Focus on blood pressure levels and variability in the early phase of acute ischemic stroke with hypertension and carotid stenosis

Abstract To investigate the optimal blood pressure (BP) levels and relative importance of BP and BP variability in the early phase of acute ischemic stroke (AIS) for hypertensive patients with carotid artery stenosis (CAS). A single‐center cohort study included 750 AIS patients with hypertension and tests were performed for CAS. Participants were categorized to Group 1 (SBP < 140 mm Hg and DBP < 90 mm Hg), Group 2: (SBP: 140–159 mm Hg and or DBP: 90–99 mm Hg), and Group 3: (SBP ≥160 mm Hg and/or DBP ≥100 mm Hg) according to the guidelines. The associations of mean BP levels and variability with outcomes (recurrent stroke, all‐cause death and the composite cardiovascular events) at 6 months were analyzed by Cox proportional hazard models. The associations of BP variability with BP levels and cerebral blood flow (CBF) were analyzed by linear regression and generalized additive models. Both for primary and secondary outcome, more events occurred in Group 1 compared with Group 2, while no significant difference was found in Group 3 with higher BP levels. Lower systolic BP variability showed better prognosis and higher CBF. The associations were more significant in patients with CAS ≥50%. BP variability exhibited a linear negative relationship with BP levels. In the early phase of AIS with hypertension and CAS, maintaining low blood pressure variability may be important to improve outcomes while low BP levels (SBP/DBP < 140/90 mm Hg) were harmful, especially in those patients with CAS ≥ 50%.

stroke. 4 Hypertensive patients with carotid artery stenosis often have high blood pressure (BP) during the acute phase of IS. 5,6 The management of high BP levels in acute phase is an unresolved issue in IS patients. High BP levels in the acute phase are related with a poor prognosis. 1,7,8 However, low BP levels are also associated with poor prognosis in patients with IS as well. 9 Our previous study confirmed that lower or higher BP levels in the early phase of IS were both correlated with increased risk of adverse outcomes. 10 Recent studies have shown that for stroke patients, especially those with stroke and hypertension, BP variability is another important risk for recurrent stroke, cardiovascular disease, renal failure, and mortality. 11 Higher long-term visit-to-visit BP variability is associated with an increased risk of recurrent stroke, as well as major cardiovascular events and all-cause death either in patients with hypertension or prior stroke. 12,13 Short-term BP variability is also associated with neurological deteriorations in the acute phase of IS. 14 Our previous study also demonstrated that higher BP variability within 7 days of onset was significantly correlated with the increased risk of recurrent stroke and composite cardiovascular events. 15 Although there are many studies have suggested reasonable BP level and low BP variability were associated with good outcome, these studies did not focus on AIS patients with hypertension and CAS. It is an interesting question how to weigh BP level and BP variability in AIS patients with hypertension and CAS in the early stage. Unfortunately, no relevant study has been reported. Therefore, this study was aimed to investigate BP variability and proper BP level in early phase of acute ischemic stroke with hypertension and CAS.

Study design and participants
We carried out a single-center, prospective cohort study. (2) internal carotid arteries (ICAs) carry about 70% of total cerebral blood flow (CBF) and the vertebral arteries (VAs) distribute about 30% of total CBF to the brainstem, cerebellum and occipital cortex. 17 The diameter stenosis percentage was calculated using the measured diam- sides. 18 The total CBF was measured for subsequent analysis.

Definitions
Hypertension was defined as a conventional BP of at least 140 mm Hg systolic or 90 mm Hg diastolic, or the use of antihypertensive drugs. 19 Carotid artery stenosis was defined as the narrowing of the lumen of the carotid artery owing to carotid atherosclerotic plaque, arteritis, or fibromuscular dysplasia. 3

Patient follow-up and outcome assessment
All participants were followed up in 6 months by trained neurologists.
Primary outcome was recurrent stroke ([fatal and non-fatal] ischemic and hemorrhagic stroke) at 6 months. 30 Secondary outcome included all-cause death and the composite cardiovascular events (recurrent stroke, non-fatal myocardial infarction) at 6 months. 30 After discharge, patients received regular review by specialist during the follow-up period. The treatment for hypertension and stroke was according to the corresponding guidelines. 19

Statistical analysis
All statistical analysis was performed with SPSS.V24.0 software packages. Continuous variables were presented as mean (SD) and were compared using the Student t test or one-way ANOVA.

Standard protocol approvals and patient consents
The study was approved by the ethic committee of Lianyungang Hospital. Written informed consent was obtained from each patient or his/her proxy.

More events in group with lower BP levels, while no significant difference in group with higher BP levels
Univariate Cox regression analysis for primary and secondary outcomes are shown in Table S2. When SBP < 140 mm Hg or SBP < 160 mm Hg, increased SBP was a significant protective factor for primary and secondary outcomes. However, when SBP≥160 mm Hg, the hazard ratio was 1.011 with no statistical significance. The relationships between BP and primary/secondary outcomes by multivariate Cox regression analysis were shown in Table 2

Low BP variability was associated with good prognosis
BP variability was also an important risk factor for prognosis. Next, we analyzed the relationship between BP variability and prognosis. Cox regression showed no significant difference between DBP variability and prognosis (Table S3 and Figure S1). Figure 3 and Table 3 in the showed patients with the lowest SBP variability had the best prognosis, including primary outcome and secondary outcome. After stratified with CAS, the association was only found in group with CAS ≥50% but not in group with CAS < 50%.

BP variability was negatively associated with CBF volume
CBF is necessary for conservation of brain function, and hypoperfusion might cause brain infarction, which in turn leads to a poor prognosis. Furthermore, we determined the association of BP variation with CBF.
Pearson correlation analysis and curve fitting showed an overall negative correlation between SBP variability and global CBF (p < 0.001).
In ischemic stroke patients with CAS ≥50%, a negative linear correlation was observed between SBP variability and CBF compared with ischemic stroke patients with CAS < 50%. The relation between BP variability and global CBF was also shown graphically as GAM plots in  Table 4 showed the association between CBF levels and prognosis.

CBF levels were associated with prognosis
Higher global CBF in the early phase was associated with better primary and secondary outcomes at 6 months. Patients in the lowest CBF group (< 457 ml/min) showed the worst primary outcome comparing to other groups. Patients with CBF < 730 ml/min were associated with poor secondary outcome. After stratified with CAS, the association still presented. Meanwhile, KM curves also revealed that the primary outcome and secondary outcome were significantly worse in the lowest CBF group compared with the highest CBF group (p < 0.001) ( Figure   S2 in the Supplement).

BP levels were negatively associated with BP variability
Low BP levels were associated with a poor prognosis, while low BP variability was associated with a good prognosis in our study. Then, F I G U R E 2 KM cumulative hazard curves demonstrating the association of the BP levels with the primary and secondary outcome. KM curves for the association of BP with the primary outcome in total (A), in group with CAS < 50% (B), and in group with CAS ≥50% (C); KM cumulative hazard curves for the association of BP with the secondary outcome in total (D), in the group with CAS < 50% (E), and in the group with CAS ≥ 50% (F). The patients were divided into three groups according to BP levels. Group1: SBP < 140 mm Hg and DBP < 90 mm Hg, Group 2: SBP :140-159 and/ or DBP: 90-99 mm Hg; Group 3: SBP ≥160 and/or DBP ≥100 mm Hg what's the relation between BP levels and its variation? The correlation between BP levels and BP variability was evaluated by Pearson correlation analysis. Pearson correlation analysis revealed there was a negative correlation between BP groups and SBP variability and DBP variability, respectively. In patients with CAS ≥ 50%, there was a still negative linear correlation was observed between BP variability and SBP (p < 0.001) and DBP (p = 0.021) ( Figure 5). In other words, when BP was maintained at relatively higher level, BP variability was generally low in the study population.

DISCUSSION
In the present study, we demonstrated that in IS patients with hypertension and CAS, lower BP levels (< 140/90 mm Hg) led to a poor prognosis, while higher BP levels (> 160/100 mm Hg) did not show better prognosis, and BP levels was negatively correlated with BP variability.
On the other hand, low BP variability in the early phase (within 3 days after onset) was associated with adequate cerebral perfusion and then reduced risks of primary and secondary outcomes at 6 months, particularly in those patients with CAS ≥50%. So, maintaining low blood pressure variability may be important to improve outcomes while low BP levels (SBP/DBP < 140/90 mm Hg) were harmful, especially in those patients with CAS ≥ 50%.
Hypertension in the acute phase is associated with a poor prognosis but lowering blood pressure might also be harmful. The Scandinavian Candesartan Acute Stroke Trial (SCAST) indicated that blood pressure lowering treatment in acute stroke was associated with an increased risk of stroke progression and poor functional outcome 32 . The International Stroke Trial study found a U-shaped relationship between BP and outcome, indicating that both high and low BP levels were prognostic factors for poor outcome in IS patients. 7 In our study, more events were found in group with the lower BP (SBP < 140 mm Hg and DBP < 90 mm Hg), especially in patients with CAS ≥50%, while there was no obvious association between the highest BP group (SBP ≥160 and/or DBP lower BP levels, which were close to the "ideal blood pressure level", were not good for both primary outcome and secondary outcome in our study.
Furthermore, in the present study, low BP variability in the early phase, measured by CV, was significantly associated with good prognosis. The trend was more obvious in these patients with CAS ≥50%. Our findings are consistent with some previous studies. Bum Joon Kim and coworkers demonstrated that increased BP variability was strongly correlated with the risk of recurrent stroke in patients with hypertension and a history of previous stroke or TIA. 33 In the VALUE trial, higher SBP variability was associated with increased risk of cardiovascular events in patients with hypertension. 13 The PRoFESS study also found that in patients with recent IS, higher BP variability was associated with an increased risk of recurrent ischemic stroke, major cardiovascular events, and all-cause death. 12 Inadequate cerebral perfusion and impaired cerebral autoregulation in the early phase of stoke increased cardiovascular complications, and secondary brain injury. These conditions in turn might cause poor outcome after acute IS. We found lower BP variability was correlated with higher global CBF, and the higher global CBF were more benefi-cial to prognosis in our study. Patients with lower CV of BP maintained a relatively high global CBF, which was in turn advantageous for prognosis.
The relationship between BP variability and prognosis was more significant in patients with CAS ≥50%, while no statistically significant differences in patients with CAS < 50%. In normal condition, cerebral autoregulation maintains blood flow to the brain and regulates cerebral perfusion pressure changes over a wide range. BP level and BP variability are major factors affecting cerebral perfusion. In the IS population with hypertension and mild CAS or none, the collateral circulation would compensate for the influence of blood pressure fluctuations on brain to prevent cerebral hypoperfusion. The circle of Willis is considered to be the primary collateral flow route which can supplement the affected brain tissue area with blood. 34 All patients were divided into tertile groups according to global CBF. Age, male, BMI, smoking, alcohol, diabetes mellitus, coronary artery disease, congestive heart failure, chronic kidney disease, NIHSS were induced for adjustment. CBF, Cerebral blood flow; HR, hazard ratio; CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale. *p < .05. **p < .01. ****p < .001.

F I G U R E 5
The correlation between BP levels and CV of BP. The correlation between SBP levels and variability in total (A), in group with CAS < 50% (B), and in group with CAS ≥50% (C); the correlation between DBP levels and variability in total (D), in the group with CAS < 50% (E), and in the group with CAS ≥50% (F) maintaining a relatively high cerebral blood flow. The relatively stable and high cerebral perfusion reduces stroke recurrence and improves the prognosis of stroke. Low BP variability and maintaining reasonable BP levels (SBP 140-160 and DBP 90-100 mm Hg) were more beneficial in the present study.
This study has limitations. First, we did not include flow volumes of vertebral arteries and only calculated stenosis of carotid arteries, the advantage bias might exist. Second, the sample size of this study was relatively small; however, it was a real clinical practice, in which strict inclusion criteria were used, data were reasonably analyzed, and conclusions was carefully scrutinized.
As a result, our study might deliver useful recommendation for BP management in the early phase of IS patients in this group of patients with CAS.

CONCLUSIONS
In our study, more events were found in group with the lower BP