Cellular, molecular and developmental neuroscience
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N-terminal probrain natriuretic peptide levels as a predictor of functional outcomes in patients with ischemic stroke Li Changa, Haiqing Yana, Hehua Lia, Zhixiu Songa, Yongkun Guia, Zhixin Yana, Tong Lia and Dongyin Duanb The prognostic value of the N-amino terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) in acute ischemic stroke (AIS) is uncertain. We sought to determine whether NT-proBNP levels were associated with functional outcomes after AIS. From August 2012 to October 2013, consecutive first-ever AIS patients admitted to the Department of Emergency of the First Affiliated Hospital of Xinxiang Medical University, China, were included in this study. Plasma NT-proBNP levels were measured from admission. Outcomes were measured as 90-day modified Rankin Scale score (‘good outcome’ = 0–2 vs. ‘poor’). Multivariate logistic regression was used to assess associations between NT-proBNP levels and outcomes. Predictive performance of NT-proBNP as compared with the clinical model was assessed by comparing receiver-operating characteristic curves. During this study period, 217 consecutive patients with AIS were included and completed 90 days of follow-up. There was a strong positive correlation between the plasma level of NTproBNP and the National Institutes of Health Stroke Scale score (r = 0.415, P = 0.000). Plasma levels of NT-proBNP in patients with an unfavorable outcome were significantly higher than those in patients with a favorable outcome [3432 (interquartile range, 1100–54991) vs. 978
Introduction Stroke is the second most common cause of death and is the leading cause of adult disability in China. Approximately 15–30% of stroke survivors are permanently disabled. Rapidly measurable biomarkers to predict stroke outcome and mortality are pivotal for optimized care and allocation of healthcare resources [1]. Brain natriuretic peptide (BNP) is a counter-regulatory hormone released by the ventricles of the heart. Its main actions are natriuresis and vasodialation [2]. BNP is produced as a prohormone (proBNP) comprising 108 amino acids and is enzymatically cleaved into physiologically active BNP (77–108) and the amino terminal portion of the prohormone [1–76; N-terminal (NT)-proBNP]. Baseline levels of BNP and NT-proBNP have recently been identified as new and useful biochemical markers under a range of circumstances [3,4]. In previous studies, BNP and NT-proBNP were established as diagnostic and prognostic markers in patients with acute coronary syndrome and heart failure [2,5,6]. Di Angelantonio et al. [7] indicated a strong association between the circulating 0959-4965 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
(interquartile range, 123–1705) pg/ml; P = 0.000]. In multivariate analyses, after adjusting for all other significant outcome predictors, the NT-proBNP level that remained can be seen as an independent unfavorable outcome predictor, with an adjusted odds ratios of 4.14 (95% confidence interval, 2.72–7.99; P = 0.000). Our results show that plasma NT-proBNP levels were significantly elevated in patients with an unfavorable outcome and might be of clinical importance as a supplementary tool for the assessment of functional outcomes in patients with AIS. NeuroReport 25:985–990 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2014, 25:985–990 Keywords: acute ischemic stroke, function outcome, N-terminal probrain natriuretic peptide a Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University and bThe Adult Education College of Xinxiang Medical University, Xinxiang, Henan province, China
Correspondence to Tong Li, 88 Jiankang Road, Weihui, Xinxiang 453100, China Tel: + 86 0373 4402307; fax: + 86 0373 4403870; e-mail: [email protected] Received 17 April 2014 accepted 22 April 2014
concentration disease risk.
of
NT-proBNP
and
cardiovascular
Folsom et al. [8] reported that elevated plasma NTproBNP concentrations were associated with an increased risk for ischemic stroke, and Iltumur et al. [9] found that plasma NT-proBNP levels might be of clinical importance as a supplementary tool for the assessment of functional outcomes in patients with acute ischemic stroke (AIS). Further, NT-proBNP has been predictive of long-term mortality [10], whereas no association between NT-proBNP levels and short-term mortality in ischemic stroke patients could be demonstrated [11]. The prognostic value of NT-proBNP in AIS is uncertain. We sought to determine whether NT-proBNP levels were associated with short-term functional outcome after AIS in a cohort Chinese population.
Methods Patients admitted to the Department of Emergency at our hospital between August 2012 and October 2013 with AIS according to the WHO criteria [12] were eligible for DOI: 10.1097/WNR.0000000000000195
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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NeuroReport 2014, Vol 25 No 13
and biochemical tests, and brain computed tomography/ MRI scanning were performed in all patients at admission. MRI with diffusion-weighted imaging was performed in some patients. In those patients, diffusionweighted imaging lesion volumes were determined by one experienced neurologist who was unaware of the clinical and laboratory results. The infarct volume was calculated using the formula 0.5 × a × b × c (where a is the maximal longitudinal diameter, b is the maximal transverse diameter perpendicular to a, and c is the number of 10-mm slices containing the infarct) [13].
participation. Enrolled patients were those with symptom onset within 24 h. All patients had undergone computed tomography scanning or MRI within 24 h after admission. Exclusion criteria were as follows: a history of heart failure (was considered in the presence of a left ventricular ejection fraction < 50% and/or if the patient was previously diagnosed with heart failure by a physician), renal failure (was defined by a plasma creatinine level > 120 μmol/l), malignant tumor, intracranial hemorrhage, severe edema, a history of atrial fibrillation, and a history of recent myocardial infarction within the preceding 3 months. Age-matched and sex-matched nonhospitalized healthy volunteers were recruited as the control group [n = 217; 67 women; median age, 61 years; interquartile range (IQR), 54–74 years]. They had no known diseases and were not using any medication. The present study has been approved by the ethics committee of The First Affiliated Hospital of Xinxiang Medical University. All participants were informed of the study protocol and their written informed consent was obtained, according to the Declaration of Helsinki.
Stroke severity was assessed according to the National Institutes of Health Stroke Scale (NIHSS) score on admission [14], and stroke subtype was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria [15]. Clinical stroke syndrome was determined by applying the criteria of the Oxfordshire Community Stroke Project: total anterior circulation syndrome, partial anterior circulation syndrome, lacunar syndrome, and posterior circulation syndrome [16]. All patients received treatment according to current guidelines.
At baseline, information on demographic factors, routine conventional risk factors (age, obesity, diabetes, hypertension, hyperlipidemia, smoking habit, alcohol abuse, and history of myocardial infarction), and medication was obtained through a structured interview. Routine blood
We considered the following end points: (i) the primary end point was functional outcomes on day 90. Functional outcomes were assessed using the modified Rankin Scale (mRS, a favorable functional outcome was defined as an mRS of 0–2 points, whereas an unfavorable outcome was
Table 1
Basal characteristics of patients with acute ischemic stroke
Characteristics N Female sex (n) Median age (IQR) (years) Hospital stays (IQR) Conventional risk factors Hypertension (%) Diabetes at baseline (%) Hypercholesterolemia (%) Family history of stroke (%) Cigarette smoking (%) Alcohol drinking (%) Stroke syndrome (%) TACS PACS LACS POCS Stroke etiology (%) Small-vessel occlusive Large-vessel occlusive Cardioembolic Other Unknown Laboratory findings Glucose [median (IQR)] (mmol/l) White cell count (IQR) (×109/l) Hs-CRP [median (IQR)] (mg/dl) HCY [median (IQR)] (μmol/l) NT-proBNP [median (IQR)] (pg/ml)
All
Good outcome (mRS 0–2)
Poor outcome (mRS 3–6)
Pa
217 67 61 (54–74) 21 (12–32)
144 43 57 (50–68) 17 (11–29)
73 24 68 (62–81) 25 (15–38)
– NS 0.000 0.031
55.8 26.7 34.6 15.2 19.8 18.0
45.8 27.8 34.0 9.0 19.4 16.7
75.3 24.7 35.6 27.4 20.5 20.5
0.006 NS NS 0.011 NS NS NS
13.4 34.6 20.2 31.8
13.2 35.4 20.1 31.3
13.7 32.9 20.5 32.9
14.8 23.5 36.4 11.5 13.8
13.9 19.4 38.9 11.8 16.0
16.4 31.5 31.5 11.0 9.6
NS 0.021 NS NS 0.032
6.12 (5.44–7.65) 7.6 (5.5–8.9) 1.18 (0.26–3.11) 15.2 (11.5–18.6) 1200 (275–3625)
5.49 (5.01–7.12) 7.0 (5.0–8.1) 0.99 (0.15–2.25) 12.5 (10.2–16.1) 213 (143–357)
6.54 (5.65–7.99) 7.9 (5.7–9.2) 2.15 (1.12–3.55) 16.2 (13.1–19.8) 559 (357–845)
0.005 0.031 0.000 0.000 0.000
HCY, homocysteine; hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; LACS, lacunar syndrome; mRS, modified Rankin Scale; NT-proBNP, N-amino terminal fragment of the prohormone brain natriuretic peptide; PACS, partial anterior circulation syndrome; POCS, posterior circulation syndrome; TACS, total anterior circulation syndrome. a P-value was assessed using the Mann–Whitney U-test or χ2-test.
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NT-proBNP as predictor of outcomes in stroke Chang et al. 987
Fig. 1
(a)
(b)
25.00
200.00
r(Spearman) = 0.415, P = 0.000
r(Spearman) = 0.205, P = 0.002
20.00
Infarct volume (ml)
150.00
NIHSS score
15.00
10.00
100.00
50.00 5.00
0.00
0.00 0.00
5000.00
10 000.00 15 000.00 20 000.00 Plasma level of NT-proBNP (pg/ml)
25 000.00
0.00
5000.00
10 000.00 15 000.00 20 000.00 Plasma level of NT-proBNP (pg/ml)
25 000.00
Correlation between plasma NT-proBNP levels and other predictors. (a) Correlation between the plasma NT-proBNP levels and the National Institutes of Health Stroke Scale (NIHSS) score; (b) correlation between plasma NT-proBNP levels and infarct volume. NT-proBNP, N-amino terminal fragment of the prohormone brain natriuretic peptide.
defined as an mRS of 3–6 points) [17]. (ii) The secondary end point was all-cause mortality within 90 days. Outcomes were assessed by one trained medical staff member blinded to NT-proBNP levels, using a structured interview or through a telephone interview if the patient had been discharged. Specimens for assessment of NT-proBNP levels were collected in heparin-containing tubes, centrifuged for 10 min at 3000g within 4 h of collection, and frozen at − 80°C until analysis. The NT-proBNP level was measured with an electrochemiluminescence immunoassay (sandwich method) on Elecsys 2010 (Roche diagnostics, Mannheim, Germany), with an analytical range of 5–35000 pg/ml. The intra-assay and interassay coefficients of variation were 1.2–1.8 and 1.4–2.1%, respectively. Results are expressed as percentages for categorical variables and as medians [interquartile ranges (IQRs)] for the continuous variables. Values of the measured parameters were checked for normal distribution using the Kolmogorov–Smirnov test before statistical analysis. The Mann–Whitney U-test and the χ2-test were used to compare the two groups. Correlations among laboratory parameters were analyzed using Spearman’s rank correlation test. The influence of NT-proBNP levels on functional outcome was assessed through binary logistic regression analysis, which allows adjustment for confounding factors (age, sex, stroke syndrome, stroke etiology, NIHSS score, infarct volume, vascular risk factors, and hospital stays). Results were expressed as adjusted odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Receiver-operating
characteristic (ROC) curves were constructed for NTproBNP values to evaluate their predictive value for functional outcome. All statistical analyses were carried out using SPSS for Windows, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Statistical significance was defined as P less than 0.05.
Results In the study, 217 consecutive patients with AIS were included and completed 90 days of follow-up. Overall, the median age was 61 years (IQR, 54–74 years) and 30.9% were women. Clinical characteristics are shown in Table 1. The median hospital stay period was 21 days (IQR, 11–30 days). The median NIHSS score on admission was 5 points (IQR, 3–8 points). An unfavorable functional outcome was found in 73 patients (33.6%), with a median mRS score of 4 (IQR, 3–6). The plasma level of NT-proBNP was significantly higher in the study group (1200 pg/ml; IQR, 275–3625 pg/ml) during the acute phase of stroke than in the healthy participants (268 pg/ml; IQR, 175–390 pg/ml; P = 0.000). The results indicated that the plasma level of NTproBNP gradually increased with increasing age [r(Spearman) = 0.136, P = 0.046]. There was no correlation between NT-proBNP levels and sex (P = 0.335). There was a strong positive correlation between the plasma level of NT-proBNP and NIHSS score [r(Spearman) = 0.415, P = 0.000; Fig. 1a]. In addition, there was a modest correlation between the plasma level of NT-proBNP and the high-sensitivity C-reactive protein level (r = 0.159, P = 0.019). In the subgroup of
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NeuroReport 2014, Vol 25 No 13
Fig. 2
25 000.00
Plasma level of NT-proBNP (pg/ml)
20 000.00
15 000.00
10 000.00
5000.00
0.00 Patients with favorable outcome (n = 144)
Patients with unfavorable outcome (n = 73)
Plasma NT-proBNP levels in acute ischemic stroke patients with favorable and unfavorable outcomes. Mann–Whitney U-test. All data are medians and interquartile ranges (IQRs). Significantly higher in stroke patients with favorable outcomes as compared with those with unfavorable outcomes (P = 0.000). NT-proBNP, N-amino terminal fragment of the prohormone brain natriuretic peptide.
patients (n = 155) in whom MRI was available, there was a weak positive correlation between the level of NT-proBNP and infarct volume (r = 0.205, P = 0.002; Fig. 1b). The plasma level of NT-proBNP in patients with an unfavorable outcome was significantly higher than that in patients with a favorable outcome [3432 pg/ml (IQR, 1100–54991 pg/ml) vs. 978 pg/ml (IQR, 123–1705 pg/ml); P = 0.000; Fig. 2]. In univariate logistic regression analysis, we calculated the ORs of log-transformed NTproBNP levels as compared with the NIHSS score and other risk factors. With an unadjusted OR of 8.78 (95% CI, 4.31–17.86), NT-proBNP had a strong association with unfavorable outcome. After adjusting for all other significant outcome predictors, the NT-proBNP levels that remained could be seen as an independent unfavorable outcome predictor with an adjusted OR of 4.14 (95% CI, 2.72–7.99; P = 0.000). On the basis of the ROC curve, the optimal cutoff value for the plasma level of NT-proBNP as an indicator for the diagnosis of unfavorable outcome was projected to be 1500 pg/ml, which yielded a sensitivity of 81.0% and a specificity of 72.4%, with an area under the ROC curve of 0.80 (95% CI, 0.72–0.87). The area under the curve for NT-proBNP was in the range of that for NIHSS [0.83 (0.74–0.92)] and showed a significantly greater discriminatory ability as compared with AUCs for high-sensitivity C-reactive protein (AUC, 0.65; 95% CI, 0.51–0.76; P < 0.001),
homocysteine (AUC, 0.63; 95% CI, 0.53–0.74; P < 0.001), and white cell count (AUC, 0.56; 95% CI, 0.49–0.64; P = 0.012). Interestingly, we found that a combination of NT-proBNP and NIHSS scores could improve the NIHSS scores (AUC of the combined model, 0.86; 95% CI, 0.80–0.94; P < 0.001).
Discussion A large body of evidence from previous studies has indicated that the plasma level of NT-proBNP is associated with an increased risk for stroke [8], and Yip et al. [18] reported that an increase in the NT-proBNP level is strongly and independently correlated with unfavorable clinical outcomes in patients after ischemic stroke. In this study, we assessed the plasma level of NT-proBNP with regard to its accuracy in predicting functional outcome in patients with AIS at 90 days in a Chinese population. Our main finding was that NT-proBNP is a strong and independent prognostic marker of functional outcome in Chinese patients with AIS even after correcting for possible confounding factors (OR, 4.14). We also found that the plasma level of NT-proBNP at admission was positively correlated with infarct volume and the admission neurological deficit (assessed using NIHSS). However, Giannakoulas et al. [19] found that there was no correlation between circulating NT-proBNP levels and stroke topography, infarct size, or severity, as assessed using NIHSS.
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NT-proBNP as predictor of outcomes in stroke Chang et al. 989
When recorded on admission, many plasma neuroendocrine biomarkers are allegedly associated with functional outcomes and mortality in stroke patients [20]. Similarly, NT-proBNP has been shown to predict vascular mortality and functional outcome after adjustment for vascular risk factors [21]. Our findings supported these results. However, Etgen et al. [11] found that NT-proBNP levels on admission were not significantly associated with functional outcome within 3 months if adjusted for vascular risk factors. This discrepancy may be due to differences in the spectrum of patients, methodology, clinical end points to be addressed, or duration of follow-up in patients after stroke. Moreover, NT-proBNP has an acceptable diagnostic value in distinguishing cardioembolic ischemic stroke from other subtypes [22]. The mechanism behind increased plasma level of NTproBNP with poor outcome following an acute stroke is unclear. The plasma level of NT-proBNP is strongly associated with stroke severity in this population. Because stroke severity is also strongly associated with outcomes and mortality after stroke, it is not surprising that NT-proBNP is also associated with outcomes. Another plausible explanation is that as BNP has both centrally and peripherally sympathoinhibitory effects, it may be hypothesized that NT-proBNP is produced in response to increased sympathetic activity during stroke [23]. Stroke-induced inflammation has a negative inotropic effect on the myocyte [24]; this may explain the elevated levels of NT-proBNP. Further, interleukin-6 might directly increase the levels of NT-proBNP by increasing BNP expression [25]. In patients with coronary artery disease, baseline NT-proBNP levels, as well as the increase in NT-proBNP levels, were associated with inducible myocardial ischemia [2]. Some limitations of this observational study should be considered. First, the time-course of NT-proBNP elevation following AIS has not been investigated; this study yielded no data on when and for how long the NT-proBNP level is elevated in these patients. Another limitation is that routine echocardiography was not performed on all study patients. Therefore, complete information on left ventricular function and the integrity of cardiac valves in some patients was not obtained. Third, the exact history is usually difficult to obtain from stroke patients. As a result, the incidences of concomitant congestive heart failure and ischemic heart disease were likely underestimated in the present study. Fourth, the present findings could not be extrapolated to all AIS patients, but could be applied only to this selected subpopulation. Finally, the effects of circulating NTproBNP levels on long-term clinical outcome were not included in the study protocol.
Conclusion Our results show that plasma NT-proBNP levels are significantly elevated in AIS and might be of clinical importance as a supplementary tool for the assessment of functional outcomes in patients with AIS. We recommend that further studies be carried out on the association between increased NT-proBNP levels and poor outcome. If it is possible to elucidate this, the prognosis of patients with stroke might be improved.
Acknowledgements All authors have contributed significantly, and all authors are in agreement with the content of the manuscript. Conflicts of interest
There are no conflicts of interest.
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N-terminal probrain natriuretic peptide levels as a predictor of functional outcomes in patients with ischemic stroke Li Changa, Haiqing Yana, Hehua Lia, Zhixiu Songa, Yongkun Guia, Zhixin Yana, Tong Lia and Dongyin Duanb The prognostic value of the N-amino terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) in acute ischemic stroke (AIS) is uncertain. We sought to determine whether NT-proBNP levels were associated with functional outcomes after AIS. From August 2012 to October 2013, consecutive first-ever AIS patients admitted to the Department of Emergency of the First Affiliated Hospital of Xinxiang Medical University, China, were included in this study. Plasma NT-proBNP levels were measured from admission. Outcomes were measured as 90-day modified Rankin Scale score (‘good outcome’ = 0–2 vs. ‘poor’). Multivariate logistic regression was used to assess associations between NT-proBNP levels and outcomes. Predictive performance of NT-proBNP as compared with the clinical model was assessed by comparing receiver-operating characteristic curves. During this study period, 217 consecutive patients with AIS were included and completed 90 days of follow-up. There was a strong positive correlation between the plasma level of NTproBNP and the National Institutes of Health Stroke Scale score (r = 0.415, P = 0.000). Plasma levels of NT-proBNP in patients with an unfavorable outcome were significantly higher than those in patients with a favorable outcome [3432 (interquartile range, 1100–54991) vs. 978
Introduction Stroke is the second most common cause of death and is the leading cause of adult disability in China. Approximately 15–30% of stroke survivors are permanently disabled. Rapidly measurable biomarkers to predict stroke outcome and mortality are pivotal for optimized care and allocation of healthcare resources [1]. Brain natriuretic peptide (BNP) is a counter-regulatory hormone released by the ventricles of the heart. Its main actions are natriuresis and vasodialation [2]. BNP is produced as a prohormone (proBNP) comprising 108 amino acids and is enzymatically cleaved into physiologically active BNP (77–108) and the amino terminal portion of the prohormone [1–76; N-terminal (NT)-proBNP]. Baseline levels of BNP and NT-proBNP have recently been identified as new and useful biochemical markers under a range of circumstances [3,4]. In previous studies, BNP and NT-proBNP were established as diagnostic and prognostic markers in patients with acute coronary syndrome and heart failure [2,5,6]. Di Angelantonio et al. [7] indicated a strong association between the circulating 0959-4965 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
(interquartile range, 123–1705) pg/ml; P = 0.000]. In multivariate analyses, after adjusting for all other significant outcome predictors, the NT-proBNP level that remained can be seen as an independent unfavorable outcome predictor, with an adjusted odds ratios of 4.14 (95% confidence interval, 2.72–7.99; P = 0.000). Our results show that plasma NT-proBNP levels were significantly elevated in patients with an unfavorable outcome and might be of clinical importance as a supplementary tool for the assessment of functional outcomes in patients with AIS. NeuroReport 25:985–990 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. NeuroReport 2014, 25:985–990 Keywords: acute ischemic stroke, function outcome, N-terminal probrain natriuretic peptide a Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University and bThe Adult Education College of Xinxiang Medical University, Xinxiang, Henan province, China
Correspondence to Tong Li, 88 Jiankang Road, Weihui, Xinxiang 453100, China Tel: + 86 0373 4402307; fax: + 86 0373 4403870; e-mail: [email protected] Received 17 April 2014 accepted 22 April 2014
concentration disease risk.
of
NT-proBNP
and
cardiovascular
Folsom et al. [8] reported that elevated plasma NTproBNP concentrations were associated with an increased risk for ischemic stroke, and Iltumur et al. [9] found that plasma NT-proBNP levels might be of clinical importance as a supplementary tool for the assessment of functional outcomes in patients with acute ischemic stroke (AIS). Further, NT-proBNP has been predictive of long-term mortality [10], whereas no association between NT-proBNP levels and short-term mortality in ischemic stroke patients could be demonstrated [11]. The prognostic value of NT-proBNP in AIS is uncertain. We sought to determine whether NT-proBNP levels were associated with short-term functional outcome after AIS in a cohort Chinese population.
Methods Patients admitted to the Department of Emergency at our hospital between August 2012 and October 2013 with AIS according to the WHO criteria [12] were eligible for DOI: 10.1097/WNR.0000000000000195
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
986
NeuroReport 2014, Vol 25 No 13
and biochemical tests, and brain computed tomography/ MRI scanning were performed in all patients at admission. MRI with diffusion-weighted imaging was performed in some patients. In those patients, diffusionweighted imaging lesion volumes were determined by one experienced neurologist who was unaware of the clinical and laboratory results. The infarct volume was calculated using the formula 0.5 × a × b × c (where a is the maximal longitudinal diameter, b is the maximal transverse diameter perpendicular to a, and c is the number of 10-mm slices containing the infarct) [13].
participation. Enrolled patients were those with symptom onset within 24 h. All patients had undergone computed tomography scanning or MRI within 24 h after admission. Exclusion criteria were as follows: a history of heart failure (was considered in the presence of a left ventricular ejection fraction < 50% and/or if the patient was previously diagnosed with heart failure by a physician), renal failure (was defined by a plasma creatinine level > 120 μmol/l), malignant tumor, intracranial hemorrhage, severe edema, a history of atrial fibrillation, and a history of recent myocardial infarction within the preceding 3 months. Age-matched and sex-matched nonhospitalized healthy volunteers were recruited as the control group [n = 217; 67 women; median age, 61 years; interquartile range (IQR), 54–74 years]. They had no known diseases and were not using any medication. The present study has been approved by the ethics committee of The First Affiliated Hospital of Xinxiang Medical University. All participants were informed of the study protocol and their written informed consent was obtained, according to the Declaration of Helsinki.
Stroke severity was assessed according to the National Institutes of Health Stroke Scale (NIHSS) score on admission [14], and stroke subtype was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria [15]. Clinical stroke syndrome was determined by applying the criteria of the Oxfordshire Community Stroke Project: total anterior circulation syndrome, partial anterior circulation syndrome, lacunar syndrome, and posterior circulation syndrome [16]. All patients received treatment according to current guidelines.
At baseline, information on demographic factors, routine conventional risk factors (age, obesity, diabetes, hypertension, hyperlipidemia, smoking habit, alcohol abuse, and history of myocardial infarction), and medication was obtained through a structured interview. Routine blood
We considered the following end points: (i) the primary end point was functional outcomes on day 90. Functional outcomes were assessed using the modified Rankin Scale (mRS, a favorable functional outcome was defined as an mRS of 0–2 points, whereas an unfavorable outcome was
Table 1
Basal characteristics of patients with acute ischemic stroke
Characteristics N Female sex (n) Median age (IQR) (years) Hospital stays (IQR) Conventional risk factors Hypertension (%) Diabetes at baseline (%) Hypercholesterolemia (%) Family history of stroke (%) Cigarette smoking (%) Alcohol drinking (%) Stroke syndrome (%) TACS PACS LACS POCS Stroke etiology (%) Small-vessel occlusive Large-vessel occlusive Cardioembolic Other Unknown Laboratory findings Glucose [median (IQR)] (mmol/l) White cell count (IQR) (×109/l) Hs-CRP [median (IQR)] (mg/dl) HCY [median (IQR)] (μmol/l) NT-proBNP [median (IQR)] (pg/ml)
All
Good outcome (mRS 0–2)
Poor outcome (mRS 3–6)
Pa
217 67 61 (54–74) 21 (12–32)
144 43 57 (50–68) 17 (11–29)
73 24 68 (62–81) 25 (15–38)
– NS 0.000 0.031
55.8 26.7 34.6 15.2 19.8 18.0
45.8 27.8 34.0 9.0 19.4 16.7
75.3 24.7 35.6 27.4 20.5 20.5
0.006 NS NS 0.011 NS NS NS
13.4 34.6 20.2 31.8
13.2 35.4 20.1 31.3
13.7 32.9 20.5 32.9
14.8 23.5 36.4 11.5 13.8
13.9 19.4 38.9 11.8 16.0
16.4 31.5 31.5 11.0 9.6
NS 0.021 NS NS 0.032
6.12 (5.44–7.65) 7.6 (5.5–8.9) 1.18 (0.26–3.11) 15.2 (11.5–18.6) 1200 (275–3625)
5.49 (5.01–7.12) 7.0 (5.0–8.1) 0.99 (0.15–2.25) 12.5 (10.2–16.1) 213 (143–357)
6.54 (5.65–7.99) 7.9 (5.7–9.2) 2.15 (1.12–3.55) 16.2 (13.1–19.8) 559 (357–845)
0.005 0.031 0.000 0.000 0.000
HCY, homocysteine; hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; LACS, lacunar syndrome; mRS, modified Rankin Scale; NT-proBNP, N-amino terminal fragment of the prohormone brain natriuretic peptide; PACS, partial anterior circulation syndrome; POCS, posterior circulation syndrome; TACS, total anterior circulation syndrome. a P-value was assessed using the Mann–Whitney U-test or χ2-test.
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NT-proBNP as predictor of outcomes in stroke Chang et al. 987
Fig. 1
(a)
(b)
25.00
200.00
r(Spearman) = 0.415, P = 0.000
r(Spearman) = 0.205, P = 0.002
20.00
Infarct volume (ml)
150.00
NIHSS score
15.00
10.00
100.00
50.00 5.00
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10 000.00 15 000.00 20 000.00 Plasma level of NT-proBNP (pg/ml)
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10 000.00 15 000.00 20 000.00 Plasma level of NT-proBNP (pg/ml)
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Correlation between plasma NT-proBNP levels and other predictors. (a) Correlation between the plasma NT-proBNP levels and the National Institutes of Health Stroke Scale (NIHSS) score; (b) correlation between plasma NT-proBNP levels and infarct volume. NT-proBNP, N-amino terminal fragment of the prohormone brain natriuretic peptide.
defined as an mRS of 3–6 points) [17]. (ii) The secondary end point was all-cause mortality within 90 days. Outcomes were assessed by one trained medical staff member blinded to NT-proBNP levels, using a structured interview or through a telephone interview if the patient had been discharged. Specimens for assessment of NT-proBNP levels were collected in heparin-containing tubes, centrifuged for 10 min at 3000g within 4 h of collection, and frozen at − 80°C until analysis. The NT-proBNP level was measured with an electrochemiluminescence immunoassay (sandwich method) on Elecsys 2010 (Roche diagnostics, Mannheim, Germany), with an analytical range of 5–35000 pg/ml. The intra-assay and interassay coefficients of variation were 1.2–1.8 and 1.4–2.1%, respectively. Results are expressed as percentages for categorical variables and as medians [interquartile ranges (IQRs)] for the continuous variables. Values of the measured parameters were checked for normal distribution using the Kolmogorov–Smirnov test before statistical analysis. The Mann–Whitney U-test and the χ2-test were used to compare the two groups. Correlations among laboratory parameters were analyzed using Spearman’s rank correlation test. The influence of NT-proBNP levels on functional outcome was assessed through binary logistic regression analysis, which allows adjustment for confounding factors (age, sex, stroke syndrome, stroke etiology, NIHSS score, infarct volume, vascular risk factors, and hospital stays). Results were expressed as adjusted odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Receiver-operating
characteristic (ROC) curves were constructed for NTproBNP values to evaluate their predictive value for functional outcome. All statistical analyses were carried out using SPSS for Windows, version 20.0 (SPSS Inc., Chicago, Illinois, USA). Statistical significance was defined as P less than 0.05.
Results In the study, 217 consecutive patients with AIS were included and completed 90 days of follow-up. Overall, the median age was 61 years (IQR, 54–74 years) and 30.9% were women. Clinical characteristics are shown in Table 1. The median hospital stay period was 21 days (IQR, 11–30 days). The median NIHSS score on admission was 5 points (IQR, 3–8 points). An unfavorable functional outcome was found in 73 patients (33.6%), with a median mRS score of 4 (IQR, 3–6). The plasma level of NT-proBNP was significantly higher in the study group (1200 pg/ml; IQR, 275–3625 pg/ml) during the acute phase of stroke than in the healthy participants (268 pg/ml; IQR, 175–390 pg/ml; P = 0.000). The results indicated that the plasma level of NTproBNP gradually increased with increasing age [r(Spearman) = 0.136, P = 0.046]. There was no correlation between NT-proBNP levels and sex (P = 0.335). There was a strong positive correlation between the plasma level of NT-proBNP and NIHSS score [r(Spearman) = 0.415, P = 0.000; Fig. 1a]. In addition, there was a modest correlation between the plasma level of NT-proBNP and the high-sensitivity C-reactive protein level (r = 0.159, P = 0.019). In the subgroup of
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NeuroReport 2014, Vol 25 No 13
Fig. 2
25 000.00
Plasma level of NT-proBNP (pg/ml)
20 000.00
15 000.00
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0.00 Patients with favorable outcome (n = 144)
Patients with unfavorable outcome (n = 73)
Plasma NT-proBNP levels in acute ischemic stroke patients with favorable and unfavorable outcomes. Mann–Whitney U-test. All data are medians and interquartile ranges (IQRs). Significantly higher in stroke patients with favorable outcomes as compared with those with unfavorable outcomes (P = 0.000). NT-proBNP, N-amino terminal fragment of the prohormone brain natriuretic peptide.
patients (n = 155) in whom MRI was available, there was a weak positive correlation between the level of NT-proBNP and infarct volume (r = 0.205, P = 0.002; Fig. 1b). The plasma level of NT-proBNP in patients with an unfavorable outcome was significantly higher than that in patients with a favorable outcome [3432 pg/ml (IQR, 1100–54991 pg/ml) vs. 978 pg/ml (IQR, 123–1705 pg/ml); P = 0.000; Fig. 2]. In univariate logistic regression analysis, we calculated the ORs of log-transformed NTproBNP levels as compared with the NIHSS score and other risk factors. With an unadjusted OR of 8.78 (95% CI, 4.31–17.86), NT-proBNP had a strong association with unfavorable outcome. After adjusting for all other significant outcome predictors, the NT-proBNP levels that remained could be seen as an independent unfavorable outcome predictor with an adjusted OR of 4.14 (95% CI, 2.72–7.99; P = 0.000). On the basis of the ROC curve, the optimal cutoff value for the plasma level of NT-proBNP as an indicator for the diagnosis of unfavorable outcome was projected to be 1500 pg/ml, which yielded a sensitivity of 81.0% and a specificity of 72.4%, with an area under the ROC curve of 0.80 (95% CI, 0.72–0.87). The area under the curve for NT-proBNP was in the range of that for NIHSS [0.83 (0.74–0.92)] and showed a significantly greater discriminatory ability as compared with AUCs for high-sensitivity C-reactive protein (AUC, 0.65; 95% CI, 0.51–0.76; P < 0.001),
homocysteine (AUC, 0.63; 95% CI, 0.53–0.74; P < 0.001), and white cell count (AUC, 0.56; 95% CI, 0.49–0.64; P = 0.012). Interestingly, we found that a combination of NT-proBNP and NIHSS scores could improve the NIHSS scores (AUC of the combined model, 0.86; 95% CI, 0.80–0.94; P < 0.001).
Discussion A large body of evidence from previous studies has indicated that the plasma level of NT-proBNP is associated with an increased risk for stroke [8], and Yip et al. [18] reported that an increase in the NT-proBNP level is strongly and independently correlated with unfavorable clinical outcomes in patients after ischemic stroke. In this study, we assessed the plasma level of NT-proBNP with regard to its accuracy in predicting functional outcome in patients with AIS at 90 days in a Chinese population. Our main finding was that NT-proBNP is a strong and independent prognostic marker of functional outcome in Chinese patients with AIS even after correcting for possible confounding factors (OR, 4.14). We also found that the plasma level of NT-proBNP at admission was positively correlated with infarct volume and the admission neurological deficit (assessed using NIHSS). However, Giannakoulas et al. [19] found that there was no correlation between circulating NT-proBNP levels and stroke topography, infarct size, or severity, as assessed using NIHSS.
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NT-proBNP as predictor of outcomes in stroke Chang et al. 989
When recorded on admission, many plasma neuroendocrine biomarkers are allegedly associated with functional outcomes and mortality in stroke patients [20]. Similarly, NT-proBNP has been shown to predict vascular mortality and functional outcome after adjustment for vascular risk factors [21]. Our findings supported these results. However, Etgen et al. [11] found that NT-proBNP levels on admission were not significantly associated with functional outcome within 3 months if adjusted for vascular risk factors. This discrepancy may be due to differences in the spectrum of patients, methodology, clinical end points to be addressed, or duration of follow-up in patients after stroke. Moreover, NT-proBNP has an acceptable diagnostic value in distinguishing cardioembolic ischemic stroke from other subtypes [22]. The mechanism behind increased plasma level of NTproBNP with poor outcome following an acute stroke is unclear. The plasma level of NT-proBNP is strongly associated with stroke severity in this population. Because stroke severity is also strongly associated with outcomes and mortality after stroke, it is not surprising that NT-proBNP is also associated with outcomes. Another plausible explanation is that as BNP has both centrally and peripherally sympathoinhibitory effects, it may be hypothesized that NT-proBNP is produced in response to increased sympathetic activity during stroke [23]. Stroke-induced inflammation has a negative inotropic effect on the myocyte [24]; this may explain the elevated levels of NT-proBNP. Further, interleukin-6 might directly increase the levels of NT-proBNP by increasing BNP expression [25]. In patients with coronary artery disease, baseline NT-proBNP levels, as well as the increase in NT-proBNP levels, were associated with inducible myocardial ischemia [2]. Some limitations of this observational study should be considered. First, the time-course of NT-proBNP elevation following AIS has not been investigated; this study yielded no data on when and for how long the NT-proBNP level is elevated in these patients. Another limitation is that routine echocardiography was not performed on all study patients. Therefore, complete information on left ventricular function and the integrity of cardiac valves in some patients was not obtained. Third, the exact history is usually difficult to obtain from stroke patients. As a result, the incidences of concomitant congestive heart failure and ischemic heart disease were likely underestimated in the present study. Fourth, the present findings could not be extrapolated to all AIS patients, but could be applied only to this selected subpopulation. Finally, the effects of circulating NTproBNP levels on long-term clinical outcome were not included in the study protocol.
Conclusion Our results show that plasma NT-proBNP levels are significantly elevated in AIS and might be of clinical importance as a supplementary tool for the assessment of functional outcomes in patients with AIS. We recommend that further studies be carried out on the association between increased NT-proBNP levels and poor outcome. If it is possible to elucidate this, the prognosis of patients with stroke might be improved.
Acknowledgements All authors have contributed significantly, and all authors are in agreement with the content of the manuscript. Conflicts of interest
There are no conflicts of interest.
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