Reperfusion Injury In Myocardial Infarction Research Articles

MicroRNA-155-5p in serum derived-exosomes promotes ischaemia-reperfusion injury by reducing CypD ubiquitination by NEDD4.

Recovery of blood flow is a therapeutic approach for myocardial infarction but paradoxically induces injury to the myocardium. Exosomes (exos) are pivotal mediators for intercellular communication that can be released by different cells and are involved in cardiovascular diseases. This study aimed to explore the possible effects and mechanisms of miR-155-5p loaded by serum-derived exos in myocardial infarction reperfusion injury (MIRI). Exos were isolated from mouse serum after induction of ischaemia reperfusion (I/R) and injected into I/R-treated mice to assess cardiac function, infarction size, and cardiomyocyte apoptosis. Primary cardiomyocytes were transfected with miR-155-5p inhibitor before treatment with oxygen-glucose deprivation and re-oxygenation (OGD/R) and exos derived from the serum of I/R-treated mice (I/R-Exos), in which Bcl-2, Bax, and cleaved-caspase-3 levels were detected. The interactions among miR-155-5p, NEDD4, and CypD were evaluated. miR-155-5p level was evidently increased in I/R-Exos than in exos from the serum of sham-operated mice (P<0.05). In comparison with the I/R group, the I/R-Exos+I/R group had increased infarct size, elevated miR-155-5p expression, and boosted apoptotic rate in mouse myocardium (P<0.05). In mice treated with I/R-Exos and I/R, miR-155-5p inhibition reduced cardiac infarct size and apoptosis (P<0.05). NEDD4 was a target gene of miR-155-5p and promoted CypD ubiquitination. Cardiomyocyte apoptosis was markedly increased in the miR-155-5p inhibitor+shNEDD4+OGD/R group versus the miR-155-5p inhibitor+OGD/R group (P<0.05), but decreased in the miR-155-5p inhibitor+shNEDD4+shCypD+OGD/R group than in the miR-155-5p inhibitor+shNEDD4+OGD/R group (P<0.05). miR-155-5p in I/R-Exos may facilitate MIRI by inhibiting CypD ubiquitination via targeting NEDD4.

Disruption of Circadian Rhythms by Shift Work Exacerbates Reperfusion Injury in Myocardial Infarction

BackgroundShift work is associated with increased risk of acute myocardial infarction (AMI) and worsened prognosis. However, the mechanisms linking shift work and worsened prognosis in AMI remain unclear. ObjectivesThis study sought to investigate the impact of shift work on reperfusion injury, a major determinant of clinical outcomes in AMI. MethodsStudy patient data were obtained from the database of the EARLY-MYO-CMR (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI) registry, which was a prospective, multicenter registry of patients with ST-segment elevation myocardial infarction (STEMI) undergoing cardiac magnetic resonance (CMR) imaging after reperfusion therapy. The primary endpoint was CMR-defined post-reperfusion infarct size. A secondary clinical endpoint was the composite of major adverse cardiac events (MACE) during follow-up. Potential mechanisms were explored with the use of preclinical animal AMI models. ResultsOf 706 patients enrolled in the EARLY-MYO-CMR registry, 412 patients with STEMI were ultimately included. Shift work was associated with increased CMR-defined infarct size (β = 5.94%; 95% CI: 2.94-8.94; P < 0.0001). During a median follow-up of 5.0 years, shift work was associated with increased risks of MACE (adjusted HR: 1.92; 95% CI: 1.12-3.29; P = 0.017). Consistent with clinical findings, shift work simulation in mice and sheep significantly augmented reperfusion injury in AMI. Mechanism studies identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that played a crucial role in mediating the detrimental effects of shift work on myocardial injury. ConclusionsThe current study provided novel findings that shift work increases myocardial infarction reperfusion injury. It identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that might play a crucial role in mediating this process. (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI [EARLY-MYO-CMR] registry; NCT03768453)

Mononuclear phagocyte system blockade using extracellular vesicles modified with CD47 on membrane surface for myocardial infarction reperfusion injury treatment

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) with anti-apoptotic and anti-inflammatory properties have been intensively studied. However, rapid clearance by the mononuclear phagocyte system remains a huge barrier for the delivery of extracellular vesicle contents into target organs and restricts its wider application, particularly in the heart. CD47 is a transmembrane protein that enables cancer cells to evade clearance by macrophages through CD47− signal regulatory proteinα binding, which initiates a “don't eat me” signal. This study aimed to explore the biodistribution and delivery efficiency of EVs carrying the membrane protein CD47 and specific anti-apoptotic miRNAs. EVs were isolated from MSCs overexpressing CD47 (CD47-EVs) and identified. Fluorescence-labeled EVs were injected through the tail vein and tracked using fluorescence imaging. In silico analysis was performed to determine miRNA profiles in MSCs and in a heart-derived H9c2 cardiomyoblast cell line under hypoxia vs. normoxia conditions. Electro CD47-EV was constructed by encapsulating purified CD47-EV with miR-21a via electroporation. The effect of miR21-EVs on the pro-apoptotic gene encoding phosphatase and tensin homolog (PTEN) was evaluated by dual-luciferase assay, qPCR, and western blotting. Exogenous miR21 distribution, PTEN protein level, blood vessel density, anti-apoptotic effect by TdT-mediated dUTP nick-end labeling staining, and macrophage and leukocyte infiltration in the myocardium were assessed by immunofluorescence staining. Cardiac functional recovery during the early stage and recovery period was evaluated using echocardiography. The results showed that CD47-EVs were still detectable in the plasma 120 min after the tail vein injection, compared to the detection time of less than 30 min observed with the unmodified EVs. More strikingly, CD47-EVs preferentially accumulated in the heart in the ischemia-reperfusion (I/R) + CD47-EV group [heart total fluorescence radiance ( × 105 Photons/sec/cm2/sr) 51.62 ± 11.30 v.s. 10.08 ± 3.15 in the I/R + unmodified EVs group] 8 h post-injection. Exogenous miR-21 is efficiently internalized into cardiomyocytes, inhibits apoptosis, alleviates inflammation, and improves cardiac function. In conclusion, electro CD47-EVs efficiently improve biodistribution in the heart, shedding new light on the application of a two-step EV delivery method (CD47 genetic modification followed by therapeutic content electrotransfection) as a potential therapeutic tool for myocardial I/R injury that may benefit patients in the future.

The Role of Complement in Myocardial Infarction Reperfusion Injury: An Underappreciated Therapeutic Target.

This article reviews the pathogenetic role of the complement system in myocardial infarction reperfusion injury. The complement activation pathways involved in myocardial tissue injury are identified, as are the complement-derived effector molecules. The results of past anti-complement therapies are reviewed; as the more recent therapeutic concept of complement depletion with humanized CVF described.

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

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&lt;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&lt;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.

Iron imaging in myocardial infarction reperfusion injury

Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.

Abstract 887: Activation of Autophagic Flux Rescues Mitochondrial Homeostasis During Cardiac Ischemia/Reperfusion Injury

Objective: Reperfusion injury accounts for ~50% of myocardial infarct size, and meaningful clinical therapies targeting this do not exist. We have shown that HDAC inhibition-enhanced cardiomyocyte autophagy blunts ischemia/reperfusion (I/R) injury given at the time of reperfusion. However, as HDAC inhibition may have off-target effects, we set out to test whether augmentation of autophagy protects myocardium through maintenance of mitochondrial homeostasis and reduction of oxidative stress during reperfusion injury. Methods: 10-week-old, wild-type, C57BL6 mice were randomized into 3 groups: vehicle control, or exposed to a Tat-Scrambled (TS) peptide, or a Tat-Beclin (TB, autophagy-inducing molecule) peptide. Each group was subjected to I/R surgery (45min coronary ligation, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were exposed to TB during simulated ischemia/reperfusion injury. ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs was used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1% (n=23, p&lt;0.05) and improved systolic function (n=11, p&lt;0.05). 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. TB increased mtDNA content in the border zone (n=10, p&lt;0.05). In NRVMs subjected to I/R, TB reduced cell death by 41% (n=12, p&lt;0.001), reduced I/R-induced mtDNA damage, and increased mtDNA content by &gt;60% (n=3, p&lt;0.05). Moreover, TB promoted expression of the gene coding for PGC-1α, which controls mitochondrial biogenesis, in the border zone (n=10, p&lt;0.05) and in NRVMs subjected to I/R (n=3, p&lt;0.05), along with expression of the mitochondrial dynamics genes Drp1, Fis1 and MFN1 / 2 (n=9, p&lt;0.05). Conversely, ATG7 knockdown in NRVMs abolished these beneficent effects of TB on mitochondria. Conclusions: Autophagy is a sufficient and essential process to mitigate reperfusion injury through maintenance of mitochondrial homeostasis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction

An injectable sulfonated reversible thermal gel for therapeutic angiogenesis to protect cardiac function after a myocardial infarction

BackgroundCardiovascular disease and myocardial infarction are associated with high mortality and morbidity and a more effective treatment remains a major clinical need. The intramyocardial injection of biomaterials has been investigated as a potential treatment for heart failure by providing mechanical support to the myocardium and reducing stress on cardiomyocytes. Another treatment approach that has been explored is therapeutic angiogenesis that requires careful spatiotemporal control of angiogenic drug delivery. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N-isopropylacrylamide) and sulfonate groups has been developed for intramyocardial injection with angiogenic factors for the protection of cardiac function after a myocardial infarction.ResultsThe thermal gel allowed for the sustained, localized release of VEGF in vivo with intramyocardial injection after two weeks. A myocardial infarction reperfusion injury model was used to evaluate therapeutic benefits to cardiac function and vascularization. Echocardiography presented improved cardiac function, infarct size and ventricular wall thinning were reduced, and immunohistochemistry showed improved vascularization with thermal gel injections. The thermal gel alone showed cardioprotective and vascularization properties, and slightly improved further with the additional delivery of VEGF. An inflammatory response evaluation demonstrated the infiltration of macrophages due to the myocardial infarction was more significant compared to the foreign body inflammatory response to the thermal gel. Detecting DNA fragments of apoptotic cells also demonstrated potential anti-apoptotic effects of the thermal gel.ConclusionThe intramyocardial injection of the sulfonated reversible thermal gel has cardioprotective and vascularization properties for the treatment of myocardial infarction.

A feasibility and safety study of intracoronary hemodilution during primary coronary angioplasty in order to reduce reperfusion injury in myocardial infarction.

We designed a pilot study to evaluate safety and feasibility of an inexpensive and simple approach to intracoronary hemodilution during primary angioplasty (PPCI) to reduce reperfusion injury. Early revascularization in acute myocardial infarction decreases infarct size and improves outcomes. However, abrupt restoration of coronary flow results in myocardial reperfusion injury and increased final infarct size. Dilution of coronary blood during revascularization may help reduce this damage. If proved effective, such an approach would need to be simple and suitable for widespread adoption. Ten patients presenting with STEMI underwent intracoronary dilution with room temperature Hartmann's solution delivered through the guiding catheter during primary angioplasty (PPCI). Infusion of perfusate began prior to crossing the occluded artery with the guidewire, continuing until 10 min after completion of the balloon and stenting procedure. Infusion was briefly interrupted for contrast injection and pressure monitoring. The outcome measures were safety, including intracoronary temperature reduction and volume of intracoronary perfusate infused, and technical feasibility. There were no significant symptomatic, hemodynamic, ECG ST/T segment or rhythm changes observed during perfusate administration. The median (interquartile range) volume of perfusate administered was 550 mL (350-725 mL) and the median intracoronary temperature reduction observed was 3.4°Celsius. Myocardial salvage was 0.54 (0.43-0.65). Transcatheter intracoronary hemodilution with room temperature perfusate during PPCI is feasible and appears safe. Such a strategy is simple and inexpensive, with potential to be widely applied. Further mechanistic and subsequent outcome powered studies are required to evaluate whether this strategy can reduce reperfusion injury in STEMI.

Clinical effects of cyclosporine A on reperfusion injury in myocardial infarction: a meta-analysis of randomized controlled trials.

Reperfusion therapy is the most crucial strategy for rescuing ischemic myocardium and reducing infarction size. Cyclosporine A (CsA) can protect against reperfusion-induced myocardial necrosis. However, the clinical effects of CsA on myocardial infarction (MI) remain uncertain. This study investigated the effects of CsA on reperfusion injury (RI) in MI. We searched for and included articles regarding randomized controlled trials investigating the effect of CsA in patients with MI from PubMed, EMBASE, and Cochrane Library databases for an analysis. We then performed quality assessment, subgroup, sensitivity, and publication bias analyses. Of the 277 potentially relevant articles retrieved from the databases, only five were eligible for our meta-analysis. Compared with the placebos used in these studies, CsA did not reduce all-cause mortality [rate ratio (RR) 1.10, 95 % confidence interval (CI) 0.75–1.61; P = 0.533; I2 = 0 %) or adverse clinical events (RR 1.0, 95 % CI 0.89–1.13; P = 0.381; I2 = 6.5 %). In the CsA treatment groups, improvement in left ventricular ejection fraction (weighted mean difference = 1.91; 95 % CI 0.89, 2.92; P = 0.064) and reduction in MI size (standard mean difference = −0.41, 95 % CI −0.84 to 0.02; P = 0.519; I2 = 0.0 %) were minimal. The current meta-analysis indicates that CsA treatment does not reduce all-cause mortality and adverse clinical events in MI and that CsA may not have significant clinical effects on RI in MI.

The Protective Effect of Puerarin on Myocardial Infarction Reperfusion Injury (MIRI): A Meta-Analysis of Randomized Studies in Rat Models.

BackgroundAlthough puerarin is generally considered as a protective agent for cardio-cerebrovascular diseases, the exact effect on reducing myocardial infarction reperfusion injury (MIRI) is not well understood. This study aimed to pool previous randomized controlled studies based on rat models to evaluate the effects of puerarin on MIRI.Material/MethodsRelevant studies were searched among PubMed, Embase, Medline, and CNKI (China National Knowledge Infrastructure). To assess the therapeutic effects of protective effects of puerarin on myocardial infarction reperfusion injury, the outcome indicators which were reported in at least 3 original studies were extracted and pooled, including size of myocardial ischemia (MIS) and myocardial infarction (MIN), creatine kinase (CK), methylene dioxyamphetamine (MDA), and superoxide dismutase (SOD).ResultsAdministration of puerarin could effectively reduce the size of MIN after MIR (mean difference: −29.20, 95%CI: −44.90 to −13.51, p=0.0003). Puerarin directly led to decreased CK (mean difference: −6.89, 95%CI: −9.40 to −4.38, p=0.00001) and MDA (mean difference: −2.41, 95%CI: −3.14 to −1.68, p<0.00001) and increased serum SOD (mean difference: 63.97, 95%CI: 38.19 to 89.75, p<0.00001).ConclusionsPuerarin might have a protective effect in myocardial tissues during MIRI through increasing SOD and decreasing CK and MDA. However, more animal studies and randomized controlled clinical trials are required to confirm these results.

Therapeutic Hypothermia for Myocardial Protection in ST Elevation Myocardial Infarction

Following the return of spontaneous circulation after cardiac arrest, the use of therapeutic hypothermia (TH) has been demonstrated to improve neurologic outcomes and mortality. The potential cardiac benefits and the role of induced hypothermia as a cardioprotective strategy are less clear. Numerous laboratory and clinical studies implicate both inciting myocardial ischemia and subsequent reperfusion damage in myocardial injury. Based on its established benefit in limiting cerebral ischemia and its widespread availability, TH is an attractive therapy for limiting myocardial ischemia and reperfusion injury in myocardial infarction. Several studies have suggested a positive effect of TH in the prevention of myocardial ischemic injury but to date no clinical trial has conclusively shown mortality benefit with the use of TH in the setting of ST elevation myocardial infarction (STEMI). Subgroup analyses however indicate that TH has the potential to limit infarct size and improve outcomes in certain patient subsets. These findings, alongside the established benefits for cerebral ischemic injury, support performing further large scale randomized controlled trials of the use of TH in STEMI.

Detection and Quantification of Myocardial Reperfusion Hemorrhage Using T2*-Weighted CMR

The purpose of this study was to validate T2*-weighted cardiac magnetic resonance (T2*-CMR) for the detection and quantification of reperfusion hemorrhage in vivo against an ex vivo gold standard, and to investigate the relationship of hemorrhage to microvascular obstruction, infarct size, and left ventricular (LV) functional parameters. Hemorrhage can contribute to reperfusion injury in myocardial infarction and may have significant implications for patient management. There is currently no validated imaging method to assess reperfusion hemorrhage in vivo. T2*-CMR appears suitable because it can create image contrast on the basis of magnetic field effects of hemoglobin degradation products. In 14 mongrel dogs, myocardial infarction was experimentally induced. On day 3 post-reperfusion, an in vivo CMR study was performed including a T2*-weighted gradient-echo imaging sequence for hemorrhage, standard sequences for LV function, and post-contrast sequences for microvascular obstruction and myocardial necrosis. Ex vivo, thioflavin S imaging and triphenyl-tetrazoliumchloride (TTC) staining were performed to assess microvascular obstruction, hemorrhage, and myocardial necrosis. Images were analyzed by blinded observers, and comparative statistics were performed. Hemorrhage occurred only in the dogs with the largest infarctions and the greatest extent of microvascular obstruction, and it was associated with more compromised LV functional parameters. Of 40 hemorrhagic segments on TTC staining, 37 (92.5%) were positive for hemorrhage on T2*-CMR (kappa = 0.96, p < 0.01 for in vivo/ex vivo segmental agreement). The amount of hemorrhage in 13 affected tissue slices as determined by T2*-CMR in vivo correlated strongly with ex vivo results (20.3 ± 2.3% vs. 17.9 ± 1.6% per slice; Pearson r = 0.91; r(2) = 0.83, p < 0.01 for both). Hemorrhage size was not different between in vivo T2*-CMR and ex vivo TTC (mean difference 2.39 ± 1.43%; p = 0.19). T2*-CMR accurately quantified myocardial reperfusion hemorrhage in vivo. Hemorrhage was associated with more severe infarct-related injury.

Evaluation of the effects of tirofiban on myocardial infarction-reperfusion injury by delayed enhancement multi-slice spiral CT

Objective To evaluate the effcets of tirofihan on myocardial no-reflow after acute myocardial infarction and reperfusion by delayed enhancement-multi-slice CT(DE-MSCT).Methods Chinese mini pigs were randomized into control group and firofiban treatment group. Acute myocardial infarction was induced by balloon occlusion of the medium segment of the left anterior descending artery for 90 minutes. Repeffusion was created by withdrawing the balloon during angiography. All successful models received DE-MSCT examinatons at 1 h, 24 h, 48 h, and 72 h after reperfusion to observe the myocardial noreflow area. Data were analyzed with Spearman rank correlation and Wilcoxon Rank Sum test. Results Six pigs were successfully induced as acute reperfusion myocardial infarction in each group. Furthermore,4 pigs in control group and 3 pigs in firofiban treatment group had no-reflow phenomenon. The no-reflow volume percent increased from 1 h to 72 h in both groups. The no-reflow volume percent was significantly reduced in tirofiban treatment group compared with control group after reperfusion at 1 h, 24 h, 48 h and 72 h respectively[(4.78±0.66)% and (9.62±3.05)%, t =6.000, P＜0.05; (5.84 ± 1.19)% and (13.44±3.33)% ,t=6.000,P＜0. 05;(6.41± 1.24)% and (15.10±3.76)%,t =6.000,P ＜0.05;(6.63 ±0. 82)% and (15.94 ±4.62)% ,t =6.000,P ＜0.05] ,as well as the infarct myocardium volume percent was significantly reduced in tirofiban treatment group compared with control group at 24 h, 48 h and 72 h after reperfusion [ (19.74± 2. 94) % and ( 25.08 ± 4.68) %, t = 25.000, P ＜ 0.05;(20.34±2.46) % and (27.07 ±5.44)%, t =26. 000,P ＜0.05; (20.72 ±2.10)% and (26.17 ±5.19)% ,t = 24.000,P ＜0.05]. Conclusions DE-MSCT can be used to detect the extent of no-reflow phenomenon. Tirofiban can reduce the volume of myocardial infarct and no-reflow area after reperfusion. Key words: Myocardial infarction; Cardiovascular drugs; Tomography, X-ray computed; Animal model, experiment

Abstract 3415: Cardiovascular Magnetic Resonance Accurately Detects Myocardial Hemorrhage in Reperfusion Injury

Introduction Hemorrhage can complicate reperfusion injury in myocardial infarction, but no in vivo imaging method exists. We hypothesized that a T2*-weighted cardiovascular magnetic resonance imaging (CMR) sequence accurately detects myocardial hemorrhage in vivo. Methods Reperfused myocardial infarcts were generated in 14 dogs by ligation of the LAD for 3– 6 hours. At day 3, a CMR study was performed using established sequences for quantification of function, microvascular obstruction and myocardial infarction in short axis slices covering the entire myocardium. For hemorrhage, a T2*-weighted multi-echo gradient-echo sequence was applied (TE=35msec, TR=1 RR, FOV 380x280mm, matrix 256 x 192). A segmental analysis was performed using 6 segments per slice: T2*-segments were considered hemorrhagic when signal intensity was &gt;2 standard deviations below the mean of remote myocardium. The contrast-to-noise ratio of hemorrhagic segments over normal segments was assessed. Post-mortem TTC staining was performed with infarcted and hemorrhagic areas analyzed with the same segmental approach. In vivo/ ex vivo correlation statistics were performed. Results In 14 dogs, 378 segments were assessed. Of the T2* CMR segments, 10.2% were excluded due to artifacts; 27 segments yielded a signal drop consistent with hemorrhage (see figure ). The correlation with ex vivo TTC staining was R=0.79 and contrast-to-noise ratio was 9.2±3.4. Sensitivity to detect a hemorrhagic segment was 77%, specificity 99%. Conclusion T2*-weighted CMR accurately detects reperfusion hemorrhage in vivo. The method may be applied in patients to study hemorrhage as a complication of reperfusion injury.

Neutrophils in human myocardial infarction with rupture of the free wall

Introduction Experimental studies have shown that neutrophils might play an important role in the pathogenesis of ischemic and reperfusion injury in myocardial infarction (MI). Our aim was to compare histologic characteristics of MI with and without rupture of the free wall (RFW), with emphasis on the density of interstitial neutrophil infiltration. Methods Autopsy samples of infarcted heart tissue from 110 patients with MI (50 with and 60 without RFW) were included. On the basis of histologic changes and clinical data, all cases were divided into three groups according to the duration of MI (≤1 day, 1–7 days, and 1–4 weeks). Neutrophils were stained immunohistochemically with antibodies against CD15. The intensity of interstitial neutrophil infiltration was determined on the basis of percentage of the infiltrated myocardial area using an image analysis system. Results In MI that were less than 1 day or more than 7 days old, we did not observe any differences in histologic characteristics between cases with and those without RFW. In MI that were more than 1 day and less than 7 days old, we observed a significantly more intensive interstitial neutrophil infiltration in cases with RFW than in those without RFW. However, there were no significant differences in neutrophil infiltration between patients who received reperfusion treatment and those who did not. Conclusions Our results suggest that intensive interstitial neutrophil infiltration in human MI might increase the risk of the RFW between the 2nd and the 7th days when the density of neutrophil infiltration is believed to reach a peak. We failed to confirm the hypothesis based on experimental studies that reperfusion treatment contributes significantly to the density of neutrophil infiltration.

Attenuation of ischemia and/or reperfusion injury during myocardial infarction using mild hypothermia in rats: An immunohistochemical study of Bcl‐2, Bax, Bak and TUNEL

The aim of the present study was to determine the beneficial effect of mild hypothermia during ischemia and/or reperfusion injury in myocardial infarction. Sprague-Dawley rats (400 +/- 20 g) were subjected to 30 min occlusion of the left coronary artery followed by 24 h reperfusion. Rats were divided into normothermic (NT; 37 degrees C) and hypothermic (HT; 34 degrees C) groups. In the HT group hypothermia was maintained during coronary occlusion and continued for 30 min following reperfusion. Histological analysis revealed dead cardiomyocytes and polymorphonuclear neutrophil infiltration after 24 h. Myocardial infarction, measured using an image analyzer, showed that the percentage area of infarction was significantly decreased in the HT group. Immunohistochemical analysis was carried out using antibodies against Bcl-2, Bax and Bak. DNA fragments were labeled in situ using the 3'-OH end-labeling method (TUNEL). In the HT group Bcl-2 was induced in many myocytes, whereas Bax and Bak were induced in only a few myocytes. A higher number of TUNEL-positive cells were recorded in the NT group than in the HT group, but these were more thinly scattered in the HT group. The expression pattern revealed that many myocytes could survive at the border zone in the HT group; in contrast, few myocytes in the NT group were able to survive. Our results suggest that mild hypothermia selectively interferes with, and mitigates, reperfusion injury.

Inhibition of delta protein kinase C protects vascular injury and microcirculation from reperfusion injury in myocardial infarction

Inhibition of delta protein kinase C protects vascular injury and microcirculation from reperfusion injury in myocardial infarction

The potential of monoclonal antibodies to reduce reperfusion injury in myocardial infarction.

Reperfusion injury is mediated, in part, by the accumulation of platelets and leucocytes in the microvasculature after reflow. These components of the blood pool form aggregates that can obstruct flow in small vessels. In addition, mediators released from leucocytes and platelets further damage the reperfused myocardium. A strategy to limit reperfusion injury exploits the important role of membrane-bound adhesion molecules that attach platelets and leucocytes to themselves and to the vascular endothelium. Monoclonal antibodies against specific adhesion receptors effectively eliminate the function of the receptor. The most widely investigated receptors are P-selectin, present on platelets and the endothelium, CD11/CD18, present on leucocytes, and the fibrinogen receptor on platelets. Numerous animal studies have strongly supported the use of these monoclonal antibodies to block adhesion receptors as adjunctive reperfusion therapy. However, recent human trials have yielded disappointing results.