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 SBPad nor mean SBP72h 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 DBP72h 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 SBPad or SBP72h 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 DBP72h was significantly lower in stroke patients with cSVD. Moreover, DBP72h 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 DBP72h 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 DBP72h 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 SBPad and SBP72h 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.