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

Abstract

Elevated and low blood pressure (BP) may lead to poor functional outcome after ischemic stroke, which is conflicting. Hence, there must be “confounders” - 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 (BP_ad) and over the first 72 hours (BP_72h). 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). SBP_ad, DBP_ad and SBP_72h were not significantly associated with outcome at any time. A significant relationship was found between DBP_72h, (p < 0.01), cSVD (p = 0.013) and outcome at discharge. At 12 months, we found a relationship between outcome and DBP_72h (p = 0.018) and a statistical tendency regarding cSVD (p = 0.08). Changes in DBP_72h were significantly related with outcome. There was a U-shaped relationship between DBP 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.

Introduction

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 ^3–5. So far, there is some evidence that raised BP early after AIS is associated with dependency, clinical deterioration and subsequent death ⁶. In contrast, some studies revealed that both low and high BP entails poor prognosis after AIS ^5,7. Further studies found no effect of BP in the acute phase of AIS on functional outcome ^8,9. 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 ^10–12. 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 ^13–15. Clinically, cSVD may lead to stroke, cognitive dysfunction and worsening of gait as well as balance ¹⁶. On brain MRI, cSVD presents with lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMB) and perivascular spaces ^13,16,17. In particular, WMH are the most common cSVD lesions that are observed on brain MR scans of most people aged over 70 years ¹⁸. CMB also increase with age although they occur less frequent compared to WMH and are unusual in the absence of WMH ¹⁴. In a recently published study on stroke patients undergoing endovascular treatment, no signs of cSVD was observed in 61%, mild and moderate or severe degree of cSVD was seen in 20.0% and 19.7%, respectively ¹⁹. 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 ^20–22. Additionally, patients with severe cSVD have an even more reduced cerebral blood flow and impaired cerebral autoregulation ^23,24.

With these considerations in mind, we aimed to investigate whether functional outcome in the short term (at discharge) and in the long term (12 months after cerebrovascular event) differs between stroke patients with a high and low burden of cSVD depending on the level of acute-phase systolic (SBP) and/or diastolic blood pressure (DBP). Additionally, we examined whether there is an interaction between BP in the acute phase and severity of cSVD regarding functional impairment, recurrent stroke/TIA and death 12 month after index event.

Methods

Results

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 index event. An unexpected finding of the present study was a significant association between mean DBP_72h and functional outcome at discharge and 12 months afterwards.

A growing number of studies suggest that cSVD in patients with AIS is independently associated with poor functional outcome in the short and long term after cerebrovascular event ^33–35 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 ^24,36,37. 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, which in itself may result in an increase of cerebral tissue damage and therefore 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, which was a surprising finding. 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 ³⁸. Furthermore, different regional distribution of WMH load and/or locations of stroke lesions might also impact functional outcome ³⁹. 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 ⁴⁰. In contrast to our study, the main focus of the aforementioned study was on SBP variability during the first 24 hours after stroke.

Although SBP decreased over the first 72 hours 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 hours 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) ²². However, patients with cSVD burden were not particularly addressed in that study.

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 hours and functional outcome, however, in the aforementioned trial, DBP was generally lower in patients with a poor outcome at day 7 and at day 90 ²². In another previously published study, DBP variability was associated with poor functional outcome at hospital discharge ⁴¹. Of note, the aforementioned studies did not focus in particular on stroke patients with/without cSVD in their analyses. Göthel-Ezzeiani and coworkers also investigated the impact of WMH and blood pressure on clinical outcome. They found a relationship between DBP and mortality but none between DBP and functional outcome at 3 months ⁴²; of note, only stroke patients undergoing mechanical recanalization were included in their study. In the present study, there was still 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 hours after stroke in patients with good and poor late functional outcome (at 3 months) ⁴³. However, that study did not specifically investigate stroke survivors presenting cSVD and enrolled only stroke patients treated with intravenous thrombolysis.

Additionally, 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 ⁵ or 6 months ⁴⁴ was provided by previous studies. In contrast to our study, the cutoff value for DBP was higher, namely at 100–110 mmHg ⁵ or 87.8–95 mmHg, respectively ⁴⁴. 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) ⁴⁵ or TIA (n > 200’000 patients) ⁴⁶ 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 ⁴⁷. 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 ⁴⁸. 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 ^49,50. There was even a decrease in CBF within normal appearing white matter surrounding the WMH ⁵¹. 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 ⁵². The most favorable functional outcome was associated with a SBP between 161 to 177 mmHg and DBP ranging from 103 to 114 mmHg ⁵². Interestingly, Park and Ovbiagele found also an independent association between DBP and vascular outcomes 2 years after non-cardioembolic stroke, showing that DBP < 70 mmHg as well as DBP > 90 mmHg was linked to an increased risk of vascular events ⁵³. 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 ⁵³. 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 ⁵⁴. 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 ⁵⁵.

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 detect. Notably, WMH may regress over time after stroke and thus, provide potentially better functional and brain tissue outcome ⁵⁶. 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 hours 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 hours 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 ^57,58. 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. This 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.

Declarations

Acknowledgments/Source of founding

This study was funded by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF), University Hospital, Würzburg. This publication was supported by the Open Access Publication Fund of the University of Würzburg.

 Author contributions

Conceived and designed the study: FF, SG. Performed the study: SG, AS, FF. Analyzed the data: SG, AS, FF. Contributed analysis tools: SG, FF, AS. Wrote the paper: SG, AS, FF. 

Conflicts of interest/Disclosures

The authors have nothing to disclose and declare no competing interests..

 Data availability

All data generated or analyzed during this study are included in this published article.

 Corresponding Author

Correspondence to Felix Fluri ([email protected])

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