Prognostic factors associated with risk of stroke following blunt cerebrovascular injury: A systematic review and meta-analysis.

BACKGROUND & OBJECTIVES: Blunt cerebrovascular injury (BCVI) includes carotid and/or vertebral artery injury following trauma, and conveys an increased stroke risk. We conducted a systematic review and meta-analysis to provide a comprehensive summary of prognostic factors associated with risk of stroke following BCVI. METHODS: We searched the EMBASE and MEDLINE databases from January 1946 to June 2023. We identified studies reporting associations between patient or injury factors and risk of stroke following BCVI. We performed meta-analyses of odds ratios (ORs) using the random effects method and assessed individual study risk of bias using the QUIPS tool. We separately pooled adjusted and unadjusted analyses, highlighting the estimate with the higher certainty. RESULTS: We included 26 cohort studies, involving 20,458 patients with blunt trauma. The overall incidence of stroke following BCVI was 7.7 %. Studies were predominantly retrospective cohorts from North America and included both carotid and vertebral artery injuries. Diagnosis of BCVI was most commonly confirmed with CT angiography. We demonstrated with moderate to high certainty that factors associated with increased risk of stroke included carotid artery injury (as compared to vertebral artery injury, unadjusted odds ratio [uOR] 1.94, 95 % CI 1.62 to 2.32), Grade III Injury (as compared to grade I or II) (uOR 2.45, 95 % CI 1.88 to 3.20), Grade IV injury (uOR 3.09, 95 % CI 2.20 to 4.35), polyarterial injury (uOR 3.11 (95 % CI 2.05 to 4.72), occurrence of hypotension at the time of hospital admission (adjusted odds ratio [aOR] 1.32, 95 % CI 0.87 to 2.03) and higher total body injury severity (aOR 5.91, 95 % CI 1.90 to 18.39). CONCLUSION: Local anatomical injury pattern, overall burden of injury and flow dynamics contribute to BCVI-related stroke risk. These findings provide the foundational evidence base for risk stratification to support clinical decision making and further research.

Ketogenic diet inhibits neointimal hyperplasia by suppressing oxidative stress and inflammation.

OBJECTIVE: Neointimal hyperplasia is the primary mechanism underlying atherosclerosis and restenosis after percutaneous coronary intervention. Ketogenic diet (KD) exerts beneficial effects in various diseases, but whether it could serve as non-drug therapy for neointimal hyperplasia remains unknown. This study aimed to investigate the effect of KD on neointimal hyperplasia and the potential mechanisms. METHODS AND RESULTS: Carotid artery balloon-injury model was employed in adult Sprague-Dawley rats to induce neointimal hyperplasia. Then, animals were subjected to either standard rodent chow or KD. For in-vitro experiment, impacts of ß-hydroxybutyrate (ß-HB), the main mediator of KD effects, on platelet-derived growth factor BB (PDGF-BB) induced vascular smooth muscle cell (VSMC) migration and proliferation were determined. Balloon injury induced event intimal hyperplasia and upregulation of protein expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA), and these changes were significantly ameliorated by KD. In addition, ß-HB could markedly inhibit PDGF-BB induced VMSC migration and proliferation, as well as inhibiting expressions of PCNA and α-SMC. Furthermore, KD inhibited balloon-injury induced oxidative stress in carotid artery, indicated by reduced ROS level, malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and increased superoxide dismutase (SOD) activity. We also found balloon-injury induced inflammation in carotid artery was suppressed by KD, indicated by decreased expressions of proinflammatory cytokines IL-1ß and TNF-α, and increased expression of anti-inflammatory cytokine IL-10. CONCLUSION: KD attenuates neointimal hyperplasia through suppressing oxidative stress and inflammation to inhibit VSMC proliferation and migration. KD may represent a promising non-drug therapy for neointimal hyperplasia associated diseases.

Trauma mechanisms and patterns of blunt cervical vascular injury: A descriptive study using a nationwide trauma registry.

OBJECTIVE: Blunt cervical vascular injury (BCVI) is a non-penetrating trauma to the carotid and/or vertebral vessels following a direct injury to the neck or by the shearing of the cervical vessels. Despite its potentially life-threatening nature, important clinical features of BCVI such as typical patterns of co-occurring injuries for each trauma mechanism are not well known. To address this knowledge gap, we described the characteristics of patients with BCVI to identify the pattern of co-occurring injuries by common trauma mechanisms. METHODS: This is a descriptive study using a Japanese nationwide trauma registry from 2004 through 2019. We included patients aged ≥13 years presenting to the emergency department (ED) with BCVI, defined as a blunt trauma to any of the following vessels: common/internal carotid artery, external carotid artery, vertebral artery, external jugular vein, and internal jugular vein. We delineated characteristics of each BCVI classified according to three damaged vessels (common/internal carotid artery, vertebral artery, and others). In addition, we applied network analysis to unravel patterns of co-occurring injuries among patients with BCVI by four common trauma mechanisms (car accident, motorcycle/bicycle accident, simple fall, and fall from a height). RESULTS: Among 311,692 patients who visited the ED for blunt trauma, 454 (0.1%) patients had BCVI. Patients with common/internal carotid artery injuries presented to the ED with severe symptoms (e.g., the median Glasgow Coma Scale was 7) and had high in-hospital mortality (45%), while patients with vertebral artery injuries presented with relatively stable vital signs. Network analysis showed that head-vertebral-cervical spine injuries were common across four trauma mechanisms (car accident, motorcycle/bicycle accident, simple fall, and fall from a height), with co-occurring injuries of the cervical spine and vertebral artery being the most common injuries due to falls. In addition, common/internal carotid artery injuries were associated with thoracic and abdominal injuries in patients with car accidents. CONCLUSIONS: Based on analyses of a nationwide trauma registry, we found that patients with BCVI had distinct patterns of co-occurring injuries by four trauma mechanisms. Our observations provide an important basis for the initial assessment of blunt trauma and could support the management of BCVI.

Adjunctive techniques in endovascular repair of postcarotid endarterectomy pseudoaneurysm: Case report and literature review.

Pseudoaneurysm (PA) following carotid endarterectomy (CEA) is a rare and dangerous complication. In recent years endovascular approach has been preferred to open surgery as it is less invasive and reduces complications in an already operated neck, especially cranial nerve injuries. We report a case of large post-CEA PA causing dysphagia, successfully treated by deployment of two balloon-expandable covered stents and coil embolization of the external carotid artery. A literature review dealing with all cases of post-CEA PAs since 2000 treated by endovascular means is also reported. The research was conducted on Pubmed database using keywords "carotid pseudoaneurysm after carotid endarterectomy," "false aneurysm after carotid endarterectomy," "postcarotid endarterectomy pseudoaneurysm," and "carotid pseudoaneurysm."

Sex differences in arterial identity correlate with neointimal hyperplasia after balloon injury.

BACKGROUND: Endovascular treatment of atherosclerotic arterial disease exhibits sex differences in clinical outcomes including restenosis. However, sex-specific differences in arterial identity during arterial remodeling have not been described. We hypothesized that sex differences in expression of the arterial determinant erythropoietin-producing hepatocellular receptor interacting protein (Ephrin)-B2 occur during neointimal proliferation and arterial remodeling. METHODS AND RESULTS: Carotid balloon injury was performed in female and male Sprague-Dawley rats without or 14 days after gonadectomy; the left common carotid artery was injured and the right carotid artery in the same animal was used as an uninjured control. Arterial hemodynamics were evaluated in vivo using ultrasonography pre-procedure and post-procedure at 7 and 14 days and wall composition examined using histology, immunofluorescence and Western blot at 14 days after balloon injury. There were no significant baseline sex differences. 14 days after balloon injury, there was decreased neointimal thickness in female rats with decreased smooth muscle cell proliferation and decreased type I and III collagen deposition, as well as decreased TNFα- or iNOS-positive CD68+ cells and increased CD206- or TGM2-positive CD68+ cells. Female rats also showed less immunoreactivity of VEGF-A, NRP1, phosphorylated EphrinB2, and increased Notch1, as well as decreased phosphorylated Akt1, p38 and ERK1/2. These differences were not present in rats pretreated with gonadectomy. CONCLUSIONS: Decreased neointimal thickness in female rats after carotid balloon injury is associated with altered arterial identity that is dependent on intact sex hormones. Alteration of arterial identity may be a mechanism of sex differences in neointimal proliferation after arterial injury.

Traumatic Internal Carotid Artery Injuries: Do We Need a Screening Strategy? Literature Review, Case Report, and Forensic Evaluation.

Internal carotid artery dissection (ICAD) represents the cause of ictus cerebri in about 20% of all cases of cerebral infarction among the young adult population. ICAD could involve the extracranial and intracranial internal carotid artery (ICA). It could be spontaneous (SICAD) or traumatic (TICAD). It has been estimated that carotid injuries could complicate the 0,32% of cases of general blunt trauma and the percentage seems to be higher in cases of severe multiple traumas. TICAD is diagnosed when neurological symptoms have already occurred, and it could have devastating consequences, from permanent neurological impairment to death. Thus, even if it is a rare condition, a prompt diagnosis is essential. There are no specific guidelines regarding TICAD screening. Nevertheless, TICAD should be taken into consideration when a young adult or middle-aged patient presents after severe blunt trauma. Understanding which kind of traumatic event is most associated with TICAD could help clinicians to direct their diagnostic process. Herein, a review of the literature concerning TICAD has been carried out to highlight its correlation with specific traumatic events. TICAD is mostly correlated to motor vehicle accidents (94/227), specifically to car accidents (39/94), and to direct or indirect head and cervical trauma (76/227). As well, a case report is presented to discuss TICAD forensic implications.

Factors associated with stroke formation in blunt cerebrovascular injury: An EAST multicenter study.

BACKGROUND: Stroke risk factors after blunt cerebrovascular injury (BCVI) are ill-defined. We hypothesized that factors associated with stroke for BCVI would include medical therapy (i.e., Aspirin), radiographic features, and protocolization of care. METHODS: An Eastern Association for the Surgery of Trauma-sponsored, 16-center, prospective, observational trial was undertaken. Stroke risk factors were analyzed individually for vertebral artery (VA) and internal carotid artery (ICA) BCVI. Blunt cerebrovascular injuries were graded on the standard 1 to 5 scale. Data were from the initial hospitalization only. RESULTS: Seven hundred seventy-seven BCVIs were included. Stroke rate was 8.9% for all BCVIs, with an 11.7% rate of stroke for ICA BCVI and a 6.7% rate for VA BCVI. Use of a management protocol (p = 0.01), management by the trauma service (p = 0.04), antiplatelet therapy over the hospital stay (p < 0.001), and Aspirin therapy specifically over the hospital stay (p < 0.001) were more common in ICA BCVI without stroke compared with those with stroke. Antiplatelet therapy over the hospital stay (p < 0.001) and Aspirin therapy over the hospital stay (p < 0.001) were more common in VA BCVI without stroke than with stroke. Percentage luminal stenosis was higher in both ICA BCVI (p = 0.002) and VA BCVI (p < 0.001) with stroke. Decrease in percentage luminal stenosis (p < 0.001), resolution of intraluminal thrombus (p = 0.003), and new intraluminal thrombus (p = 0.001) were more common in ICA BCVI with stroke than without, while resolution of intraluminal thrombus (p = 0.03) and new intraluminal thrombus (p = 0.01) were more common in VA BCVI with stroke than without. CONCLUSION: Protocol-driven management by the trauma service, antiplatelet therapy (specifically Aspirin), and lower percentage luminal stenosis were associated with lower stroke rates, while resolution and development of intraluminal thrombus were associated with higher stroke rates. Further research will be needed to incorporate these risk factors into lesion specific BCVI management. LEVEL OF EVIDENCE: Prognostic and Epidemiologic, Level IV.

Indoleamine 2,3-dioxygenase-1, a Novel Therapeutic Target for Post-Vascular Injury Thrombosis in CKD.

BACKGROUND: CKD, characterized by retained uremic solutes, is a strong and independent risk factor for thrombosis after vascular procedures . Urem ic solutes such as indoxyl sulfate (IS) and kynurenine (Kyn) mediate prothrombotic effect through tissue factor (TF). IS and Kyn biogenesis depends on multiple enzymes, with therapeutic implications unexplored. We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury. METHODS: IDO-1 expression in mice and human vessels was examined. IDO-1-/- mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used. RESULTS: Both global IDO-1-/- CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum. Further mechanistic probing of arteries from an IS-specific mouse model, and CKD mice, showed upregulation of IDO-1 protein, which was due to inhibition of its polyubiquitination and degradation by IS in vascular smooth muscle cells. In two cohorts of patients with advanced CKD, blood IDO-1 activity was significantly higher in sera of study participants who subsequently developed thrombosis after endovascular interventions or vascular surgery. CONCLUSION: Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate IS as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD.

A multi-registry analysis of military and civilian penetrating cervical carotid artery injury.

INTRODUCTION: Penetrating cervical carotid artery injury is an uncommon but high-stake scenario associated with stroke and death. The objective of this study was to characterize and compare penetrating carotid injury in the military and civilian setting, as well as provide considerations for management. METHODS: Cohorts with penetrating cervical carotid artery injury from the Department of Defense Trauma Registry (2002-2015) and the American Association for the Surgery of Trauma Prospective Observation Vascular Injury Treatment Registry (2012-2018) were analyzed. A least absolute shrinkage and selection operator multivariate analysis using random forest-based imputation was performed to identify risk factors affecting stroke and mortality. RESULTS: There were a total of 157 patients included in the study, of which 56 (35.7%) were military and 101 (64.3%) were civilian. The military cohort was more likely to have been managed with open surgery (87.5% vs. 44.6%, p < 0.001) and to have had any procedure to restore or maintain flow to the brain (71.4% vs. 35.6%, p < 0.001), while the civilian cohort was more likely to undergo nonoperative management (45.5% vs. 12.5%, p < 0.001). Stroke rate was higher within the military cohort (41.1% vs. 13.9%, p < 0.001); however, mortality did not differ between the groups (12.5% vs. 17.8%, p = 0.52). On multivariate analysis, predictors for stroke were presence of a battle injury (log odds, 2.1; p < 0.001) and internal or common carotid artery ligation (log odds 1.5, p = 0.009). For mortality outcome, protective factors included a high Glasgow Coma Scale on admission (log odds, -0.21 per point; p < 0.001). Increased admission Injury Severity Score was a predictor of mortality (log odds, 0.05 per point; p = 0.005). CONCLUSION: The stroke rate was higher in the military cohort, possibly reflecting complexity of injury; however, there was no difference in mortality between military and civilian patients. For significant injuries, concerted efforts should be made at carotid reconstruction to reduce the occurrence of stroke. LEVEL OF EVIDENCE: Retrospective cohort analysis, level III.

Hybrid Repair of a Common Carotid Pseudoaneurysm and Concomitant Internal Carotid Stenosis With Retrograde Stenting and Carotid Endarterectomy.

This report aims to present a rare case of a common carotid artery (CCA) pseudoaneurysm with a concomitant internal carotid artery (ICA) stenosis that were treated with a hybrid technique. This strategy included the retrograde placement of a CCA covered stent under ICA clamping followed by standardized carotid endarterectomy. The technique will be discussed and compared with other possible treatments.

Caso clínico: Fístula carótido-yugular: complicación inusual de cateterismo venoso central / Case report: Carotid jugular fistula: an uncommon complication of central venous access

Resumen La fístula carótido yugular es una complicación inusual del proceder de colocación del catéter venoso central en la vena yugular interna. Esto puede tener serias consecuencias, tales como infecciones, embolismo y fallo cardíaco por sobrecarga de volumen, que requieren corrección. Reportamos el caso relativo a una paciente con fístula carótido yugular de 40 años de evolución secundaria a la realización de un cateterismo en la vena yugular interna durante la infancia, con evolución natural sin complicaciones relativas a la fístula post cateterismo.

Abstract Carotid-jugular fistula is one of the uncommon complications of jugular vein catheterization. It can have serious complications such as infection, embolization, and high output cardiac failure and requires invasive repair. We describe a case of uncommon carotid artery jugular vein artiovenous fistula following the insertion of a catheter for cardiac study during childhood, with 40 years of evolution without complications in relationship with post catheterism fistula.

Persistent Trigeminal Artery as Collateral Circulation in Ischemic Stroke.

The persistent trigeminal artery is the most frequent of the persistent embryonic carotid-basilar artery anastomoses. In the literature, it has most often been described in relation to cerebrovascular pathologies such as aneurysms, vascular nerve compression, trigeminal cavernous fistulas, and thromboembolic ischemia. Its role as collateral circulation, thus supplying brain perfusion during main arterial trunk occlusion, has seldom been described. We describe the case of a patient who presented with a stroke due to a traumatic dissection of the internal carotid artery at the neck, in which the infarction may have been limited by a persistent trigeminal artery.

MicroRNA-302a promotes neointimal formation following carotid artery injury in mice by targeting PHLPP2 thus increasing Akt signaling.

The excessive proliferation and migration of smooth muscle cells (SMCs) play an important role in restenosis following percutaneous coronary interventions. MicroRNAs are able to target various genes and involved in the regulation of diverse cellular processes including cell growth and proliferation. In this study we investigated whether and how MicroRNAs regulated vascular SMC proliferation and vascular remodeling following carotid artery injury in mice. We showed that carotid artery injury-induced neointimal formation was remarkably ameliorated in microRNA (miR)-302 heterozygous mice and SMC-specific miR-302 knockout mice. In contrast, delivery of miR-302a adenovirus to the injured carotid artery enhanced neointimal formation. Upregulation of miR-302a enhanced the proliferation and migration of mouse aorta SMC (MASMC) in vitro by promoting cell cycle transition, whereas miR-302a inhibition caused the opposite results. Moreover, miR-302a promoted Akt activation by corporately decreasing Akt expression and increasing Akt phosphorylation in MASMCs. Application of the Akt inhibitor GSK690693 (5 µmol/L) counteracted the functions of miR-302a in promoting MASMC proliferation and migration. We further revealed that miR-302a directly targeted at the 3' untranslated region of PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and negatively regulated PHLPP2 expression. Restoration of PHLPP2 abrogated the effects of miR-302a on Akt activation and MASMC motility. Furthermore, knockdown of PHLPP2 largely abolished the inhibition of neointimal formation that was observed in miR-302 heterozygous mice. Our data demonstrate that miR-302a exacerbates SMC proliferation and restenosis through increasing Akt signaling by targeting PHLPP2.

A child in shock: carotid blowout syndrome.

Paediatricians commonly encounter neck lumps during their routine clinical practice; vascular abnormalities, such as (pseudo)aneurysms, are a rare cause of these. Pseudoaneurysms of the carotid artery in children are usually the result of blunt or penetrating trauma, infection or vasculitis/connective tissue disorders. They can present with a variety of symptoms including neck pain, as a pulsatile neck mass or with compressive symptoms (for example, cranial nerve palsies or dyspnoea). Pseudoaneurysms carry a risk of rupture in which case they are fatal, unless immediate treatment is provided.We report a 17-month-old male child with idiopathic carotid artery blowout syndrome presenting with acute oropharyngeal haemorrhage leading to asystolic cardiac arrest. He was successfully resuscitated and emergency embolisation controlled the bleeding. Despite extensive left hemispheric infarct, he has survived.Carotid artery blowout syndrome needs to be recognised as a potential cause of major haemorrhage in childhood. The purpose of this case report is to remind readers of the differential diagnosis and work-up of a child presenting with a neck lump, to highlight important aspects of the acute management of major haemorrhage and massive blood transfusion in paediatrics, to describe the aetiology, presentation and management of carotid artery pseudoaneurysm in children and to discuss long term rehabilitation in patients with consequent neurological sequelae (including the need for input from multiple specialty teams).

Down-regulation of Suv39h1 attenuates neointima formation after carotid artery injury in diabetic rats.

Patients with diabetes have an increased risk of vascular complications. Suv39h1, a histone methyltransferase, plays a protective role against myocardial injury in diabetes. Herein, we intend to explore whether Suv39h1 could affect neointimal formation after vascular injury in diabetic rats and reveal the underlying mechanism. In this study, we generated adenovirus expressing Suv39h1 as well as lentivirus expressing Suv39h1-targeting shRNA and evaluated the significance of Suv39h1 in vascular smooth muscle cells (VSMCs) under diabetic conditions. In vitro, we examined proliferative and migratory behaviours as well as the underlying signalling mechanisms in VSMCs in response to high glucose treatment. In vivo, we induced diabetes in SD rats with streptozocin and established the common carotid artery balloon injury model. Suv39h1 was found to be both necessary and sufficient to promote VSMC proliferation and migration under high glucose conditions. We observed corresponding changes in intracellular signalling molecules including complement C3 and phosphor-ERK1/2. However, either up-regulating or down-regulating Suv39h1, phosphor-p38 level was not significantly affected. Consistently, Suv39h1 overexpression led to accelerated neointima formation, while knocking down Suv39h1 reduced it following carotid artery injury in diabetic rats. Using microarray analyses, we showed that altering the Suv39h1 level in vivo dramatically altered the expression of myriad genes mediating different biological processes and molecular function. This study reveals the novel role of Suv39h1 in VSMCs of diabetes and suggests its potential role as a therapeutic target in diabetic vascular injury.

LncRNA GAS5 regulates vascular smooth muscle cell cycle arrest and apoptosis via p53 pathway.

Vascular remodeling is a pathological process following cardiovascular intervention. Vascular smooth muscle cells (VSMC) play a critical role in the vascular remodeling. Long noncoding RNAs (lncRNA) are a class of gene regulators functioning through various mechanisms in physiological and pathological conditions. By using cultured VSMC and rat carotid artery balloon injury model, we found that lncRNA growth arrest specific 5 (GAS5) serves as a negative regulator for VSMC survival in vascular remodeling. By manipulating GAS5 expression via adenoviral overexpression or short hairpin RNA knockdown, we found that GAS5 suppresses VSMC proliferation while promoting cell cycle arrest and inducing cell apoptosis. Mechanistically, GAS5 directly binds to p53 and p300, stabilizes p53-p300 interaction, and thus regulates VSMC cell survival via induction of p53-downstream target genes. Importantly, local delivery of GAS5 via adenoviral vector suppresses balloon injury-induced neointima formation along with an increased expression of p53 and apoptosis in neointimal SMCs. Our study demonstrated for the first time that GAS5 negatively impacts VSMC survival via activation the p53 pathway during vascular remodeling.