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TLR4 (Toll-Like Receptor 4) Mediates the Development of Intracranial Aneurysm Rupture.

ABSTRACT: Inflammation is emerging as a critical factor in the pathophysiology of intracranial aneurysm. TLR4 (toll-like receptor 4) contributes not only to the innate immune responses but also to the inflammatory processes associated with vascular disease. Therefore, we examined the contribution of the TLR4 pathway to the development of the rupture of intracranial aneurysm. We used a mouse model of intracranial aneurysm. TLR4 inhibition significantly reduced the development of aneurysmal rupture. In addition, the rupture rate and levels of proinflammatory cytokines were lower in TLR4 knockout mice than the control littermates. Macrophage/monocyte-specific TLR4 knockout mice had a lower rupture rate than the control littermate mice. Moreover, the deficiency of MyD88 (myeloid differentiation primary-response protein 88), a key mediator of TLR4, reduced the rupture rate. These findings suggest that the TLR4 pathway promotes the development of intracranial aneurysmal rupture by accelerating inflammation in aneurysmal walls. Inhibition of the TLR4 pathway in inflammatory cells may be a promising approach for the prevention of aneurysmal rupture and subsequent subarachnoid hemorrhage.

SUBMITTER: Mitsui K

PROVIDER: S-EPMC7377296 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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TLR4 (Toll-Like Receptor 4) Mediates the Development of Intracranial Aneurysm Rupture.

Mitsui Kazuha K Ikedo Taichi T Kamio Yoshinobu Y Furukawa Hajime H Lawton Michael T MT Hashimoto Tomoki T

Hypertension (Dallas, Tex. : 1979) 20191223 2

Inflammation is emerging as a critical factor in the pathophysiology of intracranial aneurysm. TLR4 (toll-like receptor 4) contributes not only to the innate immune responses but also to the inflammatory processes associated with vascular disease. Therefore, we examined the contribution of the TLR4 pathway to the development of the rupture of intracranial aneurysm. We used a mouse model of intracranial aneurysm. TLR4 inhibition significantly reduced the development of aneurysmal rupture. In addi ...[more]

PMID: 31865791

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Project description:ImportanceUnruptured intracranial aneurysms not undergoing preventive endovascular or neurosurgical treatment are often monitored radiologically to detect aneurysm growth, which is associated with an increase in risk of rupture. However, the absolute risk of aneurysm rupture after detection of growth remains unclear.ObjectiveTo determine the absolute risk of rupture of an aneurysm after detection of growth during follow-up and to develop a prediction model for rupture.Design, setting, and participantsIndividual patient data were obtained from 15 international cohorts. Patients 18 years and older who had follow-up imaging for at least 1 untreated unruptured intracranial aneurysm with growth detected at follow-up imaging and with 1 day or longer of follow-up after growth were included. Fusiform or arteriovenous malformation-related aneurysms were excluded. Of the 5166 eligible patients who had follow-up imaging for intracranial aneurysms, 4827 were excluded because no aneurysm growth was detected, and 27 were excluded because they had less than 1 day follow-up after detection of growth.ExposuresAll included aneurysms had growth, defined as 1 mm or greater increase in 1 direction at follow-up imaging.Main outcomes and measuresThe primary outcome was aneurysm rupture. The absolute risk of rupture was measured with the Kaplan-Meier estimate at 3 time points (6 months, 1 year, and 2 years) after initial growth. Cox proportional hazards regression was used to identify predictors of rupture after growth detection.ResultsA total of 312 patients were included (223 [71%] were women; mean [SD] age, 61 [12] years) with 329 aneurysms with growth. During 864 aneurysm-years of follow-up, 25 (7.6%) of these aneurysms ruptured. The absolute risk of rupture after growth was 2.9% (95% CI, 0.9-4.9) at 6 months, 4.3% (95% CI, 1.9-6.7) at 1 year, and 6.0% (95% CI, 2.9-9.1) at 2 years. In multivariable analyses, predictors of rupture were size (7 mm or larger hazard ratio, 3.1; 95% CI, 1.4-7.2), shape (irregular hazard ratio, 2.9; 95% CI, 1.3-6.5), and site (middle cerebral artery hazard ratio, 3.6; 95% CI, 0.8-16.3; anterior cerebral artery, posterior communicating artery, or posterior circulation hazard ratio, 2.8; 95% CI, 0.6-13.0). In the triple-S (size, site, shape) prediction model, the 1-year risk of rupture ranged from 2.1% to 10.6%.Conclusion and relevanceWithin 1 year after growth detection, rupture occurred in approximately 1 of 25 aneurysms. The triple-S risk prediction model can be used to estimate absolute risk of rupture for the initial period after detection of growth.

Project description:Highlights • In our department of neurosurgery, we noticed a higher rate of patients with ruptured aneurysm who had a deteriorated neurological presentation on admission during COVID-19 pandemic (2020 group, n?=?26).• A group control included 28 consecutive patients managed at the same institution for the same disease in 2019, during the same time frame (2019 group).• Rates of poor neurological presentation and severe radiological presentation on hospital admission were higher during COVID-19 pandemic (p?=?0.01 and p?=?0.02, respectively).• During COVID-19 pandemic (2020 group), the delayed hospital admission was longer (p?=?0.005). Therefore, vasospasm’s rate on presentation was also higher (p?=?0.04).• In 2020, patients with only sudden headache may have feared immediate hospital admission because of potential COVID-19 contamination.• In case of recurrent COVID-19 pandemic, educating the population concerning specific symptoms such as sudden headache, neurological deficit or even sudden chest pain should be emphasized. Background/objectives The present study aimed at evaluating the impact on the early outcome of patients with ruptured intracranial aneurysms. Methods Our study prospectively included 26 consecutive patients with ruptured intracranial aneurysm managed at our institution in context of COVID-19 pandemic between March 1st, 2020 and April, 26th, 2020 (2020 group). A group control included other 28 consecutive patients managed at the same institution for the same disease in 2019, during the same time frame (2019 group). On admission, poor neurological status was defined as WFNS score >3. Severe radiological status was defined by the presence of intracerebral hematoma, or/and acute hydrocephalus requiring further EVD or/and the presence of vasospasm on presentation. Statistical analysis was performed to compare the 2 distinct groups. Results Rates of poor neurological presentation and severe radiological presentation on hospital admission were higher in the 2020 group (p?=?0.01 and p?=?0.02, respectively). The delayed hospital admission was 2.7 days in 2020 group and 0.75 days in 2019 group (p?=?0.005). Therefore, vasospasm’s rate on presentation was also higher in the 2020 group (p?=?0.04). Conclusion To our knowledge, this is one of the first studies demonstrating influence of the COVID-19 pandemic on patients with urgent and severe intracranial aneurysmal disease. In case of recurrent COVID-19 pandemic, educating the population concerning specific symptoms such as sudden headache, neurological deficit or even sudden chest pain should be emphasized.

Dataset Information

TLR4 (Toll-Like Receptor 4) Mediates the Development of Intracranial Aneurysm Rupture.

Publications

TLR4 (Toll-Like Receptor 4) Mediates the Development of Intracranial Aneurysm Rupture.

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