Commissioning, clinical implementation, and initial experience with a new brain tumor treatment package on a low-field MR-linac.

To evaluate the image quality, dosimetric properties, setup reproducibility, and planar cine motion detection of a high-resolution brain coil and integrated stereotactic brain immobilization system that constitute a new brain treatment package (BTP) on a low-field magnetic resonance imaging (MRI) linear accelerator (MR-linac). Image quality of the high-resolution brain coil was evaluated with the 17 cm diameter spherical phantom and the American College of Radiology (ACR) Large MRI Phantom. Patient imaging studies approved by the institutional review board (IRB) assisted in selecting image acquisition parameters. Radiographic and dosimetric evaluation of the high-resolution brain coil and the associated immobilization devices was performed using dose calculations and ion chamber measurements. End-to-end testing was performed simulating a cranial lesion in a phantom. Inter-fraction setup variability and motion detection tests were evaluated on four healthy volunteers. Inter-fraction variability was assessed based on three repeat setups for each volunteer. Motion detection was evaluated using three-plane (axial, coronal, and sagittal) MR-cine imaging sessions, where volunteers were asked to perform a set of specific motions. The images were post-processed and evaluated using an in-house program. Contrast resolution of the high-resolution brain coil is superior to the head/neck and torso coils. The BTP receiver coils have an average HU value of 525 HU. The most significant radiation attenuation (3.14%) of the BTP, occurs through the lateral portion of the overlay board where the high-precision lateral-profile mask clips attach to the overlay. The greatest inter-fraction setup variability occurred in the pitch (average 1.08 degree) and translationally in the superior/inferior direction (average 4.88 mm). Three plane cine imaging with the BTP was able to detect large and small motions. Small voluntary motions, sub-millimeter in magnitude (maximum 0.9 mm), from motion of external limbs were detected. Imaging tests, inter-fraction setup variability, attenuation, and end-to-end measurements were quantified and performed for the BTP. Results demonstrate better contrast resolution and low contrast detectability that allows for better visualization of soft tissue anatomical changes relative to head/neck and torso coil systems.

Model refinement increases confidence levels and clinical agreement when commissioning a three-dimensional secondary dose calculation system.

PURPOSE: Evaluate custom beam models for a second check dose calculation system using statistically verifiable passing criteria for film analysis, DVH, and 3D gamma metrics. METHODS: Custom beam models for nine linear accelerators for the Sun Nuclear Dose Calculator algorithm (SDC, Sun Nuclear) were evaluated using the AAPM-TG119 test suite (5 Intensity Modulated Radiation Therapy (IMRT) and 5 Volumetric Modulated Arc Therapy (VMAT) plans) and a set of clinical plans. Where deemed necessary, adjustments to Multileaf Collimator (MLC) parameters were made to improve results. Comparisons to the Analytic Anisotropic Algorithm (AAA), and gafchromic film measurements were performed. Confidence intervals were set to 95% per TG-119. Film gamma criteria were 3%/3 mm (conventional beams) or 3%/1 mm (Stereotactic Radiosurgery [SRS] beams). Dose distributions in solid water phantom were evaluated based on DVH metrics (e.g., D95, V20) and 3D gamma criteria (3%/3 mm or 3%/1 mm). Film passing rates, 3D gamma passing rates, and DVH metrics were reported for HD MLC machines and Millennium MLC Machines. RESULTS: For HD MLC machines, SDC gamma film agreement was 98.76% ± 2.30% (5.74% CL) for 6FFF/6srs (3%/1 mm), and 99.80% ± 0.32% (0.83% CL) for 6x (3%/3 mm). For Millennium MLC machines, film passing rates were 98.20% ± 3.14% (7.96% CL), 99.52% ± 1.14% (2.71% CL), and 99.69% ± 0.82% (1.91% CL) for 6FFF, 6x, and 10x, respectively. For SDC to AAA comparisons: HD MLC Linear Accelerators (LINACs); DVH point agreement was 0.97% ± 1.64% (4.18% CL) and 1.05% ± 2.12% (5.20% CL); 3D gamma agreement was 99.97% ± 0.14% (0.30% CL) and 100.00% ± 0.02% (0.05% CL), for 6FFF/6srs and 6x, respectively; Millennium MLC LINACs: DVH point agreement was 0.77% ± 2.40% (5.47% CL), 0.80% ± 3.40% (7.47% CL), and 0.07% ± 2.15% (4.30% CL); 3D gamma agreement was 99.97% ± 0.13% (0.29% CL), 99.97% ± 0.17% (0.36% CL), and 99.99% ± 0.06% (0.12% CL) for 6FFF, 6x, and 10x, respectively. CONCLUSION: SDC shows agreement well within TG119 CLs for film and redundant dose calculation comparisons with AAA. In some models (SRS), this was achieved using stricter criteria. TG119 plans can be used to help guide model adjustments and to establish clinical baselines for DVH and 3D gamma criteria.

Obese Tracheostomy: A Challenging Path From Surgery to Decannulation.

PURPOSE: Well-defined or standardized tracheostomy decannulation guidelines are not available, and the long-term data on the outcomes in the obese are limited. The purpose of the present study was to determine the outcomes associated with tracheostomy for obese patients from surgery to decannulation. The specific aims were to measure 1) the rate of successful tracheostomy downsize; 2) the rate of successful tracheostomy decannulation; and 3) the associated pre-, intra-, and postoperative subject variables with tracheostomy downsizing and decannulation success. PATIENTS AND METHODS: A retrospective cohort study was implemented to determine the outcomes associated with downsizing and decannulation after obese tracheostomy. The predictive value of the independent variables from the subjects' pre-, intra-, and postoperative periods were evaluated as they related to successful downsizing and decannulation. The included subjects had undergone tracheostomy from April 2016 to December 2018. The primary outcomes were successful downsizing and successful decannulation. A downsize checklist was created with the following yes/no criteria that should reasonably be met before downsizing a tracheostomy in an obese subject. The secondary analysis was the association between the checklist criteria and successful downsize and decannulation. The data were analyzed using the χ2 test, analysis of variance, t test, likelihood ratio, Kaplan-Meier analysis with Cox regression, and logistic binary regression, with statistical significance set at P < .05. RESULTS: The study sample included 82 obese subjects (body mass index [BMI] >30 kg/m2), with a mean age of 55.7 ± 15.0 years; 56% were men. Only 62 of the subjects could be downsized (75.6%) and 39 (47.6%) could be decannulated. The general trend showed that an increased BMI resulted in an increased time to decannulation, long-term tracheostomy dependence, and less successful downsize and decannulation. For patients with a BMI of 30 kg/m2 or more, the downsize success rate was 93.5% and the decannulation success rate was 89.7%. CONCLUSIONS: Obese patients have a greater likelihood of complications and an increased risk of remaining tracheostomy dependent. Consideration of the patient's BMI is crucial when initiating the decannulation progression.

Increased lethality and defective pulmonary clearance of Streptococcus pneumoniae in microsomal prostaglandin E synthase-1-knockout mice.

The production of prostaglandin E2 (PGE2) increases dramatically during pneumococcal pneumonia, and this lipid mediator impairs alveolar macrophage (AM)-mediated innate immune responses. Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme involved in the synthesis of PGE2, and its expression is enhanced during bacterial infections. Genetic deletion of mPGES-1 in mice results in diminished PGE2 production and elevated levels of other prostaglandins after infection. Since PGE2 plays an important immunoregulatory role during bacterial pneumonia we assessed the impact of mPGES-1 deletion in the host defense against pneumococcal pneumonia in vivo and in AMs in vitro. Wild-type (WT) and mPGES-1 knockout (KO) mice were challenged with Streptococcus pneumoniae via the intratracheal route. Compared with WT animals, we observed reduced survival and increased lung and spleen bacterial burdens in mPGES-1 KO mice 24 and 48 h after S. pneumoniae infection. While we found modest differences between WT and mPGES-1 KO mice in pulmonary cytokines, AMs from mPGES-1 KO mice exhibited defective killing of ingested bacteria in vitro that was associated with diminished inducible nitric oxide synthase expression and reduced nitric oxide (NO) synthesis. Treatment of AMs from mPGES-1 KO mice with an NO donor restored bacterial killing in vitro. These results suggest that mPGES-1 plays a critical role in bacterial pneumonia and that genetic ablation of this enzyme results in diminished pulmonary host defense in vivo and in vitro. These results suggest that specific inhibition of PGE2 synthesis by targeting mPGES-1 may weaken host defense against bacterial infections.

Differential gene expression by endothelial cells under positive and negative streamwise gradients of high wall shear stress.

Flow impingement at arterial bifurcations causes high frictional force [or wall shear stress (WSS)], and flow acceleration and deceleration in the branches create positive and negative streamwise gradients in WSS (WSSG), respectively. Intracranial aneurysms tend to form in regions with high WSS and positive WSSG. However, little is known about the responses of endothelial cells (ECs) to either positive or negative WSSG under high WSS conditions. We used cDNA microarrays to profile gene expression in cultured ECs exposed to positive or negative WSSG for 24 h in a flow chamber where WSS varied between 3.5 and 28.4 Pa. Gene ontology and biological pathway analysis indicated that positive WSSG favored proliferation, apoptosis, and extracellular matrix processing while decreasing expression of proinflammatory genes. To determine if similar responses occur in vivo, we examined EC proliferation and expression of the matrix metalloproteinase ADAMTS1 under high WSS and WSSG created at the basilar terminus of rabbits after bilateral carotid ligation. Precise hemodynamic conditions were determined by computational fluid dynamic simulations from three-dimensional angiography and mapped on immunofluorescence staining for the proliferation marker Ki-67 and ADAMTS1. Both proliferation and ADAMTS1 were significantly higher in ECs under positive WSSG than in adjacent regions of negative WSSG. Our results indicate that WSSG elicits distinct EC gene expression profiles and particular biological pathways including increased cell proliferation and matrix processing. Such EC responses may be important in understanding the mechanisms of intracranial aneurysm initiation at regions of high WSS and positive WSSG.

Impact of intrafraction motion in pancreatic cancer treatments with MR-guided adaptive radiation therapy.

Purpose: The total time of radiation treatment delivery for pancreatic cancer patients with daily online adaptive radiation therapy (ART) on an MR-Linac can range from 50 to 90 min. During this period, the target and normal tissues undergo changes due to respiration and physiologic organ motion. We evaluated the dosimetric impact of the intrafraction physiological organ changes. Methods: Ten locally advanced pancreatic cancer patients were treated with 50 Gy in five fractions with intensity-modulated respiratory-gated radiation therapy on a 0.35-T MR-Linac. Patients received both pre- and post-treatment volumetric MRIs for each fraction. Gastrointestinal organs at risk (GI-OARs) were delineated on the pre-treatment MRI during the online ART process and retrospectively on the post-treatment MRI. The treated dose distribution for each adaptive plan was assessed on the post-treatment anatomy. Prescribed dose volume histogram metrics for the scheduled plan on the pre-treatment anatomy, the adapted plan on the pre-treatment anatomy, and the adapted plan on post-treatment anatomy were compared to the OAR-defined criteria for adaptation: the volume of the GI-OAR receiving greater than 33 Gy (V33Gy) should be ≤1 cubic centimeter. Results: Across the 50 adapted plans for the 10 patients studied, 70% were adapted to meet the duodenum constraint, 74% for the stomach, 12% for the colon, and 48% for the small bowel. Owing to intrafraction organ motion, at the time of post-treatment imaging, the adaptive criteria were exceeded for the duodenum in 62% of fractions, the stomach in 36%, the colon in 10%, and the small bowel in 48%. Compared to the scheduled plan, the post-treatment plans showed a decrease in the V33Gy, demonstrating the benefit of plan adaptation for 66% of the fractions for the duodenum, 95% for the stomach, 100% for the colon, and 79% for the small bowel. Conclusion: Post-treatment images demonstrated that over the course of the adaptive plan generation and delivery, the GI-OARs moved from their isotoxic low-dose region and nearer to the dose-escalated high-dose region, exceeding dose-volume constraints. Intrafraction motion can have a significant dosimetric impact; therefore, measures to mitigate this motion are needed. Despite consistent intrafraction motion, plan adaptation still provides a dosimetric benefit.

Characterization of the Response of 9L and U-251N Orthotopic Brain Tumors to 3D Conformal Radiation Therapy.

In a study employing MRI-guided stereotactic radiotherapy (SRS) in two orthotopic rodent brain tumor models, the radiation dose yielding 50% survival (the TCD50) was sought. Syngeneic 9L cells, or human U-251N cells, were implanted stereotactically in 136 Fischer 344 rats or 98 RNU athymic rats, respectively. At approximately 7 days after implantation for 9L, and 18 days for U-251N, rats were imaged with contrast-enhanced MRI (CE-MRI) and then irradiated using a Small Animal Radiation Research Platform (SARRP) operating at 220 kV and 13 mA with an effective energy of ∼70 keV and dose rate of ∼2.5 Gy per min. Radiation doses were delivered as single fractions. Cone-beam CT images were acquired before irradiation, and tumor volumes were defined using co-registered CE-MRI images. Treatment planning using MuriPlan software defined four non-coplanar arcs with an identical isocenter, subsequently accomplished by the SARRP. Thus, the treatment workflow emulated that of current clinical practice. The study endpoint was animal survival to 200 days. The TCD50 inferred from Kaplan-Meier survival estimation was approximately 25 Gy for 9L tumors and below 20 Gy, but within the 95% confidence interval in U-251N tumors. Cox proportional-hazards modeling did not suggest an effect of sex, with the caveat of wide confidence intervals. Having identified the radiation dose at which approximately half of a group of animals was cured, the biological parameters that accompany radiation response can be examined.

Endothelial cells express a unique transcriptional profile under very high wall shear stress known to induce expansive arterial remodeling.

Chronic high flow can induce arterial remodeling, and this effect is mediated by endothelial cells (ECs) responding to wall shear stress (WSS). To assess how WSS above physiological normal levels affects ECs, we used DNA microarrays to profile EC gene expression under various flow conditions. Cultured bovine aortic ECs were exposed to no-flow (0 Pa), normal WSS (2 Pa), and very high WSS (10 Pa) for 24 h. Very high WSS induced a distinct expression profile compared with both no-flow and normal WSS. Gene ontology and biological pathway analysis revealed that high WSS modulated gene expression in ways that promote an anti-coagulant, anti-inflammatory, proliferative, and promatrix remodeling phenotype. A subset of characteristic genes was validated using quantitative polymerase chain reaction: very high WSS upregulated ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motif-1), PLAU (urokinase plasminogen activator), PLAT (tissue plasminogen activator), and TIMP3, all of which are involved in extracellular matrix processing, with PLAT and PLAU also contributing to fibrinolysis. Downregulated genes included CXCL5 and IL-8 and the adhesive glycoprotein THBS1 (thrombospondin-1). Expressions of ADAMTS1 and uPA proteins were assessed by immunhistochemistry in rabbit basilar arteries experiencing increased flow after bilateral carotid artery ligation. Both proteins were significantly increased when WSS was elevated compared with sham control animals. Our results indicate that very high WSS elicits a unique transcriptional profile in ECs that favors particular cell functions and pathways that are important in vessel homeostasis under increased flow. In addition, we identify specific molecular targets that are likely to contribute to adaptive remodeling under elevated flow conditions.

Application of Continuous Positive Airway Pressure for Thoracic Respiratory Motion Management: An Assessment in a Magnetic Resonance Imaging-Guided Radiation Therapy Environment.

PURPOSE: Patient tolerability of magnetic resonance (MR)-guided radiation treatment delivery is limited by the need for repeated deep inspiratory breath holds (DIBHs). This volunteer study assessed the feasibility of continuous positive airway pressure (CPAP) with and without DIBH for respiratory motion management during radiation treatment with an MR-linear accelerator (MR-linac). METHODS AND MATERIALS: MR imaging safety was first addressed by placing the CPAP device in an MR-safe closet and configuring a tube circuit via waveguide to the magnet bore. Reproducibility and linearity of the final configuration were assessed. Six healthy volunteers underwent thoracic imaging in a 0.35T MR-linac, with one free breathing (FB) and 2 DIBH acquisitions being obtained at 5 pressures from 0 to 15 cm-H2O. Lung and heart volumes and positions were recorded; repeatability was assessed by comparing 2 consecutive DIBH scans. Blinded reviewers graded images for motion artifact using a 3-point grading scale. Participants completed comfort and perception surveys before and after imaging sessions. RESULTS: Compared with FB alone, FB-10, FB-12, and FB-15 cm H2O significantly increased lung volumes (+23%, +34%, +44%; all P <.05) and inferiorly displaced the heart (0.86 cm, 0.96 cm, 1.18 cm; all P < . 05). Lung volumes were significantly greater with DIBH-0 cm H2O compared with FB-15 cm H2O (+105% vs +44%, P = .01), and DIBH-15 cm H2O yielded additional volume increase (+131% vs +105%, P = .01). Adding CPAP to DIBH decreased lung volume differences between consecutive breath holds (correlation coefficient 0.97 at 15 cm H2O vs 0.00 at 0 cm H2O). The addition of 15 cm H2O CPAP reduced artifact scores (P = .03) compared with FB; all DIBH images (0-15 cm H2O) had less artifact (P < .01). CONCLUSIONS: This work demonstrates the feasibility of integrating CPAP in an MR-linac environment in healthy volunteers. Extending this work to a larger patient cohort is warranted to further establish the role of CPAP as an alternative and concurrent approach to DIBH in MR-guided radiation therapy.

MRI-guided Radiotherapy (MRgRT) for Treatment of Oligometastases: Review of Clinical Applications and Challenges.

PURPOSE: Early clinical results on the application of magnetic resonance imaging (MRI) coupled with a linear accelerator to deliver Magnetic Resonance-guided Radiation Therapy (MRgRT) have demonstrated feasibility for safe delivery of stereotactic body radiation therapy in treatment of oligometastatic disease. Here, we set out to review the clinical evidence and challenges associated with MRgRT in this setting. METHODS AND MATERIALS: We performed a systematic review of the literature pertaining to clinical experiences and trials on the use of MRgRT primarily for the treatment of oligometastatic cancers. We reviewed the opportunities and challenges associated with the use of MRgRT. RESULTS: Benefits of MRgRT pertaining to superior soft-tissue contrast, real-time imaging and gating, and online adaptive radiation therapy facilitate safe and effective dose escalation to oligometastatic tumors while simultaneously sparing surrounding healthy tissues. Challenges concerning further need for clinical evidence and technical considerations related to planning, delivery, quality assurance of hypofractionated doses, and safety in the MRI environment must be considered. CONCLUSIONS: The promising early indications of safety and effectiveness of MRgRT for stereotactic body radiation therapy-based treatment of oligometastatic disease in multiple treatment locations should lead to further clinical evidence to demonstrate the benefit of this technology.

Dosimetric Evaluation of Fractionated Stereotactic Radiation Therapy for Skull Base Meningiomas Using HyperArc and Multicriteria Optimization.

PURPOSE: Treatment planning of skull based meningiomas can be difficult due to the irregular shaped target volumes and proximity to critical optic structures. This study evaluated the use of HyperArc (HA) radiosurgery optimization and delivery in conjunction with multicriteria optimization (MCO) to create conformal and efficient treatment plans for conventionally fractionated radiation therapy to difficult base-of-skull (BOS) lesions. METHODS AND MATERIALS: Twelve patients with BOS meningioma were retrospectively planned with HA-specific optimization algorithm, stereotactic normal tissue objective (SRS-NTO), and conventional automatic normal tissue objective to evaluate normal brain sparing (mean dose and V20 Gy). MCO was used on both SRS-NTO and automatic normal tissue objective plans to further decrease organ-at-risk doses and target dose maximum to within clinically acceptable constraints. Delivery efficiency was evaluated based on planned monitor units. RESULTS: The SRS-NTO in HA can be used to improve the mid- and low-dose spread to normal brain tissue in the irradiation of BOS meningiomas. Improvement in normal brain sparing can be seen in larger, more irregular shaped lesions and less so in smaller spherical targets. MCO can be used in conjunction with the SRS-NTO to reduce target dose maximum and dose to organ at risk without sacrificing the gain in normal brain sparing. CONCLUSIONS: HA can be beneficial both in treatment planning by using the SRS-NTO and in delivery efficiency through the decrease in monitor units and automated delivery.

The Effect of Higher Protein Dosing in Critically Ill Patients: A Multicenter Registry-Based Randomized Trial: The EFFORT Trial.

Current randomized trials and observational studies evaluating higher versus lower protein doses in critically ill patients yield inconclusive results. Because of few studies and methodologic limitations, clinical guidelines suggest a wide range of protein intake based on weak evidence. Clinical equipoise about protein dosing exists. The purpose of the current manuscript is to provide the rationale and protocol for a randomized controlled trial (RCT) of 4000 critically ill patients randomly allocated to receive a higher or lower protein dose. We propose a global, volunteer-driven, registry-based RCT involving >100 intensive care units (ICUs). We will enroll mechanically ventilated patients with high nutrition risk, identified by low (≤25) or high (≥35) body mass index, moderate to severe malnutrition, frailty, sarcopenia, or when >96-hour duration of mechanical ventilation is expected. Exclusion criteria include patients who are >96 hours since initiation of mechanical ventilation, moribund, or pregnant, and where the clinician lacks clinical equipoise regarding protein dose. The intervention consists of higher (≥2.2 g/kg/d) or lower (≤1.2 g/kg/d) protein dose, achieved by enteral nutrition, parenteral nutrition, or both. The primary outcome will be 60-day mortality. Key secondary outcomes include time-to-discharge alive from hospital, ICU and hospital survival, and length of stay. As this is research based on existing medical practice, we will apply for a waiver of informed consent, where possible. The large sample size is a reflection of the small signal we expect to see in this large, pragmatic trial.

Maxillary and Mandibular Non-Hodgkin Lymphoma with Concurrent Periapical Endodontic Disease: Diagnosis and Management.

Extranodal non-Hodgkin lymphoma (NHL) in the oral region can present similarly to diseases of odontogenic origin. The objective of this report was to describe a rare case of maxillary and mandibular NHL that presented similarly to and concurrently with lesions of odontogenic origin.A unique case of extranodal NHL, which presented at the apices of maxillary and mandibular teeth in conjunction with lesions of odontogenic origin in a 68-year-old white man, is described. The patient sought care because of a lesion in the right maxillary paranasal region that caused him paresthesia. Radiographically, periapical radiolucencies were present along teeth #5-8, #23 and 24, and #30 and 31. Biopsies of the right maxillary and anterior mandibular lesions were completed and led to a diagnosis of NHL at the apices of teeth #5-8 extending to the hard palate and granulation tissue at the apices of teeth #23 and 24. Two years later, the patient returned because of pressure and sensitivity associated with teeth #30 and 31. Vestibular swelling was noted clinically, and a multilocular periapical radiolucency was present radiographically. Via endodontic therapy and a positron emission tomographic scan, the lesion associated with teeth #30 and 31 was determined to be of both odontogenic and nonodontogenic origin because it possessed both a sinus tract associated with tooth #30 and NHL. Lesions of odontogenic and nonodontogenic origin possess diagnostic and treatment challenges because they may present similarly and/or concurrently. Thoughtful and conservative management of odontogenic lesions with associated NHL is imperative. Interprofessional collaboration and communication among providers must be thorough and clear to properly coordinate care and prevent delays in diagnosis and treatment when these entities occur together.

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.

A critical role for proinflammatory behavior of smooth muscle cells in hemodynamic initiation of intracranial aneurysm.

BACKGROUND: Intracranial aneurysm initiation is poorly understood, although hemodynamic insult is believed to play an important role in triggering the pathology. It has recently been found in a rabbit model that while macrophages are absent during hemodynamic aneurysm initiation, matrix metalloproteinases (MMPs) are elevated and co-localize with smooth muscle cells (SMCs). This study investigates whether SMCs play a mechanistic role in aneurysm initiation triggered by hemodynamics. METHODS: Aneurysmal damage was induced at the basilar terminus via bilateral common carotid artery ligation in rabbits (n = 45, plus 7 sham controls). 16 ligated rabbits were treated with doxycycline to inhibit MMPs, 7 received clodronate liposomes to deplete circulating monocytes, and the rest received no drug. Effects of the treatments on aneurysm development were assessed histologically 5 days and 6 months after ligation. MMP production and expression of inflammatory markers by SMCs was monitored by immunohistochemistry and in situ hybridization. RESULTS: Treatment with doxycycline attenuated aneurysmal development examined at 5 days and 6 months, suggesting that MMPs contribute to aneurysm initiation. However, systemic depletion of macrophages did not decrease MMPs or suppress aneurysmal development. Immunofluorescence showed that during aneurysm initiation MMP-2 and MMP-9 were distributed in SMCs, and in situ hybridization indicated that they were transcribed by SMCs. In regions of early aneurysmal lesion, SMCs exhibited decreased expression of smooth muscle actin and increased NF-κB and MCP-1 expressions. CONCLUSIONS: During aneurysm initiation triggered by hemodynamics, SMCs rather than macrophages are responsible for MMP production that is critical for aneurysmal lesion development. These SMCs exhibit proinflammatory behavior.

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.