scholarly journals Dual Manganese-Enhanced and Delayed Gadolinium-Enhanced MRI Detects Myocardial Border Zone Injury in a Pig Ischemia-Reperfusion Model

2011 ◽  
Vol 4 (5) ◽  
pp. 574-582 ◽  
Author(s):  
Rajesh Dash ◽  
Jaehoon Chung ◽  
Fumiaki Ikeno ◽  
Annett Hahn-Windgassen ◽  
Yuka Matsuura ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Border Zone ◽  
Enhanced Mri ◽  
Myocardial Border

Abstract 14412: Activation of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/reperfusion Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jing Yang ◽  
Geoffrey W CHO ◽  
Lihao He ◽  
Yuxin Chu ◽  
Jin He ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Autophagic Flux ◽  
Hdac Inhibition ◽  
Infarct Border Zone ◽  
Infarct Border

Background and Hypothesis: Reperfusion injury accounts for ~50% of myocardial infarct size, and clinically efficacious therapies are lacking. Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. However, as HDAC inhibition has pleiotropic effects, we will test whether augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective. Methods: 8-12-week-old, wild-type, C57BL6 mice were randomized into three groups: vehicle control, Tat-Scrambled (TS) peptide, or Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were used to test for cardiomyocyte specificity. Conditional cardiomyocyte ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs were used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1±6.3% (n=23, p<0.02) and improved systolic function. Increased autophagic flux and reduced reactive oxygen species (ROS) were observed in the infarct border zone. The cardioprotective effects of TB were abolished in ATG7 KO mice. TB increased mtDNA content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by 41±6% (n=12, p<0.001), decreased ROS, and increased mtDNA content significantly by ~50%. Moreover, TB promoted expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts Drp1, Fis1, and MFN1 / 2. Conversely, ATG7 knockdown in NRVMs and cardiac ATG7 KO abolished the beneficial effects of TB on mitochondria DNA content. Conclusions: Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction.

Type II secretory phospholipase A2 binds to ischemic flip-flopped cardiomyocytes and subsequently induces cell death

2003 ◽  
Vol 285 (5) ◽  
pp. H2218-H2224 ◽  
Author(s):  
R. Nijmeijer ◽  
M. Willemsen ◽  
C. J. L. M. Meijer ◽  
C. A. Visser ◽  
R. H. Verheijen ◽  
...  
Keyword(s):  
Cell Death ◽  
Propidium Iodide ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Annexin V ◽  
Border Zone ◽  
Metabolic Inhibitors ◽  
Type Ii ◽  
Secretory Phospholipase

Type II secretory phospholipase A2 (sPLA2) is a cardiovascular risk factor. We recently found depositions of sPLA2 in the necrotic center of infarcted human myocardium and normally appearing cardiomyocytes adjacent to the border zone. The consequences of binding of sPLA2 to ischemic cardiomyocytes are not known. To explore a potential effect of sPLA2 on ischemic cardiomyocytes at a cellular level we used an in vitro model. The cardiomyocyte cell line H9c2 or adult cardiomyocytes were isolated from rabbits that were incubated with sPLA2 in the presence of metabolic inhibitors to mimic ischemia-reperfusion conditions. Cell viability was established with the use of annexin V and propidium iodide or 7-aminoactinomycin D. Metabolic inhibition induced an increase of the number of flip-flopped cells, including a population that did not stain with propidium iodide and that was caspase-3 negative. sPLA2 bound to the flip-flopped cells, including those negative for caspase-3. sPLA2 binding induced cell death in these latter cells. In addition, sPLA2 potentiated the binding of C-reactive protein (CRP) to these cells. We conclude that by binding to flip-flopped cardiomyocytes, including those that are caspase-3 negative and presumably reversibly injured, sPLA2 may induce cell death and tag these cells with CRP.

Abstract 595: Functional, Histologic, and Radiographic Characteristics of Global Ischemia-reperfusion Brain Injury in a Mouse Model Of Cardiac Arrest

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Akshay Pendyal ◽  
Cameron Dezfulian ◽  
Luhua Zhang ◽  
Jeeva Munasinghe ◽  
Mark T Gladwin
Keyword(s):  
Cardiac Arrest ◽  
Rectal Temperature ◽  
Diffusion Mri ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Global Ischemia ◽  
Neurological Injury ◽  
Strong Trend ◽  
Enhanced Mri ◽  
Neurological Score

Cardiac arrest (CA) and subsequent CPR constitute a clinically relevant form of global ischemia-reperfusion injury (IR). Global IR often results in widespread ischemic brain damage and severe neurologic sequelae. In the present study, we sought to describe the functional, histologic, and radiographic brain changes that occur following CA/CPR. 8–10 week old C57BL/6 mice were subjected to 12 minutes of normothermic cardioplegic CA and resuscitated with chest compressions, mechanical ventilation, and epinephrine. Sham mice underwent surgery, but not CA. At 3 and 24 hours, 10-point functional neurological score and rectal temperature were assessed prior to trans-cardiac perfusion with PBS and 10% buffered formalin. Sectioned brains were stained using hematoxylin and eosin (H/E) and the terminal deoxyuridine triphosphate nick end-labeling (TUNEL) technique. An additional cohort of mice underwent quantitative diffusion MRI at 24 and 72 hours, gadolinium (Gd)-enhanced MRI at 24 hours, and quantitative T2 imaging at 72 hours. Compared to shams, mice undergoing CA/CPR displayed significantly lower functional neurological score at 3 hours (3±2 vs. 10±0; P<.001) and 24 hours (8±1 vs. 10±0, P<.05), and significantly higher rectal temperature at 3 hours (35.8±1.5 vs. 34.1±0.8, P<.001) and lower rectal temperature at 24 hours (33.8±2.5 vs. 37.1±0.8, P=.08). TUNEL and H/E staining revealed injury in the cortex, thalamus, hippocampus, and cerebellum, but neither a consistent pattern nor clear temporal progression was observed. Gd-enhanced MRI revealed increased signal intensity, particularly in the cortex, after CA (3.7×105±0.96×105 vs. 0.66×105±0.017×105, P<.05), consistent with breakdown of the blood-brain barrier. Diffusion MRI revealed a strong trend towards globally decreasing diffusion coefficients at 24 and 72 hours (P=0.14), consistent with widespread cell death. In our model of CA, global IR results in poor neurological function and global injury by MRI that is not reflected by early histology. MRI thus appears to be a more sensitive measure of visualizing neurological injury in the early stages after CA and may predict the delayed neuronal death remarked upon by other authors.

Abstract 145: Apelin Reduces Myocardial Infarction Size and Promotes Angiogenesis by Increasing SDF-1/CXCR4 and AKT/eNOS/VEGF Pathways

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Lanfang Li ◽  
Heng Zeng ◽  
Jian-xiong Chen
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Ischemia ◽  
Molecular Mechanisms ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Heart Weight ◽  
Tunel Staining ◽  
Myocardial Infarct Size

Background: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and is emerging as a key player in the regulation of angiogenesis as well as ischemia/reperfusion injury. So far, little is known about the functional role of apelin in myocardial ischemia. We investigated the potential intracellular molecular mechanisms and protective role of apelin during myocardial ischemic injury. Methods and Results: Myocardial ischemia was achieved by ligation of the left anterior descending coronary artery (LAD) for 24 hours and 14 days. Myocardial apoptosis was detected by TUNEL staining. Akt, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), SDF-1 and CXCR4 expression were measured by western blot. The CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells were determined by immunostaining. Myocardial capillary and arteriole densities were analyzed in the border zone of infarcted myocardium at 14 d of ischemia. Treatment of C57BL/6J mice with apelin-13 (1 mg/Kg.d) by i.p. injection for 3 days before surgery results in significant decreases in TUNEL positive cells and myocardial infarct size at 24 hours of ischemia. Treatment with apelin increases the phosphorylation of AKT and eNOS and upregulates VEGF expression in the ischemic heart. Furthermore, treatment with apelin leads to the expression of SDF-1 and CXCR4 and increases in the number of CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells in ischemic hearts. Treatment with apelin also significantly increases myocardial capillary densities and arteriole formation together with a significant decrease in the ratio of heart weight to body weight at 14 days of ischemia. This is accompanied by a significant improvement of cardiac function after 14 days of ischemia. Conclusions: Our data demonstrate that apelin contributes to the protection of myocardial infarction and angiogenesis by the mechanisms involving in upregulation of SDF-1/CXCR4 and AKT/eNOS/VEGF pathways.

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.

scholarly journals Anatomical Model of Rat Ventricles to Study Cardiac Arrhythmias under Infarction Injury

Mathematics ◽  
2021 ◽  
Vol 9 (20) ◽  
pp. 2604
Author(s):  
Roman Rokeakh ◽  
Tatiana Nesterova ◽  
Konstantin Ushenin ◽  
Ekaterina Polyakova ◽  
Dmitry Sonin ◽  
...  
Keyword(s):  
Cardiac Arrhythmias ◽  
Rat Heart ◽  
Ischemia Reperfusion ◽  
Spiral Wave ◽  
Myocardial Damage ◽  
Experimental System ◽  
Border Zone ◽  
Ionic Model ◽  
Cellular Models ◽  
Species Specific

Species-specific computer models of the heart are a novel powerful tool in studies of life-threatening cardiac arrhythmias. Here, we develop such a model aimed at studying infarction injury in a rat heart, the most common experimental system to investigate the effects of myocardial damage. We updated the Gattoni2016 cellular ionic model by fitting its parameters to experimental data using a population modeling approach. Using four selected cellular models, we studied 2D spiral wave dynamics and found that they include meandering and break-up. Then, using an anatomically realistic ventricular geometry and fiber orientation in the rat heart, we built a model with a post-infarction scar to study the electrophysiological effects of myocardial damage. A post-infarction scar was simulated as an inexcitable obstacle surrounded by a border zone with modified cardiomyocyte properties. For cellular models, we studied the rotation of scroll waves and found that, depending on the model, we can observe different types of dynamics: anchoring, self-termination or stable rotation of the scroll wave. The observed arrhythmia characteristics coincide with those measured in the experiment. The developed model can be used to study arrhythmia in rat hearts with myocardial damage from ischemia reperfusion and to examine the possible arrhythmogenic effects of various experimental interventions.

scholarly journals Initiation and propagation of ectopic waves: insights from an in vitro model of ischemia-reperfusion injury

2002 ◽  
Vol 283 (2) ◽  
pp. H741-H749 ◽  
Author(s):  
Ara Arutunyan ◽  
Luther M. Swift ◽  
Narine Sarvazyan
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Border Zone ◽  
Ectopic Activity ◽  
Functional Layer ◽  
Rat Cardiomyocytes ◽  
Coupled Cells ◽  
Vitro Model

The objective of the present study was to directly visualize ectopic activity associated with ischemia-reperfusion and its progression to arrhythmia. To accomplish this goal, we employed a two-dimensional network of neonatal rat cardiomyocytes and a recently developed model of localized ischemia-reperfusion. Washout of the ischemia-like solution resulted in tachyarrhythmic episodes lasting 15–200 s. These episodes were preceded by the appearance of multiple ectopic sources and propagation of ectopic activity along the border of the former ischemic zone. The ectopic sources exhibited a slow rise in diastolic calcium, which disappeared upon return to the original pacing pattern. Border zone propagation of ectopic activity was followed by its escape into the surrounding control network, generating arrhythmias. Together, these observations suggest that upon reperfusion, a distinct layer, which consists of ectopically active, poorly coupled cells, is formed transiently over an injured area. Despite being neighbored by a conductive and excitable tissue, this transient functional layer is capable of sustaining autonomous waves and serving as a special conductive medium through which ectopic activity can propagate before spreading into the surrounding healthy tissue.

scholarly journals Enhanced Integrin Activation of PLD2-Deficient Platelets Accelerates Inflammation after Myocardial Infarction

2020 ◽  
Vol 21 (9) ◽  
pp. 3210 ◽  
Author(s):  
Aglaia Maria Klose ◽  
Meike Klier ◽  
Simone Gorressen ◽  
Margitta Elvers
Keyword(s):  
Myocardial Infarction ◽  
Plasma Levels ◽  
Ischemia Reperfusion ◽  
Scar Formation ◽  
Border Zone ◽  
Myocardial Ischemia And Reperfusion ◽  
Integrin Αiibβ3 ◽  
Tnf Α ◽  
The Impact ◽  
Deficient Mice

Background: Phospholipase (PL)D1 is crucial for integrin αIIbβ3 activation of platelets in arterial thrombosis and TNF-α-mediated inflammation and TGF-β-mediated collagen scar formation after myocardial infarction (MI) in mice. Enzymatic activity of PLD is not responsible for PLD-mediated TNF-α signaling and myocardial healing. The impact of PLD2 in ischemia reperfusion injury is unknown. Methods: PLD2-deficient mice underwent myocardial ischemia and reperfusion (I/R). Results: Enhanced integrin αIIbβ3 activation of platelets resulted in elevated interleukin (IL)-6 release from endothelial cells in vitro and enhanced IL-6 plasma levels after MI in PLD2-deficient mice. This was accompanied by enhanced migration of inflammatory cells into the infarct border zone and reduced TGF-β plasma levels after 72 h that might account for enhanced inflammation in PLD2-deficient mice. In contrast to PLD1, TNF-α signaling, infarct size and cardiac function 24 h after I/R were not altered when PLD2 was deleted. Furthermore, TGF-β plasma levels, scar formation and heart function were comparable between PLD2-deficient and control mice 21 days post MI. Conclusions: The present study contributes to our understanding about the role of PLD isoforms and altered platelet signaling in the process of myocardial I/R injury.

scholarly journals Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury

2021 ◽  
Author(s):  
Min Xie ◽  
Geoffrey W Cho ◽  
Yongli Kong ◽  
Dan L Li ◽  
Francisco Altamirano ◽  
...  
Keyword(s):  
Cell Death ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Border Zone ◽  
Relative Reduction ◽  
Autophagic Flux ◽  
Hdac Inhibition

Rationale: Reperfusion injury accounts for up to half of myocardial infarct size, and meaningful clinical therapies targeting it do not exist. We have reported previously that autophagy is reduced during reperfusion and that HDAC inhibition enhances cardiomyocyte autophagy and blunts ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, whether inducing autophagy per se, as opposed to other effects triggered by HDAC inhibition, is sufficent to protect against reperfusion injury is not clear. Objective: We set out to test whether augmentation of autophagy using a specific autophagy-inducing peptide, Tat-Beclin, protects the myocardium through reduction of reactive oxygen species (ROS) during reperfusion injury. Methods and Results: Eight to twelve-week-old, wild-type, C57BL6 mice and drug-inducible cardiomyocyte-specific ATG7 knockout mice (to test the dependency on autophagy) were randomized into two groups: exposed to a control Tat-Scrambled (TS) peptide or a Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min coronary ligation, 24h reperfusion). Infarct size, systolic function, autophagic flux, and ROS were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were exposed to TB during simulated ischemia/reperfusion injury. ATG7 knockdown by siRNA in NRVMs was used to evaluate the role of autophagy. TB treatment at reperfusion reduced infarct size by 20% (absolute reduction; 50% relative reduction) and improved contractile function. Improvement correlated with increased autophagic flux in the border zone with less oxidative stress. ATG7 KO mice did not manifest TB-promoted cardioprotection during I/R. In NRVMs subjected to I/R, TB reduced cell death by 41% and reduced I/R-induced ROS generation. Conversely, ATG7 knockdown in NRVMs abolished these beneficial effects of TB on cell death and ROS reduction. Conclusions: Induction of autophagy at the time of reperfusion is sufficient to mitigate myocardial reperfusion injury by reducing ROS and cell death. Maintenance of appropriate autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in acute myocardial infarction.

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