Adrenomedullin enhances therapeutic potency of bone marrow transplantation for myocardial infarction in rats

2005 ◽  
Vol 288 (3) ◽  
pp. H1444-H1450 ◽  
Author(s):  
Takafumi Fujii ◽  
Noritoshi Nagaya ◽  
Takashi Iwase ◽  
Shinsuke Murakami ◽  
Yoshinori Miyahara ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Infarct Size ◽  
Subcutaneous Administration ◽  
Capillary Density ◽  
Left Ventricular ◽  
Ischemic Myocardium ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Saline Control ◽  
Control Group

Adrenomedullin (AM), a potent vasodilator, induces angiogenesis and inhibits cell apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. Transplantation of bone marrow-derived mononuclear cells (MNC) induces angiogenesis. We investigated whether infusion of AM enhances the therapeutic potency of MNC transplantation in a rat model of myocardial infarction. Immediately after coronary ligation, bone marrow-derived MNC (5 × 106 cells) were injected into the ischemic myocardium, followed by subcutaneous administration of 0.05 μg·kg−1·min−1 AM (AM-MNC group) or saline (MNC group) for 3 days. Another two groups of rats received subcutaneous administration of AM alone (AM group) or saline (control group). Hemodynamic and histological analyses were performed 4 wk after treatment. Cardiac infarct size was significantly smaller in the MNC and AM groups than in the control group. A combination of AM infusion and MNC transplantation demonstrated a further decrease in infarct size. Left ventricular (LV) maximum change in pressure over time and LV fractional shortening were significantly improved only in the AM-MNC group. AM significantly increased capillary density in ischemic myocardium, suggesting the angiogenic potency of AM. AM infusion plus MNC transplantation demonstrated a further increase in capillary density compared with AM or MNC alone. Although MNC apoptosis was frequently observed 72 h after transplantation, AM markedly decreased the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells among the transplanted MNC. In conclusion, AM enhanced the angiogenic potency of MNC transplantation and improved cardiac function in rats with myocardial infarction. This beneficial effect may be mediated partly by the angiogenic property of AM itself and by its antiapoptotic effect on MNC.

Abstract 3400: Regeneration of Human Infarcted Heart Muscle in Chronic Coronary Artery Disease after myocardial infarction: Controlled study with Intracoronary Autologous Mononuclear Bone Marrow Cell Transplantation (IACT-Study)

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Matthias Koestering ◽  
Tobias Zeus ◽  
Michael Brehm ◽  
Thomas Bartsch ◽  
Christina M Schannwell ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Infarct Size ◽  
Mononuclear Cells ◽  
Marrow Cell ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Movement Velocity ◽  
Ventricular Ejection Fraction

Introduction: Remodeling of the left ventricle (LV) after myocardial infarction (MI) represents a major cause of infarct-related heart failure and death. After acute myocardial infarction transplantation of bone marrow cells (BMCs) leads to regeneration of infarcted zones due to neovascularization and regeneration of myocardium. We investigated cardiac performance of intracoronary transplantation of autologous BMCs in patients with chronic ischemic heart disease, suffered from transmural myocardial infarction. Methods: We treated 120 consecutive patients (51±14 years) with chronic myocardial infarction by intracoronary transplantation of autologous bone marrow mononuclear cells (BMCs) and compared them with a consecutive enrolled representative control group (n=45, 53±11 years). Bone marrow was harvested from the hip (~80 ml) and mononuclear cells were identified including CD34+, AC133+ and CD 34−, CD45−, CD14− cells. The median number of mononuclear cells harvested after overnight culture was 104 x 10 6 Results: After 3 months in the transplantation group, infarct size was reduced from (32±9 to 25±9%) significantly (p<0.001), and global left ventricular ejection fraction (45±9 to 51±10%) significantly (p<0.001); as well as infarction wall movement velocity (1.86 ± 0.72 to 3,12 ± 0.78cm/s) significantly (p<0.001), while in the control group no significant changes were observed during 3 months follow-up in infarct size (29±9 to 28±9%), in left ventricular ejection fraction (48±10 to 50±15%) and in wall movement velocity of infarcted area (1.81 ± 0.76 to 1.92 ± 0.78cm/s). After bone marrow cell transplantation, there was an significantly (p<0.05) improvement of maximum oxygen uptake (VO2max, +12%) and significantly (p<0.05) of regional 18F-Fluor-Desoxy-Glucose (FDG) uptake (PET) into infarcted tissue (+15%). Conclusions: These results demonstrate that selective intracoronary transplantation of autologous BMCs may reduce infarct size and improve LV function and myocardial glucose uptake in chronic ischemic heart disease after chronic infarcted myocardium.

Abstract 3899: SDF-1α Mediates the Therapeutic Effect of Human Adipose-Derived Stem Cells on Acute Myocardial Infarction Recruiting Bone Marrow-Derived Endothelial Progenitor Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masaaki Ii ◽  
Ayumi Yokoyama ◽  
Miki Horii ◽  
Hiroshi Akimaru ◽  
Takayuki Asahara
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Cardiac Function ◽  
Therapeutic Effect ◽  
Heart Diseases ◽  
Capillary Density ◽  
Ischemic Myocardium ◽  
Control Group ◽  
Adipose Derived Stem Cells ◽  
Ischemic Heart Diseases

Background: Recently, human multipotent adipose-derived stem cells (hMADSs) have been isolated featuring extensive expansion capacity ex vivo. However, little is known about the therapeutic efficacy of hMADS in ischemic heart diseases. We tested the hypothesis that hMADS transplantation may contribute to cardiac functional recovery following myocardial infarction (MI). Methods and Results: Nude rats were either transplanted with hMADSs (5x10 5 /rat, n=10) or PBS (control, n=9) in ischemic myocardium immediately following MI induction. The cardiac function, infarct size and capillary density in the peri-infarct area were evaluated by echocardiography and immunostaining 28 days after surgery. The cardiac function was significantly greater with increased capillary density and reduced fibrosis area in the hMADS group than that in the control group. Next, we examined tissue regeneration in the infarct heart by the transplanted hMADSs. However, remarkable differentiation of hMADSs into any cardiac cell lineages was not detected. To explore another mechanism for the favorable effect of hMADSs, we further examined mRNA expression of cytokines in hMADSs under hypoxic conditions. Although hypoxia decreased the expressions, robust VEGF, bFGF, and SDF-1α expressions were detected in hMADSs. Notably, the stem/progenitor chemokine SDF-1α expression in hMADSs was significantly greater than that in human mesenchymal stem cells that are well known to have a therapeutic effect on ischemic heart diseases. We then focused on SDF-1α /CXCR4 axis and examined the contribution of bone marrow (BM)-derived endothelial progenitor cells (EPCs), that have CXCR4 receptor for SDF-1v, to ischemic myocardium using a Tie2/LacZ BM transplantation nude mouse model. β-gal positive EPCs are frequently observed in ischemic myocardium in the hMADS group compared to the control group. Conclusion: hMADSs exhibit a therapeutic effect on cardiac function following MI with the production of VEGF, bFGF, and SDF-1α demonstrating paracrine effects rather than direct contribution to cardiac regeneration. These findings suggest that transplanted hMADSs and recruited EPCs may synergistically promote angiogenesis playing a role in ischemic myocardium.

Abstract 1612: Pharmacological Postconditioning Effect of G-csf Is Mediated through Activation of Pi3k-akt-enos Pathway and Opening the Mitochondrial Katp Channels in a Rabbit Model of Myocardial Infarction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shohei Sumi ◽  
Masamitsu Iwasa ◽  
Hiroyuki Kobayashi ◽  
Shinji Yasuda ◽  
Takahiko Yamaki ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Rabbit Model ◽  
Katp Channels ◽  
Saline Control ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Risk Area ◽  
Mitochondrial Katp Channels

It has been reported that granulocyte-colony-stimulating factor(G-CSF) improves cardiac function after myocardial infarction (MI). However, its direct effect on the myocardium and its signaling pathway remain unclear. We examined the acute beneficial effect of G-CSF on myocardial infarct size and its precise mechanisms in a rabbit model of myocardial infarction. In 80 Japanese white rabbits, MI was induced by 30 min of ischemia and 48 hours of reperfusion. Rabbits were intravenously injected with 10 μg/kg of G-CSF (G-CSF group, n=10) or saline (control group, n=10) immediately after reperfusion. The G-CSF+5HD group (n=10) was injected with 5-HD(5-hydroxydecanoate, a mitochondrial KATP channel blocker) 5 min before G-CSF injection. The G-CSF +wortmaninn group (n=10) was injected wortmaninn (0.6mg/kg) 5 min before G-CSF injection. G-CSF+L-NAME group (n=10) was injected with L-NAME (10mg/kg) 5 min before G-CSF injection. The 5HD alone (n=10), wortmannin alone (n=10), L-NAME alone (n=10) groups were respectively injected 5HD, wortmannin and L-NAME immediately after reperfusion. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot analysis was performed to examine the Akt and phospho-Akt and phospho-eNOS in the ischemic myocardium at 48 hours of reperfusion. The infarct size was significantly smaller in the G-CSF group (26.7±2.7%) than in the control group (42.3±4.6%). The infarct size-reducing effect of G-CSF was completely blocked by 5-HD (42.5±1.66%), wortmaninn(44.7±4.81) and L-NAME (42.1±4.2%). Wortmannin, L-NAME or 5HD alone did not affect the infarct size. Western blotting showed higher expression of phospho-Akt and phosho-eNOS in the infarct area in the G-CSF group than in the control group. G-CSF administered immediately after reperfusion reduces myocardial infarct size via activation of PI3K, Akt, eNOS and opening the mitochondrial KATP channels.

scholarly journals The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial

2020 ◽  
Vol 41 (38) ◽  
pp. 3702-3710 ◽  
Author(s):  
Anthony Mathur ◽  
Francisco Fernández-Avilés ◽  
Jozef Bartunek ◽  
Ann Belmans ◽  
Filippo Crea ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Bone Marrow ◽  
Adverse Events ◽  
Left Ventricular ◽  
Phase Iii ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Intracoronary Infusion ◽  
All Cause Mortality

Abstract Aims  Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent. Methods and results  Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2–8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48–7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84–7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0–5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7–12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group. Conclusions  Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.

scholarly journals Dynamic Tracking of Injected Mesenchymal Stem Cells after Myocardial Infarction in Rats: A Serial 7T MRI Study

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Xiuyu Chen ◽  
Minjie Lu ◽  
Ning Ma ◽  
Gang Yin ◽  
Chen Cui ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Capillary Density ◽  
Left Ventricular ◽  
Cine Mri ◽  
Control Group

Purpose.To track the fate of micron-sized particles of iron oxide (MPIO) labeled mesenchymal stem cells (MSCs) in vivo in a rat myocardial infarction model using 7T magnetic resonance imaging (MRI) scanner.Materials and Methods.Male MSCs (2 × 106/50 μL) dual-labeled with MPIO and CM-DiI were injected into the infarct periphery 7 days after myocardial infarction (MI). The control group received cell-free media injection. The temporal stem cell location, signal intensity, and cardiac function were dynamically assessed using a 7T MRI at 24 h before transplantation (baseline), 3 days, 2 weeks, and 4 weeks after transplantation, respectively.Results.MR hypointensities caused by MPIOs were observed on T2⁎-weighted images at all time points after MSCs injection. Cine-MRI showed that MSCs moderated progressive left ventricular remodeling. Double staining for iron and CD68 revealed that most of the iron-positive cells were CD68-positive macrophages. Real-time PCR for rat SRY gene showed the number of survival MSCs considerably decreased after transplantation. MSC-treated hearts had significantly increased capillary density in peri-infarct region and lower cardiomyocytes apoptosis and fibrosis formation.Conclusions.Iron particles are not a reliable marker for in vivo tracking the long-term fate of MSCs engraftment. Despite of poor cell retention, MSCs moderate left ventricular remodeling after MI.

scholarly journals HGF Treatment Promotes Cardiac Function and Cardiac Repair: Meta-analysis of Pig Models With Myocardial Infarction

2020 ◽  
Author(s):  
Chong Du ◽  
Xiao-Wen Chen ◽  
Ze-Mu Wang ◽  
Hao-Yu Meng ◽  
Ya-Fei Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Cardiac Function ◽  
Infarct Size ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Cardiac Repair ◽  
Control Group ◽  
Hepatocyte Growth ◽  
Better Than

Abstract Background: Previous studies reported that hepatocyte growth factor (HGF) could promote angiogenesis and cardiac function after myocardial infarction (MI) in pigs. However, the results of these studies were controversial. To clarify the therapeutic efficacy of local HGF administration after MI, we performed a systematic review and meta-analysis of data from the pig models, which could provide evidence for the feasibility of clinical HGF application.Methods: PubMed, EMBASE, and China National Knowledge Infrastructure were searched for randomized studies that correspond to our subject. The search terms included (hepatocyte growth factor OR HGF) AND (heart failure OR HF OR myocardial infarction OR MI OR AMI OR coronary heart disease OR CHD). The primary endpoint indicators were identified as the left ventricular ejection fraction (LVEF) and capillaries density. Other parameters reflecting cardiac function and ventricular remodeling were analyzed as secondary indicators, including ventricular volume, infarct size, apoptotic index and others.Results: In total, 9 studies were finally included in the meta-analysis. On comparing the cardiac function indexes, the HGF group was found to be better than the control group in regard to LVEF, stroke volume, left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV). However, no statistically significant differences were found in heart rate. Furthermore, HGF treatment promotes angiogenesis in ischemic areas, which is manifested by increased capillary density. In addition, the HGF group was found to be better than the control group when it comes to infarct size, arteriole densities, and other indicators of cardiac remodeling.Conclusions: HGF treatment can effectively promote cardiac function and cardiac repair including angiogenesis, and this strategy is a promising cardio-protective approach that merits further clinical studies.

Hyperbaric Oxygen Preconditioning Alleviates Myocardial Ischemic Injury in Rats

2008 ◽  
Vol 233 (11) ◽  
pp. 1448-1453 ◽  
Author(s):  
Cuihong Han ◽  
Li Lin ◽  
Weidong Zhang ◽  
Li Zhang ◽  
Shijun Lv ◽  
...  
Keyword(s):  
Infarct Size ◽  
Hyperbaric Oxygen ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Capillary Density ◽  
Left Ventricular ◽  
Ischemic Myocardium ◽  
Sham Surgery ◽  
Vegf Protein

It has been shown that after ischemia-reperfusion, application of hyperbaric oxygen (HBO) reduces cardiac injury. In this study we tested the hypothesis that HBO preconditioning reduces injury to the ischemic myocardium. One hundred and eight adult male Sprague-Dawley rats (250–280 g) were randomly divided into four groups: normoxia + sham surgery (CS), normoxia + permanent occlusion of the left anterior descending (LAD) coronary artery (CMI), HBO preconditioning + sham surgery (HS), and HBO preconditioning + permanent LAD occlusion (HMI). Rats receiving HBO preconditioning were intermittently exposed to 100% O2 at 2.5 atmosphere absolute (ATA) for 60 min, twice daily for 2 days followed by 12 hrs of recovery in room air prior to the myocardial ischemic insult induced by LAD ligation. Rats in the normoxia group were time-matched with the HBO group and maintained under normoxic conditions prior to LAD occlusion. At 3 and 7 days after LAD occlusion, heart function parameters were measured by inserting a catheter into the left ventricle, infarct size was calculated using the method of TTC staining, myocardial capillary density was determined by immunohistochemical staining with a monoclonal anti-CD31/PECAM-1 antibody, and VEGF protein level was determined by Western blot analysis. At 3 days after LAD ligation, the infarct size of the HMI group was significantly smaller than that of the CMI group (26 ± 2.5% vs. 38 ± 3%, P < 0.05). The heart function parameters including left ventricular systolic pressure (LVSP), +dP/dtmax and −dP/dtmax were significantly improved in the HMI group compared to the CMI group at 3 and 7 days after LAD occlusion. Capillary density and VEGF protein levels were significantly increased in the ischemic myocardium pre-exposed to HBO. We conclude that HBO preconditioning alleviates myocardial ischemia in rat model.

Growth hormone decreases phase II ventricular tachyarrhythmias during acute myocardial infarction in rats

2007 ◽  
Vol 112 (7) ◽  
pp. 385-391 ◽  
Author(s):  
Dimitrios A. Elaiopoulos ◽  
Dimitrios G. Tsalikakis ◽  
Maria G. Agelaki ◽  
Giannis G. Baltogiannis ◽  
Agathokleia C. Mitsi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Hormone ◽  
Phase I ◽  
Infarct Size ◽  
Phase Ii ◽  
Ventricular Tachyarrhythmia ◽  
Left Ventricular ◽  
Monophasic Action Potential ◽  
Control Group ◽  
Coronary Artery Ligation

GH (growth hormone) administration during acute MI (myocardial infarction) ameliorates subsequent LV (left ventricular) dysfunction. In the present study, we examined the effects of such treatment on arrhythmogenesis. A total of 53 Wistar rats (218±17 g) were randomized into two groups receiving two intraperitoneal injections of either GH (2 international units/kg of body weight; n=26) or normal saline (n=27), given at 24 h and 30 min respectively, prior to MI, which was generated by left coronary artery ligation. A single-lead ECG was recorded for 24 h post-MI, using an implanted telemetry system. Episodes of VT (ventricular tachyarrhythmia) and VF (ventricular fibrillation) during the first hour (phase I) and the hours following (phase II) MI were analysed. Monophasic action potential was recorded from the lateral LV epicardium at baseline and 24 h post-MI, and APD90 (action duration at 90% of repolarization) was measured. Infarct size was calculated 24 h post-MI. Infarct size and phase I VT+VF did not differ significantly between groups, but phase II hourly duration of VT+VF episodes was 82.8±116.6 s/h in the control group and 18.3±41.2 s/h in the GH group (P=0.0027), resulting in a lower arrhythmic (P=0.016) and total (P=0.0018) mortality in GH-treated animals. Compared with baseline, APD90 was prolonged significantly 24 h post-MI in the control group, displaying an increased beat-to-beat variation, but remained unchanged in the GH group. We conclude that GH decreases phase II VTs during MI in the rat. This finding may have implications in cardiac repair strategies.

scholarly journals Isoflurane Protects against Myocardial Infarction during Early Reperfusion by Activation of Phosphatidylinositol-3-Kinase Signal Transduction: Evidence for Anesthetic-induced Postconditioning in Rabbits

2005 ◽  
Vol 102 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Pascal C. Chiari ◽  
Martin W. Bienengraeber ◽  
Paul S. Pagel ◽  
John G. Krolikowski ◽  
Judy R. Kersten ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Coronary Occlusion ◽  
Minimum Alveolar Concentration ◽  
Left Ventricular ◽  
Saline Control ◽  
Phosphatidylinositol 3 Kinase ◽  
Area At Risk ◽  
Early Reperfusion ◽  
Phosphatidylinositol 3

Background Brief episodes of ischemia during early reperfusion after coronary occlusion reduce the extent of myocardial infarction. Phosphatidylinositol-3-kinase (PI3K) signaling has been implicated in this "postconditioning" phenomenon. The authors tested the hypothesis that isoflurane produces cardioprotection during early reperfusion after myocardial ischemia by a PI3K-dependent mechanism. Methods Pentobarbital-anesthetized rabbits (n = 80) subjected to a 30-min coronary occlusion followed by 3 h reperfusion were assigned to receive saline (control), three cycles of postconditioning ischemia (10 or 20 s each), isoflurane (0.5 or 1.0 minimum alveolar concentration), or the PI3K inhibitor wortmannin (0.6 mg/kg, intravenously) or its vehicle dimethyl sulfoxide. Additional groups of rabbits were exposed to combined postconditioning ischemia (10 s) and 0.5 minimum alveolar concentration isoflurane in the presence and absence of wortmannin. Phosphorylation of Akt, a downstream target of PI3K, was assessed by Western blotting. Results Postconditioning ischemia for 20 s, but not 10 s, reduced infarct size (P &lt; 0.05) (triphenyltetrazolium staining; 20 +/- 3% and 34 +/- 3% of the left ventricular area at risk, respectively) as compared with control (41 +/- 2%). Exposure to 1.0, but not 0.5, minimum alveolar concentration isoflurane decreased infarct size (21 +/- 2% and 43 +/- 3%, respectively). Wortmannin abolished the protective effects of postconditioning (20 s) and 1.0 minimum alveolar concentration isoflurane. Combined postconditioning (10 s) and 0.5 minimum alveolar concentration isoflurane markedly reduced infarct size (17 +/- 5%). This action was also abolished by wortmannin (44 +/- 2%). Isoflurane (1.0 minimum alveolar concentration) increased Akt phosphorylation after ischemia (32 +/- 6%), and this action was blocked by wortmannin. Conclusions Isoflurane acts during early reperfusion after prolonged ischemia to salvage myocardium from infarction and reduces the threshold of ischemic postconditioning by activating PI3K.

scholarly journals Elastin Stabilizes an Infarct and Preserves Ventricular Function

Circulation ◽  
2005 ◽  
Vol 112 (9_supplement) ◽  
Author(s):  
Tomohiro Mizuno ◽  
Terrence M. Yau ◽  
Richard D. Weisel ◽  
Chris G. Kiani ◽  
Ren-Ke Li
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Left Ventricular ◽  
Myocardial Scar ◽  
Elastic Fibers ◽  
Control Group ◽  
Lv Function ◽  
Infarct Region ◽  
Lv Volume

Background— After a myocardial infarction, the injured region becomes fibrotic and the myocardial scar may expand if the ventricular wall lacks elasticity. Cardiac dilatation may precipitate the vicious cycle of progressive heart failure. The present study evaluated the functional benefits of increasing elastin within a myocardial scar using cell based gene therapy. Methods and Results— A myocardial infarction was generated by ligation of the left anterior descending artery in rats. Six days later, 2×10 6 syngeneic rat endothelial cells transfected with the rat elastin gene (elastin group, n=14) or an empty plasmid (control group, n=14) were transplanted into the infarct scar. Cardiac function, left ventricular (LV) volume, and infarct size were monitored over 3 months by echocardiography, Langendorff measurements, and planimetry. Elastin deposition was evaluated in the cells and in the infarct region by Western blot assay and by histological examination. Recombinant elastin was found in the scar in the elastin group but not the control group during the 3 months after cell transplantation. Histological assessment demonstrated organized elastic fibers within the infarct region. LV volume and infarct size were significantly smaller ( P <0.05) in the elastin group than in the control group. Cardiac function evaluated by echocardiography and during Langendorff perfusion was significantly better ( P <0.05) in the elastin group than in the control group. Conclusions— Expressing recombinant elastin within the myocardial scar reduced scar expansion and prevented LV enlargement after a myocardial infarction. Altering matrix remodeling after an infarct preserved the LV function for at least 3 months.

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