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Heart failure may be associated with the onset of ischemic stroke with atrial fibrillation
Journal of the Neurological Sciences 281 (2009) 55–57
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Heart failure may be associated with the onset of ischemic stroke with atrial fibrillation A brain natriuretic peptide study ☆ Kensaku Shibazaki ⁎, Kazumi Kimura, Yoko Okada, Yasuyuki Iguchi, Yuka Terasawa, Junya Aoki Department of Stroke Medicine, Kawasaki Medical School, Japan
a r t i c l e
i n f o
Article history: Received 15 October 2008 Received in revised form 15 January 2009 Accepted 17 February 2009 Available online 24 March 2009 Keywords: Brain natriuretic peptide Atrial fibrillation Congestive heart failure
a b s t r a c t Background and purpose: Congestive heart failure is a risk factor for ischemic stroke. Brain natriuretic peptide (BNP) is used as a biological marker of heart failure. We hypothesized that heart failure was associated with the onset of ischemic stroke patients with atrial fibrillation (AF). Methods: Between June 2006 and December 2007, we prospectively enrolled consecutive acute ischemic stroke patients with AF within 24 h of onset. Plasma BNP was measured twice, on admission and on days 28 or at discharge. As a control, we measured plasma BNP of chronic phase of stroke outpatients with AF. We investigated whether plasma BNP was elevated in the acute phase of stroke. Results: One hundred and nine patients (58 females; mean age, 76.3 years) were enrolled in the present study. Mean ± SD of NIHSS score on admission and mRS score at discharge were 12.6 ± 8.3 and 3.7 ± 1.8, respectively. The interval from stroke onset to plasma BNP measurement on admission was 6.8 ± 6.3 h. Moreover, follow up BNP was measured at mean of 26 ± 9 days after stroke onset. The plasma BNP level in the acute phase of stroke was significantly higher than that of the subacute phase of stroke (median (interquartile range, IQR) 299.0 (176.8–469.5) vs. 149.5 (68.1–347.0) pg/ml, p b 0.001). There was no significant difference in plasma BNP level between the subacute phase of stroke and control group (median (IQR) 149.5 (68.1–347.0) vs. 165.0 (64.6–224.0) pg/ml, p = 0.543). Conclusion: Plasma BNP was elevated in the acute phase of stroke. Heart failure may be associated with the onset of ischemic stroke patients with AF. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Brain natriuretic peptide (BNP) is a 32-amino acid polypeptide containing a 17-amino acid ring structure that was isolated from porcine brain in 1988 [1]. It is a diuretic factor with vasodilator activity. That is mainly released from the ventricular myocardium. Recent studies have shown that plasma BNP level was related to cardiac function [2,3] and it was reported to be useful in the assessment of patients with congestive heart failure [4]. In addition, plasma BNP levels have also been shown to be elevated in patients with acute ischemic stroke [5–10], in particular when accompanied with atrial fibrillation (AF) [5,7,10]. The embolic mechanism of stroke patients with AF has shown abnormalities of hemostasis, which are compatible with a prothrombotic or hypercoagulable state. We hypothesized that congestive heart failure induced the onset of ischemic stroke in patients with AF. Therefore, we suspected that plasma BNP levels was elevated in the
☆ Financial disclosure: This study has not been supported by any grant and we do not have any relevant financial disclosures. ⁎ Corresponding author. Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Tel.: +81 86 462 1111; fax: +81 86 464 1199. E-mail address: [email protected] (K. Shibazaki). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.02.374
acute phase of stroke and declined in the chronic phase of stroke. The present study investigated whether our hypothesis was correct. 2. Subjects and methods Between June 2006 and December 2007, we prospectively enrolled consecutive acute ischemic stroke patients with AF within 24 h of onset. The plasma BNP level was measured twice, on admission and 4 weeks after stroke onset or at discharge. The patients with dialysisdependent chronic renal failure and a history of ischemic heart disease were excluded in the present study because plasma BNP level is increased in such patients [11,12]. Diagnosis of acute ischemic stroke was made by stroke neurologists, and confirmed by computed tomography or magnetic resonance imaging. We documented the diagnosis of AF using routine 12-lead electrocardiography (ECG) on admission, continuous ECG monitoring, and 24-h Holter ECG. The following factors were assessed: age, gender, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score [13] on admission, modified Rankin Scale (mRS) score [14] at discharge, and cardio-thoracic ratio (CTR) on chest X ray. We also evaluated the following vascular risk factors: hypertension (defined as the use of antihypertensive agents, a systolic blood pressure ≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg before stroke
56
K. Shibazaki et al. / Journal of the Neurological Sciences 281 (2009) 55–57
onset or 2 weeks after stroke onset); diabetes mellitus (defined as the use of oral hypoglycemic agents or insulin, fasting blood glucose level ≥126 mg/dl, or a glycosylated hemoglobin level ≥6.4%); hyperlipidemia (defined as the use of antihyperlipidemic agents or a serum cholesterol level ≥220 mg/dl); current smoking habit (defined as a history of smoking during the preceding 3 months). Between August 2007 and October 2007, stroke outpatients with AF who did not have ischemic stroke within 6 months, were studied as controls. Control group did not include any follow up patients in stroke group at all. 2.1. Measurement of plasma BNP levels Plasma BNP measurement were performed twice, on admission and on day 28 or at discharge. Samples were collected from a peripheral vein into tubes containing aprotinin and ethylene diamine tetra acetic acid, and the plasma isolated and then stored at −80 °C until analysis. The plasma BNP concentration was measured using a chemiluminesence enzyme immunoassay for human BNP (Shionogi & Co., Ltd., Osaka, Japan). Briefly, this assay uses two monoclonal antibodies against human BNP, one recognizing a carboxyl-terminal sequence and the other the ring structure of BNP, respectively, and measures BNP by sandwiching it between the two antibodies. BNP can be accurately quantified within 11 min. Normal value of BNP is 18.4 pg/ml or under in our hospital. The minimal detectable quantity of BNP is 3.9 pg/ml. 2.2. Statistical analysis We investigated the differences in plasma BNP level between on admission and on days 28 or at discharge using Wilcoxon signed rank test. The Mann–Whitney U test and linear regression analysis were used to examine factors associated with plasma BNP level. Furthermore, we compared clinical characteristics, including BNP level, between in the subacute phase of stroke and control by using the chi-squared test and Mann–Whitney U test. Statistical analysis was performed using a commercially available software package (StatView, version 5; SAS Institute Inc., Cary, NC). Differences were considered statistically significant at the level of p b 0.05. 3. Results One hundred and seventeen acute ischemic stroke patients with AF within 24 h of onset admitted to our hospital. Of these, eight patients were excluded because of the following; dialysis-dependent chronic renal failure, two; a history of ischemic heart disease, six. Therefore, one hundred and nine patients (58 female; mean age, 76.3 years) were enrolled in the present study. Eighteen patients Table 1 Baseline clinical and laboratory findings. Patients, n Age, year, mean (SD) Female, n (%) Vascular risk factors, n (%) Hypertension Diabetes mellitus Hyperlipidemia Smoking NIHSS score on admission, mean (SD) mRS score at discharge, mean (SD) Cardio–thoracic ratio, mean (SD) D-dimer, μg/ml BNP, pg/ml Median (interquartile range) Mean (SD)
109 76.3 (10.2) 58 (53.2) 79 (72.5) 26 (23.9) 16 (14.7) 39 (35.8) 12.6 (8.3) 3.7 (1.8) 62.2 (6.2) 2.8 (4.1) 299.0 (176.8–469.5) 425.0 (550.4)
SD, standard deviation; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; BNP, brain natriuretic peptide.
Fig. 1. Graph showing the serial change of plasma BNP level. Plasma BNP levels are significantly higher in the acute phase of stroke than in the subacute phase of stroke.
developed AF after admission. Mean ± SD of NIHSS score on admission and mRS score at discharge were 12.6 ± 8.3 and 3.7 ± 1.8, respectively. Baseline characteristics and laboratory findings are listed in Table 1. The interval from stroke onset to blood sample collection on admission was 6.8 ± 6.3 h. Female had higher plasma BNP levels than male (median (interquartile range, IQR) 326.0 (180.0–561.8) vs. 262.0 (117.8–349.8), p = 0.022). Furthermore, the plasma BNP level was related to CTR (r = 0.383, p b 0.001). Age, hypertension, diabetes mellitus, hyperlipidemia, smoking, NIHSS score on admission, mRS score at discharge, and D-dimer were not significantly associated with plasma BNP. Follow up BNP was measured at mean of 26 ± 9 days after stroke onset. Eleven patients could not be measured plasma BNP in the subacute phase of stroke because of the following; death, nine; transfer to another department, two. The plasma BNP level in the acute phase of stroke was significantly higher than that of the subacute phase of stroke (median (IQR) 299.0 (176.8–469.5) vs. 149.5 (68.1–347.0) pg/ml, p b 0.001)(Fig. 1). Female (54.1% for the stroke group vs. 25.0% for the control group, p = 0.007) and smoking (35.7% vs. 14.3, p = 0.037) were significantly higher in the stroke group than the control group (Table 2). There were no significant differences in other variables, such as mean ± SD age (75.8 ± 10.3 vs. 72.1 ± 10.0 years, p = 0.139), hypertension (73.5% vs. 82.1%, p = 0.458), diabetes mellitus (22.4% vs. 7.1%, p = 0.100), and hyperlipidemia (16.3% vs. 28.6%, p = 0.146). There was no significant difference in plasma BNP levels between the patients in the subacute phase of stroke and control (median (IQR) 149.5 (68.1–347.0) vs. 165.0 (64.6–224.0) pg/ml, p = 0.565). Table 2 Clinical and laboratory findings between stroke group and control group. Stroke (n = 98) Age, years, mean (SD) Female, n (%) Vascular risk factors, n (%) Hypertension Diabetes mellitus Hyperlipidemia Smoking BNP, pg/ml Median (interquartile range) Mean (SD)
Control (n = 28)
p value
75.8 (10.3) 53 (54.1)
72.1 (10.0) 7 (25.0)
0.139 0.007
72 (73.5) 22 (22.4) 16 (16.3) 35 (35.7)
23 (82.1) 2 (7.1) 8 (28.6) 4 (14.3)
0.458 0.100 0.146 0.037
149.5 (68.1–347.0) 307.7 (691.3)
SD, standard deviation; BNP, brain natriuretic peptide.
165.0 (64.6–224.0) 173.9 (129.0)
0.565
K. Shibazaki et al. / Journal of the Neurological Sciences 281 (2009) 55–57
4. Discussion In the acute ischemic stroke patients with AF, the median plasma BNP level in the acute phase of stroke was significantly higher than the subacute phase of stroke. Possible explanations for the increase in plasma BNP level in the acute phase of ischemic stroke patients with AF are as follows. First, AF patients have already suffered a congestive heart failure prior to stroke onset. Congestive heart failure is well known to frequently complicate ischemic stroke with AF, and is known to increase the risk of stroke by 2 to 3 fold [15]. Abnormalities of hemostasis, blood constituents, and endothelial dysfunction are considered the mechanism of ischemic stroke onset in patients with heart failure [16]. Previous report demonstrated that high plasma BNP was independent predictor of stroke event in hospitalized congestive heart failure patients [17]. Therefore, congestive heart failure may induce ischemic stroke in patients with AF. Second, neuroendocrine changes due to stroke introduce an increased load on the cardiac ventricles, which induced congestive heart failure. In the present study, plasma BNP level was elevated noticeably in the acute phase of stroke, and declined substantially thereafter, which is compatible with previous reports [5,7–9]. To the best of our knowledge, no previous reports revealed serial change of plasma BNP level in stroke patients with AF. On the other hand, a recent report concluded that plasma BNP may be a useful marker to predict vulnerability to thromboembolism in patients with nonvalvular AF [18]. We believe that high plasma BNP level in patients with AF was at high risk of onset of ischemic stroke. Further prospective study should be needed to clarify whether high levels of plasma BNP in patients with AF can provide as a biological marker of development of ischemic stroke. Recently, an assay to easily and rapidly (approximately 15 min) measure plasma BNP level was developed. Several authors have reported the usefulness of this rapid BNP assay in the emergency diagnosis of heart failure [19,20]. If plasma BNP level is high, we should assess for the presence of heart disease, and should pay attention to volume of intravenous drip and urine not to induce congestive heart failure. Therefore, we propose measurement of BNP routinely to evaluate heart function in stroke patients, in particular associated with AF. This study had several limitations. First, we did not evaluate cardiac function on admission. Further detail investigation of cardiac function, such as ejection fraction and left appendage flow velocity, should be performed. Second, we did not investigate plasma BNP level in patients without AF. Serial change of plasma BNP in patients with ischemic heart disease or cardiomyopathy may be also similar to AF patients. In conclusion, heart failure may be associated with the onset of ischemic stroke in patients with AF.
57
References [1] Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature 1988;332:78–81. [2] Yamamoto K, Burnett Jr JC, Jougasaki M, Nishimura RA, Bailey KR, Saito Y, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988–94. [3] McDonagh TA, Robb SD, Murdoch DR, Morton JJ, Ford I, Morrison CE, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet 1998;351:9–13. [4] Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: Prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96:509–16. [5] Nakagawa K, Yamaguchi T, Seida M, Yamada S, Imae S, Tanaka Y, et al. Plasma concentrations of brain natriuretic peptide in patients with acute ischemic stroke. Cerebrovasc Dis 2005;19:157–64. [6] Makikallio AM, Makikallio TH, Korpelainen JT, Vuolteenaho O, Tapanainen JM, Ylitalo K, et al. Natriuretic peptides and mortality after stroke. Stroke 2005;36:1016–20. [7] Giannakoulas G, Hatzitolios A, Karvounis H, Koliakos G, Charitandi A, Dimitroulas T, et al. N-terminal pro-brain natriuretic peptide levels are elevated in patients with acute ischemic stroke. Angiology 2005;56:723–30. [8] Yip HK, Sun CK, Chang LT, Chen MC, Liou CW. Time course and prognostic value of plasma levels of N-terminal pro-brain natriuretic peptide in patients after ischemic stroke. Circ J 2006;70:447–52. [9] Jensen JK, Mickley H, Bak S, Korsholm L, Kristensen SR. Serial measurements of Nterminal pro-brain natriuretic peptide after acute ischemic stroke. Cerebrovasc Dis 2006;22:439–44. [10] Di Angelantonio E, De Castro S, Toni D, Sacchetti ML, Biraschi F, Prencipe M, et al. Determinants of plasma levels of brain natriuretic peptide after acute ischemic stroke or TIA. J Neurol Sci 2007;260:139–42. [11] Buckley MG, Sethi D, Markandu ND, Sagnella GA, Singer DR, MacGregor GA. Plasma concentrations and comparisons of brain natriuretic peptide and atrial natriuretic peptide in normal subjects, cardiac transplant recipients and patients with dialysis-independent or dialysis-dependent chronic renal failure. Clin Sci (Lond) 1992;83:437–44. [12] Suzuki S, Yoshimura M, Nakayama M, Mizuno Y, Harada E, Ito T, et al. Plasma level of Btype natriuretic peptide as a prognostic marker after acute myocardial infarction: a long-term follow-up analysis. Circulation 2004;110:1387–91. [13] Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the NIH stroke scale using video training. NINDS TPA Stroke Study Group. Stroke 1994;25:2220–6. [14] Sulter G, Steen C, De Keyser J. Use of the Barthel index and modified Rankin scale in acute stroke trials. Stroke 1999;30:1538–41. [15] Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 1987;147:1561–4. [16] Lip GY, Gibbs CR. Does heart failure confer a hypercoagulable state? Virchow's triad revisited. J Am Coll Cardiol 1999;33:1424–6. [17] Komori T, Eguchi K, Tomizawa H, Ishikawa J, Hoshide S, Shimada K, et al. Factors associated with incident ischemic stroke in hospitalized heart failure patients: a pilot study. Hypertens Res 2008;31:289–94. [18] Shimizu H, Murakami Y, Inoue S, Ohta Y, Nakamura K, Katoh H, et al. High plasma brain natriuretic polypeptide level as a marker of risk for thromboembolism in patients with nonvalvular atrial fibrillation. Stroke 2002;33:1005–10. [19] Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. [20] Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol 2002;39:202–9.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Heart failure may be associated with the onset of ischemic stroke with atrial fibrillation A brain natriuretic peptide study ☆ Kensaku Shibazaki ⁎, Kazumi Kimura, Yoko Okada, Yasuyuki Iguchi, Yuka Terasawa, Junya Aoki Department of Stroke Medicine, Kawasaki Medical School, Japan
a r t i c l e
i n f o
Article history: Received 15 October 2008 Received in revised form 15 January 2009 Accepted 17 February 2009 Available online 24 March 2009 Keywords: Brain natriuretic peptide Atrial fibrillation Congestive heart failure
a b s t r a c t Background and purpose: Congestive heart failure is a risk factor for ischemic stroke. Brain natriuretic peptide (BNP) is used as a biological marker of heart failure. We hypothesized that heart failure was associated with the onset of ischemic stroke patients with atrial fibrillation (AF). Methods: Between June 2006 and December 2007, we prospectively enrolled consecutive acute ischemic stroke patients with AF within 24 h of onset. Plasma BNP was measured twice, on admission and on days 28 or at discharge. As a control, we measured plasma BNP of chronic phase of stroke outpatients with AF. We investigated whether plasma BNP was elevated in the acute phase of stroke. Results: One hundred and nine patients (58 females; mean age, 76.3 years) were enrolled in the present study. Mean ± SD of NIHSS score on admission and mRS score at discharge were 12.6 ± 8.3 and 3.7 ± 1.8, respectively. The interval from stroke onset to plasma BNP measurement on admission was 6.8 ± 6.3 h. Moreover, follow up BNP was measured at mean of 26 ± 9 days after stroke onset. The plasma BNP level in the acute phase of stroke was significantly higher than that of the subacute phase of stroke (median (interquartile range, IQR) 299.0 (176.8–469.5) vs. 149.5 (68.1–347.0) pg/ml, p b 0.001). There was no significant difference in plasma BNP level between the subacute phase of stroke and control group (median (IQR) 149.5 (68.1–347.0) vs. 165.0 (64.6–224.0) pg/ml, p = 0.543). Conclusion: Plasma BNP was elevated in the acute phase of stroke. Heart failure may be associated with the onset of ischemic stroke patients with AF. © 2009 Elsevier B.V. All rights reserved.
1. Introduction Brain natriuretic peptide (BNP) is a 32-amino acid polypeptide containing a 17-amino acid ring structure that was isolated from porcine brain in 1988 [1]. It is a diuretic factor with vasodilator activity. That is mainly released from the ventricular myocardium. Recent studies have shown that plasma BNP level was related to cardiac function [2,3] and it was reported to be useful in the assessment of patients with congestive heart failure [4]. In addition, plasma BNP levels have also been shown to be elevated in patients with acute ischemic stroke [5–10], in particular when accompanied with atrial fibrillation (AF) [5,7,10]. The embolic mechanism of stroke patients with AF has shown abnormalities of hemostasis, which are compatible with a prothrombotic or hypercoagulable state. We hypothesized that congestive heart failure induced the onset of ischemic stroke in patients with AF. Therefore, we suspected that plasma BNP levels was elevated in the
☆ Financial disclosure: This study has not been supported by any grant and we do not have any relevant financial disclosures. ⁎ Corresponding author. Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan. Tel.: +81 86 462 1111; fax: +81 86 464 1199. E-mail address: [email protected] (K. Shibazaki). 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.02.374
acute phase of stroke and declined in the chronic phase of stroke. The present study investigated whether our hypothesis was correct. 2. Subjects and methods Between June 2006 and December 2007, we prospectively enrolled consecutive acute ischemic stroke patients with AF within 24 h of onset. The plasma BNP level was measured twice, on admission and 4 weeks after stroke onset or at discharge. The patients with dialysisdependent chronic renal failure and a history of ischemic heart disease were excluded in the present study because plasma BNP level is increased in such patients [11,12]. Diagnosis of acute ischemic stroke was made by stroke neurologists, and confirmed by computed tomography or magnetic resonance imaging. We documented the diagnosis of AF using routine 12-lead electrocardiography (ECG) on admission, continuous ECG monitoring, and 24-h Holter ECG. The following factors were assessed: age, gender, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score [13] on admission, modified Rankin Scale (mRS) score [14] at discharge, and cardio-thoracic ratio (CTR) on chest X ray. We also evaluated the following vascular risk factors: hypertension (defined as the use of antihypertensive agents, a systolic blood pressure ≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg before stroke
56
K. Shibazaki et al. / Journal of the Neurological Sciences 281 (2009) 55–57
onset or 2 weeks after stroke onset); diabetes mellitus (defined as the use of oral hypoglycemic agents or insulin, fasting blood glucose level ≥126 mg/dl, or a glycosylated hemoglobin level ≥6.4%); hyperlipidemia (defined as the use of antihyperlipidemic agents or a serum cholesterol level ≥220 mg/dl); current smoking habit (defined as a history of smoking during the preceding 3 months). Between August 2007 and October 2007, stroke outpatients with AF who did not have ischemic stroke within 6 months, were studied as controls. Control group did not include any follow up patients in stroke group at all. 2.1. Measurement of plasma BNP levels Plasma BNP measurement were performed twice, on admission and on day 28 or at discharge. Samples were collected from a peripheral vein into tubes containing aprotinin and ethylene diamine tetra acetic acid, and the plasma isolated and then stored at −80 °C until analysis. The plasma BNP concentration was measured using a chemiluminesence enzyme immunoassay for human BNP (Shionogi & Co., Ltd., Osaka, Japan). Briefly, this assay uses two monoclonal antibodies against human BNP, one recognizing a carboxyl-terminal sequence and the other the ring structure of BNP, respectively, and measures BNP by sandwiching it between the two antibodies. BNP can be accurately quantified within 11 min. Normal value of BNP is 18.4 pg/ml or under in our hospital. The minimal detectable quantity of BNP is 3.9 pg/ml. 2.2. Statistical analysis We investigated the differences in plasma BNP level between on admission and on days 28 or at discharge using Wilcoxon signed rank test. The Mann–Whitney U test and linear regression analysis were used to examine factors associated with plasma BNP level. Furthermore, we compared clinical characteristics, including BNP level, between in the subacute phase of stroke and control by using the chi-squared test and Mann–Whitney U test. Statistical analysis was performed using a commercially available software package (StatView, version 5; SAS Institute Inc., Cary, NC). Differences were considered statistically significant at the level of p b 0.05. 3. Results One hundred and seventeen acute ischemic stroke patients with AF within 24 h of onset admitted to our hospital. Of these, eight patients were excluded because of the following; dialysis-dependent chronic renal failure, two; a history of ischemic heart disease, six. Therefore, one hundred and nine patients (58 female; mean age, 76.3 years) were enrolled in the present study. Eighteen patients Table 1 Baseline clinical and laboratory findings. Patients, n Age, year, mean (SD) Female, n (%) Vascular risk factors, n (%) Hypertension Diabetes mellitus Hyperlipidemia Smoking NIHSS score on admission, mean (SD) mRS score at discharge, mean (SD) Cardio–thoracic ratio, mean (SD) D-dimer, μg/ml BNP, pg/ml Median (interquartile range) Mean (SD)
109 76.3 (10.2) 58 (53.2) 79 (72.5) 26 (23.9) 16 (14.7) 39 (35.8) 12.6 (8.3) 3.7 (1.8) 62.2 (6.2) 2.8 (4.1) 299.0 (176.8–469.5) 425.0 (550.4)
SD, standard deviation; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; BNP, brain natriuretic peptide.
Fig. 1. Graph showing the serial change of plasma BNP level. Plasma BNP levels are significantly higher in the acute phase of stroke than in the subacute phase of stroke.
developed AF after admission. Mean ± SD of NIHSS score on admission and mRS score at discharge were 12.6 ± 8.3 and 3.7 ± 1.8, respectively. Baseline characteristics and laboratory findings are listed in Table 1. The interval from stroke onset to blood sample collection on admission was 6.8 ± 6.3 h. Female had higher plasma BNP levels than male (median (interquartile range, IQR) 326.0 (180.0–561.8) vs. 262.0 (117.8–349.8), p = 0.022). Furthermore, the plasma BNP level was related to CTR (r = 0.383, p b 0.001). Age, hypertension, diabetes mellitus, hyperlipidemia, smoking, NIHSS score on admission, mRS score at discharge, and D-dimer were not significantly associated with plasma BNP. Follow up BNP was measured at mean of 26 ± 9 days after stroke onset. Eleven patients could not be measured plasma BNP in the subacute phase of stroke because of the following; death, nine; transfer to another department, two. The plasma BNP level in the acute phase of stroke was significantly higher than that of the subacute phase of stroke (median (IQR) 299.0 (176.8–469.5) vs. 149.5 (68.1–347.0) pg/ml, p b 0.001)(Fig. 1). Female (54.1% for the stroke group vs. 25.0% for the control group, p = 0.007) and smoking (35.7% vs. 14.3, p = 0.037) were significantly higher in the stroke group than the control group (Table 2). There were no significant differences in other variables, such as mean ± SD age (75.8 ± 10.3 vs. 72.1 ± 10.0 years, p = 0.139), hypertension (73.5% vs. 82.1%, p = 0.458), diabetes mellitus (22.4% vs. 7.1%, p = 0.100), and hyperlipidemia (16.3% vs. 28.6%, p = 0.146). There was no significant difference in plasma BNP levels between the patients in the subacute phase of stroke and control (median (IQR) 149.5 (68.1–347.0) vs. 165.0 (64.6–224.0) pg/ml, p = 0.565). Table 2 Clinical and laboratory findings between stroke group and control group. Stroke (n = 98) Age, years, mean (SD) Female, n (%) Vascular risk factors, n (%) Hypertension Diabetes mellitus Hyperlipidemia Smoking BNP, pg/ml Median (interquartile range) Mean (SD)
Control (n = 28)
p value
75.8 (10.3) 53 (54.1)
72.1 (10.0) 7 (25.0)
0.139 0.007
72 (73.5) 22 (22.4) 16 (16.3) 35 (35.7)
23 (82.1) 2 (7.1) 8 (28.6) 4 (14.3)
0.458 0.100 0.146 0.037
149.5 (68.1–347.0) 307.7 (691.3)
SD, standard deviation; BNP, brain natriuretic peptide.
165.0 (64.6–224.0) 173.9 (129.0)
0.565
K. Shibazaki et al. / Journal of the Neurological Sciences 281 (2009) 55–57
4. Discussion In the acute ischemic stroke patients with AF, the median plasma BNP level in the acute phase of stroke was significantly higher than the subacute phase of stroke. Possible explanations for the increase in plasma BNP level in the acute phase of ischemic stroke patients with AF are as follows. First, AF patients have already suffered a congestive heart failure prior to stroke onset. Congestive heart failure is well known to frequently complicate ischemic stroke with AF, and is known to increase the risk of stroke by 2 to 3 fold [15]. Abnormalities of hemostasis, blood constituents, and endothelial dysfunction are considered the mechanism of ischemic stroke onset in patients with heart failure [16]. Previous report demonstrated that high plasma BNP was independent predictor of stroke event in hospitalized congestive heart failure patients [17]. Therefore, congestive heart failure may induce ischemic stroke in patients with AF. Second, neuroendocrine changes due to stroke introduce an increased load on the cardiac ventricles, which induced congestive heart failure. In the present study, plasma BNP level was elevated noticeably in the acute phase of stroke, and declined substantially thereafter, which is compatible with previous reports [5,7–9]. To the best of our knowledge, no previous reports revealed serial change of plasma BNP level in stroke patients with AF. On the other hand, a recent report concluded that plasma BNP may be a useful marker to predict vulnerability to thromboembolism in patients with nonvalvular AF [18]. We believe that high plasma BNP level in patients with AF was at high risk of onset of ischemic stroke. Further prospective study should be needed to clarify whether high levels of plasma BNP in patients with AF can provide as a biological marker of development of ischemic stroke. Recently, an assay to easily and rapidly (approximately 15 min) measure plasma BNP level was developed. Several authors have reported the usefulness of this rapid BNP assay in the emergency diagnosis of heart failure [19,20]. If plasma BNP level is high, we should assess for the presence of heart disease, and should pay attention to volume of intravenous drip and urine not to induce congestive heart failure. Therefore, we propose measurement of BNP routinely to evaluate heart function in stroke patients, in particular associated with AF. This study had several limitations. First, we did not evaluate cardiac function on admission. Further detail investigation of cardiac function, such as ejection fraction and left appendage flow velocity, should be performed. Second, we did not investigate plasma BNP level in patients without AF. Serial change of plasma BNP in patients with ischemic heart disease or cardiomyopathy may be also similar to AF patients. In conclusion, heart failure may be associated with the onset of ischemic stroke in patients with AF.
57
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