Abstract 20227: Global Myocardial Injury as a New Criterion Independent of Infarct Size and Area-at-risk

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Steven E Johnson ◽  
Daniel C Lee ◽  
Brandon C Benefield ◽  
Thomas A Holly ◽  
Rishi Arora ◽  
...  
Keyword(s):  
At Risk ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Myocardial Injury ◽  
Ischemia Reperfusion ◽  
Pig Model ◽  
Area At Risk ◽  
Infarct Zone ◽  
Myocardial Ischemia And Reperfusion ◽  
New Criterion

Introduction: In acute coronary syndromes, the extent of myocardial injury can be substantially greater than the infarct zone. Existing imaging methods identify the infarct zone but do not assess “global myocardial injury” (GMI), which measures the total area of myocardium that sustained injuries including and beyond the infarct zone per se. Hypothesis: GMI can be detected based on changes in cellular membrane organization as a surrogate marker, using Tc-99m-duramycin. Methods: Balloon angioplasty was used for coronary occlusion in a pig model of myocardial ischemia and reperfusion (n = 9). Tc-99m-duramycin scans were acquired on a SPECT/CT scanner on day 1. On day 2, the infarct zone was assessed with Tc-99m-tetrofosmin. In an open-chest pig model of myocardial ischemia/reperfusion (n = 4) we used Evans Blue dye to facilitate the measurement of area-at-risk (AAR). Tc-99m-duramycin uptake was measured by gamma counting after tetrazolium (TTC) staining and physically dissecting the AAR, infarct zone and the noninfarcted-but-ischemically-damaged tissues. Histopathology was used to document cellular damages. Results: Quantitatively, Tc-99m-duramycin uptake delineated an area of myocardium that included but was substantially more extensive than the infarct zone. Under the current experimental condition, this area accounted for 81.0 ± 9.6% of the AAR, whereas the infarct zone was 25.5 ± 14.0% of the AAR. This was consistent with in vivo imaging, where the size of Tc-99m-duramycin positive tissue was visually larger than the perfusion defect in the Tc-99m-tetrofosmin scan. By histopathology, the noninfarcted-but-ischemically-damaged tissues contained features associated with cellular damages, and a heterogeneous mix of viable and dead cells. Conclusions: Tc-99m-duramycin has significant uptake in infarcted as well as noninfarcted-but-ischemically-damaged myocardium, thus reflecting global myocardial injury. The data support GMI as a new criterion independent of infarct size and AAR. The noninfarcted-but-ischemically-damaged myocardium is pathologically heterogeneous, thus a potential substrate for ventricular arrhythmias. The ability to detect such tissues may have important diagnostic and prognostic value.

scholarly journals Leukocyte trafficking and myocardial reperfusion injury in ICAM-1/P-selectin-knockout mice

2001 ◽  
Vol 280 (1) ◽  
pp. H60-H67 ◽  
Author(s):  
Stephanie A. Briaud ◽  
Zhi-Ming Ding ◽  
Lloyd H. Michael ◽  
Mark L. Entman ◽  
Sherita Daniel ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Intercellular Adhesion Molecule ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Area At Risk ◽  
Myocardial Ischemia And Reperfusion ◽  
Significant Difference ◽  
Deficient Mice

P-selectin and intercellular adhesion molecule-1 (ICAM-1) mediate early interaction and adhesion of neutrophils to coronary endothelial cells and myocytes after myocardial ischemia and reperfusion. In the present study, we examined the physiological consequences of genetic deletions of ICAM-1 and P-selectin in mice. In wild-type mice, after 1 h of ischemia followed by reperfusion, neutrophil influx into the area of ischemia was increased by 3 h with a peak at 24 h and a decline by 72 h. ICAM-1/P-selectin-deficient mice showed a significant reduction in neutrophils by immunohistochemistry or by myeloperoxidase activity at 24 h but no significant difference at 3 h. Infarct size (area of necrosis/area at risk) assessed 24 h after reperfusion was not different between wild-type and deficient mice after 30 min and 1 h of occlusion. Mice with a deficiency in both ICAM-1 and P-selectin have impaired neutrophil trafficking without a difference in infarct size due to myocardial ischemia-reperfusion.

Abstract 350: Toll-like Receptor 2 Activation, Especially In Circulating Leukocytes, Mediates Myocardial Ischemia/Reperfusion Injury In Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Fatih Arslan ◽  
Gerard Pasterkamp ◽  
Leo Timmers ◽  
Ben van Middelaar ◽  
Pieter A Doevendans ◽  
...  
Keyword(s):  
At Risk ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Blue Dye ◽  
Tlr2 Expression ◽  
Area At Risk ◽  
Saline Treatment ◽  
Myocardial Ischemia Reperfusion

OBJECTIVES. Myocardial ischemia/reperfusion (MI/R) injury is characterized by an inflammatory response through NF-κB, increase of infarct size and worsening of cardiac function. Toll-like receptors (TLRs) are part of innate immunity and initiate the same inflammatory reaction. Here we studied in vivo to what extent TLR2 is involved in myocardial damage and what the relative contribution is of TLR2 expression in parenchymal cells and leukocytes to myocardial damage during MI/R in mice. METHODS. C57Bl6J mice underwent 30 minutes ischemia - 24 hours of reperfusion. Four experimental groups were studied: TLR2 knock-out (TLR2 KO) mice (n=10), saline treated wild-type (WT) mice (n=10), generated chimeric WT mice with TLR2 KO bone marrow (BLOOD KO; n=7) and chimeric TLR2 KO mice with WT hematopoietic cells (ORGAN KO; n=7). Saline was administered via the tail vein 5 minutes prior to reperfusion. After 24 hours, the LCA was ligated again at the level marked by the suture left in place. Mice were terminated and infarct size (IS) was measured as a percentage of the area at risk (AAR) using 4% Evans’ blue dye injection in the aortic root and triphenyltetrazolium chloride (TTC) staining (fig. 1). Data are presented as Mean±SEM. RESULTS. The AAR as percentage of the left ventricle was similar between groups: TLR2 KO 41%, saline 41%, Blood KO 41%, Organ KO 42%. Saline treatment resulted in 34.5%±3.3 of infarction, whereas in TLR2 KO mice infarct size decreased to 23.0%±2.9 (p=0.029 vs. saline). Infarct size in BLOOD KO mice was 22.9%±2.7 (p=0.024 vs. saline), while ORGAN KO mice had 33.9%±3.2 (p=0.998 vs. saline) of infarction within the area at risk (fig. 2). CONCLUSION. TLR2 deficiency significantly reduces infarct size with ~33% compared to saline treatment in mice after 30 minutes of ischemia and 24 hours of reperfusion. We show for the first time that TLR2 expression in circulating leukocytes plays an important role in infarction after MI/R injury. Systemic inhibition of TLR2 may be a potential therapeutic target in the treatment of patients with acute myocardial infarction.

Abstract 212: Cd4+ T-cell Activation By T-cell Receptor Engagement Contributes To Myocardial Ischemia-reperfusion Injury

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ulrich Hofmann ◽  
Denise Mathes ◽  
Johannes Weirather ◽  
Niklas Beyersdorf ◽  
Thomas Kerkau ◽  
...  
Keyword(s):  
At Risk ◽  
T Cells ◽  
T Cell ◽  
Infarct Size ◽  
T Cell Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Receptor ◽  
Area At Risk ◽  
Infarct Area

Background: We have recently shown that CD4 + but not CD8 + T-cells contribute to ischemia-reperfusion injury of the myocardium. We therefore hypothesized that CD4 + T-cells become activated by autoantigen recognition via their T-cell receptor during reperfusion. Methods and Results: Infarct size as percent of the area-at-risk was determined by combined Evans` blue and triphenyltetrazolium (TTC) staining after 30 minutes of in vivo ischemia followed by 24 hours reperfusion in mice. After 24 hours of reperfusion there was a significantly increased population of CD4 + T-cells which expressed the surface protein CD40L in comparison to sham operated mice [n≥7; p<0.05; WT 10.8 ± 0.2% vs. sham 6.4 ± 0.5%]. CD40L is typically expressed in T-cells activated by T-cell receptor engagement. OT-II mice carry a transgenic T-cell receptor with specificity for an ovalbumin-derived peptide. These mice have a limited T-cell receptor repertoire, dominated by specificity for the irrelevant antigen ovalbumin. After 30 minutes of ischemia and 24 hours of reperfusion OT-II mice showed significantly reduction in infarct size [n≥4; p= 0.02; infarct/area at risk: OTII mice 38.9 ± 2.4% vs. WT mice 63.7 ± 6.6 % ]. Administration of a CD40L blocking antibody to wildtype mice also reduced infarct size when compared to administration of isotype-matched antibodies [n≥6; p = 0.03; infarct/ area at risk: anti-CD154 treatment 60.4 ± 3.4% vs. control 75.3 ± 4.1%]. CD4 + CD25 + Foxp3 + T-cells (natural T-regulatory cells) have a low activation threshold and constitute a T-cell subset with reactivity against autoantigens. Depletion of these cells by diphtheria-toxin application in a mouse model expressing the diphtheria-toxin receptor under the Foxp3 promotor also resulted in a significant reduction of infarct size when compared to diphtheria-toxin treated wildtype mice [n≥4; p=0.03; infarct/ area at risk: T reg -depleted DEREG mice 51.9± 3% vs. WT littermates 72.3± 2%]. Conclusion: Our results indicate that CD4 + T-cells that have been activated by an MHC class II/ T-cell receptor dependent mechanism, presumably by autoantigen recognition, contribute to myocardial ischemia-reperfusion injury.

Beneficial effects of SPM-5185, a cysteine-containing NO donor in myocardial ischemia-reperfusion

1992 ◽  
Vol 263 (3) ◽  
pp. H771-H777 ◽  
Author(s):  
M. R. Siegfried ◽  
C. Carey ◽  
X. L. Ma ◽  
A. M. Lefer
Keyword(s):  
At Risk ◽  
Endothelial Dysfunction ◽  
Myocardial Ischemia ◽  
Ethyl Ester ◽  
Ischemia Reperfusion ◽  
Myocardial Oxygen Demand ◽  
Area At Risk ◽  
No Donor ◽  
Beneficial Effects ◽  
Myocardial Ischemia Reperfusion

Intravenous administration of SPM-5185 [N-nitratopivaloyl-S-(N–-acetylalanyl)-cysteine ethyl ester], a cysteine-containing nitric oxide (NO) donor, or SPM-5267 [pivaloyl-S-(N–-acetylalanyl)-cysteine ethyl ester], an analogue of SPM-5185 that lacks the NO moiety, was studied in a feline myocardial ischemia-reperfusion model. Administration of SPM-5185 (1 mg/kg), followed by a 2-mg.kg-1.h-1 infusion starting 10 min before reperfusion, resulted in significant protection 4.5 h postreperfusion. In the myocardial ischemia (MI)+SPM-5267 group, 38 +/- 4% of the area at risk was necrotic, whereas the necrotic area/area at risk was only 7 +/- 2% in the MI+SPM-5185 group (P less than 0.01). Moreover, SPM-5185 treatment markedly attenuated the endothelial dysfunction observed in the left anterior descending coronary artery after reperfusion by 50%. These beneficial effects occurred despite the absence of a significant change in myocardial oxygen demand, as measured by the pressure-rate index. In vitro experiments demonstrated that SMP-5185, but not SPM-5267, decreased adherence of neutrophils to the coronary vascular endothelium and decreased production of superoxide radicals. Therefore, a likely mechanism of the observed cardioprotection by SPM-5185 involves attenuation of polymorphonuclear leukocyte-induced endothelial dysfunction.

Role of heme oxygenase-1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion

2009 ◽  
Vol 296 (1) ◽  
pp. H84-H93 ◽  
Author(s):  
Dylan Burger ◽  
Fuli Xiang ◽  
Lamis Hammoud ◽  
Xiangru Lu ◽  
Qingping Feng
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion ◽  
Primary Cultures ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Myocardial Ischemia And Reperfusion ◽  
Cardioprotective Effects

We have recently demonstrated that erythropoietin (EPO) protects cardiomyocytes from apoptosis during myocardial ischemia-reperfusion (I/R). The objective of the present study was to investigate the role of heme oxygenase (HO)-1 in the antiapoptotic effects of EPO. Primary cultures of neonatal mouse cardiomyocytes were subjected to anoxia-reoxygenation (A/R). Pretreatment with EPO significantly reduced apoptosis in A/R-treated cells. This reduction in apoptosis was preceded by an increase in the mRNA and protein expression of HO-1. Selective inhibition of HO-1 using chromium mesoporphyrin (CrMP) significantly diminished the ability of EPO to inhibit apoptosis. Cotreatment of EPO with SB-202190, an inhibitor of p38 activation, blocked the EPO-mediated HO-1 expression and antiapoptotic effects, suggesting a p38-dependent mechanism. The in vivo significance of p38 and HO-1 as mediators of EPO's cardioprotection was investigated in mice subjected to myocardial I/R. Pretreatment with EPO decreased infarct size as well as I/R-induced apoptosis in wild-type mice. However, these effects were significantly diminished in HO-1−/−mice. Furthermore, EPO given during ischemia reduced infarct size in mice subjected to I/R, and this effect was blocked by CrMP treatment in wild-type mice. Moreover, inhibition of p38 diminished the cardioprotective effects of EPO. We conclude that upregulation of HO-1 expression via p38 signaling contributes to EPO-mediated cardioprotection during myocardial I/R.

Long-term infusion of Met5-enkephalin fails to protect murine hearts against ischemia-reperfusion injury

2005 ◽  
Vol 288 (4) ◽  
pp. H1717-H1723 ◽  
Author(s):  
Koh Kuzume ◽  
Kazuyo Kuzume ◽  
Zhiping Cao ◽  
Lijuan Liu ◽  
Donna M. Van Winkle
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Opioid Peptide ◽  
Area At Risk ◽  
Regional Myocardial Ischemia ◽  
Chronic Infusion ◽  
Myocardial Ischemia Reperfusion

Recently, we reported that exogenous administration of Met5-enkephalin (ME) for 24 h reduces infarct size after ischemia-reperfusion in rabbits. In the present study, we tested whether ME-induced cardioprotection is exhibited in murine hearts and whether chronic infusion of this peptide can render hearts tolerant to ischemia. Barbiturate-anesthetized open-chest mice (C57BL/6J) were subjected to regional myocardial ischemia-reperfusion (45 min of occlusion and 20 min of reperfusion). Mice received saline vehicle or ME for 24 h or 2 wk before undergoing regional myocardial ischemia-reperfusion or for 24 h followed by a 24-h delay before regional myocardial ischemia-reperfusion. Infarct size was measured with propidium iodide and is expressed as a percentage of the area at risk. Infarcts were smaller after infusion of ME for 24 h than with vehicle control: 49.2 ± 9.0% vs. 22.2 ± 3.2% ( P < 0.01). In contrast, administration of ME for 2 wk failed to elicit cardioprotection: 36.5 ± 9.1% and 41.4 ± 8.2% for control and ME, respectively ( P = not significant). When a 24-h delay was imposed between the end of drug treatment and the onset of the ischemic insult, cardioprotection was lost: 38.5 ± 6.1% and 42.8 ± 6.6% for control and ME, respectively ( P = not significant). Chronic sustained exogenous infusion of the endogenously produced opioid peptide ME is associated with loss of the cardioprotection that is observed with 24 h of infusion. Furthermore, in this in vivo murine model, ME failed to induce delayed tolerance to myocardial ischemia-reperfusion.

Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury

1998 ◽  
Vol 275 (5) ◽  
pp. H1865-H1872 ◽  
Author(s):  
Anthony J. Palazzo ◽  
Steven P. Jones ◽  
Donald C. Anderson ◽  
D. Neil Granger ◽  
David J. Lefer
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Wild Type ◽  
Area At Risk ◽  
Myocardial Ischemia Reperfusion

We investigated in vivo coronary P-selectin expression and its pathophysiological consequences in a murine model of myocardial ischemia-reperfusion (MI/R) using wild-type and P-selectin deficient (−/−) mice. Coronary P-selectin expression [μg monoclonal antibody (MAb)/g tissue] was measured using a radiolabeled MAb method after 30 min of myocardial ischemia and 20 min of reperfusion. P-selectin expression in wild-type mice was significantly ( P< 0.01) elevated in the ischemic zone (0.070 ± 0.010) compared with the nonischemic zone (0.037 ± 0.008). Myocardial P-selectin expression was nearly undetectable in P-selectin −/− mice after MI/R. Furthermore, myocardial infarct size (% of area at risk) after 30 min of myocardial ischemia and 120 min of reperfusion was 42.5 ± 4.4 in wild-type mice and 24.4 ± 4.0 in P-selectin −/− mice ( P < 0.05). In additional experiments of prolonged myocardial ischemia (60 min) and reperfusion (120 min), myocardial infarct size was similar in P-selectin −/− mice and wild-type mice. Our results clearly demonstrate the involvement of coronary P-selectin in the development of myocardial infarction after MI/R.

Anesthetic-induced Preconditioning 

1997 ◽  
Vol 87 (5) ◽  
pp. 1182-1190 ◽  
Author(s):  
Brian A. Cason ◽  
A. Kurt Gamperl ◽  
Robert E. Slocum ◽  
Robert F. Hickey
Keyword(s):  
At Risk ◽  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Coronary Occlusion ◽  
Myocardial Infarct ◽  
Group Analysis ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Myocardial Preconditioning

Background Experimental evidence suggests that ATP-sensitive potassium channels are involved in myocardial ischemic preconditioning. Because some pharmacologic effects of isoflurane are mediated by K(ATP) channels, the authors tested the hypothesis: Isoflurane administration, before myocardial ischemia, can induce or mimic myocardial preconditioning. Methods Myocardial infarct size was measured in three groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed in their pretreatment: Group 1 (control, N = 13) no pretreatment, Group 2 (ischemic preconditioning, N = 8), 5 min of coronary occlusion and 15 min of reperfusion; Group 3 (isoflurane pretreatment; N = 15), 15 min of isoflurane (1.1% end-tidal) and 15 min of washout. Hemodynamics were monitored serially. Myocardial infarct size and the area at risk were defined using triphenyltetrazolium chloride staining and fluorescent microspheres, respectively, and both were measured using computerized planimetry. Results Infarct size expressed as a percentage of area at risk was 23.4 +/- 8.5% (mean +/- SD) in the isoflurane group compared with 33.1 +/- 13.3% in controls, and 8.7 +/- 6.2% in the ischemia-preconditioned group. Analysis for coincidental regressions, followed by tests for equality of slope and elevation, showed that the linear relationship between infarct size and area at risk was significantly (P &lt; 0.05) different in all three groups because of differences in line elevation. Minor differences in hemodynamic variables were found between groups, which were unlikely to account for the significant differences in infarct size. Conclusion Preadministration of isoflurane, before myocardial ischemia, reduces myocardial infarct size, and mimics myocardial preconditioning.

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