Porcine Model Of Acute Myocardial Infarction Research Articles

An open secret in porcine acute myocardial infarction models: The relevance of anaesthetic regime and breed in ischaemic outcomes.

Large animal models of acute myocardial infarction (AMI) play a crucial role in translating novel therapeutic approaches to patients as denoted by their use in the right-before-human testing platform. At present, the porcine model of AMI is used most frequently as it mimics the human condition and its anatomopathological features accurately. We want to describe to, and share with, the translational research community our experience of how different anaesthetic protocols (sevoflurane, midazolam, ketamine+xylazine+midazolam, and propofol) and pig breeds [Large White and Landrace x Large White (LLW)] can dramatically modify the outcomes of a well-established porcine model of closed-chest AMI. Our group has extensive experience with the porcine model of reperfused AMI and, over time, we reduced the time of ischaemia used to induce the disease from 90 to 50 min to increase the salvageable myocardium for cardioprotection studies. For logistical reasons, we changed both the anaesthetic protocol and the pig breed used, but these resulted in a dramatic reduction in the size of the myocardial infarct, to almost zero in some cases (sevoflurane, 50-min ischaemia, LLW, 2.4 ± 3.9% infarct size), and the cardiac function was preserved. Therefore, we had to re-validate the model by returning to 90 min of ischaemia. Here, we report the differences in infarct size and cardiac function, measured by different modalities, for each combination of anaesthetic protocol and pig breed we have used. Furthermore, we discuss these combinations and the limited literature pertaining to how these two factors influence cardiac function and infarct size in the porcine model of AMI.

Intrapericardial Administration of Secretomes from Menstrual Blood-Derived Mesenchymal Stromal Cells: Effects on Immune-Related Genes in a Porcine Model of Myocardial Infarction

Acute myocardial infarction (AMI) is a manifestation of ischemic heart disease where the immune system plays an important role in the re-establishment of homeostasis. We hypothesize that the anti-inflammatory activity of secretomes from menstrual blood-derived mesenchymal stromal cells (S-MenSCs) and IFNγ/TNFα-primed MenSCs (S-MenSCs*) may be considered a therapeutic option for the treatment of AMI. To assess this hypothesis, we have evaluated the effect of S-MenSCs and S-MenSCs* on cardiac function parameters and the involvement of immune-related genes using a porcine model of AMI. Twelve pigs were randomly divided into three biogroups: AMI/Placebo, AMI/S-MenSCs, and AMI/S-MenSCs*. AMI models were generated using a closed chest coronary occlusion-reperfusion procedure and, after 72 h, the different treatments were intrapericardially administered. Cardiac function parameters were monitored by magnetic resonance imaging before and 7 days post-therapy. Transcriptomic analyses in the infarcted tissue identified 571 transcripts associated with the Gene Ontology term Immune response, of which 57 were differentially expressed when different biogroups were compared. Moreover, a prediction of the interactions between differentially expressed genes (DEGs) and miRNAs from secretomes revealed that some DEGs in the infarction area, such as STAT3, IGFR1, or BCL6 could be targeted by previously identified miRNAs in secretomes from MenSCs. In conclusion, the intrapericardial administration of secretome early after infarction has a significant impact on the expression of immune-related genes in the infarcted myocardium. This confirms the immunomodulatory potential of intrapericardially delivered secretomes and opens new therapeutic perspectives in myocardial infarction treatment.

Secretome of Stressed Peripheral Blood Mononuclear Cells Alters Transcriptome Signature in Heart, Liver, and Spleen after an Experimental Acute Myocardial Infarction: An In Silico Analysis.

Simple SummaryAcute myocardial infarction is characterized by impaired coronary blood flow, which leads to cardiac ischemia and, ultimately, compromised heart function. Damage and cellular responses are not limited to the non-perfused area, but rather affect the entire heart, as well as distal organs, such as the liver and spleen. We found that the therapeutic secretome of stressed white blood cells improved short-term and long-term cardiac performance in a porcine infarction model. In order to unravel the molecular events governing secretome-mediated tissue regeneration, we performed transcriptional analyses of the non-perfused, transition, and perfused heart, as well as the liver and spleen 24 h after myocardial infarction. We observed a highly tissue-specific effect of the secretome and, except for the transition zone, a uniform downregulation of pro-inflammatory factors and pathways. Simultaneously, the secretome strongly promoted the expression of genes that are essential for heart function in the non-perfused area. In the liver and spleen, different metabolic processes were induced. Together, our data suggest several plausible mechanisms by which the secretome improves heart function after cardiac ischemia. Deepening our understanding of the molecular processes identified here might uncover further pharmacologic strategies aiming at delimiting adverse cardiac remodeling and sequelae after myocardial infarction.Acute myocardial infarction (AMI) is a result of cardiac non-perfusion and leads to cardiomyocyte necrosis, inflammation, and compromised cardiac performance. Here, we showed that the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCsec) improved heart function in a porcine AMI model and displayed beneficial long- and short-term effects. As an AMI is known to strongly affect gene regulation of the ischemia non-affected heart muscle and distal organs, we employed a transcriptomics approach to further study the immediate molecular events orchestrated using the PBMCsec in myocardium, liver, and spleen 24 h post ischemia. In the infarcted area, the PBMCsec mainly induced genes that were essential for cardiomyocyte function and simultaneously downregulated pro-inflammatory genes. Interestingly, genes associated with pro-inflammatory processes were activated in the transition zone, while being downregulated in the remote zone. In the liver, we observed a pronounced inhibition of immune responses using the PBMCsec, while genes involved in urea and tricarboxylic cycles were induced. The spleen displayed elevated lipid metabolism and reduced immunological processes. Together, our study suggested several types of pharmacodynamics by which the PBMCsec conferred immediate cardioprotection. Furthermore, our data supported the assumption that an AMI significantly affects distal organs, suggesting that a holistic treatment of an AMI, as achieved by PBMCsec, might be highly beneficial.

Coronary circulatory indices in non-infarct related vascular territories in a porcine acute myocardial infarction model

Abstract Background There has been debate on the reliability of fractional flow reserve (FFR) or resting pressure-derived indices in non-IRA of patients with acute ST-segment elevation myocardial infarction. Purpose This study aimed to evaluate temporal changes of coronary hemodynamic and physiologic indices in non-infarct related artery (non-IRA), which might be affected by adjacent infarcted myocardium, using an experimental animal model of acute myocardial infarction (AMI). Methods In Yorkshire swine, acute myocardial infarction was simulated with selective balloon occlusion at left circumflex artery (LCX) as IRA for 30 minutes. Non-IRA stenosis was created using bare metal stent implantation in left anterior descending artery (LAD) 4 weeks before the experiments. Serial changes of systemic hemodynamics, coronary pressure, and Doppler-derived coronary flow velocity were measured in a non-occluded LAD as non-IRA from baseline, balloon occlusion of LCX, and 15 minutes after reperfusion of LCX. Results Among the 6 experimental subjects, the median diameter stenosis of non-IRA was 33.9% (Q1-Q3: 21.7%-46.1%). During balloon occlusion of IRA, there were transient significant changes in both resting and hyperemic aortic pressure (Pa), distal coronary pressure (Pd), averaged peak velocity (APV), trans-stenotic pressure gradient (PG), and microvascular resistance of non-IRA (all P values<0.020). After reperfusion of IRA, the resting APV (P=0.002) and resting trans-stenotic PG (P=0.004) were significantly increased and resting microvascular resistance (P=0.004) was significantly decreased than those in baseline phase. However, the hyperemic APV (P=0.479), hyperemic trans-stenotic PG (P=0.778), and hyperemic microvascular resistance (P=0.816) were not significantly different compared with those in the baseline phase. After reperfusion, the FFR in non-IRA was not significantly different (0.94±0.01 vs. 0.93±0.01, P=0.353), while the CFR (1.93±0.07 vs. 1.36±0.07, P=0.025) and resting Pd/Pa (0.98±0.01 vs. 0.94±0.01, P=0.017) were significantly lower than baseline values. Conclusions In a porcine AMI model, occlusion of IRA induced significant changes of systemic hemodynamics and coronary circulatory indices of non-IRA. However, after reperfusion of IRA, FFR did not change significantly, while resting Summarizing Figure Funding Acknowledgement Type of funding source: Other. Main funding source(s): 1. Philips/Volcano, 2. Bio & Medical Technology Development Program of the National Research Foundation of the Korean government

Intracoronary Administration of Allogeneic Cardiosphere-Derived Cells Immediately Prior to Reperfusion in Pigs With Acute Myocardial Infarction Reduces Infarct Size and Attenuates Adverse Cardiac Remodeling.

Allogeneic cardiosphere-derived cells (CDCs) exert cardioprotective effects when administered intracoronarily after reperfusion in animal models of acute myocardial infarction (AMI). The "no-reflow" phenomenon develops rapidly post-reperfusion and may undermine the efficacy of cell therapy, due to poor cell delivery in areas of microvascular obstruction (MVO). We hypothesized that CDC-induced cardioprotection would be enhanced by cell administration prior to reperfusion, when microvasculature is still relatively intact, to facilitate widespread cell delivery within the ischemic area. We studied 81 farm pigs; 55 completed the specified protocols. A dose-optimization study in infarcted pigs demonstrated that the doses of 5 million and 10 million CDCs are the maximum safe doses that can be administered intracoronarily at 5 minutes prior to and at 5 minutes post-reperfusion, respectively, without aggravating MVO. Quantification of acute cell retention by polymerase chain reaction demonstrated that cell delivery prior to reperfusion resulted in higher cardiac cell retention compared to delivery post-reperfusion. We then performed a randomized, placebo-controlled study to assess the long-term efficacy of intracoronary infusion of 5 million allogeneic CDCs, delivered at 5 minutes prior to reperfusion, in a porcine model of AMI. The CDC therapy resulted in decreased scar size, improved regional systolic function, and attenuation of adverse cardiac remodeling (manifested as preserved global systolic function, preserved end-systolic volume, and decreased interstitial fibrosis) compared to placebo at 30 days post-MI. Dose-optimized intracoronary infusion of allogeneic CDCs prior to reperfusion in a porcine model of AMI is feasible, safe and confers long-term benefits.

Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model

Insulin-like growth factor-1 (IGF-1) has demonstrated beneficial effects after myocardial infarction (MI). Microencapsulation of IGF-1 could potentially improve results. We aimed to test the effect of an intracoronary (IC) infusion of microencapsulated IGF-1 in a swine acute MI model. For that purpose IC injection of a 10 ml solution of 5 × 106 IGF-1 loaded microspheres (MSPs) (n = 8, IGF-1 MSPs), 5 × 106 unloaded MSPs (n = 9; MSPs) or saline (n = 7; CON) was performed 48 hours post-MI. Left ventricular ejection fraction (LVEF), indexed ventricular volumes and infarct size (IS) were determined by cardiac magnetic resonance at pre-injection and 10 weeks. Animals were euthanized at 10 weeks, and myocardial fibrosis and vascular density were analysed. End-study LVEF was significantly greater in IGF-1 MSPs compared to MSPs and CON, while ventricular volumes exhibited no significant differences between groups. IS decreased over time in all groups. Collagen volume fraction on the infarct area was significantly reduced in IGF-1 MSPs compared to CON and MSPs. Vascular density analysis of infarct and border zones showed no significant differences between groups. In conclusion, the IC injection of 5 × 106 IGF-1 loaded MSPs in a porcine acute MI model successfully improves cardiac function and limits myocardial fibrosis, which could be clinically relevant.

Action of iron chelator on intramyocardial hemorrhage and cardiac remodeling following acute myocardial infarction.

Intramyocardial hemorrhage is an independent predictor of adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Iron deposition resulting from ischemia-reperfusion injury (I/R) is pro-inflammatory and has been associated with adverse remodeling. The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) has never been explored. The purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling. Two groups of animals underwent a reperfused AMI procedure: control and DFP treated (N = 7 each). A comprehensive MRI examination was performed in healthy state and up to week 4 post-AMI, followed by histological assessment. Infarct size was not significantly different between the two groups; however, the DFP group demonstrated earlier resolution of hemorrhage (by T2* imaging) and edema (by T2 imaging). Additionally, ventricular enlargement and myocardial hypertrophy (wall thickness and mass) were significantly smaller with DFP, suggesting reduced adverse remodeling, compared to control. The histologic results were consistent with the MRI findings. To date, there is no effective targeted therapy for reperfusion hemorrhage. Our proof-of-concept study is the first to identify hemorrhage-derived iron as a therapeutic target in I/R and exploit the cardioprotective properties of an iron-chelating drug candidate in the setting of AMI. Iron chelation could potentially serve as an adjunctive therapy in hemorrhagic AMI.

PULSED ULTRASOUND COMBINED WITH ACOUSTIC PHASE-CHANGE NANOPARTICLES DISSOLVE PORCINE CORONARY ARTERY THROMBUS IN VIVO

The culprit coronary artery in acute myocardial infarction (AMI) were occluded and caused myocardial ischemia. Based on stable cavitation, we sought to investigate a novel phase-change contrast agent (perfluoropentane-loaded nanoparticles, PFP@NPs) for the treatment using AMI porcine model. 9

A Pilot Study of Third-Generation Dual-Source Computed Tomography for the Assessment of Global Dynamic Changes in Left Ventricular Structure and Function in a Porcine Model of Acute Myocardial Infarction.

BackgroundFirst-generation and second-generation dual-source computed tomography (DSCT) are useful for analyzing left ventricle (LV) structure and function. This pilot study aimed to investigate the feasibility and role of third-generation DSCT for the evaluation of dynamic changes in LV structural and functional characteristics in a Diannan small-ear pig model of acute myocardial infarction (AMI).Material/MethodsThe model of AMI was established by balloon occlusion of the distal third of the left anterior descending (LAD) coronary artery in 14 Diannan small-eared pigs. Third-generation DSCT was performed to observe dynamic changes in LV structure and function before and after AMI was induced, with a follow-up period of 30 days.ResultsThe mean structural measurements at baseline included interventricular septum thickness (8.50±0.90 mm), LV anterior wall thickness (8.40±1.30 mm), LV posterior wall thickness (7.80±1.20 mm), LV end-diastolic dimension (LVEDD) (45.00±4.90 mm), and LV end-systolic dimension (LVESD) (25.90±4.10 mm). The mean functional measurements at baseline included the LV end-diastolic volume (LVEDV) (74.62±13.54 ml), LV end-systolic volume (LVESV) (23.06±7.46 ml), LV ejection fraction (LVEF) (69.29±6.83%), LV mass (86.35±14.02 g), stroke volume (SV) (51.56±9.77 ml), and cardiac output (CO) (4.22±2.14 l/min). Trends of time-dependent changes were observed for LVESV, LVEF, SV, and CO, but not for LVEDV or LV mass.ConclusionsThird-generation DSCT was validated as a tool for assessing dynamic changes in LV global function in a porcine model of AMI.

PentraSorb C-Reactive Protein: Characterization of the Selective C-Reactive Protein Adsorber Resin.

C-reactive protein (CRP) is well known as a general marker of inflammation. It furthermore represents a reliable risk factor for cardiac events and mediates tissue damage in acute myocardial infarction (AMI). It has been demonstrated that selective CRP depletion by extracorporeal apheresis in a porcine AMI model had beneficial effects on the infarcted area and the cardiac output. We therefore developed a novel adsorber for CRP apheresis from human plasma (PentraSorb CRP). It is intended for use in the clinic as therapy for patients suffering from AMI or other acute inflammatory diseases with elevated CRP plasma levels. The PentraSorb resin specifically bound CRP from human blood plasma and almost no other proteins as determined via Sodium dodecyl sulfate polyacrylamide gel electropheresis (SDS-PAGE). The resin further efficiently and selectively depleted CRP from plasma with low as well as high CRP concentrations (10-100 mg/L) at different flow rates, ranging from 17 to 40 mL/min. The resin was regenerable for up to 200 times without losing its CRP binding capacity or affecting biocompatibility. The depletion of CRP from plasma was comparable between the utilized small-scale column (0.5 mL resin) and the PentraSorb CRP adsorber (20 mL resin volume). The established features can therefore be applied to the clinical setting. In summary, PentraSorb CRP provides a novel, specific, and efficient CRP-binding resin that could be used in apheresis therapy for patients suffering from inflammatory diseases such as AMI, stroke, acute pancreatitis, and Crohn's disease.

Two novel direct SPIO labels and invivo MRI detection of labeled cells after acute myocardial infarct.

BackgroundAcute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. Cellular decay due hypoxia requires rapid and validated methods for possible therapeutic cell transplantation.PurposeTo develop direct and rapid superparamagnetic iron oxide (SPIO) cell label for a large-animal model and to assess in vivo cell targeting by magnetic resonance imaging (MRI) in an experimental AMI model.Material and MethodsBone marrow mononuclear cells (BMMNCs) were labeled with SPIO particles using two novel direct labeling methods (rotating incubation method and electroporation). Labeling, iron incorporation in cells and label distribution, cellular viability, and proliferation were validated in vitro. An AMI porcine model was used to evaluate the direct labeling method (rotating incubation method) by examining targeting of labeled BMMNCs using MRI and histology.ResultsLabeling (1 h) did not alter either cellular differentiation potential or viability of cells in vitro. Cellular relaxation values at 9.4 T correlated with label concentration and MRI at 1.5 T showing 89 ± 4% signal reduction compared with non-labeled cells in vitro. In vivo, a high spatial correlation between MRI and histology was observed. The extent of macroscopic pathological myocardial changes (hemorrhage) correlated with altered function detected on MRI.ConclusionWe demonstrated two novel direct SPIO labeling methods and demonstrated the feasibility of clinical MRI for monitoring targeting of the labeled cells in animal models of AMI.

Garlicin Post-Conditioning Suppresses Adhesion Molecules in a Porcine Model of Myocardial Ischemia-Reperfusion Injury.

To evaluate whether garlicin post-conditioning can attenuate myocardial ischemiareperfusion injury in a catheter-based porcine model of acute myocardial infarction (AMI) by affecting adhesion molecules integrin β1/CD29 and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31). Twenty-two swine were devided into 3 groups: 6 in a sham-operation group, and 8 each in the model and garlicin groups. AMI porcine model was established in the model and garlicin groups. The distal parts of the left anterior descending coronary artery in the animals of the model and garlicin groups were occluded by dilated balloon for 2 h, followed by reperfusion for 3 h. Garlicin (1.88 mg/kg) was injected over a period of 1 h, beginning just before reperfusion, in the garlicin group. Real-time polymerase chain reaction, immunohistochemistry and Western blot were carried out to detect mRNA and protein expressions of CD29 and CD31 3 h after reperfusion. Hematoxylin-eosin staining showed a better myocardial structure in the garlicin group after reperfusion. Compared to the model group, garlicin inhibited both the mRNA and protein expression of CD29 and CD31 in reperfusion area and no-reflflow area (P<0.05 respectively). Garlicin post-conditioning induced cardio-protection against myocardial ischemia-reperfusion injury in this catheter-based porcine model of AMI. The cardio-protective effect of garlicin is possibly owing to suppression of production of CD29 and CD31, by inhibition of the mRNA expression of CD29 and CD31.

Intracoronary Administration of Allogeneic Adipose Tissue-Derived Mesenchymal Stem Cells Improves Myocardial Perfusion But Not Left Ventricle Function, in a Translational Model of Acute Myocardial Infarction.

BackgroundAutologous adipose tissue–derived mesenchymal stem cells (ATMSCs) therapy is a promising strategy to improve post–myocardial infarction outcomes. In a porcine model of acute myocardial infarction, we studied the long‐term effects and the mechanisms involved in allogeneic ATMSCs administration on myocardial performance.Methods and ResultsThirty‐eight pigs underwent 50 minutes of coronary occlusion; the study was completed in 33 pigs. After reperfusion, allogeneic ATMSCs or culture medium (vehicle) were intracoronarily administered. Follow‐ups were performed at short (2 days after acute myocardial infarction vehicle‐treated, n=10; ATMSCs‐treated, n=9) or long term (60 days after acute myocardial infarction vehicle‐treated, n=7; ATMSCs‐treated, n=7). At short term, infarcted myocardium analysis showed reduced apoptosis in the ATMSCs‐treated animals (48.6±6% versus 55.9±5.7% in vehicle; P=0.017); enhancement of the reparative process with up‐regulated vascular endothelial growth factor, granulocyte macrophage colony‐stimulating factor, and stromal‐derived factor‐1α gene expression; and increased M2 macrophages (67.2±10% versus 54.7±10.2% in vehicle; P=0.016). In long‐term groups, increase in myocardial perfusion at the anterior infarct border was observed both on day‐7 and day‐60 cardiac magnetic resonance studies in ATMSCs‐treated animals, compared to vehicle (87.9±28.7 versus 57.4±17.7 mL/min per gram at 7 days; P=0.034 and 99±22.6 versus 43.3±14.7 22.6 mL/min per gram at 60 days; P=0.0001, respectively). At day 60, higher vascular density was detected at the border zone in the ATMSCs‐treated animals (118±18 versus 92.4±24.3 vessels/mm2 in vehicle; P=0.045). Cardiac magnetic resonance–measured left ventricular ejection fraction of left ventricular volumes was not different between groups at any time point.ConclusionsIn this porcine acute myocardial infarction model, allogeneic ATMSCs‐based therapy was associated with increased cardioprotective and reparative mechanisms and with better cardiac magnetic resonance–measured perfusion. No effect on left ventricular volumes or ejection fraction was observed.

Changes in Coronary Blood Flow After Acute Myocardial Infarction: Insights From a Patient Study and an Experimental Porcine Model.

The aim of this study was to determine the effects of an acute myocardial infarction (AMI) on baseline and hyperemic flow in both culprit and nonculprit arteries. An impaired coronary flow reserve (CFR) after AMI is related to worse outcomes. The individual contribution of resting and hyperemic flow to the reduction of CFR is unknown. Furthermore, it is unclear whether currently used experimental models of AMI resemble the clinical situation with respect to coronary flow parameters. Intracoronary Doppler flow velocity measurements were obtained in culprit and nonculprit arteries immediately after successfully revascularized ST-segment elevation myocardial infarction (n = 40). Stable patients without obstructive coronary artery disease served as control subjects and were selected by propensity-score matching (n = 40). Similar measurements in an AMI porcine model were taken both before and immediately after 75-min balloon occlusion of the left circumflex artery (n = 11). In the culprit artery, CFR was 36% lower than in matched control subjects (Δ = -0.9; 1.8 ± 0.9 vs. 2.8 ± 0.7; p < 0.001) with consistent observations in swine (Δ = -0.9; 1.5 ± 0.4 vs. 2.4 ± 0.9 for after and before AMI, respectively; p = 0.04). An increased baseline and a decreased hyperemic flow contributed to the reduction in CFR in both patients (baseline flow: Δ = +5 and hyperemic flow: Δ = -7 cm/s) and swine (baseline flow: Δ = +8 and hyperemic flow: Δ = -6 cm/s). Similar changes were observed in nonculprit arteries (CFR: 2.8 ± 0.7 vs. 2.0 ± 0.7 for STEMI patients and control subjects; p < 0.001). CFR significantly correlated with infarct size as a percentage of the left ventricle in both patients (r = -0.48; p = 0.001) and swine (r = -0.61; p = 0.047). CFR in both culprit and nonculprit coronary arteries decreases after AMI with contributions from both an increased baseline flow and a decreased hyperemic flow. The decreased CFR after AMI in culprit and nonculprit vessels is not a result of pre-existing microvascular dysfunction, but represents a combination of post-occlusive hyperemia, myocardial necrosis, hemorrhagic microvascular injury, compensatory hyperkinesis, and neurohumoral vasoconstriction.

Effect of Shen-yuan on haemodynamic and anti-inflammatory factors in a porcine model of acute myocardial infarction

We previously found that Shen-yuan exerted cardioprotective activities in rodent and porcine myocardial infarction (MI) models because of its antioxidative and anti-apoptotic properties. This study aimed to investigate whether the cardioprotective effects from Shen-yuan are due to regulation of haemodynamics and inflammation in a porcine model of acute MI. Myocardial infarction was induced by left anterior descending coronary artery ligation. Low, moderate, and high doses of Shen-yuan treatment were started 1 week before MI and continued for 2 weeks after MI. Whole blood viscosity at 15 s−1 and platelet aggregation rate were significantly increased in the MI group, but were markedly attenuated by high doses of Shen-yuan. A moderate dose of Shen-yuan also restored decreased values of the peak rise of left ventricular pressure and left ventricular mean pressure after MI. Expression of the T regulatory cell marker forkhead box P3 (Foxp3)+ at 14 days post-MI was lower than that in the sham-operated group. Foxp3 was significantly up-regulated in the infarcted and non-infarcted zones of the left ventricle in the Shen-yuan treatment groups. Plasma interleukin-10 and transforming growth factor-β levels were elevated by Shen-yuan treatment in a dose-dependent manner. Shen-yuan elicits cardiovascular protection by its haemodynamic stabilization and anti-inflammatory effects after onset of MI in a porcine model.

Non-contrast myocardial perfusion assessment in porcine acute myocardial infarction using arterial spin labeled CMR

Background Following acute myocardial infarction (AMI), microvascular integrity and function may be compromised as a result of microvascular obstruction (MVO) and vasodilator dysfunction [1,2]. It has been observed that both infarct and remote myocardial territories may exhibit impaired myocardial blood flow (MBF) patterns associated with abnormal vasodilator response [3]. Arterial spin labeled (ASL) CMR is a novel non-contrast technique that can quantitatively measure MBF [4-6]. The aim of this study was to investigate the feasibility of ASL-CMR in assessing MBF in a porcine model of AMI.

Bone Marrow-Derived Mesenchymal Stem Cells Have Innate Procoagulant Activity and Cause Microvascular Obstruction Following Intracoronary Delivery: Amelioration by Antithrombin Therapy.

Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI. Expression of the initiator of the coagulation cascade tissue factor (TF) on MSC was detected and quantified by immunofluorescence, FACS, and immunoblotting. MSC-derived TF antigen was catalytically active and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet thrombus deposition on collagen at arterial shear, an effect abolished by heparin coadministration. In a porcine AMI model, IC infusion of 25 × 10(6) MSC during reperfusion was associated with a decrease in coronary flow reserve but not when coadministered with an antithrombin agent (heparin). Heparin reduced MSC-associated thrombosis incorporating platelets and VWF within the microvasculature. Heparin-assisted therapeutic MSC delivery also reduced apoptosis in the infarct border zone at 24 hours, significantly improved infarct size, left ventricular (LV) ejection fraction, LV volumes, wall motion, and attenuated histologic evidence of scar formation at 6 weeks post-AMI. Heparin alone or heparin-assisted fibroblast control cell delivery had no such effect. Procoagulant TF activity of therapeutic MSCs is associated with reductions in myocardial perfusion when delivered IC may be successfully managed by heparin coadministration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic IC MSC delivery for AMI.

VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function.

Angiogenesis induced by growth factor-releasing microspheres can be an off-the-shelf and immediate alternative to stem cell therapy for acute myocardial infarction (AMI), independent of stem cell yield and comorbidity-induced dysfunction. Reliable and prolonged local delivery of intact proteins such as VEGF is, however, notoriously difficult. Our objective was to create a platform for local angiogenesis in human-sized hearts, using polyethylene-glycol/polybutylene-terephthalate (PEG-PBT) microsphere-based VEGF165A delivery. PEG-PBT microspheres were biocompatible, distribution was size dependent, and a regimen of 10 × 10(6) 15-μm microspheres at 0.5 × 10(6)/min did not induce cardiac necrosis. Efficacy, studied in a porcine model of AMI with reperfusion rather than chronic ischemia used for most reported VEGF studies, shows that microspheres were retained for at least 35 days. Acute VEGF165A release attenuated early cytokine release upon reperfusion and produced a dose-dependent increase in microvascular density at 5 wk following AMI. However, it did not improve major variables for global cardiac function, left ventricular dimensions, infarct size, or scar composition (collagen and myocyte content). Taken together, controlled VEGF165A delivery is safe, attenuates early cytokine release, and leads to a dose-dependent increase in microvascular density in the infarct zone but does not translate into changes in global or regional cardiac function and scar composition.

Cardioprotective effect of fimasartan, a new angiotensin receptor blocker, in a porcine model of acute myocardial infarction.

Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F-18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI.

INTERLEUKIN 6 MEDIATES POST INFARCT REPAIR BY HUMAN CARDIAC STEM CELLS

s S59 implantation attenuated the decline of fractional shortening after MI and the scar was significantly thicker in both BMMC groups compared to the media injected controls (p<0.05). However, ventricular function was consistently better in the BMMC-Y than the BMMC-O group after MI (p<0.05). CONCLUSION: After MI, BMMC transplantation induced a more robust inflammatory and regenerative cell response and cytokine release than the media injected controls. However, BMMC implantation did not completely restore the regenerative defects in aged mice. Although important for infarct healing, mast cell implantation did not restore youthful regeneration to old mice after an MI. 009 THE EFFECTS OF DISTAL CORONARY EMBOLIZATION ON INFARCT SIZE AND CARDIAC REMODELING IN A PORCINE ACUTE MYOCARDIAL INFARCTION MODEL RM Thomas, S Lim, B Qiang, A Osherov, NR Ghugre, H Noyan, X Qi, R Wolff, M Ladouceur-Wodzak, T Berk, J Butany, M Husain, GA Wright, BH Strauss