Regional Ischemia Research Articles

Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease.

Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD, independently of comorbid diabetes or obesity, are lacking. Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014). This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.

Microglia through MFG-E8 signaling decrease the density of degenerating neurons and protect the brain from the development of cortical infarction after stroke.

Neuronal loss is a hallmark of stroke and other neurodegenerative diseases, and as such, neuronal loss caused by microglia has been thought to be a contributing factor to disease progression. Here, we show that microglia indeed contribute significantly to neuronal loss in a mouse model of stroke, but this microglial-dependent process of neuronal clearance specifically targets stressed and degenerating neurons in the ischemic cortical region and not healthy non-ischemic neurons. Nonspecific stimulation of microglia decreased the density of neurons in the ischemic cortical region, whereas specific inhibition of MFG-E8 signaling, which is required for microglial phagocytosis of neurons, had the opposite effect. In both scenarios, the effects were microglia specific, as the same treatments had no effect in mice whose microglia were depleted prior to stroke. Finally, even though the inhibition of MFG-E8 signaling increased neuronal density in the ischemic brain region, it substantially exacerbated the development of cortical infarction. In conclusion, microglia through MFG-E8 signaling contribute to the loss of ischemic neurons and, in doing so, minimize the development of cortical infarction after stroke.

Dye-less quantification of tissue perfusion by laser speckle contrast imaging is equivalent to quantified indocyanine green in a porcine model.

Subjective surgeon interpretation of near-infrared perfusion video is limited by low inter-observer agreement and poor correlation to clinical outcomes. In contrast, quantification of indocyanine green fluorescence video (Q-ICG) correlates with histologic level of perfusion as well as clinical outcomes. Measuring dye volume over time, however, has limitations, such as it is not on-demand, has poor spatial resolution, and is not easily repeatable. Laser speckle contrast imaging quantification (Q-LSCI) is a real-time, dye-free alternative, but further validation is needed. We hypothesize that Q-LSCI will distinguish ischemic tissue and correlate over a range of perfusion levels equivalent to Q-ICG. Nine sections of intestine in three swine were devascularized. Pairs of indocyanine green fluorescence imaging and laser speckle contrast imaging video were quantified within perfused, watershed, and ischemic regions. Q-ICG used normalized peak inflow slope. Q-LSCI methods were laser speckle perfusion units (LSPU), the base unit of laser speckle imaging, relative perfusion units (RPU), a previously described methodology which utilizes an internal control, and zero-lag normalized cross-correlation (X-Corr), to investigate if the signal deviations convey accurate perfusion information. We determine the ability to distinguish ischemic regions and correlation to Q-ICG over a perfusion gradient. All modalities distinguished ischemic from perfused regions of interest; Q-ICG values of 0.028 and 0.155 (p < 0.001); RPU values of 0.15 and 0.68 (p < 0.001); and X-corr values of 0.73 and 0.24 (p < 0.001). Over a range of perfusion levels, RPU had the best correlation with Q-ICG (r = 0.79, p < 0.001) compared with LSPU (r = 0.74, p < 0.001) and X-Corr (r = 0.46, p < 0.001). These results demonstrate that Q-LSCI discriminates ischemic from perfused tissue and represents similar perfusion information over a broad range of perfusion levels comparable to clinically validated Q-ICG. This suggests that Q-LSCI might offer clinically predictive real-time dye-free quantification of tissue perfusion. Further work should include validation in histologic studies and human clinical trials.

A novel nitric oxide-driven nanomotor for synergistic treatment of ischaemic stroke: Enhanced deep brain penetration and therapeutic efficacy

Ischaemic stroke is a medical condition characterised by neuroinflammation and oxidative damage. Its treatment faces challenges related to drug delivery, particularly in overcoming the blood–brain barrier (BBB) and effectively targeting the stroke’s core. To overcome this challenge, we developed a novel nitric oxide (NO)-driven chemotactic nanomotor to increase the efficacy of ischaemic stroke treatment. The mesoporous nanomotor is loaded with tanshinone IIA, which actively inhibits pyroptosis and regulates the inflammatory response. Additionally, we conjugated a chemotactic nanomotor with a stroke-afflicted region-homing peptide, precisely guiding them to target damaged neurons within the ischaemic region. Notably, the chemotactic nanomotor reacts with ROS in the ischaemic microenvironment to produce NO, thereby not only reducing brain oxidative stress but also providing the driving force for deep brain penetration. The multifunctional nanomotor efficiently decreases reactive oxygen species (ROS) production and significantly mitigates inflammation-related pathology, thus imparting dual anti-oxidative and anti-inflammatory effects to remodel the ischaemic core microenvironment. In vitro and in vivo studies confirmed the synergistic role of antioxidant and anti-inflammatory effects in improving the ischaemic microenvironment. These findings suggest that an NO-driven nanomotor with synergistic therapeutic functions is highly effective to enhance therapeutic performance and clinical outcomes in ischaemic stroke.

Dynamically crosslinked ECM-like hydrogels loaded with ROS-responsive drug nanoparticles for treating inflammation in myocardial infarction and stroke

Following a myocardial infarction (MI) or stroke, the excessive generation of reactive oxygen species (ROS) within a brief timeframe may induce a pronounced inflammatory reaction, which exacerbates the progression of the disease. Thus, there is an urgent need to design a biomaterial to inhibit the inflammatory response associated with MI and stroke. In this study, we designed a reversible extracellular matrix (ECM)-like hydrogel via borate ester crosslinking, which responds to the inflammatory microenvironment affected by MI and stroke. At the same time, we developed a new type of loaded polymer nanoparticle (TK-DA) that can respond to ROS in ischemic regions and release the anti-inflammatory drug dexamethasone. Ultimately, we integrated the nanoparticles and ECM-like hydrogel to fabricate a functional hydrogel. To verify the therapeutic effect of the functional hydrogel, we established two models of typical ischemic diseases, MI and stroke. The results showed that the hydrogel substantially reduced ROS levels and inflammation in vitro. Moreover, the results of the two in vivo animal models demonstrated that this functional hydrogel can effectively treat MI and stroke by suppressing inflammatory responses, mitigating apoptosis, and promoting neovascularization. In conclusion, the functional hydrogel strategy presents a universally applicable treatment approach for ischemic cardiovascular and cerebrovascular diseases, which are not limited solely to the treatment of MI and stroke, but also hold future potential for clinical applications.

Effects of dapagliflozin on myoglobin efflux from cardiomyocyte during myocardial ischemia/reperfusion in anesthetized rats

It has been suggested that sodium-glucose cotransporter 2 (SGLT2) inhibitors have cardioprotective effects during myocardial ischemia/reperfusion (I/R) independent of glucose-lowering action. However, the effects of SGLT2 inhibitors on structural damage to cardiomyocytes in the ischemic region during I/R remain unknown. We applied a microdialysis technique to the heart of anesthetized rats and investigated the effects of an SGLT2 inhibitor, dapagliflozin, on myocardial interstitial myoglobin levels in the ischemic region during coronary occlusion followed by reperfusion. Dapagliflozin was administered systemically (40 μg/body iv) or locally via a dialysis probe (100 μM and 1 mM) 30 min before coronary occlusion. In the vehicle group, coronary occlusion increased the dialysate myoglobin concentration in the ischemic region. Reperfusion further increased the dialysate myoglobin concentration. Intravenous administration of dapagliflozin reduced dialysate myoglobin concentration during ischemia and at 0–15 min after reperfusion, but local administration (100 μM and 1 mM) did not. Therefore, acute systemic administration of dapagliflozin prior to ischemia has cardioprotective effects on structural damage during I/R.

Ischemic perfusion radiomics: assessing neurological impairment in acute ischemic stroke.

Accurate neurological impairment assessment is crucial for the clinical treatment and prognosis of patients with acute ischemic stroke (AIS). However, the original perfusion parameters lack the deep information for characterizing neurological impairment, leading to difficulty in accurate assessment. Given the advantages of radiomics technology in feature representation, this technology should provide more information for characterizing neurological impairment. Therefore, with its rigorous methodology, this study offers practical implications for clinical diagnosis by exploring the role of ischemic perfusion radiomics features in assessing the degree of neurological impairment. This study employs a meticulous methodology, starting with generating perfusion parameter maps through Dynamic Susceptibility Contrast-Perfusion Weighted Imaging (DSC-PWI) and determining ischemic regions based on these maps and a set threshold. Radiomics features are then extracted from the ischemic regions, and the t-test and least absolute shrinkage and selection operator (Lasso) algorithms are used to select the relevant features. Finally, the selected radiomics features and machine learning techniques are used to assess the degree of neurological impairment in AIS patients. The results show that the proposed method outperforms the original perfusion parameters, radiomics features of the infarct and hypoxic regions, and their combinations, achieving an accuracy of 0.926, sensitivity of 0.923, specificity of 0.929, PPV of 0.923, NPV of 0.929, and AUC of 0.923, respectively. The proposed method effectively assesses the degree of neurological impairment in AIS patients, providing an objective auxiliary assessment tool for clinical diagnosis.

Hypersensitive MR Angiography for Diagnosis of Ischemic Stroke and Reperfusion Subarachnoid Hemorrhage.

Stroke is an acute injury of the central nervous system caused by the disorders of cerebral blood circulation, which has become one of the major causes of disability and death. Hemorrhage, particularly subarachnoid hemorrhage (SAH), is one of the poorest prognostic factors in stroke, which is related to the thrombolytic therapy, and has been considered very dangerous. In this context, the MR angiography with high sensitivity and resolution has been developed based on biocompatible paramagnetic ultrasmall NaGdF4 nanoprobes. Owing to the appropriate hydrodynamic diameter, the nanoprobe can be confined inside the blood vessels and it only extravasates at the vascular injury site when the bleeding occurs. Relying on this property, the three-dimensional (3D) anatomic structures of artery occlusion of stroke rat can be precisely visualized; reperfusion-related SAH has been successfully visualized and identified. Benefiting from the long blood half-life of the nanoprobe, the observation window of MR angiography can last for the whole period of reperfusion, thereby monitoring the probable SAH in real time during thrombolytic therapy. More importantly, through reconstruction of multiparametric MRI, the arterial occlusion, cerebral ischemic region, and SAH can be simultaneously visualized in vivo in a 3D manner for the first time. Therefore, the current study provides a novel approach for both noninvasive 3D vascular visualization and hemorrhage alert, which possesses great prospects for clinical translation.

Research progress of propofol in alleviating cerebral ischemia/reperfusion injury.

Ischemic stroke is a leading cause of adult disability and death worldwide. The primary treatment for cerebral ischemia patients is to restore blood supply to the ischemic region as quickly as possible. However, in most cases, more severe tissue damage occurs, which is known as cerebral ischemia/reperfusion (I/R) injury. The pathological mechanisms of brain I/R injury include mitochondrial dysfunction, oxidative stress, excitotoxicity, calcium overload, neuroinflammation, programmed cell death and others. Propofol (2,6-diisopropylphenol), a short-acting intravenous anesthetic, possesses not only sedative and hypnotic effects but also immunomodulatory and neuroprotective effects. Numerous studies have reported the protective properties of propofol during brain I/R injury. In this review, we summarize the potential protective mechanisms of propofol to provide insights for its better clinical application in alleviating cerebral I/R injury.

Improving acute stroke assessment in non-enhanced computed tomography: automated tool for early ischemic lesion volume detection.

ASPECTs is a widely used marker to identify early stroke signs on non-enhanced computed tomography (NECT), yet it presents interindividual variability and it may be hard to use for non-experts. We introduce an algorithm capable of automatically estimating the NECT volumetric extension of early acute ischemic changes in the 3D space. We compared the power of this marker with ASPECTs evaluated by experienced practitioner in predicting the clinical outcome. We analyzed and processed neuroimaging data of 153 patients admitted with acute ischemic stroke. All patients underwent a NECT at admission and on follow-up. The developed algorithm identifies the early ischemic hypodense region based on an automatic comparison of the gray level in the images of the two hemispheres, assumed to be an approximate mirror image of each other in healthy patients. In the two standard axial slices used to estimate the ASPECTs, the regions identified by the algorithm overlap significantly with those identified by experienced practitioners. However, in many patients, the regions identified automatically extend significantly to other slices. In these cases,the volume marker provides supplementary and independent information.Indeed,theclinical outcome of patients with volume marker = 0 can be distinguished with higher statistical confidence than the outcome of patients with ASPECTs = 10. The volumetric extension and the location of acute ischemic region in the 3D-space, automatically identified by our algorithm, provide data that are mostly in agreement with the ASPECTs value estimated by expert practitioners, and in some cases complementary and independent.

New advances in the protective mechanisms of acidic pH after ischemia: Participation of NO

BackgroundIt has been previously demonstrated that the maintenance of ischemic acidic pH or the delay of intracellular pH recovery at the onset of reperfusion decreases ischemic-induced cardiomyocyte death. ObjectiveTo examine the role played by nitric oxide synthase (NOS)/NO-dependent pathways in the effects of acidic reperfusion in a regional ischemia model. MethodsIsolated rat hearts perfused by Langendorff technique were submitted to 40 min of left coronary artery occlusion followed by 60 min of reperfusion (IC). A group of hearts received an acid solution (pH = 6.4) during the first 2 min of reperfusion (AR) in absence or in presence of l-NAME (NOS inhibitor). Infarct size (IS) and myocardial function were determined. In cardiac homogenates, the expression of P-Akt, P-endothelial and inducible isoforms of NOS (P-eNOS and iNOS) and the level of 3-nitrotyrosine were measured. In isolated cardiomyocytes, the intracellular NO production was assessed by confocal microscopy, under control and acidic conditions. Mitochondrial swelling after Ca2+ addition and mitochondrial membrane potential (Δψ) were also determined under control and acidosis. ResultsAR decreased IS, improved postischemic myocardial function recovery, increased P-Akt and P-eNOS, and decreased iNOS and 3-nitrotyrosine. NO production increased while mitochondrial swelling and Δψ decreased in acidic conditions. l-NAME prevented the beneficial effects of AR. ConclusionsOur data strongly supports that a brief acidic reperfusion protects the myocardium against the ischemia-reperfusion injury through eNOS/NO-dependent pathways.

Risk Factors of Poststroke Cognitive Impairment: A Meta-Analysis

Objective To explore the potential risk factors of post stroke cognitive impairment (PSCI) by conducting a meta-analysis. Methods Literature search was performed in databases (PubMed, Embase, Web of Science, CNKI) using keywords of PSCI. Cochrane ROB tool was adopted for evaluating the quality of the included studies. Afterwards, data was independently extracted by 2 investigators. Heterogeneity was quantified across studies by Chi-squared-based Q statistic test and I2 statistic. The random-effects model or fixed-effects model was employed to compute the pooled estimates depends on whether the heterogeneity was significant (I2 &gt; 50% or P &lt; .05) or not. Publication bias was evaluated by the funnel plot and Egger’s test. Sensitivity analysis was accomplished through eliminating studies 1 at a time to evaluate the stability of the pooled estimates. Results 23 high-quality studies with 13322 patients were included. Compared with patients with no cognitive impairment, PSCI was more likely to develop in the elderly (pooled MD = 3.58, 95% CI = [1.82, 5.34]), female (pooled RR = 1.23, 95% CI = [1.07, 1.41]), or less-educated (pooled MD = −1.63, 95% CI = [-2.96, −.31]) patients with a history of hypertension (pooled RR = 1.07, 95% CI = [1.03, 1.11]), diabetes mellitus (pooled RR = 1.10, 95% CI = [1.03, 1.17]), atrial fibrillation (pooled RR = 1.38, 95% CI = [1.10, 1.74]), or stroke (pooled RR = 1.36, 95% CI = [1.09, 1.70]). Smoking did not affect the development of PSCI in patients (pooled RR = .96, 95% CI = [.78, 1.19]). Ischemic heart disease and region represented the sources of significant heterogeneity across studies. The pooled estimates were robust, and no publication bias was seen. Conclusion Age, gender, education, hypertension, diabetes mellitus, atrial fibrillation, and stroke were the risk factors of PSCI. Controlling these risk factors can help prevent PSCI.

Erastin promotes random-pattern skin flaps survival by inducing mTORC1-TFEB mediated autophagy

Random-pattern skin flaps are important method for skin reconstruction after defect; however, the distal end of flaps is not easily viable due to inadequate nutrient supply. Erastin is a well-established ferroptosis inducer, but our study found that low-dose of erastin (2 μM) may reduce nutrient deficiency induced cell death in human umbilical vein endothelial cells (HUVECs). RNA-seq analysis suggested that its role was related to autophagy regulation. Follow-up studies have shown that the use of autophagy inhibitors or the knockdown of TFEB in HUVECs can both reduce the anti-apoptotic effect of erastin in HUVECs. Mechanism study demonstrated that erastin can suppress mTORC1 and promote TFEB activity in HUVECs, suggesting that the effect of erastin on the survival of HUVECs under nutrient deprivation conditions is regulated by mTORC1/TFEB. Subsequently, we evaluated the effect of erastin on the survival of random-pattern skin flaps in mice in vivo. On the postoperative day 7, we observed a significant increase in flap survival area, blood perfusion, and microvascular density after erastin treatment; also, erastin treatment showed enhanced autophagy within the ischemic region. In summary, our study demonstrates that low-dose of erastin may suppress cell death in endothelial cells under nutrient deficiency condition, and its effects may relate to the mTORC1-TFEB medicated autophagy regulation, erastin treatment may be a potential therapy for random-pattern skin flaps.

Is ischemic stimulus involved for J wave augmentation during coronary angiography and intracoronary administration of normal saline?

J waves may be augmented by coronary angiography (CAG) or intracoronary drug administration but the underlying mechanism is unknown. The effect of intracoronary normal saline (NS) on J waves were investigated. After the standard CAG using iopamidol (IopamiroR Inj), NS was injected into the right coronary artery in 10 patients with and eight patients without J waves at the baseline. The 12-lead ECG was monitored, stored on a computer and retrieved later for measurement of the J wave amplitude before or during the coronary interventions. J waves in leads II, III and aVF at baseline increased significantly in each lead during the right CAG and NS injection into the right coronary artery. The J wave changes were similar between the two interventions and distinct similar alterations were observed in the QRS complex. We postulated that the ischemic myocardium that was induced during CAG or intracoronary NS administration slowed the conduction velocity of depolarization in the perfusion territory and delayed the timing of J waves to appear. Then, the delayed appearance of J waves would be less opposed by electromotive force from other areas resulting in augmentation. J wave augmentation was observed during CAG and intracoronary NS administration. As a mechanism of augmentation, we postulated that contrast media and NS induce myocardial ischemia and delay the timing of J waves to a point of less opposition by electromotive force from other areas. J wave augmentation has been reported during intracoronary injection of contrast media or drugs. The present study confirmed that normal saline alone was able to augment J waves. Mechanistically, coronary interventions using anoxic solutions can cause regional myocardial ischemia and reduce the conduction velocity of depolarization. Then, delayed J waves are less opposed by the electromotive force from remote areas which leads to augmentation. When a drug is diluted in normal saline and given intracoronarily, changes in J waves can be due to normal saline. The pathophysiological and clinical significance of J waves augmented during coronary interventions need to be established.

Revolutionizing Stroke Care: Nanotechnology-Based Brain Delivery as a Novel Paradigm for Treatment and Diagnosis.

Stroke, a severe medical condition arising from abnormalities in the coagulation-fibrinolysis cycle and metabolic processes, results in brain cell impairment and injury due to blood flow obstruction within the brain. Prompt and efficient therapeutic approaches are imperative to control and preserve brain functions. Conventional stroke medications, including fibrinolytic agents, play a crucial role in facilitating reperfusion to the ischemic brain. However, their clinical efficacy is hampered by short plasma half-lives, limited brain tissue distribution attributed to the blood-brain barrier (BBB), and lack of targeted drug delivery to the ischemic region. To address these challenges, diverse nanomedicine strategies, such as vesicular systems, polymeric nanoparticles, dendrimers, exosomes, inorganic nanoparticles, and biomimetic nanoparticles, have emerged. These platforms enhance drug pharmacokinetics by facilitating targeted drug accumulation at the ischemic site. By leveraging nanocarriers, engineered drug delivery systems hold the potential to overcome challenges associated with conventional stroke medications. This comprehensive review explores the pathophysiological mechanism underlying stroke and BBB disruption in stroke. Additionally, this review investigates the utilization of nanocarriers for current therapeutic and diagnostic interventions in stroke management. By addressing these aspects, the review aims to provide insight into potential strategies for improving stroke treatment and diagnosis through a nanomedicine approach.

Cardio- and Vasoprotective Effects of Quinacrine in an In Vivo Rat Model of Myocardial Ischemia/Reperfusion Injury.

This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size.

Targeted Delivery of Macrophage Membrane Biomimetic Liposomes Through Intranasal Administration for Treatment of Ischemic Stroke.

Ginsenoside Rg3 (Rg3) and Panax notoginseng saponins (PNS) can be used for ischemic stroke treatment, however, the lack of targeting to the ischemic region limits the therapeutic effect. To address this, we leveraged the affinity of macrophage membrane proteins for inflamed brain microvascular endothelial cells to develop a macrophage membrane-cloaked liposome loaded with Rg3 and PNS (MM-Lip-Rg3/PNS), which can precisely target brain lesion region through intranasal administration. MM-Lip-Rg3/PNS was prepared by co-extrusion method and was performed by characterization, stability, surface protein, and morphology. The cellular uptake, immune escape ability, and blood-brain barrier crossing ability of MM-Lip-Rg3/PNS were studied in vitro. The in vivo brain targeting, biodistribution and anti-ischemic efficacy of MM-Lip-Rg3/PNS were evaluated in MACO rats, and we determined the diversity of the nasal brain pathway through the olfactory nerve blockade model in rats. Finally, the pharmacokinetics and brain targeting index of MM-Lip-Rg3/PNS were investigated. Our results indicated that MM-Lip-Rg3/PNS was spherical with a shell-core structure. MM-Lip-Rg3/PNS can avoid mononuclear phagocytosis, actively bind to inflammatory endothelial cells, and have the ability to cross the blood-brain barrier. Moreover, MM-Lip-Rg3/PNS could specifically target ischemic sites, even microglia, increase the cumulative number of drugs in the brain, improve the inflammatory environment of the brain, and reduce the infarct size. By comparing olfactory nerve-blocking rats with normal rats, it was found that there are direct and indirect pathways for nasal entry into the brain. Pharmacokinetics demonstrated that MM-Lip-Rg3/PNS exhibited stronger brain targeting and prolonged drug half-life. MM-Lip-Rg3/PNS might contribute to the accumulation of Rg3 and PNS in the ischemic brain area to improve treatment efficacy. This biomimetic nano-drug delivery system provides a new and promising strategy for the treatment of ischemic stroke.

Arrhythmogenic right ventricular cardiomyopathy with sustained ventricular tachycardia: a case report

IntroductionArrhythmogenic right ventricular cardiomyopathy (ARVC) is an infrequent hereditary disorder distinguished by fibrofatty replacement of the myocardium in the right ventricular, which predisposes individuals to life-threatening arrhythmias. This case delineates an ARVC patient who suffered recurrent bouts of sustained ventricular tachycardia (VT). In this case, we mainly discuss the application of myocardial contrast echocardiography (MCE) in displaying myocardial fibrosis in patients with ARVC.Case presentationA 43-year-old male experienced three episodes of unexplained VT over an eight-year period, accompanied by symptoms of chest discomfort, palpitations and dizziness. Coronary angiography revealed no significant coronary stenosis. The electrocardiogram (ECG) results indicated characteristic epsilon waves in right precordial leads, and subsequent echocardiography identified right ventricular enlargement and right ventricular systolic dysfunction. MCE further disclosed regional myocardial ischemia at the epicardium of the left ventricular apex. Ultimately, cardiovascular magnetic resonance imaging (CMR) corroborated the ARVC diagnosis, highlighting linear intensification in the right ventricle during the delayed enhancement.ConclusionPrompt identification of ARVC is crucial for timely intervention and management. MCE may offer an effective and valuable technique for the detection of myocardial involvement in ARVC patient.

An-Gong-Niu-Huang-Wan (AGNHW) regulates cerebral blood flow by improving hypoperfusion, cerebrovascular reactivity and microcirculation disturbances after stroke

BackgroundThe restoration of cerebrovascular regulation and improvement of cerebral blood flow in ischaemic regions are crucial for improving the clinical prognosis after stroke. An-Gong-Niu-Huang-Wan (AGNHW) is a famous traditional compound Chinese medicine that has been used for over 220 years to treat acute ischaemic stroke; however, its role in the regulation of cerebral blood flow is still unclear. The aim of the present study was to investigate the regulatory effect of AGNHW on cerebral blood flow and microcirculation after ischaemic stroke and to elucidate the underlying mechanisms involved.MethodsMale C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO) and randomly assigned to the sham, MCAO, or AGNHW groups. AGNHW was administered intragastrically 1 h after dMCAO. The rotarod test was utilized to evaluate behavioural function; TTC was used to determine the infarct volume; and ischaemic injury was assessed by detecting brain levels of SOD, MDA and NO. Then, cortical perfusion and acetazolamide-induced cerebrovascular reactivity were assessed using laser speckle contrast imaging, and the velocity and flux of red blood cells in cortical capillaries were detected using two-photon laser scanning microscopy. In addition, we employed RNA-Seq to identify variations in gene expression profiles and assessed endothelium-dependent changes in microcirculatory dysfunction by measuring vasoactive mediator levels.ResultsAGNHW significantly increased cerebral blood flow, reduced the infarct volume, and promoted functional recovery after cerebral ischaemia. AGNHW increased the velocity and flux of red blood cells in capillaries and improved cerebrovascular reactivity in the ischaemic cortex. Furthermore, AGNHW regulated endothelium-dependent microcirculation, as evidenced by decreases in the expression of endothelins (Edn1, Edn3 and Ednrb) and the ratios of brain and serum TXB2/6-keto-PGF1α and ET-1/CGRP.ConclusionsAGNHW improved cerebral hypoperfusion, regulated cerebrovascular reactivity and attenuated microcirculatory dysfunction within the ischaemic cortex after stroke. This outstanding effect was achieved by modulating the expression of genes related to vascular endothelial cell function and regulating endothelium-dependent vasoactive mediators.

Rapid identification and prognosis evaluation by dual-phase computed tomography angiography for stroke patients with a large ischemic region in the anterior circulation treated with endovascular thrombectomy.

To investigate the value of dual-phase head-and-neck computed tomography angiography (CTA) in assessing advantages and risks associated with mechanical thrombectomy for stroke with a large ischemic region in the anterior circulation within 6 h of onset. We retrospectively analyzed the data of patients with acute occlusion of the internal carotid artery or middle cerebral artery-M1 segment. Baseline dual-phase CTA was performed for collateral grading using the 4-point visual collateral score (0, 0% filling; 1, >0% and ≤50% filling; 2, >50 and <100% filling; 3, 100% filling). The rates of modified Rankin score (MRS) ≤ 3 at 90 days, any intracranial hemorrhage (ICH) within 48 h, malignant cerebral edema within 24 h, and all-cause 90-day mortality were analyzed. Among the 69 study patients, 15, 26, 17, and 11 patients had collateral grades of 0, 1, 2, and 3, respectively. At 90 days, the MRS was ≤3 in 0, 8.33, 29.41, and 36.36% of patients with grades 0, 1, 2, and 3, respectively. ICH incidence was 73.33, 57.69, 29.41, and 18.18% for grades 0, 1, 2, and 3, respectively, while the incidence of malignant brain edema was 100, 76.92, 35.29, and 0%, respectively. All-cause 90-day mortality was 53.33% for grade 0 and 30.77% for grade 1; no deaths occurred at grades 2 and 3. Collateral grading based on dual-phase CTA enables simple and rapid preoperative evaluation prior to mechanical thrombectomy for acute anterior-circulation stroke with a large ischemic focus, particularly for patients presenting within the 6-h time window.