Macrophage membrane camouflaged reactive oxygen species responsive nanomedicine for efficiently inhibiting the vascular intimal hyperplasia

Background Intimal hyperplasia caused by vascular injury is an important pathological process of many vascular diseases, especially occlusive vascular disease. In recent years, Nano-drug delivery system has attracted a wide attention as a novel treatment strategy, but there are still some challenges such as high clearance rate and insufficient targeting. Results In this study, we report a biomimetic ROS-responsive MM@PCM/RAP nanoparticle coated with macrophage membrane. The macrophage membrane with the innate “homing” capacity can superiorly regulate the recruitment of MM@PCM/RAP to inflammatory lesion to enhance target efficacy, and can also disguise MM@PCM/RAP nanoparticle as the autologous cell to avoid clearance by the immune system. In addition, MM@PCM/RAP can effectively improve the solubility of rapamycin and respond to the high concentration level of ROS accumulated in pathological lesion for controlling local cargo release, thereby increasing drug availability and reducing toxic side effects. Conclusions Our findings validate that the rational design, biomimetic nanoparticles MM@PCM/RAP, can effectively inhibit the pathological process of intimal injury with excellent biocompatibility. Graphical Abstract

National trends in cerebral bypass surgery in the United States, 2002–2014

OBJECTIVECerebral bypass procedures are microsurgical techniques to augment or restore cerebral blood flow when treating a number of brain vascular diseases including moyamoya disease, occlusive vascular disease, and cerebral aneurysms. With advances in endovascular therapy and evolving evidence-based guidelines, it has been suggested that cerebral bypass procedures are in a state of decline. Here, the authors characterize the national trends in cerebral bypass surgery in the United States from 2002 to 2014.METHODSUsing the National (Nationwide) Inpatient Sample, the authors extracted for analysis the data on all adult patients who had undergone cerebral bypass as indicated by ICD-9-CM procedure code 34.28. Indications for bypass procedures, patient demographics, healthcare costs, and regional variations are described. Results were stratified by indication for cerebral bypass including moyamoya disease, occlusive vascular disease, and cerebral aneurysms. Predictors of inpatient complications and death were evaluated using multivariable logistic regression analysis.RESULTSFrom 2002 to 2014, there was an increase in the annual number of cerebral bypass surgeries performed in the United States. This increase reflected a growth in the number of cerebral bypass procedures performed for adult moyamoya disease, whereas cases performed for occlusive vascular disease or cerebral aneurysms declined. Inpatient complication rates for cerebral bypass performed for moyamoya disease, vascular occlusive disease, and cerebral aneurysm were 13.2%, 25.1%, and 56.3%, respectively. Rates of iatrogenic stroke ranged from 3.8% to 20.4%, and mortality rates were 0.3%, 1.4%, and 7.8% for moyamoya disease, occlusive vascular disease, and cerebral aneurysms, respectively. Multivariate logistic regression confirmed that cerebral bypass for vascular occlusive disease or cerebral aneurysm is a statistically significant predictor of inpatient complications and death. Mean healthcare costs of cerebral bypass remained unchanged from 2002 to 20014 and varied with treatment indication: moyamoya disease $38,406 ± $483, vascular occlusive disease $46,618 ± $774, and aneurysm $111,753 ± $2381.CONCLUSIONSThe number of cerebral bypass surgeries performed for adult revascularization has increased in the United States from 2002 to 2014. Rising rates of surgical bypass reflect a greater proportion of surgeries performed for moyamoya disease, whereas bypasses performed for vascular occlusive disease and aneurysms are decreasing. Despite evolving indications, cerebral bypass remains an important surgical tool in the modern endovascular era and may be increasing in use. Stagnant complication rates highlight the need for continued interest in advancing available bypass techniques or technologies to improve patient outcomes.

A study on prostaglandin E1 therapy in critical limb ischaemia patients to evaluate the improvement in vascularity

Background: Diffuse peripheral arterial disease or peripheral occlusive vascular disease (POVD) involving the lower limb is a debilitating illness with high incidence of morbidity and mortality. The objective of this study was to assess the improvement of ulcer healing and improvement of the level of amputation in patients with diffuse peripheral arterial disease after administration of prostaglandin E1.Methods: From June 2013 to November 2014, a total of 45 patients having critical limb ischaemia (Fontaine’s grade III and IV) not suitable for angioplasty and stenting or bypass procedures received different courses of Prostaglandin E1 (PGE1). 20 patients (44.44%) received 6 full courses of PGE1, 3 patients (6.66%) received 5 courses, 5 patients (11.11%) received 4 courses, 4 patients (8.8%) received 3 courses, 4 patients (8.8%) received 2 courses and 9 patients (20%) received one course. PGE1 was administered through intravenous infusion (Alprastodil 100mcg) over 10 hours a day for 5 days in one month (1course). They were followed up for 3 years till June 2017.The improvement in level of amputation, ulcer healing and complications were assessed.Results: 14 patients (31.1%) did not require amputation of limbs/ toes, 24 patients (53.3%) have the same amputated status while 7 patients (15.6%) required higher amputation. This study justifies the role of PGE1 therapy in improving the peripheral arterial pulsations and thereby augmenting ulcer healing and improving the level of amputation.Conclusions: After diagnosing a patient with advanced CLI where angioplasty and stenting or bypass procedures are not possible, aggressive treatment for the non-healing ulcer, amputation of gangrenous limbs or toes and starting the PGE1 therapy early not only arrest the progression of POVD but even reverses it to some extent.

Arterial Spin Labeling and Blood Oxygen Level-Dependent MRI Cerebrovascular Reactivity in Cerebrovascular Disease: A Systematic Review and Meta-Analysis

Background: The cerebrovascular reactivity (CVR) results of blood oxygen level-dependent (BOLD) and arterial spin labeling (ASL) MRI studies performed in patients with cerebrovascular disease (steno-occlusive vascular disease or stroke) were systematically reviewed. Summary: Thirty-one articles were included. Twenty-three (74.2%) studies used BOLD MRI to evaluate the CVR, 4 (12.9%) studies used ASL MRI and 4 (12.9%) studies used both BOLD and ASL MRI. Thirteen studies (3 significant) found a lower BOLD CVR, 2 studies found a similar CVR and 3 studies found a higher CVR in the ipsilateral compared to the contralateral hemisphere. Nine (5 significant) out of 10 studies found a lower BOLD CVR in the ipsilateral hemispheres of patients compared to controls. Six studies (2 significant) found a lower ASL CVR in the ipsilateral compared to the contralateral hemispheres. Three out of 5 studies found a significant lower ASL CVR in the ipsilateral hemispheres of patients compared to controls. Key Messages: This review brings support for a reduced BOLD and ASL CVR in the ipsilateral hemisphere of patients with cerebrovascular disease. We suggest that future studies will be performed in a uniform way so reference values can be established and could be used to guide treatment decisions in patients with cerebrovascular disease.

CD44 sensitivity of platelet activation, membrane scrambling and adhesion under high arterial shear rates

SummaryCD44 is required for signalling of macrophage migration inhibitory factor (MIF), an anti-apoptotic pro-inflammatory cytokine. MIF is expressed and released from blood platelets, key players in the orchestration of occlusive vascular disease. Nothing is known about a role of CD44 in the regulation of platelet function. The present study thus explored whether CD44 modifies degranulation (P-selectin exposure), integrin activation, caspase activity, phosphatidylserine exposure on the platelet surface, platelet volume, Orai1 protein abundance and cytosolic Ca2+-activity ([Ca2+]i). Platelets from mice lacking CD44 (cd44-/- ) were compared to platelets from corresponding wild-type mice (cd44+/+ ). In resting platelets, P-selectin abundance, αllbβ3 inte-grin activation, caspase-3 activity and phosphatidylserine exposure were negligible in both genotypes and Orai1 protein abundance, [Ca2+]i, and volume were similar in cd44-/- and cd44+/+ platelets. Platelet degranulation and αllbβ3 integrin activation were significantly increased by thrombin (0.02 U/ml), collagen related peptide (CRP, 2 µg/ml and Ca2+-store depletion with thapsigargin (1 µM), effects more pronounced in cd44-/- than in cd44+/+ platelets. Thrombin (0.02 U/ml) increased platelet [Ca2+]i, caspase-3 activity, phosphatidylserine exposure and Orai1 surface abundance, effects again significantly stronger in cd44-/- than in cd44+/+ platelets. Thrombin further decreased forward scatter in cd44-/- and cd44+/+ platelets, an effect which tended to be again more pronounced in cd44-/- than in cd44+/+ platelets. Platelet adhesion and in vitro thrombus formation under high arterial shear rates (1,700 s-1) were significantly augmented in cd44-/- mice. In conclusion, genetic deficiency of CD44 augments activation, apoptosis and prothrombotic potential of platelets.

Abstract 12334: A Flavor of Metabolic Disease in Pulmonary Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a severe occlusive vascular disease of the lungs. One of the primary origin of PAH is pulmonary endothelial dysfunction driving vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Interestingly, endothelial dysfunction is maintained in culture, out of fluid and hemodynamic stress, humoral/hormonal, and inflammatory environment. Hypothesis: This aberrant phenotype may be imprinted in pulmonary endothelial cells (PEC) DNA though a specific pattern of DNA methylations. Methods: Genomic DNA was extracted from cultured PEC (passage 3): idiopathic PAH (n=11), heritable PAH (BMPR2 mutation carriers, n=10), controls (n=18). DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. We normalized all arrays against each other using functional normalization. Differentially methylated sites were clustered with Cluster3.0 and heatmap were obtained with Treeview. Results: We discriminated controls vs PAH into 2 clusters of hypermethylated loci (119 probes= 31 promoters) and hypomethylated loci (331 probes= 116 promoters). Interestingly, 46 promoters/147 (clusters 1+2) (31%) were related to metabolic diseases (Ingenuity pathway analysis), and top molecules (fold changes up- and down regulated) includes molecules highly involved in cellular lipid metabolic process (ABCA1, Q=0.002 and ABCB4, Q=0.003), regulation of glucogenesis (ACN9, Q=2.78.10-5), lipid and glucose metabolism (ADIPOQ, Q=10-4), and insulin sensitivity and metabolism of glucose and lipids (miR-26a, Q=0.005), among others. Conclusions: the methylation fingerprint of PAH highlighted a set of molecules involved in metabolic disease and metabolism regulation. This may have fundamental and clinical implications in PAH.