Steve Leu

Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day clinical outcomes in patients with ST-segment elevation myocardial infarction complicated with profound cardiogenic shock

Objectives:This study tested the hypothesis that early extracorporeal membrane oxygenator offered additional benefits in improving 30-day outcomes in patients with acute ST-segment elevation myocardial infarction complicated with profound cardiogenic shock undergoing primary percutaneous coronary intervention. Methods:Between May 1993 and July 2002, 920 patients with acute ST-segment elevation myocardial infarction underwent primary percutaneous coronary intervention. Of these patients, 12.5% (115) with cardiogenic shock were enrolled in this study (group 1). Between August 2002 and December 2009, 1650 patients with acute ST-segment elevation myocardial infarction underwent primary percutaneous coronary intervention. Of these patients, 13.3% (219) complicated with cardiogenic shock were enrolled (group 2). Results:The incidence of profound shock (defined as systolic blood pressure remaining ≤75 mm Hg after intra-aortic balloon pump and inotropic agent supports) was similar in both groups (21.7% vs. 21.0%, p > .5). Extracorporeal membrane oxygenator support, which was available only for patients in group 2, was performed in the catheterization room. The results demonstrated that final thrombolysis in myocardial infarction grade 3 flow in infarct-related artery was similar between the two groups (p = .678). However, total 30-day mortality and the mortality of patients with profound shock were lower in group 2 than in group 1 (all p < .04). Additionally, the hospital survival time was remarkably longer in patients in group 2 than in patients in group 1 (p = .0005). Furthermore, multivariate analysis demonstrated that unsuccessful reperfusion, presence of advanced congestive heart failure, profound shock, and age were independent predictors of 30-day mortality (all p < .02). Conclusion:Early extracorporeal membrane oxygenator-assisted primary percutaneous coronary intervention improved 30-day outcomes in patients with ST-segment elevation myocardial infarction with complicated with profound cardiogenic shock.

Adipose-Derived Mesenchymal Stem Cell Protects Kidneys against Ischemia-Reperfusion Injury through Suppressing Oxidative Stress and Inflammatory Reaction

BackgroundReactive oxygen species are important mediators exerting toxic effects on various organs during ischemia-reperfusion (IR) injury. We hypothesized that adipose-derived mesenchymal stem cells (ADMSCs) protect the kidney against oxidative stress and inflammatory stimuli in rat during renal IR injury.MethodsAdult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus immediate intra-renal administration of 1.0 × 106 autologous ADMSCs, followed by intravenous ADMSCs at 6 h and 24 h after IR). The duration of ischemia was 1 h, followed by 72 hours of reperfusion before the animals were sacrificed.ResultsSerum creatinine and blood urea nitrogen levels and the degree of histological abnormalities were markedly lower in group 3 than in group 2 (all p < 0.03). The mRNA expressions of inflammatory, oxidative stress, and apoptotic biomarkers were lower, whereas the anti-inflammatory, anti-oxidative, and anti-apoptotic biomarkers were higher in group 3 than in group 2 (all p < 0.03). Immunofluorescent staining showed a higher number of CD31+, von Willebrand Factor+, and heme oxygenase (HO)-1+ cells in group 3 than in group 2 (all p < 0.05). Western blot showed notably higher NAD(P)H quinone oxidoreductase 1 and HO-1 activities, two indicators of anti-oxidative capacity, in group 3 than those in group 2 (all p < 0.04). Immunohistochemical staining showed higher glutathione peroxidase and glutathione reductase activities in group 3 than in group 2 (all p < 0.02)ConclusionADMSC therapy minimized kidney damage after IR injury through suppressing oxidative stress and inflammatory response.

Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats

BackgroundThe therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on brain infarction area (BIA) and neurological status in a rat model of acute ischemic stroke (IS) was investigated.MethodsAdult male Sprague-Dawley (SD) rats (n = 30) were divided into IS plus intra-venous 1 mL saline (at 0, 12 and 24 h after IS induction) (control group) and IS plus intra-venous ADMSCs (2.0 × 106) (treated interval as controls) (treatment group) after occlusion of distal left internal carotid artery. The rats were sacrificed and brain tissues were harvested on day 21 after the procedure.ResultsThe results showed that BIA was larger in control group than in treatment group (p < 0.001). The sensorimotor functional test (Corner test) identified a higher frequency of turning movement to left in control group than in treatment group (p < 0.05). mRNA expressions of Bax, caspase 3, interleukin (IL)-18, toll-like receptor-4 and plasminogen activator inhibitor-1 were higher, whereas Bcl-2 and IL-8/Gro were lower in control group than in treatment group (all p < 0.05). Western blot demonstrated a lower CXCR4 and stromal-cell derived factor-1 (SDF-1) in control group than in treatment group (all p < 0.01). Immunohistofluorescent staining showed lower expressions of CXCR4, SDF-1, von Willebran factor and doublecortin, whereas the number of apoptotic nuclei on TUNEL assay was higher in control group than in treatment group (all p < 0.001). Immunohistochemical staining showed that cellular proliferation and number of small vessels were lower but glial fibrillary acid protein was higher in control group than in treatment group (all p < 0.01).ConclusionsADMSC therapy significantly limited BIA and improved sensorimotor dysfunction after acute IS.

Autologous Transplantation of Adipose-Derived Mesenchymal Stem Cells Markedly Reduced Acute Ischemia-Reperfusion Lung Injury in a Rodent Model

BackgroundThis study tested the hypothesis that autologous transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can effectively attenuate acute pulmonary ischemia-reperfusion (IR) injury.MethodsAdult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus intravenous transplantation of 1.5 × 106 autologous ADMSCs at 1h, 6h, and 24h following IR injury). The duration of ischemia was 30 minutes, followed by 72 hours of reperfusion prior to sacrificing the animals. Blood samples were collected and lungs were harvested for analysis.ResultsBlood gas analysis showed that oxygen saturation (%) was remarkably lower, whereas right ventricular systolic pressure was notably higher in group 2 than in group 3 (all p < 0.03). Histological scoring of lung parenchymal damage was notably higher in group 2 than in group 3 (all p < 0.001). Real time-PCR demonstrated remarkably higher expressions of oxidative stress, as well as inflammatory and apoptotic biomarkers in group 2 compared with group 3 (all p < 0.005). Western blot showed that vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, oxidative stress, tumor necrosis factor-α and nuclear factor-κB were remarkably higher, whereas NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 activities were lower in group 2 compared to those in group 3 (all p < 0.004). Immunofluorescent staining demonstrated notably higher number of CD68+ cells, but significantly fewer CD31+ and vWF+ cells in group 2 than in group 3.ConclusionADMSC therapy minimized lung damage after IR injury in a rodent model through suppressing oxidative stress and inflammatory reaction.

Melatonin treatment improves adipose-derived mesenchymal stem cell therapy for acute lung ischemia–reperfusion injury

This study investigated whether melatonin‐treated adipose‐derived mesenchymal stem cells (ADMSC) offered superior protection against acute lung ischemia–reperfusion (IR) injury. Adult male Sprague‐Dawley rats (n = 30) were randomized equally into five groups: sham controls, lung IR–saline, lung IR–melatonin, lung IR–melatonin–normal ADMSC, and lung IR–melatonin–apoptotic ADMSC. Arterial oxygen saturation was lowest in lung IR–saline; lower in lung IR–melatonin than sham controls, lung IR–melatonin–normal ADMSC, and lung IR–melatonin–apoptotic ADMSC; lower in lung IR–melatonin–normal ADMSC than sham controls and lung IR–melatonin–apoptotic ADMSC; lower in lung IR–melatonin–apoptotic ADMSC than sham controls (P < 0.0001 in each case). Right ventricular systolic blood pressure (RVSBP) showed a reversed pattern among all groups (all P < 0.0001). Changes in histological scoring of lung parenchymal damage and CD68+ cells showed a similar pattern compared with RVSBP in all groups (all P < 0.001). Changes in inflammatory protein expressions such as VCAM‐1, ICAM‐1, oxidative stress, TNF‐α, NF‐κB, PDGF, and angiotensin II receptor, and changes in apoptotic protein expressions of cleaved caspase 3 and PARP, and mitochondrial Bax, displayed identical patterns compared with RVSBP in all groups (all P < 0.001). Numbers of antioxidant (GR+, GPx+, NQO‐1+) and endothelial cell biomarkers (CD31+ and vWF+) were lower in sham controls, lung IR–saline, and lung IR–melatonin than lung IR–melatonin–normal ADMSC and lung IR–melatonin–apoptotic ADMSC, and lower in lung IR–melatonin–normal ADMSC than lung IR–melatonin–apoptotic ADMSC (P < 0.001 in each case). In conclusion, when the animals were treated with melatonin, the apoptotic ADMSC were superior to normal ADMSC for protection of lung from acute IR injury.

Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke

IntroductionErythropoietin (EPO) enhances the circulating level of endothelial progenitor cells (EPCs), which has been reported to be associated with prognostic outcome in ischemic stroke (IS) patients. The aim of this study was to evaluate the time course of circulating EPC level and the impact of EPO therapy on EPC level and clinical outcome in patients after acute IS.MethodsIn total, 167 patients were prospectively randomized to receive either EPO therapy (group 1) (5,000 IU each time, subcutaneously) at 48 h and 72 h after acute IS, or serve as placebo (group 2). The circulating level of EPCs (double-stained markers: CD31/CD34 (E1), CD62E/CD34 (E2) and KDR/CD34 (E3)) was determined using flow cytometry at 48 h and on days 7 and 21 after IS. EPC level was also evaluated once in 60 healthy volunteers.ResultsCirculating EPC (E1 to E3) level at 48 h after IS was remarkably higher in patients than in control subjects (P < 0.02). At 48 h and on Day 7 after IS, EPC (E1 to E3) level did not differ between groups 1 and 2 (all P > 0.1). However, by Day 21, EPC (E1 to E3) level was significantly higher in group 1 than in group 2 (all P < 0.03). Additionally, 90-day recurrent stroke rate was notably lower in group 1 compared with group 2 (P = 0.022). Multivariate analysis demonstrated that EPO therapy (95% confidence interval (CI), 0.153 to 0.730; P = 0.006) and EPC (E3) (95% CI, 0.341 to 0.997; P = 0.049) levels were significantly and independently predictive of a reduced 90-day major adverse neurological event (MANE) (defined as recurrent stroke, National Institutes of Health Stroke scale ≥8, or death).ConclusionsEPO therapy significantly improved circulating EPC level and 90-day MANE.Trial registration numberISRCTN: ISRCTN96340690

Systemic administration of autologous adipose-derived mesenchymal stem cells alleviates hepatic ischemia–reperfusion injury in rats

Objectives:Mesenchymal stem cells have previously been shown to offer significant therapeutic benefit in ischemic organ injuries. This study aimed at investigating the therapeutic role of adipose tissue-derived mesenchymal stem cells in hepatic ischemia–reperfusion injury and the underlying mechanisms. Design:Adult male Fisher rats (n = 30) were equally divided into three groups (group 1: Sham-operated normal controls; group 2: Ischemia-reperfusion injury with intravenous fresh culture medium; group 3: Ischemia-reperfusion injury with intravenous adipose tissue-derived mesenchymal stem cells). Ischemia-reperfusion injury was induced by occluding the vascular supplies of left lobe liver for 60 minutes followed by reperfusion for 72 hrs. Adipose tissue-derived mesenchymal stem cells (1.2 × 106) were administered through tail vein immediately after reperfusion and at 6 hrs and 24 hrs after reperfusion in group 3. All animals were sacrificed 72 hrs after reperfusion. Setting:Animal laboratory at a medical institute. Measurements and Main Results:Histologic features, plasma aspartate aminotransferase, hepatic cytokine profile, oxidative stress, and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling were analyzed. Seventy-two hrs after reperfusion, plasma aspartate aminotransferase, hepatic oxidative stress, messenger RNA expressions of tumor necrosis factor-a, transforming growth factor-b, interleukin-1b, interleukin-6, endothelin-1, matrix metalloproteinase-9, plasminogen activator inhibitor-1, Bax and caspase-3, protein expression of intercellular adhesion molecule as well as the number of apoptotic nuclei were significantly increased in group 2 compared with group 3, whereas messenger RNA expressions of endothelial nitric oxide synthase, Bcl-2, interleukin-10, protein expressions of reduced nicotinamide-adenine dinucleotide phosphate:quinone oxidoreductase 1, and heme oxygenase-1 were lower in group 2 than group 3. Conclusions:The results showed that systemic adipose tissue-derived mesenchymal stem cell administration significantly preserved hepatocyte integrity and suppressed inflammatory responses, oxidative stress, and apoptosis in a rodent model of hepatic ischemia–reperfusion injury. (Crit Care Med 2012; 40:–1290)

Melatonin prevents maternal fructose intake-induced programmed hypertension in the offspring: roles of nitric oxide and arachidonic acid metabolites

Fructose intake has increased globally and is linked to hypertension. Melatonin was reported to prevent hypertension development. In this study, we examined whether maternal high fructose (HF) intake causes programmed hypertension and whether melatonin therapy confers protection against the process, with a focus on the link to epigenetic changes in the kidney using next‐generation RNA sequencing (NGS) technology. Pregnant Sprague–Dawley rats received regular chow or chow supplemented with HF (60% diet by weight) alone or with additional 0.01% melatonin in drinking water during the whole period of pregnancy and lactation. Male offspring were assigned to four groups: control, HF, control + melatonin (M), and HF + M. Maternal HF caused increases in blood pressure (BP) in the 12‐wk‐old offspring. Melatonin therapy blunted the HF‐induced programmed hypertension and increased nitric oxide (NO) level in the kidney. The identified differential expressed gene (DEGs) that are related to regulation of BP included Ephx2, Col1a2, Gucy1a3, Npr3, Aqp2, Hba‐a2, and Ptgs1. Of which, melatonin therapy inhibited expression and activity of soluble epoxide hydrolase (SEH, Ephx2 gene encoding protein). In addition, we found genes in arachidonic acid metabolism were potentially involved in the HF‐induced programmed hypertension and were affected by melatonin therapy. Together, our data suggest that the beneficial effects of melatonin are attributed to its ability to increase NO level in the kidney, epigenetic regulation of genes related to BP control, and inhibition of SEH expression. The roles of DEGs by the NGS in long‐term epigenetic changes in the adult offspring kidney require further clarification.

Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice

BackgroundObesity is an important cardiovascular risk factor. This study tested the effect of obesity reduction on preserving left ventricular ejection fraction (LVEF) and attenuating inflammation, oxidative stress and LV remodeling in obese mice.Methods and resultsEight-week-old C57BL/6 J mice (n=24) were equally divided into control (fed a control diet for 22 weeks), obesity (high-fat diet, 22 weeks), and obese reduction (OR) (high-fat diet, 14 weeks; then control diet, 8 weeks). Animals were sacrificed at post 22-week high-fat diet and the LV myocardium collected. Heart weight, body weight, abdominal-fat weight, total cholesterol level and fasting blood glucose were higher in obesity than in control and OR (all p<0.001). Inflammation measured by mRNA expressions of IL-6, MMP-9, PAI-1 and leptin and protein expression of NF-κB was higher, whereas anti-inflammation measured by mRNA expressions of adiponectin and INF-γ was lower in obesity than in control and OR (all p<0.003). Oxidative protein expressions of NOX-1, NOX-2 and oxidized protein were higher, whereas expression of anti-oxidant markers HO-1 and NQO-1 were lower (all p<0.01); and apoptosis measured by Bax and caspase 3 was higher, whereas anti-apoptotic Bcl-2 was lower in obesity as compared with control and OR (all p<0.001). The expressions of fibrotic markers phosphorylated Smad3 and TGF-β were higher, whereas expression of anti-fibrotic phosphorylated Smad1/5 and BMP-2 were lower (all p<0.02); and LVEF was lower, whereas the LV remodeling was higher in obesity than in control and OR (all p<0.001).ConclusionImpaired LVEF, enhanced LV remodeling, inflammation, fibrosis, oxidative stress and apoptosis were reversed by reduction in mouse obesity.

Additional benefit of combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cell against sepsis-induced kidney injury

This study tested whether combined therapy with melatonin and apoptotic adipose‐derived mesenchymal stem cells (A‐ADMSCs) offered additional benefit in ameliorating sepsis‐induced acute kidney injury. Adult male Sprague–Dawley rats (n = 65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal‐ligation and puncture (CLP), CLP‐melatonin, CLP‐A‐ADMSC, and CLP‐melatonin‐A‐ADMSC. Circulating TNF‐α level at post‐CLP 6 hr was highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Immune reactivity as reflected in the number of splenic helper‐, cytoxic‐, and regulatory‐T cells at post‐CLP 72 hr exhibited the same pattern as that of circulating TNF‐α among all groups (P < 0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups, and higher in CLP‐A‐ADMSC than in CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Changes in protein expressions of inflammatory (RANTES, TNF‐1α, NF‐κB, MMP‐9, MIP‐1, IL‐1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF‐β) markers, reactive‐oxygen‐species (NOX‐1, NOX‐2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all P < 0.001). Expressions of antioxidants (GR+, GPx+, HO‐1, NQO‐1+) were lowest in SC group and highest in CLP‐melatonin‐A‐ADMSC group, lower in CLP than in CLP‐melatonin and CLP‐A‐ADMSC groups, and lower in CLP‐melatonin‐ than in CLP‐A‐ADMSC‐tretaed animals (all P < 0.001). In conclusion, combined treatment with melatonin and A‐ADMSC was superior to A‐ADMSC alone in protecting the kidneys from sepsis‐induced injury.