Periods Of Coronary Occlusion Research Articles

Hypertrophic preconditioning attenuates post-myocardial infarction injury through deacetylation of isocitrate dehydrogenase 2.

Ischemic preconditioning induced by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischemic insult. In this study we investigated whether a short-term nonischemic stimulation of hypertrophy renders the heart resistant to subsequent ischemic injury. Male mice were subjected to transient transverse aortic constriction (TAC) for 3 days followed aortic debanding on D4 (T3D4), as well as ligation of the left coronary artery to induce myocardial infarction (MI). The TAC preconditioning mice showed markedly improved contractile function and significantly reduced myocardial fibrotic area and apoptosis following MI. We revealed that TAC preconditioning significantly reduced MI-induced oxidative stress, evidenced by increased NADPH/NADP ratio and GSH/GSSG ratio, as well as decreased mitochondrial ROS production. Furthermore, TAC preconditioning significantly increased the expression and activity of SIRT3 protein following MI. Cardiac-specific overexpression of SIRT3 gene through in vivo AAV-SIRT3 transfection partially mimicked the protective effects of TAC preconditioning, whereas genetic ablation of SIRT3 in mice blocked the protective effects of TAC preconditioning. Moreover, expression of an IDH2 mutant mimicking deacetylation (IDH2 K413R) in cardiomyocytes promoted myocardial IDH2 activation, quenched mitochondrial reactive oxygen species (ROS), and alleviated post-MI injury, whereas expression of an acetylation mimic (IDH2 K413Q) in cardiomyocytes inactivated IDH2, exacerbated mitochondrial ROS overload, and aggravated post-MI injury. In conclusion, this study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Therapeutic strategies targeting IDH2 are promising treatment approaches for cardiac ischemic injury.

Hypertrophic Preconditioning Attenuates Myocardial Ischaemia-Reperfusion Injury by Modulating SIRT3-SOD2-mROS-Dependent Autophagy.

BackgroundIschaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short‐term non‐ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury.Methods and ResultsTransient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia‐reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R‐induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3‐dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral‐mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R‐induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning.ConclusionsThe present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self‐defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway‐dependent manner.

Myocardial Ischemia Reperfusion Injury: Apoptotic, Inflammatory and Oxidative Stress Role of Galectin-3

Background/Aims: Myocardial reperfusion has the potential to salvage the ischemic myocardium after a period of coronary occlusion. Reperfusion, however, can cause a wide spectrum of deleterious effects. Galectin-3 (GAL-3), a beta galactoside binding lectin, is closely associated with myocardial infarction (MI), myocardial fibrosis and heart failure. In our study, we investigated its role in ischemia-reperfusion injuries (IR) as this phenomenon is extremely relevant to the early intervention after acute MI. Methods: C57B6/J wild type (WT) mice and GAL-3 knockout (KO) mice were used for murine model of IR injury in the heart where a period of 30 minutes ischemia was followed by 24 hours of reperfusion. Heart samples were processed for immunohistochemical and immunofluorescent labeling, morphometric analysis, western blot and enzyme-linked immunosorbent assay to identify the apoptotic, inflammatory and oxidative stress role of GAL-3. Results: Our results show that there was a significant increase in GAL-3 levels in the heart which shows GAL-3 is playing a role in the ischemia reperfusion injury. Troponin I was also significantly higher in GAL-3-KO group than wild type. Our study shows that GAL-3 is associated with an increase in the antioxidant activity in the IR injured myocardium. Antioxidant enzymes superoxide dismutase, glutathione and catalase were found to be significantly raised in the GAL-3 wild type IR as compared to the GAL-3 KO IR group. A significant increase in apoptotic activity is seen in GAL-3 KO IR group as compared with GAL-3 wild IR group. Conclusion: Our study shows that GAL-3 can affect the redox pathways, controlling cell survival and death, and plays a protective role on the myocardium following IR injury.

Nonantithrombotic medical options in acute coronary syndromes: old agents and new lines on the horizon.

Acute coronary syndromes (ACS) constitute a spectrum of clinical presentations ranging from unstable angina and non-ST-segment elevation myocardial infarction to ST-segment myocardial infarction. Myocardial ischemia in this context occurs as a result of an abrupt decrease in coronary blood flow and resultant imbalance in the myocardial oxygen supply-demand relationship. Coronary blood flow is further compromised by other mechanisms that increase coronary vascular resistance or reduce coronary driving pressure. The goals of treatment are to decrease myocardial oxygen demand, increase coronary blood flow and oxygen supply, and limit myocardial injury. Treatments are generally divided into disease-modifying agents or interventions that improve hard clinical outcomes and other strategies that can reduce ischemia. In addition to traditional drugs such as β-blockers and inhibitors of the renin-angiotensin-aldosterone system, newer agents have expanded the number of molecular pathways targeted for treatment of ACS. Ranolazine, trimetazidine, nicorandil, and ivabradine are medications that have been shown to reduce myocardial ischemia through diverse mechanisms and have been tested in limited fashion in patients with ACS. Attenuating the no-reflow phenomenon and reducing the injury compounded by acute reperfusion after a period of coronary occlusion are active areas of research. Additionally, interventions aimed at ischemic pre- and postconditioning may be useful means by which to limit myocardial infarct size. Trials are also underway to examine altered metabolic and oxygen-related pathways in ACS. This review will discuss traditional and newer anti-ischemic therapies for patients with ACS, exclusive of revascularization, antithrombotic agents, and the use of high-intensity statins.

Isoflurane post-conditioning stimulates the proliferative phase of myocardial recovery in an ischemia-reperfusion model of heart injury in rats.

The application of isoflurane in a post-conditioning manner, during early reperfusion following a period of coronary occlusion, has numerous beneficial effects on the ischemic myocardium, including reduction of infarct size. It does so by stimulating a sequence of well studied anti-apoptotic pro-survival mechanisms in a similar manner to various 'ischemic' pre-/post-conditioning approaches which achieve their cardio protective effects in both laboratory and clinical situations. Proliferation of newly formed blood vessels, resulting in formation of highly vascularized granulation tissue, is an essential stage of infarct healing. It can be evaluated by detecting various angiogenic factors, including vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) or by quantification of expression of vascular smooth muscle progenitors, such as Nestin. Expression of these three markers was used to evaluate the effect of early isoflurane post-conditioning in ischemia-reperfusion type cardiac injury. A large reduction in infarct size (59.3% of control), and marked increase of expression of VEGF (43.4%), PECAM-1/CD31 (136%) and Nestin (77.9%) was found in experimental animals when compared to control animals that did not receive isoflurane treatment. Hence, based on our results, we can emphasize two morphologically detectable benefits of isoflurane post-conditioning: a marked reduction in infarct size and much better organization/vascularization of necrotic tissue.

In vivo protein transduction: delivery of PEP-1-SOD1 fusion protein into myocardium efficiently protects against ischemic insult.

Myocardial ischemia-reperfusion injury is a medical problem occurring as damage to the myocardium following blood flow restoration after a critical period of coronary occlusion. Oxygen free radicals (OFR) are implicated in reperfusion injury after myocardial ischemia. The antioxidant enzyme, Cu, Zn-superoxide dismutase (Cu, Zn-SOD, also called SOD1) is one of the major means by which cells counteract the deleterious effects of OFR after ischemia. Recently, we reported that a PEP-1-SOD1 fusion protein was efficiently delivered into cultured cells and isolated rat hearts with ischemia-reperfusion injury. In the present study, we investigated the protective effects of the PEP-1-SOD1 fusion protein after ischemic insult. Immunofluorescecnce analysis revealed that the expressed and purified PEP-1-SOD1 fusion protein injected into rat tail veins was efficiently transduced into the myocardium with its native protein structure intact. When injected into Sprague-Dawley rat tail veins, the PEP-1- SOD1 fusion protein significantly attenuated myocardial ischemia-reperfusion damage; characterized by improving cardiac function of the left ventricle, decreasing infarct size, reducing the level of malondialdehyde (MDA), decreasing the release of creatine kinase (CK) and lactate dehydrogenase (LDH), and relieving cardiomyocyte apoptosis. These results suggest that the biologically active intact forms of PEP-1-SOD1 fusion protein will provide an efficient strategy for therapeutic delivery in various diseases related to SOD1 or to OFR.

Trans-esophageal echocardiography in off-pump coronary artery bypass grafting

Two features of off-pump coronary artery bypass (OPCAB) can lead to hemodynamic instability: transient occlusion of coronary arteries during distal anastomosis construction and displacement of the heart to provide access to distal coronary arteries. The position of the heart during OPCAB trans-esophageal echocardiography (TEE) can often provide an indication as to how much compression of the right or left ventricle has occurred. If either chamber is not filling, repositioning of the heart will be necessary. Close observation of the heart with TEE during periods of coronary occlusion may facilitate detection of worsening cardiac function as evidenced by weakening contraction, ventricular dilatation, or increasing mitral or tricuspid regurgitation. Haemodynamic changes are more pronounced with displacement of the heart to access posterior coronary arteries than anterior vessels. Cardiac manipulations during off-pump coronary artery bypass grafting (OPCABG) can lead to haemodynamic instability. This, along with distal anastomosis causing transient occlusion of coronary arteries, may cause transient hypotension with increased filling pressures. TEE is more helpful in this scenario. In these patients, TEE helps differentiate between cardiac dysfunction and secondary to myocardial ischemia in which regional wall motion abnormalities will be present from a much more common scenario where the increase in filling pressure is secondary to extra cardiac compression and provides the ability to detect mitral regurgitation (MR) with a color-flow Doppler, as well as assess right heart function.

Myocardial oedema: a forgotten entity essential to the understanding of regional function after ischaemia or reperfusion injury

It is well established that extracellular myocardial oedema is induced during reperfusion of an acute myocardial infarction and that the presence of oedema is related to cell death.1 With the...

CDP-choline prevents cardiac arrhythmias and lethality induced by short-term myocardial ischemia–reperfusion injury in the rat: involvement of central muscarinic cholinergic mechanisms

In the present study, we aimed to determine whether cytidine-5'-diphosphatecholine (CDP-choline or citicoline) can improve the outcome of short-term myocardial ischemia-reperfusion injury in rats. Ischemia was produced in anesthetized rats by ligature of the left anterior descending coronary artery for 7 min followed by a reperfusion period of 7 min. Reperfusion-induced ventricular tachycardia (VT), ventricular fibrillation (VF), survival rate, and changes in arterial pressure were evaluated. Saline (1 ml/kg), CDP-choline (100, 250,and 500 mg/kg), or lidocaine (5 mg/kg) was intravenously injected in the middle of the ischemic period. Intracerebroventricular (i.c.v.) mecamylamine (50 microg) or atropine sulfate (10 microg) pretreatments were made 10 min before the coronary occlusion period. Pretreatment with intravenous (i.v.) atropine methylnitrate (2 and 5 mg/kg; i.v.) or bilateral vagotomy was performed 5 min before the induction of ischemia. An in vivo microdialysis study was performed in the nucleus ambiguus area (NA); choline and acetylcholine levels were measured in extracellular fluids. In control rats, VT, VF, and lethality were observed in 85%, 60% and 50% of the animals, respectively. Intravenous CDP-choline produced a short-term increase in blood pressure and reduced the incidence of VT, VF, and lethality dose-dependently when injected in the middle of the ischemic period. CDP-choline at doses of 250 and 500 mg/kg completely prevented death. Intracerebroventricular atropine sulfate pretreatment completely abolished the protective effect of CDP-choline, while mecamylamine pretreatment had no effect on the drug. CDP-choline increased the levels of extracellular choline and acetylcholine in the NA area. Bilateral vagotomy completely abolished the protective effect of CDP-choline in the reperfusion period. Moreover, the intravenous pretreatment with atropine methylnitrate produced dose-dependent blockade in the reduction of VT, VF, and mortality rates induced by CDP-choline. Neither of these pretreatments except mecamylamine affected the pressor effect of CDP-choline. Intracerebroventricular mecamylamine attenuated the increase in blood pressure induced by CDP-choline. In conclusion, intravenously injected CDP-choline prevents cardiac arrhythmias and death induced by short-term myocardial ischemia-reperfusion injury. Activation of central muscarinic receptors and vagal pathways mediates the protective effect of CDP-choline. The protective effect of CDP-choline is not related to its pressor effect.

Warm ischemia provokes inflammation and regional hypercoagulability within the heart during off-pump coronary artery bypass: a possible target for serine protease inhibition.

Accumulating evidence suggests that a hypercoagulable state influences early graft failure after off-pump coronary artery bypass (OPCAB). We hypothesized that regional myocardial ischemia caused by obligatory periods of coronary occlusion during OPCAB is an important trigger for this prothrombotic state. Using a series of biomarkers, 60 consecutive patients undergoing OPCAB were monitored for myocardial injury (myoglobin), inflammation (TNF-alpha, IL-8) and thrombosis (thrombin generation-F1.2, contact activation pathway-FXII-a, platelet derived microparticles-via flow cytometry). The transcardiac gradients of these markers were determined by assaying both arterial and coronary sinus blood just after protamine administration. Intramyocardial pH was monitored continuously during coronary occlusion in a subset (N=30 grafts, 11 patients). The influence of management strategies affecting hemostasis (e.g. antiplatelet therapy, anti-fibrinolytics, peak activated clotting time (ACT) during heparinization) was analyzed. Ischemic injury, depicted by the transcardiac myoglobin gradient, significantly correlated with intramyocardial acidosis during coronary occlusion (R=0.96, p<0.0001) and predicted the transcardiac gradients of TNF-alpha (R=0.83, p<0.001) and F1.2 (R=0.72, p<0.0001). Transcardiac F1.2 strongly correlated with TNF-alpha (R=0.73, p=0.01) and IL-8 (R=0.51, p=0.02). Patients receiving aprotinin (N=20) showed significantly lower transcardiac gradients for myoglobin (4.1+/-7.5% vs 72.9+/-108.8% change, p=0.002), F1.2 (31+/-37% vs 89+/-149%, p=0.03), FXII-a (2.6+/-4.1% vs 19.2+/-34%, p=0.04) and microparticles (7+/-3.9% vs 12.9+/-8%, p=0.01). Strong correlations between myocardial ischemia and the transcardiac gradients of markers for inflammation and thrombosis suggest that even brief episodes of coronary occlusion in the beating heart may have pathophysiologic consequences. Aprotinin, but not other factors that influence the coagulation system, appears to mitigate this process during OPCAB.

Invited commentary

Invited commentary

Pharmacological preconditioning by levosimendan is mediated by inducible nitric oxide synthase and mitochondrial K ATP channel activation in the in vivo anesthetized rabbit heart model

Background Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Levosimendan (LEV) is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-dependent potassium channels. Objectives and methods The aim of this investigation was to test whether the administration of LEV has cardioprotective and antiarrhythmic effects against ischemia and reperfusion injury in a manner similar to ischemic preconditioning (IPC) in a well-standardized model of reperfusion arrhythmias in anesthetized adult male rabbits ( n = 122) subjected to 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. Results Pretreatment with either 1 cycle of IPC, LEV (0.1 μmol/kg, i.v.), or IPC + LEV prior to the period of coronary occlusion offers significant infarct size reduction (21.6 ± 1.6%, 22.1 ± 2.2%, and 21.4 ± 1.4%, respectively vs 38.7 ± 3.6% in saline control group; P < 0.01) and antiarrhythmic effects. IPC, LEV and IPC + LEV treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13%, 13% and 13%, respectively vs 100% in saline control group; P < 0.005) and other arrhythmias (25%, 25% and 13%, respectively vs 100% in saline control group; P < 0.005), and increased the number of surviving animals without arrhythmias. Pretreatment with 5-HD, N ω-nitro- l-arginine methyl ester ( l-NAME, a nonspecific NOS inhibitor) and the specific iNOS inhibitor 1400W [ N-(-3-(aminomethyl)benzyl) acetamidine] abolished the beneficial effects of IPC, and LEV on reperfusion induced arrhythmias and cardioprotection suggesting that benefits have been achieved via both the selective activation of cardiomyocyte mitochondrial K ATP channels and NO. One cycle of IPC and LEV pretreatment significantly preserved the level of ATP in the 30 min ischemic heart and 120 min reperfused heart. Conclusions The present study demonstrates similarities between acute LEV treatment and IPC of the rabbit myocardium in terms of survival, cardioprotection, antiarrhythmic activity, and metabolic status.

Pretreatment with Sarafotoxin 6c Prior to Coronary Occlusion Protects Against Infarction and Arrhythmias via Cardiomyocyte Mitochondrial KATP Channel Activation in the Intact Rabbit Heart During Ischemia/Reperfusion

Endothelial ET(B) receptor activation by exogenously administered sarafotoxin 6c(a snake venom peptide with a sequence homology to ET-1 prior to ischemia activates release of nitric oxide(NO) and previous studies have shown that NO facilitates mitochondrial K(ATP) activation in cardiac cells and cardioprotection. The aim of this investigation was to test whether the administration of sarafotoxin 6c(a selective ET(B) receptor agonist) has cardioprotective and antiarrhythmic effects against ischemia and reperfusion injury in a well-standardized model of reperfusion arrhythmias in anesthetized adult male rabbits (n = 53) subjected to 30 min occlusion of the left coronary artery followed by 120 min of reperfusion. Pretreatment with sarafotoxin 6c (0.24 nmol/kg, i.v.) prior to the period of coronary occlusion offers significant infarct size reduction (19.1 +/- 2.0% versus 39.7 +/- 3.7% in the saline control group; P < 0.01) and antiarrhythmic effects. Sarafotoxin 6c treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13 versus 100% in the saline control group; P < 0.005) and other arrhythmias (25 versus 100% in the saline control group; P < 0.005), and increased the number of surviving animals without arrhythmias. Pretreatment with 5-HD but not HMR 1883 abolished the beneficial effects of sarafotoxin 6c on reperfusion induced arrhythmias and cardioprotection suggesting that benefits have been achieved via the selective activation of cardiomyocyte mitochondrial K(ATP) channels. Sarafotoxin 6c evoked NO release and selective activation of mitoK(ATP) channels in cardiomyocytes contributes to cardioprotection and antiarrhythmic activity during ischemia-reperfusion in the anesthetized rabbit. We conclude that the selective activation of ET(B) receptors by sarafotoxin 6c prior to coronary occlusion contributes to cardioprotective and antiarrhythmic properties.

Potent mitochondria-targeted peptides reduce myocardial infarction in rats

Previously, we demonstrated that a novel opiate peptide, 2',6'-dimethyl-tyrosine-D-Arg-Phe-Lys-NH2, provided cardioprotection against myocardial stunning in vivo. We subsequently showed that this peptide targeted mitochondria and can scavenge reactive oxygen species. The objective of this study was to determine the role of opioid versus antioxidant activity in cardioprotection. We compared two mitochondria-targeted peptide analogs that lacked opioid activity: SS-31 (D-Arg-2',6'-dimethyl-tyrosine-Lys-Phe-NH2) and SS-20 (Phe-D-Arg-Phe-Lys-NH2). They differ in that only SS-31 has scavenging ability. Rats (n=8/group) were randomized to SS-31, SS-20 or placebo. The drugs (3 mg/kg) or saline was administered intraperitoneally 30 min before ligation of the left anterior descending artery for 60 min, and another dose given intraperitoneally 5 min before reperfusion for 60 min. Study endpoints included myocardial infarct size, cardiac arrhythmia and myocardial lipid peroxidation. The area at risk was similar among the groups. The infarct area/area at risk, however, was significantly smaller in the treatment groups (53.9+/-1.1% in SS-31 group, 47.1+/-1.4% in SS-20 group, versus 59.9+/-1% in the controls, P<0.01). Lipid peroxidation was significantly reduced by both SS-31 and SS-20 treatment. Arrhythmia occurred only during the early period of coronary occlusion and was less frequent and less severe in the peptide treatment groups than in the controls (Lambeth score 5 points, 3 points, versus 13 points in the controls, P<0.05). This study shows that pretreatment with both SS-31 and SS-20 significantly reduced myocardial lipid peroxidation and infarct size in ischemia-reperfusion injury, and suggests that the cardioprotective properties of 2',6'-dimethyl-tyrosine-D-Arg-Phe-Lys-NH2 was primarily mediated by its antioxidant properties. As SS-20 does not scavenge reactive oxygen species, it most likely reduces reactive oxygen species production during ischemia-reperfusion.

Similarities between Ischemic Preconditioning and 17??-Estradiol Mediated Cardiomyocyte KATP Channel Activation Leading to Cardioprotective and Antiarrhythmic Effects during Ischemia/Reperfusion in the Intact Rabbit Heart

The aims of our present work were to assess whether treatment with either ischemic preconditioning (IPC) or 17beta-estradiol or both combined produce proarrhythmic or antiarrhythmic effects, and whether opening of the sarcolemmal or mitochondrial KATP channels is relatable to this effect; to assess biochemically the effects of IPC and/or 17beta-estradiol on oxidant stress and antioxidant defenses in the myocardium; to examine the effects of nitric oxide (NO) synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME) pretreatment in rabbits treated with either IPC or 17beta-estradiol (because 17beta-estradiol evoked NO release has been implicated in KATP activation and IPC); and examine the effects of ischemic preconditioning and 17beta-estradiol on myocardial energy metabolism during ischemia and reperfusion in a well-standardized model of reperfusion arrhythmias in anesthetized adult male New Zealand White rabbits (n = 124) subjected to 30 minutes occlusion of the left coronary artery followed by 120 minutes of reperfusion. Pretreatment with either 17beta-estradiol (10 microg/kg, i.v.) or one cycle of ischemic preconditioning prior to the period of coronary occlusion offers significant infarct size reduction (18.6 +/- 2.2% and 19.4 +/- 1.9%, respectively versus 40.1 +/- 3.9% in saline control and 39.2 +/- 3.2% in vehicle control groups; P < 0.01) and antiarrhythmic effects. Both 17beta-estradiol and ischemic preconditioning treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13% and 13%, respectively versus 100% in saline control and 100% in vehicle control groups; P < 0.001) and other arrhythmias (25% and 25%, respectively versus 100% in saline control and 100% in vehicle control groups; P < 0.001), and were quite effective in increasing the number of animals that survived without developing any arrhythmia during ischemia and reperfusion. 5-hydroxydecanoate(5-HD; 5 mg/kg, i.v.) alone offered no cardioprotective and antiarrhythmic activities. Pretreatment with 5-HD but not HMR 1883 (3 mg/kg, i.v.) abolished the beneficial effects of 17beta-estradiol and ischemia preconditioning on reperfusion-induced arrhythmias and cardioprotection suggesting that such effects have been achieved via the selective activation of cardiomyocyte mitochondrial KATP channels rather than sarcolemmal KATP channels. The reduced reperfusion arrhythmic incidence and durations induced by estrogen was not significantly altered by ICI 182 720 (2.5 mg/kg, i.v.). The lack of effect of ICI 182 720 on antiarrhythmic and infarct-limiting effects of 17beta-estradiol and ischemic preconditioning suggest that these favorable effects are rapid, direct, and non-genomic effects. This study demonstrates similarities between 17beta-estradiol and ischemic preconditioning of the rabbit myocardium in terms of cardioprotection, antiarrhythmic, and metabolic activities. Ischemic preconditioning and 17beta-estradiol appear to share a final common effector; the mitochondrial KATP channel.

Endotoxemia in coronary artery bypass surgery: A comparison of the off-pump technique and conventional cardiopulmonary bypass

Objectives: The endotoxemia associated with cardiac surgery is thought to be dominantly influenced by the use of cardiopulmonary bypass. The objectives of this study were to assess the relative contribution of cardiopulmonary bypass on endotoxemia apart from cardiac surgical access and to improve our understanding of the potential benefits of off-pump procedures. Methods: Thirty patients undergoing coronary artery bypass grafting were followed up prospectively. The patients were divided into 2 equal groups: those who underwent bypass grafting through a sternotomy incision without cardiopulmonary bypass (off-pump group) and those who underwent bypass grafting through a sternotomy incision with cardiopulmonary bypass (CPB group). Blood sampling for endotoxin, lactate, and cardiac index measurements were performed during the following time points: (1) after sternotomy; (2) during the coronary occlusion period in the off-pump group and during aortic clamping in the CPB group; (3) after removal of the coronary occlusion sutures in the off-pump group and after removal of the aortic clamp in the CPB group; (4) 30 minutes after the completion of all distal anastomoses in the off-pump group and immediately after weaning from cardiopulmonary bypass in the CPB group; (5) 1 hour postoperatively; and (6) 12 hours postoperatively. Results: Endotoxin and lactate levels were significantly (P <.05) lower in the off-pump group at all sampling time points, except after sternotomy. Conclusions: In conclusion, this study has shown that endotoxemia during coronary artery bypass surgery seems mainly to be associated with cardiopulmonary bypass procedure. The relatively lower endotoxin levels observed in off-pump surgery might contribute to improved postoperative recovery.

Reperfusion Arrhythmias and Sudden Cardiac Death

The observation that ventricular fibrillation may occur within seconds after restoration of blood flow to myocardium turned ischemic by a period of coronary occlusion (reperfusion) was originally made in the experimental laboratory in the 19th century by Cohnheim and Von Schulthess-Rechberg1 and later confirmed in the early 20th century by Tennant and Wiggers.2 In fact, it was found in subsequent laboratory experiments that ventricular fibrillation may occur more frequently after reperfusion than after coronary artery occlusion.3 It took until the latter part of the 20th century for these early laboratory studies to be translated to clinical medicine. It was noticed that only a minority of those individuals who have been successfully resuscitated from sudden ventricular fibrillation associated with coronary artery disease subsequently developed a myocardial infarction,4,5 suggesting that, if indeed myocardial ischemia caused by coronary occlusion was involved, it was transient. Reperfusion must have occurred. This proposed relationship between transient ischemia, reperfusion, and arrhythmias was corroborated by studies in patients with transient coronary artery spasm in whom ventricular arrhythmias, including ventricular fibrillation, occurred within minutes after the beginning of electrocardiographic signs of myocardial ischemia caused by the spasm6 but also after ST segment changes had returned to normal, when reperfusion had occurred.6–9 What is the mechanism responsible for this occurrence of fibrillation? This is a subject that has been pursued in more than a century of experimentation with slow but continued progress. The most recent advance, now in the 21st century, is the article by Cascio et al10 in this issue of Circulation Research . The initial information on mechanisms of reperfusion arrhythmias came from experiments on in situ hearts of large animals subjected to periods of coronary artery occlusion followed by release of the occlusion that allowed reperfusion. In these experiments, the …

High tissue affinity angiotensin-converting enzyme inhibitors improve endothelial function and reduce infarct size

Background. Angiotensin-converting enzyme (ACE) inhibitors differ in their ability to inhibit tissue ACE. This study was, therefore, undertaken to determine whether high tissue affinity ACE inhibitors would improve endothelial function and thereby decrease tissue necrosis during ischemia. Methods. In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion. During the period of coronary occlusion, 10 pigs received enalaprilat (low affinity tissue ACE inhibitor), 0.05 mg/kg intravenously, 10 received quinaprilat (high affinity tissue ACE inhibitor), 10 mg intravenously, and 10 others received no ACE inhibitor. Results. Wall motion scores (4, normal, to −1, dyskinesia) were higher in animals treated with ACE inhibitors (3.20 ± 0.15 SE enalaprilat versus 3.08 ± 0.23 quinaprilat versus 1.52 ± 0.07 no ACE; both p < 0.0001 from no ACE). Endothelial-dependent relaxation to bradykinin was best preserved in the quinaprilat-treated hearts (32.1% ± 7.6% enalaprilat versus 65.8% ± 12.6% quinaprilat versus 30.6% ± 10.7% no ACE; p < 0.0001 from no ACE; p < 0.005 from enalaprilat). This was associated with a greater reduction in infarct size: area necrosis/area risk 24.3% ± 0.8% enalaprilat ( p < 0.0001 from no ACE) versus 14.3% ± 3.2% quinaprilat ( p < 0.0001 from no ACE; p < 0.005 from enalaprilat) versus 40.0% ± 1.7% no ACE. Conclusions. ACE inhibitors with higher affinity to tissue ACE result in better preservation of endothelial function and less tissue necrosis during coronary revascularization.

Energy-related metabolites during and after induced myocardial infarction with special emphasis on the reperfusion injury after extracorporeal circulation.

In the clinical setting great efforts have been made with contradictory results to operate upon acutely myocardial ischaemic patients. The reasons for the absence of clear-cut results are not well understood nor are they scientifically explored. To resolve this problem further, we attempted to design an experimental in vivo model to mimic acute myocardial ischaemia followed by extracorporeal circulation (ECC) and reperfusion. One of the main targets of our protocol was monitoring of myocardial energy metabolism by microdialysis (MCD) during the periods of coronary occlusion (60 min), hypothermic (30 degrees C) ECC and cardioplegia (45 min), followed by reperfusion with (30 min) and without (60 min) ECC. In eight anaesthetized, open-chest pigs, myocardial lactate, pyruvate, adenosine, taurine, inosine, hypoxanthine and guanosine were sampled with MCD in both ischaemic and non-ischaemic areas. Myocardial area at risk and infarct size were quantified with the modified topographical evaluation methods. The principal finding with this experimental setup was a biphasic release pattern of lactate, adenosine, taurine, inosine, hypoxanthine and guanosine from ischaemic myocardium. Lactate levels were equally high in reperfused ischaemic and non-ischaemic myocardial tissue. Pyruvate demonstrated consistently higher values in non-ischaemic myocardium throughout the experiment. A pattern was discernible, lactate being a marker of compromised cell energy metabolism, and taurine being a marker of disturbed cell integrity. Of special interest was the increased level of pyruvate in microdialysates of non-ischaemic myocardium as compared with its ischaemic counterpart. In conclusion, we found disturbances in energy metabolism and cell integrity not only in ischaemic but also in non-ischaemic tissue during reperfusion implying that non-ischaemic myocardium demonstrated an unexpected accumulation of lactate and pyruvate. These new findings could at least partly be explicatory to the increased risk of heart surgery in connection with acute myocardial infarction.

Plasma F 2α-isoprostane levels are lowered in pigs fed an (n-3) polyunsaturated fatty acid supplemented diet following occlusion of the left anterior descending coronary artery

F 2α-isoprostanes, produced non-enzymatically from arachidonic acid are potent vasoconstrictors. Dietary supplementation with (n-3) polyunsaturated fatty acids has been shown to reduce arachidonic acid levels in the body. In the present study, alterations in plasma levels of the F 2α-isoprostane, 8-iso-prostaglandin F 2α, were assessed by enzyme immunoassay in pigs following (n-3) polyunsaturated fatty acid supplementation and during occlusion of the left anterior descending coronary artery. Pigs were fed diets supplemented with either fish oil (rich in n-3 polyunsaturated fatty acids) or beef tallow (high content of saturated fatty acids) for a 6 week period. The animals were then anesthetised and plasma samples were collected. The coronary artery was occluded and the blood samples were collected during the following 10 minutes. While plasma 8-iso-prostaglandin F 2α levels were generally lower in pigs fed the (n-3) fatty acid supplemented diet as compared with those fed the diet high in saturated fats, this response only reached statistical significance (P<0.05) during the 10 minute period of coronary occlusion. Notwithstanding this, plasma 8-iso-prostaglandin F 2α remained unchanged in both dietary groups once occlusion was initiated. Significant differences (P<0.05) in the fatty acid profile of blood plasma were detected between the two dietary groups, but occlusion failed to alter these parameters. The results demonstrate that (n-3) polyunsaturated fatty acid dietary supplementation lowers 8-iso-prostaglandin F 2α levels in the porcine circulation in comparison with animals fed beef tallow, particularly after coronary occlusion. This effect compliments the well established action of (n-3) fatty acids in reducing the production of vasoconstrictive eicosanoids.