Intra-arterial administration of cell-based biological agents for ischemic stroke therapy

Introduction: Ischemic stroke is becoming a primary cause of disability and death worldwide. To date, therapeutic options remain limited focusing on mechanical thrombolysis or administration of thrombolytic agents. However, these therapies do not promote neuroprotection and neuro-restoration of the ischemic area of the brain.

Areas covered: This review highlights the option of minimal invasive, intra-arterial, administration of biological agents for stroke therapy. The authors provide an update of all available studies, discuss issues that influence outcomes and describe future perspectives which aim to improve clinical outcomes. New therapeutic options based on cellular and molecular interactions following an ischemic brain event, will be highlighted.

Expert opinion: Intra-arterial administration of biological agents during trans-catheter thrombolysis or thrombectomy could limit neuronal cell death and facilitate regeneration or neurogenesis following ischemic brain injury. Despite the initial progress, further meticulous studies are needed in order to establish the clinical use of stem cell-induced neuroprotection and neuroregeneration.     

Exosomes from miRNA‐126‐modified endothelial progenitor cells alleviate brain injury and promote functional recovery after stroke

AimsWe previously showed that the protective effects of endothelial progenitor cells (EPCs)‐released exosomes (EPC‐EXs) on endothelium in diabetes. However, whether EPC‐EXs are protective in diabetic ischemic stroke is unknown. Here, we investigated the effects of EPC‐EXs on diabetic stroke mice and tested whether miR‐126 enriched EPC‐EXs (EPC‐EXs^miR126) have enhanced efficacy.MethodsThe db/db mice subjected to ischemic stroke were intravenously administrated with EPC‐EXs 2 hours after ischemic stroke. The infarct volume, cerebral microvascular density (MVD), cerebral blood flow (CBF), neurological function, angiogenesis and neurogenesis, and levels of cleaved caspase‐3, miR‐126, and VEGFR2 were measured on day 2 and 14.ResultsWe found that (a) injected EPC‐EXs merged with brain endothelial cells, neurons, astrocytes, and microglia in the peri‐infarct area; (b) EPC‐EXs^miR126 were more effective than EPC‐EXs in decreasing infarct size and increasing CBF and MVD, and in promoting angiogenesis and neurogenesis as well as neurological functional recovery; (c) These effects were accompanied with downregulated cleaved caspase‐3 on day 2 and vascular endothelial growth factor receptor 2 (VEGFR2) upregulation till day 14.ConclusionOur results indicate that enrichment of miR126 enhanced the therapeutic efficacy of EPC‐EXs on diabetic ischemic stroke by attenuating acute injury and promoting neurological function recovery.     

电针对缺血性脑卒中大鼠记忆功能及脑内突触囊泡蛋白的影响

观察电针对缺血性脑卒中大鼠记忆功能及脑内突触囊泡蛋白（synaptic vesicular protein，SYN）的影响，探讨其可能的作用机制。方法 选取90 只SD大鼠随机分为模型组、电针组、假手术组，每组各30只。线拴法制作急性大脑中动脉缺血大鼠模型。电针组取“百会”“水沟”“内关”“三阴交”穴位，应用“醒脑开窍”法进行电针，每天电针30 min，连续电针6 d休1 d，7 d为一个疗程，首次电针干预在造模成功24 h后进行。模型组和假手术组不进行电针干预。大鼠分别按7、14、21 d 3个亚组进行运动及记忆功能评分，TTC染色测定脑梗死体积、Western blot检测脑内SYN的蛋白表达。结果 电针组运动功能评分较模型组显著降低（P<0.01），电针组进入隐藏区潜伏期时间较模型组显著缩短（P<0.01），电针组脑梗死率较模型组显著缩小（P<0.01），SYN的蛋白表达电针组较模型组明显增强（P<0.01）。假手术组无神经功能缺损及脑梗死灶，SYN表达最弱。结论 电针干预能减小脑梗死体积，上调脑内SYN的表达，进而促进缺血性脑卒中大鼠的记忆及运动等神经功能的恢复。     

丹参川芎嗪注射液联合西药对急性缺血性脑卒中患者脑组织的保护作用及对预后的影响

目的:观察丹参川芎嗪注射液联合西药治疗对急性缺血性脑卒中患者脑组织的保护作用及对预后的影响。方法:以268例急性缺血性脑卒中患者为研究对象,按随机数字表法分为研究组和对照组各134例,2组均予西药治疗,研究组予以丹参川芎嗪注射液联合治疗,2组均随访至12周。治疗前后检测2组患者的血清炎症相关因子[超敏C-反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6 (IL-6)、白细胞介素-8 (IL-8)]、血管内皮生长因子(VEGF)、神经元特异性烯醇化酶(NSE)和S-100β水平,随访评定患者治疗12周内的美国国立卫生研究院卒中量表(NIHSS)评分和日常生活能力量表(BI)评分。结果:治疗3周,2组hs-CRP、TNF-α、IL-6和IL-8水平均低于入院时(P<0.01);研究组各因子水平均低于对照组(P<0.01)。2组血清NSE和S-100β水平均较入院时降低(P<0.01),而VEGF水平较入院时升高(P<0.01)。研究组血清NSE和S-100β水平均低于对照组,VEGF水平高于对照组,差异均有统计学意义(P<0.01)。2组治疗后一时间点的NIHSS评分均低于同组治疗前一时间点(P<0.01),而2组治疗后一时间点的BI评分均高于同组治疗前一时间点水平(P<0.01)。治疗6周和12周,研究组的NIHSS评分均低于对照组(P<0.01),而BI评分均高于对照组(P<0.01)。结论:丹参川芎嗪注射液联合西药治疗可以有效减轻急性缺血性脑卒中患者的血管炎症反应程度、血管内皮细胞和脑组织的损伤程度,促进大脑神经细胞修复,提高患者卒中后的生活能力,防止卒中后肢体发生功能障碍,改善患者预后。     

Severe periodontitis is associated with the serum levels of hypersensitive C reactive protein and lipoprotein-associated phospholipase A2 in the patients of acute ischemic stroke

BackgroundPeriodontitis is associated with the pathogenesis of atherosclerotic plaque, and hypersensitive C reactive protein (hs-CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) are the serum biomarkers of the stability of atherosclerotic plaque. Whether periodontitis is associated with the serum level of hs-CRP and Lp-PLA2 of acute ischemic stroke remains unclear.Material and MethodsWe recruited 103 cases with acute ischemic stroke within 7 days after stroke onset. Pocket depth and clinical attachment loss were assessed by oral examination to define the severe periodontitis. Demographic information including gender, age and body weight index, income level, education level, past medical history include smoking history, drinking history, ischemic stroke history, coronary heart disease, hypertension, diabetes and hyperlipidemia were collected, and serum biomarkers including white blood cell (WBC), fibrinogen, total cholesterol (TC), triglyceride (TG), lower density lipoprotein (LDL-C), high density lipoprotein (HDL-C), hs-CRP, HemoglobinA1c (HbAlc), Homocysteine (HCY) and Lp-PLA2 were tested.Results65 (63.1%) cases were diagnosed as severe periodontitis. Severe periodontitis group showed more male, age, drinking history, higher levels of hs-CRP and Lp-PLA2. Multivariate logistic regression showed that severe periodontitis was were significantly associated with hs-CRP (OR = 2.367, 95%CI: 1.182–4.738; P = .015) and Lp-PLA2 (OR = 2.577, 95% CI: 1.010–6.574; P = .048).ConclusionsSevere periodontitis is independently associated with the serum Level of hs-CRP and Lp-PLA2 in patients with acute ischemic stroke. Whether the improvement of periodontitis could decrease the occurrence and re-occurrence of ischemic stroke by stablizating atherosclerotic plaque need be further studied in future.     

Clinical Outcomes at 1 Year Following Transcatheter Left Atrial Appendage Occlusion in the United States

ObjectivesThe aim of this study was to report 1-year clinical outcomes following commercial transcatheter left atrial appendage occlusion (LAAO) in the United States.BackgroundThe National Cardiovascular Data Registry LAAO Registry was initiated to meet a condition of Medicare coverage and allow the assessment of clinical outcomes. The 1-year rates of thromboembolic events after transcatheter LAAO in such a large cohort of “real-world” patients have not been previously reported.MethodsPatients entered into the National Cardiovascular Data Registry LAAO Registry for a Watchman procedure between January 1, 2016, and December 31, 2018, were included. The primary endpoint was ischemic stroke. Key secondary endpoints included the rate of ischemic stroke or systemic embolism, mortality, and major bleeding. Major bleeding was defined as any bleeding requiring hospitalization, and/or causing a decrease in hemoglobin level > 2g/dL, and/or requiring blood transfusion that was not hemorrhagic stroke. The Kaplan-Meier method was used for 1-year estimates of cumulative event rates.ResultsThe study population consisted of 36,681 patients. The mean age was 76.0 ± 8.1 years, the mean CHA₂DS₂-VASc score was 4.8 ± 1.5, and the mean HAS-BLED score was 3.0 ± 1.1. Prior stroke was present in 25.5%, clinically relevant bleeding in 69.5%, and intracranial bleeding in 11.9%. Median follow-up was 374 days (IQR: 212-425 days). The Kaplan-Meier–estimated 1-year rate of ischemic stroke was 1.53% (95% CI: 1.39%-1.69%), the rate of ischemic stroke or systemic embolism was 2.19% (95% CI: 2.01%-2.38%), and the rate of mortality was 8.52% (95% CI: 8.19%-8.87%). The 1-year estimated rate of major bleeding was 6.93% (95% CI: 6.65%-7.21%). Most bleeding events occurred between discharge and 45 days following the procedure.ConclusionsThis study characterizes important outcomes in a national cohort of patients undergoing transcatheter LAAO in the United States. Clinicians and patients can integrate these data in shared decision making when considering this therapy.     

Outcomes of coronary artery bypass grafting in patients with heart failure with a midrange ejection fraction

BackgroundCoronary artery bypass grafting (CABG) improves survival in patients with heart failure and severely reduced left ventricular systolic function (LVEF). Limited data exist regarding adverse cardiovascular event rates after CABG in patients with heart failure with midrange ejection fraction (HFmrEF; LVEF > 40% and < 55%).MethodsWe analyzed data on isolated CABG patients from the Veterans Affairs national database (2010-2019). We stratified patients into control (normal LVEF and no heart failure), HFmrEF, and heart failure with reduced LVEF (HFrEF) groups. We compared all-cause mortality and heart failure hospitalization rates between groups with a Cox model and recurrent events analysis, respectively.ResultsIn 6533 veterans, HFmrEF and HFrEF was present in 1715 (26.3%) and 566 (8.6%) respectively; the control group had 4252 (65.1%) patients. HFrEF patients were more likely to have diabetes mellitus (59%), insulin therapy (36%), and previous myocardial infarction (31%). Anemia was more prevalent in patients with HFrEF (49%) as was a lower serum albumin (mean, 3.6 mg/dL). Compared with the control group, a higher risk of death was observed in the HFmrEF (hazard ratio [HR], 1.3 [1.2-1.5)] and HFrEF (HR, 1.5 [1.2-1.7]) groups. HFmrEF patients had the higher risk of myocardial infarction (subdistribution HR, 1.2 [1-1.6]; P = .04). Risk of heart failure hospitalization was higher in patients with HFmrEF (HR, 4.1 [3.5-4.7]) and patients with HFrEF (HR, 7.2 [6.2-8.5]).ConclusionsHeart failure with midrange ejection fraction negatively affects survival after CABG. These patients also experience higher rates myocardial infarction and heart failure hospitalization.     

乌司他丁与连续性血液净化联合治疗热射病的效果及对机体炎性反应影响研究

目的 分析乌司他丁与连续性血液净化联用对热射病患者所产生的影响。方法 选取2017年5月—2019年2月在海南医学院第二附属医院进行治疗的88例热射病患者作为研究对象,将其分为研究组和常规组,常规组患者接受常规治疗,研究组患者在常规治疗基础上,将乌司他丁与连续性血液净化联用。分析两种治疗措施的效果。结果 治疗前两组患者的IL-17、TNF-α、cTnⅠ、β₂-MG、PT、D-D、ET和TM水平,差异无统计学意义（P>0.05）。经治疗两组患者的上述指标水平都表现出下降的趋势,相对于常规组,研究组患者下降水平更明显,差异具有统计学意义（P<0.05）。研究组治疗的总有效率为95.5%,高于常规组的72.7%,差异具有统计学意义（P<0.05）。结论 运用乌司他丁与连续性血液净化联用的疗法对热射病患者进行治疗,可获得十分理想的治疗效果,可在临床工作中推广。     

基于调控肠道菌群探讨中药防治脑卒中

肠道菌群是一个独特的生态系统,被称为人体"被遗忘的器官",被誉为人类的"第二基因组"。肠道菌群失调与许多中枢神经系统疾病相关,例如帕金森病、阿尔茨海默症、精神分裂症及多发性硬化等。脑卒中具有高的发病率、复发率、死亡率和致残率的特点。肠道菌群在脑卒中的发生、发展中起着关键的作用,可通过影响机体的吸收、代谢、血压、血糖、血脂及动脉粥样斑块等因素,进一步影响脑卒中的发病。中医认为脾胃气血流注失度、阴阳盛衰失衡,机体生理功能失调,化生"风、火、痰、虚、瘀"等病理产物,可致中风的发生。脾胃主腐熟运化水谷,肠道菌群影响饮食的消化吸收,现代研究的肠道菌群功能与中医之脾胃功能失调相关。因此,调整肠道菌群的稳态,可作为一个潜在的干预靶点预防和治疗缺血性脑卒中。中药干预脑卒中已经取得了很好的疗效,是否与调节肠道菌群有关,值得未来做进一步的研究。同时对中药有效成分(小檗碱、黄芩苷、白藜芦醇等),中药单方(丹参、红景天等)和中药组方(补阳还五汤、脑心通胶囊、补中益气汤等)防治脑缺血的研究进展进行综述,为缺血性脑卒中的预防和开发提供新的途径和思路。