Somatic PDGFRB activating variants promote smooth muscle cell phenotype modulation in intracranial fusiform aneurysm.

BACKGROUND: The fusiform aneurysm is a nonsaccular dilatation affecting the entire vessel wall over a short distance. Although PDGFRB somatic variants have been identified in fusiform intracranial aneurysms, the molecular and cellular mechanisms driving fusiform intracranial aneurysms due to PDGFRB somatic variants remain poorly understood. METHODS: In this study, single-cell sequencing and immunofluorescence were employed to investigate the phenotypic changes in smooth muscle cells within fusiform intracranial aneurysms. Whole-exome sequencing revealed the presence of PDGFRB gene mutations in fusiform intracranial aneurysms. Subsequent immunoprecipitation experiments further explored the functional alterations of these mutated PDGFRB proteins. For the common c.1684 mutation site of PDGFRß, we established mutant smooth muscle cell lines and zebrafish models. These models allowed us to simulate the effects of PDGFRB mutations. We explored the major downstream cellular pathways affected by PDGFRBY562D mutations and evaluated the potential therapeutic effects of Ruxolitinib. RESULTS: Single-cell sequencing of two fusiform intracranial aneurysms sample revealed downregulated smooth muscle cell markers and overexpression of inflammation-related markers in vascular smooth muscle cells, which was validated by immunofluorescence staining, indicating smooth muscle cell phenotype modulation is involved in fusiform aneurysm. Whole-exome sequencing was performed on seven intracranial aneurysms (six fusiform and one saccular) and PDGFRB somatic mutations were detected in four fusiform aneurysms. Laser microdissection and Sanger sequencing results indicated that the PDGFRB mutations were present in smooth muscle layer. For the c.1684 (chr5: 149505131) site mutation reported many times, further cell experiments showed that PDGFRBY562D mutations promoted inflammatory-related vascular smooth muscle cell phenotype and JAK-STAT pathway played a crucial role in the process. Notably, transfection of PDGFRBY562D in zebrafish embryos resulted in cerebral vascular anomalies. Ruxolitinib, the JAK inhibitor, could reversed the smooth muscle cells phenotype modulation in vitro and inhibit the vascular anomalies in zebrafish induced by PDGFRB mutation. CONCLUSION: Our findings suggested that PDGFRB somatic variants played a role in regulating smooth muscle cells phenotype modulation in fusiform aneurysms and offered a potential therapeutic option for fusiform aneurysms.

Aneurysm wall enhancement, hemodynamics, and morphology of intracranial fusiform aneurysms.

Background and objective: Intracranial fusiform aneurysms (IFAs) are considered to have a complex pathophysiology process and poor natural history. The purpose of this study was to investigate the pathophysiological mechanisms of IFAs based on the characteristics of aneurysm wall enhancement (AWE), hemodynamics, and morphology. Methods: A total of 21 patients with 21 IFAs (seven fusiform types, seven dolichoectatic types, and seven transitional types) were included in this study. Morphological parameters of IFAs were measured from the vascular model, including the maximum diameter (Dmax), maximum length (Lmax), and centerline curvature and torsion of fusiform aneurysms. The three-dimensional (3D) distribution of AWE in IFAs was obtained based on high-resolution magnetic resonance imaging (HR-MRI). Hemodynamic parameters including time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), gradient oscillatory number (GON), and relative residence time (RRT) were extracted by computational fluid dynamics (CFD) analysis of the vascular model, and the relationship between these parameters and AWE was investigated. Results: The results showed that Dmax (p = 0.007), Lmax (p = 0.022), enhancement area (p = 0.002), and proportion of enhancement area (p = 0.006) were significantly different among three IFA types, and the transitional type had the largest Dmax, Lmax, and enhancement area. Compared with the non-enhanced regions of IFAs, the enhanced regions had lower TAWSS but higher OSI, GON, and RRT (p < 0.001). Furthermore, Spearman's correlation analysis showed that AWE was negatively correlated with TAWSS, but positively correlated with OSI, GON, and RRT. Conclusion: There were significant differences in AWE distributions and morphological features among the three IFA types. Additionally, AWE was positively associated with the aneurysm size, OSI, GON, and RRT, while negatively correlated with TAWSS. However, the underlying pathological mechanism of the three fusiform aneurysm types needs to be further studied.

Stenting After Coiling Using a Single Microcatheter for Treatment of Ruptured Intracranial Fusiform Aneurysms with Parent Arteries Less Than 1.5 mm in Diameter.

BACKGROUND: Ruptured intracranial fusiform aneurysms involving small-diameter parent arteries are difficult to treat. Parent artery occlusion is a relatively simple and reliable treatment. However, occasionally, the parent arteries have to be retained. The arrival of the low-profile stent (LVIS Jr.) has made reconstructive endovascular treatment for fusiform aneurysms involving small-diameter parent arteries possible. CASE DESCRIPTION: This report describes an innovative method for stent-assisted coiling (stenting after coiling technique using only 1 microcatheter) and describes our initial experience and feasibility of this technique. However, this report carries all limitations of a technical case report of a single patient, including reproducibility, unknown potential of complications, absence of long-term follow-up, and comparative effectiveness or safety with current known techniques. CONCLUSIONS: Stenting after a coiling technique using the LVIS Jr. stent provides a possible method for reconstructive endovascular treatment of intracranial fusiform aneurysms with parent arteries <1.5 mm in diameter.

Multiple overlapping stents combined with coils for the treatment of intracranial fusiform aneurysms:clinical technique and therapeutic results / 介入放射学杂志

Objective To investigate the safety and feasibility of multiple overlapping stents combined with coils in treating intracranial fusiform aneurysms, and to evaluate its therapeutic efficacy. Methods During the period from Aug. 2012 to Aug. 2013, three patients with intracranial fusiform aneurysm were admitted to authors’ hospital. The diagnosis was confirmed by CT angiography and whole cerebral angiography. Multiple overlapping stents combined with coils was carried out in all the three patients. All the patients were followed up and the clinical results were analyzed. Results Multiple overlapping stents combined with coils was successfully accomplished in all the three patients. Greater part of the aneurysmal cavity was occluded, and immediately after the procedure obvious blood whirling in the aneurysmal sac was seen. A total of 7 stents and 17 coils were used in treating the three patients. No aneurysm rupture or thrombosis occurred. The patients were followed up for 3 - 8 months. In one case the headache disappeared in 8 months, no dysneuria was detected, and angiography showed that the aneurysmal sac disappeared and the parent artery was patent. In another patient the headache disappeared in 3 months, and the angiography showed that the aneurysmal cavity had slight visualization and the parent artery was patent. The remaining patient was asymptomatic at 3-month follow-up. Conclusion For the treatment of intracranial fusiform aneurysms, multiple overlapping stents combined with coils is clinically feasible and safe with excellent short-term efficacy although its long-term results need to be further studied. (J Intervent Radiol, 2014, 23: 277-280).