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Association between nocturnal blood pressure variation and wake-up ischemic stroke
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case report
Association between nocturnal blood pressure variation and wake-up ischemic stroke Hyuk Sung Kwon a,1, Ji Young Kim b,1, Hojin Choi a, Seok Joon Lee a, Seong-Ho Koh a, Young Joo Lee a, Hyun Young Kim a, Hee-Tae Kim a, Juhan Kim a, Young Seo Kim a,⇑ a b
Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea Department of Nuclear Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 11 April 2017 Accepted 21 June 2017 Available online xxxx Keywords: Wake-up stroke Ambulatory blood pressure monitoring Nocturnal dipping Morning surge Metabolic syndrome Ischemic stroke
a b s t r a c t Ischemic stroke during nocturnal sleep, known as wake-up stroke (WUS), has been reported to have more severe symptoms and worse outcomes than non-WUS. However, studies on risk factors for WUS are scarce and the association between nocturnal blood pressure (BP) and WUS is unclear. In this study, we used ambulatory blood pressure monitoring (ABPM) to examine the association between WUS and variation in nocturnal BP. A total of 369 patients with ischemic stroke within one week were consecutively enrolled. ABPM was applied 1–2 weeks after the ictus because of possible reactive increments of BP; antihypertensive medications were delayed until ABPM. Patients were classified into two groups: WUS and non-WUS. Clinical characteristics, including ABPM parameters, were compared. Sixty-seven (18%) patients had WUS. In univariate analysis, patients with WUS had more severe stroke symptoms than patients with non-WUS. There were no differences in clinical characteristics. In addition, ABPM parameters, including nocturnal BP dipping and morning BP surge, were not associated with occurrence of WUS. Patients with WUS had more severe stroke symptoms and worse outcomes than those with nonWUS. Variation in nocturnal BP may not associated with the occurrence of WUS. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction The occurrence of ischemic stroke shows a circadian pattern with a higher rate in the morning [1]. Approximately 25% of ischemic strokes occur during nocturnal sleep and are known as wake-up stroke (WUS) [2–7]. Differences in the clinical characteristics of WUS and non-WUS are controversial: some reports show similarity between the two [2–4], whereas others show more severe stroke symptoms with worse outcomes in WUS [5–7]. Risk factors for WUS are also unclear, though obstructive sleep apnea [8], smoking [6], high blood pressure (BP) [6], and obesity [5] have been suggested. BP also shows circadian variation and is typically lower during the night, increasing upon waking [9]. However, in some patients,
Abbreviations: WUS, wake-up stroke; BP, blood pressure; ABPM, ambulatory blood pressure monitoring; mRS, modified Rankin scale; NIHSS, National Institute of Health stroke scale; SBP, systolic blood pressure; DBP, diastolic blood pressure. ⇑ Corresponding author at: Department of Neurology, Hanyang University College of Medicine, Department of Neurology, College of Medicine, Hanyang University, 17 Haengdangdong, Seongdong-gu, Seoul 133-792, Republic of Korea. E-mail address: [email protected] (Y.S. Kim). 1 These authors contributed equally to this work.
the night-time reduction of BP is less pronounced or does not occur: such patients are known as non-dippers (BP drop <10%), or they may be reverse dippers (BP increases during sleep). Previous report suggested that morning BP surge was associated with ischemic stroke occurrence in patients with dipper but not in non-dippers [10]. Since, either variation of nocturnal BP or surge of morning BP occurs in the early morning period and exaggerated BP increase might lead to arterial wall disorganization and plaque rupture, it could be associated with the occurrence of WUS. To our knowledge, there have been no large studies on the association between WUS and nocturnal BP variation based on 24-h ambulatory BP monitoring (ABPM). In this study, we hypothesized that WUS is associated with nocturnal BP variation or morning BP surge and investigated their correlation. 2. Methods 2.1. Patients Between March 2011 and February 2014 we identified 509 consecutive patients admitted to Hanyang University Hospital with acute ischemic stroke that had occurred within the previous week.
http://dx.doi.org/10.1016/j.jocn.2017.06.066 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kwon HS et al. Association between nocturnal blood pressure variation and wake-up ischemic stroke. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.066
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H.S. Kwon et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Of these patients, 25 were excluded as they had unknown stroke onset with unclear last normal time. Patients with previous modified Rankin scale (mRS) scores of 3, 4, or 5 and/or a discharge mRS score of 4, 5, or 6 (99 patients) were also excluded as they were not able to walk during ABPM. Patients were also excluded for the following reasons (n = 16): severe hypertension with immediate treatment (systolic blood BP > 220 mmHg or diastolic BP > 120 mmHg), secondary hypertension, life-threatening conditions, shift working, or unable to complete the study. Finally, a total of 369 patients were included. The diagnosis and treatment of stroke followed standard guidelines, and the severity of stroke was assessed using the National Institute of Health stroke scale (NIHSS). Stroke etiologies were defined according to the TOAST classification. We performed a retrospective analysis after approval by the Institutional Review Board of Hanyang University Hospital (HYUH 2013-02-001). 2.2. Clinical information and 24-h ambulatory blood pressure monitoring Demographic and clinical information was collected as previously described [11]. Metabolic syndrome was defined as having 3 or more following risk factors: elevated waist circumference
(men 90 cm, women 80 cm), elevated triglyceride (150 mg/ dl), reduced high-density lipoprotein (men <40 mg/dl, women <50 mg/dl), elevated blood pressure (systolic 130 mmHg and/or diastolic 85 mmHg), and elevated fasting glucose (100 mg/dl) [12]. Since BP is known to rise after a stroke and resolve seven days later [13]; ambulatory BP (TM-2430, A&D Medical, Milpitas, CA, USA) was monitored after one or two weeks after stroke onset. Antihypertensive medication was suspended from the time of the ictus. BP in the non-paretic upper extremity was measured every 15 min during the day and every 30 min during the night. Patients were free to move around the hospital and to engage in the usual activities of in-patients not confined to bed. The following parameters were calculated from the raw data: 24-h mean systolic/diastolic BP (SBP/DBP), awake SBP/DBP, sleep SBP/DBP, 24-h HR, and nocturnal BP fall (dipper, non-dipper, reverse dipper). The definitions of the individual parameters have been described previously [11]. In addition, morning BP surge were evaluated by pre-waking surge and sleep-through surge. Pre-waking surge is defined as the morning SBP (Average SBP of 2-h after wake-up) minus the prewaking SBP (Average SBP of 2-h before wake-up) and sleepthrough surge is defined as morning SBP minus lowest nocturnal SBP. As highest 10 percentile is known as threshold for pathologi-
Table 1 Baseline characteristics of wake-up versus non-wake-up strokes. Wake-up strokes (n = 67)
Non-wake-up strokes (n = 302)
p
Demographic Age, years Sex, male (%) Waist circumference (cm) Body mass index (kg/m2)
67.4 ± 14.1 40 (59.7) 85.7 ± 10.7 23.4 ± 3.4
65.8 ± 12.7 191 (63.2) 86.2 ± 9.0 23.6 ± 2.9
0.364* 0.588 0.724* 0.564*
Risk factor Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Previous stroke (%) Smoking (%) Atrial fibrillation (%) Metabolic syndrome (%) Metabolic syndrome components (number)
40 (59.7) 35 (52.2) 19 (28.4) 9 (13.4) 23 (34.3) 13 (19.4) 31 (46.3) 2.3 ± 1.3
191 (63.2) 124 (41.1) 64 (21.2) 42 (13.9) 112 (37.1) 56 (18.5) 128 (42.4) 2.4 ± 1.4
0.588 0.095 0.204 0.919 0.672 0.870 0.561 0.484*
Laboratory finding Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglyceride (mg/dl) Fasting glucose (mg/dl)
181.2 ± 44.9 42.9 ± 14.1 117.9 ± 34.6 128.7 ± 64.8 124.2 ± 46.5
177.5 ± 39.3 42.8 ± 11.3 109.2 ± 31.9 123.8 ± 92.5 116.9 ± 41.1
0.493* 0.960* 0.050* 0.685* 0.202*
Medication history Anti-hypertensive (%) Anti-diabetes (%) Anti-platelet (%) Anti-coagulation (%) Statin (%)
34 (50.7) 19 (28.4) 17 (25.4) 2 (3.0) 8 (11.9)
153 (50.7) 66 (21.9) 85 (28.1) 8 (2.6) 39 (12.9)
0.990 0.253 0.646 0.878 0.829
Stroke subtype Small vessel occlusion (%) Large artery disease (%) Cardioembolism (%) Other determined (%) Undetermined (%)
22 (32.8) 21 (31.3) 11 (16.4) 3 (4.5) 10 (14.9)
101 (33.4) 92 (30.4) 59 (19.5) 12 (4.0) 38 (12.6)
Stroke location Anterior circulation, n (%) Posterior circulation, n (%) Combined, n (%)
39 (58.2) 24 (35.8) 4 (6.0)
174 (57.6) 118 (39.1) 10 (3.3)
Stroke severity Initial NIHSS score Discharge NIHSS score Discharge mRS score
4.1 ± 3.6 2.0 ± 2.2 1.6 ± 0.9
3.4 ± 3.5 1.3 ± 1.6 1.1 ± 0.8
0.967
0.555
0.002y 0.003y <0.001y
Pearson’s chi-square test, Student’s t-test*, and the Mann–Whitney U-testy were used. NIHSS, National Institute of Health stroke scale; mRS, modified Rankin scale.
Please cite this article in press as: Kwon HS et al. Association between nocturnal blood pressure variation and wake-up ischemic stroke. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.066
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H.S. Kwon et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
cal morning BP surge, we compared mean and highest 10 percentile of morning BP surge between patients with WUS and NWUS [14].
ing surge (25.0 mmHg) and sleep through morning surge (55.7 mmHg) were also not associated with WUS (Table 2).
2.3. Statistical analyses
4. Discussion
The stroke patients were initially divided into two groups: WUS and non-WUS. In order to assess the relationship between various parameters, including ABPM and WUS, we used Pearson’s chisquare tests for categorical variables, and Student’s t-tests and the Mann–Whitney U test for continuous variables, as appropriate. Two-sided values of p < 0.05 were considered significant. The software package SPSS 21.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.
In this study, patients with WUS had more severe clinical symptoms of stroke and worse clinical outcomes at discharge than patients with non-WUS, which is in line with some previous reports [5–7]. Otherwise, demographic and clinical findings, including ABPM parameters, did not differ between the two groups. These are unique findings comparing ischemic stroke patients with WUS and non-WUS based on 24-h ABPM. WUS has recently received much attention because symptoms are more severe, and they could be a candidate for thrombolysis [15]. Thus, multimodal MRI has been widely studied for selection of patient who were eligible to thrombolytic therapy [16]. It is also important to identify possible risk factors for WUS. Circadian BP variation could be an important factor because the change from night-time to morning BP differs between individuals. In one study, reverse dipping and extreme dipping were associated with occurrence of ischemic stroke, and WUS was reported to be associated with extreme BP dipping. Since extreme BP dipping may result in more pronounce morning BP surge, it could be associated with WUS. Although extreme BP dipping was not associated with WUS in our study, it should be interpreted cautiously due to small sample size (only 7 patients with WUS) with extreme BP dipping [17]. Nocturnal dipping pattern or morning BP surge were expected to increase risk of the rupture of fragile atherosclerotic plaque and trigger cardiovascular events [14,15]. But in our study, WUS had no association with nocturnal dipping pattern or morning BP surge. As ischemic stroke is multifactorial disease with diverse mechanisms, various factors other than BP, such as increase in platelet aggregation and peak in prothrombotic factor which affects blood viscosity might also contribute to WUS [15]. In addition, morning BP surge represents elevation of BP after wake-up not before awakening of patients. Thus, morning BP surge may associ-
3. Results Of the 369 stroke patients in the study, 67 (18%) had WUS and 231 (62.6%) were male. Overall, the mean age (SD) was 66.1 (12.9) years, and initial NIHSS score (mean, SD) was 3.3 ± 3.5. Baseline characteristics of patients with WUS and non-WUS are described in Table 1. Demographic findings, proportions of risk factors, and laboratory findings did not differ between the two groups. In patients with WUS, two patients (3%) received thrombolytic therapy, while 24 (8%) of non-WUS patients received thrombolytic therapy (p = 0.151). Numbers of metabolic components were also compared but there were no significant differences (p = 0.385). However, patients with WUS had more severe symptoms and poorer short-term outcomes than non-WUS patients. WUS patients had higher initial NIHSS (4.1 ± 3.6 vs 3.4 ± 3.5; p = 0.002), discharge NIHSS (2.0 ± 2.2 vs 1.3 ± 1.6; p = 0.003), and discharge mRS scores (1.6 ± 0.9 vs 1.1 ± 0.8; p < 0.001). ABPM parameters, including 24-h mean SBP/DBP, awake SBP/ DBP, sleep SBP/DBP, and 24-h HR did not differ between the two groups. The circadian pattern of BP, such as morning BP surge and nocturnal dipping BP, also showed no association with the occurrence of WUS. The highest 10 percentile of pre-waking morn-
Table 2 ABPM parameters of wake-up versus non-wake-up strokes. Wake-up strokes (n = 67)
Non-wake-up strokes (n = 302)
p
143.8 ± 21.6 82.7 ± 10.8 69.0 ± 10.5 145.4 ± 20.7 84.7 ± 11.3 70.6 ± 10.3 137.8 ± 24.2 77.8 ± 10.9 64.7 ± 9.8 143.7 ± 23.5 136.0 ± 25.0
140.6 ± 17.6 81.0 ± 9.1 68.0 ± 9.8 142.6 ± 17.6 82.2 ± 9.6 71.4 ± 32.3 135.2 ± 20.2 79.7 ± 12.2 63.7 ± 10.7 141.0 ± 20.4 135.6 ± 20.7
0.196 0.180 0.452 0.265 0.073 0.844 0.374 0.192 0.516 0.360 0.893
Morning surge in SBP (pre-waking surge) Mean 25.0 mmHg (%)
7.7 ± 19.0 11 (16.7)
4.9 ± 17.5 28 (9.4)
0.264 0.084*
Morning surge in SBP (sleep-through surge) Mean 55.7 mmHg (%)
34.9 ± 20.3 8 (12.1)
30.9 ± 20.6 29 (9.7)
0.158 0.508*
Awake nocturnal falls in SBP Dipper (%) Non-dipper (%) Reverse dipper (%) Extreme dipper (%)
19 (28.4) 31 (46.3) 15 (22.4) 2 (2.7)
78 (25.8) 140 (46.4) 76 (25.2) 8 (2.6)
ABPM parameter 24-h SBP 24-h DBP 24-h heart rate Awake SBP Awake DBP Awake heart rate Sleep SBP Sleep DBP Sleep heart rate Morning SBP Pre-awake SBP
0.955*
Student’s t-test and Pearson’s chi-square test* were used. SBP, systolic blood pressure; DBP, diastolic blood pressure; ABPM, ambulatory blood pressure monitoring.
Please cite this article in press as: Kwon HS et al. Association between nocturnal blood pressure variation and wake-up ischemic stroke. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.066
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H.S. Kwon et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
ated with morning onset of ischemic stroke not WUS. Further investigation should be needed to confirm these phenomenon. Another noteworthy finding is the lack of association between metabolic syndrome and WUS. We evaluated this association because obstructive sleep apnea is known to be linked to WUS and metabolic syndrome [8]. However, prevalence of metabolic syndrome, the number of metabolic syndrome components, and abdominal circumference, did not differ between the two groups of stroke patients. Since, obesity and sleep apnea has been linked to WUS in previous studies [5,8], focused symptoms rather than metabolic syndrome should be assessed in the future. Although we report new findings based on ABPM, there are also some limitations in our study. First, it was a retrospective observational study in a single tertiary hospital which could not avoid selection bias. Second, we excluded stroke patients with severe symptoms who were not able to walk during ABPM. This exclusion criterion resulted in lower mean NIHSS scores which should not be generalized to all ischemic stroke patients. Nevertheless, we believe that including patients with severe symptoms could lead to less clear findings, because ABPM may not reflect a bed ridden patient’s real status. Third, patients underwent ABPM only once before discharge. Although BP is known to fall to the original level by one week after a stroke, repeated ABPM in an out-patient setting may reflect a patient’s status more accurately. However, the inconvenience to patients and issues of cost prevented us from doing this. Finally, we could not exclude anti-hypertensive drug effect which was used before stroke onset. Those drugs may affect circadian variation of patients which may be different from antihypertensive drug free status. Despite these limitations, our study will add to current knowledge of WUS. We suggest that a nocturnal dipping pattern of BP and morning BP surge is not associated with WUS. Moreover, metabolic syndrome is also not associated with WUS. In order to decrease the incidence of WUS, more risk factors need to be identified. Funding This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (2016R1C1B1010056).
Conflict of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing the paper. References [1] Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 1998;29:992–6. [2] Koton S, Tanne D, Bornstein NM. Ischemic stroke on awakening: patients’ characteristics, outcomes and potential for reperfusion therapy. Neuroepidemiology 2012;39:149–53. [3] Silva GS, Lima FO, Camargo EC, et al. Wake-up stroke: clinical and neuroimaging characteristics. Cerebrovasc Dis 2010;29:336–42. [4] Mackey J, Kleindorfer D, Sucharew H, et al. Population-based study of wake-up strokes. Neurology 2011;76:1662–7. [5] Jimenez-Conde J, Ois A, Rodriguez-Campello A, et al. Does sleep protect against ischemic stroke? Less frequent ischemic strokes but more severe ones. J Neurol 2007;254:782–8. [6] Nadeau JO, Fang J, Kapral MK, et al. Outcome after stroke upon awakening. Can J Neurol Sci 2005;32:232–6. [7] Kim BJ, Lee SH, Shin CW, et al. Ischemic stroke during sleep: its association with worse early functional outcome. Stroke 2011;42:1901–6. [8] Hsieh SW, Lai CL, Liu CK, et al. Obstructive sleep apnea linked to wake-up strokes. J Neurol 2012;259:1433–9. [9] Redon J. The normal circadian pattern of blood pressure: implications for treatment. Int J Clin Pract Suppl 2004:3–8. [10] Pierdomenico SD, Pierdomenico AM, Cuccurullo F. Morning blood pressure surge, dipping, and risk of ischemic stroke in elderly patients treated for hypertension. Am J Hypertens 2014;27:564–70. [11] Kwon HS, Lim YH, Kim HY, et al. Association of ambulatory blood pressure and heart rate with advanced white matter lesions in ischemic stroke patients. Am J Hypertens 2014;27:177–83. [12] Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–5. [13] Morfis L, Schwartz RS, Poulos R, et al. Blood pressure changes in acute cerebral infarction and hemorrhage. Stroke 1997;28:1401–5. [14] Kario K. Morning surge in blood pressure and cardiovascular risk: evidence and perspectives. Hypertension 2010;56:765–73. [15] Wouters A, Lemmens R, Dupont P, et al. Wake-up stroke and stroke of unknown onset: a critical review. Front Neurol 2014;5:153. [16] Kim BJ, Kang HG, Kim HJ, et al. Magnetic resonance imaging in acute ischemic stroke treatment. J Stroke 2014;16:131–45. [17] Kario K, Pickering TG, Matsuo T, et al. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001;38:852–7.
Please cite this article in press as: Kwon HS et al. Association between nocturnal blood pressure variation and wake-up ischemic stroke. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.066
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Case report
Association between nocturnal blood pressure variation and wake-up ischemic stroke Hyuk Sung Kwon a,1, Ji Young Kim b,1, Hojin Choi a, Seok Joon Lee a, Seong-Ho Koh a, Young Joo Lee a, Hyun Young Kim a, Hee-Tae Kim a, Juhan Kim a, Young Seo Kim a,⇑ a b
Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea Department of Nuclear Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 11 April 2017 Accepted 21 June 2017 Available online xxxx Keywords: Wake-up stroke Ambulatory blood pressure monitoring Nocturnal dipping Morning surge Metabolic syndrome Ischemic stroke
a b s t r a c t Ischemic stroke during nocturnal sleep, known as wake-up stroke (WUS), has been reported to have more severe symptoms and worse outcomes than non-WUS. However, studies on risk factors for WUS are scarce and the association between nocturnal blood pressure (BP) and WUS is unclear. In this study, we used ambulatory blood pressure monitoring (ABPM) to examine the association between WUS and variation in nocturnal BP. A total of 369 patients with ischemic stroke within one week were consecutively enrolled. ABPM was applied 1–2 weeks after the ictus because of possible reactive increments of BP; antihypertensive medications were delayed until ABPM. Patients were classified into two groups: WUS and non-WUS. Clinical characteristics, including ABPM parameters, were compared. Sixty-seven (18%) patients had WUS. In univariate analysis, patients with WUS had more severe stroke symptoms than patients with non-WUS. There were no differences in clinical characteristics. In addition, ABPM parameters, including nocturnal BP dipping and morning BP surge, were not associated with occurrence of WUS. Patients with WUS had more severe stroke symptoms and worse outcomes than those with nonWUS. Variation in nocturnal BP may not associated with the occurrence of WUS. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction The occurrence of ischemic stroke shows a circadian pattern with a higher rate in the morning [1]. Approximately 25% of ischemic strokes occur during nocturnal sleep and are known as wake-up stroke (WUS) [2–7]. Differences in the clinical characteristics of WUS and non-WUS are controversial: some reports show similarity between the two [2–4], whereas others show more severe stroke symptoms with worse outcomes in WUS [5–7]. Risk factors for WUS are also unclear, though obstructive sleep apnea [8], smoking [6], high blood pressure (BP) [6], and obesity [5] have been suggested. BP also shows circadian variation and is typically lower during the night, increasing upon waking [9]. However, in some patients,
Abbreviations: WUS, wake-up stroke; BP, blood pressure; ABPM, ambulatory blood pressure monitoring; mRS, modified Rankin scale; NIHSS, National Institute of Health stroke scale; SBP, systolic blood pressure; DBP, diastolic blood pressure. ⇑ Corresponding author at: Department of Neurology, Hanyang University College of Medicine, Department of Neurology, College of Medicine, Hanyang University, 17 Haengdangdong, Seongdong-gu, Seoul 133-792, Republic of Korea. E-mail address: [email protected] (Y.S. Kim). 1 These authors contributed equally to this work.
the night-time reduction of BP is less pronounced or does not occur: such patients are known as non-dippers (BP drop <10%), or they may be reverse dippers (BP increases during sleep). Previous report suggested that morning BP surge was associated with ischemic stroke occurrence in patients with dipper but not in non-dippers [10]. Since, either variation of nocturnal BP or surge of morning BP occurs in the early morning period and exaggerated BP increase might lead to arterial wall disorganization and plaque rupture, it could be associated with the occurrence of WUS. To our knowledge, there have been no large studies on the association between WUS and nocturnal BP variation based on 24-h ambulatory BP monitoring (ABPM). In this study, we hypothesized that WUS is associated with nocturnal BP variation or morning BP surge and investigated their correlation. 2. Methods 2.1. Patients Between March 2011 and February 2014 we identified 509 consecutive patients admitted to Hanyang University Hospital with acute ischemic stroke that had occurred within the previous week.
http://dx.doi.org/10.1016/j.jocn.2017.06.066 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kwon HS et al. Association between nocturnal blood pressure variation and wake-up ischemic stroke. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.066
2
H.S. Kwon et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Of these patients, 25 were excluded as they had unknown stroke onset with unclear last normal time. Patients with previous modified Rankin scale (mRS) scores of 3, 4, or 5 and/or a discharge mRS score of 4, 5, or 6 (99 patients) were also excluded as they were not able to walk during ABPM. Patients were also excluded for the following reasons (n = 16): severe hypertension with immediate treatment (systolic blood BP > 220 mmHg or diastolic BP > 120 mmHg), secondary hypertension, life-threatening conditions, shift working, or unable to complete the study. Finally, a total of 369 patients were included. The diagnosis and treatment of stroke followed standard guidelines, and the severity of stroke was assessed using the National Institute of Health stroke scale (NIHSS). Stroke etiologies were defined according to the TOAST classification. We performed a retrospective analysis after approval by the Institutional Review Board of Hanyang University Hospital (HYUH 2013-02-001). 2.2. Clinical information and 24-h ambulatory blood pressure monitoring Demographic and clinical information was collected as previously described [11]. Metabolic syndrome was defined as having 3 or more following risk factors: elevated waist circumference
(men 90 cm, women 80 cm), elevated triglyceride (150 mg/ dl), reduced high-density lipoprotein (men <40 mg/dl, women <50 mg/dl), elevated blood pressure (systolic 130 mmHg and/or diastolic 85 mmHg), and elevated fasting glucose (100 mg/dl) [12]. Since BP is known to rise after a stroke and resolve seven days later [13]; ambulatory BP (TM-2430, A&D Medical, Milpitas, CA, USA) was monitored after one or two weeks after stroke onset. Antihypertensive medication was suspended from the time of the ictus. BP in the non-paretic upper extremity was measured every 15 min during the day and every 30 min during the night. Patients were free to move around the hospital and to engage in the usual activities of in-patients not confined to bed. The following parameters were calculated from the raw data: 24-h mean systolic/diastolic BP (SBP/DBP), awake SBP/DBP, sleep SBP/DBP, 24-h HR, and nocturnal BP fall (dipper, non-dipper, reverse dipper). The definitions of the individual parameters have been described previously [11]. In addition, morning BP surge were evaluated by pre-waking surge and sleep-through surge. Pre-waking surge is defined as the morning SBP (Average SBP of 2-h after wake-up) minus the prewaking SBP (Average SBP of 2-h before wake-up) and sleepthrough surge is defined as morning SBP minus lowest nocturnal SBP. As highest 10 percentile is known as threshold for pathologi-
Table 1 Baseline characteristics of wake-up versus non-wake-up strokes. Wake-up strokes (n = 67)
Non-wake-up strokes (n = 302)
p
Demographic Age, years Sex, male (%) Waist circumference (cm) Body mass index (kg/m2)
67.4 ± 14.1 40 (59.7) 85.7 ± 10.7 23.4 ± 3.4
65.8 ± 12.7 191 (63.2) 86.2 ± 9.0 23.6 ± 2.9
0.364* 0.588 0.724* 0.564*
Risk factor Hypertension (%) Diabetes mellitus (%) Hyperlipidemia (%) Previous stroke (%) Smoking (%) Atrial fibrillation (%) Metabolic syndrome (%) Metabolic syndrome components (number)
40 (59.7) 35 (52.2) 19 (28.4) 9 (13.4) 23 (34.3) 13 (19.4) 31 (46.3) 2.3 ± 1.3
191 (63.2) 124 (41.1) 64 (21.2) 42 (13.9) 112 (37.1) 56 (18.5) 128 (42.4) 2.4 ± 1.4
0.588 0.095 0.204 0.919 0.672 0.870 0.561 0.484*
Laboratory finding Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglyceride (mg/dl) Fasting glucose (mg/dl)
181.2 ± 44.9 42.9 ± 14.1 117.9 ± 34.6 128.7 ± 64.8 124.2 ± 46.5
177.5 ± 39.3 42.8 ± 11.3 109.2 ± 31.9 123.8 ± 92.5 116.9 ± 41.1
0.493* 0.960* 0.050* 0.685* 0.202*
Medication history Anti-hypertensive (%) Anti-diabetes (%) Anti-platelet (%) Anti-coagulation (%) Statin (%)
34 (50.7) 19 (28.4) 17 (25.4) 2 (3.0) 8 (11.9)
153 (50.7) 66 (21.9) 85 (28.1) 8 (2.6) 39 (12.9)
0.990 0.253 0.646 0.878 0.829
Stroke subtype Small vessel occlusion (%) Large artery disease (%) Cardioembolism (%) Other determined (%) Undetermined (%)
22 (32.8) 21 (31.3) 11 (16.4) 3 (4.5) 10 (14.9)
101 (33.4) 92 (30.4) 59 (19.5) 12 (4.0) 38 (12.6)
Stroke location Anterior circulation, n (%) Posterior circulation, n (%) Combined, n (%)
39 (58.2) 24 (35.8) 4 (6.0)
174 (57.6) 118 (39.1) 10 (3.3)
Stroke severity Initial NIHSS score Discharge NIHSS score Discharge mRS score
4.1 ± 3.6 2.0 ± 2.2 1.6 ± 0.9
3.4 ± 3.5 1.3 ± 1.6 1.1 ± 0.8
0.967
0.555
0.002y 0.003y <0.001y
Pearson’s chi-square test, Student’s t-test*, and the Mann–Whitney U-testy were used. NIHSS, National Institute of Health stroke scale; mRS, modified Rankin scale.
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cal morning BP surge, we compared mean and highest 10 percentile of morning BP surge between patients with WUS and NWUS [14].
ing surge (25.0 mmHg) and sleep through morning surge (55.7 mmHg) were also not associated with WUS (Table 2).
2.3. Statistical analyses
4. Discussion
The stroke patients were initially divided into two groups: WUS and non-WUS. In order to assess the relationship between various parameters, including ABPM and WUS, we used Pearson’s chisquare tests for categorical variables, and Student’s t-tests and the Mann–Whitney U test for continuous variables, as appropriate. Two-sided values of p < 0.05 were considered significant. The software package SPSS 21.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses.
In this study, patients with WUS had more severe clinical symptoms of stroke and worse clinical outcomes at discharge than patients with non-WUS, which is in line with some previous reports [5–7]. Otherwise, demographic and clinical findings, including ABPM parameters, did not differ between the two groups. These are unique findings comparing ischemic stroke patients with WUS and non-WUS based on 24-h ABPM. WUS has recently received much attention because symptoms are more severe, and they could be a candidate for thrombolysis [15]. Thus, multimodal MRI has been widely studied for selection of patient who were eligible to thrombolytic therapy [16]. It is also important to identify possible risk factors for WUS. Circadian BP variation could be an important factor because the change from night-time to morning BP differs between individuals. In one study, reverse dipping and extreme dipping were associated with occurrence of ischemic stroke, and WUS was reported to be associated with extreme BP dipping. Since extreme BP dipping may result in more pronounce morning BP surge, it could be associated with WUS. Although extreme BP dipping was not associated with WUS in our study, it should be interpreted cautiously due to small sample size (only 7 patients with WUS) with extreme BP dipping [17]. Nocturnal dipping pattern or morning BP surge were expected to increase risk of the rupture of fragile atherosclerotic plaque and trigger cardiovascular events [14,15]. But in our study, WUS had no association with nocturnal dipping pattern or morning BP surge. As ischemic stroke is multifactorial disease with diverse mechanisms, various factors other than BP, such as increase in platelet aggregation and peak in prothrombotic factor which affects blood viscosity might also contribute to WUS [15]. In addition, morning BP surge represents elevation of BP after wake-up not before awakening of patients. Thus, morning BP surge may associ-
3. Results Of the 369 stroke patients in the study, 67 (18%) had WUS and 231 (62.6%) were male. Overall, the mean age (SD) was 66.1 (12.9) years, and initial NIHSS score (mean, SD) was 3.3 ± 3.5. Baseline characteristics of patients with WUS and non-WUS are described in Table 1. Demographic findings, proportions of risk factors, and laboratory findings did not differ between the two groups. In patients with WUS, two patients (3%) received thrombolytic therapy, while 24 (8%) of non-WUS patients received thrombolytic therapy (p = 0.151). Numbers of metabolic components were also compared but there were no significant differences (p = 0.385). However, patients with WUS had more severe symptoms and poorer short-term outcomes than non-WUS patients. WUS patients had higher initial NIHSS (4.1 ± 3.6 vs 3.4 ± 3.5; p = 0.002), discharge NIHSS (2.0 ± 2.2 vs 1.3 ± 1.6; p = 0.003), and discharge mRS scores (1.6 ± 0.9 vs 1.1 ± 0.8; p < 0.001). ABPM parameters, including 24-h mean SBP/DBP, awake SBP/ DBP, sleep SBP/DBP, and 24-h HR did not differ between the two groups. The circadian pattern of BP, such as morning BP surge and nocturnal dipping BP, also showed no association with the occurrence of WUS. The highest 10 percentile of pre-waking morn-
Table 2 ABPM parameters of wake-up versus non-wake-up strokes. Wake-up strokes (n = 67)
Non-wake-up strokes (n = 302)
p
143.8 ± 21.6 82.7 ± 10.8 69.0 ± 10.5 145.4 ± 20.7 84.7 ± 11.3 70.6 ± 10.3 137.8 ± 24.2 77.8 ± 10.9 64.7 ± 9.8 143.7 ± 23.5 136.0 ± 25.0
140.6 ± 17.6 81.0 ± 9.1 68.0 ± 9.8 142.6 ± 17.6 82.2 ± 9.6 71.4 ± 32.3 135.2 ± 20.2 79.7 ± 12.2 63.7 ± 10.7 141.0 ± 20.4 135.6 ± 20.7
0.196 0.180 0.452 0.265 0.073 0.844 0.374 0.192 0.516 0.360 0.893
Morning surge in SBP (pre-waking surge) Mean 25.0 mmHg (%)
7.7 ± 19.0 11 (16.7)
4.9 ± 17.5 28 (9.4)
0.264 0.084*
Morning surge in SBP (sleep-through surge) Mean 55.7 mmHg (%)
34.9 ± 20.3 8 (12.1)
30.9 ± 20.6 29 (9.7)
0.158 0.508*
Awake nocturnal falls in SBP Dipper (%) Non-dipper (%) Reverse dipper (%) Extreme dipper (%)
19 (28.4) 31 (46.3) 15 (22.4) 2 (2.7)
78 (25.8) 140 (46.4) 76 (25.2) 8 (2.6)
ABPM parameter 24-h SBP 24-h DBP 24-h heart rate Awake SBP Awake DBP Awake heart rate Sleep SBP Sleep DBP Sleep heart rate Morning SBP Pre-awake SBP
0.955*
Student’s t-test and Pearson’s chi-square test* were used. SBP, systolic blood pressure; DBP, diastolic blood pressure; ABPM, ambulatory blood pressure monitoring.
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ated with morning onset of ischemic stroke not WUS. Further investigation should be needed to confirm these phenomenon. Another noteworthy finding is the lack of association between metabolic syndrome and WUS. We evaluated this association because obstructive sleep apnea is known to be linked to WUS and metabolic syndrome [8]. However, prevalence of metabolic syndrome, the number of metabolic syndrome components, and abdominal circumference, did not differ between the two groups of stroke patients. Since, obesity and sleep apnea has been linked to WUS in previous studies [5,8], focused symptoms rather than metabolic syndrome should be assessed in the future. Although we report new findings based on ABPM, there are also some limitations in our study. First, it was a retrospective observational study in a single tertiary hospital which could not avoid selection bias. Second, we excluded stroke patients with severe symptoms who were not able to walk during ABPM. This exclusion criterion resulted in lower mean NIHSS scores which should not be generalized to all ischemic stroke patients. Nevertheless, we believe that including patients with severe symptoms could lead to less clear findings, because ABPM may not reflect a bed ridden patient’s real status. Third, patients underwent ABPM only once before discharge. Although BP is known to fall to the original level by one week after a stroke, repeated ABPM in an out-patient setting may reflect a patient’s status more accurately. However, the inconvenience to patients and issues of cost prevented us from doing this. Finally, we could not exclude anti-hypertensive drug effect which was used before stroke onset. Those drugs may affect circadian variation of patients which may be different from antihypertensive drug free status. Despite these limitations, our study will add to current knowledge of WUS. We suggest that a nocturnal dipping pattern of BP and morning BP surge is not associated with WUS. Moreover, metabolic syndrome is also not associated with WUS. In order to decrease the incidence of WUS, more risk factors need to be identified. Funding This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (2016R1C1B1010056).
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Please cite this article in press as: Kwon HS et al. Association between nocturnal blood pressure variation and wake-up ischemic stroke. J Clin Neurosci (2017), http://dx.doi.org/10.1016/j.jocn.2017.06.066