Effects of HELP therapy on acute ischemic stroke and vascular endothelial cell function.
ABSTRACT To evaluate the therapeutic effects of the HELP system (heparin-induced extracorporeal low-density lipoprotein-apolipoprotein(a)-fibrinogen precipitation) in patients with acute ischemic stroke and probe into its possible mechanism, 10 patients with acute ischemic stroke were included in this study and received the HELP therapy in addition to low molecular weight dextran, salvia miltiorrhiza and aspirin. Matched with gender, age, European Stroke Scale (ESS) and fibrinogen, 20 patients with cerebral infarction treated with low molecular heparin were chosen as controls during the same period. We compared the efficacy and prognosis between the two groups. In order to clarify the effects of HELP treatment on endothelial function, human umbilical vein endothelial cells (HUVEC) were cultured with the serum of pre- and post-HELP therapy and control patients, then endothelial permeability and biomarkers of endothelial dysfunction or activation in the supernatant of incubated HUVEC, such as soluble thrombomodulin (sTM), soluble intracellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1), were tested. Twenty-one days after treatment, ESS scores in the HELP group (70.4 +/- 23.06) were higher than those in control group (60.7 +/- 18.94), but there was no statistical significance (P > 0.05). In the HELP group, total efficacy rate reached 60% with ESS score (6 cases of recovery and efficacy, 4 cases of inefficacy), while it was 40% in control group (8 cases of recovery and efficacy, 12 cases of inefficacy), but unfortunately there was no significant difference between both groups using the chi(2)-test (P > 0.05). Interestingly, with the activities of daily living (ADL) score, the efficacy rate in the HELP group (60%) was markedly higher than that in the control group (20%) (P < 0.05). Furthermore, Pearson correlation analysis showed that the therapeutic window (the time from the patient's onset to receiving the therapy) was correlated to final ADL scores (P = 0.044) and the mean therapeutic window was 14.08 +/- 3.41 h in patients who achieved efficacy criteria. After therapy, no difference was found in hemorheology, fibrinogen, blood lipid, oxidized low-density lipoprotein (oxLDL) or C-reactive protein (CRP) in the control group, while there was a significant decrease in the HELP group immediately after treatment (P < 0.01). But the hospital stay time was similar between the HELP group and the controls (23.11 +/- 10.65 vs. 21.53 +/- 8.73 days; P > 0.05) and 21 days later, the dimension of the largest cross-sectioned infarction area by CT scan did not significantly change for the two groups' of patients (P > 0.05). When cultured with the patient's serum after HELP therapy, the concentration of sTM, sICAM-1, and MCP-1 in the supernatant of cultured HUVEC remained unchanged at 24 h (P > 0.05), while it was remarkably higher when HUVEC was cultured with the serum of the controls and patients before HELP therapy (P < 0.01), except for sTM. The endothelial permeability was also improved after the HELP treatment. With the effects of improving hemorheology, decreasing acute phase reactive proteins such as CRP and fibrinogen, ameliorating endothelial cell function, HELP system may be a novel therapy for acute ischemic stroke.
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ABSTRACT: A delipid extracorporeal lipoprotein filter (DELP) system has been used to treat patients with stroke and has shown favorable prognosis. However, the mechanism for the neuronal functional recovery remains unclear. This study aimed to investigate the neuronal histological assessment, and the levels of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and oxidized low-density lipoprotein (oxLDL) after ischemic stroke following DELP treatment. Hyperlipidemic rabbits underwent middle cerebral artery occlusion. After 30 min, the animals received an extracorporeal apheresis treatment with a DELP filter. Total cholesterol (TC), triglyceride, and low-density lipoprotein (LDL) of the plasma were measured. The levels of CRP, TNF-α, and oxLDL in brain tissue were also measured by enzyme-linked immunosorbent assay. Hematoxylin and eosin staining, cresyl violet staining, neuron-specific enolase (NSE) and glial fibrillary acidic protein immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed. DELP apheresis reduced TC and LDL by >30%. The number of neurons at day 7 (P < 0.01) and the integrated optical density of NSE at day 1 (P < 0.05) and day 7 (P < 0.01) were significantly increased in the DELP group. TUNEL-positive cells were significantly decreased (P < 0.05). Astrocytes were moderately activated, and this activation persisted up to 7 days. Gliosis was not found in the DELP group. After treatment, the level of CRP declined at day 1 (P < 0.05); TNF-α and oxLDL declined at day 7 (P < 0.05). DELP apheresis decreased neuronal apoptosis, reduced inflammatory markers and oxidative stress in cerebral ischemia, and improved neuronal survival.Artificial Organs 07/2011; 35(7):E145-54. · 1.87 Impact Factor
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ABSTRACT: Therapeutic plasmapheresis is a recognized medical procedure in which various techniques are used to separate and remove undesirable or excessively elevated plasma elements from blood. The main purpose of the procedure is to remove the substances responsible for the disease (autoantibodies, circulating immune complexes, lipoproteins and other molecules) from the patient's blood. Low-Density-Lipoproteins-apheresis (LDL_a) is the selective removal of all apolipoprotein-B100-containing lipoproteins: LDL, very low-density lipoprotein, and lipoprotein (a). They are lowered acutely by 65-75%. There is little effect on other plasma lipidic and non-lipidic components. LDL_a was reported to increase resistance of LDL to oxidation, counteract procoagulatory state and relief disturbances of hemorheology associated with atherosclerosis. These effects are likely to be regarded as to be pleiotropic effects. In the sense that they are not necessarily related to the apolipoprotein-B100-containing lipoproteins level in plasma. There is robust evidence that LDL_a can induce the stabilization of atherosclerotic plaques through its lipid-lowering action. However, other effects unrelated to the apolipoprotein-B100-containing lipoproteins extracorporeal removal, such as the decrease of cytokines and adhesion molecules induced by LDL_a were also reported. Altogether these actions are thought to favorably influence regression of florid, nonfibrous atherosclerotic lesions through a blockade of lipid deposition in the vessel wall, plaque stabilization, and ultimately, coronary and extracoronary artery disease progression. This brief review provides some indication on existing evidence of Heparin-induced Extracorporeal Low-density-lipoprotein Precipitation LDL_a effects on plasma mediators of inflammation.Cytokine 10/2011; 56(3):850-4. · 2.87 Impact Factor
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ABSTRACT: Vascular comorbidities are inherently linked to the pathogenesis of central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO). However, the endothelial-mediated pathogenic mechanisms that precede, and therefore modulate, luminal occlusion have not been clarified. The aim of this study was to delineate the pattern of endothelial morphometric alteration in the central retinal artery and vein in patients with vascular comorbidities. Eyes with a previous history of vascular occlusion were not included in this study in order to avoid the confounding effects of post-occlusion endothelial changes. This study also sought to determine if vascular comorbidities had a disparate effect on arterial and venous endothelium in the optic nerve head. Comparisons were made between 13 human eyes from patients with vascular comorbidities and 22 control eyes from patients with no known systemic disease. Novel micro-cannulation techniques developed in our laboratory were used to label the cytoskeleton and nuclei of endothelial cells in the central retinal artery and vein following which images were captured using confocal microscopy. Endothelial and nuclear morphometric parameters were quantified in different laminar regions of the optic nerve head. F-actin stress fibre expression was also quantified. Analysis of covariance was used to determine statistical differences between the two groups. Interestingly, age did not influence endothelial morphometry, nuclear morphometry or f-actin expression in central retinal vessels. There were also no arterial endothelial differences between control and disease groups in any laminar region. Endothelial f-actin stress fibre expression increased significantly in the central retinal vein in patients with vascular comorbidities. The greatest change in these eyes was found to occur at the posterior lamina cribrosa. Increased venous endothelial f-actin stress fibre expression may reflect vascular comorbid disease-induced alterations to hemodynamic properties and coagulation cascades in the central retinal vein. The posterior lamina may be an important site for thrombus formation in CRVO as venous endothelia in this region are most influenced by the presence of vascular comorbidities. The findings of this study suggest that the role of endothelial dysfunction in CRVO and CRAO pathogenesis could be different.Experimental Eye Research 03/2013; · 3.02 Impact Factor