Abstract P333: The Vascular Barrier: A Common Anti-arrhythmic Target In Atrial Fibrillation And Myocardial Infarction

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Louisa Mezache ◽  
Gerard Nuovo ◽  
Rengasayee Veeraraghavan
Keyword(s):  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Early Stage ◽  
Border Zone ◽  
Vascular Endothelial ◽  
Vascular Leak ◽  
Localization Analysis ◽  
Inflammatory Insult ◽  
Antiarrhythmic Efficacy

Vascular leak is a major sequela of inflammation, which is associated with arrhythmic pathologies such as atrial fibrillation (AF) and myocardial infarction (MI). We recently demonstrated that the vascular leak-inducing cytokine vascular endothelial growth factor (VEGF; 90-580 pg/ml - levels found in AF patients) induces acute remodeling (30-60 minutes) of sodium channel (Na V 1.5) -rich intercalated disk (ID) nanodomains, disrupting their ultrastructure and prompting translocation of Na V 1.5 from these sites. This in turn disrupted impulse propagation and promoted arrhythmias in murine atria. Here, we tested the hypotheses that i) similar acute pro-arrhythmic remodeling occurs in the ventricles of MI patients, and ii) protecting the vascular barrier may prevent arrhythmias following an acute inflammatory insult. First, we examined myocardial samples from five human MI patients. VEGF was overexpressed in both cardiomyocytes and vascular endothelium in the border zone surrounding <6 month-old infarcts. Notably, co-localization analysis showed significantly reduced Na V 1.5 near both connexin43 and N-cadherin within the border zone in 1-, 3-, and 9-day-old infarcts, paralleling our observations in mouse atria. Next, we returned to our murine model of AF induced by acute inflammatory insult (100 pg/ml VEGF for 60 minutes) to test the antiarrhythmic efficacy of protecting the vascular endothelial barrier. Overall, median in vivo arrhythmia burden was higher in VEGF-treated mice relative to vehicle controls (7.5±11 vs. 0±6 s/hr). We tested two strategies shown to prevent vascular barrier breakdown: Blocking connexin43 hemichannels (αCT11 peptide) decreased in vivo arrhythmia burden to 0 ± 6.07 s/hr. Panx1-IL2 (a peptide inhibitor of Panx1 channels) treatment decreased also in vivo arrhythmia burden (0 ± 15.57 s/hr with 1.6 μM Panx1-IL2). Similar antiarrhythmic efficacy was also achieved with small molecule inhibitors of Cx43 and Panx1. These results highlight VEGF-induced vascular leak as a novel mechanism for acute arrhythmias both in the early stage AF and following MI. Indeed, this mechanism may contribute to post-MI AF. Importantly, vascular-barrier protection may be a viable strategy to prevent these arrhythmias.

Abstract 13383: The Vascular Endothelial Barrier: A Novel Therapeutic Target for Preventing Atrial Fibrillation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Louisa Mezache ◽  
Heather Struckman ◽  
Anna Phillips ◽  
Stephen Baine ◽  
Amara Greer-short ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Super Resolution ◽  
Vascular Endothelial ◽  
Vascular Leak ◽  
Barrier Breakdown ◽  
Endothelial Growth Factor ◽  
Intercalated Disk

Atrial fibrillation (AF), the most common arrhythmia, is associated with inflammation and vascular dysfunction. AF patients have elevated levels of vascular endothelial growth factor (VEGF; 90-580 pg/ml), which promotes vascular leak and edema. We have previously identified edema-induced disruption of sodium channel (Na V 1.5) -rich intercalated disk (ID) nanodomains as a novel arrhythmia mechanism. We hypothesized that (i) elevated VEGF levels promote AF by disrupting ID nanodomains, and slowing atrial conduction, and (ii) protection of the vascular barrier can prevent these arrhythmias. Clinically-relevant VEGF levels (500 pg/ml, 60 minutes) increased FITC-dextran extravasation (99.3% vs. 24.3% in vehicle controls) in WT mouse hearts, consistent with increased vascular leak. Electron microscopy revealed ID nanodomain swelling, near both gap junctions (perinexi; 64±9nm vs 17±1nm) and mechanical junctions (63±4nm vs 27±2nm) in VEGF-treated hearts relative to controls. Super-resolution STORM microscopy revealed Na V 1.5 enrichment at perinexi (9±2 fold) and N-cadherin-rich sites (7±1 fold) relative to non-junctional ID sites in control hearts. VEGF reduced Na V 1.5 enrichment at both sites (6±1 and 4±1 fold, respectively), consistent with Na V 1.5 translocation from ID nanodomains. Atrial conduction, assessed by optical mapping, was slowed by VEGF (10±0.4 cm/s vs 21.3±1.3 cm/s at baseline). VEGF increased atrial arrhythmia burden both ex vivo (80% vs 0% in vehicle controls) and in vivo (70% vs 20% in vehicle controls). Next, we tested two strategies shown to prevent vascular barrier breakdown. Blocking connexin43 hemichannels (αCT11 peptide) decreased both incidence (40%) and duration (1.45±3.42s) of VEGF-induced arrhythmias. Likewise, blocking pannexin1 channels (Panx1-IL2 peptide) shortened VEGF-induced arrhythmias (2.48±0.83s). Mefloquine and spironolactone, which are small molecules that respectively inhibit Cx43 hemichannels and pannexin channels, were also found to effectively prevent VEGF-induced atrial arrhythmias. These results highlight VEGF-induced vascular leak as a novel mechanism for AF, and suggest vascular barrier protection as an anti-arrhythmic strategy.

scholarly journals Integration of “omics” techniques: Dronedarone affects cardiac remodeling in the infarction border zone

2018 ◽  
Vol 243 (11) ◽  
pp. 895-910 ◽  
Author(s):  
Ravi K Chilukoti ◽  
Josefine Lendeckel ◽  
Katrin Darm ◽  
Alicja Bukowska ◽  
Andreas Goette ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Acute Myocardial Infarction ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Matricellular Proteins ◽  
Integrated Network ◽  
And Function

Dronedarone improves microvascular flow during atrial fibrillation and reduces the infarct size in acute models of myocardial infarction. However, dronedarone might be harmful in patients with recent decompensated heart failure and increases mortality in patients with permanent atrial fibrillation. A pathophysiological explanation for these discrepant data is lacking. This study investigated the effects of dronedarone on gene and protein expression in the infarcted area and border zone in pigs subjected to anterior ischemia/reperfusion myocardial infarction. The ischemia/reperfusion myocardial infarction was induced in 16 pigs. Eight pigs were treated with dronedarone for 28 days after myocardial infarction, the remaining pigs served as control. Microarray-based transcriptome profiling and 2D-DIGE-based proteome analysis were used to assess the effects of dronedarone on left ventricular gene expression in healthy (LV), infarcted (MI), and border zone tissue. Selected targets were validated by RT-qPCR or immunoblot analyses, with special emphasize given to the transcriptome/proteome overlap. Combined “omics” analysis was performed to identify most significant disease and function charts affected by dronedarone and to establish an integrated network. The levels of 879 (BZ) or 7 (MI) transcripts and 51 (LV) or 15 (BZ) proteins were significantly altered by dronedarone, pointing to a substantial efficacy of dronedarone in the border zone. Transcriptome and proteome data indicate that dronedarone influences post-infarction remodeling processes and identify matricellular proteins as major targets of dronedarone in this setting. This finding is fully supported by the disease and function charts as well as by the integrated network established by combined “omics”. Dronedarone therapy alters myocardial gene expression after acute myocardial infarction with pronounced effects in the border zone. Dronedarone promotes infarct healing via regulation of periostin and might contribute to the limitation of its expansion as well as cardiac rupture. Thus, there are no experimental hints that dronedarone per se has direct harmful effects after MI in ventricular tissue. Impact statement Dronedarone reduced the infarct size in models of acute myocardial infarction (MI). Here, we show that dronedarone attenuates many of the substantial changes in gene expression that are provoked by acute myocardial infarction (AMI) in pigs. Dronedarone modifies the expression of gene panels related to post-infarction cardiac healing and remodeling processes and, most remarkably, this occurs predominantly in the infarction border-zone and much less so in the vital or infarcted myocardium. Combined “omics” identified matricellular proteins and ECM as major dronedarone-regulated targets and emphasizes their relevance for Disease Charts and Tox Function Charts associated with tissue remodeling and cellular movement. The results demonstrate dronedarone’s capability of regulating cardiac repair and remodeling processes specifically in the infarction border zone and identify underlying mechanisms and pathways that might be employed in future therapeutic strategies to improve long-term cardiac tissue function and stability.

Cytokine signaling during myocardial infarction: sequential appearance of IL-1 beta and IL-6

1995 ◽  
Vol 269 (2) ◽  
pp. R229-R235 ◽  
Author(s):  
I. Guillen ◽  
M. Blanes ◽  
M. J. Gomez-Lechon ◽  
J. V. Castell
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Protein Synthesis ◽  
Proinflammatory Cytokines ◽  
Early Stage ◽  
Myocardial Infarct ◽  
Cytokine Signaling ◽  
Target Cells ◽  
Necrosis Factor Alpha

The purpose of this study was to investigate the significance of the sequential changes in proinflammatory cytokines observed in the plasma of patients early after myocardial infarct: a rise in interleukin (IL)-1 beta (308 +/- 126 vs. 141 +/- 78 pg/ml, P < 0.01) between 0 and 2 h followed by an IL-6 peak (49 +/- 24 vs. 14.5 +/- 13 pg/ml, P < 0.01) 4-9 h later. No significant changes in tumor necrosis factor-alpha (TNF-alpha) were observed at this early stage. The linkage between IL-1 beta and IL-6 secretions is supported by 1) the ability of patient's plasma drawn early after myocardial infarction to induce IL-6 mRNA and protein synthesis in cells that may be potential targets in vivo (fibroblasts and endothelial cells), 2) suppression of this activity by antibodies against IL-1 beta, and 3) a delay between IL-1 beta and IL-6 peaks in vivo (4-9 h), which is similar to the time required for maximal IL-6 production in IL-1 beta stimulated target cells in vitro (6 h). This sequential signaling might serve as the basis for an amplification mechanism of proinflammatory cytokines. In fact, a much greater synthesis of C-reactive protein was observed in hepatocytes when stimulated with conditioned medium of fibroblasts or endothelial cells that had previously been incubated with plasma of patients. The results of our work strongly suggest that, by inducing IL-6 in potential target cells, IL-1 beta could act as the primary, but indirect, signal that stimulates acute-phase protein synthesis after myocardial injury.

Early upregulation of myocardial CXCR4 expression is critical for dimethyloxalylglycine-induced cardiac improvement in acute myocardial infarction

2016 ◽  
Vol 310 (1) ◽  
pp. H20-H28 ◽  
Author(s):  
Mari Mayorga ◽  
Matthew Kiedrowski ◽  
Patricia Shamhart ◽  
Farhad Forudi ◽  
Kristal Weber ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Hypoxia Inducible Factor ◽  
Cardiac Repair ◽  
Cxcr4 Expression ◽  
Border Zone ◽  
H9c2 Cells ◽  
Myocardial Repair ◽  
Infarct Zone ◽  
Cxcr4 Axis

The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1α requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.

scholarly journals Interleukin-37b inhibits the growth of murine endometriosis-like lesions by regulating proliferation, invasion, angiogenesis and inflammation

2020 ◽  
Vol 26 (4) ◽  
pp. 240-255
Author(s):  
Yongpei He ◽  
Ting Xiong ◽  
Fang Guo ◽  
Zhenzhen Du ◽  
Yixian Fan ◽  
...  
Keyword(s):  
Early Stage ◽  
Inflammatory Factors ◽  
Epithelial Cell Line ◽  
Vascular Endothelial ◽  
Gynecological Disease ◽  
Endothelial Growth Factor ◽  
In Vitro Treatment

Abstract Endometriosis is a gynecological disease with abnormal expression of interleukin (IL)-37 which can suppress inflammation and the immune system. Here we investigated the role of the IL-37b splice variant in endometriosis in vivo and in vitro. In a murine model of endometriosis, in vivo administration of IL-37b significantly inhibited the development of lesions judged by the number (P = 0.0213), size (P = 0.0130) and weight (P = 0.0152) of lesions. IL-37b had no effect on the early stage of lesion formation, however administration in the growth stage of lesions decreased the number (P = 0.0158), size (P = 0.0158) and weight (P = 0.0258) of lesions compared with PBS control, an effect that was not reversed by macrophage depletion. Expressions of inflammatory factors, matrix metalloproteinases and vascular endothelial growth factor-A mRNA/protein were significantly inhibited in ectopic lesions following IL-37b administration, and in uterine segments treated in vitro. In vitro treatment of uterine segments with IL-37b inhibited phosphorylation of Akt and Erk1/2 in uterine segments. Isolated mouse endometrial stromal treated with IL-37b and transfected with pIL-37b plasmid got suppressed cell proliferation, invasion, angiogenesis and the expression of inflammatory factors. In addition, transfection with pIL-37b significantly decreased the phosphorylation of Akt and Erk1/2. IL-37b also inhibited proliferation and the expression of inflammatory and angiogenesis factors in epithelial cell line RL95–2. These findings suggest that IL-37b may inhibit the growth of lesions by regulating proliferation, invasion, angiogenesis and inflammation through Akt and Erk1/2 signaling pathway.

Abstract 217: Long Non-coding RNA Myocardial Infarction-associated Transcript (MIAT) Protects Cardiac Progenitor Cells From Oxidative Stress-induced Cell Death

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Liu Yang ◽  
Yang Yu ◽  
Baron Arnone ◽  
Chan Boriboun ◽  
Jiawei Shi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cell Death ◽  
Progenitor Cells ◽  
Cardiac Cells ◽  
Border Zone ◽  
Mouse Heart ◽  
Cardiac Progenitor Cells

Background: Long non-coding RNAs (lncRNAs) are an emerging class of RNAs with no or limited protein-coding capacity; a few of which have recently been shown to regulate critical biological processes. Myocardial infarction-associated transcript (MIAT) is a conserved mammalian lncRNA, and single nucleotide polymorphisms (SNPs) in 6 loci of this gene have been identified to be strongly associated with the incidence and severity of human myocardial infarction (MI). However, whether and how MIAT impacts on the pathogenesis of MI is unknown. Methods & Results: Quantitative RT-PCR analyses revealed that MIAT is expressed in neonatal mouse heart and to a lesser extent in adult heart. After surgical induction of MI in adult mice, MIAT starts to increase in 2 hours, peaks at 6 hours in atria and 12 hours in ventricles, and decreases to baseline at 24 hours. Fluorescent in situ hybridization (FISH) revealed a slight increase in the number of MIAT-expressing cells in the infarct border zone at 12 hours post-MI. Moreover, qRT-PCR analyses of isolated cardiac cells revealed that MIAT is predominantly expressed in cardiosphere-derived cardiac progenitor cells (CPCs). Treatment of CPCs with H 2 O 2 led to a marked upregulation of MIAT, while knockdown (KD) of MIAT resulted in a significantly impaired cell survival in vitro with H 2 O 2 treatment and in vivo after administered in the ischemic/reperfused heart. Notably, bioinformatics prediction and RNA immunoprecipitation identified FUS (fused in sarcoma) as a novel MIAT-interacting protein. FUS-KD CPCs displayed reduced cell viability and increased apoptosis under oxidative stress. Furthermore, MIAT overexpression enhanced survival of WT CPCs but not FUS-KD CPCs, suggesting that the protective role of MIAT is mediated by FUS. Conclusions: MIAT interacts with FUS to protect CPCs from oxidative stress-induced cell death.

Abstract 12105: Targeted Delivery of Therapeutic Agents After Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Siva Sai Krishna Dasa ◽  
Marc E Seamen ◽  
Brent A French ◽  
Kimberly A Kelly
Keyword(s):  
Myocardial Infarction ◽  
Phage Display ◽  
Targeted Delivery ◽  
Cell Types ◽  
Phage Display Library ◽  
Border Zone ◽  
Cell Type ◽  
Cellular Targets ◽  
Cell Type Specific

Introduction: Current therapies for heart failure (HF) after myocardial infarction (MI) only slow the progression of LV remodeling and have little capacity to regenerate cardiac muscle lost to MI. To expedite targeted delivery of regenerative therapies post-MI, we hypothesized that suitable targets could be identified by biopanning the heart with a phage display library in a mouse model of MI. Methods: A phage display library was biopanned in vivo to identify peptides specific for the infarct/border zone 4 days post-MI. Fluorescence molecular tomography (FMT) followed by tissue immunofluorescence was performed to interrogate the specificity of phage groups and individual clones with targeted phage at VT680 and neg control phage at VT750. The VT680 fluorophore on the targeted phage clones was then used to identify the cellular targets of those clones by counter-staining with antibodies against cell types of interest. Results: We identified phage clones specific for endothelium, cardiomyocytes, inflammatory fibroblasts and c-Kit+ cells present in the border zone post-MI. Liposomes conjugated with different cell type specific peptides had different accumulation rates in the post-infarct heart as visualized by FMT imaging (Fig. 1a). Immunofluorescence analysis demonstrated cell-type specific association of the targeted liposomes with cells expressing c-Kit, CD31 and Hrnr (Figs. 1b&c). We have also been successful in remote loading of anti-apoptotic and immune suppresive drugs into these liposomes and are currently studying their effect in mice after MI. Conclusions: Peptides identified by this screen enable the targeting of different cell types present in the border zone with different drugs. Identifying the molecular binding partners for these peptides may yield insight into the various events/pathways that evolve after a myocardial infarction.

Abstract 17202: Synthetic Modified RNA Driven Delivery of Insulin-Like Growth Factor-1 Promotes Early Cardiomyocyte Survival Post-Acute Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Chien-Ling Huang ◽  
Anne-Laure Leblond ◽  
Elizebeth C Turner ◽  
Arun H Kumar ◽  
Donnchadh M O’Sullivan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Border Zone ◽  
Insulin Like Growth Factor ◽  
Area At Risk ◽  
Akt Phosphorylation ◽  
Post Transfection ◽  
Erk Phosphorylation ◽  
Induced Apoptosis

To extend the temporal window for cytoprotection in cardiomyocytes undergoing apoptosis after hypoxia and myocardial infarction (MI), a synthetic modified RNA (modRNA) was used to drive delivery of insulin-like growth factor-1 (IGF1) within the area at risk in a murine model of MI. Transient transfection of synthetic GFP modRNA as an tracking indicator, with polyethylenimine (PEI)-based nanoparticle, showed efficient delivery of modRNA derived protein and minimum cytotoxicity in HL-1 cardiomyocytes (CM; 44±5%). ModRNA-IGF1 protein expression and secreted levels increased 3.5 fold ( p <0.05) at 24 hours and peaked at 48 hours post-transfection. The expression efficiency of modRNA was further enhanced (~2 fold at 24 hours post-transfection; p <0.05) under hypoxia-induced apoptosis conditions. ModRNA augmented secreted and cell associated IGF1 promoting CM survival and abrogating cell apoptosis (71±5% in controls to 37±7%, p <0.05). Translation of modRNA-IGF1 was sufficient to induce downstream increases in Akt and Erk phosphorylation (3 fold and 2 fold, respectively; p <0.01). Downregulation of IGF1 specific miRNA-1 and -133 (52% and 56%, respectively; p <0.01) but not miR-145 expression, was also confirmed. As proof of concept, intramyocardial delivery of modRNA-IGF1 but not control modRNA-GFP significantly decreased in TUNEL-positive cells within the infarct border zone (BZ) at 24 hours (22±3% versus 53±8% in controls, p <0.01). Akt phosphorylation was augmented while caspase-9 activity and cleavage was downregulated in the infarct BZ compared to controls ( p <0.05). These findings demonstrate extended in vivo cytoprotective effect of IGF1 24 hours post-MI driven by synthetic modRNA delivery. This provides a novel strategy to reduce ischemic injury by controlled release of IGF1 using a controllable bioactive nanoparticle for ‘short burst’ IGF1 cytoprotective therapy.

P5385Development and preclinical testing of upscaled engineered heart tissue for use in translational studies

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Jabbour ◽  
T Owen ◽  
M Reinsch ◽  
P Pandey ◽  
B Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Tissue Engineering ◽  
Stem Cell ◽  
Ex Vivo ◽  
Rabbit Model ◽  
Heart Tissue ◽  
Border Zone ◽  
Preclinical Testing ◽  
Engineered Heart Tissue

Abstract Introduction The lack of efficacy of stem cell therapy for the treatment of heart failure may be related to the poor retention rates offered by existing delivery methods (intra-coronary/ intramyocardial). Tissue engineering strategies improve cell retention in small animal models but data regarding engineered heart tissue (EHT) patches large enough for human studies are lacking. Purpose To upscale EHT to a clinically relevant size and mature the patch in-vitro. Once matured to undergo preclinical testing in a rabbit model of myocardial infarction. Methods We developed an upscaled EHT patch (3cm x 2cm x 1.5mm) able to contain up to 50 million human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM; Fig A/B). Myocardial infarction model was performed by permanent ligation. Results The patches began to beat spontaneously within 3 days of fabrication and after 28 days of dynamic culture (Late EHTs) showed the development of several mature characteristics when compared to early patches (<14 days from fabrication). For example, late EHTs contained hiPSC-CMs which were more aligned (hiPSC-CM accumulative angle change: early 2702±778 degrees [n=4] vs late 922±186 [n=5], p=0.042); showed better contraction kinetics (early peak contraction amplitude 87.9±5.8a.u. versus late 952±304a.u.; p<0.001) and faster calcium transients (time to peak: early 200.8±8.8ms [n=5] vs late 147.7±10.2ms [n=6], p=0.004; time to 75% decay: early 274±9.7ms vs late 219.9±2.7ms, p=0.0003). We then tested the EHT patch in-vivo using a rabbit model (Fig C). Patches were applied to normal (n=5) or infarcted hearts (n=8). Sham operations used non-cellular fibrin patches (n=5). The mean fraction of troponin positive cells in the graft was 27.8±10.3% at 25.2±1.7 days relative to day 0 [n=5] and KU80 (human specific marker) staining confirmed that this was of human origin. CD31 (Fig D) and KU80 staining revealed that the grafts were well vascularized and that the vasculature was not human in origin (therefore were originating from the host). Ex-vivo optical mapping revealed evidence of electrical coupling between the graft and host at 2 weeks and preliminary experiments indicated that the patch improved left ventricular function when grafted onto infarcted hearts. Telemetry recordings in vivo and arrhythmia provocation protocols (ex vivo) indicated that the patch was not proarrhythmic. Figure 1. A/B) EHT Images; C) 20x troponin T (brown) of rabbit myocardium/EHT (2 weeks after grafting), blue counterstain = haematoxylin, red lines = EHT borders; D) 63x CD31 staining (brown) rabbit/EHT border zone (2 weeks after grafting), blue stain = haematoxylin, red lines = graft/host border zones. Conclusion We successfully upscaled hiPSC-CM derived EHT to a clinically relevant size and demonstrated feasibility and integration using a rabbit model of myocardial infarction. Tissue engineering strategies may be the preferred modality of cell delivery for future cardiac regenerative medicine studies.

scholarly journals Direct Cardiac Reprogramming: Advances in Cardiac Regeneration

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Olivia Chen ◽  
Li Qian
Keyword(s):  
Myocardial Infarction ◽  
Heart Disease ◽  
Cell Fate ◽  
Early Stage ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Scar Tissue ◽  
Coronary Events

Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate bothin vitroandin vivo. Several experiments show functional improvements in mouse models of myocardial infarction followingin situgeneration of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming.

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