Endogenous animal models of intracranial aneurysm development: a review

Neurosurgical Review - The pathogenesis and natural history of intracranial aneurysm (IA) remains poorly understood. To this end, animal models with induced cerebral vessel lesions mimicking human...     

High Wall Shear Stress and Spatial Gradients in Vascular Pathology: A Review

Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.     

Aneurysmal remodeling in the circle of Willis after carotid occlusion in an experimental model

Carotid occlusions are associated with de novo intracranial aneurysm formation in clinical case reports, but this phenomenon is not widely studied. We performed bilateral carotid ligation (n=9) in rabbits to simulate carotid occlusion, and sham surgery (n=3) for control. Upon euthanasia (n=3 at 5 days, n=6 at 6 months post ligation, and n=3 at 5 days after sham operation), vascular corrosion casts of the circle of Willis (CoW) were created. Using scanning electron microscopy, we quantified gross morphologic, macroscopic, and microscopic changes on the endocasts and compared findings with histologic data. At 5 days, CoW arteries of ligated animals increased caliber. The posterior communicating artery (PCom) increased length and tortuosity, and the ophthalmic artery (OA) origin presented preaneurysmal bulges. At 6 months, calibers were unchanged from 5 days, PComs further increased tortuosity while presenting segmental dilations, and the OA origin and basilar terminus presented preaneurysmal bulges. This exploratory study provides evidence that flow increase after carotid occlusion produces both compensatory arterial augmentation and pathologic remodeling such as tortuosity and saccular/fusiform aneurysm. Our findings may have considerable clinical implications, as these lesser-known consequences should be considered when managing patients with carotid artery disease or choosing carotid ligation as a therapeutic option.     

Increased Perviousness on CT for Acute Ischemic Stroke is Associated with Fibrin/Platelet-Rich Clots

BACKGROUND AND PURPOSE:Clot perviousness in acute ischemic stroke is a potential CT imaging biomarker for mechanical thrombectomy efficacy. We investigated the association among perviousness, clot cellular composition, and first-pass effect.MATERIALS AND METHODS:In 40 mechanical thrombectomy–treated cases of acute ischemic stroke, we calculated perviousness as the difference in clot density on CT angiography and noncontrast CT. We assessed the proportion of fibrin/platelet aggregates, red blood cells, and white blood cells on clot histopathology. We tested for linear correlation between histologic components and perviousness, differences in components between “high” and “low” pervious clots defined by median perviousness, and differences in perviousness/composition between cases that did and did not achieve a first-pass effect.RESULTS:Perviousness significantly positively and negatively correlated with the percentage of fibrin/platelet aggregates (P = .001) and the percentage of red blood cells (P = .001), respectively. Higher pervious clots had significantly greater fibrin/platelet aggregate content (P = .042). Cases that achieved a first-pass effect (n = 14) had lower perviousness, though not significantly (P = .055). The percentage of red blood cells was significantly higher (P = .028) and the percentage of fibrin/platelet aggregates was significantly lower (P = .016) in cases with a first-pass effect. There was no association between clot density on NCCT and clot composition or first-pass effect. Receiver operating characteristic analysis indicated that clot composition was the best predictor of first-pass effect (area under receiver operating characteristic curve: percentage of fibrin/platelet aggregates  = 0.731, percentage of red blood cells  = 0.706, perviousness = 0.668).CONCLUSIONS:Clot perviousness on CT is associated with a higher percentage of fibrin/platelet aggregate content. Histologic data and, to a lesser degree, perviousness may have value in predicting first-pass outcome. Imaging metrics that more strongly reflect clot biology than perviousness may be needed to predict a first-pass effect with high accuracy.

CT is the most common imaging technique used to evaluate patients with acute ischemic stroke (AIS). Together, NCCT and CTA can provide valuable information about the occlusive clot, such as its location, length, and density.^1-3 One parameter derived from these images is clot permeability, or perviousness, which indicates the amount of contrast that diffuses through the clot tissue.^1,4 Several clinical studies have claimed that perviousness may be an important indicator of how easily occlusive clots can be treated by tPA or mechanical thrombectomy (MT).^1,5 However, the underlying biology behind why some clots are more pervious than others remains largely unknown.The advent of MT for the treatment of AIS has enabled the biologic investigation of retrieved clots by histopathology.⁶ Recent studies have shown large-scale heterogeneity in the composition of retrieved clots, in terms of the percentage of fibrin/platelet aggregates (FP), red blood cell (RBC), and white blood cells (WBC).⁷ Differences in clot composition have been associated with stroke etiology and MT treatment outcomes. In several studies, FP-rich clots have been found to be cardioembolic in origin^8-10 and less responsive to revascularization attempts.^6,10,11 Intrinsically, perviousness is likely to be related to the cellular composition of a clot because different biologic components have different densities and thus alter how soluble molecules diffuse through them.^4,5 Experimental studies have shown that thrombi composed of higher fibrin fractions allowed greater contrast agent permeation than those packed with RBC.¹² Nevertheless, this association has not been established in clinical studies.To this end, the goal of this study was to investigate the relationship between clot perviousness calculated at the time of admission CT and its histopathologic composition after retrieval by MT. Furthermore, to explore whether perviousness could be used to indicate MT effectiveness, we also explored the relationships among perviousness, composition, and MT outcome, measured by the first-pass effect (FPE).¹³ Characterization of the occlusive clot based on pretreatment NCCT/CTA could impact the clinical management of patients with AIS.     

The association between hemodynamics and wall characteristics in human intracranial aneurysms: a review

Neurosurgical Review - Hemodynamics plays a key role in the natural history of intracranial aneurysms (IAs). However, studies exploring the association between aneurysmal hemodynamics and the...     

High fluid shear stress and spatial shear stress gradients affect endothelial proliferation, survival, and alignment

Cerebral aneurysms develop near bifurcation apices, where complex hemodynamics occur: Flow impinges on the apex, accelerates into branches, then slows again distally, creating high wall shear stress (WSS) and positive and negative spatial gradients in WSS (WSSG). Endothelial responses to these kinds of high WSS hemodynamic environments are not well characterized. We examined endothelial cells (ECs) under elevated WSS and positive and negative WSSG using a flow chamber with constant-height channels to create regions of uniform WSS and converging and diverging channels to create positive and negative WSSG, respectively. Cultured bovine aortic ECs were subjected to 3.5 and 28.4 Pa with and without WSSG for 24 and 36 h. High WSS inhibited EC alignment to flow, increased EC proliferation assessed by bromodeoxyuridine incorporation, and increased apoptosis determined by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling. These responses to high WSS were either accentuated or ameliorated by WSSG: Positive WSSG (+980 Pa/m) inhibited alignment and stimulated proliferation and apoptosis, whereas negative WSSG (−1120 Pa/m) promoted alignment and suppressed proliferation and apoptosis. These results demonstrate that ECs discriminate between positive and negative WSSG under high WSS conditions. EC responses to positive WSSG may contribute to pathogenic remodeling that occurs at bifurcations preceding aneurysm formation.     

The effect of pentadecapeptide BPC 157 on inflammatory,non-inflammatory,direct and indirect pain and capsaicin neurotoxicity

The anti-nociceptive effects of a newly synthesized pentadecapeptide coded BPC 157 (an essential fragment of new organoprotective gastric juice peptide BPC) was evaluated in comparison with aspirin and morphine reference standards, in various experimental models of indirect/direct nociception and neurotoxicity: writhing (acetic acid/magnesium sulphate), tail pinching, hot-plate, and capsaicin application. BPC 157 administered either in the ng or μg per kg range, intraperitoneally, significantly reduced the reactions in the writhing (inflammatory and non-inflammatory, prostaglandin-dependent and independent) and tail pinching tests. In the hot-plate test, unlike morphine, BPC 157 had no effect on normal animals. However, when given to capsaicin treated rats, BPC 157 strongly reduced capsaicin-allodynia, either given as pretreatment or once daily for 14 days after the capsaicin injection. This reduction in capsaicin’s effect could not be obtained when BPC 157 was applied in the presence of established capsaicin-somatosensory neuron degeneration (application only on the 14th day after capsaicin), so it is possible that the effects of BPC 157 could be related specifically to the integrity of capsaicin-sensitive somatosensory neurons and their protection (e.g. primary afferent neurons having small-diameter somata and unmyelinated (C-) or thinly myelinated (A6-) fibres).