Global Cardiac Ischemia Research Articles

Protein Phosphatase 2A Improves Cardiac Functional Response to Ischemia and Sepsis.

Reversible protein phosphorylation is a posttranslational modification of regulatory proteins involved in cardiac signaling pathways. Here, we focus on the role of protein phosphatase 2A (PP2A) for cardiac gene expression and stress response using a transgenic mouse model with cardiac myocyte-specific overexpression of the catalytic subunit of PP2A (PP2A-TG). Gene and protein expression were assessed under basal conditions by gene chip analysis and Western blotting. Some cardiac genes related to the cell metabolism and to protein phosphorylation such as kinases and phosphatases were altered in PP2A-TG compared to wild type mice (WT). As cardiac stressors, a lipopolysaccharide (LPS)-induced sepsis in vivo and a global cardiac ischemia in vitro (stop-flow isolated perfused heart model) were examined. Whereas the basal cardiac function was reduced in PP2A-TG as studied by echocardiography or as studied in the isolated work-performing heart, the acute LPS- or ischemia-induced cardiac dysfunction deteriorated less in PP2A-TG compared to WT. From the data, we conclude that increased PP2A activity may influence the acute stress tolerance of cardiac myocytes.

Impact of the Duration of Global Cardiac Ischaemia on Outcomes of Acute Type A Aortic Dissection Repair

The current management of acute type A aortic dissection (ATAD) repair does not consider the safe duration of cardiac ischaemia as an operative strategy. We aimed to evaluate whether the duration of cardiac ischaemia during ATAD repair can predict operative mortality and to determine the optimum cardiac ischaemia time that is associated with better outcomes. This was a retrospective observational study. Patients who underwent ATAD repair from 2003 to 2020 were identified from our hospital records. Three hundred and sixty three (363) ATAD patients met eligibility criteria. The median patient age was 61 years, 221 (61%) patients were male. Duration of cardiac ischaemia was associated with operative mortality (Odds ratio [OR]=1.01; p<0.0005). Its optimal cut-off point was equal to or above 149.5 minutes (95% CI: 126.2-172.8). In patients with a shorter period (less than 150 mins) of cardiac ischaemia, a valve-sparing root repair was used more often (OR=2.5; 95% CI: 1.6-3.9; p<0.001). Procedures that had the longer period of cardiac ischaemia included the Bentall procedure (OR=10.9; 95% CI: 4.9-27.4; p<0.001), descending thoracic aorta replacement (OR=4.3; 95% CI: 1.007-18.7; p=0.049) and concomitant cardiac surgery (OR=4.7; 95% CI: 2-11.1; p<0.001). Operations associated with shorter cardiac ischaemia were associated with lower in-hospital mortality and better long-term survival. This study determined that the duration of cardiac ischaemia in ATAD repair is linked to operative mortality. Further studies are required to confirm that ATAD patients with surgical repair involving less than 150 minutes of cardiac ischaemic time have lower in-hospital mortality and better long-term survival.

On-pump beating-heart coronary artery bypass grafting: a literature review

Coronary artery bypass grafting techniques have been unchangeable for many years, whereas development and enhancement of myocardial protection methods in coronary bypass grafting for patients with ischemic heart disease are still actual issues of current coronary surgery. Coronary artery bypass grafting techniques include the traditional/conventional technique with cardiopulmonary bypass, aortic cross-clamping and cardioplegia, off-pump and on-pump beating heart coronary artery bypass grafting. Coronary artery bypass grafting with cardiopulmonary bypass and cardioplegia remains the most common method of coronary revascularization. However the cardiac arrest inevitably leads to global cardiac ischemia, and current cardioplegias do not prevent ischemic damage to the myocardium in all cases, especially in high-risk surgical patients. Off-pump coronary artery bypass grafting allows preventing global myocardial ischemia (due to the constant native coronary blood-flow) and avoiding possible negative consequences of cardiopulmonary bypass use. The main limitations of this technique are associated with high risk of hemodynamic instability due to low cardiac output and systolic output caused by target arteries exposition. On-pump beating heart technique is a reasonable compromise between conventional on-pump coronary artery bypass grafting, cardioplegia and off-pump procedure. It is a safe and effective technique with outcomes that are equivalent or superior to the outcomes reported for conventional coronary artery bypass grafting in patients with unstable hemodynamics, low left ventricular ejection fraction and in high-risk patients. The literature review presents the results of on-pump beating heart coronary artery bypass grafting.

Ischemic Stroke Increases Heart Vulnerability to Ischemia-Reperfusion and Alters Myocardial Cardioprotective Pathways.

Background and Purpose- For years, the relationship between cardiac and neurological ischemic events has been limited to overlapping pathophysiological mechanisms and common risk factors. However, acute stroke may induce dramatic changes in cardiovascular function. The aim of this study was to evaluate how prior cerebrovascular lesions affect myocardial function and signaling in vivo and ex vivo and how they influence cardiac vulnerability to ischemia-reperfusion injury. Methods- Cerebral embolization was performed in adult Wistar male rats through the injection of microspheres into the left or right internal carotid artery. Stroke lesions were evaluated by microsphere counting, tissue staining, and assessment of neurological deficit 2 hours, 24 hours, and 7 days after surgery. Cardiac function was evaluated in vivo by echocardiography and ex vivo in isolated perfused hearts. Heart vulnerability to ischemia-reperfusion injury was investigated ex vivo at different times post-embolization and with varying degrees of myocardial ischemia. Left ventricles (LVs) were analyzed with Western blotting and quantitatve real-time polymerase chain reaction. Results- Our stroke model produced large cerebral infarcts with severe neurological deficit. Cardiac contractile dysfunction was observed with an early but persistent reduction of LV fractional shortening in vivo and of LV developed pressure ex vivo. Moreover, after 20 or 30 minutes of global cardiac ischemia, recovery of contractile function was poorer with impaired LV developed pressure and relaxation during reperfusion in both stroke groups. Following stroke, circulating levels of catecholamines and GDF15 (growth differentiation factor 15) increased. Cerebral embolization altered nitro-oxidative stress signaling and impaired the myocardial expression of ADRB1 (adrenoceptor β1) and cardioprotective Survivor Activating Factor Enhancement signaling pathways. Conclusions- Our findings indicate that stroke not only impairs cardiac contractility but also worsens myocardial vulnerability to ischemia. The underlying molecular mechanisms of stroke-induced myocardial alterations after cerebral embolization remain to be established, insofar as they may involve the sympathetic nervous system and nitro-oxidative stress.

Effect of global cardiac ischemia on human ventricular fibrillation: insights from a multi-scale mechanistic model of the human heart.

Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements.

Moderate hypothermia diminishes death of HL-1 cardiomyocytes following ischemia

Introduction: Therapeutic hypothermia (TH) is an established protective strategy in patients suffering from cardiac arrest involving global cardiac ischemia. Although the neuroprotective properties of TH have been investigated, the effects of hypothermia on heart muscle tissue are not yet fully understood. We investigated the effects of moderate hypothermia (33.5°C) during ischemia and reperfusion in cardiomyocytes.

Increased Oxidized Phosphatidylcholines During Global Cardiac Ischemia Correlates to Reduced Cardiac Function: Implications as Potential Target for Ischemia Reperfusion Injury

Ischemia-reperfusion injury (IRI) is damage to ischemic myocardium after blood flow is restored. This is most pronounced in cardiac transplantation when there is prolonged global cardiac ischemia followed by reperfusion with oxygen rich blood. The generation of reactive oxygen species in subsequent reperfusion results in lipid peroxidation. However, there has been no investigation to identify the specific phospholipid oxidation products generated during cardiac ischemia-reperfusion and their correlation with cardiac function. Utilizing a swine model of global ischemia, our goal was to determine the particular species of myocardial derived oxidized phosphatidylcholines (OxPC) and their correlation to myocardial damage and inflammation as potential mediators of IRI.

Mild hypothermia during global cardiac ischemia opens a window of opportunity to develop heart donation after cardiac death

Although heart donation after cardiac death (DCD) could greatly improve graft availability, concerns regarding warm ischemic damage typically preclude transplantation. Improving tolerance to warm ischemia may thus open a window of opportunity for DCD hearts. We investigated the hypothesis that, compared with normothermia, mild hypothermia (32°C) initiated after ischemic onset improves cardiac functional recovery upon reperfusion. Isolated, working hearts from adult, male Wistar rats underwent global, no-flow ischemia, and reperfusion (n=28). After ischemic onset, temperature was maintained at either 37°C for 20 or 30min or reduced to 32°C for 40, 50, or 60min. Recovery was measured after 60-min reperfusion. Following normothermic ischemia, recovery of rate-pressure product (RPP; per cent of preischemic value) was almost complete after 20-min ischemia (97±9%), whereas no recovery was detectable after 30-min ischemia. After mildly hypothermic ischemia (32°C), RPP also recovered well after 40min (86±4%). Markers of metabolism and necrosis were similar in 37°C/20min and 32°C/40min groups. Simple reduction in cardiac temperature by a few degrees after the onset of global ischemia dramatically prolongs the interval during which the heart remains resistant to functional deterioration. Preservation of hemodynamic function is associated with improved metabolic recovery and reduced necrosis. The application of mild hypothermia may be a simple first step towards development of clinical protocols for DCD heart recovery.

P21-activated kinase improves cardiac contractility during ischemia-reperfusion concomitant with changes in troponin-T and myosin light chain 2 phosphorylation

p21-activated kinase 1 (Pak1) is a serine/threonine kinase that activates protein phosphatase 2a, resulting in the dephosphorylation of cardiac proteins and increased myofilament Ca(2+) sensitivity. Emerging evidence indirectly indicates a role for Pak1 in ischemia-reperfusion (I/R), but direct evidence is lacking. We hypothesize that activation of the Pak1 signaling pathway is a cardioprotective mechanism that prevents or reverses the detrimental effects of ischemic injury by inducing posttranslational modifications in myofilament proteins that ultimately improve cardiac contractility following ischemic insult. In the present study, we subjected ex vivo hearts from wild-type (WT) and Pak1-knockout (KO) mice to 20 min of global cardiac ischemia followed by 30 min of reperfusion. In the absence of Pak1, there was an exacerbation of the increased end-diastolic pressure and reduced left ventricular developed pressure occurring after I/R injury. ProQ analysis revealed an increase in troponin-T phosphorylation at baseline in Pak1-KO hearts compared with WT. Significantly decreased myosin light chain 2 (MLC2) phosphorylation in Pak1-KO hearts compared with WT after I/R injury was confirmed by Western immunoblotting. These data indicate that Pak1-KO hearts have reduced recovery of myocardial performance after global I/R injury concomitant with changes in troponin-T and MLC2 phosphorylation. Finally, a protein-protein association between Pak1 and MLC2, and Pak1 and troponin-T, was determined by coimmunoprecipitation. Thus, results of our study provide a basis for targeting a novel pathway, including Pak1, in the therapies for patients with ischemic events.

Experiment-model interaction for analysis of epicardial activation during human ventricular fibrillation with global myocardial ischaemia

We describe a combined experiment-modelling framework to investigate the effects of ischaemia on the organisation of ventricular fibrillation in the human heart. In a series of experimental studies epicardial activity was recorded from 10 patients undergoing routine cardiac surgery. Ventricular fibrillation was induced by burst pacing, and recording continued during 2.5 min of global cardiac ischaemia followed by 30 s of coronary reflow. Modelling used a 2D description of human ventricular tissue. Global cardiac ischaemia was simulated by (i) decreased intracellular ATP concentration and subsequent activation of an ATP sensitive K+ current, (ii) elevated extracellular K+ concentration, and (iii) acidosis resulting in reduced magnitude of the L-type Ca2+ current ICa,L. Simulated ischaemia acted to shorten action potential duration, reduce conduction velocity, increase effective refractory period, and flatten restitution. In the model, these effects resulted in slower re-entrant activity that was qualitatively consistent with our observations in the human heart. However, the flattening of restitution also resulted in the collapse of many re-entrant waves to several stable re-entrant waves, which was different to the overall trend we observed in the experimental data. These findings highlight a potential role for other factors, such as structural or functional heterogeneity in sustaining wavebreak during human ventricular fibrillation with global myocardial ischaemia.

Activation of ASK1, downstream MAPKK and MAPK isoforms during cardiac ischaemia

p38 MAPK is activated potently during cardiac ischaemia, although the precise mechanism by which it is activated is unclear. We used the isolated perfused rat heart to investigate the signalling pathways activated upstream of p38 during global cardiac ischaemia. Ischaemia strongly activated p38α but not the JNK pathway. The MAPKKs, MKK3, MKK4 and MKK6 have previously been identified as potential upstream activators of p38; however, in the ischaemic perfused heart, we saw activation of MKK3 and MKK6 but not MKK4. MKK3 and MKK6 showed different temporal patterns of activity, indicating distinct modes of activation and physiological function. Consistent with a lack of JNK activation, we saw no activation of MKK4 or MKK7 at any time point during ischaemia. A lack of MKK4 activation indicates, at least in the ischaemic heart, that MKK4 is not a physiologically relevant activator of p38. The MAPKKK, ASK1, was strongly activated late during ischaemia, with a similar time course to that of MKK6 and in ischaemic neonatal cardiac myocytes ASK1 expression preferentially activated MKK6 rather than MKK3. These observations suggest that during ischaemia ASK1 is coupled to p38 activation primarily via MKK6. Potent activation of ASK1 during ischaemia without JNK activation shows that during cardiac ischaemia, ASK1 preferentially activates the p38 pathway. These results demonstrate a specificity of responses seldom seen in previous studies and illustrate the benefits of using direct assays in intact tissues responding to physiologically relevant stimuli to unravel the complexities of MAPK signalling.

Propofol with N-Acetylcysteine Reduces Global Myocardial Ischemic Reperfusion Injury More than Ketamine in a Rat Model

Objective: We examined the cardioprotective effects of propofol and ketamine with and without N-acetylcysteine (NAC). Methods: 60 rats were divided into six groups of 10 rats each. Anesthesia induction was produced with an intraperitonal injection of ketamine in Groups 1–3 and propofol in Groups 4–6. NAC (200 mg kg− 1) was given intraperitonally during anesthesia induction in Groups 3 and 6. Groups 2, 3, 5, and 6 were subjected to 90 s of myocardial ischemia by clamping the ascending aorta, and then reperfusion was begun by unclamping the ascending aorta. After 60 min of reperfusion, blood samples were taken from the ascending aorta for biochemical analyses, and heart tissue samples were taken for biochemical and histopathological analyses. Results: Creatine kinase (CK), myocardial band of creatine kinase (CK-MB), and troponin-I (Tn-I) levels were significantly higher in the ischemia–reperfusion groups (2, 3, 5, 6) compared to the nonischemic groups (1, 4). CK, CK-MB, and Tn-I levels did not differ significantly between the ketamine groups (1–3) and the propofol groups (4–6) p >. 05). Malondialdehyde levels were significantly higher in Groups 2 and 3 than in Group 1 and were significantly lower in Groups 4 and 6 than in Group 5 (p <. 05). Malondialdehyde levels in the propofol groups (4–6) were significantly lower than in the ketamine groups (1–3; p <. 05). Catalase levels in propofol groups were higher than ketamine groups. Superoxide dismutase levels were significantly higher in Group 6 than in Group 3 (p <. 05). Conclusions: In this rat model of global cardiac ischemia, propofol with NAC attenuates myocardial injury more than ketamine (with or without NAC).

HO-1 Activation Can Attenuate Cardiomyocytic Apoptosis via Inhibition of NF-κB and AP-1 Translocation Following Cardiac Global Ischemia and Reperfusion

NF-kappaB and AP-1 play important roles in regulation of inflammatory responses that lead to cardiomyocytic injury following cardiopulmonary bypass (CPB) and cardiac global ischemia and reperfusion. It has been reported that heme oxygenase-1 (HO-1) can block those responses. Our aim was to determine whether HO-1 activation could decrease myocardial ischemia-reperfusion injury with cardioplegia during CPB and attenuate apoptosis of cardiomyocytes. Rabbits (10 in each group) were randomized to receive either bypass only (Group 1), CPB plus intravenous normal saline (Group 2), hemin (HO-1 inducer; Group 3), SnPP (HO-1 inhibitor; Group 4), or hemin + SnPP (Group 5) 2 d before CPB. In all groups except Group 1, cold (4 degrees C) antegrade intermittent crystalloid cardioplegia was delivered every 20 min for a total of 60 min of cardiac arrest, after CPB was established. Rabbits were weaned from CPB and reperfused for 4 h. Blood was sampled at various time points. The reperfused hearts were harvested for Western blotting and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) experiments. The postoperative elevation of serum levels of IL-10, IL-6, and TNF-alpha were significantly decreased in Group 3, but HO-1 inhibitor abolished this effect (Group 4). Moreover in Group 3, the number of apoptotic cardiomyocytes, level of apoptosis-related activated fragments of caspase-3 and Akt, and level of nuclear NF-kappaB and AP-1 translocation were significantly decreased. HO-1 activation can dampen the surge of inflammation-related cytokines during CPB and decrease the occurrence of cardiomyocytic apoptosis via inhibition of NF-kappaB and AP-1 translocation.

Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, Inhibits Apoptosis in Experimental Acute Myocardial Infarction

Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction. Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline (P=0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose (P=0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1+/-0.2% versus 0.5+/-0.3% [P<0.001] and 4.2+/-0.4% versus 1.1+/-0.2% [P<0.001], respectively). Compared with saline-treated animals, anakinra-treated mice and rats showed signs of more favorable ventricular remodeling. In vitro, anakinra significantly prevented apoptosis induced by simulated ischemia and inhibited caspase-1 and -9 activities. Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.

Rapid detection of acute regional and global myocardial ischemia using non-invasive visible light spectroscopy

Aims: Monitoring of tissue oxygenation (StO2) by visible-light-spectroscopy (VLS) can be useful for rapidly detecting myocardial ischemia during cardiac surgery, but its' feasibility for cardiac tissue is not known. We tested the ability of VLS to detect changes of StO2 in animals subjected to acute regional and global cardiac ischemia.

Electrocardiogram detection of acute global cardiac ischemia in patients presenting with acute chest pain

Electrocardiogram detection of acute global cardiac ischemia in patients presenting with acute chest pain

High-performance liquid chromatography (HPLC) determination of inosine, a potential biomarker for initial cardiac ischaemia, using isolated mouse hearts

Each year in the USA approximately 7–8 million patients with non-traumatic chest pain come to hospital emergency rooms. It is estimated that approximately 2–5% of these patients are experiencing cardiac ischaemia, but due to the shortcomings of the available testing methods they are incorrectly diagnosed and discharged without appropriate therapy having been provided. Preliminary data with a globally ischaemic mouse heart model has demonstrated that endogenous inosine might be a potential biomarker of initial cardiac ischaemia before cardiac tissue necrosis. A high-performance liquid chromatographic diode array detection (HPLC-DAD) method was utilized for the detection and quantification of inosine in Krebs–Henseleit (Krebs) buffer solution perfusing from surgically removed and isolated mouse hearts undergoing global cardiac ischaemia. A C18 column at a flow rate of 0.6 ml min−1 with an aqueous mobile phase of trifluoroacetic acid (0.05% trifluoroacetic acid in deionized water, pH 2.2, v/v) and methanol gradient was used for component separation. The assay detection limit for inosine in Krebs buffer solution was 500 ng ml−1 using a 100-µl neat injection. The HPLC results were used to determine total cardiac effluxed inosine into the Krebs effluent for each mouse during oxidative stress and compared with the per cent cardiac ventricular functional recovery rate to determine if a relationship exists amongst this cardiovascular parameter during periods of cardiac oxidative stress.

Cytochrome p450 2C inhibition reduces post-ischemic vascular dysfunction

Cytochrome p450 (CYP) inhibitors provide protection against myocardial infarction following both global and focal cardiac ischemia and reperfusion (I/R). We hypothesized that sulfaphenazole, an inhibitor of CYP2C6 and 9, also attenuates post-ischemic endothelial dysfunction by reducing CYP-mediated superoxide generation (which scavenges nitric oxide (NO)), thereby restoring NO bioavailability and vascular tone. Rat hearts were perfused in the Langendorff mode for 20 min in the presence, or absence, of sulfaphenazole and then subjected to 30 min global no-flow ischemia followed by 15 min reperfusion. Septal coronary resistance arteries were isolated and mounted on glass cannulae for measurements of luminal diameter. Preconstricted arteries were exposed to acetylcholine to elicit endothelium-dependent, NO-mediated vasodilation. Acetylcholine caused near maximal dilation in control tissues not subjected to I/R. Following I/R, endothelium-dependent vasodilation was reduced. Pretreatment with sulfaphenazole restored endothelial sensitivity to acetylcholine. Vasoresponsiveness to endothelium-independent vasodilators, sodium nitroprusside and isoproterenol, were also reduced following I/R. However, sensitivity to endothelium-independent vasodilators was not restored by pretreatment with sulfaphenazole. I/R-induced superoxide production was assessed by dihydroethidium staining of flash frozen hearts. Sulfaphenazole treatment significantly reduced superoxide production in arterial walls following I/R injury. We conclude that sulfaphenazole restores post-ischemic endothelium-dependent, NO-mediated vasodilation by reducing superoxide production, suggesting that CYP2C9 plays a key role in post-ischemic vascular dysfunction.

Inhibition of NFκB Activation with Curcumin Attenuates Plasma Inflammatory Cytokines Surge and Cardiomyocytic Apoptosis Following Cardiac Ischemia/Reperfusion 1

Following cardiopulmonary bypass (CPB) and cardiac global ischemia and reperfusion, pro-inflammatory cytokines are activated and cause cardiomyocytic injury. Nuclear factor (NF)-kappaB is involved in regulating inflammatory signal transduction. Curcumin inhibits NF-kappaB activation and blocks the inflammatory responses. We studied whether curcumin could decrease myocardial ischemia/reperfusion injury with cardioplegia during CPB and attenuate the appearance of apoptosis of cardiomyocytes. Rabbits received normal saline (group 1) or curcumin (70 mum/kg, group 2; 100 mum/kg, group 3) injection 2 h before CPB. Total CPB was initiated and cold (4 degrees C) antegrade intermittent crystalloid cardioplegia was delivered every 20 min for 60 min of cardiac arrest. Rabbits were weaned from CPB and reperfused for 4 h. Blood was sampled at various time points and then the reperfused hearts were harvested. Postoperative elevation of plasma levels of interleukin (IL)-8 (14.5, 0.9, 2.9 times over baseline in groups 1-3, respectively, P < 0.05), IL-10 (201.1, 6.0, 14.9 times over baseline in groups 1-3, respectively, P < 0.05), TNF-alpha (9.4, 3.1, 3.9 times over baseline in groups 1-3, respectively, P < 0.05), and cardiac troponin I (141.2, 14.9, 15.0 times over baseline) significantly decreased in the curcumin groups. Appearance of apoptotic cardiomyocytes significantly decreased in the curcumin groups (5.69 +/- 1.64, 1.51 +/- 0.41, 2.43 +/- 0.49 per 1000 nuclei in groups 1-3, respectively, P < 0.01). The activation of neutrophil in the myocardium, which was measured using myocardial myloperoxidase activity assay, was significantly attenuated in the curcumin group. There was a significant increase in apoptosis-related cleavage fragments of caspase-3 and poly-ADP-ribose polymerase in group 1 compared to the other groups. Curcumin, an inhibitor of NF-kappaB, ameliorated the surge of pro-inflammatory cytokines during CPB and decreased the occurrence of cardiomyocytic apoptosis after global cardiac ischemia/reperfusion injury.

Inhibition of NF-κB Activation Can Attenuate Ischemia/Reperfusion-Induced Contractility Impairment Via Decreasing Cardiomyocytic Proinflammatory Gene Up-Regulation and Matrix Metalloproteinase Expression

Following cardiopulmonary bypass (CPB) and cardiac global ischemia and reperfusion, proinflammatory genes are up-regulated, and nuclear factor (NF)-kappaB is involved in this regulation. We studied whether inactivation of NF-kappaB could decrease myocardial ischemia/reperfusion injury with cardioplegia during CPB, attenuate matrix metalloproteinase (MMP) activation, and prevent cardiac mechanical dysfunction. Rabbits received normal saline (group 1) or curcumin (70 and 7 micromol/kg in groups 2 and 3) injection 2 hours before CPB. Total CPB was initiated, and myocardial protection was delivered every 20 minutes for 60 minutes of cardiac arrest. Rabbits were weaned from CPB and reperfused for 4 hours before the hearts were harvested. Blood was sampled at various time points. Postoperative expression of myocardial mRNA levels of interleukin 6, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha, postreperfusion plasma level of troponin I, and cardiac mechanical dysfunction were significantly decreased in the curcumin groups. The myocardial levels of activated MMP-2 and -9 were also significantly reduced compared with the control group. In conclusion, by inhibiting NF-kappaB activation, the up-regulation of cardiac proinflammatory genes can be ameliorated, and the activation of MMPs can be decreased during CPB, thereby lessening severity of cardiac mechanical dysfunction after global cardiac ischemia/reperfusion injury.