Porcine Model Of Myocardial Infarction Research Articles

Role of iron chelation in hemorrhagic myocardial infarction: a quantitative CMR study

Summary Reperfusion hemorrhage is an independent predictor of adverse left-ventricular remodeling following acute myocardial infarction. Iron chelation may potentially alleviate the toxic and pro-inflammatory effects of iron degradation products. CMR can provide insights into the interaction between hemorrhage and iron chelator. Background It has been speculated that iron chelation may be beneficial in acute myocardial infarction (AMI) and that early treatment can limit ischemia-reperfusion injury and also reduce infarct size. However, the role of iron chelation in hemorrhagic myocardial infarction, where it would be most suited, has not yet been explored. Reperfusion hemorrhage results in accumulation of iron degradation products of hemoglobin that may be proinflammatory as free iron is toxic in nature. The purpose of the study was to investigate the interaction between iron chelating agent deferiprone (DFP) and hemorrhage in a porcine model of myocardial infarction and monitor remodeling by cardiovascular magnetic resonance (CMR). Methods The study involved two groups of animals that were subjected to a 90 min balloon occlusion of the LAD followed by reperfusion - untreated (N=2) and DFP treated (N=2). DFP (supported by ApoPharma Inc., Toronto, ON) was administered (orally) a few hours before the procedure (pre-loading) and treatment was continued with a daily dose of 100 mg/kg. Imaging was performed on a 3T MRI scanner (MR 750, GE Healthcare) preAMI (healthy) and day 2-week 4 post-AMI. Edema was evaluated by T2 quantification using a T2-prepared spiral sequence and hemorrhage was identified by T2* determined using a multi-echo gradient-echo acquisition. Infarct assessment was performed by delayed hyperenhancement (DHE) using an IR-GRE sequence. Results Figure 1 demonstrates representative images from the two groups while Figure 2 shows the cumulative time course of the CMR measurements. In the DFP group, hemorrhage was observed only on day 2 and by week 1 it had completely resolved. This was in contrast to the untreated group where resolution of hemorrhage was delayed to week 4. With DFP, inflammation or edema was substantially reduced by week 4 with T2 values approaching control levels. In the untreated group, edema persisted up to week 4. Ejection fraction (EF) was depressed by week 4 in both groups. However, enddiastolic and end-systolic volumes were relatively unchanged in the DFP group while they increased significantly in the untreated group. Conclusions

Effects of intracoronary delivery of allogenic bone marrow-derived stem cells expressing heme oxygenase-1 on myocardial reperfusion injury

Heme oxygenase-1 (HO-1) decreases apoptosis, inflammation and oxidative stress. The aim of the study was to investigate the effects of intracoronary infusion of allogenic bone marrow cells (BMC) overexpressing HO-1 in the porcine model of myocardial infarction (MI). MI was produced by balloon occlusion of a coronary artery. BMC were transduced with adenoviruses encoding for HO-1 (HO-1 BMC) or GFP (GFP-BMC) genes. Prior to reperfusion animals received HO-1 BMC, control BMC (unmodified or GFP-BMC) or placebo. Left ventricular (LV) ejection fraction (EF), shortening fraction (SF), end-systolic and end-diastolic diameters (EDD, ESD) were assessed by echocardiography before, 30 minutes (min) and 14 days after reperfusion. BMC significantly improved LVEF and SF early (30 min) after reperfusion as well as after 14 days. Early after reperfusion HO-1 BMC were significantly more effective than control BMC, but after 14 days, there were no differences. There were no effect of cells on LV remodelling and diastolic function. Both HO-1 BMC and control BMC significantly reduced the infarct size vs. placebo (17.2 ± 2.7 and 18.8 ± 2.5, respectively, vs. 27.5 ± 5.1, p= 0.02) in histomorphometry. HO-1-positive donor BMC were detected in the infarct border area in pigs receiving HO-1-cells. No significant differences in expression of inflammatory genes (SDF-1, TNF-α, IL-6, miR21, miR29a and miR133a) in the myocardium were found. In conclusion, intracoronary delivery of allogeneic BMC immediately prior to reperfusion improved the LVEF and reduced the infarct size. HO-1 BMC were not superior to control cells after 14 days, however, produced faster recovery of LVEF. Transplanted cells survived in the peri-infarct zone.

Assessment of distribution and evolution of mechanical dyssynchrony in a porcine model of myocardial infarction by cardiovascular magnetic resonance.

BackgroundWe sought to investigate the relationship between infarct and dyssynchrony post- myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality.MethodsCine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 ± 2 days (early post-MI), and 33 ± 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro-anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice.ResultsMean infarct size was 21 ± 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 ± 1.6% vs. -18 ± 2.5% (early) and -17 ± 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early (440 ± 40 ms vs. 329 ± 40 ms and 332 ± 36 ms, respectively; p = 0.0002) and late post-MI (442 ± 63 ms vs. 321 ± 40 ms and 355 ± 61 ms, respectively; p = 0.012). The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 ± 7 ms to 50 ± 10 ms (early, p = 0.012) to 54 ± 19 ms (late, p = 0.004), with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 ± 2.4 cm/s), when compared to peri-infarct (18.7 ± 10.3 cm/s) and remote myocardium (39 ± 20.5 cm/s).ConclusionsMechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct.

Novel regenerative therapy using cell-sheet covered with omentum flap delivers a huge number of cells in a porcine myocardial infarction model

A key challenge to applying cell transplantation to treat severely damaged myocardium is in delivering large numbers of cells with minimum cell loss. We developed a new implantation method using skeletal myoblast (SMB) sheets, wrapped with an omentum flap as a blood supply to deliver huge numbers of SMBs to the damaged heart. We examined whether this method could be used to deliver a large amount of cells to deteriorated porcine myocardium. Cell sheets were obtained by culturing mini-pig autologous SMB cells on temperature-responsive culture dishes. Myocardial infarction was induced by placing an ameroid constrictor around the left anterior descending artery. The mini-pigs were divided into 4 treatment groups (n = 6 in each): cell sheets with omentum, cell sheets only, omentum only, and sham operation. Each animal implant consisted of 30 cell sheets (1.5 × 10(7) cells per sheet). Six 5-layer constructs were each placed on a different area, immediately adjacent to but not overlapping one another, to cover the infarct and border regions. The new regenerative cell delivery system using SMB sheets covered and wrapped with omentum resulted in (1) a significantly reduced infarct size causing, at least in part, a thin scar with thick well-vascularized cardiac tissue; (2) increased angiogenesis, as determined by a significantly higher vascular density; and (3) improved cardiac function, as determined by echocardiography, compared with the conventional method (SMB sheet implantation). This cell delivery system shows potential for repairing the severely failed heart.

Imaging Long-Term Fate of Intramyocardially Implanted Mesenchymal Stem Cells in a Porcine Myocardial Infarction Model

The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [18F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [18F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33–35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC–associated [18F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [18F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI.

Cardioprotective effect of liposomal prostaglandin E1 on a porcine model of myocardial infarction reperfusion no-reflow

To evaluate whether liposomal prostaglandin E1 (lipo-PGE1) can decrease reperfusion no-reflow in a catheter-based porcine model of acute myocardial infarction (AMI). Twenty-two male Chinese mini-swines were randomized into three groups: six in a sham-operation group, and eight each in the control and lipo-PGE1 groups. The distal part of the left anterior descending coronary artery (LAD) in the latter two groups was completely occluded for 2 h, and then reperfused for 3 h. Lipo-PGE1 (1 μg/kg) was injected 10 min before LAD occlusion until reperfusion for 1 h in the lipo-PGE1 group. Hemodynamic data and proinflammatory cytokines were examined before AMI, 2 h after occlusion, and 1, 2, and 3 h after reperfusion. Myocardial contrast echocardiography (MCE) and double staining were performed to evaluate the myocardial no-reflow area (NRA). Left ventricular systolic pressure and end-diastolic pressure significantly improved in the lipo-PGE1 group after reperfusion compared with the control group and also 2 h after AMI (P<0.05 for both). MCE and double staining both showed that lipo-PGE1 decreased reperfusion NRA after AMI (P<0.05, P<0.01). Lipo-PGE1 decreased serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) after myocardial infarction reperfusion (P<0.05 for both). Lipo-PGE1 is cardioprotective in our porcine model of myocardial infarction reperfusion no-reflow, decreasing NRA and attenuating the inflammatory response.

Postreperfusion myocardial technetium-99m–sestamibi defect corresponds to area at risk

Technetium-99m-sestamibi (MIBI) is the most frequently used myocardial perfusion tracer in patients with ischemic heart disease. In patients with acute ST-elevation myocardial infarction, we previously found that the defect in myocardial MIBI uptake was the same in patients injected with MIBI before primary angioplasty and in patients injected immediately after successful treatment. Thus, reperfusion may not be followed by increased uptake of MIBI. Instead, the MIBI defect after reperfusion may reflect the area at risk (AAR) defined by MIBI injected before treatment. We intended to investigate whether myocardial imaging with MIBI administered after reperfusion reflects myocardial perfusion or rather the ischemic AAR. In 12 pigs, left anterior descending coronary artery was totally occluded for 45 min with an angioplasty balloon. After a 2-h reperfusion, MIBI was injected intravenously, and (153)Gd-microspheres were injected in left atrium. AAR and infarct size (IS) were determined by histochemical staining. MIBI and microsphere distribution were evaluated by counting the sliced left ventricle on a gamma camera. Defects were defined as uptake less than 45% of maximum uptake. The mean±S.D. defect size as a fraction of left ventricle was for MIBI 21%±5.5%, AAR 25%±6.3%, IS 13%±3.9% and microspheres defect size 7.3%±5.5%. MIBI defect size overestimated IS (P=.0005) and microspheres defect size (P=.0001), but it was not significantly different from AAR (P=.30). In a porcine model of myocardial infarction after 45 min of ischemia, MIBI administered 120 min after reperfusion delineates AAR.

Delivery of gelfoam-enabled cells and vectors into the pericardial space using a percutaneous approach in a porcine model

Intrapericardial drug delivery is a promising procedure, with the ability to localize therapeutics with the heart. Gelfoam particles are nontoxic, inexpensive, nonimmunogenic and biodegradable compounds that can be used to deliver therapeutic agents. We developed a new percutaneous approach method for intrapericardial injection, puncturing the pericardial sac safely under fluoroscopy and intravascular ultrasound (IVUS) guidance. In a porcine model of myocardial infarction (MI), we deployed gelfoam particles carrying either (a) autologous mesenchymal stem cells (MSCs) or (b) an adenovirus encoding enhanced green fluorescent protein (eGFP) 48 h post-MI. The presence of MSCs and viral infection at the infarct zone was confirmed by immunoflourescence and PCR. Puncture was performed successfully in 16 animals. Using IVUS, we successfully determined the size of the pericardial space before the puncture, and safely accessed that space in setting of pericardial effusion and also adhesions induced by the MI. Intrapericardial injection of gelfoam was safe and reliable. Presence of the MSCs and eGFP expression from adenovirus in the myocardium were confirmed after delivery. Our novel percutaneous approach to deliver (stem-) cells or adenovirus was safe and efficient in this pre-clinical model. IVUS-guided delivery is a minimally invasive procedure that seems to be a promising new strategy to deliver therapeutic agents locally to the heart.

ELEVATION OF PLASMA COPEPTIN IN ACUTE MYOCARDIAL INFARCTION IN PIGS IS RELATED TO CHANGES IN MEAN ARTERIAL BLOOD PRESSURE BUT NOT TO MYOCARDIAL ISCHEMIA

Background: Copeptin increases early after myocardial infarction (MI). We used a porcine MI model with serial copeptin-testing and assessment of hemodynamic variables to evaluate the trigger for copetin-release and the liberation kinetics of copeptin in MI. Methods: AMI was induced by percutaneous transluminal coronary angioplasty (PTCA). Blood samples were taken in 30-minute intervals. Results: All animals (n=4) had a comparable infarction size (10.02 ± 2.11% of the left ventricle) and elevated troponin T levels. Highest copeptin levels were measured 30 minutes after the beginning of ischemia with a rapid decrease at 60 minutes, while coronary occlusion was still persisting. Animals with high copeptin values showed a significant drop of MAP (37.24% and 54.20% reduction from MAP-baseline). Conclusions: In experimental AMI in four pigs, the infarction-related decrease of MAP seemed to be the trigger for the copeptin increase. Remarkably, copeptin liberation was not correlated with infarction size and copeptin values already decreased while coronary artery occlusion was ongoing.

Intracoronary adiponectin at reperfusion reduces infarct size in a porcine myocardial infarction model

Reperfusion injury (RI) remains an important limitation of myocardial revascularization. The aim of the present study was to evaluate the influence of the intracoronary injection of adiponectin on RI and cardiomyocyte death in a porcine myocardial infarction model. Acute infarction in 14 Polish domestic pigs was induced by inflation of an over the wire balloon (OTW) catheter in the medial left anterior descending artery for 60min. The study group consisted of 7 pigs in which intracoronary adiponectin (50µg) was infused through the OTW catheter immediately before reperfusion. The control group (n=7) was administered placebo. Animals were sacrificed after two days of follow-up. The infarct area (IA) was stained with tetrazoline and the area at risk (AAR) with intracoronary administration of Evans Blue dye before euthanasia. Hearts in each group had similar AARs (46.2±9.9% vs. 48.4±6.2% of the whole myocardium, p=ns). The IA/AAR% and IA were smaller in the study group when compared to the control (24.7±4.0% vs. 45.3±22.5%, p=0.005; and 11.7±4.9% vs. 20.5±5.6%, p=0.01, respectively). These outcomes corresponded well with the peak troponin levels after 12h (109.9±60.9 ng/ml vs. 185.5±39.4 ng/ml, p=0.017). After two days there was a significantly higher LVEF in the study group (51.4±8.5% vs. 33.9±8.6%, p=0.002). There was also a trend toward lower apoptosis enhancement in the viable myocardium in the study group (3.11±2.3 vs. 8.92±6.3; p=0.07). The administration of adiponectin into the infarct- related artery is safe and feasible. The treatment significantly reduced the infarct size.

Quantitative tracking of edema, hemorrhage, and microvascular obstruction in subacute myocardial infarction in a porcine model by MRI

Pathophysiological responses after acute myocardial infarction include edema, hemorrhage, and microvascular obstruction along with cellular damage. The in vivo evolution of these processes simultaneously throughout infarct healing has not been well characterized. The purpose of our study was to quantitatively monitor the time course of these mechanisms by MRI in a porcine model of myocardial infarction. Ten pigs underwent MRI before coronary occlusion with subgroups studied at day 2 and weeks 1, 2, 4, and 6 post-infarction. Tissue characterization was performed using quantitative T2 and T2* maps to identify edema and hemorrhage, respectively. Contrast-enhanced MRI was used for infarct/ microvascular obstruction delineation. Inflammation was reflected by T2 fluctuations, however at day 2, edema and hemorrhage had counter-acting effects on T2. Hemorrhage (all forms) and mineralization (calcium) could be identified by T2* in the presence of edema. Simultaneous resolution of microvascular obstruction and T2* abnormality suggested that the two phenomenon were closely associated during the healing process. Our study demonstrates that quantitative T2 and T2* mapping techniques allow regional, longitudinal, and cross-subject comparisons and give insights into histological and tissue remodeling processes. Such in vivo characterization will be important in grading severity and evaluating treatment strategies for myocardial infarction, potentially improving clinical outcomes.

YIA6 Effects of GLP-1 eluting stem cell therapy on collagen remodelling, infarct size and apoptosis in a porcine model of myocardial infarction

Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone with cardioprotective effects. Human stem cells secreting a GLP-1 fusion protein and encapsulated in an alginate matrix (GLP-1 CellBeads) have been developed...

Regional Diastolic and Systolic Function by Strain Rate Imaging for the Detection of Intramural Viability during Dobutamine Stress Echocardiography in a Porcine Model of Myocardial Infarction

The aim of this study was to evaluate diastolic and systolic strain rate measurements for differentiation of transmural/nontransmural infarction during dobutamine stress echocardiography (DSE). An ameroid constrictor was placed around the circumflex artery in 23 pigs inducing chronic vessel occlusion. Five pigs without constrictor served as controls. During high-dose DSE systolic strain rates (SR(sys)), systolic and postsystolic strain values (epsilon(sys), epsilon(ps)) and early and late diastolic strain rates (SR(E) and SR(A)) were determined. At week 6, animals were evaluated regarding myocardial fibrosis. Histology revealed nontransmural in 14 and transmural infarction in 9 animals. In controls, dobutamine induced a linear increase of SR(sys) to 12.3 + or - 0.4 s(-1) at 40 microg/kg per minute (P = 0.001) and a linear decrease of SR(E) to -6.6 + or - 0.3 s(-1) (P = 0.001). In the nontransmural group, SR(sys), epsilon(sys), epsilon(ps) at rest, and during DSE were higher and SR(E) was lower than in the transmural infarction group (P = 0.01). Best predictors for viability were SR(sys) (ROC 0.96, P = 0.0003), SR(E) at 10 microg/kg per minute dobutamine stimulation (ROC 0.94, P = 0.001) and positive SR values during isovolumetric relaxation at 40 microg/kg per minute dobutamine (ROC 0.86, P = 0.004). The extension of fibrosis correlated with SR(sys) at rest, epsilon(sys) at rest, and SR(E) at rest (P < 0.001). For the detection of viability similar diagnostic accuracies of SR(E) and SRsys were seen (sensitivity 93%/93%, specificity 96%/94%, respectively). Diastolic SR analysis seems to be equipotent for the identification of viable myocardium in comparison to systolic SR parameters and allows the differentiation of nontransmural from transmural myocardial infarction with high diagnostic accuracy. (Echocardiography 2010;27:552-562).

Prolonged Therapy With Erythropoietin is Safe and Prevents Deterioration of Left Ventricular Systolic Function in a Porcine Model of Myocardial Infarction

Background Erythropoietin (EPO) has generated interest as a novel therapy after myocardial infarction (MI), but the safety and efficacy of prolonged therapy have not been studied in a large animal model of reperfused MI. Methods and Results MI was induced in pigs by a 90-minute balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either EPO or saline (control group). Inflammatory markers, bone marrow cell mobilization, and left ventricular function (by both echocardiography and pressure-volume measurements) were assessed at baseline, 1 and 6 weeks post-MI. EPO therapy was associated with a significant increase in hemoglobin and mononuclear counts. D-dimer and C-reactive protein levels did not differ between groups. At week 6, EPO therapy prevented further deterioration of left ventricular ejection fraction (39 ± 2% vs. 33 ± 1%, P < .01) and improved wall motion score index ( P < .02). Histopathology revealed increased areas of viable myocardium, vascular density, and capillary-to-myocyte ratio in the EPO therapy compared with the control (all P < .05). Conclusion Prolonged EPO therapy after MI in a large animal model is safe and leads to an increase in viable myocardium, increased vascular density, and prevents further deterioration of left ventricular function. These results support future clinical studies in post-MI patients.

Effects of Adipose Tissue-Derived Stem Cell Therapy After Myocardial Infarction: Impact of the Route of Administration

Background Cell-based therapies offer a promising approach to reducing the short-term mortality rate associated with heart failure after a myocardial infarction. The aim of the study was to analyze histological and functional effects of adipose tissue-derived stem cells (ADSCs) after myocardial infarction and compare 2 types of administration pathways. Methods and Results ADSCs from 28 pigs were labeled by transfection. Animals that survived myocardial infarction (n = 19) received: intracoronary culture media (n = 4); intracoronary ADSCs (n = 5); transendocardial culture media (n = 4); or transendocardial ADSCs (n = 6). At 3 weeks' follow-up, intracoronary and transendocardial administration of ADSCs resulted in similar rates of engrafted cells (0.85 [0.19-1.97] versus 2 [1-2] labeled cells/cm 2, respectively; P = NS) and some of those cells expressed smooth muscle cell markers. The intracoronary administration of ADSCs was more effective in increasing the number of small vessels than transendocardial administration (223 ± 40 versus 168 ± 35 vessels/mm 2; P < .05). Ejection fraction was not modified by stem cell therapy. Conclusions This is the first study to compare intracoronary and transendocardial administration of autologous ADSCs in a porcine model of myocardial infarction. Both pathways of ADSCs delivery are feasible, producing a similar number of engrafted and differentiated cells, although intracoronary administration was more effective in increasing neovascularization.

238: Imaging of Transplanted Bone Marrow Derived Stem Cells for Therapy of Ischemic Cardiomyopathy

Transplantation of bone marrow derived stem cells is currently being used as a therapy for ischemic heart disease. An important aspect in clinical studies is the inability to track the fate of the transplanted cells. In this study, our aim was to assess a clinically applicable technique by using 1.5-Tesla Magnetic Resonance Imaging [MRI] of nano-particle labeled, transplanted bone marrow derived mononuclear cells (MNCs) in a porcine model of myocardial infarction.

Regional evolution of mechanical dyssynchrony in a closed-chest porcine model of myocardial infarction as assessed by cardiac magnetic resonance

Methods In six pigs, cine, late gadolinium enhancement, and tagged cardiac magnetic resonance imaging were performed at baseline (before MI) and early (10 ± 2 days) and late (34 ± 10 days) after balloon induced occlusionreperfusion myocardial injury. Infarct, peri-infarct, and remote normal regions were defined as previously described. Cardiac morphology, function, location and extent of MI, and regional mechanics (circumferential strain (eC)) were measured.

Analysis of Different Routes of Administration of Heterologous 5-Azacytidine–Treated Mesenchymal Stem Cells in a Porcine Model of Myocardial Infarction

Stem cell therapy constitutes an exciting, powerful therapy to repair the heart. Nevertheless, there are numerous doubts about the best route of stem cell administration to achieve implantation into the injured myocardium. Development of a preclinical, large animal model may be useful to obtain a better approach to clinical situations. The aim of this work was to study the effectiveness of various routes of heterologous bone marrow mesenchymal stem cell (MSCs) administration in a porcine model of myocardial infarction. MSC treated with 5-azacytidine were stained with a fluorescent compound (DiO) before their administration to previously infarcted pigs via 3 routes: intracoronary (IC), intramyocardial (IM), or endocardial (EC; n = 5 each group). Healthy, noninfarcted animals were used as a control group. At 30 days after delivery, hearts were divided into 12 parts: infarcted zone (1-6), right-left atria, interatrial and interventricular septa, and right-left ventricles. In each zone we looked for and quantified, injected fluorescence-stained cells. In the animals in which presence of DiO-stained cells was detected, cells were located preferentially in the infarcted zone and not in the atria, ventricles, or septa. Comparing various administration routes, the mean number of engrafted cells within the infarct zone was significantly greater after IC infusion than either IM or EC injection. Fluorescent cells were not observed in healthy zones of the myocardium or in healthy animals.

Comparison of Gene Expression Profiles in a Porcine Infarct Model After Intracoronary, Transthoracic, or Transendocardiac Injection of Heterologous Bone Marrow Mesenchymal Cells

An in vivo porcine model of myocardial infarction was developed with the aim of comparing the effectiveness for cardiac repair of intracoronary, transthoracic, or transendocardial delivery strategies for bone marrow mesenchymal stem cells (BMMSC) using an analysis of expression levels of transcripts related to various cellular processes at 8 heart regions using quantitative reverse transcriptase polymerase chain reaction. We observed significant rises in cardiomyogenic markers Mef2C, Gata4 and Nkx2.5, and contractibility marker Serca2A at infarcted regions for cell-treated pigs. We also observed differences in Sdf1 expression related to the organ stress response between delivery strategies. Unexpectedly, increased expression of Col1A1 was detected in 2 cell-treated groups at various heart regions. Our results suggest improvements in both contractility and cardiomyogenic capability of damaged tissue after BMMSC injection, but also warned us about the relevance of the chosen delivery strategy and potential undesired effects like increasing fibrosis after treatment.

Usefulness of MRI to Differentiate Between Temporary and Long-Term Coronary Artery Occlusion in a Minimally Invasive Model of Experimental Myocardial Infarction

The surgical technique employed to determine an experimental ischemic damage is a major factor in the subsequent process of myocardial scar development. We set out to establish a minimally invasive porcine model of myocardial infarction using cardiac contrast-enhanced magnetic resonance imaging (ce-MRI) as the basic diagnostic tool. Twenty-seven domestic pigs were randomized to either temporary or permanent occlusion of the left anterior descending artery (LAD). Temporary occlusion was achieved by inflation of a percutaneous balloon in the left anterior descending artery directly beyond the second diagonal branch. Occlusion was maintained for 30 or 45 min, followed by reperfusion. Permanent occlusion was achieved via thrombin injection. Thirteen animals died peri- or postinterventionally due to arrhythmias. Fourteen animals survived the 30-min ischemia (four animals; group 1), the 45-min ischemia (six animals; group 2), or the permanent occlusion (4 animals; group 3). Coronary angiography and ce-MRI were performed 8 weeks after coronary occlusion to document the coronary flow grade and the size of myocardial scar tissue. The LAD was patent in all animals in groups 1 and 2, with normal TIMI flow; in group 3 animals, the LAD was totally occluded. Fibrosis of the left ventricle in group 1 (4.9 +/- 4.4%; p = 0.008) and group 2 (9.4 +/- 2.9%; p = 0.05) was significantly lower than in group 3 (14.5 +/- 3.9%). Wall thickness of the ischemic area was significantly lower in group 3 versus group 1 and group 2 (2.9 +/- 0.3, 5.9 +/- 0.7, and 6.1 +/- 0.7 mm; p = 0.005). The extent of late enhancement of the left ventricle was also significantly higher in group 3 (16.9 +/- 2.1%) compared to group 1 (5.3 +/- 5.4%; p = 0.003) and group 2 (9.7 +/- 3.4%, p = 0.013). In conclusion, the present model of minimally invasive infarction coupled with ce-MRI may represent a useful alternative to the open chest model for studies of myocardial infarction and scar development.