Myocardial Infarction In Swine Research Articles

Is Cyclosporine Immunosuppression Required to Effect Improved Myocardial Function Following Global Intracoronary Cardiosphere‐Derived Cells After Acute Myocardial Infarction in Swine?

ObjectiveWe previously demonstrated that allogeneic cardiosphere‐derived cells (CDCs) improve myocardial function after infarction via paracrine effects when animals are pretreated with oral cyclosporine (CsA) prior to injury. The present study directly compared the efficacy of CDCs with and without CsA administered at the time of reperfusion after acute myocardial infarction (AMI) in a 3‐armed, blinded pre‐clinical study.MethodsStudies were completed in closed‐chest, propofol‐anesthetized swine (n=29). After assessing baseline hemodynamics, the LAD artery was occluded with a balloon catheter for 90 minutes and contrast‐enhanced cardiac CT performed to assess the area‐at‐risk (AAR). Thirty minutes after reperfusion, animals were randomized to receive a global intracoronary infusion of saline, CDCs (20×106 cells), or CDCs with CsA (2.5 mg/kg, iv; 200 mg, po qd). LV function and TTC infarct size (IS) were assessed 1 month later.ResultsBaseline hemodynamics and LV function were similar between groups. There was no difference between the CT AAR (% of LV mass; Saline: 22.2±1.0%, CDC: 23.7±0.7%, CDC+CsA: 24.7±1.4%, p=0.26). Infarct size was not different between groups (% of LV mass; Saline: 6.7±0.7%, CDC: 6.7±0.3%, CDC+CsA: 6.9±0.6%, p=0.95), or when normalized to risk area (% of AAR; Saline: 46.2±4.0%, CDC: 46.4±2.1%, CDC+CsA: 49.2±3.1%, p=0.79). There was no difference in CT ejection fraction (Saline: 49±2% vs. CDC: 46±2% vs. CDC+CsA: 47±2%, p=0.72). Wall thickening by echocardiography in the LAD‐perfused (Saline: 26±8% vs. CDC: 18±4% vs. CDC+CsA: 18±5%, p=0.56) and the remote, non‐infarcted (Saline: 100±7% vs. CDC: 111±10% vs. CDC+CsA: 119±11%, p=0.40) areas of the LV were also similar between groups.ConclusionGlobal infusion of allogeneic CDCs in the absence of CsA immunosuppression does not reduce chronic myocardial infarct size nor improve global or regional measures of LV function. Surprisingly, CDC therapy with IV CsA administered at the time of reperfusion does not appear to elicit previously demonstrated reparative effects. These data indicate that oral CsA pretreatment may be required to effect improved LV function with global intracoronary CDC therapy.Support or Funding InformationSupported by the National Heart Lung and Blood Institute (HL‐061610), the American Heart Association (17SDG33660200), the National Center for Advancing Translational Sciences (UL1TR001412), the Department of Veterans Affairs (1IO1BX002659), the New York State Department of Health (NYSTEM CO24351), and the Albert and Elizabeth Rekate Fund in Cardiovascular Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Altered hematological, biochemical and immunological parameters as predictive biomarkers of severity in experimental myocardial infarction

Preclinical studies in cardiovascular medicine are necessary to translate basic research to the clinic. The porcine model has been widely used to understand the biological mechanisms involved in cardiovascular disorders for which purpose different closed-chest models have been developed in the last years to mimic the pathophysiological events seen in human myocardial infarction.In this work, we studied hematological, biochemical and immunological parameters, as well as Magnetic resonance derived cardiac function measurements obtained from a swine myocardial infarction model. We identified some blood parameters which were significantly altered after myocardial infarction induction. More importantly, these parameters (gamma-glutamyl transferase, glutamic pyruvic transaminase, red blood cell counts, hemoglobin concentration, hematocrit, platelet count and plateletcrit) correlated positively with cardiac function, infarct size and/or cardiac enzymes (troponin I and creatine kinase-MB).Thus several blood-derived parameters have allowed us to predict the severity of myocardial infarction in a clinically relevant animal model. Therefore, here we provide a simple, affordable and reliable way that could prove useful in the follow up of myocardial infarction and in the evaluation of new therapeutic strategies in this animal model.

Effect of Intracoronary Metformin on Myocardial Infarct Size in Swine.

Metformin has been demonstrated to decrease infarct size (IS) and prevent postinfarction left ventricular (LV) remodeling in rodents when given intravenously at the time of reperfusion. It remains unclear whether similar cardioprotection can be achieved in a large animal model. The objective of this study was to determine whether intravascular infusion of metformin at the time of reperfusion reduces myocardial IS in a porcine model of acute myocardial infarction. In a blinded and randomized preclinical study, closed-chest swine (n=20) were subjected to a 60-minute left anterior descending coronary artery occlusion to produce myocardial infarction. Contrast-enhanced computed tomography was performed during left anterior descending coronary artery occlusion to assess the ischemic area-at-risk. Animals were randomized to receive either metformin or vehicle as an initial intravenous bolus (5 mg/kg) 8 minutes before reperfusion, followed by a 15-minute left coronary artery infusion (1 mg/kg per minute) commencing with the onset of reperfusion. Echocardiography and computed tomographic imaging of LV function were performed 1 week later, at which time the heart was removed for postmortem pathological analysis of area-at-risk and IS (triphenyltetrazolium chloride). Baseline variables including hemodynamics and LV function were similar between groups. Peak circulating metformin concentrations of 374±35 µmol/L were achieved 15 minutes after reperfusion. There was no difference between the area-at-risk as a percent of LV mass by computed tomography (vehicle: 20.7%±1.1% versus metformin: 19.7%±1.3%; P=0.59) or postmortem pathology (22.4%±1.2% versus 20.2%±1.2%; P=0.21). IS relative to area-at-risk averaged 44.5%±5.0% in vehicle-treated versus 38.2%±6.8% in metformin-treated animals ( P=0.46). There was no difference in global function 7 days after myocardial infarction as assessed by echocardiography or computed tomographic ejection fraction (56.2%±2.6% versus 56.3%±2.4%; P=0.98). In contrast to rodent hearts, postconditioning with high-dose metformin administered immediately before reperfusion does not reduce IS or improve LV function 7 days after myocardial infarction in swine. These results reinforce the importance of rigorously testing therapies in large animal models to facilitate clinical translation of novel cardioprotective therapies.

Head-to-head comparison of two engineered cardiac grafts for myocardial repair: From scaffold characterization to pre-clinical testing

Cardiac tissue engineering, which combines cells and supportive scaffolds, is an emerging treatment for restoring cardiac function after myocardial infarction (MI), although, the optimal construct remains a challenge. We developed two engineered cardiac grafts, based on decellularized scaffolds from myocardial and pericardial tissues and repopulated them with adipose tissue mesenchymal stem cells (ATMSCs). The structure, macromechanical and micromechanical scaffold properties were preserved upon the decellularization and recellularization processes, except for recellularized myocardium micromechanics that was ∼2-fold stiffer than native tissue and decellularized scaffolds. Proteome characterization of the two acellular matrices showed enrichment of matrisome proteins and major cardiac extracellular matrix components, considerably higher for the recellularized pericardium. Moreover, the pericardial scaffold demonstrated better cell penetrance and retention, as well as a bigger pore size. Both engineered cardiac grafts were further evaluated in pre-clinical MI swine models. Forty days after graft implantation, swine treated with the engineered cardiac grafts showed significant ventricular function recovery. Irrespective of the scaffold origin or cell recolonization, all scaffolds integrated with the underlying myocardium and showed signs of neovascularization and nerve sprouting. Collectively, engineered cardiac grafts -with pericardial or myocardial scaffolds- were effective in restoring cardiac function post-MI, and pericardial scaffolds showed better structural integrity and recolonization capability.

Native T1 mapping for characterization of acute and chronic myocardial infarction in swine: Comparison with contrast‐enhanced MRI

Native T₁ mapping for characterization of acute and chronic myocardial infarction in swine: Comparison with contrast‐enhanced MRI

Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell-Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine.

Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform. In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch. The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival. We have fabricated a clinically relevant size of hCMP with trilineage cardiac cells derived from human induced-pluripotent stem cells. The hCMP matures in vitro during 7 days of dynamic culture. Transplantation of this type of hCMP results in significantly reduced infarct size and improvements in cardiac function that are associated with reduction in left ventricular wall stress. The hCMP treatment is not associated with significant changes in arrhythmogenicity.

Atrial Infarction and Ischemic Mitral Regurgitation Contribute to Post-MI Remodeling of the Left Atrium

BackgroundLeft atrial (LA) remodeling after an acute myocardial infarction (MI) is poorly characterized regarding its determinants or its effect on ischemic mitral regurgitation (MR) development. ObjectivesThe purpose of this study was: 1) to compare LA structural remodeling in experimental MI swine models recapitulating the effects of left ventricular (LV) dysfunction, ischemic MR, and left atrial infarction (LAI); and 2) to analyze how LA remodeling influences ischemic MR development. MethodsThree models of MI were generated: 1) proximal left circumflex (LCx) coronary artery occlusion involving the LA branch (LAI group); 2) proximal LCx occlusion not involving the LA branch (LCx group); and 3) left anterior descending (LAD) occlusion (LAD group). Serial cardiac magnetic resonance scans were performed to define LA and LV remodeling and ischemic MR, and were correlated with histology. ResultsOcclusion of the LA branch (LAI group) induced a greater degree of LA dilation at 1 and 8 weeks post-MI than the LCx and LAD groups, along with early and severe impairment of LA function. In the LCx and LAD groups, LA dysfunction was less pronounced and not consistent. Development of ischemic MR was more pronounced in the LAI group than in the LCx group. Histology confirmed atrial infarction with extensive fibrosis in the LAI group and interstitial fibrosis in the LCx group. In the LAD group, LA remodeling was not observed by cardiac magnetic resonance or histology. ConclusionsWe provide the first experimental evidence of the deleterious effect of acute LAI on atrial structural remodeling, characterized by early LA dilation, dysfunction, and fibrosis, and early occurrence of ischemic MR.

Native T1 mapping for characterization of acute and chronic myocardial infarction in swine: Comparison with contrast-enhanced MRI.

Both acute and chronic myocardial infarction (AMI and CMI, respectively) exhibit delayed enhancement; however, clinical decision-making processes frequently require the differentiation of these two types of myocardial injury. To investigate the reliability of AMI and CMI characterization using native T1 mapping and its feasibility for discriminating AMI from CMI. Case-control. The study cohort comprised 12 AMI (mean post-MI, 3.75 ± 1.29 days) and 15 CMI (mean post-MI, 39.53 ± 6.10 days) Bama mini-pigs. Balanced steady-state free precession (bSSFP), segmented-turbo-FLASH-PSIR, and modified Look-Locker inversion recovery (MOLLI) sequences at 3.0T. The infarct sizes were compared on matching short-axis slices of late-gadolinium-enhanced (LGE) images and T1 maps by two experienced radiologists. The infarct sizes were compared on matching short-axis slices of LGE images and T1 maps, and agreement was determined using linear regression and Bland-Altman analyses. The native T1 values were compared between AMI and CMI models (independent sample t-test). The intraclass correlation coefficient was used to assess inter- and intraobserver variability. Measured infarct sizes did not differ between native T1 mapping and LGE images (AMI: P = 0.913; CMI: P = 0.233), and good agreement was observed between the two techniques (AMI: bias, -3.38 ± 19.38%; R2 = 0.96; CMI: bias, -10.55 ± 10.90%; R2 = 0.90). However, the native infarction myocardium T1 values and the T1 signal intensity ratio of infarct and remote myocardium (T1 SI ratio) did not differ significantly between AMI and CMI (P = 0.173). Noncontrast native T1 mapping can accurately determine acute and chronic infarct areas as well as conventional LGE imaging; however, it cannot distinguish acute from chronic MI. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1406-1414.

Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells.

The phenotypes of vascular smooth muscle cells (vSMCs) comprise a continuum bounded by predominantly contractile and synthetic cells. Some evidence suggests that contractile vSMCs can assume a more synthetic phenotype in response to ischemic injury, but the mechanisms that activate this phenotypic switch are poorly understood. To determine whether lactate, which increases in response to regional ischemia, may promote the synthetic phenotype in vSMCs. Experiments were performed with vSMCs that had been differentiated from human induced pluripotent stem cells and then cultured in glucose-free, lactate-enriched (L+) medium or in standard (L-) medium. Compared with the L- medium, the L+ medium was associated with significant increases in synthetic vSMC marker expression, proliferation, and migration and with significant declines in contractile and apoptotic activity. Furthermore, these changes were accompanied by increases in the expression of monocarboxylic acid transporters and were generally attenuated both by the blockade of monocarboxylic acid transporter activity and by transfection with iRNA for NDRG (N-myc downstream regulated gene). Proteomics, biomarker, and pathway analyses suggested that the L+ medium tended to upregulate the expression of synthetic vSMC markers, the production of extracellular proteins that participate in tissue construction or repair, and the activity of pathways that regulate cell proliferation and migration. Observations in hypoxia-cultured vSMCs were similar to those in L+-cultured vSMCs, and assessments in a swine myocardial infarction model suggested that measurements of lactate levels, lactate-dehydrogenase levels, vSMC proliferation, and monocarboxylic acid transporter and NDRG expression were greater in the ischemic zone than in nonischemic tissues. These results demonstrate for the first time that vSMCs assume a more synthetic phenotype in a microenvironment that is rich in lactate. Thus, mechanisms that link glucose metabolism to vSMC phenotypic switching could play a role in the pathogenesis and treatment of cardiovascular disease.

Pulmonary vasodilation by phosphodiesterase 5 inhibition is enhanced and nitric oxide independent in early pulmonary hypertension after myocardial infarction.

Myocardial infarction (MI) may result in pulmonary hypertension (PH). Inhibition of phosphodiesterase 5 (PDE5), the enzyme responsible for the breakdown of cGMP in vascular smooth muscle, has become part of the contemporary therapeutic armamentarium for pulmonary arterial hypertension and may also be beneficial for PH secondary to MI. Nitric oxide (NO) is an important activator of cGMP synthesis and can be enhanced in early PH and decreased in severe PH. In the present study, we investigated if PDE5 inhibition ameliorates pulmonary hemodynamics in swine with PH secondary to MI and whether NO is essential. The PDE5 inhibitor EMD360527 was administered in awake, chronically instrumented swine with or without MI. At rest, PDE5 inhibition produced pulmonary vasodilation as evidenced by a decrease in pulmonary vascular resistance, which was more pronounced in MI ( n = 5) compared with normal swine ( n = 10, P ≤ 0.01) and was accompanied by an increase in stroke volume in MI swine. Both pulmonary vasodilation and increased stroke volume were maintained during exercise, suggesting that this therapy may improve exercise capacity in patients with PH secondary to MI. Interestingly, prior inhibition of NO significantly enhanced ( P ≤ 0.01) pulmonary vasodilation by PDE5 inhibition in both normal ( n = 8) and MI swine ( n = 5, P ≤ 0.05 vs. normal). This suggests that the increased vasodilator responses to PDE5 inhibition after MI were not due to an increase in NO-induced cGMP production. These observations indicate that PDE5 inhibition represents an interesting pharmacotherapeutic approach in early PH after a recent MI to prevent overt PH. NEW & NOTEWORTHY This research article is the first to describe that pulmonary vasodilation to phosphodiesterase 5 inhibition is enhanced and nitric oxide independent in resting and exercising swine with pulmonary hypertension as a result of myocardial infarction. This suggests that phosphodiesterase 5 inhibition can normalize pulmonary hemodynamics in postcapillary pulmonary hypertension after a recent myocardial infarction and may improve exercise capacity.

GW28-e0343 Engineered bioactive graft reduces infarct size and improves cardiac function in swine myocardial infarction

GW28-e0343 Engineered bioactive graft reduces infarct size and improves cardiac function in swine myocardial infarction

P2562Comparison between two different natural decellularized scaffolds after myocardial infarction in swine

P2562Comparison between two different natural decellularized scaffolds after myocardial infarction in swine

Time course of VCAM-1 expression in reperfused myocardial infarction in swine and its relation to retention of intracoronary administered bone marrow-derived mononuclear cells.

BackgroundIntracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC), after acute myocardial infarction (AMI), has been shown to improve myocardial function. However, therapeutic efficacy is limited, possibly because cell retention rates are low, suggesting that optimization of cell retention might increase therapeutic efficacy. Since retention of injected BMMNC is observed only within infarcted, but not remote, myocardium, we hypothesized that adhesion molecules on activated endothelium following reperfusion are essential. Consequently, we investigated the role of vascular cell adhesion molecule 1 (VCAM-1) in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion.Methods and resultsVCAM-1 expression in the infarct and remote region was quantified at 1, 3, 7, 14, and 35 days, post-reperfusion (n≥6 swine per group). Since expression levels were significantly higher at 3 days (2.41±0.62%) than at 7 days (0.98±0.28%; p<0.05), we compared the degree of cell retention at those time points in a follow-up study, in which an average of 43·106 autologous BMMNCs were infused intracoronary at 3, or 7 days, post-reperfusion (n = 6 swine per group) and retention was histologically quantified one hour after intracoronary infusion of autologous BMMNCs. Although VCAM-1 expression correlated with retention of BMMNC within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3±1.3% vs. 3.1±1.4%, p = 0.72). This was not due to the composition of infused bone marrow cell fractions (analyzed with flow cytometry; n = 5 per group), as cell composition of the infused BMMNC fractions was similar.ConclusionThese findings suggest that VCAM-1 expression influences to a small degree, but is not the principal determinant of, BMMNC retention.

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling.

Noninvasive Assessment of an Engineered Bioactive Graft in Myocardial Infarction: Impact on Cardiac Function and Scar Healing.

Cardiac tissue engineering, which combines cells and biomaterials, is promising for limiting the sequelae of myocardial infarction (MI). We assessed myocardial function and scar evolution after implanting an engineered bioactive impedance graft (EBIG) in a swine MI model. The EBIG comprises a scaffold of decellularized human pericardium, green fluorescent protein‐labeled porcine adipose tissue‐derived progenitor cells (pATPCs), and a customized‐design electrical impedance spectroscopy (EIS) monitoring system. Cardiac function was evaluated noninvasively by using magnetic resonance imaging (MRI). Scar healing was evaluated by using the EIS system within the implanted graft. Additionally, infarct size, fibrosis, and inflammation were explored by histopathology. Upon sacrifice 1 month after the intervention, MRI detected a significant improvement in left ventricular ejection fraction (7.5% ± 4.9% vs. 1.4% ± 3.7%; p = .038) and stroke volume (11.5 ± 5.9 ml vs. 3 ± 4.5 ml; p = .019) in EBIG‐treated animals. Noninvasive EIS data analysis showed differences in both impedance magnitude ratio (−0.02 ± 0.04 per day vs. −0.48 ± 0.07 per day; p = .002) and phase angle slope (−0.18° ± 0.24° per day vs. −3.52° ± 0.84° per day; p = .004) in EBIG compared with control animals. Moreover, in EBIG‐treated animals, the infarct size was 48% smaller (3.4% ± 0.6% vs. 6.5% ± 1%; p = .015), less inflammation was found by means of CD25+ lymphocytes (0.65 ± 0.12 vs. 1.26 ± 0.2; p = .006), and a lower collagen I/III ratio was detected (0.49 ± 0.06 vs. 1.66 ± 0.5; p = .019). An EBIG composed of acellular pericardium refilled with pATPCs significantly reduced infarct size and improved cardiac function in a preclinical model of MI. Noninvasive EIS monitoring was useful for tracking differential scar healing in EBIG‐treated animals, which was confirmed by less inflammation and altered collagen deposit. Stem Cells Translational Medicine 2017;6:647–655

Erratum: Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects.

Scientific Reports 6: Article number: 28250; published online: 20 June 2016; updated: 02 September 2016 In this Article, Min Cai is incorrectly affiliated with ‘Department of Radiology, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center of Cardiovascular Disease, PekingUnion Medical College &amp; Chinese Academy of Medical Sciences, Beijing, China.

Bone Marrow Mesenchymal Stem Cells (BM-MSCs) Improve Heart Function in Swine Myocardial Infarction Model through Paracrine Effects.

Stem cells are promising for the treatment of myocardial infarction (MI) and large animal models should be used to better understand the full spectrum of stem cell actions and preclinical evidences. In this study, bone marrow mesenchymal stem cells (BM-MSCs) were transplanted into swine heart ischemia model. To detect glucose metabolism in global left ventricular myocardium and regional myocardium, combined with assessment of cardiac function, positron emission tomography-computer tomography (PET-CT) and magnetic resonance imaging (MRI) were performed. To study the changes of glucose transporters and glucose metabolism-related enzymes and the signal transduction pathway, RT-PCR, Western-blot, and immunohistochemistry were carried out. Myocardium metabolic evaluation by PET-CT showed that mean signal intensity (MSI) increased in these segments at week 4 compared with that at week 1 after BM-MSCs transplantation. Moreover, MRI demonstrated significant function enhancement in BM-MSCs group. The gene expressions of glucose transporters (GLUT1, GLUT4), glucose metabolism-related enzymes phosphofructokinase (PFK), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)) and 70-kDa ribosomal protein S6 kinase (p70s6k) in BM-MSCs injected areas were up-regulated at week 4 after BM-MSCs transplantation and this was confirmed by Western-blot and immunohistochemistry. In conclusions, BM-MSCs transplantation could improve cardiac function in swine MI model by activation of mTOR signal transduction pathway.

A Multidisciplinary Assessment of Remote Myocardial Fibrosis After Reperfused Myocardial Infarction in Swine and Patients.

In extensive nonreperfused myocardial infarction (MI), remote fibrosis has been documented. Early reperfusion by primary angioplasty represents the gold standard method to minimize the extension of the infarction. We aimed to ascertain whether fibrosis also affects remote regions in reperfused MI in swine and patients. Swine were subjected to a transient occlusion of the left anterior descending artery followed by 1-week or 1-month reperfusion. Collagen content in the remote area macroscopically, microscopically, by magnetic resonance microimaging, and at the molecular level was similar to controls. In patients with previous MI, samples from autopsies displayed a significant increase in collagen content only in the infarct region. In patients with previous MI submitted to cardiac magnetic resonance-T1 mapping, the extracellular volume fraction in remote segments was similar to that for controls. In all scenarios, the remote region did not show a significant increase of collagen content in comparison with controls.

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (−41±10%), whereas infarct mass remained stable in the Control-MI group (+3±17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53±0.43% vs 3.38±0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling.

Magnetic resonance microimaging of a swine infarcted heart: Performing cardiac virtual histologies.

The aim of this study is to develop a computer-aided intuitive software tool based on MATLAB to reproduce the functions of a virtual histology over Magnetic Resonance (MR) microimages of small samples of swine's infarcted hearts. The basic characterization consists of selecting regions of interest (ROIs) of that MR microimage and extracting the most important information of these regions. The software tool will implement intuitive and sophisticated tools that allow the user to define ROIs on the different types of images provided by the MR scanner. The final purpose of this tool will be to analyze the acquired data in order to characterize some aspects of the later possible events after a myocardial infarction in swine's hearts and expand the study to human cases.