Embolic Model Research Articles

Effects of ML351 and tissue plasminogen activator combination therapy in a rat model of focal embolic stroke.

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by risks of hemorrhagic transformation (HT). We have reported that a new 12/15-lipoxygenase (12/15-LOX) inhibitor ML351 reduced tPA related HT in mice subjected to experimental stroke under anticoagulation. In this study, we asked whether ML351 can ameliorate tPA induced HT in an embolic stroke model. Rats were subjected to embolic middle cerebral artery occlusion with 2 or 3hr ischemia and tPA infusion, with or without ML351. Regional cerebral blood flow was monitored 2hr after ischemia and continuously monitored for 1hr after treatment for determining reperfusion. Hemoglobin was determined in brain homogenates and infarct volume was quantified at 24hr after stroke.12/15-LOX, cluster of differentiation 68(CD68), immunoglobulin G (IgG), and tight junction proteins expression was detected by immunohistochemistry. ML351 significantly reduced tPA related hemorrhage after stroke without affecting its thrombolytic efficacy. ML351 also reduced blood-brain barrier disruption and improved preservation of junction proteins. ML351 and tPA combination improved neurological deficit of rats even though ML351 did not further reduce the infarct volume compared to tPA alone treated animals. Pro-inflammatory cytokines were suppressed by ML351 both in vivo and in vitro experiments. We further showed that ML351 suppressed the expression of c-Jun-N-terminal kinase (JNK) in brains and microglia cultures, whereas exogenous 12-HETE attenuated this effect in vitro. In conclusion, ML351 and tPA combination therapy is beneficial in ameliorating HT after ischemic stroke. This protective effect is probably because of 12/15-LOX inhibition and suppression of JNK-mediated microglia/macrophage activation.

The Mechanism of Gastrodin Participating in Improving the Cerebral Ischemia-Reperfusion Injury Through Notch 1 and NF-κB Signaling Pathways

Background: The purpose of this study was to investigate whether Gastrodin can activate the Notch 1 signaling pathway in the ischemic brain area to produce neuroprotective effects against cerebral ischemia-reperfusion injury, and to elucidate the role of Notch 1 and NF-κB signaling pathways in the Gastrodin-induced cerebral ischemic tolerance. Material and methods: The focal cerebral ischemia reperfusion model of middle cerebral artery embolism was established. TTC staining was applied to detect cerebral infarction. Tunel/NeuN immunofluorescence double labeling was employed to detect apoptosis. WB was used to detect the expressions of proteins related to the Notch 1 and NF-κB pathways. Results: Gastrodin can reduce neuron apoptosis in hippocampus after MCAO/R injury. After DAPT blocked Notch 1 signaling, the neuroprotective effects of Gastrodin improving neural function score, reducing cerebral infarction volume, and inhibiting neuronal apoptosis, were all reversed. Compared with the MCAO/R group, DAPT blocking Notch 1 signaling can also improve the neurological score of rats after MCAO/R injury, reduce cerebral infarct volume, and reduce neuronal apoptosis. Gastrodin can activate Notch 1 and NF-κB signaling pathways in cerebral ischemic areas and increase the expression of related proteins. After DAPT inhibited the Notch 1 signaling in the ipsilateral brain region, the phosphorylation level was significantly decreased, indicating that the activity of the NF-κB pathway was regulated by the Notch 1 signaling. Conclusion: Gastrodin-mediated protection against cerebral ischemia-reperfusion injury is related to the activation of Notch 1 signaling and the up-regulation of NF-κB signaling pathway activity in neurons of ischemic brain area.

Restoration of early deficiency of axonal guidance signaling by guanxinning injection as a novel therapeutic option for acute ischemic stroke

Despite of its high morbidity and mortality, there is still a lack of effective treatment for ischemic stroke in part due to our incomplete understanding of molecular mechanisms of its pathogenesis. In this study, we demonstrate that SHH-PTCH1-GLI1-mediated axonal guidance signaling and its related neurogenesis, a central pathway for neuronal development, also plays a critical role in early stage of an acute stroke model. Specifically, in vivo, we evaluated the effect of GXNI on ischemic stroke mice via using the middle cerebral artery embolization model, and found that GXNI significantly alleviated cerebral ischemic reperfusion (I/R) injury by reducing the volume of cerebral infarction, neurological deficit score and cerebral edema, reversing the BBB permeability and histopathological changes. A combined approach of RNA-seq and network pharmacology analysis was used to reveal the underlying mechanisms of GXNI followed by RT-PCR, immunohistochemistry and western blotting validation. It was pointed out that axon guidance signaling pathway played the most prominent role in GXNI action with Shh, Ptch1, and Gli1 genes as the critical contributors in brain protection. In addition, GXNI markedly prevented primary cortical neuron cells from oxygen-glucose deprivation/reoxygenation damage in vitro, and promoted axon growth and synaptogenesis of damaged neurons, which further confirmed the results of in vivo experiments. Moreover, due to the inhibition of the SHH-PTCH1-GLI1 signaling pathway by cyclopropylamine, the effect of GXNI was significantly weakened. Hence, our study provides a novel option for the clinical treatment of acute ischemic stroke by GXNI via SHH-PTCH1-GLI1-mediated axonal guidance signaling, a neuronal development pathway previously considered for after-stroke recovery.

Immobilized thrombin on X-ray radiopaque polyvinyl alcohol/chitosan embolic microspheres for precise localization and topical blood coagulation

Trans-catheter arterial embolization (TAE) plays an important role in treating various diseases. The available embolic agents lack X-ray visibility and do not prevent the reflux phenomenon, thus hindering their application for TAE therapy. Herein, we aim to develop a multifunctional embolic agent that combines the X-ray radiopacity with local procoagulant activity. The barium sulfate nanoparticles (BaSO4 NPs) were synthesized and loaded into the polyvinyl alcohol/chitosan (PVA/CS) to prepare the radiopaque BaSO4/PVA/CS microspheres (MS). Thereafter, thrombin was immobilized onto the BaSO4/PVA/CS MS to obtain the thrombin@BaSO4/PVA/CS MS. The prepared BaSO4/PVA/CS MS were highly spherical with diameters ranging from 100 to 300 μm. In vitro CT imaging showed increased X-ray visibility of BaSO4/PVA/CS MS with the increased content of BaSO4 NPs in the PVA/CS MS. The biocompatibility assessments demonstrated that the MS were non-cytotoxic and possessed permissible hemolysis rate. The biofunctionalized thrombin@BaSO4/PVA/CS MS showed improved hemostatic capacity and facilitated hemostasis in vitro. Additionally, in vivo study performed on a rabbit ear embolization model confirmed the excellent X-ray radiopaque stability of the BaSO4/PVA/CS MS. Moreover, both the BaSO4/PVA/CS and thrombin@BaSO4/PVA/CS MS achieved superior embolization effects with progressive ischemic necrosis on the ear tissue and induced prominent ultrastructural changes in the endothelial cells. The findings of this study suggest that the developed MS could act as a radiopaque and hemostatic embolic agent to improve the embolization efficiency.

Simulation analysis of aneurysm embolization surgery: Hemorheology of aneurysms with different embolization rates (CTA).

Embolization degree acts as an important factor affecting recurrence of aneurysm. To analyze the role of hemodynamics parameters of different degrees of embolization in the occurrence, development and post-treatment of aneurysms, and to determine the specific factors causing the occurrence and recurrence of aneurysms after hemodynamics treatment. Our study provides a theoretical basis for the prevention and treatment of aneurysms. Computed tomography angiography data of a patient with cerebral aneurysm was used to model 0%, 24%, 52%, 84% and 100% of endovascular embolization, respectively. The time average wall shear stress, time average wall shear stress, oscillatory shear index, hemodynamics formation index and relative retentive time were used to analyze the changes of hemodynamics indexes in different embolic models. With the increase of embolic rate, the values of time average wall shear stress, time average wall shear stress grade and aneurysm index formation gradually increased, and the values of relative retention time gradually decreased. Oscillatory shear index was higher in patients with incomplete embolization and decreased in patients with complete embolization. As the degree of embolization increased, the blood flow tended to stabilize, reducing the risk of cerebral aneurysm rupture, and finding that the wall of the vessel junction was susceptible to injury.

Construction of a Risk Prediction Model for Hospital-Acquired Pulmonary Embolism in Hospitalized Patients.

The purpose of this study is to establish a novel pulmonary embolism (PE) risk prediction model based on machine learning (ML) methods and to evaluate the predictive performance of the model and the contribution of variables to the predictive performance. We conducted a retrospective study at the Shanghai Tenth People's Hospital and collected the clinical data of in-patients that received pulmonary computed tomography imaging between January 1, 2014 and December 31, 2018. We trained several ML models, including logistic regression (LR), support vector machine (SVM), random forest (RF), and gradient boosting decision tree (GBDT), compared the models with representative baseline algorithms, and investigated their predictability and feature interpretation. A total of 3619 patients were included in the study. We discovered that the GBDT model demonstrated the best prediction with an area under the curve value of 0.799, whereas those of the RF, LR, and SVM models were 0.791, 0.716, and 0.743, respectively. The sensibilities of the GBDT, LR, RF, and SVM models were 63.9%, 68.1%, 71.5%, and 75%, respectively; the specificities were 81.1%, 66.1, 72.7%, and 65.1%, respectively; and the accuracies were 77.8%, 66.5%, 72.5%, and 67%, respectively. We discovered that the maximum D-dimer level contributed the most to the outcome prediction, followed by the extreme growth rate of the plasma fibrinogen level, in-hospital duration, and extreme growth rate of the D-dimer level. The study demonstrates the superiority of the GBDT model in predicting the risk of PE in hospitalized patients. However, in order to be applied in clinical practice and provide support for clinical decision-making, the predictive performance of the model needs to be prospectively verified.

Efficacy and Safety of Lyophilized Articular Cartilage Matrix as an Injectable Facial Filler.

To evaluate the efficacy and safety of an injectable lyophilized articular cartilage matrix (LACM) which is in the form of cartilage powder that may increase the convenience of use and become unaffected by donor site morbidity as a potential filler. The safety test was conducted using 20 rabbits with an intravascular embolization model. Commonly used commercial hyaluronic acid (HA), acellular dermal matrix (ADM), polymethyl methacrylate (PMMA), and polylactic acid (PLA) products were selected for comparison of efficacy and adverse effect of LACM. The efficacy test was performed using 30 mice subcutaneous buttock-injection model. Gross assessments of the changes in size of injected materials and histological examinations were conducted. Regarding the safety test, in one rabbit in the HA group, complete blurring occurred in the left eye, and necrosis of the posterior auricular artery was observed in one rabbit in the ADM group. In the ADM, severe ecchymosis around the injection sites was observed, and the bruises lasted longer than in the other groups. The LACM exhibited faster bruise resolution. Comparing the changes in size between weeks 4 and 12 in the mouse model, no significant changes in size were observed in the LACM (p = 0.359), HA (p = 0.421), and ADM (p = 0.097), but a significant change was observed in the PMMA (p = 0.001). In the histological examination, LACM exhibited well-demarcated margins with good biocompatibility. The LACM shows potential as a facial filler according to the in vivo safety and efficacy tests LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Abstract 14150: Long-pulsed Ultrasound Mediated Microbubble Thrombolysis: Is There an Upper Limit?

Introduction: Long-pulsed ultrasound (US) mediated microbubble (MB) has shown successful thrombolystic effects in recent years. Compared to traditional short-pulse US(<5 cycles), long-pulsed US induced more sustained cavitation followed by more complete thrombolysis. It was found more micro-thrombi were dissolved when pulse lengths were increased. However, taking the US safety into consideration, the upper limit of long pulse in vivo remains unknown. Hypothesis: Long-tone-burst US is able to cause successful thrombolysis through microbubble cavitation, and there is an upper limit for the safe long-pulse length in vivo. Methods: Different long- pulse lengths (5,100,500,1000, 5000, 50,000 cycles) were used and their thrombolytic effects in a rat model were observed. About 200μm micro-thrombi were injected into common iliac artery on rats hindlimb to make an embolization model. 1MHz long-pulsed US were delivered at mechanical index 1.8 every 3 seconds (pulse repetition frequency 0.33). The control group was given MBs only without therapeutic US. Contrast echocardiography was performed at three stages: baseline, embolization and 10 minutes post embolization. Peak plateau video intensity ( A ) were obtained for assessment of thrombolytic effects. Finally muscular samples were taken for pathology for assessment of both beneficial and potential detrimental effects from long-tone-burst US. Results: 100 and 500 cycles long-pulsed US showed successful thrombolysis and peak plateau video intensity ( A ) was significantly elevated post US treatment ( P<0.01 vs. baseline ). Pathology revealed 1000 and 5000 cycles groups were the best parameters to induce optimal sonothrombolysis ( P<0.01 vs. other groups), possibly by more sustained cavitation. However, 50,000 cycles showed endothelial injury and tissue bleeding that may be detrimental and hazard. Conclusions: Long-tone-burst US with more than 100 cycles were proved to induce very good micro-thrombi resolution in a rat model of embolization. It seems there is an upper limit for the cycle length to generate beneficial biomechanical effects, and detrimental effect may occur if it was exceeded.

Blood-Derived Biomaterial for Catheter-Directed Arterial Embolization.

Vascular embolization is a life-saving minimally invasive catheter-based procedure performed to treat bleeding vessels. Through these catheters, numerous metallic coils are often pushed into the bleeding artery to stop the blood flow. While there are numerous drawbacks to coil embolization, physician expertise, availability of these coils, and their costs further limit their use. Here, a novel blood-derived embolic material (BEM) with regenerative properties, that can achieve instant and durable intra-arterial hemostasis regardless of coagulopathy, is developed. In a large animal model of vascular embolization, it is shown that the BEM can be prepared at the point-of-care within 26 min using fresh blood, it can be easily delivered using clinical catheters to embolize renal and iliac arteries, and it can achieve rapid hemostasis in acutely injured vessels. In swine arteries, the BEM increases cellular proliferation, angiogenesis, and connective tissue deposition, suggesting vessel healing and durable vessel occlusion. The BEM has significant advantages over embolic materials used today, making it a promising new tool for embolization.

GSK669, a NOD2 receptor antagonist, inhibits thrombosis and oxidative stress via targeting platelet GPVI

Background and PurposePreviously, we discovered that the activation of nucleotide-binding oligomerization domain 2 (NOD2) enhances platelet activation. We here investigated the antiplatelet and antithrombotic potential of GSK669, a NOD2 antagonist. Experimental ApproachEffects of GSK669 on platelet functions, reactive oxygen species (ROS) and proinflammatory cytokine generation were detected. NOD2-/- platelets were used to confirm GSK669 target. The interaction between GSK669 and glycoprotein VI (GPVI) was detected using surface plasmon resonance (SPR) spectroscopy. GPVI downstream signaling was examined by Western blot. The antithrombotic and antioxidative effects were investigated using mouse mesenteric arteriole thrombosis model and pulmonary embolism model. Key ResultsGSK669 significantly inhibits platelet proinflammatory cytokine release induced by muramyl dipeptide, platelet aggregation, ATP release, and ROS generation induced by collagen and collagen related peptide (CRP). Platelet spreading and clot retraction are also inhibited. GSK669 also decreases collagen-induced phosphorylation of Src, Syk, PLCγ2, and Akt. The antiplatelet effect of GSK669 is NOD2-independent and mediated by GPVI antagonism. Consistent with its antiplatelet activity as a GPVI antagonist, GSK669 inhibits platelet adhesion on collagen in flow condition. Notably, GSK669 inhibits mouse mesenteric arteriole thrombosis similarly to aspirin without bleeding. The antithrombotic effect of GSK669 is further confirmed in the pulmonary embolism model; decreased malonaldehyde (MDA) and increased superoxide dismutase (SOD) levels in mouse plasma reveal a significant antioxidant effect of GSK669. Conclusion and ImplicationsBeyond its anti-inflammatory effect as a NOD2 antagonist, GSK669 is also an efficient and safe antiplatelet agent combined with antioxidant effect by targeting GPVI. An antiplatelet agent bearing antioxidative and anti-inflammatory activities without bleeding risk may have therapeutic advantage over current antiplatelet drugs for atherothrombosis.

TPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation. We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke. Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.

Impact of Preload on Right Ventricular Hemodynamics in Acute Pulmonary Embolism

To compare the hemodynamic effects of increased versus decreased preload in a porcine model of acute intermediate-risk pulmonary embolism. Randomized, controlled animal study. Tertiary medical center, animal research laboratory. Female, Danish slaughter pigs (n = 22, ~ 60 kg). Acute pulmonary embolism was induced by large emboli made from clotting of autologous blood. Sixteen animals were randomized to either fluid loading (n = 8, isotonic saline, 1 L/hr for 2 hr) or diuretic treatment (n = 8, furosemide, 40 mg every 30 min, total 160 mg) and compared with a vehicle group (n = 6, no treatment). Hemodynamics were evaluated at baseline, after pulmonary embolism and after each dose by biventricular pressure-volume loops, invasive pressures, diuretic output, respiratory variables, and blood analysis. Pulmonary embolism increased mean pulmonary arterial pressure (p < 0.0001), pulmonary vascular resistance (p = 0.008), right ventricular arterial elastance (p = 0.003), and right ventricular end-systolic volume (p = 0.020) while right ventricular stroke volume and right ventricular ejection fraction were decreased (p = 0.047 and p = 0.0003, respectively) compared with baseline. Fluid loading increased right ventricular end-diastolic volume (+31 ± 13 mL; p = 0.004), right ventricular stroke volume (+23 ± 10 mL; p = 0.009), cardiac output (+2,021 ± 956 mL; p = 0.002), and right ventricular ejection fraction (+7.6% ± 1.5%; p = 0.032), whereas pulmonary vascular resistance decreased (-202 ± 65 dynes; p = 0.020) compared with vehicle. Diuretic treatment decreased right ventricular end-diastolic volume (-84 ± 11 mL; p < 0.001), right ventricular stroke volume (-40 ± 6 mL; p = 0.001), cardiac output (-3,327 ± 451 mL; p = 0.005), and mean pulmonary arterial pressure (-7 ± 1 mm Hg; p < 0.001) and increased right ventricular end-systolic elastance (+0.72 ± 0.2 mm Hg/mL; p < 0.001) and systemic vascular resistance (+1,812 ± 767 dynes; p < 0.001) with no effects on mean arterial pressure. In a porcine model of acute intermediate-risk pulmonary embolism, fluid loading increased right ventricular preload and right ventricular stroke volume, whereas diuretics decreased right ventricular preload and right ventricular stroke volume without affecting mean arterial pressure.

Association Between Inflammatory Mediators and Pulmonary Blood Flow in a Rabbit Model of Acute Pulmonary Embolism Combined With Shock.

BackgroundThe pro-inflammatory cytokines were detected in pulmonary embolism (PE) and non-pulmonary embolism (non-PE) tissues to explore the role of inflammation responses and their relationship with the pulmonary blood flow in a rabbit model of acute pulmonary embolism combined with shock.Methods and ResultsNineteen rabbits were randomly divided into sham operation group (S group, n = 8) and massive PE (MPE group, n = 11). The MPE model was established by injecting the autologous blood clots into the main pulmonary artery of rabbit. Pulmonary angiography showed that the pulmonary circulation time was significantly prolonged in the MPE group, and pulmonary blood flow was attenuated at 120 min post PE. Hematoxylin–eosin (HE) staining revealed enhanced inflammatory cell infiltration around the pulmonary vessels in PE and non-PE tissues, and obvious edema on the perivascular region. Meanwhile, the expressions of inducible nitric oxide synthase (iNOS) and arginase 1 (Arg-1) in pulmonary vascular and alveolar tissues were significantly upregulated and the iNOS/Arg-1 ratio was significantly higher in the MPE group than in the S group. Moreover, the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were also significantly increased in PE and non-PE tissues, and interleukin-6 (IL-6) level was significantly increased in non-PE tissues in the MPE group as compared to the S group. Thromboxane A2 (TXA2) and alpha smooth muscle actin (α-SMA) levels were significantly higher in both PE and non-PE tissues in the MPE group than in the S group.ConclusionActivation of inflammation mediators in PE and non-PE tissues might be one of the crucial factors responsible for pulmonary vasculature constriction and pulmonary blood flow attenuation in this MPE model.

Three-Dimensional Augmented Reality Visualization Informs Locoregional Therapy in a Translational Model of Hepatocellular Carcinoma

PurposeTo evaluate the utility of visualizing preprocedural MR images in 3-dimensional (3D) space using augmented reality (AR) before transarterial embolization of hepatocellular carcinoma (HCC) in a preclinical model. Materials and MethodsA total of 28 rats with diethylnitrosamine-induced HCCs > 5 mm treated with embolization were included in a prospective study. In 12 rats, 3D AR visualization of preprocedural MR images was performed before embolization. Procedural metrics including catheterization time and radiation exposure were compared vs a prospective cohort of 16 rats in which embolization was performed without AR. An additional cohort of 15 retrospective cases was identified and combined with the prospective control cohort (n = 31) to improve statistical power. ResultsA 37% reduction in fluoroscopy time, from 11.7 min to 7.4 minutes, was observed with AR when compared prospectively, which did not reach statistical significance (P = .12); however, when compared with combined prospective and retrospective controls, the reduction in fluoroscopy time from 14.1 min to 7.4 minutes (48%) was significant (P = .01). A 27% reduction in total catheterization time, from 42.7 minutes to 31.0 minutes, was also observed with AR when compared prospectively, which did not reach statistical significance (P = .11). No significant differences were seen in dose–area product or air kerma prospectively. ConclusionsThree-dimensional AR visualization of preprocedural imaging may aid in the reduction of procedural metrics in a preclinical model of transarterial embolization. These data support the need for further studies to evaluate the potential of AR in endovascular oncologic interventions.

Modelling of the arteriovenous malformation embolization optimal scenario.

Cerebral arteriovenous malformation (AVM) is a congenital brain vessels pathology, in which the arterial and venous blood channels are connected by tangles of abnormal blood vessels. It is a dangerous disease that affects brain functioning causing the high risk of intracerebral haemorrhage. One of AVM treatment methods is embolization—the endovascular filling of the AVM vessel bundle with a special embolic agent. This method is widely used, but still in some cases is accompanied by intraoperative AVM vessels rupture. In this paper, the optimal scenario of AVM embolization is studied from the safety and effectiveness of the procedure point of view. The co-movement of blood and embolic agent in the AVM body is modelled on the basis of a one-dimensional two-phase filtration model. Optimal control problem with phase constraints arising from medicine is formulated and numerically solved. In numerical analysis, the monotone modification of the CABARET scheme is used. Optimal embolization model is constructed on the basis of real patients' clinical data collected during neurosurgical operations. For the special case of embolic agent, input admissible and optimal embolization scenarios were calculated.

Bioactive-Tissue-Derived Nanocomposite Hydrogel for Permanent Arterial Embolization and Enhanced Vascular Healing.

Transcatheter embolization is a minimally invasive procedure that uses embolic agents to intentionally block diseased or injured blood vessels for therapeutic purposes. Embolic agents in clinical practice are limited by recanalization, risk of non-target embolization, failure in coagulopathic patients, high cost, and toxicity. Here, a decellularized cardiac extracellular matrix (ECM)-based nanocomposite hydrogel is developed to provide superior mechanical stability, catheter injectability, retrievability, antibacterial properties, and biological activity to prevent recanalization. The embolic efficacy of the shear-thinning ECM-based hydrogel is shown in a porcine survival model of embolization in the iliac artery and the renal artery. The ECM-based hydrogel promotes arterial vessel wall remodeling and a fibroinflammatory response while undergoing significant biodegradation such that only 25% of the embolic material remains at 14 days. With its unprecedented proregenerative, antibacterial properties coupled with favorable mechanical properties, and its superior performance in anticoagulated blood, the ECM-based hydrogel has the potential to be a next-generation biofunctional embolic agent that can successfully treat a wide range of vascular diseases.

Right ventricular adaptation in the critical phase after acute intermediate-risk pulmonary embolism.

The haemodynamic response following acute, intermediate-risk pulmonary embolism is not well described. We aimed to describe the cardiovascular changes in the initial, critical phase 0-12 hours after acute pulmonary embolism in an in-vivo porcine model. Pigs were randomly allocated to pulmonary embolism (n = 6) or sham (n = 6). Pulmonary embolism was administered as autologous blood clots (20 × 1 cm) until doubling of mean pulmonary arterial pressure or mean pulmonary arterial pressure was greater than 34 mmHg. Sham animals received saline. Cardiopulmonary changes were evaluated for 12 hours after intervention by biventricular pressure-volume loop recordings, invasive pressure measurements, arterial and central venous blood gas analyses. Mean pulmonary arterial pressure increased (P < 0.0001) and stayed elevated for 12 hours in the pulmonary embolism group compared to sham. Pulmonary vascular resistance and right ventricular arterial elastance (right ventricular afterload) were increased in the first 11 and 6 hours, respectively, after pulmonary embolism (P < 0.01 for both) compared to sham. Right ventricular ejection fraction was reduced (P < 0.01) for 8 hours, whereas a near-significant reduction in right ventricular stroke volume was observed (P = 0.06) for 4 hours in the pulmonary embolism group compared to sham. Right ventricular ventriculo-arterial coupling was reduced (P < 0.05) for 6 hours following acute pulmonary embolism despite increased right ventricular mechanical work in the pulmonary embolism group (P < 0.01) suggesting right ventricular failure. In a porcine model of intermediate-risk pulmonary embolism, the increased right ventricular afterload caused initial right ventricular ventriculo-arterial uncoupling and dysfunction. After approximately 6 hours, the right ventricular afterload returned to pre-pulmonary embolism values and right ventricular function improved despite a sustained high pulmonary arterial pressure. These results suggest an initial critical and vulnerable phase of acute pulmonary embolism before haemodynamic adaptation.

Preparation of Peptide and Recombinant Tissue Plasminogen Activator Conjugated Poly(Lactic-Co-Glycolic Acid) (PLGA) Magnetic Nanoparticles for Dual Targeted Thrombolytic Therapy.

Recombinant tissue plasminogen activator (rtPA) is the only thrombolytic agent that has been approved by the FDA for treatment of ischemic stroke. However, a high dose intravenous infusion is required to maintain effective drug concentration, owing to the short half-life of the thrombolytic drug, whereas a momentous limitation is the risk of bleeding. We envision a dual targeted strategy for rtPA delivery will be feasible to minimize the required dose of rtPA for treatment. For this purpose, rtPA and fibrin-avid peptide were co-immobilized to poly(lactic-co-glycolic acid) (PLGA) magnetic nanoparticles (PMNP) to prepare peptide/rtPA conjugated PMNPs (pPMNP-rtPA). During preparation, PMNP was first surface modified with avidin, which could interact with biotin. This is followed by binding PMNP-avidin with biotin-PEG-rtPA (or biotin-PEG-peptide), which was prepared beforehand by binding rtPA (or peptide) to biotin-PEG-maleimide while using click chemistry between maleimide and the single –SH group in rtPA (or peptide). The physicochemical property characterization indicated the successful preparation of the magnetic nanoparticles with full retention of rtPA fibrinolysis activity, while biological response studies underlined the high biocompatibility of all magnetic nanoparticles from cytotoxicity and hemolysis assays in vitro. The magnetic guidance and fibrin binding effects were also confirmed, which led to a higher thrombolysis rate in vitro using PMNP-rtPA or pPMNP-rtPA when compared to free rtPA after static or dynamic incubation with blood clots. Using pressure-dependent clot lysis model in a flow system, dual targeted pPMNP-rtPA could reduce the clot lysis time for reperfusion by 40% when compared to free rtPA at the same drug dosage. From in vivo targeted thrombolysis in a rat embolic model, pPMNP-rtPA was used at 20% of free rtPA dosage to restore the iliac blood flow in vascular thrombus that was created by injecting a blood clot to the hind limb area.

In This Issue

HomeCirculation ResearchVol. 126, No. 8In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published9 Apr 2020https://doi.org/10.1161/RES.0000000000000339Circulation Research. 2020;126:943is related toNfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in ZebrafishA Computational Pipeline to Predict Cardiotoxicityis related toCrystal Clots as Therapeutic Target in Cholesterol Crystal EmbolismCardiotoxicity From the Atom to the Cardiac Rhythm (p 947)Yang et al’s new computational method predicts proarrhythmic tendencies of drugs.Download figureDownload PowerPointCardiotoxicity is a common side effect of otherwise promising drugs that can lead to their removal from the market, or failure to get there. A chief cause of drug-induced arrhythmias is inhibition of the cardiac potassium channel hERG, which interacts with a variety of pharmacological agents. To determine a drug’s effect on hERG, researchers measure the heart’s QT interval—the time taken for ventricles to contract and relax—via electrocardiograms. However, while a number of drugs prolong QT intervals, they don’t all result in severe arrhythmias. Yang and colleagues have thus developed an approach to help differentiate damaging drugs from less risky ones. They show that computational modeling of drug interactions—using the atomic structures of hERG and the candidate drug—as well as the resulting cell and tissue effects can predict a drug’s proarrhythmic potential. The approach was tested with two drugs, doletilide and monofloxacin, both of which block hERG but which differ in arrhythmia risk. Comparing the results of the computer modeling with actual clinical data for the drugs showed tight agreement. This proof-of-principle study now lays the foundation for assessing more drugs and, ultimately, for applying the method as a screening aid during drug development.Nfatc1 in Zebrafish Cardiac Valve Development (p 968)Gunawan et al investigate the role of transcription factor Nfatc1 in heart valve development.Download figureDownload PowerPointBy ensuring the unidirectional flow of blood, the cardiac valves are critical to heart function. In humans, congenital valve defects have been associated with polymorphisms at the gene encoding transcription factor Nfatc1. Furthermore, mice lacking functional Nfatc1 die from cardiac valve defects during embryogenesis. The precise mechanisms by which Nfatc1 mediates valve development, however, are unknown. To investigate Nfatc1 activity, Gunawen and colleagues turned to zebrafish—because their transparent bodies facilitate heart imaging during development. By 96 hours postfertilization, fish that lacked functional Nfatc1 were noticeably different from wild-type controls, showing pericardial edema, retrograde blood flow, and significantly fewer valve interstitial cells (VICs)—fibroblast-like cells that secrete and maintain the extracellular matrix material of the valves. Indeed, fewer VICs was associated with reduced valve ECM. The team went on to show that Nfatc1 regulates the development and proliferation of VICs, in part by the activation of twist1b—a cell lineage determination factor. The work not only uncovers the role of Nfatc1 and twist1b in VIC production, but also highlights zebrafish as useful model organisms for further studies of this process.Crystal Clots in Cholesterol Embolism (p e37)Shi et al examine the formation, composition and dismantling of cholesterol clots.Download figureDownload PowerPointWhen an atherosclerotic plaque ruptures releasing crystals of cholesterol, it’s not the crystals themselves that are the major cause of vessel occlusion, but the cells and molecules that surround them, according to Shi and colleagues’ new findings. The team developed a mouse model of cholesterol crystal embolism (CCE) wherein they inject cholesterol crystals into the animal’s left kidney artery. The animals quickly develop an arterial blockage, infarct, and reduced kidney function—measured by glomerular filtration rate (GFR). The vessel occlusions consisted of typical thrombus components, including platelets, neutrophils, and fibrin, as well as extracellular DNA from dying neutrophils and endothelial cells, the team showed. Inhibition of platelet activation, or the use of anticoagulants prevented vascular obstruction, reduced infarct size and maintained GFR, even though the cholesterol crystals remained. As an alternative to anticoagulants, which cannot be used if patients need arterial surgery, the team examined DNase I treatment as a way to dismantle the clots showing it too decreased vessel occlusion. The work shows that clotting components are the critical factors leading to vessel blockage in CCE, and provides a model system in which to study CCE pathogenesis and treatments. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesNfatc1 Promotes Interstitial Cell Formation During Cardiac Valve Development in ZebrafishFelix Gunawan, et al. Circulation Research. 2020;126:968-984Crystal Clots as Therapeutic Target in Cholesterol Crystal EmbolismChongxu Shi, et al. Circulation Research. 2020;126:e37-e52A Computational Pipeline to Predict CardiotoxicityPei-Chi Yang, et al. Circulation Research. 2020;126:947-964 April 10, 2020Vol 126, Issue 8 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000339PMID: 32271676 Originally publishedApril 9, 2020 PDF download Advertisement

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