Discussion
This is the first report to determine the characteristics of intracranial plaque proximal to LVO in non-cardioembolic stroke by HR-MRI, which has been demonstrated to have high agreement of plaque signal features with histology.20 28 We found that intracranial plaque was more prevalent in the ipsilateral versus contralateral side. Importantly, in subgroup with <50% stenotic plaque, the high-risk feature of ipsilateral plaque was more likely to be closely related to an ischaemic stroke, a finding that was not identified in the subgroup with ≥50% stenotic plaque.
The relationship between plaque and acute ischaemic stroke had been proved previously.1 As a specific subtype, ICAS-LVO has been widely studied about early diagnosis and treatment, but the underlying mechanisms were seldom investigated.29 Previous studies showed histological evidence of FCR, IPH and subintimal dissection of the involved vessel segment in autopsy patients.30 31 In the current study, we found that the morphological characteristics of ipsilateral plaque proximal to LVO such as PB and RI were independent predictors for an index ischaemic stroke in the population of non-cardiogenic stroke with intracranial LVO, which was in line with prior studies finding that RI and PB were closely related with stroke.32 33 We also found that stenosis also interacted with plaque morphology such as RI and PB. These results suggest that the correlation between events and high-risk plaque may be dynamic at different stages of plaque formation, indicating potentially different mechanisms underlying acute LVO (figure 5).
Figure 5The possible underlying aetiology of LVO in <50% stenosis versus ≥50% stenosis group In <50% stenosis group, a positive remodelling plaque was highly associated with increased vulnerability (disrupted fibrous cap, IPH or mural thrombus) and the index stroke, while in ≥50% stenosis group, a negative remodelling plaque with thick fibrous cap erosion to index stroke. Upper: showed a positive remodelling plaque with IPH and thin, ruptured fibrous cap ipsilateral to stroke. Lower: showed a negative remodelling plaque with thick fibrous cap erosion ipsilateral to stroke. Green=vessel wall/fibrous tissue, yellow=LRNC, red=IPH/mural thrombus. IPH, intraplaque haemorrage; LVO, large vessel occlusion
In <50% stenotic subgroup, we found that the high-risk morphological components of plaque were more closely related to stroke events, suggesting that an important role of adaptive positive remodelling in the early stage of plaque formation. In coronary disease studies, positive remodelling occurs in response to plaque formation by releasing matric metalloproteinases from a LRNC.34 35 Before reaching the maximum of remodelling and causing stenosis, the lumen stenosis can be adjusted, but there is a greater PB coupled with the vessel wall outward enlargement, which eventually led to the rupture of fibrous cap and the formation of thrombosis.36 Collectively, these results suggest that embolism or local thrombosis secondary to proximal plaque rupture may be the main cause of LVO in patients with <50% stenotic plaque (figure 5).
In ≥50% stenotic subgroup, we found no correlation between high-risk plaque and stroke events. Prior findings showed that the vessel wall would stop expanding outwardly when reaching a maximum cut-off of PB, and at this time the lumen began to narrow,36 and the remodelling was no longer positive but negative. This could explain why there was no difference in plaque morphology between the ipsilateral and contralateral sides, while the remodelling is intermediate in ≥50% stenotic subgroup. As to the component of plaques, as the plaques advanced, they experienced self-repair and healing, when the fibrous components of the plaque gradually increased, so the plaque may become relatively mature and stable despite significant retractive stenosis,8 37 which may explain no difference of plaque components in ipsilateral versus contralateral side. In this condition, there were more fibrous components in ≥50% stenotic versus <50% stenotic plaques. Due to more fibrous components on the surface of stenotic plaques, glycoproteins were easily eroded by metalloproteinases, which may lead to mural thrombus although the plaques do not rupture.8 34 Therefore, local thrombosis formation secondary to plaque erosion may be involved in stroke with stenotic plaque proximal to LVO (figure 5).
The main strength of the current study is the first report of a high proportion of intracranial plaques proximal to LVO ipsilateral to non-cardioembolic stroke, suggesting that the plaque may play an aetiological role in this specific subtype. In addition, significant differences in ipsilateral plaque characteristics and infarct pattern were observed in the plaque ipsilateral in <50% vs ≥50% stenotic subgroups. Collectively, there may be two potential mechanisms underlying LVO at different stages of plaque, that is, local thrombosis or embolism secondary to <50% stenotic plaque rupture versus mural thrombus secondary to ≥50% stenotic plaque erosion. These findings could inform future studies of secondary prevention in this population.
On the other hand, the retrospective nature and the sample size are limitations of our study, although current rigorous inclusion/exclusion criteria may restrict this effect. Second, the low resolution of intracranial HR-MRI was an intrinsic limitation for evaluating the nature of the vessel wall thickening, which would make it difficult to accurately distinguish an embolus, especially at the initiation site of occlusive thrombus from a plaque, or lipid core from IPH in some cases. Third, RI might be underrated because the remodelling status at the reference location may respond to early phases of atherosclerosis. Additionally, an overestimation of PB margin may be unavoidable due to a partial volume averaging effect, although we used 3D-rendering technology to minimise the obliquity and tortuous curvature of intracranial vessels, especially in angled lesions.38 Unfortunately, we did not include plaque enhancement in the analysis, but suppression of MRI signal in blood and CSF was used for accurate measurement of plaque and better delineation of the outer edge of the vessel.14 19 Fourth, there were missing data which might have confounded our results: (1) no long-term ECG monitoring was performed, which may mix some patients with occult AF; (2) aortic arch atherosclerosis was not estimated; (3) due to lack of follow-up, the relationship between following recurrent events and plaque with high-risk characteristics is unknown. Fifth, the patients with severe NIHSS were not included in the current study based on the tolerance and safety concerns, which may result in selection bias with overestimate of the patients in ≥50% stenosis group. Sixth, it is hard to differentiate between acute LVO versus acute on chronic LVO cases, which was an important concern. Taken together with previous studies in coronary artery,39 40 we contend that acute LVO may be more likely to occur in <50% stenosis cases while acute on chronic LVO more likely in ≥50% stenosis cases. Finally, our findings in non-Chinese population would need to be further confirmed.
In conclusion, this is the first study to report the features of intracranial plaque proximal to LVO in non-cardioembolic stroke and provided some potential evidence for different aetiological roles of <50% stenotic versus ≥50% stenotic intracranial plaque in these population.