Randomized controlled clinical study on Yiqi Liangxue Shengji prescription for intervention cardiac function of acute myocardial infarction with ischemia-reperfusion injury.

INTRODUCTION: The morbidity and mortality of acute myocardial infarction patients still remains high after percutaneous coronary intervention (PCI). Myocardial ischemia-reperfusion (MIR) injury is one of the important reasons. Although the phenomenon of MIR injury can paradoxically reduce the beneficial effects of myocardial reperfusion, there currently remains no effective therapeutic agent for preventing MIR. Previous studies have shown that Yiqi Liangxue Shengji prescription (YLS) is effective in improving clinical symptoms and ameliorating the major adverse cardiovascular events of coronary heart disease patients undergoing PCI. This study aims to evaluate the effectiveness and safety of YLS in patients with acute myocardial infarction (AMI) after PCI. METHODS: This study is a randomized, double-blinded, placebo-controlled, single-central clinical trial. A total of 140 participants are randomly allocated to 2 groups: the intervention group and the placebo group. Based on routine medications, the intervention group will be treated with YLS and the placebo group will be treated with YLS placebo. All participants will receive a 8-week treatment and then be followed up for another 12 months. The primary outcome measures are N terminal pro B type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction. Secondary outcomes are plasma levels of microRNA-145, plasma cardiac enzyme, and Troponin I levels in blood samples, changes in ST-segment in ECG, Seattle Angina Questionnaire, the efficacy of angina symptoms, and occurrence of major adverse cardiac events. All the data will be recorded in case report forms and analyzed by SPSS V.17.0. DISCUSSION: The trial will investigate whether the postoperative administration of YLS in patients with AMI after PCI will improve cardiac function. And it explores microRNAs (miRNA)-145 as detection of blood-based biomarkers for AMI by evaluating the relation between miRNAs in plasma and cardiac function. TRIAL REGISTRATION: Chinese Clinical Trials Registry identifier ChiCTR2000038816. Registered on October 10, 2020.

Cardiac intramural electrical mapping reveals focal delays but no conduction velocity slowing in the peri-infarct region.

Altered electrical behavior alongside healed myocardial infarcts (MIs) is associated with increased risk of sudden cardiac death. However, the multidimensional mechanisms are poorly understood and described. This study characterizes, for the first time, the intramural spread of electrical activation in the peri-infarct region of chronic reperfusion MIs. Four sheep were studied 13 wk after antero-apical reperfusion infarction. Extracellular potentials (ECPs) were recorded in a ~20 × 20-mm2 region adjacent to the infarct boundary (25 plunge needles <0.5-mm diameter with 15 electrodes at 1-mm centers) during multisite stimulation. Infarct geometry and electrode locations were reconstructed from magnetic resonance images. Three-dimensional activation spread was characterized by local activation times and interpolated ECP fields (n = 191 records). Control data were acquired in 4 non-infarcted sheep (n = 96 records). Electrodes were distributed uniformly around 15 ± 5% of the intramural infarct boundary. There were marked changes in pacing success and ECP morphology across a functional border zone (BZ) ±2 mm from the boundary. Stimulation adjacent to the infarct boundary was associated with low-amplitude electrical activity within the BZ and delayed activation of surrounding myocardium. Bulk tissue depolarization occurred 3.5-14.6 mm from the pacing site for 39% of stimuli with delays of 4-37 ms, both significantly greater than control (P < 0.0001). Conduction velocity (CV) adjacent to the infarct was not reduced compared with control, consistent with structure-only computer model results. Insignificant CV slowing, irregular stimulus-site specific activation delays, and obvious indirect activation pathways strongly suggest that the substrate for conduction abnormalities in chronic MI is predominantly structural in nature.NEW & NOTEWORTHY Intramural in vivo measurements of peri-infarct electrical activity were not available before this study. We use pace-mapping in a three-dimensional electrode array to show that a subset of stimuli in the peri-infarct region initiates coordinated myocardial activation some distance from the stimulus site with substantial associated time delays. This is site dependent and heterogeneous and occurs for <50% of ectopic stimuli in the border zone. Furthermore, once coordinated activation is initiated, conduction velocity adjacent to the infarct boundary is not significantly different from control. These results give new insights to peri-infarct electrical activity and do not support the widespread view of uniform electrical remodeling in the border zone of chronic myocardial infarcts, with depressed conduction velocity throughout.

A critical courier role of volatile oils from Dalbergia odorifera for cardiac protection in vivo by QiShenYiQi.

Component-based Chinese medicine (CCM) is derived from traditional Chinese medicine but produced with modern pharmaceutical standard and clearer clinical indications. However, it still faces challenges of defining individual component contribution in the complex formula. Using QiShenYiQi (QSYQ) as a model CCM, we investigated the role of Dalbergia odorifera (DO), an herbal component, in preventing myocardial damage. We showed that in vitro, QSYQ exerted considerable protective activities on cardiomyocytes from H2O2-induced mitochondrial dysfunction with or without DO. However, in isolated rat hearts, myocardial protection by QSYQ was significantly weakened without DO. In everted gut sac model, DO significantly enhanced absorption of the major QSYQ ingredients in different regions of rat intestine. Finally, in in vivo mouse model of doxorubicin (DOX)-induced myocardial damage, only QSYQ, but not QiShenYiQi without DO (QSYQ-DO), exerted a full protection. Taken together, our results showed that instead of directly contributing to the myocardial protection, Dalbergia odorifera facilitates the major active ingredients absorption and increases their efficacy, eventually enhancing the in vivo potency of QSYQ. These findings may shed new lights on our understanding of the prescription compatibility theory, as well as the impacts of "courier herbs" in component-based Chinese medicine.

Comparative metabonomics of Wenxin Keli and Verapamil reveals differential roles of gluconeogenesis and fatty acid ß-oxidation in myocardial injury protection.

Metabonomics/metabolomics is a rapid technology for comprehensive profiling of small molecule metabolites in cells, tissues, or whole organisms, the application of which has led to understanding pathophysiologic mechanisms of cardiometabolic diseases, defining predictive biomarkers for those diseases, and also assessing the efficacious effects of incident drugs. In this study, proton nuclear magnetic resonance (NMR)-based metabonomics was employed to identify the metabolic changes in rat plasma caused by myocardial ischemia-reperfusion injury (MIRI), and to compare the metabolic regulatory differences between traditional Chinese medicine Wenxin Keli (WXKL) and Western medicine verapamil. The results revealed that energy-substrate metabolism were significantly disturbed by ischemia-reperfusion (I/R) in myocardium and bulk of the key metabolites could be further modulated by verapamil and/or WXKL. Lipid metabolism and amino acid transamination occurred mainly following the treatment of verapamil, whereas glucose oxidation and BCAA degradation were prominently ameliorated by WXKL to content the energy demands of heart. Moreover, both WXKL and verapamil improved the secretions of taurine and ketone bodies to overcome the oxidative stress and the shortage of energy sources induced by ischemia-reperfusion.

Low-Level Tragus Stimulation for the Treatment of Ischemia and Reperfusion Injury in Patients With ST-Segment Elevation Myocardial Infarction: A Proof-of-Concept Study.

OBJECTIVES: The aim of this study was to investigate whether low-level tragus stimulation (LL-TS) treatment could reduce myocardial ischemia-reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The authors' previous studies suggested that LL-TS could reduce the size of myocardial injury induced by ischemia. METHODS: Patients who presented with STEMI within 12 h of symptom onset, treated with primary percutaneous coronary intervention, were randomized to the LL-TS group (n = 47) or the control group (with sham stimulation [n = 48]). LL-TS, 50% lower than the electric current that slowed the sinus rate, was delivered to the right tragus once the patients arrived in the catheterization room and lasted for 2 h after balloon dilatation (reperfusion). All patients were followed for 7 days. The occurrence of reperfusion-related arrhythmia, blood levels of creatine kinase-MB, myoglobin, N-terminal pro-B-type natriuretic peptide and inflammatory markers, and echocardiographic characteristics were evaluated. RESULTS: The incidence of reperfusion-related ventricular arrhythmia during the first 24 h was significantly attenuated by LL-TS. In addition, the area under the curve for creatine kinase-MB and myoglobin over 72 h was smaller in the LL-TS group than the control group. Furthermore, blood levels of inflammatory markers were decreased by LL-TS. Cardiac function, as demonstrated by the level of N-terminal pro-B-type natriuretic peptide, the left ventricular ejection fraction, and the wall motion index, was markedly improved by LL-TS. CONCLUSIONS: LL-TS reduces myocardial ischemia-reperfusion injury in patients with STEMI. This proof-of-concept study raises the possibility that this noninvasive strategy may be used to treat patients with STEMI undergoing primary percutaneous coronary intervention.

Cardioprotective effects of low-level carotid baroreceptor stimulation against myocardial ischemia-reperfusion injury in canine model.

PURPOSE: The modulation of the autonomic nervous system (ANS) has been shown to prevent myocardial ischemia-reperfusion injury (MIRI). Carotid baroreceptor stimulation modulates the ANS by sympathetic withdrawal and vagal activation. The aim of this study was to assess whether low-level carotid baroreceptor stimulation (LL-CBS) attenuated MIRI and test its underlying molecular mechanisms. METHODS: Forty adult healthy mongrel dogs were randomly assigned to three groups as follows: (1) I/R group (n = 15): left anterior descending artery (LAD) was occluded for 1 h and allowed for 1 h reperfusion; (2) LL-CBS group (n = 15): I/R plus LL-CBS; and (3) sham group (n = 10): sham surgery without stimulation. The voltage-reducing blood pressure by 5% was defined as the threshold. LL-CBS was performed at a voltage that is 80% below the threshold. Infarct size was assessed with Evans blue and TTC staining. The inflammatory cytokines, biomarker of oxidative stress and apoptosis, and connexin 43 (Cx43) expression were measured to assess the injury. RESULTS: The number of ventricular tachycardia/ventricular fibrillation (VT/VF) episodes was significantly decreased in the LL-CBS group compared with the I/R group (2.8 ± 0.8 vs. 7.0 ± 2.6, P < 0.05). LL-CBS reduced tumor necrosis factor α, interleukin (IL)-1, IL-6, and malondialdehyde levels but increased superoxide dismutase level compared with the I/R group (P < 0.05). Meanwhile, LL-CBS significantly decreased the percentage of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL)-positive cardiomyocytes (20 ± 8 vs. 47 ± 12, P < 0.05). Western blotting and real-time polymerase chain reaction (RT-PCR) in Cx43 revealed that LL-CBS caused an increase, respectively, compared with the I/R group (0.75 ± 0.3 vs. 0.3 ± 0.2 and 1.0 ± 0.3 vs. 0.4 ± 0.1, respectively, both P < 0.05). CONCLUSIONS: LL-CBS exerted cardioprotective effects during ischemic reperfusion period potentially by inhibiting inflammation, oxidative stress, and apoptosis and modulating the Cx43 expression.

Setting Up an Efficient Therapeutic Hypothermia Team in Conscious ST Elevation Myocardial Infarction Patients: A UK Heart Attack Center Experience.

Patients presenting with ST elevation myocardial infarction (STEMI) are routinely treated with percutaneous coronary intervention to restore blood flow in the occluded artery to reduce infarct size (IS). However, there is evidence to suggest that the restoration of blood flow can cause further damage to the myocardium through reperfusion injury (RI). Recent research in this area has focused on minimizing damage to the myocardium caused by RI. Therapeutic hypothermia (TH) has been shown to be beneficial in animal models of coronary artery occlusion in reducing IS caused by RI if instituted early in an ischemic myocardium. Data in humans are less convincing to date, although exploratory analyses suggest that there is significant clinical benefit in reducing IS if TH can be administered at the earliest recognition of ischemia in anterior myocardial infarction. The Essex Cardiothoracic Centre is the first UK center to have participated in administering TH in conscious patients presenting with STEMI as part of the COOL-AMI case series study. In this article, we outline our experience of efficiently integrating conscious TH into our primary percutaneous intervention program to achieve 18 minutes of cooling duration before reperfusion, with no significant increase in door-to-balloon times, in the setting of the clinical trial.

Cardioprotection of vitexin on myocardial ischemia/reperfusion injury in rat via regulating inflammatory cytokines and MAPK pathway.

This study was conducted to demonstrate myocardial protective effects and possible underlying mechanisms of vitexin on myocardial ischemia/reperfusion (I/R) injury in rats. Occluding the anterior descending artery for 30 min and restoring blood perfusion for 60 min in rat established a model of myocardial I/R. The elevation of the ST segment of Electrocardiograph (ECG) was observed. The infarct size of the rat heart was assessed by triphenyltetrazolium chloride staining (TTC). LDH, CK, SOD activities and MDA content were determined. An immunohistochemical analysis was applied to measure the expression of myocardial NF-κBp65 and TNF-α. ERK/phospho-ERKand c-Jun/phospho-c-Jun protein expression was examined via Western Blot. Vitexin significantly reduced the elevation of the ST segment of ECG and myocardial infarct size. LDH and CK activities and MDA content were attenuated in serum, while SOD activity was markedly enhanced. Vitexin significantly attenuated I/R-induced increases of myocardial NF-κB and TNF-α. Moreover, Western Blot analysis presented that vitexin markedly enhanced the expression of phospho-ERK and weakened the expression of phospho-c-Jun compared to I/R group. The significant protective effect against myocardial ischemical/reperfusion injury in rat, which is exhibited by vitexin, may be related to its antioxidative and anti-inflammatory effects by regulating inflammatory cytokines and the MAPK pathway.

Inhibition of heart transplant injury and graft coronary artery disease after prolonged organ ischemia by selective protein kinase C regulators.

OBJECTIVE: Transplanted hearts subjected to prolonged ischemia develop ischemia-reperfusion injury and graft coronary artery disease. To determine the effect of delta-protein kinase C and -protein kinase C on ischemia-reperfusion injury and the resulting graft coronary artery disease induced by prolonged ischemia, we used a delta-protein kinase C-selective inhibitor peptide and an -protein kinase C-selective activator peptide after 30 or 120 minutes of ischemia. METHODS: Hearts of piebald viral glaxo (PVG) rats were heterotopically transplanted into allogeneic August Copenhagen Irish (ACI) rats. After cardioplegic arrest of the donor heart, -protein kinase C activator was injected antegrade into the coronary arteries. Hearts were procured and bathed in -protein kinase C activator, and before reperfusion, delta-protein kinase C inhibitor was injected into the recipient inferior vena cava. Controls were treated with saline. To analyze ischemia-reperfusion injury, grafts were procured at 4 hours after transplantation and analyzed for superoxide generation; myeloperoxidase activity; tumor necrosis factor alpha, interleukin 1beta, and monocyte/macrophage chemoattractant protein 1 production; and cardiomyocyte apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and caspase 2, 3, 8, and 9 activity. To analyze graft coronary artery disease, another set of animals underwent equal ischemic times and treatment strategies and then after 90 days were analyzed for graft coronary artery disease indexes. RESULTS: All measures of ischemia-reperfusion injury and graft coronary artery disease after 120 minutes of ischemia in the saline-treated group were significantly increased relative to those observed after 30 minutes of ischemia. It is important to note that all ischemia-reperfusion injury parameters and graft coronary artery disease indexes decreased significantly in the protein kinase C regulator-treated group in comparison to saline-treated controls; additionally, these values were equivalent to those in saline-treated controls with 30 minutes of ischemia. CONCLUSIONS: Combined treatment with -protein kinase C activator and delta-protein kinase C inhibitor reduces ischemia-reperfusion injury and decreases the resulting graft coronary artery disease induced by prolonged ischemia.

Very early cardiac magnetic resonance imaging for quantification of myocardial tissue perfusion in patients receiving tirofiban before percutaneous coronary intervention for ST-elevation myocardial infarction.

BACKGROUND: Assessment of myocardial blood flow is important for identification and monitoring of microvascular effects of glycoprotein IIb/IIIa inhibitors. Magnetic resonance imaging is a novel noninvasive method providing complementary information on myocardial blood flow and cardiac function. METHODS AND RESULTS: Patients (n = 53) admitted within 12 (mean, 5.8) hours after onset of symptoms were randomized to tirofiban or standard therapy before primary percutaneous coronary intervention (PCI) with stenting. Myocardial blood flow was graded by measurement of corrected Thrombolysis in Myocardial Infarction frame counts and by semiquantitative analysis of signal intensity curves from first-pass contrast-enhanced magnetic resonance perfusion. Pretreatment with tirofiban proved safe and resulted in a significantly lower corrected Thrombolysis in Myocardial Infarction frame counts (21 vs 34, P = .008) indicating improved myocardial blood flow. Magnetic resonance imaging revealed higher normalized peak signal intensities (2.19 vs 1.63, P = .046) and a trend to steeper upslopes (0.79 vs 0.48, P = .1). Cardiac left ventricular wall motion analysis resulted in a significantly lower number of myocardial segments with abnormal wall thickening (6.4 vs 8.5, P = .025). CONCLUSIONS: Pretreatment with tirofiban appears safe and improves myocardial flow after primary PCI with stenting. Magnetic resonance imaging proved useful as a complementary method for noninvasive assessment of myocardial blood flow and cardiac function in patients with ST-segment elevation myocardial infarction undergoing primary PCI.

Myocardial protective effects of electroacupuncture and hypothermia on porcine heart after ischemia/reperfusion.

The study was carried out in order to observe the protective effects of electroacupuncture (EA) and hypothermia on myocardial ischemic and reperfusion injury in pigs. Blood superoxide dismutase (SOD), malondialdehyde (MDA), creatine phosphokinase (CPK) and its isoenzyme (CK-MB), coronary artery flow (CAF) and myocardial heat-shock protein (HSP) mRNA expression were detected. It was observed that the MDA content increased and SOD activities decreased more significantly in control group compared with EA and EA+ hypothermia groups. CPK and CK-MB were found significantly increased in all three groups, but more remarkable in control group than in EA and EA+ hypothermia groups. HSP70 mRNA expression was found to be more in EA and EA+ hypothermia groups than that in control group 60 min after reperfusion. The results indicated that EA enhance the myocardial protection of hypothermia on ischemia/reperfusion injury. The mechanism may be related to the improvement of antioxidation and increased expression of HSP70 gene.

Irreversibly damaged myocardium at MR imaging with a necrotic tissue-specific contrast agent in a cat model.

PURPOSE: To investigate the capability of a necrosis-avid magnetic resonance (MR) contrast agent, bis-gadolinium mesoporphyrins, for assessment of irreversibly damaged myocardium and to evaluate the time course of signal enhancement in the reperfused myocardium. MATERIALS AND METHODS: Nine cats were subjected to 90 minutes of occlusion of the left anterior descending coronary artery followed by 90 minutes of reperfusion. Contrast material-enhanced T1-weighted spin-echo images were obtained for 12 hours in five cats and 6 hours in four cats. Pathologic examinations of the resected specimens were performed with 2'3'5-triphenyl tetrazolium chloride (TTC) histochemical staining and electron microscopy. The size of enhanced area on MR images was compared with that of irreversibly damaged myocardium with TTC staining. The time course of signal enhancement was evaluated. RESULTS: The size of enhanced area on MR images was well correlated with that of irreversibly damaged myocardium with TTC staining. Maximum enhancement occurred 1-3 hours after administration of the contrast material, with mean enhancement of 171% that of normal myocardium. Electron microscopic examinations showed severe myocardial damage in the irreversibly damaged myocardium but only mild edematous changes in the reversibly damaged myocardium. CONCLUSION: MR images enhanced with bis-gadolinium mesoporphyrins provide accurate sizing of irreversibly damaged myocardium with a strong and persistent signal enhancement in the reperfused myocardium.

Warm blood hyperkalaemic reperfusion ('hot shot') prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery.

OBJECTIVE: A significant metabolic derangement occurs in the ischaemic-reperfused heart of patients undergoing coronary artery bypass surgery using cold blood cardioplegia. The aim of the present study was to investigate whether this effect could be reversed by complementing cold blood cardioplegia with a short terminal exposure of warm blood hyperkalaemic cardioplegia ('hot shot'). METHODS: Thirty-five patients undergoing primary elective coronary revascularisation were randomized to one of two different techniques of myocardial protection. In the cold blood group (n = 17) myocardial protection was induced using antegrade hyperkalaemic cold blood cardioplegic solution. In the hot shot group (n = 18) this was supplemented with a short exposure to hyperkalaemic warm blood cardioplegia prior to removal of the cross clamp. Intracellular substrates (ATP and amino acids) were measured in left ventricular biopsies collected 5 min after institution of cardiopulmonary bypass, after 30 min of ischaemic arrest and 20 min after reperfusion. RESULTS: Biopsies taken at the end of the period of myocardial ischaemia, when compared to control, did not show any significant change in the intracellular concentration of ATP (from 2.71 +/- 0.32 to 2.43 +/- 0.37 micromol g wet for cold blood group and from 2.6 +/- 0.3 to 2.5 +/- 0.34 micromol/g wet weight for hot shot group) or total free intracellular amino acids pool (from 33.0 +/- 1.4 to 30.0 +/- 1.4 micromol/g wet weight for cold blood group and from 34.0 +/- 1.4 to 34.5 +/- 2.3 micromol/g wet weight for hot shot group). Upon reperfusion, however, there was a significant fall in ATP (23.7 +/- 1.6 micromol/g wet weight amino acids, P < 0.05) and in amino acids (1.53 +/- 0.24 micromol/g wet weight, P < 0.05) in the group receiving only cold blood cardioplegia but not in the hot shot group (2.27 +/- 0.27 micromol/g wet weight ATP and 30.5 +/- 1.6 micromol/g wet weight amino acids). CONCLUSIONS: The data suggest that warm blood hyperkalaemic reperfusion hot shot prevents myocardial metabolic derangement seen during coronary artery surgery.

Impact of transfusion of mediastinal shed blood on serum levels of cardiac enzymes.

BACKGROUND: Infusion of shed mediastinal blood using an autotransfusion system is a widely applied technique of blood conservation in cardiac surgery. Serial determinations of serum creatine kinase (CK), its MB isoenzyme (CK-MB), and lactate hydrogenase (LDH) levels have been used to monitor perioperative myocardial injury. We investigated the impact of postoperative autotransfused blood infusion on serum levels of these enzymes. METHODS: We performed a retrospective analysis of postoperative serum CK, CK-MB, and LDH levels of 300 patients who had elective uncomplicated aortocoronary bypass grafting. Shed mediastinal blood samples from 26 patients were analyzed for CK, CK-MB (enzymatic activity and mass), and LDH levels before infusion. RESULTS: High postoperative serum levels of CK and LDH were observed after infusion of autotransfused blood. Shed mediastinal blood contained extremely high levels of these enzymes, particularly from patients who had internal mammary artery dissection. There was a strong correlation (r = 0.96) between measured CK-MB enzyme activities and those calculated from the CK-MB mass units. CONCLUSIONS: Infusion of autotransfused blood containing high concentrations of CK and LDH results in elevated serum levels of these enzymes. Hemolysis, frequently present in shed blood, does not interfere with the routine biochemical assays for CK and CK-MB enzyme activities. Caution should be taken when postoperative cardiac enzyme levels are used to determine myocardial injury after aortocoronary bypass grafting if autotransfusion is used as a method of blood conservation.

Decreased free radical scavengers with reperfusion after coronary angioplasty in patients with acute myocardial infarction.

Early reperfusion after myocardial infarction improves survival rate and is thought to preserve myocardial function, but the reperfusion of ischemic tissue may release oxygen free radicals, which could adversely affect left ventricular function and diminish the beneficial effects of reperfusion. Measurements related to free radical scavenging (plasma and erythrocyte enzyme systems, which are involved in free radical control, alpha-tocopherol, selenium, and manganese superoxide dismutase) may be indirect markers of free radical production. We evaluated 10 patients undergoing coronary angioplasty within 4 hours of myocardial infarction to measure the impact of abrupt reperfusion on free radical scavenger-related indexes. Pulmonary artery samples were taken before, immediately after, and 3 hours after angioplasty. During reperfusion, significant reductions occurred in alpha-tocopherol (1.1 +/- 0.3 mg/dl before, 0.9 +/- 0.2 mg/dl immediately after [p = 0.03], and 0.8 +/- 0.2 mg/dl 3 hours after percutaneous transluminal coronary angioplasty [p = 0.02]), and selenium levels (13.7 +/- 2.4 micrograms/dl before, 12.9 +/- 2.4 micrograms/dl immediately after, and 10.2 +/- 3.0 micrograms/dl 3 hours after angioplasty [p = 0.0006]). Erythrocyte markers (glutathione peroxidase and superoxide dismutase) were not altered by reperfusion, possibly reflecting the relatively long half-life of the erythrocyte. The erythrocyte glutathione peroxidase value before reperfusion in patients (30.8 +/- 5.1 IU/gm of hemoglobin) was lower than in a control group (36.1 +/- 6.5 IU/gm of hemoglobin; p = 0.01). Thus the decrease in plasma alpha-tocopherol and selenium after reperfusion in this group of patients may reflect a general alteration in plasma free radical scavenger levels, suggesting consumption of plasma free radical scavengers with reperfusion after acute myocardial infarction.

AUR Memorial Award. Identification of myocardial cell death in reperfused myocardial injury using dual mechanisms of contrast-enhanced magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Because the magnitude of dysprosium-induced signal loss depends on the microheterogeneity of its distribution (exclusion from intracellular space), we proposed that loss of myocardial cell integrity would be reflected by decreased potency of dysprosium in the injured compared with normal myocardium. We measured the effect of dysprosium on magnetic resonance (MR) imaging signal intensity of reperfused infarcted and nonischemic myocardium and related it to tissue concentration of the contrast media. METHODS: Rats were subjected to 1 hr coronary artery occlusion followed by 1 hr reperfusion. After 45 min of reflow, group 1 (n = 9) received 1.0 and 0.2 mmol/kg dysprosium diethylenetriamine pentaacetic acid-bismethylamide (Dy-DTPA-BMA) and gadodiamide (Gd-DTPA-BMA), respectively. Group 2 (n = 7) received no contrast agents. Excised hearts were imaged with spin-echo T1- and T2-weighted sequences. After imaging, hearts were stained (triphenyltetrazolium chloride) to define the injured zones. Concentrations of Dy-DTPA-BMA and Gd-DPTA-BMA in regional myocardial tissue were determined by induction coupled plasma-atomic emission spectrometry. Separate groups received one or the other contrast medium alone to control for potential error from the mixed effects of the two agents. RESULTS: Gd-DTPA-BMA delineated reperfused infarcted myocardium as a bright zone on T1-weighted images, thus indicating delivery of the agent and reperfusion at the tissue level. Dy-DTPA-BMA delineated the reperfused infarction as a bright region by decreasing the signal intensity of nonischemic myocardium significantly more than that of injured myocardium, despite being present in greater concentration (by 2.46-fold) in the injured myocardium. CONCLUSION: These findings are consistent with the hypothesis that the failure of myocardial cells to exclude the dysprosium compound is responsible for the diminished potency of dysprosium to cause MR imaging signal intensity loss in reperfused myocardial infarction. The combination of the two contrast media may define reperfusion of the myocardium at the tissue level (Gadolinium distribution) and the presence and extent of myocardial necrosis (diminished dysprosium effect) in reperfused myocardial infarctions.

Direct measurement of myocardial free radical generation in an in vivo model: effects of postischemic reperfusion and treatment with human recombinant superoxide dismutase.

OBJECTIVES: The purpose of this study was to determine whether postischemic reperfusion of the heart in living rabbits induces a burst of oxygen free radical generation that can be attenuated by recombinant human superoxide dismutase administered at the moment of reflow. BACKGROUND: This phenomenon was previously demonstrated in crystalloid perfused, globally ischemic rabbit hearts. METHODS: Thirty-two open chest rabbits were assigned to one of four groups of eight animals each: Group I (control animals), no coronary artery occlusion; Group II, 30 min of circumflex marginal coronary artery occlusion without reperfusion; Group III, 30 min of coronary occlusion followed by 60 s of reperfusion, and Group IV, 30 min of coronary occlusion followed by treatment with recombinant human superoxide dismutase (a 20-mg/kg body weight bolus 90 s before reperfusion and a 0.17-mg/kg infusion during 60 s of reperfusion). Full thickness biopsy specimens taken from the ischemic region were then rapidly freeze clamped and electron paramagnetic resonance spectroscopy was performed at 77 degrees K. RESULTS: Three radical signals similar to those previously identified in the isolated, crystalloid perfused rabbit heart were observed: an isotropic signal with g = 2.004 suggestive of a semiquinone, an anisotropic signal with g parallel = 2.033 and g perpendicular = 2.005 suggestive of an oxygen-centered alkyl peroxy radical, and a triplet with g = 2.000 and aN = 24 G suggestive of a nitrogen-centered radical. In addition, a fourth signal consistent with an iron-sulfur center was seen. The oxygen-centered free radical concentration during normal perfusion (Group I) was 1.8 +/- 0.8 mumol compared with 4.4 +/- 0.9 mumol after 30 min of regional ischemia without reperfusion (Group II) and 13.0 +/- 2.5 mumol after 60 s of reperfusion (Group III) (p < 0.05 among all three groups). In contrast, superoxide dismutase treated-rabbits (Group IV) demonstrated a peak oxygen radical concentration of only 5.9 +/- 1.2 mumol (p < 0.05 vs. Group III). CONCLUSIONS: This study demonstrates that reperfusion after regional myocardial ischemia in the intact rabbit is associated with a burst of oxygen-centered free radicals. The magnitude of this burst is greater than that seen after a comparable duration of global ischemia in the isolated, buffer-perfused rabbit heart preparation and is significantly reduced by superoxide dismutase administration begun just before reflow.