8 Brain natriuretic peptide (BNP) is a cardiac neurohormone specifically secreted from the ventricles in response to volume expansion and pressure overload.9 Also, BNP inhibits the sympathetic nervous system and the activities of several other hormone systems, including the renin-angiotensin–aldosterone system.10 Measurement of BNP or its N-terminal pro-brain natriuretic peptide (NT-proBNP) has recently become valuable in the rapid diagnosis of heart failure,11 has been used for risk stratification,12,13 and is predictive of short-term mortality.14 The role of BNP or NT-proBNP in acute stroke has not been investigated previously, but because heart failure is associated with raised cTnT8 and with dependency after stroke,15 early recognition and initiation of therapy might influence clinical outcome.
Because of the uncertain value of cardiac troponins and NT-proBNP in acute ischemic stroke, we evaluated the short-term prognostic value of early serial measurement of cTnT, cTnI, and NT-proBNP in the hyperacute phase of ischemic stroke.
Subjects and Methods
Subjects
866 consecutive patients admitted with an acute ischemic stroke according to the World Health Organization criteria,16 220 patients were eligible with symptom onset within 12 hours. From these 220 patients, 175 were included in this prospective study. Forty-five potential patients were excluded because they had signs of acute or recent (within the last 4 weeks) myocardial events (n=3), because blood samples could not be obtained completely (n=20) or not in time (n=10), or because presumed stroke could not be confirmed (n=12). Severity of stroke was assessed using the National Institutes of Health Stroke Scale (NIHSS),17 Barthel index,18 and Rankin scale.19 Follow-up information on new cardiovascular events, morbidity, and mortality (Barthel index and Rankin scale) after 90 days was obtained by telephone interview with the patient or, if not possible, with the nearest relative or doctor. All procedures were followed in accordance with institutional guidelines, and informed consent was obtained from each patient.
Risk Factors
Risk factors determined included the following: arterial hypertension (treatment with antihypertensive medication or documented blood pressure raised >140 mm Hg systolic or >90 mm Hg diastolic at 2 independent readings before admission), diabetes mellitus (treatment with antidiabetic medication or diagnosis of diabetes during hospital stay), hyperlipidemia (treatment with lipid-lowering medication or diagnosis during hospital stay), smoking (duration and amount of smoking), body mass index, prevalent ischemic heart disease (proven by angiography or a documented myocardial infarction), and heart failure (documented New York Heart Association classes II–IV).
Imaging
Imaging was performed on an MRI scanner with 1.5T (Magnetom Symphony; Siemens Medical Systems) and included routinely coronal T1, transversal T2, and transversal and sagittal diffusion-weighted imaging sequences. Lesion volume was measured using specific MRI software (Numaris 3.5 VA13C; Siemens Medical Systems).
Blood Samples
Blood samples were collected at 3 different times: first, at the time of admission, within 12 hours after onset of symptoms; second, on the day after admission; and third, 24 hours after the second measurement. Serum cTnT concentration was measured using the Elecsys 2010 immunoassay system (Roche Diagnostics). Upper reference limit for apparently healthy individuals is 0.01 μg/L. The diagnostic cut-off value (10% coefficient of variation) is 0.03 μg/L. Concentrations above this cut-off indicate myocardial damage.20 Serum cTnI concentration was measured using a LIAISON analyzer (Byk-Diasorin). A concentration >0.03 μg/L is considered pathologically increased.21 Serum NT-proBNP concentration was measured using an Elecsys 2010 analyzer. The reference interval is age and sex dependent, but in all situations, a concentration >227 pg/mL in men and >334 pg/mL in women is considered pathologically increased according to manufacturer information.
Diagnostic
All patients underwent intensive diagnostic follow-up, which included standard 12-lead electrocardiography, monitor electrocardiography, 24-hour electrocardiography, echocardiography (usually transthoracically, if indicated transesophageally), neurosonography (extracranial continuous wave and duplex sonography and transcranial sonography), routine laboratory (including creatine kinase–MB), coagulation, and vasculitis screening. If indicated, magnetic resonance angiography or conventional angiography was performed additionally.
Stroke Classification
Etiology of strokes was determined according to Trial of Org 10172 in Acute Treatment (TOAST) stroke subtype classification, which differs between large-artery atherosclerosis, cardioembolism, small-artery occlusion, other etiology, and undetermined etiology.22 Concurrent etiology was defined if a patient had 2 probable etiologies, and it was not possible to determine the causative one.
Statistical Analysis
Nominal or ordinal variables (such as stroke scales) are given as median with 25th and 75th percentiles; continuous variables are given as mean with 95% CI. Multiple regression analysis was performed as follows: nominal variables (sex, insular involvement, heart failure, hypertension, smoking, diabetes, coronary heart disease, hyperlipidemia, cardiac thrombi, left ventricular hypertrophy, and atrial fibrillation) and laboratory values (normal versus pathologically increased) were dichotomized. All variables were first tested one by one against the dependent variable unfavorable outcome (defined either as Barthel index <85 or modified Rankin scale 3 to 6) for the presence of a significant association (P<0.05). Only variables significantly associated with the outcome were assessed in a multivariate model performed separately for each significant laboratory parameter. 2 test assessed significance in 4 table calculations. For all calculations, JMP version 5.0.1. (SAS Institute) was used.
Results
Baseline and Stroke Characteristics
One patient was lost for follow-up because he moved abroad and no relative could be found, thus the study group consisted of 174 patients (71 females and 103 males), with a mean age of 67.7 years (95% CI, 66.0 to 69.4) and a mean body mass index of 25.9 (95% CI, 25.4 to 26.5). The mean lesion volume was 20.7 cm3 (95% CI, 13.8 to 27.6), ranging from 0.1 up to 353.3 cm3. Echocardiography could be performed in 154 (89%) patients; of those, 81 (53%) had signs of left ventricular hypertrophy, and in 6 (4%) patients, cardiac thrombi were detected. No patient had elevated creatine kinase–MB. Intermittent or continuous atrial fibrillation was recorded in 60 (34%) patients; no patient had changes during electrocardiography suggesting cardiac ischemia. All other baseline and stroke characteristics are listed in Table 1.
Morbidity and Mortality
At admission, the median NIHSS score was 8.0 with an interquartile range (IQR) between 4 and 14. At baseline, the median Barthel index was 40 (IQR, 10 to 75); that increased after 3 months to 100 (IQR, 80 to 100). After 3 months, 19 patients (10.9%) had died. No new cardiovascular events occurred during follow-up. Overall, an unfavorable outcome after 3 months was observed in 58 (33.3%) patients, defined as Barthel index <85, and in 60 patients (34.5%), defined as Rankin scale 3 to 6.
Blood Samples
Serial measurement of cTnT and NT-proBNP was performed in all 174 patients, cTnI in 103 patients. There were no significant differences for all baseline parameters between the complete group of 174 patients and the subgroup of 103 patients with cTnI measurements. In 8 patients (4.6%), cTnT was raised >0.03 μg/L at the third sample, whereas in the first and second sample, only 4 (2.3%) and 5 (2.9%) patients were cTnT positive. cTnI was raised >0.03 μg/L in 5 (4.9%) patients at the first sample, in 8 (7.8%) patients in the second, and in 7 patients (6.8%) in the third sample. NT-proBNP was elevated in 102 patients (58.6%) in the first sample, in 112 patients (64.4%) in the second sample, and raised to 114 patients (65.5%) in the third sample. Table 2 shows the mean and CI of all laboratory parameters for those patients with raised values.
Relation to Outcome
Morbidity
The univariate analysis showed a significant influence on morbidity for many baseline factors (age, sex, lesion size, heart failure, NIHSS, smoking, atrial fibrillation, and ischemic heart disease; Table 3) and a variety of laboratory values at different time points (Table 4). Multivariate analysis performed separately for each significant laboratory parameter revealed a significant impact on outcome for lesion size, sex, and NIHSS. All laboratory parameters failed to show a significant influence if these 3 other parameters were taken into account. A separate analysis of NT-proBNP quartiles in relation to outcome revealed a significantly decreased proportion of patients with good outcome in the quartiles with the highest NT-proBNP (Figure).
Proportion of patients with good outcome (Rankin scale 0 to 2) in each quartile of NT-proBNP at all 3 time points (first quartile vs fourth quartile; P=0.0011; P=0.0006; P=0.0174).
Mortality
In the multivariate analysis calculated separately for each significant laboratory parameter, the only significant prognostic factors for mortality were lesion size and heart failure; all other factors did not reach statistical significance.
Discussion
We investigated the time course of cTnT, cTnI, and NT-proBNP changes in acute ischemic stroke in relation to short-term morbidity and mortality. In our study, cTnT was raised only in 4.6% of patients with acute ischemic stroke. We could not confirm the recently reported high rate of 17% cTnT-positive patients with acute ischemic stroke who had a mean of 3.29 μg/L and a 3-fold increase in mortality.2 However, no radiological confirmation of ischemic stroke was reported in that study, so an unknown number of false-positive ischemic strokes or transient ischemic attacks could be included. Moreover, in the investigation by James et al,2 no precise relationship between first increase and clinical symptoms could be established because only 1 measurement of cTnT was performed between 12 and 72 hours after admission (and not from onset of symptoms). A concurrent myocardial lesion was not evaluated because no further cardiac diagnostic was presented (echocardiography, electrocardiography changes, or other enzyme values). The high mean of 3.29 μg/L cTnT suggests coexisting myocardial damage or severe heart failure and could explain the high mortality.2 Our result of only a small group of ischemic stroke patients with raised cTnT is consistent with another study in which cTnT was normal in 32 stroke patients during daily measurement.3 However, no details about neuroradiological results or further cardiac diagnostic studies were published in that study.3
We discovered similar results for cTnI that was elevated at the maximum in 7.8% of all stroke patients. Two non-English reports described an increased proportion of cTnI in acute stroke, but the available data of the English abstracts are too limited to compare their studies with our results.4,23 However, a recent study reported a higher percentage of troponin I–positive acute stroke patients.5
Heart failure is an independent predictive factor for death after first cerebral infarction.24–26 In patients with chronic heart failure, cTnT is increased and the level parallels the severity of the disease.8 Elevated levels of cTnT also identify patients with latent and progressive myocardial damage and with an increased risk of cardiac events.27 Measurement of NT-proBNP has recently become valuable in the rapid diagnosis of heart failure,11 has been used for risk stratification,12,13 and is even predictive of short-term mortality.14 Because heart failure is associated with dependency after stroke,15 early recognition using NT-proBNP could help rapid initiation of an adequate therapy and might consecutively improve clinical outcome. According to our study, which is the first providing data about the role of NT-proBNP in acute stroke, nearly two thirds of acute stroke patients show raised NT-proBNP levels. This may indicate the presence of at least slight ventricular dysfunction or heart failure in a major proportion of ischemic stroke patients. Another reason for a generally higher level of NT-proBNP in stroke patients could be the sympathetic activation after stroke.6,28 This is supported by the fact that NT-proBNP levels increase within the observed time frame and that the rate is much higher than the proportion of patients with known heart failure. Although NT-proBNP shows a significant influence on the outcome in the univariate analysis, this effect is outweighed if other important predictors of outcome such as initial NIHSS and lesion volume are taken into account.
There are some limitations of our study. First, our sample size is too small to calculate a multivariate analysis with all those factors showing an influence in the univariate analysis. Second, we have taken a reference level for NT-proBNP that is used in patients with heart failure but without stroke. Further data on the magnitude of concomitant heart failure and sympathetic activity in acute ischemic stroke patients would be useful to better understand the clinical significance of our observation. According to our data, the reference range of NT-proBNP used in cardiac patients might not be the same as in stroke patients. The use of a different cut-off limit of NT-proBNP in stroke patients might help identify those patients with early heart failure, which could lead to a more adequate therapy. However, according to our current data, no prognostic implication can be drawn from this increase.
In summary, our study does not confirm that a major subgroup of patients with acute cerebral ischemia show pathologically raised cTnT or cTnI concentrations. According to our analysis, elevated cTnT or cTnI concentration without evident myocardial lesion is found only in 4.6% to 7.8% of all acute ischemic strokes. Measurement of cTnT or cTnI should not currently be included in the routine diagnostic, and it has no impact on the outcome. NT-proBNP is raised in nearly two thirds of patients with acute stroke; and high values are associated with increased morbidity, but its determination has no prognostic implications if other stroke risk factors are considered.
Acknowledgments
The kits for measuring NT-proBNP, cTnT, and cTnI were provided by Roche Diagnostics, Basel, Switzerland, and Byk-Diasorin, Dietzenbach, Germany, which were not involved in study design, collection, analysis, and interpretation of data, writing, or approval of the report.
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