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Homocysteine is Associated with Exaggerated Morning Blood Pressure Surge in Patients with Acute Ischemic Stroke
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Homocysteine is Associated with Exaggerated Morning Blood Pressure Surge in Patients with Acute Ischemic Stroke TagedPJun-Chao Xie, MD,1 Ying-Ying Lin, MD,1 Xiao-Hui Liu, MD, Yi-Chen Zhao, MD, Xiao-Ye Ma, MD, Jia Yu, MD, Xue-Yuan Liu, PhD, and Yan-Xin Zhao, PhD
Background: Considerable researches suggest that high level of homocysteine (Hcy) is associated with the risk of ischemic stroke. Ambulatory blood pressure monitoring (ABPM) parameters have also been confirmed associated with cardio-cerebrovascular events. However, the relationship between Hcy and ABPM parameters remains unclear in patients with acute ischemic stroke. In this study, we aim to investigate the association between Hcy level and ABPM parameters in patients with acute ischemic stroke. Methods: We enrolled 60 patients with acute ischemic stroke who received ABPM. We calculated ABPM parameters like morning blood pressure surge (MBPS), ambulatory arterial stiffness index, blood pressure variability, and night dipping patterns. Results: Multivariate logistic regression analysis indicated that patients in the top quartile of Hcy level tended to have a higher level of prewaking and sleep-trough MBPS compared with patients in the lower 3 quartiles after adjusted for age and gender (P = .028 and P = .030, respectively). When treating Hcy as a continuous variable, the linear regression showed the association between Hcy level and both MBPS parameters remained significant (prewaking MBPS, r = .356, P = .022; sleep-trough MBPS, r = .365, P = .017, respectively). However, there is no association between Hcy level and ambulatory arterial stiffness index, blood pressure variability or night dipping patterns (P = .635, P = .348 and P = .127 respectively). Conclusions: There is a relationship between the 2 major cerebrovascular risk factorsD:6X3 X MBPS and Hcy. K TagedP ey Words: Morning blood pressure surge—Acute ischemic stroke— Homocysteine—Ambulatory blood pressure monitoring © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction TagedPHomocysteine (Hcy), a sulfur-containing amino acid, is found associated with increased risk of cardioFrom the Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Received November 27, 2017; revision received May 17, 2018; accepted May 22, 2018. Grant support: This project was supported by the National Natural Science Foundation of China (grant numbers 81571033 and 81371212), and the Science and Technology Commission of Shanghai Municipality [grant numbers 18140901900 and 17411950101]. Address correspondence to Xue-Yuan Liu, PhD or Yan-Xin Zhao, PhD, Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China. E-mailes: [email protected] [email protected], [email protected] 1 These authors contributed equally to this work. 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.05.032
cTagedP erebrovascular diseases and metabolic syndrome in hypertension patients.1 The association between Hcy levels and first stroke risk was reported in the analysis of the China Stroke Primary Prevention Trial.2 Studies also suggested that elevated Hcy levels in patients with acute ischemic stroke might predict mortality, especially in the large-vessel atherosclerosis subtype.3 Hcy level was discovered positively associated with the presence of ischemic stroke in Chinese hypertensive patients.4 Besides Hcy, The 24-hour ambulatory blood pressure monitoring (ABPM) parameters like morning blood pressure surge (MBPS), night dipping patterns, ambulatory arterial stiffness index (AASI), and blood pressure (BP) variability have also been confirmed as predictors for not only occurrence but also recurrence of cardio-cerebrovascular events.5-12 The ABPM is considered as a gold standard for evaluating blood pressure (BP) condition especially in hypertension patients. In stroke patients, BP variability is associated with cardio-cerebrovascular outcomes.13,14 AASI predicts future cardiovascular events, particularly
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TagedPstroke, and mortality of cardio-cerebrovascular events, and is associated with arterial function.11,15,16 Thus, recording ABPM parameters is necessary for patients with cardio-cerebrovascular diseases and should be included in the secondary prevention scheme. Studies indicated that ABPM parameters may be associated with other cardiocerebral vascular risk factors like total cholesterol, lowdensity lipoprotein and C-reactive protein values.17,18 Since both Hcy level and ABPM parameters are risk factors and predictors of cardio-cerebrovascular events for individuals with or without cardio-cerebrovascular event,14,19,20 we questioned whether there are some underlying specific links between them. However, few studies focused in this topic in acute ischemic stroke patients. Herein, we conducted this study to reveal the possible relationship between ABPM parameters (including MBPS, night dipping pattern, BP variability, and AASI) and plasma Hcy level in first-ever ischemic stroke patients.
Patients and Methods Patients TagedPThis study was approved by the ethnic committee of Shanghai Tenth People's Hospital. We included consecutive cases with first-ever acute ischemic stroke that admitted to the Department of Neurology of Shanghai Tenth People's Hospital from March, 2014 to October, 2014. Acute ischemic stroke is defined as abrupt neurological dysfunction caused by focal brain ischemia leading to persistent neurologic deficit that accompanied by characteristic abnormalities on brain imaging. In our study, we enrolled patients who developed an acute ischemic stroke conformed by computed tomography or magnetic resonance imaging of the brain within 48 hours of symptom onset. Patients were diagnosed as ischemic stroke according to the World Health Organization criteria.21 Patients with a history of chronic stroke or myocardial infarction were excluded. Blood samples were taken after the patients were hospitalized.
Ambulatory Blood Pressure Monitoring TagedPABPM was performed from the first 8:00 AM after the patients were admitted to our hospital to 8:00 AM the next day with a portable device (Welch Allyn ABPM 6100, Welch Allyn Inc, Skaneateles Falls, NY, USA). ABPM was performed with an adequate cuff on the patient's nondominant arm and automatic BP measurements were programmed to take place at 30-minute intervals while awake and 60-minute intervals while resting. Readings were excluded if less than 80% of the total measurements were obtained.
ABPM Parameters TagedPIn this study, we focused in 4 ABPM parameters: MBPS, AASI, BP variability, and night dipping patterns. For MBPS, we calculated both pre-awaking MBPS which
cTagedP alculated as the morning BP (the mean BP during 2 hours after wake-up) minus the pre-waking BP (2 hours average BP before wake-up) and sleep-trough MBPS which defined as the morning BP minus the lowest nighttime BP (Daverage 38X X of 3 BP readings centered on the lowest nocturnal BP reading). TagedPNight BP dipping was defined as 10% reduction in average systolic blood pressure (SBP) during sleep compared with average daytime SBP,22 and nondipping as the reduction was less than 10%. The nocturnal SBP reduction (%) was calculated as 100 (1—night-time SBP/ daytime SBP ratio). TagedPBP variability was defined as standard deviation (SD) of SBP in 24 hours within a 24-hour period. TagedPAASI was calculated as 1 minus the regression slope of diastolic over SBP values as recorded by the ABPM.23
Statistical Analysis TagedPNormally distributed data was expressed as mean § SD. For skewed distributed data, median and interquartile range was calculated. The baseline characteristics of patients in the top quartile and the lower 3 quartiles were compared with chi-square test or Mann Whitney U test, as appropriate. Univariate and multivariate logistic regression analysis were applied to analyze dichotomies variables. For continuous variables univariate and multivariate linear regression analysis were conducted. Mann Whitney U test was used to compare continuous variables between groups. All comparisons were 2-sided. Analysis of outcome variable was adjusted for age and gender. All analyses were performed using STATA software package (version 12.0; Stata Corp., College Station, TX). Statistical significance was considered when a P value less than .05.
Results Baseline Characteristics TagedPA total of 60 patients (mean age 63.85 § 10.91; median age: 63, interquartile range: 56-74; male%: 60%) with firstever acute ischemic stroke hospitalized in the Department of Neurology, Shanghai Tenth People's Hospital were consecutively enrolled according to our criteria. Baseline characteristics were shown in Table 1.
Analysis of the Dichotomised Hcy Level TagedPHcy level was ranged from 5.5 mmol/L to 19.9 mmol/L (mean § SD: 11.64 § 3.28 mmol/L). We dichotomized the Hcy level at the top quartile, and binary variables were created with 15 patients in the top quartile (Hcy level: 15.70 § 2.87 mmol/L), and with 45 patients in the lower 3 quartiles (Hcy level: 10.29 § 2.09 mmol/L). The baseline characteristics in the top quartile and the lower 3 quartiles were shown in Table 2. MBPS parameters (prewaking MBPS and sleep-trough MBPS) tended to be higher in the top quartile. Compared with patients in the lower 3
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Table 1. Baseline characteristics and ambulatory blood pressure data Variables Age (years) Gender, male (%) Body mass index (kg/m2) Hypertension (%) Coronary heart disease (%) Diabetes (%) Current smoking (%) Homocysteine (mmol/L) Total cholesterol (mmol/L) Triglyceride (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) 24-h mean SBP (mm Hg) 24-h mean DBP (mm Hg) 24-h mean heart rate (beats/min) Daytime mean SBP (mm Hg) Daytime mean DBP (mm Hg) Nighttime mean SBP (mm Hg) Nighttime mean DBP (mm Hg) PreDwaking 8X X MS Sleep-trough MS AASI BP variability Nondipping pattern
Total N = 60 63.85 § 10.91 36 (60.00%) 24.01 § 2.98 5D42X X (9D0.00%) 3X X 8D5X4 X (13.33%) D7X6 X (53.33%) 32 26 (43.33%) 11.64 § 3.28 4.36 (3.88, 5.41) 1.42 (1.07, 2.00) 1.12 (.97, 1.30) 2.79 § .93 140.60 § 16.24 75.57 § 10.75 70.37 § 10.59 141.85 § 16.83 76.25 § 11.01 136.81 § 18.55 73.50 § 11.49 5.01 § 15.03 11.59 § 14.78 .52 § .17 14.08 § 3.85 43 (D72%) 9X X
Abbreviations: AASI, ambulatory arterial stiffness index; BP, blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; MS, morning surge; SBP, systolic blood pressure. Results presented as mean § s.d. or median (interquartile range).
TagedPquartiles, patients in the top quartile of Hcy level tended to have a higher level of prewaking and sleep-trough MBPS (odds ratio [OR]: 1.050, 95% confidence interval [CI]: 1.003-1.098, P = .034; and OR: 1.051, 95% CI: 1.0021.102, P = .039, respectively) (Table 3). The associations remained significant after adjusting for age and gender (OR: 1.056, 95% CI: 1.006-1.109, P = .028; and OR: 1.057, 95% CI: 1.005-1.112, P = .030, respectively) (Table 3). TagedPHowever, there was no significant association between Hcy level and AASI as well as BP variability (OR: .429, 95% CI: .013-14.157, P = .635; and OR: 1.077, 95% CI: .9231.257, P = .348, respectively) (Table 3). After adjusted for age and gender, there was still no association between Hcy level and AASI or BP variability (OR: .680, 95% CI: 1.016-28.52, P = .840; and OR: 1.090, 95% CI: .930-1.277, P = .289, respectively) (Table 3).
Analysis of the Lineal Hcy Level TagedPWe calculated prewaking and sleep-trough MBPS based on the ABPM readings. Both of the MBPS measures were normally distributed. A scatterplot of the Hcy against prewaking MBPS and the sleep-trough MBPS suggested a significant relationship (r = .332, P = .010; and
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rTagedP = .340, P = .008, respectively) (Fig 1, A,B, Table 4). After adjusted for age and gender, both MBPS measures were still significantly associated with Hcy (r = .356, P = .022; r = .365, P = .017, respectively). Patients with MBPS tend to had higher level of Hcy. TagedPBesides, the linear regression of the data indicated no correlation between AASI and plasma Hcy level (r = .196, P = .133, Fig 1, C). Scatterplot of the Hcy level against BP viability suggest no association between these 2 variables (r = .161, P = .219, Fig 1, D). After adjusted for age and gender, neither AASI nor BP viability was associated with Hcy (r = .256, P = .220; r = .286, P = .115, respectively). TagedPNext, the patients were stratified into 2 groups according to the dipping pattern, and Mann Whitney U test showed that Hcy level in patients with dipping or nondipping patterns showed no difference (P = .127) (Fig 1, E).
Discussion TagedPIn the present study, we revealed a correlation between plasma Hcy level and MBPS in patients with acute ischemic stroke. This finding established an intriguing link between these 2 cardio-cerebrovascular risk factors. TagedPIt has been suggest that lowering Hcy could reduce the risk of cerebral infarction (CI). Huang et al found that a 20% reduction in Hcy level was related to a 7% decline in stroke risk.2 The association between Hcy and atherothrombosis is supported by several biologically plausible mechanisms involving increased oxidative stress, coagulation of the blood, impaired endothelial function, induction of thrombosis, alterations of lipid metabolism, and intracellular mechanisms.24,25 Increased Hcy is associated with impaired endothelial function by mechanisms like inducing calcium as a second messenger in smooth muscle cells,24 altering components of NO metabolism and disrupting NO synthesis.26 TagedPThere is considerable evidence suggesting significant associations between morning BP surge and cardiac, cerebral, renal, and vascular damage.12 Some studies suggested that MBPS was associated with endothelial dysfunction.12 Yoda et al found that poor glycemic control as well as insulin resistance was related to the occurrence of MBPS in type 2 diabetes mellitus patients, which might be associated with vascular endothelial dysfunction.27 Therefore, the endothelial dysfunction might be one of the possible mechanisms linking HCY and MBPS. Kario et al found that a 10 mm Hg rise in sleep-trough MBPS might increase the risk of stroke by 22%, and it is supposed that an excessive MBPS might leads to enhanced shear stress on the atherosclerotic vessels, platelet hyperactivity, hypercoagulability, increased vascular spasm, and enhanced sympathetic nervous activity, especially a-adrenergic activity, which might finally trigger stroke.28 Oliver et al recently found that a1B-adrenoceptors expression was higher in peripheral mononuclear cells from hypertensive patients and was correlated with plasmatic
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Table 2. Baseline characteristics between the top quartile of Hcy level and the lower 3 quartiles Variables Age (years) Gender, male (%) Body mass index (kg/m2) Hypertension (%) Coronary heart disease (%) Diabetes (%) Current smoking (%) Homocysteine(mmol/L) Total cholesterol(mmol/L) Triglyceride (mmol/L) HDL-C(mmol/L) LDL-C(mmol/L) 24-h mean SBP(mm Hg) 24-h mean DBP(mm Hg) 24-h mean heart rate(beats/min) Daytime mean SBP(mm Hg) Daytime mean DBP(mm Hg) Nighttime mean SBP(mm Hg) Nighttime mean DBP(mm Hg) PreDwaking 14X X MS Sleep-trough MS AASI BP variability Nondipping pattern
Top quartile
Lower 3 quartiles
P
61.40 § 10.63 10 (66.7%) 24.57 § 2.63 15 (100.0%) 0D1X0 X (.0%) 8 (53.3%) 9 (60.0%) 15.70 § 2.87 4.75 (4.17,5.86) 1.58 (1.08, 1.99) 1.19 (1.07, 1.36) 2.99 § .97 139.20 § 10.92 79.67 § 10.69 72.13 § 12.76 142.91 § 11.45 80.80 § 9.70 130.65 § 13.37 75.13 § 12.93 12.52 § 12.46 18.70 § 10.72 .5007 § .1671 14.88 § 4.97 8 (53.3%)
64.67 § 10.99 26 (57.8%) 23.81 § 3.09 39 (86.7%) D13X2 X (17.8%) 8 24 (53.3%) 17 (37.8%) 10.29 § 2.09 4.28 (3.84, 5.23) 1.38 (1.03, 2.01) 1.07 (.97, 1.27) 2.72 § .92 141.07 § 17.74 74.20 § 10.54 69.78 § 9.85 141.50 § 18.38 74.73 § 11.09 138.87 § 19.68 72.96 § 11.08 2.51 § 15.10 9.21 § 15.28 .5244 § .1706 13.81 § 3.42 35 (77.8%)
.427 .543 .458 .321 .182 1.000 .133 .000* .177 .639 .083 .314 .932 .124 .688 .651 .056 .186 .651 .010* .009* .752 .408 .069
Abbreviations: AASI, ambulatory arterial stiffness index; BP, blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol;; MS, morning surge; SBP, systolic blood pressure. Results presented as mean§s.d. or median (interquartile range). * P < .05.
T cy and BP.29 Because a1-adrenoceptors play a major role agedPH in sympathetic stimulus and may contribute to MBPS, there might be a potential link between MBPS and Hcy. In our study, we found that MBPS and Hcy had associations in ischemic stroke, and patients with MBPS tend to had higher level of Hcy. TagedPResearches have revealed the risk of CI was significantly higher in subjects with nondipping pattern compared with subjects with night BP dipping,30 and reversed dipper in the acute stage of CI was associated with total mortality during long-term follow-up.31 As for the potential interactions of Hcy and hypertension, Dong et al recently found a relationship between plasma Hcy
aTagedP nd circadian BP variation that Hcy was an independent factor associated with nondipping pattern, and Hcy was higher in patients with TT genotype than CC/CT genotypes in an older Chinese cohort of hypertensive adults.32 In our study, Hcy levels in dippers and nondippers showed no association. We speculated that because our study objects were patients with acute ischemic stroke, and the percentage of nondippers were much higher in stroke patients than hypertensive patients. Although Hcy level was suggested associated with nondipping patterns in hypertensive adults, there might be no direct connection between Hcy level and night dipping patterns in ischemic stroke patients.
Table 3. Analysis of dichotomised Hcy and MBPS measures among acute ischemic stroke patients Variables PreDwaking 15X X MS Sleep-trough MS AASI BP variability
OR (95% CI)
P value
Adjusted OR (95% CI)
P value
1.050 (1.003-1.098) 1.051 (1.002-1.102) .429 (.013-14.157) 1.077 (.923-1.257)
.034 .039 .635 .348
1.056 (1.006-1.109) 1.057 (1.005-1.112) .680 (1.016-28.52) 1.090 (.930-1.277)
.028 .030 .840 .289
The dichotomisation of Hcy level at the 75th percentile created binary variables with 15 subjects in the top quartile. Univariate and multivariate logistic regression was used to analyze the dichotomisation of each measure of the Hcy in the highest quartiles (versus remainder) among acute ischemic stroke patients. Abbreviations: AASI, ambulatory arterial stiffness index; Adjusted OR, adjusted for age and gender; BP, blood pressure; CI, confidence interval; Hcy, homocysteine; MBPS, morning blood pressure surge; MS, morning surge; OR, odds ratio. P value <.05 was considered statistically significant.
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RELATIONSHIP BETWEEN HCY AND MBPS IN STROKE PATIENTS Figure 1. Scatterplot of ABPM parameters measures and Homocysteine (Hcy) levels. Simple linear analysis between Hcy and preDwaking 1X X morning surge (A), sleep-trough morning surge (B), AASI (C), BP variability (D) in acute ischemic stroke patients. (E) The Hcy level (mmol/L) in acute ischemic stroke patients with nondipping or dipping patterns, respectively.
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Table 4. Lineal regression analysis of ABPM parameters for each levels of Hcy among acute ischemic stroke patients
PreDwaking 16X X MS Sleep-trough MS AASI BP variability
R
P value
Adjusted R
P value
.332 .340 .196 .161
.010 .008 .133 .219
.356 .365 .256 .286
.022 .017 .220 .115
Abbreviations: AASI, ambulatory arterial stiffness index; ABPM, Ambulatory blood pressure monitoring; Adjusted R, adjusted for age and gender; BP, blood pressure; CI, confidence interval; Hcy, homocysteine; MS, morning surge. P value <.05 was considered statistically significant.
TagedPTaken together, our results add new insights into the association between the MBPS and Hcy in patients with acute ischemic stroke, although we could not clarify the underlining mechanisms now. More high-quality original studies are needed and the mechanisms of the association between MBPS and Hcy in pathological change of ischemic stroke should be further investigated.
Conclusion TagedPIn this study, we can infer that there are intriguing links between Hcy levels and MBPS in acute ischemic stroke patients. Conflict of Interest Disclosure: flict of interest.
TagedPThe authors declare no con-
References TagedP 1. Catena C, Colussi G, Nait F, et al. Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients. Am J Hypertens 2015;28:943-950. TagedP 2. Huang X, Li Y, Li P, et al. Association between percent decline in serum total homocysteine and risk of first stroke. Neurology 2017;89:2101-2107. TagedP 3. Markaki I, Klironomos S, Kostulas K, et al. Elevated plasma homocysteine upon ischemic stroke is associated with increased long-term mortality in women. PLoS One 2017;12:e0183571. TagedP 4. Wang CY, Chen ZW, Zhang T, et al. Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients. Eur J Intern Med 2014;25:538-544. TagedP 5. 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;27:564-570. TagedP 6. Bombelli M, Fodri D, Toso E, et al. Relationship among morning blood pressure surge, 24-hour blood pressure variability, and cardiovascular outcomes in a white population. Hypertension 2014;64:943-950. TagedP 7. Pierdomenico SD, Pierdomenico AM, Coccina F, et al. Prognostic value of nondipping and morning surge in elderly treated hypertensive patients with controlled ambulatory blood pressure. Am J Hypertens 2017;30:159165.
TagedP 8. Sheppard JP, Hodgkinson J, Riley R, et al. Prognostic significance of the morning blood pressure surge in clinical practice: a systematic review. Am J Hypertens 2015;28:30-41. TagedP 9. Xie JC, Yan H, Zhao YX, et al. Prognostic value of morning blood pressure surge in clinical events: a meta-analysis of longitudinal studies. J Stroke Cerebrovasc Dis 2015;24:362-369. TagedP10. Geeganage C, Tracy M, England T, et al. Relationship between baseline blood pressure parameters (including mean pressure, pulse pressure, and variability) and early outcome after stroke: data from the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST). Stroke 2011;42:491-493. TagedP11. Kollias A, Stergiou GS, Dolan E, et al. Ambulatory arterial stiffness index: a systematic review and meta-analysis. Atherosclerosis 2012;224:291-301. TagedP12. Yano Y, Kario K. Nocturnal blood pressure, morning blood pressure surge, and cerebrovascular events. Curr Hypertens Rep 2012;14:219-227. TagedP13. Chen BX, Tian JP, Wang HX, et al. Effect of blood pressure variability on cardiovascular outcome in diabetic and nondiabetic patients with stroke. J Stroke Cerebrovasc Dis 2014;23:2450-2457. TagedP14. Shi Z, Guan Y, Huo YR, et al. Elevated total homocysteine levels in acute ischemic stroke are associated with long-term mortality. Stroke 2015;46:2419-2425. TagedP15. Kikuya M, Staessen JA, Ohkubo T, et al. Ambulatory arterial stiffness index and 24-hour ambulatory pulse pressure as predictors of mortality in Ohasama, Japan. Stroke 2007;38:1161-1166. TagedP16. Dolan E, Thijs L, Li Y, et al. Ambulatory arterial stiffness index as a predictor of cardiovascular mortality in the Dublin Outcome Study. Hypertension 2006;47:365370. TagedP17. Martin CA, Cameron JD, Head GA, et al. The morning blood pressure surge is related to serum cholesterol. J Hum Hypertens 2013;27:315-320. TagedP18. Sezer S, Karakan S, Colak T, et al. Nocturnal nondipping hypertension is related to dyslipidemia and increased renal resistivity index in renal transplant patients. Transplant Proc 2011;43:530-532. TagedP19. Tu WJ, Zhao SJ, Liu TG, et al. Combination of high-sensitivity C-reactive protein and homocysteine predicts the short-term outcomes of Chinese patients with acute ischemic stroke. Neurol Res 2013;35:912-921. TagedP20. Wu XQ, Ding J, Ge AY, et al. Acute phase homocysteine related to severity and outcome of atherothrombotic stroke. Eur J Intern Med 2013;24:362-367. TagedP21. Thorvaldsen P, Asplund K, Kuulasmaa K, et al. Stroke incidence, case-fatality, and mortality in the who Monica project. Stroke 1995;26:361-367. TagedP22. O'Brien E, Sheridan J, O'Malley K. Dippers and non-dippers. Lancet 1988;2:397. TagedP23. Dolan E, Li Y, Thijs L, et al. Ambulatory arterial stiffness index: rationale and methodology. Blood Press Monit 2006;11:103-105. TagedP24. Spence JD. Homocysteine-lowering therapy: a role in stroke prevention. Lancet Neurol 2007;6:830-838. TagedP25. Petras M, Tatarkova Z, Kovalska M, et al. Hyperhomocysteinemia as a risk factor for the neuronal system disorders. J Physiol Pharmacol 2014;65:15-23. TagedP26. Zhao J, Chen H, Liu N, et al. Role of hyperhomocysteinemia and hyperuricemia in pathogenesis of atherosclerosis. J Stroke Cerebrovasc Dis 2017. TagedP27. Yoda K, Inaba M, Hamamoto K, et al. Association between glycemic control and morning blood pressure
ARTICLE IN PRESS RELATIONSHIP BETWEEN HCY AND MBPS IN STROKE PATIENTS TagedPsurge with vascular endothelial dysfunction in type 2 diabetic patients. Diabetes Care 2014;37:644-650. TagedP28. Kario K, Pickering TG, Umeda Y, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation 2003;107:14011406. agedP2T 9. Oliver E, Monto F, Rovira E, et al. Changes in the expression of alpha1B-adrenoceptor in peripheral mononuclear cells correlates with blood pressure and plasmatic homocysteine. Biomed Pharmacother Biomed Pharmacother 2017;88:721-727.
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TagedP30. Metoki H, Ohkubo T, Kikuya M, et al. Prognostic significance for stroke of a morning pressor surge and a nocturnal blood pressure decline: the Ohasama study. Hypertension 2006;47:149-154. TagedP31. Park JH, Lee HS, Kim JH, et al. Reverse dipper and high night-time heart rate in acute stage of cerebral infarction are associated with increased mortality. J Stroke Cerebrovasc Dis 2014;23:1171-1176. TagedP32. Dong YF, Zhan BM, Hao QY, et al. Plasma homocysteine levels are associated with circadian blood pressure variation in Chinese hypertensive adults. Am J Hypertens 2017;30:1203-1210.
Homocysteine is Associated with Exaggerated Morning Blood Pressure Surge in Patients with Acute Ischemic Stroke TagedPJun-Chao Xie, MD,1 Ying-Ying Lin, MD,1 Xiao-Hui Liu, MD, Yi-Chen Zhao, MD, Xiao-Ye Ma, MD, Jia Yu, MD, Xue-Yuan Liu, PhD, and Yan-Xin Zhao, PhD
Background: Considerable researches suggest that high level of homocysteine (Hcy) is associated with the risk of ischemic stroke. Ambulatory blood pressure monitoring (ABPM) parameters have also been confirmed associated with cardio-cerebrovascular events. However, the relationship between Hcy and ABPM parameters remains unclear in patients with acute ischemic stroke. In this study, we aim to investigate the association between Hcy level and ABPM parameters in patients with acute ischemic stroke. Methods: We enrolled 60 patients with acute ischemic stroke who received ABPM. We calculated ABPM parameters like morning blood pressure surge (MBPS), ambulatory arterial stiffness index, blood pressure variability, and night dipping patterns. Results: Multivariate logistic regression analysis indicated that patients in the top quartile of Hcy level tended to have a higher level of prewaking and sleep-trough MBPS compared with patients in the lower 3 quartiles after adjusted for age and gender (P = .028 and P = .030, respectively). When treating Hcy as a continuous variable, the linear regression showed the association between Hcy level and both MBPS parameters remained significant (prewaking MBPS, r = .356, P = .022; sleep-trough MBPS, r = .365, P = .017, respectively). However, there is no association between Hcy level and ambulatory arterial stiffness index, blood pressure variability or night dipping patterns (P = .635, P = .348 and P = .127 respectively). Conclusions: There is a relationship between the 2 major cerebrovascular risk factorsD:6X3 X MBPS and Hcy. K TagedP ey Words: Morning blood pressure surge—Acute ischemic stroke— Homocysteine—Ambulatory blood pressure monitoring © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction TagedPHomocysteine (Hcy), a sulfur-containing amino acid, is found associated with increased risk of cardioFrom the Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Received November 27, 2017; revision received May 17, 2018; accepted May 22, 2018. Grant support: This project was supported by the National Natural Science Foundation of China (grant numbers 81571033 and 81371212), and the Science and Technology Commission of Shanghai Municipality [grant numbers 18140901900 and 17411950101]. Address correspondence to Xue-Yuan Liu, PhD or Yan-Xin Zhao, PhD, Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China. E-mailes: [email protected] [email protected], [email protected] 1 These authors contributed equally to this work. 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.05.032
cTagedP erebrovascular diseases and metabolic syndrome in hypertension patients.1 The association between Hcy levels and first stroke risk was reported in the analysis of the China Stroke Primary Prevention Trial.2 Studies also suggested that elevated Hcy levels in patients with acute ischemic stroke might predict mortality, especially in the large-vessel atherosclerosis subtype.3 Hcy level was discovered positively associated with the presence of ischemic stroke in Chinese hypertensive patients.4 Besides Hcy, The 24-hour ambulatory blood pressure monitoring (ABPM) parameters like morning blood pressure surge (MBPS), night dipping patterns, ambulatory arterial stiffness index (AASI), and blood pressure (BP) variability have also been confirmed as predictors for not only occurrence but also recurrence of cardio-cerebrovascular events.5-12 The ABPM is considered as a gold standard for evaluating blood pressure (BP) condition especially in hypertension patients. In stroke patients, BP variability is associated with cardio-cerebrovascular outcomes.13,14 AASI predicts future cardiovascular events, particularly
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TagedPstroke, and mortality of cardio-cerebrovascular events, and is associated with arterial function.11,15,16 Thus, recording ABPM parameters is necessary for patients with cardio-cerebrovascular diseases and should be included in the secondary prevention scheme. Studies indicated that ABPM parameters may be associated with other cardiocerebral vascular risk factors like total cholesterol, lowdensity lipoprotein and C-reactive protein values.17,18 Since both Hcy level and ABPM parameters are risk factors and predictors of cardio-cerebrovascular events for individuals with or without cardio-cerebrovascular event,14,19,20 we questioned whether there are some underlying specific links between them. However, few studies focused in this topic in acute ischemic stroke patients. Herein, we conducted this study to reveal the possible relationship between ABPM parameters (including MBPS, night dipping pattern, BP variability, and AASI) and plasma Hcy level in first-ever ischemic stroke patients.
Patients and Methods Patients TagedPThis study was approved by the ethnic committee of Shanghai Tenth People's Hospital. We included consecutive cases with first-ever acute ischemic stroke that admitted to the Department of Neurology of Shanghai Tenth People's Hospital from March, 2014 to October, 2014. Acute ischemic stroke is defined as abrupt neurological dysfunction caused by focal brain ischemia leading to persistent neurologic deficit that accompanied by characteristic abnormalities on brain imaging. In our study, we enrolled patients who developed an acute ischemic stroke conformed by computed tomography or magnetic resonance imaging of the brain within 48 hours of symptom onset. Patients were diagnosed as ischemic stroke according to the World Health Organization criteria.21 Patients with a history of chronic stroke or myocardial infarction were excluded. Blood samples were taken after the patients were hospitalized.
Ambulatory Blood Pressure Monitoring TagedPABPM was performed from the first 8:00 AM after the patients were admitted to our hospital to 8:00 AM the next day with a portable device (Welch Allyn ABPM 6100, Welch Allyn Inc, Skaneateles Falls, NY, USA). ABPM was performed with an adequate cuff on the patient's nondominant arm and automatic BP measurements were programmed to take place at 30-minute intervals while awake and 60-minute intervals while resting. Readings were excluded if less than 80% of the total measurements were obtained.
ABPM Parameters TagedPIn this study, we focused in 4 ABPM parameters: MBPS, AASI, BP variability, and night dipping patterns. For MBPS, we calculated both pre-awaking MBPS which
cTagedP alculated as the morning BP (the mean BP during 2 hours after wake-up) minus the pre-waking BP (2 hours average BP before wake-up) and sleep-trough MBPS which defined as the morning BP minus the lowest nighttime BP (Daverage 38X X of 3 BP readings centered on the lowest nocturnal BP reading). TagedPNight BP dipping was defined as 10% reduction in average systolic blood pressure (SBP) during sleep compared with average daytime SBP,22 and nondipping as the reduction was less than 10%. The nocturnal SBP reduction (%) was calculated as 100 (1—night-time SBP/ daytime SBP ratio). TagedPBP variability was defined as standard deviation (SD) of SBP in 24 hours within a 24-hour period. TagedPAASI was calculated as 1 minus the regression slope of diastolic over SBP values as recorded by the ABPM.23
Statistical Analysis TagedPNormally distributed data was expressed as mean § SD. For skewed distributed data, median and interquartile range was calculated. The baseline characteristics of patients in the top quartile and the lower 3 quartiles were compared with chi-square test or Mann Whitney U test, as appropriate. Univariate and multivariate logistic regression analysis were applied to analyze dichotomies variables. For continuous variables univariate and multivariate linear regression analysis were conducted. Mann Whitney U test was used to compare continuous variables between groups. All comparisons were 2-sided. Analysis of outcome variable was adjusted for age and gender. All analyses were performed using STATA software package (version 12.0; Stata Corp., College Station, TX). Statistical significance was considered when a P value less than .05.
Results Baseline Characteristics TagedPA total of 60 patients (mean age 63.85 § 10.91; median age: 63, interquartile range: 56-74; male%: 60%) with firstever acute ischemic stroke hospitalized in the Department of Neurology, Shanghai Tenth People's Hospital were consecutively enrolled according to our criteria. Baseline characteristics were shown in Table 1.
Analysis of the Dichotomised Hcy Level TagedPHcy level was ranged from 5.5 mmol/L to 19.9 mmol/L (mean § SD: 11.64 § 3.28 mmol/L). We dichotomized the Hcy level at the top quartile, and binary variables were created with 15 patients in the top quartile (Hcy level: 15.70 § 2.87 mmol/L), and with 45 patients in the lower 3 quartiles (Hcy level: 10.29 § 2.09 mmol/L). The baseline characteristics in the top quartile and the lower 3 quartiles were shown in Table 2. MBPS parameters (prewaking MBPS and sleep-trough MBPS) tended to be higher in the top quartile. Compared with patients in the lower 3
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Table 1. Baseline characteristics and ambulatory blood pressure data Variables Age (years) Gender, male (%) Body mass index (kg/m2) Hypertension (%) Coronary heart disease (%) Diabetes (%) Current smoking (%) Homocysteine (mmol/L) Total cholesterol (mmol/L) Triglyceride (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) 24-h mean SBP (mm Hg) 24-h mean DBP (mm Hg) 24-h mean heart rate (beats/min) Daytime mean SBP (mm Hg) Daytime mean DBP (mm Hg) Nighttime mean SBP (mm Hg) Nighttime mean DBP (mm Hg) PreDwaking 8X X MS Sleep-trough MS AASI BP variability Nondipping pattern
Total N = 60 63.85 § 10.91 36 (60.00%) 24.01 § 2.98 5D42X X (9D0.00%) 3X X 8D5X4 X (13.33%) D7X6 X (53.33%) 32 26 (43.33%) 11.64 § 3.28 4.36 (3.88, 5.41) 1.42 (1.07, 2.00) 1.12 (.97, 1.30) 2.79 § .93 140.60 § 16.24 75.57 § 10.75 70.37 § 10.59 141.85 § 16.83 76.25 § 11.01 136.81 § 18.55 73.50 § 11.49 5.01 § 15.03 11.59 § 14.78 .52 § .17 14.08 § 3.85 43 (D72%) 9X X
Abbreviations: AASI, ambulatory arterial stiffness index; BP, blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; MS, morning surge; SBP, systolic blood pressure. Results presented as mean § s.d. or median (interquartile range).
TagedPquartiles, patients in the top quartile of Hcy level tended to have a higher level of prewaking and sleep-trough MBPS (odds ratio [OR]: 1.050, 95% confidence interval [CI]: 1.003-1.098, P = .034; and OR: 1.051, 95% CI: 1.0021.102, P = .039, respectively) (Table 3). The associations remained significant after adjusting for age and gender (OR: 1.056, 95% CI: 1.006-1.109, P = .028; and OR: 1.057, 95% CI: 1.005-1.112, P = .030, respectively) (Table 3). TagedPHowever, there was no significant association between Hcy level and AASI as well as BP variability (OR: .429, 95% CI: .013-14.157, P = .635; and OR: 1.077, 95% CI: .9231.257, P = .348, respectively) (Table 3). After adjusted for age and gender, there was still no association between Hcy level and AASI or BP variability (OR: .680, 95% CI: 1.016-28.52, P = .840; and OR: 1.090, 95% CI: .930-1.277, P = .289, respectively) (Table 3).
Analysis of the Lineal Hcy Level TagedPWe calculated prewaking and sleep-trough MBPS based on the ABPM readings. Both of the MBPS measures were normally distributed. A scatterplot of the Hcy against prewaking MBPS and the sleep-trough MBPS suggested a significant relationship (r = .332, P = .010; and
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rTagedP = .340, P = .008, respectively) (Fig 1, A,B, Table 4). After adjusted for age and gender, both MBPS measures were still significantly associated with Hcy (r = .356, P = .022; r = .365, P = .017, respectively). Patients with MBPS tend to had higher level of Hcy. TagedPBesides, the linear regression of the data indicated no correlation between AASI and plasma Hcy level (r = .196, P = .133, Fig 1, C). Scatterplot of the Hcy level against BP viability suggest no association between these 2 variables (r = .161, P = .219, Fig 1, D). After adjusted for age and gender, neither AASI nor BP viability was associated with Hcy (r = .256, P = .220; r = .286, P = .115, respectively). TagedPNext, the patients were stratified into 2 groups according to the dipping pattern, and Mann Whitney U test showed that Hcy level in patients with dipping or nondipping patterns showed no difference (P = .127) (Fig 1, E).
Discussion TagedPIn the present study, we revealed a correlation between plasma Hcy level and MBPS in patients with acute ischemic stroke. This finding established an intriguing link between these 2 cardio-cerebrovascular risk factors. TagedPIt has been suggest that lowering Hcy could reduce the risk of cerebral infarction (CI). Huang et al found that a 20% reduction in Hcy level was related to a 7% decline in stroke risk.2 The association between Hcy and atherothrombosis is supported by several biologically plausible mechanisms involving increased oxidative stress, coagulation of the blood, impaired endothelial function, induction of thrombosis, alterations of lipid metabolism, and intracellular mechanisms.24,25 Increased Hcy is associated with impaired endothelial function by mechanisms like inducing calcium as a second messenger in smooth muscle cells,24 altering components of NO metabolism and disrupting NO synthesis.26 TagedPThere is considerable evidence suggesting significant associations between morning BP surge and cardiac, cerebral, renal, and vascular damage.12 Some studies suggested that MBPS was associated with endothelial dysfunction.12 Yoda et al found that poor glycemic control as well as insulin resistance was related to the occurrence of MBPS in type 2 diabetes mellitus patients, which might be associated with vascular endothelial dysfunction.27 Therefore, the endothelial dysfunction might be one of the possible mechanisms linking HCY and MBPS. Kario et al found that a 10 mm Hg rise in sleep-trough MBPS might increase the risk of stroke by 22%, and it is supposed that an excessive MBPS might leads to enhanced shear stress on the atherosclerotic vessels, platelet hyperactivity, hypercoagulability, increased vascular spasm, and enhanced sympathetic nervous activity, especially a-adrenergic activity, which might finally trigger stroke.28 Oliver et al recently found that a1B-adrenoceptors expression was higher in peripheral mononuclear cells from hypertensive patients and was correlated with plasmatic
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Table 2. Baseline characteristics between the top quartile of Hcy level and the lower 3 quartiles Variables Age (years) Gender, male (%) Body mass index (kg/m2) Hypertension (%) Coronary heart disease (%) Diabetes (%) Current smoking (%) Homocysteine(mmol/L) Total cholesterol(mmol/L) Triglyceride (mmol/L) HDL-C(mmol/L) LDL-C(mmol/L) 24-h mean SBP(mm Hg) 24-h mean DBP(mm Hg) 24-h mean heart rate(beats/min) Daytime mean SBP(mm Hg) Daytime mean DBP(mm Hg) Nighttime mean SBP(mm Hg) Nighttime mean DBP(mm Hg) PreDwaking 14X X MS Sleep-trough MS AASI BP variability Nondipping pattern
Top quartile
Lower 3 quartiles
P
61.40 § 10.63 10 (66.7%) 24.57 § 2.63 15 (100.0%) 0D1X0 X (.0%) 8 (53.3%) 9 (60.0%) 15.70 § 2.87 4.75 (4.17,5.86) 1.58 (1.08, 1.99) 1.19 (1.07, 1.36) 2.99 § .97 139.20 § 10.92 79.67 § 10.69 72.13 § 12.76 142.91 § 11.45 80.80 § 9.70 130.65 § 13.37 75.13 § 12.93 12.52 § 12.46 18.70 § 10.72 .5007 § .1671 14.88 § 4.97 8 (53.3%)
64.67 § 10.99 26 (57.8%) 23.81 § 3.09 39 (86.7%) D13X2 X (17.8%) 8 24 (53.3%) 17 (37.8%) 10.29 § 2.09 4.28 (3.84, 5.23) 1.38 (1.03, 2.01) 1.07 (.97, 1.27) 2.72 § .92 141.07 § 17.74 74.20 § 10.54 69.78 § 9.85 141.50 § 18.38 74.73 § 11.09 138.87 § 19.68 72.96 § 11.08 2.51 § 15.10 9.21 § 15.28 .5244 § .1706 13.81 § 3.42 35 (77.8%)
.427 .543 .458 .321 .182 1.000 .133 .000* .177 .639 .083 .314 .932 .124 .688 .651 .056 .186 .651 .010* .009* .752 .408 .069
Abbreviations: AASI, ambulatory arterial stiffness index; BP, blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol;; MS, morning surge; SBP, systolic blood pressure. Results presented as mean§s.d. or median (interquartile range). * P < .05.
T cy and BP.29 Because a1-adrenoceptors play a major role agedPH in sympathetic stimulus and may contribute to MBPS, there might be a potential link between MBPS and Hcy. In our study, we found that MBPS and Hcy had associations in ischemic stroke, and patients with MBPS tend to had higher level of Hcy. TagedPResearches have revealed the risk of CI was significantly higher in subjects with nondipping pattern compared with subjects with night BP dipping,30 and reversed dipper in the acute stage of CI was associated with total mortality during long-term follow-up.31 As for the potential interactions of Hcy and hypertension, Dong et al recently found a relationship between plasma Hcy
aTagedP nd circadian BP variation that Hcy was an independent factor associated with nondipping pattern, and Hcy was higher in patients with TT genotype than CC/CT genotypes in an older Chinese cohort of hypertensive adults.32 In our study, Hcy levels in dippers and nondippers showed no association. We speculated that because our study objects were patients with acute ischemic stroke, and the percentage of nondippers were much higher in stroke patients than hypertensive patients. Although Hcy level was suggested associated with nondipping patterns in hypertensive adults, there might be no direct connection between Hcy level and night dipping patterns in ischemic stroke patients.
Table 3. Analysis of dichotomised Hcy and MBPS measures among acute ischemic stroke patients Variables PreDwaking 15X X MS Sleep-trough MS AASI BP variability
OR (95% CI)
P value
Adjusted OR (95% CI)
P value
1.050 (1.003-1.098) 1.051 (1.002-1.102) .429 (.013-14.157) 1.077 (.923-1.257)
.034 .039 .635 .348
1.056 (1.006-1.109) 1.057 (1.005-1.112) .680 (1.016-28.52) 1.090 (.930-1.277)
.028 .030 .840 .289
The dichotomisation of Hcy level at the 75th percentile created binary variables with 15 subjects in the top quartile. Univariate and multivariate logistic regression was used to analyze the dichotomisation of each measure of the Hcy in the highest quartiles (versus remainder) among acute ischemic stroke patients. Abbreviations: AASI, ambulatory arterial stiffness index; Adjusted OR, adjusted for age and gender; BP, blood pressure; CI, confidence interval; Hcy, homocysteine; MBPS, morning blood pressure surge; MS, morning surge; OR, odds ratio. P value <.05 was considered statistically significant.
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RELATIONSHIP BETWEEN HCY AND MBPS IN STROKE PATIENTS Figure 1. Scatterplot of ABPM parameters measures and Homocysteine (Hcy) levels. Simple linear analysis between Hcy and preDwaking 1X X morning surge (A), sleep-trough morning surge (B), AASI (C), BP variability (D) in acute ischemic stroke patients. (E) The Hcy level (mmol/L) in acute ischemic stroke patients with nondipping or dipping patterns, respectively.
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Table 4. Lineal regression analysis of ABPM parameters for each levels of Hcy among acute ischemic stroke patients
PreDwaking 16X X MS Sleep-trough MS AASI BP variability
R
P value
Adjusted R
P value
.332 .340 .196 .161
.010 .008 .133 .219
.356 .365 .256 .286
.022 .017 .220 .115
Abbreviations: AASI, ambulatory arterial stiffness index; ABPM, Ambulatory blood pressure monitoring; Adjusted R, adjusted for age and gender; BP, blood pressure; CI, confidence interval; Hcy, homocysteine; MS, morning surge. P value <.05 was considered statistically significant.
TagedPTaken together, our results add new insights into the association between the MBPS and Hcy in patients with acute ischemic stroke, although we could not clarify the underlining mechanisms now. More high-quality original studies are needed and the mechanisms of the association between MBPS and Hcy in pathological change of ischemic stroke should be further investigated.
Conclusion TagedPIn this study, we can infer that there are intriguing links between Hcy levels and MBPS in acute ischemic stroke patients. Conflict of Interest Disclosure: flict of interest.
TagedPThe authors declare no con-
References TagedP 1. Catena C, Colussi G, Nait F, et al. Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients. Am J Hypertens 2015;28:943-950. TagedP 2. Huang X, Li Y, Li P, et al. Association between percent decline in serum total homocysteine and risk of first stroke. Neurology 2017;89:2101-2107. TagedP 3. Markaki I, Klironomos S, Kostulas K, et al. Elevated plasma homocysteine upon ischemic stroke is associated with increased long-term mortality in women. PLoS One 2017;12:e0183571. TagedP 4. Wang CY, Chen ZW, Zhang T, et al. Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients. Eur J Intern Med 2014;25:538-544. TagedP 5. 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;27:564-570. TagedP 6. Bombelli M, Fodri D, Toso E, et al. Relationship among morning blood pressure surge, 24-hour blood pressure variability, and cardiovascular outcomes in a white population. Hypertension 2014;64:943-950. TagedP 7. Pierdomenico SD, Pierdomenico AM, Coccina F, et al. Prognostic value of nondipping and morning surge in elderly treated hypertensive patients with controlled ambulatory blood pressure. Am J Hypertens 2017;30:159165.
TagedP 8. Sheppard JP, Hodgkinson J, Riley R, et al. Prognostic significance of the morning blood pressure surge in clinical practice: a systematic review. Am J Hypertens 2015;28:30-41. TagedP 9. Xie JC, Yan H, Zhao YX, et al. Prognostic value of morning blood pressure surge in clinical events: a meta-analysis of longitudinal studies. J Stroke Cerebrovasc Dis 2015;24:362-369. TagedP10. Geeganage C, Tracy M, England T, et al. Relationship between baseline blood pressure parameters (including mean pressure, pulse pressure, and variability) and early outcome after stroke: data from the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST). Stroke 2011;42:491-493. TagedP11. Kollias A, Stergiou GS, Dolan E, et al. Ambulatory arterial stiffness index: a systematic review and meta-analysis. Atherosclerosis 2012;224:291-301. TagedP12. Yano Y, Kario K. Nocturnal blood pressure, morning blood pressure surge, and cerebrovascular events. Curr Hypertens Rep 2012;14:219-227. TagedP13. Chen BX, Tian JP, Wang HX, et al. Effect of blood pressure variability on cardiovascular outcome in diabetic and nondiabetic patients with stroke. J Stroke Cerebrovasc Dis 2014;23:2450-2457. TagedP14. Shi Z, Guan Y, Huo YR, et al. Elevated total homocysteine levels in acute ischemic stroke are associated with long-term mortality. Stroke 2015;46:2419-2425. TagedP15. Kikuya M, Staessen JA, Ohkubo T, et al. Ambulatory arterial stiffness index and 24-hour ambulatory pulse pressure as predictors of mortality in Ohasama, Japan. Stroke 2007;38:1161-1166. TagedP16. Dolan E, Thijs L, Li Y, et al. Ambulatory arterial stiffness index as a predictor of cardiovascular mortality in the Dublin Outcome Study. Hypertension 2006;47:365370. TagedP17. Martin CA, Cameron JD, Head GA, et al. The morning blood pressure surge is related to serum cholesterol. J Hum Hypertens 2013;27:315-320. TagedP18. Sezer S, Karakan S, Colak T, et al. Nocturnal nondipping hypertension is related to dyslipidemia and increased renal resistivity index in renal transplant patients. Transplant Proc 2011;43:530-532. TagedP19. Tu WJ, Zhao SJ, Liu TG, et al. Combination of high-sensitivity C-reactive protein and homocysteine predicts the short-term outcomes of Chinese patients with acute ischemic stroke. Neurol Res 2013;35:912-921. TagedP20. Wu XQ, Ding J, Ge AY, et al. Acute phase homocysteine related to severity and outcome of atherothrombotic stroke. Eur J Intern Med 2013;24:362-367. TagedP21. Thorvaldsen P, Asplund K, Kuulasmaa K, et al. Stroke incidence, case-fatality, and mortality in the who Monica project. Stroke 1995;26:361-367. TagedP22. O'Brien E, Sheridan J, O'Malley K. Dippers and non-dippers. Lancet 1988;2:397. TagedP23. Dolan E, Li Y, Thijs L, et al. Ambulatory arterial stiffness index: rationale and methodology. Blood Press Monit 2006;11:103-105. TagedP24. Spence JD. Homocysteine-lowering therapy: a role in stroke prevention. Lancet Neurol 2007;6:830-838. TagedP25. Petras M, Tatarkova Z, Kovalska M, et al. Hyperhomocysteinemia as a risk factor for the neuronal system disorders. J Physiol Pharmacol 2014;65:15-23. TagedP26. Zhao J, Chen H, Liu N, et al. Role of hyperhomocysteinemia and hyperuricemia in pathogenesis of atherosclerosis. J Stroke Cerebrovasc Dis 2017. TagedP27. Yoda K, Inaba M, Hamamoto K, et al. Association between glycemic control and morning blood pressure
ARTICLE IN PRESS RELATIONSHIP BETWEEN HCY AND MBPS IN STROKE PATIENTS TagedPsurge with vascular endothelial dysfunction in type 2 diabetic patients. Diabetes Care 2014;37:644-650. TagedP28. Kario K, Pickering TG, Umeda Y, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation 2003;107:14011406. agedP2T 9. Oliver E, Monto F, Rovira E, et al. Changes in the expression of alpha1B-adrenoceptor in peripheral mononuclear cells correlates with blood pressure and plasmatic homocysteine. Biomed Pharmacother Biomed Pharmacother 2017;88:721-727.
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TagedP30. Metoki H, Ohkubo T, Kikuya M, et al. Prognostic significance for stroke of a morning pressor surge and a nocturnal blood pressure decline: the Ohasama study. Hypertension 2006;47:149-154. TagedP31. Park JH, Lee HS, Kim JH, et al. Reverse dipper and high night-time heart rate in acute stage of cerebral infarction are associated with increased mortality. J Stroke Cerebrovasc Dis 2014;23:1171-1176. TagedP32. Dong YF, Zhan BM, Hao QY, et al. Plasma homocysteine levels are associated with circadian blood pressure variation in Chinese hypertensive adults. Am J Hypertens 2017;30:1203-1210.