Burden of cerebral small vessel disease and changes of diastolic blood pressure affect clinical outcome after acute ischemic stroke

Elevated and low blood pressure (BP) may lead to poor functional outcome after ischemic stroke, which is conflicting. Hence, there must be another factor—such as cerebral small vessel disease (cSVD) -interacting with BP and thus, affecting outcome. Here, we investigate the relationship between BP and cSVD regarding outcome after stroke. Data of 423/503 stroke patients were prospectively analyzed. Diastolic (DBP) and systolic BP (SBP) were collected on hospital admission (BPad) and over the first 72 h (BP72h). cSVD-burden was determined on MR-scans. Good functional outcome was defined as a modified Rankin Scale score ≤ 2 at hospital discharge and 12 months thereafter. cSVD was a predictor of poor outcome (OR 2.8; p < 0.001). SBPad, DBPad and SBP72h were not significantly associated with outcome at any time. A significant relationship was found between DBP72h, (p < 0.01), cSVD (p = 0.013) and outcome at discharge. At 12 months, we found a relationship between outcome and DBP72h (p = 0.018) and a statistical tendency regarding cSVD (p = 0.08). Changes in DBP72h were significantly related with outcome. There was a U-shaped relationship between DBP72h and outcome at discharge. Our results suggest an individualized stroke care by either lowering or elevating DBP depending on cSVD-burden in order to influence functional outcome.

Increased blood pressure (BP) is found in around 80% of all patients with acute ischemic stroke (AIS) on hospital admission as well as in the acute phase of AIS 1 .However, the impact of BP in the acute phase of AIS on functional outcome remains an matter of debate [2][3][4] .So far, there is some evidence that raised BP early after AIS is associated with dependency, clinical deterioration and subsequent death 5 .In contrast, some studies revealed that both low and high BP entails poor prognosis after AIS 4,6 .Further studies found no effect of BP in the acute phase of AIS on functional outcome 7,8 .Of note, some other studies even suggested that an increase of BP in the acute phase of AIS may be a protective response to reduced cerebral perfusion and thus, may enhance decreasing blood flow to the infarcted zone and surrounding penumbra [9][10][11] .Hence, these different and partially contradictory findings suggest that additional factors such as cerebral small vessel disease (cSVD) may interfere prognosis and clinical outcome after AIS.The term cSVD refers to the dysfunction of cerebral microvessel endothelium affecting cell-cell interactions and finally resulting in brain damage [12][13][14] .Clinically, cSVD may lead to stroke, cognitive dysfunction and worsening of gait as well as balance 15 .On brain MRI, cSVD presents with lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMB) and perivascular spaces 12,15,16 .In particular, WMH are the most common cSVD lesions that are observed on brain MR scans of most people aged over 70 years 17 .CMB also increase with age although they occur less frequent compared to WMH and are unusual in the absence of WMH 13 .In a recently published study on stroke patients undergoing endovascular treatment, no signs of cSVD was observed in 61%, mild to moderate and severe degree of cSVD was seen in 20.0% and 19.7%, respectively 18 .Hence the question arises whether patients with AIS and no cSVD profit e.g., from a lower BP than stroke patients with a moderate or severe degree of cSVD.Of note, autoregulation of cerebral blood flow is hampered in the acute phase of AIS making cerebral perfusion directly dependent on BP [19][20][21] .Additionally, patients with severe cSVD have an even more reduced cerebral blood flow and impaired cerebral autoregulation 22,23 .

Data collection
During hospitalization, data on demographic characteristics (age, sex), vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, coronary heart disease, myocardial infarction, atrial fibrillation, previous stroke or TIA, peripheral artery occlusive disease and current cigarette smoking), comorbidities (liver and kidney dysfunction), previous medication (antihypertensives, antiplatelets, anticoagulants, statins), previous degree of disability (according to modified Rankin scale (mRS)), recanalization therapy (intravenous thrombolysis; endovascular treatment), discharge medication (antihypertensives, antiplatelets, anticoagulants, statins) and stroke/TIA characteristics were collected prospectively in a database (Table 1).Stroke characteristics included (1) stroke severity on admission and at discharge assessed by the National Institutes of Health Stroke Scale (NIHSS) score 25 and (2) stroke subtype classified according to the criteria of Trial of Org 10,172 in Acute Stroke Treatment (TOAST) 26 .
All patients underwent brain MRI within 72 h after admission to identify acute ischemic stroke or TIA.WMH were categorized visually on fluid-attenuated inversion recovery (FLAIR) scans using the Fazekas scale and rated as mild (Fazekas 0-1) or severe (Fazekas 2-3) 27 .CMB were defined as small, circular or rounded, hypointense lesions within brain parenchyma ranging from 2 to 10 mm in size 28 .Assessment of CMB was performed on T2*weighted gradient-recalled echo (T2*-GRE) scans or on susceptibility-weighted images (SWI).Lacunes were defined as CSF-filled cavities with a diameter of at least 3 mm 29 .cSVD burden was visually rated on MR scans and divided in absent/mild cSVD (Fazekas 0-1, no CMB) and moderate/severe cSVD (Fazekas 2-3 and/or ≥ 1 CMB).
Blood pressure (BP) was measured on the non-paralytic arm in the supine position by doctors or trained nurses using a noninvasive BP monitoring device according to our in-hospital guidelines for acute stroke management.BP values obtained on patients' admission and during their stay in the stroke unit were entered in the electronic health record system.From this health record system, we retrieved the very first SBP and DBP value of each patient at the time of admission (i.e., BP at entry).SBP and DBP values measured every 8 h during the first three days after hospital admission were also extracted from the electronic health record system.To obtain the mean SBP and DBP value for each of these three days, the three SBP and DBP values of day 1, 2 and 3 respectively, were averaged.Finally, the mean values of each day were averaged resulting in the mean SBP and DBP value over the first 72 h.In addition, patients with known and treated hypertension continued antihypertensive treatment, unless BP was below 120/70 mmHg (intern guidelines).When SBP at the stroke unit was > 160 mmHg, antihypertensive treatment was adjusted accordingly and BP was measured every 15 min., until SBP was below 160 mmHg.Patients without antihypertensive treatment until admission received angiotensin-converting enzyme inhibitor as the drug of first choice when SBP was > 160 mmHg.The number of patients with newly diagnosed arterial hypertension on hospital was 7.35%.Change in SBP or DBP over the time was calculated as SBP or DBP at time point-SBP or DBP at baseline (i.e. at hospital admission) 21 .
In order to evaluate functional outcome of TIA and stroke patients, the mRS score was assessed prospectively on discharge (outcome disc ) and at 12 months after cerebrovascular event (outcome 12mo ) through a structured follow-up telephone interview by a trained stroke fellow (S.G.).During the interview, current medication and BP were collected.The mRS score on discharge as well as at 12 months was dichotomized into good (mRS score 0-2) and poor outcome (mRS score of 3-6) 30 .

Statistical analysis
The baseline data of all patients are demonstrated as mean ± SD or median (first quartile, Q1; third quartile, Q3) for continuous variables or frequency (percentage) for categorical variables.First, study parameters were compared in a descriptive manner regarding good and poor functional outcome at discharge and at 12 months after stroke.Metric or ordinal variables have been compared with unpaired t-test, or Mann-Whitney-U-test as appropriate.For dichotomous traits like hypertension or diabetes mellitus, Chi-square-test was used.Second, multivariable logistic regression was used to estimate the influence of the different study variables in respect to functional outcome at discharge and at 12 months thereafter.Multivariable logistic regression was adjusted for age and sex as well as for each selected parameter (i.e., cSVD, mean DBP over 72 h).DBP and age were modelled in a non-linear way using a 3-knot restricted cubic spline, as described in detail elsewhere 31 .Results of the regression analysis were depicted as odds ratios (OR) and 95% confidence interval (95%CI).Possible interactions between selected variables were calculated using Likelihood-ratio Chi-square-tests.P < 0.05 was regarded statistically significant.Statistical analyses were performed using R version 4.0.4(R: a Language and Environment for Statistical Computing; Vienna, Austria, 2021-03-15).

Study population and baseline characteristics
A total of 503 patients with either ischemic stroke or TIA were screened for this study.Out of them, full data set was available for 423 patients at discharge (stroke-patients 76% (n = 322); TIA-patients 24% (n = 101)), and 369 patients completed follow-up 12 months after event (stroke-patients 75% (n = 276); TIA-patients 25% (n = 93)) (Fig. 1).The baseline characteristics for the final cohort are summarized in Tables 1 and 2.
In multivariable logistic regression, significant predictors for poor clinical outcome at discharge were mean DBP measured during the first 72 h after admission (OR 0.73; 95%CI 0.54-0.99;p < 0.001) and cSVD (OR 2.07; 95%CI 1.17-3.68;p = 0.013), whereas the variable age and sex were not significantly associated with poor clinical outcome (Fig. 3).Additionally, we found a significant U-shaped dependence of the mean DBP 72h and clinical outcome (Fig. 4).Mean DBP < 66 mmHg and mean DBP > 80 mmHg over the first 72 h after admission were associated with a poor outcome at discharge.
One year after cerebrovascular event, new ischemic stroke or TIA was reported in 11.9% of patients with a good and in 9.89% of those with a poor clinical outcome at discharge (p = 0.62).Among patients with good and poor outcome, 5.78% and 12.9%, respectively, died within one year (p = 0.035).
Twelve months after cerebrovascular event, recurrent ischemic stroke or TIA was diagnosed in 9.58% of patients with a good outcome and in 15.9% of those with a poor clinical outcome (p = 0.09).

Discussion
This prospective study of 423 patients with an AIS or TIA showed that cSVD burden was significantly higher in patients with a poor functional outcome at discharge and 12 months after cerebrovascular event.However, neither SBP ad nor mean SBP 72h was significantly related to functional outcome at discharge or at 12 months after  A growing number of studies suggests that cSVD in patients with AIS is independently associated with poor functional outcome in the short and long term after cerebrovascular event [32][33][34] which is in line with our findings.The impact of cSVD on functional outcome after AIS is poorly understood.It has been shown that severe cSVD may lead to a reduction of cerebral blood flow and is associated with impaired cerebral autoregulation 23,35,36 .Thus, one might argue that low SBP during the acute phase of IS may result in a drop in cerebral blood flow of those patients with severe cSVD.A low SBP might lead to an even faster and more extensive damage of cerebral tissue surrounding the infarcted core than a high SBP, which finally may result in a poor functional outcome.Though, we did not find a statistically significant relationship between SBP ad or SBP 72h and functional outcome in stroke patients with or without cSVD.This might be due to the small sample size in this study.Additionally, we included patients with AIS as well as with TIA who were treated for hypertension; furthermore, some patients had a mRS > 0 prior to study enrollment, which might-to some extent-influence the results.Another reason for the missing effect of SBP on functional outcome in patients with cSVD could be the fact that SBP only impacts functional outcome when cerebral perfusion is severely compromised as one would expect in patients with high burden of cSVD (e.g., Fazekas grade 3, multiple lacunes and/or CMB).Importantly, we combined patients with Fazekas grade 2 and 3 in one group which could have biased the results.In addition, cSVD burden was determined by using a qualitative and not by a quantitative approach, i.e., we did not assess the volume of WMH in our patients.However, a higher Fazekas scale score is highly correlated with higher WMH volume 37 .Furthermore, different regional distribution of WMH load and/or locations of stroke lesions might also impact functional outcome 38 .Furthermore, factors independent of blood pressure such as variations in the cerebral autoregulation, especially in the acute phase as well as genetics are also of great importance in this context.On the other hand, a large randomized trial (n = 3035) has also revealed that SBP is not likely to explain a relationship between cSVD and poor functional outcome after stroke when adjusting for age 39 .In contrast to our study, the main focus of the aforementioned study was on SBP variability during the first 24 h after stroke.
Although SBP decreased over the first 72 h after admission, there was no statistically significant relationship between SBP decline and functional outcome at discharge and at 12 months after AIS, and thus, an interaction between these parameters and cSVD burden was not expected.Our results are in contrast with findings of a previously published study, showing that a large change of SBP over the first 24 h after stroke is related with a poor functional outcome in the short term (i.e. at day 7 after stroke) as well as in the long term (90 days after stroke) 21 .However, patients with cSVD burden were not particularly addressed in that study.Although all patients have been recommended to take continuously antihypertensive drugs, adherence of drug intake is low; nearly a quarter of patients are non-adherent to their cardiovascular medicaments [40][41][42] .Hence, repeated high SBP values (> 150 mmHg) during the 12 months might occur in these stroke patients and further impair cerebral tissue which has been already damaged by pre-existing cSVD.This might further bias our results.
Little is known about the impact of DBP on functional outcome in stroke survivors with and without cSVD.Here, we found that mean DBP 72h was significantly lower in stroke patients with cSVD.Moreover, DBP 72h and cSVD burden were associated with a poor outcome at discharge.In contrast to our findings, a previously published trial revealed no consistent association between the level of DBP measured over 24 h and functional outcome 21 , however, in the aforementioned trial, DBP was generally lower in patients with a poor outcome at day 7 and at day 90 21 .In another previously published study, DBP variability was associated with poor functional outcome at hospital discharge 43 .However, the aforementioned studies did not focus on stroke patients with/without cSVD.Göthel-Ezzeiani and coworkers also investigated the impact of WMH and blood pressure on functional outcome.They found a relationship between DBP and mortality but none between DBP and functional outcome at 3 months 44 ; of note, only stroke patients undergoing mechanical recanalization were included in their study.In the present study, there was a significant linear relationship between DBP 72h and late functional outcome (at 12 months) but only a statistical trend for cSVD burden when adjusting for sex and age.In contrast, a previous trial reported similar DBP measured over 24 h after stroke in patients with good and poor late functional outcome (at 3 months) 45 .However, that study did not specifically investigate stroke survivors presenting cSVD and enrolled only stroke patients treated with intravenous thrombolysis.2222Additionally, we observed a U-shaped relationship between mean DBP 72h and functional outcome at discharge among stroke patients with and without cSVD meaning that only a DBP of about 60-80 mmHg was related to a better functional outcome.A U-shaped relationship between DBP on admission and early deterioration as well as functional outcome at 3 months 4 or 6 months 46 was provided by previous studies.In contrast to our study, the cutoff value for DBP was higher, namely at 100-110 mmHg 4 or 87.8-95 mmHg, respectively 46 .In the latter study however, this association was no longer significant, when assessed with logistic regression.Other large studies on patients with ischemic stroke (n > 300′000 patients) 47 or TIA (n > 200′000 patients) 48 reported a U-shaped relationship between DBP on admission and independent ambulation at discharge, likelihood of being discharged at home, and in-hospital death such that below and above 70 mmHg the unadjusted and adjusted odds of these outcomes increased.This value is in the same range as observed in our study.In a cohort study of patients with ischemic stroke treated with endovascular therapy, DBP on admission and functional outcome at 3 months showed a J-shaped relationship with an inflection point at the median value of DBP of 81 mmHg 49 .In contrast to our work, cSVD was not in the scope of these studies.
The reason why there was a U-shaped relationship between DBP and functional outcome whereas this was not true for SBP in the present study remains elusive.One possible explanation of this observation could be the small number of patients.The U-shaped association between low and high DBP and poor functional outcome might be closely linked to the state of cerebral perfusion for several reasons.First of all, there is some evidence that cerebral perfusion might be lower in patients with arterial hypertension irrespective of the presence of WMH compared to healthy controls 50 .Patients with WMH have been reported to exhibit a reduction of cerebral blood flow of the white matter (up to 38%) compared with those without WMH 51,52 .There was even a decrease in CBF within normal appearing white matter surrounding the WMH 53 .On the other hand, levels of cerebral perfusion especially in the early phase of AIS display a reverse U-shaped curve depending on SBP and DBP levels and-in turn-impact functional outcome at 3 months after stroke 54 .The most favorable functional outcome was associated with a SBP between 161 to 177 mmHg and DBP ranging from 103 to 114 mmHg 54 .Interestingly, Park and Ovbiagele found also an independent association between DBP and vascular outcomes 2 years after noncardioembolic stroke, showing that DBP < 70 mmHg as well as DBP > 90 mmHg was linked to an increased risk of vascular events 55 .Although this study revealed that patients with low DBP had higher comorbidities of diabetes mellitus, heart failure and carotid artery disease, DBP < 70 mmHg (but not DBP > 90 mmHg) was an independent predictor of vascular events, in particular recurrent stroke, after multivariable adjustment 55 .Notably, when the BP in the brachial artery is 117/75 mmHg in normotensive subjects, the pressure in the lenticulostriate vascular bed would be 91/58 mmHg and that in the same-size parietal arterioles 59/38 mmHg according to the calculation of Blanco and coworkers 56 .Given that there is a BP gradient in the brain, a decrease in peripheral DBP may result in a critical undersupply of cerebral tissue, since more than half of cerebral perfusion is during diastole 57 .
The present study has some limitations.First, the sample size of this work is relatively small.Second, we included patients receiving intravenous thrombolysis and/or undergoing mechanical thrombectomy as well as those with neither of these acute stroke therapies.However, this reflects the real, less than ideal clinical everyday practice.Third, the patients showed mild symptoms of stroke making a generalization of the study data difficult.Fourth, no additional cerebral MRI was performed at 12 months (except in patients with recurrent stroke or TIA) and thus, new or enlarged WMH were not able to be detected.Notably, WMH may regress over time after stroke and thus, provide potentially better functional and brain tissue outcome 58 .The strength of this work are the prospective study design and well-characterized patients.Furthermore, we used mean SBP and DBP over the first 72 h along with BP on admission.In contrast, a plenty of studies investigating the effect of acute-phase BP on functional outcome after AIS have used a single BP value (mainly the BP on admission) or BP values over the first 24 h as a predictor for the functional outcome.However, different mechanisms may be responsible for an elevation of BP values measured on admission.Beside a physiological response to cerebral ischemia, untreated arterial hypertension as well as increased sympathetic activation, fear of serious illness and hospitalization may contribute to increased BP values on admission 59,60 .Moreover, data collection and functional assessment by means of a structured telephone interview were carried out by one mRS-experienced person (S.G.).
In conclusion, this observational prospective study demonstrates that cSVD predicts a poor outcome among stroke survivors and thus corroborates findings of previous studies.We did not find a statistically significant relationship between cSVD, level of SBP, and functional outcome probably due to the fact that SBP ad and SBP 72h values ranged between 145 and 160 mmHg, values that have been associated with a good functional outcome after AIS.However, DBP and cSVD were associated with poor outcome depending on the level of DBP; additionally, DBP showed a U-shaped relationship with functional outcome.When comparing our work to other studies which investigate the impact of BP on stroke outcome, a lot of them only focus on the effect of SBP and reperfusion grade after mechanical thrombectomy, without including cSVD 21,[43][44][45] , or refer to cSVD alone [32][33][34] , making comparisons with our study difficult.Here, we have examined the impact of BP in relating with cSVD on stroke outcome in the acute phase, that has been rarely investigated from this point of view.Furthermore, our study suggests a prognostic significance for functional outcome after stroke depending on DBP value and degree of cSVD burden, which has scarcely been addressed so far, since most studies on stroke outcome analyze only the significance of SBP.Our findings may suggest an individualized stroke care by either lowering or elevating DBP in order to influence functional outcome.However additional large randomized studies are required to further investigate an association between DBP, cSVD and functional outcome after IS.

Figure 2 .
Figure 2. Trajectories of blood pressure over time of stroke patients regarding outcome at discharge.BP, blood pressure, SBP, systolic blood pressure; DBP, diastolic blood pressure.

Figure 3 .
Figure 3. Odds Ratio and 95% confidence interval for age, gender, DBP over the first 72h after admission and cSVD of stroke patients regarding functional outcome at discharge.Odds Ratio for age and DBP over 72 h indicates the ratio of the odds from the third to the first quartile.Age: 1. Quartile = 61.5 years; 3. Quartile = 80 years; DBP over 72 h: 1. Quartile = 66 mmHg; 3. Quartile = 80.3 mmHg.DBP, diastolic blood pressure, cSVD, cerebral small vessel disease.

Figure 4 .
Figure 4. Log odds for cSVD dependent on DBP over the first 72 h after admission for patients regarding functional outcome at discharge.Adjusted for age and gender.

Figure 5 .
Figure 5. Odds Ratio and 95% confident interval for age, gender, DBP over the first 72 h after admission and cSVD of stroke patients regarding outcome at 12 months.OR for age and DBP over 72 h indicates the ratio of the odds from the third to the first quartile.Age: 1. Quartile = 61.5 years; 3. Quartile = 80 years; DBP over 72 h: 1. Quartile = 66 mmHg; 3. Quartile = 80.3 mmHg.DBP, diastolic blood pressure, cSVD, cerebral small vessel disease.

Table 4 .
2lood pressure characteristics of stroke patients regarding outcome at 12 months.mRS,modifiedRankin Scale, SBP, systolic blood pressure; DBP, diastolic blood pressure. 1lculated with t-Test.2Calculatedwith Chi y -Test or Fishers-Exact-Test when expected frequencies were < 5.