Mst1 regulates post-infarction cardiac injury through the JNK-Drp1-mitochondrial fission pathway.

BACKGROUND: Post-infarction cardiac injury is closely associated with cardiac remodeling and heart dysfunction. Mammalian STE20-like kinase 1 (Mst1), a regulator of cellular apoptosis, is involved in cardiac remodeling in post-infarction heart, but the mechanisms remain poorly defined. We aimed to explore the role of Mst1 in regulating chronic post-infarction cardiac injury, with a focus on mitochondrial homoeostasis. METHODS: Wild-type (WT) and Mst1-knockout mice were as the cardiac myocardial infarction model. Cardiac fibrosis, myocardial inflammation response, heart dysfunction and cardiomyocyte death were measured in vivo using immunohistochemistry, immunofluorescence, western blot, qPCR and TUNEL assays. Cardiomyocytes were isolated from WT and Mst1-knockout mice, and a chronic hypoxia model was used to induce damage. Mitochondrial function was determined via JC1 staining, ROS measurement, cyt-c leakage detection and mitochondrial apoptotic pathways analysis. Mitochondrial fission was observed using immunofluorescence. A pathway activator and inhibitor were applied to establish the signaling pathways involved in regulating mitochondrial homeostasis. RESULTS: Our study demonstrated that Mst1 expression was significantly upregulated in the heart post-infarction. Activated Mst1 induced cardiac fibrosis, an excessive inflammatory response, and cardiomyocyte death, whereas the genetic ablation of Mst1 protected the myocardium against chronic post-infarction injury. Function assays showed that upregulation of Mst1 activity contributed to JNK pathway activation, which led to Drp1 migration from the cytoplasm onto the surface of the mitochondria, indicative of mitochondrial fission activation. Excessive mitochondrial fission caused mitochondrial fragmentation, resulting in mitochondrial potential collapse, ROS overproduction, mitochondrial pro-apoptotic leakage into the cytoplasm, and the initiation of caspase-9-mediated mitochondrial apoptosis. By contrast, Mst1 deletion helped to maintain mitochondrial structure and function, sending pro-survival signals to the cardiomyocytes. CONCLUSIONS: Our results identify Mst1 as a malefactor in the development of post-infarction cardiac injury and that it acts through the JNK-Drp1-mitochondrial fission pathway.

Effects of defibrillation shock in patients implanted with a subcutaneous defibrillator: a biomarker study.

Aims: Implantable cardioverter defibrillator (ICD) shocks are associated with a subsequent increased risk of death, and an elevation of cardiac enzymes has been measured after defibrillation testing (DFT). In an experimental swine study, subcutaneous ICD (S-ICD) shocks caused less myocardial damage than traditional ICD shocks. The aim of our study was to investigate the association between S-ICD shock and acute cardiac damage in humans, as evaluated by means of sensitive and highly specific circulating biomarkers. Methods and results: We calculated the variation in the serum levels of high-sensitivity cardiac troponin I (hs-CTnI) and creatine kinase-MB mass concentration (CK-MB mass), measured before and after an S-ICD shock delivered during intraoperative DFT. We also measured the degree of haemodynamic stress, as the variation in the serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and copeptin (CP), after the S-ICD shock. We analysed 30 consecutive patients who received an S-ICD and who underwent DFT by means of a single 65 J shock. The levels of biomarkers did not change from baseline to 1 h post-shock, i.e. hs-CTnI (from 0.029 ± 0.005 ng/mL to 0.030 ± 0.005 ng/mL, P = 0.079) and CK-MB mass (from 1.37 ± 0.17 ng/mL to 1.41 ± 0.18, P = 0.080) and remained stable 6 and 24 h after DFT. The plasma NT-proBNP did not change, whereas CP levels were significantly higher at 1 h post-shock evaluation. However, 6 h after DFT, the levels had returned to the baseline and remained stable at 24 h. Conclusion: The S-ICD shock did not seem to cause myocardial injuries. Although CP levels temporarily rose after DFT, they returned to basal levels within 6 h, which suggests that DFT does not have long-term prognostic implications. ICD shocks are associated with a subsequent increased risk of death, and an elevation of cardiac enzymes has been measured after DFT. We showed that serum levels of biomarkers of myocardial damage did not increase after high-energy DFT in patients who had undergone S-ICD device implantation. This suggests that S-ICD shock does not have long-term prognostic implications.

Protective effect of the extract of Yi-Qi-Fu-Mai preparation on hypoxia-induced heart injury in mice.

Yi-Qi-Fu-Mai (YQFM) is extensively used clinically to treat cardiovascular diseases in China. To explore the anti-hypoxia effect of the extract of YQFM preparation (EYQFM), the EYQFM (1.4, 2.8, and 5.5 g·kg(-1)·d(-1)) was assessed for its heart-protective effect in a chronic intermittent hypoxia (CIH) animal model (oxygen pressure 7%-8%, 20 min per day) for 28 days of treatment. Betaloc (0.151 6 g·kg(-1)·d(-1)) was used as a positive control. The histopathological analyses of heart in CIH mice were conducted. Several cardiac state parameters, such as left ventricular ejection fractions (EF), stroke volume (SV), expression of creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. The results showed that treatment with EYQFM markedly reversed swelling of the endothelial cells and vacuolization in the heart when compared with the model group. Further study demonstrated that EYQFM significantly improved ventricular myocardial contractility by increasing EF and SV. In addition, EYQFM inhibited the activity of CK, LDH, decreased the level of MDA and improved SOD activity. The results demonstrated that EYQFM significantly improved the tolerability of myocardium to hypoxia and ameliorated the cardiac damage in the CIH model.

Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury.

We sought to explore the effect of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced cardiac injury. The rats were divided randomly into five groups including normal control, CTX 100 mg/kg, BAE 80mg/kg, CTX+BAE 20mg/kg and CTX+BAE 80mg/kg groups. The rats in the three BAE-treated groups were administered BAE for four weeks. Seven days after BAE administration, rats in CTX group and two BAE-treated groups were intraperitoneally injected with a single dose of 100 mg/kg CTX. Cardiac injury was assessed using physiological parameters, Echo, morphological staining, real-time PCR and western blot. In addition, cardiotoxicity indices, inflammatory cytokines expression and oxidative stress markers were also detected. Four weeks 20mg/kg and 80mg/kg dose of BAE treatment following CTX exposure attenuated mean arterial blood pressure, heart rate and activities of heart enzymes, improved cardiac dysfunction, left ventricular hypertrophy and fibrosis. Importantly, BAE also attenuated CTX-induced LV leukocyte infiltration and inflammatory cytokines expression, ameliorated oxidative stress as well as cardiomyocyte apoptosis. In conclusion, BAE attenuated the CTX-induced cardiac injury and the protective mechanisms were related closely to the anti-inflammatory, antioxidant and anti-inflammatory characteristics of BAE.

Correlation of angiotensin converting enzyme gene polymorphism with perioperative myocardial protection under extracorporeal circulation.

OBJECTIVE: To observe the expression of angiotensin converting enzyme (ACE), angiotensin II (Ang II), cardiac troponin (cTn I), creatine kinase isozymes (CK-MB) and muscle red protein(Myo) after cardiopulmonary bypass (CPB), and to investigate the association of polymorphisms in angiotensin converting enzyme genes and myocardial injury. METHODS: Sixty-three patients suffered from rheumatic mitral stenosis and scheduled for mitral valve replacement with CPB, were randomly divided into three groups according polymorphisms in angiotensin converting enzyme genes: type II, type ID, type DD (each=21). Blood samples were withdrawn from artery before operation (T1), at the beginning of CPB (T2), 30 min after CPB (T3), (T4) at the end of CPB (T5), 2 h after CPB (T6), 6 h after CPB (T7) to measure the expression of ACE, Ang II, cTn I, CK-MB, Myo. RESULTS: The level of ACE during and after CPB were significantly higher than those before CPB (P<0.05). As extension of CPB time, the expression of ACE was increased. The level of cTn I, CK-MB, Myo after CPB were significantly higher than those before CPB(P<0.05). The level of cTn I, CK-MB and Myo were highest at T7, T6 and T5 and T7, respectively. The level of ACE, Ang II cTn I in patients with DD genotype was significantly higher than the ID and II genotype (P< 0.05). Besides, the level of ACE, Ang II in patients with ID genotype was significantly higher than the II (P< 0.05). CONCLUSIONS: There is certain correlation between CPB perioperative midterm ACE and cTn I, Myo, CK-MB. ACE DD genotype is a susceptibility gene of the CPB perioperative myocardial injury.

Early treatment of radiation-induced heart damage in rats by caffeic acid phenethyl ester.

UNLABELLED: The study is designed to determine the therapeutic effect of caffeic acid phenethyl ester (CAPE) in minimizing radiation-induced injuries in rats. Rats were exposed to 7Gy gamma radiation, 30min later rats were injected with CAPE (10µmol/kg body, i.p.) for 7 consecutive days. Rats were sacrificed at 8 and 15 days after starting the experiment. Gamma-irradiation induced significant increase in malondialdehyde (MDA) level and xanthine oxidase (XO) and adenosine deaminase (ADA) activities, and significant decrease in total nitrate/nitrite (NO(x)) level and glutathione peroxidise (GPx), superoxide dismutase (SOD) and catalase activities in heart tissue and augmented lipid fractions levels and activities of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and aspartate transaminase (AST) in serum. Irradiated rats early treated with CAPE showed significant decrease in MDA, XO and ADA and significant increase in NO(x) and SOD in heart tissue and in serum enzymes compared with irradiated group. Serum lipid profiles and cardiac enzymes were restored. CONCLUSION: CAPE could exhibits curable effects on gamma irradiation-induced cardiac-oxidative impairment in rats.

A novel intracellular isoform of matrix metalloproteinase-2 induced by oxidative stress activates innate immunity.

BACKGROUND: Experimental and clinical evidence has pinpointed a critical role for matrix metalloproteinase-2 (MMP-2) in ischemic ventricular remodeling and systolic heart failure. Prior studies have demonstrated that transgenic expression of the full-length, 68 kDa, secreted form of MMP-2 induces severe systolic failure. These mice also had unexpected and severe mitochondrial structural abnormalities and dysfunction. We hypothesized that an additional intracellular isoform of MMP-2, which affects mitochondrial function is induced under conditions of systolic failure-associated oxidative stress. METHODOLOGY AND PRINCIPAL FINDINGS: Western blots of cardiac mitochondria from the full length MMP-2 transgenics, ageing mice and a model of accelerated atherogenesis revealed a smaller 65 kDa MMP-2 isoform. Cultured cardiomyoblasts subjected to transient oxidative stress generated the 65 kDa MMP-2 isoform. The 65 kDa MMP-2 isoform was also induced by hypoxic culture of cardiomyoblasts. Genomic database analysis of the MMP-2 gene mapped transcriptional start sites and RNA transcripts induced by hypoxia or epigenetic modifiers within the first intron of the MMP-2 gene. Translation of these transcripts yields a 65 kDa N-terminal truncated isoform beginning at M(77), thereby deleting the signal sequence and inhibitory prodomain. Cellular trafficking studies demonstrated that the 65 kDa MMP-2 isoform is not secreted and is present in cytosolic and mitochondrial fractions, while the full length 68 kDa isoform was found only in the extracellular space. Expression of the 65 kDa MMP-2 isoform induced mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-κB, NFAT and IRF transcriptional pathways. By microarray, the 65 kDa MMP-2 induces an innate immunity transcriptome, including viral stress response genes, innate immunity transcription factor IRF7, chemokines and pro-apoptosis genes. CONCLUSION: A novel N-terminal truncated intracellular isoform of MMP-2 is induced by oxidative stress. This isoform initiates a primary innate immune response that may contribute to progressive cardiac dysfunction in the setting of ischemia and systolic failure.

[Clinical monitoring of myocardial injury in neonates with intrauterine distress].

OBJECTIVE: To investigate whether no asphyxia neonates with intrauterine distress are complicated with myocardial injury and determine the sensitive biochemical diagnostic parameters. METHODS: A total of 89 neonates born in the First Affiliated Hospital of Sun Yat-sen University from July 2009 to December 2009 were enrolled. Fifty-three fetal distress cases with Apgar score > 7 at 1 and 5 minutes were enrolled in the study group; while the rest 36 healthy neonates, whose Apgar score = 10 at 1 and 5 minutes, were the control group. Umbilical artery blood samples of all cases were collected for blood gas analysis and biochemical measurement. RESULTS: (1) pH (7.23 ± 0.07) and BE [(-4.8 ± 3.0) mmol/L] in the study group were significantly lower than pH (7.31 ± 0.03) and BE [(-2.1 ± 1.5) mmol/L ] in the control group(P < 0.05). The lactic acid of study group [(5.2 ± 2.3) mmol/L] was higher than that of the control group [(2.3 ± 1.1) mmol/L], and the difference was significant (P < 0.01). However, there was no significant difference between the two groups in PaO2 [(16.2 ± 7.9) mm Hg (1 mm Hg = 0.133 kPa) vs. (17.5 ± 6.7) mm Hg] and PaCO2 [(54.0 ± 11.2) mm Hg vs. (48.5 ± 5.4) mm Hg; P > 0.05]. (2) The level of CK-MB in neonates with fetal distress[ (48 ± 59) U/L] was significantly higher than that of healthy neonates [(36 ± 27) U/L]. However, no significant difference was found in CK [(194 ± 73) U/L vs. (162 ± 95) U/L] and BNP levels [(519 ± 309) ng/L vs. (481 ± 216) ng/L; P > 0.05]. (3) Spearman rank correlation analysis showed that CK-MB level was negatively correlated with pH (r = -0.296, P < 0.05) and BE (r = -0.318, P < 0.05) of umbilical artery blood, while BNP level was positively correlated with umbilical lactic acid (r = 0.278, P < 0.05). No correlation was found between other parameters (P > 0.05). CONCLUSIONS: Intrauterine distress without neonatal asphyxia had effect on fetal myocardial injury. CK-MB can be used as a sensitive parameter for monitoring the development of myocardial injury. The severity of myocardial injury was related to fetal acidosis.

Myeloperoxidase increased cardiomyocyte protein nitration in mice subjected to nonlethal mechanical trauma.

Nonlethal mechanical trauma causes cardiomyocyte apoptosis which contributes to posttraumatic cardiac dysfunction. Apoptosis is positively correlated with protein nitration in the traumatic heart. However, the mechanisms responsible for the cardiomyocyte protein nitration remain unclear. The present study was designed to identify whether myeloperoxidase may contribute to protein nitration in nonlethal mechanical trauma and subsequent cardiomyocyte apoptosis, and, if so, to determine the possible mechanisms responsible. We used Noble-Collip drum to make nonlethal traumatic mice models. Male adult C57B16/J mice were placed in the Noble-Collip drum and subjected to a total of 200 revolutions at a rate of 40 r/min. Then myeloperoxidase activity and release, protein nitration, cardiomyocyte apoptosis, endothelial function and intercellular adhesion molecule-1 expression were determined. Nonlethal mechanical trauma was characterized by the 100% survival rate during the first 24 h after trauma, the lack of circulatory shock and without direct heart injury. However, myeloperoxidase activity significantly increased 6 h after trauma, and reached a maximum level 12 h after trauma. Obviously, protein nitration and cardiomyocyte apoptosis increased 12h after trauma and could be blocked by administration of R15.7, a monoclonal antibody that blocks polymorphonuclear neutrophils adhesion. Moreover, endothelial dysfunction and intercellular adhesion molecule-1 upregulation were observed in traumatic mice. Our present study demonstrated for the first time that myeloperoxidase caused protein nitration and cardiomyocyte apoptosis in nonlethal traumatic mice. Inhibition of polymorphonuclear neutrophils adhesion and antinitration treatments may be novel measures in reducing posttraumatic cardiomyocyte apoptosis and secondary heart injury.

Misunderstood cardiac involvement with heart impairment in traumatic sternal fracture: an enzyme-guided evaluation.

BACKGROUND: Isolated sternal fractures occur more and more frequently in traffic road accidents in particular after the introduction of the seat-belt law. This study sets out to assess by laboratory parameters the incidence and consequences of pericardial and myocardial involvement in sternal injury. PATIENTS AND METHODS: Between June 1997 and March 2007, 50 consecutive patients were admitted to our Thoracic Surgical Unit with acute traumatic sternal fractures. X-ray, CT scan, standard 12-lead electrocardiogram (ECG) and echocardiographic evaluation were obtained in all patients. (28 males, 22 females), with displaced and undisplaced fractures. The patients were hospitalised for cardiorespiratory monitoring, pain control and physiotherapy. Oxygen implementation was performed to obtain an arterial saturation above 96%. Supplementary investigations or therapeutic interventions were assessed if clinically indicated. RESULTS: Our data, according to literature, show that sternal trauma must be careful evaluated by monitoring of vital parameters. In our collection we have no mortality with complex comorbidity. The interparametric relation between laboratory values and cardiac involvement was not significant anyway . The prolonged CK-MB peak level in a large number of patients is related with cardiac impairment. CONCLUSIONS: Our results suggest that in traumatic sternal fractures enzymatic activity of CK-MB, echocardiographic investigation and careful monitoring for the first 96 hours are necessary. The cardiac compliance is inadequate in polytrauma patients and can lead to cardiac impairment.

Two cases in which myocardial injury could be only evaluated by nuclear medicine studies on electric shock patients whose electrocardiogram and myocardial enzyme levels were normal.

Heart injury due to electric shock is currently diagnosed based on electrocardiogram (ECG) changes or elevated levels of myocardial enzymes or both. However, the rate at which ECG detects abnormalities is very low; thus, the estimated rate of the diagnosis of myocardial damage due to electric shock is lower than the actual rate. The method of nuclear medicine study of the heart is superior with regard to evaluating transient ischemia, such as angina pectoris, in patients whose ECG and myocardial enzyme levels are normal. Therefore, we attempted to diagnose transient myocardial damage in electric shock patients by using nuclear medicine study of the heart.

Protection from cardiac injury by induction of heme oxygenase-1 and nitric oxide synthase in a focal ischaemia-reperfusion model.

The enzymes heme oxygenase (HO) generate carbon monoxide (CO) in living organisms during heme degradation. Carbon monoxide has recently been shown to dilate blood vessels and to possess anti-inflammatory properties. It is also known that nitric oxide (NO) donors ameliorate cardiac ischaemia-reperfusion injury in experimental models of global or focal ischaemia-reperfusion (FIR). The two gaseous mediators share the same mechanism of action via the stimulation of soluble guanylyl cyclase and the increase in cellular levels of cyclic GMP. We studied the effects of manipulating the HO system and the possible interaction between CO and NO in an experimental in vivo model of FIR in the rat heart. FIR-subjected rats had necrotic area in the left ventricle, ventricular arrhythmias and a shortening of survival time in comparison to sham-operated animals. Resident mast cells underwent a heavy degranulation, malonyldialdehyde was produced by myocardial cell membranes, and tissue calcium levels were increased. High levels of myeloperoxidase were also detected, suggesting a FIR-related inflammatory process. In animals pre-treated with the HO-1 inducer, hemin, all the biochemical and morphometric markers of FIR were minimized or fully abated. Consistently, the biochemical and morphometric markers of FIR were reversed in rats treated with the HO-1 blocker, ZnPP-IX, prior to hemin administration. Pre-treatment with hemin significantly increases the expression and activity of both cardiac HO-1 and iNOS, suggesting that CO and NO cooperate in the cardioprotective effect against FIR-induced damage, and that there is a therapeutic synergism between NO-donors and CO-releasing molecules, via the common stimulation of increase in cGMP levels and decrease in calcium overload.

Time-dependent changes in myocardial structure following discrete injury in mice deficient of matrix metalloproteinase-3.

Myocardial scars from radiofrequency (RF) ablation can increase in size in the post-injury period, resulting in remodeling of the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) contribute to adverse myocardial remodeling following injury. However, the role of specific MMP types in RF scar enlargement remains unclear. One MMP type, MMP-3, degrades a wide range of ECM substrates and can activate other MMPs. This project examined LV remodeling in wild type (WT) and MMP-3 deficient (mmp-3-/-) mice following RF injury. RF lesions (0.5 mm probe, 80 degrees C, 30 s) were created on the LV epicardium of WT (C57/BL6) and mmp-3-/- mice and were terminally studied at 1 h, 3, 7, and 28 days post-RF (n=10 each). Heart mass indexed to tibial length (mg/mm) was similar in the WT and mmp-3-/- mice at 1 h (8.1+/-0.3 vs. 7.6+/-0.3), but lower in the mmp-3-/- mice at 28 days post-RF (11.9+/-0.4 vs. 10.5+/-0.4, P<0.05). Scar volumes were greater in the mmp-3-/- mice at 3 days, but similar in the two groups at 28 days. Immunohistochemical localization showed fewer macrophages and lymphocytes at the scar border at 3 days in the mmp-3-/- hearts, but similar staining for these cells in WT and mmp-3-/- hearts at 7 and 28 days post-RF. Post-RF, the early increase in scar volume was accelerated in mmp-3-/- mice and associated with abnormal inflammatory cell infiltration/migration to the area of injury. These findings define a mechanistic role for MMP-3 in RF scar expansion and provide a temporal window during which interruption of MMP-3 activation may impair post-RF myocardial wound healing.

Case reports. 1. An autopsy case of fatal arrhythmia induced by injuries of the atrioventricular conduction system: a case report.

A 65-year-old woman died three days after being involved in a traffic accident, following an episode of ventricular fibrillation. She was diagnosed as having suffered cardiac contusion, liver contusion, mediastinal hematoma and rib fracture on admission. Her electrocardiogram showed complete right bundle branch block, complete atrioventricular block, and right axis deviation. Aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and creatine kinase-MB were found to be elevated on biochemical blood analysis. These findings recovered and her condition appeared to improve daily. At autopsy, epicardial and intramyocardial haemorrhage were macroscopically seen in the posterior wall of the bilateral ventricles. On microscopic examination, there was evidence of fresh haemorrhage and coagulative necrosis with inflammatory reaction in the ordinary myocardium and adipose tissue around the atrioventricular node, which had spread to the proximal portion of the His' bundle. It is considered that these findings caused ventricular fibrillation to occur, and that the cause of death in this case was myocardial contusion due to blunt thoracic injury. This case would indicate that myocardium nearby atrioventricular junction is vulnerable to external force. Moreover, it would seem that fatal arrhythmia occasionally occurs during the follow-up stage, despite the lack of any significant clinical findings.

The effects of inhaled nitric oxide on cardiac pathology and energy metabolism in a canine model of smoke inhalation injury.

OBJECTIVE: The effects of inhaled nitric oxide (NO) on cardiac pathology and energy metabolism were studied in a canine model of smoke inhalation injury. MATERIAL AND METHOD: Twenty-one dogs were randomly divided into three groups: four dogs constituted the normal control group (group N), eight dogs subjected to smoke inhalation followed by O(2) inhalation (FiO(2)=0.45) constituted the injury control group (group C), and nine dogs inhaling a mixture of O(2) and 45ppm nitric oxide after smoke exposure served as the treatment group (group T). Myocardial zymograms were continuously measured, and ventricular muscles were examined for histopathology in the end of the experiment. RESULTS: Lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (alpha-HBD), creatine kinase (CK) and glutamic oxalacetic transaminase (GOT) in group T were less than those in group C(P<0.05, or P<0.01). ATP content and energy charge (EC) in group T were higher significantly than those in group C(P<0.01). Light microscopy and electron microscopy indicated that the ventricular pathologic changes in group T were milder than in control group. CONCLUSION: Nitric oxide inhalation relieved myocardial damage and improved energy metabolism.

Protective role of DLalpha-lipoic acid against adriamycin-induced cardiac lipid peroxidation.

The cytoprotective activity of alpha-lipoic acid against free radical toxicity manifested during adriamycin (ADR)-induced cardiotoxicity has been investigated. ADR is a potent antitumour drug known to cause severe cardiotoxicity. Although ADR generates free radicals, the role of these radicals in the development of cardiac toxicity is still not well understood. In the present study, we evaluated the influence of chronic ADR treatment on the cellular defence mechanism against free radicals and the effect of alpha-lipoic acid supplementation on ADR-induced cardiotoxicity in male Wistar rats. The increase in lipid peroxidation (LPO) and activities of serum myocardial enzymes, namely lactate dehydrogenase (LDH) and creatinephosphokinase, associated with the decrease in activities of enzymatic (SOD, CAT, GPx, G6PD and GR) and non-enzymatic (GSH, Vit C and Vit E) antioxidants levels were the salient features observed in ADR-induced cardiotoxicity. Lipoic acid pretreated groups showed significant increase in activities of both enzymatic and non-enzymatic antioxidant levels. These observations highlight the antioxidant property of alpha-lipoic acid and its cytoprotective action against ADR-induced cardiotoxicity.

Impact of perioperative myocardial injury on early and long-term outcome after coronary artery bypass grafting.

AIMS: To establish the influence of perioperative myocardial injury on short- and long-term survival after coronary artery bypass grafting (CABG). METHODS AND RESULTS: The correlation of postoperative serum aspartate aminotransferase and creatine kinase MB to early cardiac-related death and to late survival was evaluated in 4911 patients who underwent CABG consecutively during a 6-year period. There were 93 early deaths (1.9%), 73 of them cardiac-related (1.5% of 4911). After a mean follow-up of 5 years, 409 additional deaths (8.5% of 4818) had occurred. Elevated enzyme levels on day 1 postoperatively highly increased the risk of early cardiac death (serum aspartate aminotransferase >or=2.35 microkat.l(-1): odds ratio 9.2; serum creatine kinase MB >or=61 microg.l(-1): odds ratio 6.0), and increased the risk of late death by approximately 50% (serum aspartate aminotransferase >or=2.35 microkat.l(-1): relative hazard 1.5; serum creatine kinase MB >or=61 microg.l(-1): relative hazard 1.4). This increased risk of death was independent of other risk factors and remained constant over time. CONCLUSIONS: Enzyme elevation after CABG implied an increased risk of both early and late death. The long-term effect persisted many years after surgery.

Cytokine responses and myocardial injury in coronary artery bypass grafting.

OBJECTIVE: Cardiopulmonary bypass is acknowledged to be one of the major causes of a complex systemic inflammatory response after cardiac surgery, and it may contribute to postoperative complications and even multiple organ dysfunction. We here compared the cytokine responses and the degree of myocardial injury after coronary artery bypass grafting with or without cardiopulmonary bypass. METHODS: Nine patients underwent off-pump revascularization and 13 with cardiopulmonary bypass. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-10 were measured before anesthesia induction, and 5 min, 1, 4, and 20 h after reperfusion to the myocardium. Levels of the MB isoenzyme of creatine kinase (CK-MB) were also measured after the operation. RESULTS: Levels of TNF-alpha were low in both groups. A delayed elevation of IL-6 was noted in the off-pump group. IL-8 and IL-10 levels were significantly higher in the CPB than in the off-pump patients after reperfusion (p=0.006 and 0.001 respectively). Postoperative CK-MB levels were significantly higher in the CPB than in the off-pump group (p=0.001). Cytokine levels correlated with CK-MB values. CONCLUSION: The results indicated that off-pump revascularization was associated with reduced cytokine responses and less severe myocardial injury. The degree of myocardial injury, as defined by CK-MB release, correlated with cytokine release. Intervention designed to reduce cytokine responses in cardiac surgery may be advantageous for patients with severe comorbidity.