Methods Myocardial Infarction Research Articles

Naoxintong inhibits myocardial infarction injury by VEGF/eNOS signaling-mediated neovascularization

Ethnopharmacological relevanceNaoxintong capsules (NXT), a traditional Chinese Medical preparation, are widely used for treatment of cardiovascular diseases, while the mechanism is still unclear. Materials and methodsMyocardial infarction (MI) was induced by ligation of the left coronary artery in mice. Echocardiographic measurements were performed to do physiological assessments of left ventricle (LV) function. Histological and immunohistochemical staining was used to determine infarct size, capillary density, tissue endothelial nitric oxide synthase (eNOS) expression. Bone Marrow Transplantation (BMT) model and flow cytometric (FCM) analyses were applied to assay endothelial progenitor cells (EPCs) mobilization. Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (qRT-PCR), Western blotting and enzyme-linked immunosorbent assay (ELISA) were performed to detect the expressions of vascular endothelial growth factor (VEGF), kinase domain region (KDR), phosphorylated-Akt (p-Akt), phosphorylated-eNOS (p-eNOS). ResultsNXT administration reduced myocardium fibrosis and increased myocardium capillary density in response to MI. NXT increased circulating Sca1+/ Fetal liver kinase 1 (Flk1)+ mononuclear cells (MNCs) and soluble Kit ligand (sKitL) of bone marrow (BM) in response to MI. In mice transplanted with green fluorescent protein (GFP) BM cells, NXT increased the numbers of GFP-positive cells at the border zone of the ischemic region in MI-induced mice. NXT increased the numbers of eNOS-expressing BM-derived cells in tissues, which was involved in increased the expressions of VEGF, KDR, p-eNOS, p-Akt in the myocardium. ConclusionNXT-mediated recovery in MI-induced mice was involved in mobilization and incorporation of bone marrow–derived EPCs/circulating angiogenic cells (CACs) leading to enhancement of neovascularization via VEGF/eNOS signaling.

206 The transplantation of sca-1+/pw1+/pax7- skeletal muscle-derived interstitial progenitor cells (pics) improves cardiac function in mice subjected to myocardial infarction

IntroductionStem cell-based regenerative therapies are fast becoming an attractive and highly promising treatment for heart disease and failure. Sca-1+/PW1+/Pax7-skeletal muscle-derived interstitial progenitor cells (PICs) regenerate adult skeletal and smooth muscle....

Luhong formula inhibits myocardial fibrosis in a paracrine manner by activating the gp130/JAK2/STAT3 pathway in cardiomyocytes

Ethnopharmacological relevanceLuhong formula (LHF)—a traditional Chinese medicine containing Cervus nippon Temminck, Carthamus tinctorius L., Cinnamomum cassia Presl, Codonopisis pilosula( Franch.) Nannf., Astragalus membranaceus ( Fisch.) Bge. var. mongholicus ( Bge.) Hsiao, Lepidium apetalum Willd—is used in the treatment of heart failure. Aim of the studyTo investigate the antifibrotic efficacy of LHF in a myocardial infarction-induced rat model of heart failure and to determine its mechanism of action. Material and methodsMyocardial infarction was induced in rats by coronary artery ligation, and cardiac fibroblasts were isolated. Neonatal rat cardiomyocytes (NRCMs) were isolated from 2 to 3-day-old Sprague-Dawley male rats, and cardiomyocyte hypertrophy was induced by isoprenaline. Histological examination was carried out to estimate the degree of myocardial fibrosis. Expression of gp130/JAK2/STAT3 pathway proteins was measured by western blot. The mRNA levels of downstream genes of gp130/JAK2/STAT3 pathway (i.e., CTGF, TSP-1, and TIMP1) were determined by RT-PCR; while CTGF, TSP-1, and TIMP1 protein levels were measured by ELISA. To investigate paracrine effects, cell proliferation and collagen synthesis was measured after treating cardiac fibroblasts with the conditioned media from isoprenaline-treated NRCMs. ResultsHistopathological changes showed that LHF inhibited myocardial fibrosis in heart failure rats. Treatment with LHF up-regulated gp130, JAK2, and STAT3 protein expression in heart tissue, and down-regulated CTGF, TSP-1, and TIMP1 gene expression. Isoprenaline-treated NRCMs displayed lower expression of the gp130, JAK2, and STAT3 pathway proteins and higher secretion of its downstream signaling molecules (CTGF, TSP-1, TIMP1). LHF inhibited cardiac fibroblast proliferation and collagen synthesis after treatment with the conditioned media from isoprenaline-treated NRCMs. ConclusionLHF treatment attenuates myocardial fibrosis in vivo. LHF inhibits cardiac fibroblasts proliferation and collagen synthesis in a paracrine manner by activating the gp130/JAK2/STAT3 pathway in cardiomyocytes, thereby inhibiting the secretion of downstream profibrogenic cytokines.

Bilateral sympathectomy improves postinfarction left ventricular remodeling and function

ObjectivesTo evaluate the influence of bilateral or left sympathectomy on left ventricular remodeling and function after myocardial infarction in rats. MethodsMyocardial infarction was induced in rats by ligation of the left anterior descending coronary. Seven days later, rats were divided into 4 groups: the myocardial infarction, myocardial infarction with left sympathectomy, myocardial infarction with bilateral sympathectomy, and sham groups. After 8 weeks, left ventricular function was evaluated with the use of a pressure-volume conductance catheter under steady-state conditions and pharmacological stress. Infarct size and extracellular matrix fibrosis were evaluated, and cardiac matrix metalloproteinases and myocardial inflammatory markers were analyzed. ResultsThe myocardial infarction and left sympathectomy group had an increased end diastolic volume, whereas the bilateral sympathectomy group had a mean end-diastolic volume similar to that of the sham group (P < .002). Significant reduction in ejection fraction was observed in the myocardial infarction and left sympathectomy group, whereas it was preserved after bilateral sympathectomy (P < .001). In response to dobutamine, left ventricular contractility increased in sham rats, rising stroke work, cardiac output, systolic volume, end-diastolic volume, ejection fraction, and dP/dt max. Only bilateral sympathectomy rats had significant increases in ejection fraction (P < .001) with dobutamine. Fibrotic tissue and matrix metalloproteinase expression decreased in the bilateral sympathectomy group compared to that in the myocardial infarction group (P < .001) and was associated with left ventricular wall thickness maintenance and better apoptotic markers in noninfarcted myocardium. ConclusionsBilateral sympathectomy effectively attenuated left ventricular remodeling and preserved systolic function after myocardial infarction induction in rats.

Cardiac stem cells transplantation enhances the expression of connexin 43 via the ANG II/AT1R/TGF-beta1 signaling pathway in a rat model of myocardial infarction

BackgroundIn this study, we hypothesized that CSCs mediated the expression of Cx43 after transplantation post MI via the ANG II/AT1R/TGF-beta1 signaling pathway. MethodsMyocardial infarction (MI) was induced in twenty male Sprague–Dawley rats. The rats were randomized into two groups and were then received the injection of 5×106 CSCs labeled with PKH26 in phosphate buffer solution (PBS) or equal PBS alone into the infarct anterior ventricular free wall two weeks after MI. Six weeks later, relevant signaling molecules involved were all examined. ResultsIn the CSCs group, an increased expression of Cx43 could be observed in different zones of the left ventricle (P<0.01). There was a significant reduction of the angiotensin II (ANG II) level in plasma and different regions of the left ventricular cardiac tissues (P<0.05; P<0.01). The angiotensin II type I receptor (AT1R) was decreased accompanied with an enhanced expression of angiotensin II type II receptor (AT2R) (P<0.01). Transforming growth factor beta-1(TGF-beta1) was downregulated (P<0.01). The expression of mothers against decapentaplegic homolog (SMAD) proteins including SMAD2 and SMAD3 was attenuated whereas SMAD7 was elevated (P<0.01, P<0.01, P<0.05). In addition, the expression of mitogen-activated protein kinases (MAPKs) including extracellular kinases 1/2 (ERK1/2) and p38 was also found to be reduced (P<0.01). ConclusionCSCs transplantation could enhance the level of Cx43 after MI. They might function through intervening the ANGII/AT1R/TGF-beta1 signaling pathway to regulate the expression of Cx43.

Intracoronary Infusion of Thioflavin-S to Study Microvascular Obstruction in a Model of Myocardial Infarction

Introduction and objectivesMicrovascular obstruction exerts deleterious effects after myocardial infarction. To elucidate the role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction, we performed a preliminary methodological study to accurately define this process in an in vivo model. MethodsMyocardial infarction was induced in swine by means of 90-min of occlusion of the mid left anterior descending coronary artery using angioplasty balloons. Intracoronary infusion of thioflavin-S was applied and compared with traditional intra-aortic or intraventricular instillation. The left anterior descending coronary artery perfused area and microvascular obstruction were quantified in groups with no reperfusion (thioflavin-S administered through the lumen of an inflated over-the-wire balloon) and with 1-min, 1-week, and 1-month reperfusion (thioflavin-S administered from the intracoronary catheter after balloon deflation). ResultsIn comparison with intra-aortic and intraventricular administration, intracoronary infusion of thioflavin-S permitted a much clearer assessment of the left anterior descending coronary artery perfused area and of microvascular obstruction. Ischemia-reperfusion injury exerted a decisive role on the occurrence and dynamics of microvascular obstruction. The no-reperfusion group displayed completely preserved perfusion. With the same duration of coronary occlusion, microvascular obstruction was already detected in the 1-min reperfusion group (14%±7%), peaked in the 1-week reperfusion group (21%±7%), and significantly decreased in the 1-month reperfusion group (4%±3%; P<.001). ConclusionsWe present proof-of-concept evidence on the crucial role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction. The described porcine model using intracoronary injection of thioflavin-S permits accurate characterization of microvascular obstruction after myocardial infarction.

Infusión intracoronaria de tioflavina-S para el estudio de la obstrucción microvascular en un modelo de infarto de miocardio

Introduction and objectivesMicrovascular obstruction exerts deleterious effects after myocardial infarction. To elucidate the role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction, we performed a preliminary methodological study to accurately define this process in an in vivo model. MethodsMyocardial infarction was induced in swine by means of 90-min of occlusion of the mid left anterior descending coronary artery using angioplasty balloons. Intracoronary infusion of thioflavin-S was applied and compared with traditional intra-aortic or intraventricular instillation. The left anterior descending coronary artery perfused area and microvascular obstruction were quantified in groups with no reperfusion (thioflavin-S administered through the lumen of an inflated over-the-wire balloon) and with 1-min, 1-week, and 1-month reperfusion (thioflavin-S administered from the intracoronary catheter after balloon deflation). ResultsIn comparison with intra-aortic and intraventricular administration, intracoronary infusion of thioflavin-S permitted a much clearer assessment of the left anterior descending coronary artery perfused area and of microvascular obstruction. Ischemia-reperfusion injury exerted a decisive role on the occurrence and dynamics of microvascular obstruction. The no-reperfusion group displayed completely preserved perfusion. With the same duration of coronary occlusion, microvascular obstruction was already detected in the 1-min reperfusion group (14%±7%), peaked in the 1-week reperfusion group (21%±7%), and significantly decreased in the 1-month reperfusion group (4%±3%; P<.001). ConclusionsWe present proof-of-concept evidence on the crucial role of ischemia-reperfusion injury on the occurrence and dynamics of microvascular obstruction. The described porcine model using intracoronary injection of thioflavin-S permits accurate characterization of microvascular obstruction after myocardial infarction.Full English text available from:www.revespcardiol.org/en

Cardioprotective potential of hydro-alcoholic fruit extract of Ananas comosus against isoproterenol induced myocardial infraction in Wistar Albino rats.

ObjectivesTo evaluate the cardioprotective effects of hydro alcoholic extract of Ananas comosus (A. comosus) (HEAC), on Isoproterenol (ISO) induced myocardial infarction in Albino Wistar rats. MethodsMyocardial infarction was induced by Isoproterenol (85 mg/kg, s.c.) for two consecutive days at an interval of 24 h. Rats were pretreated with HEAC (200–400 mg/kg/day, oral) for a period of 30 days and Isoproterenol (ISO) was injected on 31st and 32nd day and after 24 h blood was collected through retro-orbital plexus for the estimation of biochemical parameters and histopathological studies were also performed. ResultsIn the present study, ISO administration significantly elevated the cholesterol, low density lipoprotein, very low density lipoprotein, triglycerides, alanine aminotransferase and aspartate aminotransferase levels while it decreases high density lipoprotein and total protein in plasma and administration of HEAC decreases the level of cholesterol, low density lipoprotein, very low density lipoprotein, triglycerides, alanine aminotransferase and aspartate aminotransferase levels while it increases high density lipoprotein and total protein levels. Pretreatment with the HEAC protected the cardiotoxicity induced by Isoproterenol. The histopathological findings of the ISO-induced myocardium showed infracted zone with inflammatory cells, lipid droplets, myocardial necrosis and vacuolization of myofibrils which were reduced by the pretreatment of HEAC. ConclusionIt can be concluded that HEAC possess cardioprotective activity against Isoproterenol induced myocardial infarction in rats.

A preliminary experimental study on the cardiac toxicity of glutamate and the role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor in rats

Background Monosodium L-glutamate (MSG) is a food flavour enhancer and its potential harmfulness to the heart remains controversial. We investigated whether MSG could induce cardiac arrhythmias and apoptosis via the α-amino-3-hydro×y-5-methyl-4-iso×azolepropionic acid (AMPA) receptor. Methods Myocardial infarction (MI) was created by ligating the coronary artery and ventricular arrhythmias were monitored by electrocardiogram in the rat in vivo. Neonatal rat cardiomyocytes were isolated and cultured. Cell viability was estimated by 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay. Calcium mobilization was monitored by confocal microscopy. Cardiomyocyte apoptosis was evaluated by acridine orange staining, flow cytometry, DNA laddering, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Results MSG (i.v.) decreased the heart rate at 0.5 g/kg and serious bradycardia at 1.5 g/kg, but could not induce ventricular tachyarrhythmias in normal rats in vivo. In rats with acute MI in vivo, however, MSG (1.5 g/kg, i.v.) induced ventricular tachyarrhythmias and these arrhythmias could be prevented by blocking the AMPA and N-methyl-d-aspartate (NMDA) receptors. Selectively activating the AMPA or NMDA receptor induced ventricular tachyarrhythmias in MI rats. At the cellular level, AMPA induced calcium mobilization, oxidative stress, mitochondrial dysfunction and apoptosis in cultured cardiomyocytes, especially when the AMPA receptor desensitization were blocked by cyclothiazide. The above toxic cellular effects of AMPA were abolished by AMPA receptor blockade or by H2O2 scavengers. Conclusions MSG induces bradycardia in normal rats, but triggers lethal tachyarrhythmias in myocardial infarcted rats probably by hindering AMPA receptors. AMPA receptor overstimulation also induces cardiomyocyte apoptosis, which may facilitate arrhythmia.

The functional effect of soybean extract and isolated isoflavone on myocardial infarction and ventricular dysfunction: The soybean extract on myocardial infarction

BackgroundMyocardial infarction is a public health problem. Functional food is an alternative treatment for cardiovascular diseases. ObjectiveThe objective was to analyze the functional and anatomopathological post-myocardial-infarction effects of soybean extract (SE) and isoflavone (IF). MethodsMyocardial infarction was induced in adult Wistar rats. After 5 days, an echocardiogram was performed to determine heart rate (HR), ejection fraction (EF), systolic volume (LVESV) and diastolic volume (LVEDV). Animals with ventricular dysfunction (EF<45%) were selected for study. The animals were divided into three groups: control (n=14), SE (n=15) and IF (n=12). The IF group received 120 mg/kg/day isolated IF, and the SE group received 12.52 g/day. After 30 days, a new echocardiogram was performed. A histological exam was carried out to determine the collagen. Activity of biochemical markers [arginase, lactate dehydrogenase (LDH) and malate dehydrogenase] was measured. ResultsThe animals of the control, IF and SE groups showed a reduction in EF after the infarction (P=.432, P=.017 and P=.320, respectively). An increase of LVESV and LVEDV was observed in all groups (P=.009, P=.001 and P=.140; and P=.003, P=.008 and P=.205, respectively). A reduction of HR was found in the SE group (P=.020). There was a greater activity of LDH in the SE group. A smaller quantity of mature collagen was found in the region proximal to the myocardial infarction in the SE group. ConclusionA protective effect in the SE group was observed 30 days after the myocardial infarction.

Erythropoietin improves the efficiency of endothelial progenitor cell therapy after myocardial infarction in mice: Effects on transplanted cell survival and autologous endothelial progenitor cell mobilization

BackgroundEndothelial progenitor cells (EPCs) participate in vascular repair and angiogenesis. Thus, EPC transplantation into ischemic myocardium might improve cardiac function; however, the vast majority of cells die within a short period. The present study was designed to investigate whether exogenous erythropoietin (EPO) delivery could improve the survival of transplanted EPCs and enhance the efficiency of EPC-based cell therapy. MethodsMyocardial infarction was induced in wild-type mice by ligating the left anterior descending coronary artery. Enhanced green fluorescent protein-EPCs with or without EPO were transplanted into peri-infarct myocardium. Enhanced green fluorescent protein-EPCs were detected 7 and 28 d after surgery. The amount of circulating EPCs was analyzed 3 and 28 d after surgery. The stromal cell-derived factor-1α and vascular endothelial growth factor concentrations, microvessel density, apoptosis, fibrosis in the peri-infarct myocardium, and cardiac function were compared among the groups. ResultsMore enhanced green fluorescent protein-EPCs were found in the hearts treated with EPC + EPO than in those treated with EPC alone. The circulating EPC level was markedly elevated after EPC + EPO treatment compared with EPC application alone. Stromal cell-derived factor-1α and vascular endothelial growth factor were increased accordingly, along with increased microvessel density, decreased apoptosis, and reduced fibrosis in the peri-infarct myocardium. Left ventricular fractional shortening was greater and the interventricular septum was thicker after EPC + EPO treatment compared with EPC treatment alone. ConclusionsEPO improved the efficiency of EPC therapy in mice with myocardial infarction. This effect was associated with enhanced transplanted EPC survival and autologous EPC mobilization.

Tomato lycopene attenuates myocardial infarction induced by isoproterenol: Electrocardiographic, biochemical and anti–apoptotic study

ObjectiveTo assess the protective effects of lycopene on electrocardiographic, hemodynamic, biochemical and apoptotic changes in isoproterenol induced myocardial infarction. MethodsMyocardial infarction was induced in rats by subcutaneous injection of isoproterenol (200 mg/kg) for two consecutive days at an interval of 24 h. Rats were treated with lycopene (10 mg/kg/day,p.o.) for a period of 30 days and isoproterenol (ISO) was injected on the 29th and 30th day. At the end of experiment i.e. on the 31st day electrocardiographic, hemodynamic, biochemical and apoptotic changes were monitored from control and experimental groups. ResultsISO injected rats showed a significant alteration in electrocardiograph pattern and hemodynamic changes (i.e. systolic, diastolic and mean arterial pressure). It also showed significant increase in C-reactive protein, myeloperoxidase, nitrite levels and Caspase-3 protease activity. In addition, it also exhibited alteration in the levels of electrolytes (Na+, K+ and Ca2+), vitamin E, uric acid and serum protein. Gel electrophoresis of ISO injected rats showed increase in DNA fragmentation. Triphenyl tetrazolium chloride staining of the heart section shows increase area of infarction in ISO injected rats. Pre-co-treatment with lycopene significantly prevented the ISO induced alteration in ECG, haemodynamic, biochemical and apoptotic changes. ConclusionsThe present result shows that treatment of lycopene in ISO injected rats significantly attenuates induced myocardial infarction.

Coptisine exert cardioprotective effect through anti-oxidative and inhibition of RhoA/Rho kinase pathway on isoproterenol-induced myocardial infarction in rats

ObjectiveBecause myocardial infarction is a major cause of morbidity and mortality worldwide, protecting the heart from the ischemia is the focus of intense research. Coptisine is an isoquinoline alkaloid extracted form Coptidis Rhizoma. This study aims to elucidate if coptisine is responsible for cardioprotection using myocardial infarction (MI) rat models and investigate its potential mechanism of action. MethodsMyocardial infarction was produced in rats with 85mgkg−1 isoproterenol administered subcutaneously twice at an interval of 24h. The rats were randomized into 7 groups: (I) Normal; (II) ISO; (III) ISO+fasudil; (IV) ISO+isosorbide dinitrate (ISDN) and (V–VII) ISO+coptisine (25, 50 and 100mgkg−1). Cardiac function and markers of cardiac ischemic were assessed after MI. ResultsRats pretreated with coptisine (25, 50 and 100mgkg−1) for 21 days and received subcutaneously injected with ISO (85mgkg−1) on the 20th and 21st day at an interval of 24h. The results suggested that coptisine has strong antioxidant activity, and it can maintain cell membrane integrity, ameliorate mitochondrial respiratory dysfunction, reduce myocardial cells apoptosis, inhibit RhoA/ROCK expression induced by high-dose isoproterenol administration. ConclusionsCoptisine provided cardioprotection in a model of myocardial infarction, and therefore should be considered as a novel adjunctive therapy for attenuating myocardial damage.

Post-infarction scar coverage using a pericardial-derived vascular adipose flap. Pre-clinical results

BackgroundMyocardial salvage after coverage with a fat flap was recently demonstrated in acute coronary occlusion. The effect of this novel therapeutic strategy on a chronic myocardial scar is unknown. MethodsMyocardial infarction (MI) was induced by coil deployment in the mid circumflex artery in the swine model. Two weeks after infarction, a pericardial-derived adipose flap was transposed, fully covering the scar, in the treated group. Infarct size and histopathology were analyzed on post mortem sections. To assess cell migration, adenoviral eGFP vectors were injected in the adipose flap and expression was evaluated upon sacrifice both at the flap and myocardium. Magnetic resonance imaging (MRI) was used to measure left ventricular (LV) ejection fraction and ventricular volumes at baseline, 2weeks post-MI, and at 6weeks. ResultsOne month after flap transposition, histopathology confirmed a 34% reduction in infarct size (8.7% vs. 5.7%; P=0.04) and the presence of vascular connections at the flap-myocardium interface. High eGFP expression was detected at the infarct core both at the gene and protein level (negligible signal was detected at the flap on sacrifice). At the functional level, changes in LV ejection fraction and volumes (end-systolic and end-diastolic) were not significantly different between groups (all P values>0.1). ConclusionsOur data support the use of post-infarction scar coverage with a pericardial-derived fat flap to reduce infarct size, due partly to neovascular connections and cell trafficking at the flap-myocardium interface. Further studies are needed to validate the functional and clinical relevance of this intervention.

Controlled Reperfusion with Intravenous Bivalirudin and Intracoronary Abciximab Combination Therapy in the Porcine Myocardial Infarction Model

IntroductionThe reperfusion injury (RI) remains a significant limitation of primary PCI, therefore we evaluated the role of intracoronary abciximab and bivalirudin for anticoagulation on myocardial salvage and RI in the porcine model of ischemia/reperfusion. Materials and MethodsMyocardial infarction was induced in 23 pigs by 60-minute over-the-wire (OTW) balloon occlusion of the LAD. Animals received intravenous bivalirudin and then five minutes prior to reperfusion, either a coronary downstream infusion of abciximab (n=11) or saline (n=12) through the central lumen of an OTW catheter. All animals were followed for 48 hours. ResultsHistological analysis showed that infarct area (IA) and area at risk (AAR) were comparable between groups (IA/AAR%: 57.6±8% vs. 57.1±7%, p=0.8). Confirming this trend, biochemical markers (troponin I, TNF-alpha, IL-6, hsCRP, adiponectin, and VCAM) and left ventricular ejection fraction were also similar at 48 hours. Adhesion markers like ICAM and P-selectin were significantly decreased in the study group, nevertheless histological evidence of leukocyte extravasation was similar. The enhancement of apoptosis by TUNEL was comparable in both groups. The number of hemorrhagic infarctions confirmed by micro and macroscopic evaluation tended to be higher in the study group (70% vs. 20%, p=0.07). ConclusionsDespite lowered concentrations of adhesion molecules, intracoronary abciximab with peripheral bivalirudin is not superior to bivalirudin unaided in terms of myocardial salvage caused by RI in the porcine ischemia/reperfusion model. This might be due to local hemorrhage caused by abciximab.

Anoxic preconditioning: A way to enhance the cardioprotection of mesenchymal stem cells

Objective We hypothesized that anoxic preconditioning (AP) could enhance the cardioprotective effect of mesenchymal stem cells (MSCs). Methods Myocardial infarction (MI) was set up in Sprague–Dawley rats and left ventricles were randomly injected with the following: DMEM, MSCs and AP-MSCs. Cardiac function was assessed by echocardiography 4 weeks after transplantation, hematoxylin–eosin staining and Masson trichrome were performed subsequently. Results Increased fractional shortening, ejection fraction and decreased infarct size were observed most obviously in AP-MSCs group, accompanied by increased arteriole density and cell survival. Conclusions AP enhanced the capacity of MSCs to repair infarcted myocardium, attributable to increased cell survival and angiogenesis.

17-Beta-Estradiol increases cardiac remodeling and mortality in mice with myocardial infarction

ObjectivesThis study was designed to examine the effects of estrogen replacement on infarct size, ventricular remodeling, and mortality after myocardial infarction (MI) in mice. BackgroundObservational and clinical studies suggest that the cardiovascular effects of hormone replacement therapy can differ depending on the patient population studied. No prospective studies have examined the effect of estrogen on outcomes following MI. We now examine the effects of estrogen replacement on infarct size, ventricular remodeling, and mortality after MI in mice. MethodsMyocardial infarction was induced by left coronary artery ligation in ovariectomized female mice treated with 17-beta-estradiol (E2) or placebo. At either one day or six weeks after MI, hemodynamic function was assessed, animals were euthanized, and infarct size was determined. Results17-Beta-estradiol–treated mice had smaller infarcts than placebo-treated animals both one day (18% decrease; p < 0.01), and six weeks (14% decrease; p < 0.05) following MI. E2 reduced cardiomyocyte apoptosis as assessed by the terminal deoxynucleotidyl transferase uridine nucleotide end-labeling method (50% reduction, p < 0.05) and caspase 3 activation (33% reduction, p < 0.05). Despite having smaller infarcts, however, left ventricular mass increased more in the E2-treated animals (16% greater; p < 0.01). Left ventricular weight was positively correlated with infarct size in the estrogen-treated animals (R2 = 0.79, p = 0.0001). 17-Beta-estradiol treatment also significantly increased mortality in the infarcted animals (relative risk of death = 2.4; 95% confidence interval 1.2 to 5.3). ConclusionsEstrogen replacement therapy reduces infarct size and cardiomyocyte apoptosis in mice. However, estrogen increased post-MI ventricular remodeling and mortality. Further studies will be necessary to elucidate the mechanisms underlying the complex effects of estrogen observed in the present study.

Left ventricular support by Catheter-Mountedaxial flow pump reduces infarct size

ObjectivesWe sought to investigate the effect of a catheter-mounted microaxial blood pump (Impella, Aachen, Germany) on myocardial infarct size. BackgroundThe small rotary blood pump Impella provides unloading of the left ventricle and is introducible via the femoral artery. MethodsMyocardial infarction was induced by occlusion of major branches of the left anterior descending coronary artery for 60 min followed by 120 min of reperfusion in 26 sheep. The animals were allocated to four groups: group 1 had no support; group 2 was fully supported with the pump during ischemia and reperfusion; group 3 was supported during reperfusion only; and group 4 was partially supported during reperfusion. Infarct size, hemodynamics, myocardial oxygen consumption, lactate extraction, and myocardial flow were analyzed. ResultsInfarct size was significantly reduced in the pump-supported animals (percent area at risk in group 1: 67.2 ± 4.6%; group 2: 18.1 ± 10%; group 3: 41.6 ± 5.8%; group 4: 54 ± 8%; p = 0.00001). The pump produced 4.1 ± 0.1 l/min at full support and 2.4 ± 0.1 l/min at partial support. The pump significantly increased the diastolic and mean blood pressures (groups 2, 3, and 4) and significantly decreased the left ventricular end-diastolic pressure (groups 2 and 3). During ischemia, myocardial flow was not influenced by pump support. At reperfusion, the fully supported group had significantly higher myocardial flow. Pump support reduced myocardial oxygen consumption significantly, and this reduction correlates strongly with the reduction in infarct size (r = 0.9). ConclusionsSupport by a microaxial blood pump reduces myocardial oxygen consumption during ischemia and reperfusion and leads to a reduction of infarct size. This reduction in infarct size correlates with the degree of unloading during reperfusion.

Comparison of the effects of an angiotensin-converting enzyme inhibitor and a vasopeptidase inhibitor after myocardial infarction in the rat

ObjectivesThe goal of this study was to compare the effects of the vasopeptidase inhibitor omapatrilat and the angiotensin-converting enzyme inhibitor (ACEI) captopril in the postmyocardial infarction (MI) rat model. BackgroundThe cardioprotective effects of ACEIs after MI are thought to be partially due to an increase in bradykinin (BK). Vasopeptidase inhibitors inhibit both ACE and neutral endopeptidase (NEP), further reduce BK metabolism and increase natriuretic peptides, which may result in better cardioprotective effects than with ACEIs after MI. MethodsMyocardial infarction was induced in 514 Wistar male rats by ligation of the anterior coronary artery. Rats surviving 4 h after MI (n = 282) were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, neurohumoral, hemodynamic, ventricular remodeling, morphometry, immunohistochemistry and cardiac cytokine expression were measured. ResultsOmapatrilat and captopril resulted in similarly improved survival, cardiac hemodynamics and reduced cardiac fibrosis and hypertrophy after MI. The pattern of left ventricular (LV) remodeling differed, omapatrilat causing less attenuation of the rightward shift of the LV pressure-volume relation at lower filling pressures than captopril. Both interventions reduced messenger ribonucleic acid expression of the profibrotic cytokine transforming growth factor-β1; neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Expression of TNF-α was in cardiomyocytes. Both medications reduced circulating endothelin-1, angiotensin II and catecholamines, but only omapatrilat increased atrial natriuretic peptides. ConclusionsThis study indicates that both omapatrilat and captopril markedly improve post-MI survival, cardiac function and cardiac remodeling in the rat. It would appear that the addition of NEP inhibition to those of ACEIs does not result in significant further benefit after MI.