Episodes Of Reperfusion Research Articles

Delayed Cardioprotection by Inhaled Anesthetics

SCHEMIC PRECONDITIONING (IPC) is a process by which a brief ischemic insult confers protection against a subsequent ischemic episode of similar or greater magnitude. Murry et al 1 first described IPC in the canine myocardium. The investigators showed that 4 transient (5 minutes) periods of coronary artery occlusion interspersed with 5 minutes of reperfusion did not enlarge as anticipated but rather paradoxically reduced the size of a myocardial infarction resulting from a subsequent more prolonged (40 minutes) episode of ischemia and reperfusion. This seminal article showed, for the first time, that the heart was capable of recognizing and rapidly adapting to stress, thereby becoming more resistant to subsequent injury. 1 Bolli et al 2-4 described this IPC phenomenon as a form of “vaccination” that stimulated the “innate plasticity” of myocardium by altering its phenotype and promoting its “self-preservation” as a primary defense mechanism. In the 25 years since IPC was first described, basic science and clinical research examining the mechanisms, limitations, and potential applicability of this process have expanded exponentially. Indeed, a recent PubMed search of the key words “myocardial ischemic preconditioning” indicated that more than 900 articles addressing this subject were published in the peer-reviewed literature in 2009 alone. 5 A large portion of this extraordinary body of work showed that a remarkable plethora of other stimuli, including a diverse variety of drugs, nitric oxide (NO), reactive oxygen species (ROS), endotoxins, inflammatory cytokines, heat stress, rapid pacing, and strenuous exercise, are capable of inducing this prosurvival phenotype, thereby protecting against irreversible ischemic injury independent of an antecedent period of brief myocardial ischemia. 6 Of most immediate relevance to this review, modern volatile anesthetics and the anesthetic noble gas xenon are among the drugs that have been shown to mimic IPC through nearly identical intracellular mechanisms. 7,8

Short Period of Early Reperfusion Aggravates Blood–Brain Barrier Dysfunction During Permanent Focal Ischemia in Rats

Unintentional reperfusion is considered a complication in various experimental models of focal brain ischemia. In the present study, we evaluated whether short intermittent reperfusion affects ischemic brain damage and blood-brain barrier (BBB) integrity in a model of permanent focal ischemia. Focal brain ischemia was induced in male Sprague-Dawley rats using the filament method. A 20-s reperfusion period was allowed 0.5, 2, or 10min after thread occlusion of the middle cerebral artery. In control animals, the transient reperfusion episode was omitted. The infarct volume and extent of swelling was examined 24h after permanent thread occlusion. Immunohistochemical staining for thrombin extravasation was performed. Transient reperfusion early after thread occlusion augmented brain swelling (control, 12.4 ± 8.5%; reperfusion after 0.5min, 24.7 ± 7.0%*; after 2min, 36.7 ± 4.8%*; after 10min, 33.8 ± 4.9%*; *p < 0.01 vs. control) and significantly enhanced leakage of the plasma protein thrombin, whereas the ischemic volume was unaffected. Early intermittent reperfusion may be responsible for increased BBB disruption in permanent ischemia. Similar reperfusion episodes during early ischemia sequelae in patients-due to incomplete adherence or distal movements of a clot-may be causative for increased BBB damage, more severe edema, and potentially hemorrhagic transformation.

Possible involvement of α1-adrenergic receptor and KATP channels in cardioprotective effect of remote aortic preconditioning in isolated rat heart

Background:Remote preconditioning is a phenomenon in which brief episodes of ischemia and reperfusion to remote organs protect the target organ against sustained ischemia/reperfusion (I/R)-induced injury. Protective effects of remote aortic preconditioning (RAPC) are well established in the heart, but their mechanisms still remain to be elucidated.Objective:This study has been designed to investigate the possible involvement of α-1-adrenergic receptor (AR) and KATP channels in cardio-protective effect of RAPC in isolated rat heart.Materials and Methods:Four episodes of ischemia and reperfusion, each comprising of 5 min occlusion and 5 min reperfusion, were used to produce RAPC. Isolated perfused rat heart was subjected to global ischemia for 30 min followed by reperfusion for 120 min. Coronary effluent was analyzed for LDH and CK-MB release to assess the degree of cardiac injury. Myocardial infarct size was estimated macroscopically using TTC staining.Results:Phenylephrine (20 μ/kg i.p.), as α-1-AR agonist, was noted to produce RAPC-like cardio-protection. However, administration of glibenclamide concomitantly or prior to phenylephrine abolished cardioprotection. Moreover, prazocin (1 mg/kg. i.p), as α-1-AR antagonist and glibenclamide (1 mg/kg i.p), a KATP channel blocker, abolished the cardioprotective effect of RAPC.Conclusion:These data provide the evidence that α-1-AR activation involved in cardioprotective effect of RAPC-mediated trough opening of KATP channels.

Cell Membrane Repair as a Mechanism for Ischemic Preconditioning?

Since its original description nearly 25 years ago, the phenomenon of ischemic preconditioning (IPC) continues to captivate a great amount of research interest. The ability to render the myocardium resistant to lethal ischemia/reperfusion injury by preconditioning it with a brief episode of ischemia and reperfusion1 has remained largely a laboratory phenomenon, with only a handful of proof-of-concept clinical studies realizing its true potential.2–4 Of course, the need to apply the IPC protocol before the index myocardial ischemic event has restricted its clinical application to planned cardiac surgery3 or percutaneous coronary intervention,4 settings in which the index myocardial ischemic event can be reliably predicted. The ability to noninvasively reproduce IPC cardioprotection by applying the IPC stimulus to the upper arm or leg with a blood pressure cuff to induce ischemia and reperfusion has also facilitated its clinical translation.3,4 In contrast, interrupting myocardial reperfusion with short-lived episodes of myocardial ischemia, as in ischemic postconditioning,5 an intervention that can be applied at the time of myocardial reperfusion, has been rapidly translated into the clinical setting.6 Article see p 2565 Although an enormous research effort has been invested in elucidating the underlying mechanism of IPC, the actual pathway that mediates cardioprotection remains unclear. The current paradigm suggests that ≥1 brief episodes of ischemia and reperfusion that make up the IPC stimulus generate autoacoids such as adenosine, bradykinin, and opioids, which then recruit a number of signaling pathways through the activation of their respective receptors (see the Figure).7 Many of these signal transduction pathways converge on the mitochondria, resulting in the generation of oxidative stress, which activates downstream kinase mediators of cardioprotection. The sheer number and diversity of these signal transduction pathways linked to IPC, and the complexity with which they interact, can at times be …

Remote Ischemic Preconditioning for Cerebral and Cardiac Protection During Carotid Endarterectomy: Results From a Pilot Randomized Clinical Trial

Remote ischemic preconditioning (RIPC) is a physiological mechanism whereby brief ischemia-reperfusion episodes attenuate damage by subsequent prolonged ischemic insults. It reduces myocardial injury following cardiac and aortic aneurysm surgery. We aimed to determine whether RIPC affects neurological or cardiac injury following carotid endarterectomy (CEA). Patients were preconditioned using 10 minutes of lower limb ischemia-reperfusion. The primary neurological outcome was saccadic latency deterioration. The primary cardiac outcome measure was increased in serum troponin I >0.15 mg/dL. In all, 70 patients were randomized, of whom 55 completed the neurological surveillance protocol. Although there were fewer saccadic latency deteriorations in the RIPC arm, this did not reach statistical significance (32% versus 53%; P = .11). The primary cardiac outcome occurred in 1 patient in each arm (P = .97). There were no adverse events related to the preconditioning protocol. Remote ischemic preconditioning appears safe in patients with CEA. Large-scale trials are required to determine whether RIPC confers clinical benefits.

Postconditioning reduces infarct size and cardiac myocyte apoptosis via the opioid receptor and JAK-STAT signaling pathway

Brief intermittent episodes of ischemia and reperfusion could reduce infarct size, a phenomenon called "postconditioning" at the onset of reperfusion after a prolonged period of ischemia. To investigate whether the opioid receptors and signaling factor JAK-STAT might be responsible for the cardioprotection in ischemic postconditioning, and the possible molecular machinery of cardioprotection. Hundred and twenty healthy New Zealand rabbits were divided into six groups. The myocardial infarct size, cardiac myocyte apoptosis, BCL-2 and P-Stat3 protein expression were tested in the current study. The results suggested that ischemic postconditioning might increase BCL-2 protein expression by activating the opioid receptors and JAK-STAT signaling pathway, and also to reduce ischemia-reperfusion-induced cardiomyocyte apoptosis and to play a key role in myocardial protection. However, further research still needs to be done to unravel the underlying mechanisms.

Chronic morpho-functional damage as a consequence of transient ischemia/reperfusion injury of the small bowel.

The prevailing notion is that ischemia reperfusion injury of the small bowel induces transient changes that resolve within a few days post-occurrence. However, chronic injury has been described following a single ischemia reperfusion in the kidney. We proceeded to ascertain if a similar outcome is also witnessed in the small bowel. ACI rats (n=32) underwent 1, 2 or 3 episodes of ischemia reperfusion by clamping the superior mesenteric artery for 45 minutes at 7-day intervals. Control groups included sham-operated (n=6) or non-operated (n=5) rats. Morphology was examined at day ninety post-ischemia reperfusion and immunostaining was used to evaluate macrophage infiltration, microvascular distribution, and apoptosis. RT-PCR was used to evaluate expression of Inter-Cellular Adhesion Molecule-1 (ICAM-1), transforming growth factor-beta (TGF-beta), Insulin Growth Factor-I (IGF-1), and Insulin Growth Factor-I Receptor (IGF-R). Intestinal function was evaluated by D-xylose performed 24 hours and 4, 8, and 12 weeks after reperfusion. Chronic morphologic changes were observed with degeneration of crypts, endothelial damage, matrix degeneration, and heightened lymphocyte degeneration within the Payer's patches. Major structural changes were characterized by villous atrophy from partial to total. The grade of histological injuries was significantly increased (P<0.001) after multiple ischemia reperfusion episodes. A higher number of apoptotic cells (P<0.001) and a prominent macrophage infiltration (P<0.05) was also witnessed. Altered expression of ICAM-1, TGF-beta, and IGF-1 was observed. At 24 hours after ischemia reperfusion D-xylose absorption was diminished, returning to baseline values within 4 weeks and becoming abnormal again at 8 and 12 weeks (P<0.05). Unlike the prevailing conviction, these data demonstrate that transient ischemia reperfusion repeated injuries of the small bowel result in chronic intestinal damage.

Cardiac Effects of Postconditioning Depend Critically on the Duration of Reperfusion and Reocclusion Episodes

The objective of the present study was to evaluate the effects of ischemic postconditioning on left ventricular function in isolated rat hearts. The hearts of 24 Wistar rats were were isolated, perfused immediately, and distributed into 3 groups: GI, control (n = 8); GII, three 10-second cycles of postconditioning (n = 8); and GIII, three 30-second cycles of postconditioning (n = 8). After a 15-minute stabilization period, all hearts underwent 20 minutes of global ischemia following 20 minutes of reperfusion. At times t0 (control), t5, t10, t15, and t20 (0, 5, 10, 15, and 20 minutes of reperfusion, respectively), we recorded the heart rate, coronary flow, systolic pressure, +(dP/dt)max (maximum speed of increase in the left ventricular pressure), and -(dP/dt)max (maximum speed of decrease in the left ventricular pressure). Data were analyzed by a 1-way analysis of variance, followed by the Tukey test; a P value <.05 was considered statistically significant. There were no significant differences among the analyzed groups with respect to heart rate, coronary flow, systolic pressure, and -(dP/dt)max (P > .05); however, statistically significant differences in +(dP/dt)max between GII and GI and between GII and GIII occurred at t20 (GI, 1409.0 +/- 415.1 mm Hg/s; GII, 1917.3 +/- 403.0 mm Hg/s; GIII, 1344.8 +/- 355.8 mm Hg/s) (GII versus GI, P = .04; GII versus GIII, P = .02). Ischemic postconditioning with three 10-second cycles of reperfusion/reocclusion was demonstrated effective for preserving +(dP/dt)max in isolated rat hearts that underwent 20 minutes of ischemia following 20 minutes of reperfusion.

Landiolol does not enhance the effect of ischemic preconditioning in isolated rat hearts

To determine the effect of landiolol on ischemic preconditioned rat hearts. Isolated perfused rat hearts were divided into 8 groups. In the control group, there was no treatment before the 30-min global ischemia. In the landiolol infused groups, landiolol (100, 300, and 500 microM) was infused without ischemic preconditioning (IPC). In other groups, hearts were pretreated with 2 episodes of 5-min global ischemia and reperfusion before the 30-min ischemia. During the preconditioning, landiolol (0, 100, 300, and 500 microM) was infused. Recoveries of coronary flow (CF) and myocardial oxygen consumption (MVO(2)) at the 120th min after global ischemia to 86 +/- 18 and 112 +/- 19% of the baseline in the IPC group was, respectively, significantly greater than that to 65 +/- 10 and 72 +/- 10% in the control group. Landiolol 300 microM also increased the CF and MVO(2) significantly (97 +/- 19 and 98 +/- 39%) compared to the control. IPC + landiolol 500 microM reduced the increase in LV end-diastolic pressure significantly compared to the control. IPC, landiolol (100, 300, and 500 microM), and IPC + landiolol (100, 300, and 500 microM) all decreased infarct sizes significantly to 23.5 +/- 15.2, 29.8 +/- 12.1, 30.2 +/- 13.3, 22.8 +/- 14.8, 21.6 +/- 7.8, 34.2 +/- 14.7 and 25.5 +/- 11.3% of the total left ventricular mass, respectively, compared to the control (53.3 +/- 12.5%), but there were no significant differences among these groups. IPC and landiolol have cardioprotective effects on ischemia-reperfusion injury in isolated rat hearts, but pretreatment with landiolol does not enhance the cardioprotective effect of IPC.

Epicardial measurement of alterations in extracellular pH and electrolytes during ischemia and reperfusion in cardiac surgery

Simultaneous measurements of extracellular pH, potassium (K(+)), and calcium (Ca(2+)) activity might be indicative of myocardium vitality or ischemia. Ten consecutive patients undergoing elective coronary artery bypass grafting were studied. Epicardial extracellular pH, potassium, and calcium were measured by a miniaturized disposable multi-sensor probe. Blood gases and electrolytes were derived with measurements of arterial and mixed venous blood samples at intervals during surgery. The mean epicardial baseline levels for pH in all patients were 8.04+/-0.22 arbitrary units (AU) for the right ventricle (RV) and 8.03+/-0.21 AU for the left ventricle (LV); for Ca(2+) 0.23+/-0.07 mmol/l (RV) and 0.20+/-0.10 mmol/l (LV); and for K(+) 4.54+/-1.51 mmol/l (RV) and 4.38+/-0.57 mmol/l (LV). Before ischemia, epicardial pH was moderately (p<0.05), and K(+), and Ca(2+) were closely correlated (p<0.001) with blood values. During reperfusion, epicardial measurements were weakly correlated (p<0.001) with blood values for pH, venous K(+) and Ca(2+), but moderately correlated with arterial K(+) and Ca(2+) (p<0.01). The measurements indicated intraoperative episodes of ischemia and reperfusion with reproducible trends of extracellular pH, K(+), and Ca(2+), which results in electrolyte patterns applicable for detecting inadequate myocardial protection during cardiac surgery in patients.

Cardiac preconditioning for ischaemia: lost in translation

Coronary heart disease (CHD) is the leading cause of death worldwide. The development of novel treatment strategies for protecting the myocardium against the detrimental effects of acute ischaemia-reperfusion injury, termed cardioprotection, and for improving clinical outcomes in patients with CHD requires the use of appropriate animal disease models. The concept of cardioprotection was first conceived in the late 1960s and has evolved to include the endogenous cardioprotective phenomenon of ischaemic conditioning, a concept in which the heart can be protected from an episode of acute lethal ischaemia-reperfusion injury by applying brief non-lethal episodes of ischaemia and reperfusion either to the heart itself or to an organ or tissue that is remote from the heart. The brief conditioning episodes of ischaemia and reperfusion can be applied prior to the index ischaemic episode (ischaemic preconditioning), after the onset of the index ischaemic episode (ischaemic perconditioning), or at the onset of reperfusion (ischaemic postconditioning). Elucidation of the signal transduction pathways underlying ischaemic conditioning has identified a variety of pharmacological agents that are capable of reproducing its cardioprotective actions. Despite a wealth of preclinical, experimental animal data demonstrating clear cardioprotective benefits with these treatment strategies, their translation into clinical therapy has been hugely disappointing. This review explores the potential reasons behind this failure; it will focus primarily on the inadequacy of the experimental animal disease models that are currently being used to investigate novel cardioprotective strategies, which on the whole are not adequately representative of the clinical scenario, and finally, we will discuss potential solutions to remedy this problem.

Cardiac stunning in the clinic: the full picture

Cardiac stunning refers to different dysfunctional levels occurring after an episode of acute ischemia, despite blood flow is near normal or normal. The phenomenon was initially identified in animal models, where it has been very well characterized. After being established in the experimental setting, it remained unclear, whether a similar syndrome occurs in humans. In addition, it remained controversial, whether stunning was of any clinical relevance as it is spontaneously reversible. Hence, many studies continue to focus on the properties and mechanisms of stunning, although therapies seem more relevant for attenuating and treating myocardial ischemia/reperfusion (I/R) injury, i.e. to bridge until recovery. This article reviews the different facets of cardiac stunning, i.e. myocardial, vascular/microvascular/endothelial, metabolic, neural/neuronal, and electrical stunning. This review also displays where these facets exist and which clinical relevance they might have. Particular attention is directed to the different therapeutic interventions that the various facets of this I/R-induced cardiac injury might require. A final outlook considers possible alternatives to further reduce the detrimental consequences of brief episodes of ischemia and reperfusion.

Cardiovascular Regenerative Medicine

Despite recent advances, heart disease kills more people than all other major diseases combined. Most commonly, coronary occlusion attributable to plaque rupture results in episodes of ischemia and reperfusion that destroy significant number of cardiac myocytes, causing impairment in cardiac function and heart failure. In the absence of transplantation, the long-term survival of heart failure patients is worse than that associated with several types of cancer. This is because existing therapies can only slow the inexorable downward progression of patients with heart failure but do not tackle the fundamental problem, ie, progressive loss of myocytes. A recent explosion of studies aimed at repairing and regenerating heart tissue with cell therapy, however, promises to radically change the landscape of cardiovascular disease mortality and morbidity. The excitement is palpable everywhere. However, these are still early days and the field is rife with controversy and debate about how to proceed. A panoply of daunting questions face investigators who seek to study cell therapy. How to safely and ethically use embryonic stem cells to reconstruct damaged areas of the heart? Which specific types of stem cells are likely to be most effective? If adult stem cells are safe and efficacious, why use embryonic stem cells? Should we avoid embryonic cells all together and focus on the use of stem cells present in the adult bone marrow or the adult heart? Alternatively, or in addition, can induced pluripotent stem cells replicate the properties of embryonic stem cells and possibly supplant them? Can heart cells divide, and, if so, can we develop strategies to stimulate the growth and differentiation of the cardiac cells left in the injured heart to promote recovery of tissue mass and function? Clearly, these are important questions that require thoughtful research, analysis, and debate. In this brief update, we highlight a spate …

The tail of Cx43: its crucial protective role in acute myocardial infarction

In the heart, synchronized contractile activity is facilitated by gap junctions, intercellular channels that underlie electrical and molecular communications between cardiac myocytes. In the ventricles of the mammalian heart, gap junctions are predominately constructed of connexin43 (Cx43) subunits. In heterozygous Cx43 knockout (Cx43/KO) mice, expression of Cx43 is roughly halved and electrical conduction in the ventricles is impaired.1 Cx43/KO mice have increased susceptibility to arrhythmias after acute myocardial infarction (MI).2 Although low-resistance communication is typically desirable, a reduction of intercellular conduction during ischaemia–reperfusion episodes can be beneficial by limiting the spread of toxic metabolites that promote tissue damage.3 Decoupling the gap junctions during acute ischaemia has been shown to reduce infarct size,4 and Cx43/KO mice are reported to have smaller infarcts than their wild-type counterparts.5 Conduction via gap junctions can be post-transcriptionally regulated by the phosphorylation of various amino acids6 and by pH,7 both of which are dependent on the carboxyl terminal (CT) domain of Cx43. Maass et al. demonstrate that loss of the CT domain of Cx43 results in gap junctions that are no longer chemically regulated during ischaemia–reperfusion episodes. They show that this leads to an increased infarct size and an increased susceptibility to arrhythmias.8 To do this, they used a … *Corresponding author. Tel: +1 216 445 7823; fax: +1 216 445 4166, E-mail address : chengy{at}ccf.org

F019 Postconditioning still beneficial if applied 30 minutes after the onset of reperfusion in mice

Brief intermittent episodes of ischemia and reperfusion applied at the onset of reperfusion after a prolonged period ischemia confer cardioprotection, a phenomenon termed postconditioning (postC). The aim of our study was to study the time window of protection offered by postconditioning in mice submitted to ischemia/reperfusion-injury. 12 Mice (C57BL/6) underwent an IR (ischemia reperfusion) protocol corresponding to 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion. An other group of 12 mice underwent a postC protocol comprising, after the 40 minutes of ischemia, 3 cycles of 1-minute reperfusion and 1-minute reocclusion preceding the 60 minutes of reperfusion. In addition, 5 other groups were subjected to a PostC protocol applied at various times after the onset of reperfusion. In the group named PostC dt5 (n=6), the three cycles of PostC algorithm were applied 5 min after the onset of reperfusion; for the PostC dt10 (n=6), PostC dt15 (n=6), PostC dt30 (n=6) and PostC dt45 (n=6) groups, the 3 cycles were applied respectively 10, 15, 30 and 45 min after the onset of reperfusion. A Preconditioning (PreC group: n=7) was performed applying 3 cycles IR of 1 min. before the 40 min. of ischemia. Determination of area at risk (AR) and infarct size (Inf) was assessed by TTC staining and planimetry. Infarct size was significantly reduced in PreC and PostC animals compared to IR: (Inf/AR: 9±2, n=7 and 14.8 ± 2.7, n=12 respectively versus 50.1 ± 2.1, n=14). This cardioprotection was also observed in the PostC dt5, PostC dt10, PostC dt15 and PostC dt30 groups, compared to IR wild-type animals (Inf/AR: 14.8, 20.2, 23.1, 22.1, 28.6 % versus 50.1, respectively; p<0.05). When the postconditioning protocol was delayed 45 minutes, the cardioprotective effect was lost (infarct size/area at risk: 42.2 % for postC dt 45 versus 14.8 % for postC; p<0.05). This study clearly shows that postconditioning reduces infarct size in this mouse model of ischemia-reperfusion and that the efficiency of cardioprotection is maintained even if the protocol is applied until 30 minutes after the onset of reperfusion.

Cardioprotection by adaptation to ischaemia augments autophagy in association with BAG-1 protein.

Autophagy is an intracellular process in which a cell digests its own constituents via lysosomal degradative pathway. Though autophagy has been shown in several cardiac diseases like heart failure, hypertrophy and ischaemic cardiomyopathy, the role and the regulation of autophagy is still largely unknown. Bcl-2-associated athanogene (BAG-1) is a multifunctional pro-survival molecule that binds with Hsp70/Hsc70. In this study, myocardial adaptation to ischaemia by repeated brief episodes of ischaemia and reperfusion (I/R) prior to lethal I/R enhanced the expression of autophagosomal membrane specific protein light chain 3 (LC3)-II, and Beclin-1, a molecule involved in autophagy and BAG-1. Autophagosomes structures were found in the adapted myocardium through electron microscopy. Co-immunoprecipitation and co-immunofluorescence analyses revealed that LC3-II was bound with BAG-1. Inhibition of autophagy by treating rats with Wortmannin (15 μg/kg; intraperitoneally) abolished the ischaemic adaptation-induced induction of LC3-II, Beclin-1, BAG-1 and cardioprotection. Intramyocardial injection of BAG-1 siRNA attenuated the induction of LC3-II, and abolished the cardioprotection achieved by adaptation. Furthermore, hypoxic adaptation in cardiac myoblast cells induced LC3-II and BAG-1. BAG-1 siRNA treatment attenuated hypoxic adaptation-induced LC3-II and BAG-1, and abolished improvement in cardiac cell survival and reduction of cell death. These results clearly indicate that myocardial protection elicited by adaptation is mediated at least in part via up-regulation of autophagy in association with BAG-1 protein.

Epicardial measurement of alterations in extracellular pH and electrolytes during ischemia and reperfusion in cardiac surgery / Epikardiale Messung von pH-Wert- und Elektrolyt-Veränderungen während Ischämie und Reperfusion in der Herzchirurgie

Simultaneous measurements of extracellular pH, potassium (K(+)), and calcium (Ca(2+)) activity might be indicative of myocardium vitality or ischemia. Ten consecutive patients undergoing elective coronary artery bypass grafting were studied. Epicardial extracellular pH, potassium, and calcium were measured by a miniaturized disposable multi-sensor probe. Blood gases and electrolytes were derived with measurements of arterial and mixed venous blood samples at intervals during surgery. The mean epicardial baseline levels for pH in all patients were 8.04+/-0.22 arbitrary units (AU) for the right ventricle (RV) and 8.03+/-0.21 AU for the left ventricle (LV); for Ca(2+) 0.23+/-0.07 mmol/l (RV) and 0.20+/-0.10 mmol/l (LV); and for K(+) 4.54+/-1.51 mmol/l (RV) and 4.38+/-0.57 mmol/l (LV). Before ischemia, epicardial pH was moderately (p<0.05), and K(+), and Ca(2+) were closely correlated (p<0.001) with blood values. During reperfusion, epicardial measurements were weakly correlated (p<0.001) with blood values for pH, venous K(+) and Ca(2+), but moderately correlated with arterial K(+) and Ca(2+) (p<0.01). The measurements indicated intraoperative episodes of ischemia and reperfusion with reproducible trends of extracellular pH, K(+), and Ca(2+), which results in electrolyte patterns applicable for detecting inadequate myocardial protection during cardiac surgery in patients.

Abstract P50: Ischemic Post-Conditioning Following Global Ischemia Due to Cardiac Arrest Failed to Improve Cardiac Function and Survival

Introduction : Repetitive episodes of ischemia and reperfusion following regional myocardial and cerebral ischemia, representing ischemic post-conditioning (IPC), protect against ischemic injury. The possibility that such may have functional application for myocardial injury and survival in settings of cardiac arrest and resuscitation was examined. We hypothesized that repetitive cycles of ventricular fibrillation and reperfusion following resuscitation, representing IPC, would improve cardiovascular function and survival. Methods : Ventricular fibrillation (VF) was electrically induced in 10 SD rats weighing 536±15 g and left untreated for 8 minutes prior to 6 minutes of uninterrupted pre-cordial compressions followed by attempted defibrillation. Resuscitated animals were randomized to either IPC or control. IPC was induced at 5 minutes with electrical re-fibrillation lasting 30 sec followed by spontaneous reversion to a perfusing rhythm. The IPC was repeated 5 minutes later. Except for IPC, controls were identically treated. Frontal plane ECG, mean arterial blood pressure, left ventricular pressures and end tidal CO 2 were continuously recorded. Left ventricular ejection fraction (EF) and cardiac output (CO) were measured echocardiographically at hourly intervals together with blood gases for a total of four hours. Survival was documented at the end of 72 hours. Results : Baseline values did not differ between the IPC and control group. No statistically significant differences between the groups were demonstrated. A power calculation indicates that a minimum of 240 animals would be required to find a difference that would be potentially significant, accordingly the study was concluded. Table . Mean values with standard deviation. Conclusion : The potential value of ischemic post-conditioning represented by repetitive episodes of VF, under the conditions of global ischemia of cardiac arrest, failed to demonstrate a survival value.

A hibernating kidney – ischemic preconditioning in a renal transplant recipient with a proximal stenosis of the iliac artery

Ischemic preconditioning has been first described by Murry and coworkers as the protection conferred to ischemic myocardium by preceding brief periods of sublethal ischemia separated by periods of reperfusion. Another phenomenon closely associated to IPC is hibernation and stunning. The hibernating myocardium refers to resting left ventricular dysfunction due to reduced coronary blood flow that can be partially or completely reversed by myocardial revascularization and/or by reducing myocardial oxygen demand. Similarly as for the myocardium, these effects are reproducible for other solid organs. Here we report a case of a renal transplant recipient with decompensated proximal transplant artery stenosis due to ACE inhibition resulting in acute renal failure. The transplant perfusion was strictly dependent on systemic arterial blood pressure leading to intermittent episodes of renal ischemia and reperfusion. Renal function was severely decreased (glomerular filtration rate approximately 8 ml/min) with the need of hemodialysis treatment over a period of 4 weeks after transplantation. After dilatation of the stenosis, the patient's renal function improved rapidly and achieved values better than ever before. Referring to the definition of hibernating myocardium, here we postulate a case of a hibernating kidney in context of ischemic preconditioning.

Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases

Remote preconditioning is a unique phenomenon in which brief episodes of ischemia and reperfusion to remote organ protect the target organ against sustained ischemia-reperfusion (I/R)-induced injury. Protective effects of remote renal preconditioning (RRPC) are well established in heart, but their mechanisms still remain to be elucidated. So, the present study was designed to investigate the possible role of oxygen-sensing hypoxia inducible factor-prolyl 4-hydroxylases (HIF-P4Hs) in RRPC-induced cardioprotection in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion and reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Ethyl 3,4-dihydroxybenzoate (EDHB) and alpha-ketoglutarate (alpha-KG) were employed as HIF-P4Hs inhibitor and activator, respectively. Diethyldithiocarbamic acid (DDCA) was employed as NFkB inhibitor. Remote renal preconditioning prevented I/R-induced myocardial injury and produced cardioprotective effects. Pharmacological preconditioning with EDHB (100 mg kg(-1) i.p.) mimicked the cardioprotective effects of RRPC. However, alpha-KG (200 mg kg(-1) i.p.) and DDCA (150 mg kg(-1) i.p.) abolished cardioprotective effects of RRPC and EDHB. So, it may be concluded that inhibition of HIF-P4H has a key role in RRPC-induced cardioprotection. Further, remote preconditioning-induced HIF-P4H inhibition may have triggered a transduction pathway involving activation of NFkB.