In the present study, we found that CA was similar in symptomatic and non-symptomatic hemispheres of SAO-associated stroke patients. MAP on admission and diabetes mellitus were both significant independent predictors of CA impairment in ischaemic stroke due to SAO, while our results indicate that CSVD may not be the main factor affecting bilateral CA in patients with SAO. Furthermore, our results indicate that an appropriate increase in MAP in the acute phase after stroke may help to improve CA.
Impairment of CA after ischaemic stroke has long been a concern. Animal models have demonstrated impaired CA in peri-infarct tissue within 24 h after stroke [17]. The presence or absence of CA in ischaemic stroke has a critical effect on the maintenance of stable blood flow in the ischaemic penumbra and on excessive hyperperfusion. In recent years, it has been reported that impaired CA is associated with various cerebrovascular diseases and that it often indicates a poor prognosis. CA has been shown to vary characteristically among the different stroke subtypes. Using the TFA approach to derive the CA parameters of gain and phase, Immink et al. found that dynamic CA is impaired ipsilaterally in ischaemic stroke in the MCA territory, but bilaterally in ischaemic stroke involving lacunae [9]. Using the same measurement method, another study demonstrated that dynamic CA is impaired ipsilaterally in LAA-associated stroke, but bilaterally in SAO-associated stroke [11]. In our study, we observed similar CA in both hemispheres in patients with SAO-associated stroke, which was consistent with previous reports of bilaterally impaired CA. The factors influencing CA impairment in both hemispheres, rather than only the symptomatic side in SAO-associated stroke warrant further investigation.
Generally, the gain CA parameter (amplitude) quantifies the damping effect of CA on the magnitude of oscillations in blood pressure [1]. Gain is a continuous variable. For example, a value of 0.5 suggests that 50% of the relative amplitude of CBF velocity is attenuated with respect to a unit of change in ABP. Effective CA attenuates gain; thus, a low gain indicates the presence of CA, whereas a high gain indicates diminished effectiveness of the CA. Moreover, a high gain indicates that a greater relative amplitude of CBF velocity is attenuated with fluctuations in blood pressure, suggesting that the distal arterioles and capillaries do not respond to changes in blood pressure. Data from previous studies have shown that impaired CA is likely associated with the loss of endothelial and smooth muscle function after ischaemia. Thus, in stroke due to SAO, functional and structural changes in the small vessels may play a role in global cerebral haemodynamic impairment.
However, it remains unclear whether the globally impaired CA in SAO is caused by acute infarction or chronic small-vessel disease. Existing hypotheses tend to attribute it to bilateral small vessel disease. CSVD is associated with changes in cerebral small vessels and consequent brain damage in the white and grey matter [18]. A recent study in patients with CSVD demonstrated that CA was compromised, and some specific neuroimaging characteristics (total CSVD burden, white matter hyperintensities, severe PVS, and lobar cerebral microbleeds) might indicate more severe CA impairment [19]. Another study in patients with Alzheimer’s disease demonstrated an interrelationship between Alzheimer's disease pathology, CSVD, and CA [20]. However, in the present study in SAO-associated stroke patients, no significant correlations were found between CA parameters and CSVD characteristics (neither CSVD markers nor the total CSVD burden score). Nonetheless, it is worth noting that diabetes mellitus, a common risk factor for small-vessel disease, was significantly associated with impaired CA. This suggests that globally impaired CA in patients with SAO may be induced by acute stimulation of vascular events based on extensive chronic small vessel dysfunction. More robust longitudinal studies are needed to investigate the mechanism underlying bilateral CA impairment. Controlling such risk factors affecting cerebral small vessels may be a feasible method for protecting against CA.
To date, few studies have explored the risk factors of CA impairment in ischaemic stroke. Recently, one study that enrolled 67 stroke patients regardless of their etiological subtypes suggested that increasing age, subtype of LAA, and higher uric acid levels had prognostic value in terms of disturbed autoregulation [4]. In the present study, we found that MAP on admission and diabetes mellitus were significant independent predictors of CA impairment in ischaemic stroke patients with SAO. These inconsistent results may be attributed to the varied stroke aetiology among the patients enrolled in the two studies. Considering the different subtypes of stroke with highly variable features, exploring CA characteristics on an individual etiological basis in this population is imperative.
Following ischaemic stroke, a significant number of patients present with hypertension, and some trials have tested approaches for blood pressure management in the acute and subacute stages [21–23]. Because of the complexity of CA, significant controversies exist regarding blood pressure management after ischaemic stroke. The ideal blood pressure range after ischaemic stroke is unknown. Current guidelines recommend permissive hypertension after an ischaemic stroke. In patients who do not receive thrombolysis, it is recommended that blood pressure treatment should be avoided unless SBP > 220 mmHg or DBP > 120 mmHg within the initial 24 h after stroke [24]. However, in the era of precision medicine, an optimal blood pressure range should probably depend on individual CA variability, temporal and spatial heterogeneity of stroke pathophysiology, and stroke subtype.
Currently, the blood pressure control strategy for patients with SAO is not conclusive. In this study, we found that a low MAP on admission was a significant independent predictor of CA impairment in ischaemic stroke due to SAO, and an appropriate increase in MAP (likely MAP > 105 mmHg) in the acute phase after stroke may help to improve CA. This is consistent with the suggestion of permissive hypertension after an ischaemic stroke. Our results suggest that CA in patients with SAO may be more sensitive to low blood pressure and hypoperfusion injury. In ischaemic stroke, there is an assumption that CA would be impaired, and that CBF would need to be maintained within safe limits by controlling ABP. In patients with Moyamoya disease, CBF was found to be susceptible to small blood pressure changes, and that CA might be affected by short dynamic blood pressure modifications [25]. Thus, an increase in MAP could be hypothesised to serve the purpose of maintaining CBF (specifically in the penumbra), and lowering MAP may therefore be disadvantageous. Our results helped to establish a relatively ideal blood pressure range following ischaemic stroke with SAO. However, more precise CA-oriented blood pressure management in SAO patients still needs to be established and verified by sufficient preclinical and clinical evidence in a future study.
This study had several limitations. First, the proportion of women among the enrolled patients was low because they tended to have poor bilateral temporal windows. Second, post-stroke changes in CA over time and the association of CA with clinical outcomes were not evaluated. Third, the sample size was small. Large-sample multicentre studies are needed in future to provide more evidence in this regard.