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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.58 no.5 Campinas Sept./Oct. 2008
Myocardial protection by pre- and post-anesthetic conditioning*
Protección miocárdica por el pre y el poscondicionamiento anestésico
Rubens Campana Pasqualin, M.D.I; José Otávio Costa Auler Jr., TSA, M.D.II
de Doutorado do Programa de Pós-Graduação da FMUSP
IIDiretor do Serviço de Anestesiologia e UTI Cirúrgica do InCor - Hospital das Clínicas da FMUSP; Professor Titular da Disciplina de Anestesiologia da FMUSP; Coordenador do Programa de Pós-Graduação Senso Stricto - Área de Anestesiologia
OBJECTIVES: Perioperative myocardial ischemia is commonly observed, and
it can increase significantly postoperative morbidity and mortality. The cardioprotective
properties of volatile anesthetics and opioids have been studied during several
decades and currently constitute powerful tools in the management of patients
with ischemic coronariopathy. The objective of this review was to provide the
fundaments of myocardial protection by preconditioning.
CONTENTS: The concepts of cellular damage secondary to ischemia and reperfusion, ischemic preconditioning (IPC), and anesthetic preconditioning (APC), as well as the mechanisms of myocardial protection, are discussed. Recent studies in cardiac surgery demonstrated that the use of short periods of ischemia during reperfusion can reduce the area of myocardial infarction. Volatile anesthetic can also have a protective effect in myocardial reperfusion. Independently of the signaling pathway that leads to preconditioning, both anesthetic and ischemic, mitochondrial dependent KATP channels are considered the final mediators of cardioprotection by controlling the mitochondrial influx of calcium and, therefore, preventing the induction of necrosis and apoptosis. Although IPC and APC effectively reduce the area of myocardial infarction and improve postoperative ventricular function, it is important to stress that those treatments should be instituted before ischemic events to justify their clinical applicability.
CONCLUSIONS: Phenomena known as myocardial ischemic preconditioning and anesthetic preconditioning are well known, and the mechanism of protection is similar in both situations; however, not every step that leads to this protection has been fully explained. Further studies are necessary to increase the clinical applicability of the cardioprotective properties of anesthetics.
Key Words: ANESTHETICS, inhalational, intravenous; COMPLICATIONS: myocardial ischemia; PATHOPHYSIOLOGY, Cardiovascular: ischemic preconditioning, reperfusion.
Y OBJETIVO: La isquemia miocárdica perioperatoria es un evento generalmente
observado en el período perioperatorio pudiendo aumentar significativamente
para la morbi-mortalidad posquirúrgica. Las propiedades cardioprotectoras
de los anestésicos volátiles y de los opioides, han sido estudiadas
durante algunas décadas y hoy por hoy se han convertido en poderosas
herramientas para el manejo de pacientes con enfermedad coronaria isquémica.
El objetivo de esta revisión fue el de ofrecer bases sobre la protección
miocárdica por precondicionamiento.
CONTENIDO: Se discutirán los conceptos sobre lesión celular proveniente de la isquemia y de la reperfusión, precondicionamiento isquémico (PCI), precondicionamiento anestésico (PCA), como también los mecanismos de Protección miocárdica. Recientes estudios en cirugía cardíaca demostraron que la aplicación de cortos períodos de isquemia, durante la reperfusión, puede reducir el área de infarto del miocardio. Los anestésicos volátiles también pueden presentar un efecto protector en la reperfusión miocárdica. Independientemente de la vía de señalización que conlleva al precondicionamiento, tanto los que envuelven anestésicos como el isquémico, se considera que los canales de KATP dependientes mitocondriales sean los mediadores finales de la cardio protección por controlar el influjo de calcio en la mitocondria y prevenir la inducción de la necrosis y de la apoptosis. A pesar de que el PCI y el PCA de hecho reduzcan el área de infarto del miocardio y mejoren la función ventricular postoperatoria, es importante destacar que esos tratamientos deben ser anteriores al evento isquémico en el sentido de justificar su aplicabilidad clínica.
CONCLUSIONES: Los fenómenos conocidos como precondicionamiento isquémico y precondicionamiento anestésico del miocardio, son muy conocidos, siendo el mecanismo de protección similar en ambas situaciones, sin embargo no todos los pasos que conllevan a esa protección fueron completamente aclarados. Más investigaciones se hacen necesarias para que las propiedades cardioprotectoras de los agentes anestésicos puedan tener aumentada su aplicabilidad clínica.
Perioperative myocardial ischemia is a common occurrence, and it can increase significantly postoperative morbidity and mortality in cardiac and non-cardiac surgeries. Nowadays, anesthesia in patients with cardiac disease is increasingly more frequent due to the increase in life expectancy. Between 18% and 74% of the cases of ischemic cardiomyopathy develop perioperative myocardial ischemia 1. Since myocardial ischemia and reperfusion can lead to serious complications, such as reduction in contractile force (stunning) 2, reperfusion arrhythmias 3, and infarction and necrosis of myocytes 4, in the last several years many researchers have studied measures to minimize ischemic and reperfusion damage (I/R). Some treatment protocols are aimed at controlling the modulation of myocardial oxygen supply and demand indices like beta-blockers, calcium channel blockers, and alpha2-agonists. Other protocols are aimed at controlling cellular or mitochondrial ischemia, although the clinical benefits of those treatments have yet to be demonstrated 5.
The cardioprotective properties of anesthetics have been studied since Freedman 6 demonstrated, in 1985, that enflurane was capable of preventing post-ischemic ventricular dysfunction in isolated mice hearts submitted to global myocardial ischemia. In 1995, Schultz et al. 7 demonstrated that opioid receptors are one of the mediators of ischemic preconditioning (IPC) of the myocardium, which can reduce the area of myocardial infarction. This same group demonstrated, in 1996, that morphine was capable of protecting the heart against acute myocardial infarction through mechanisms similar to ICP 8. This review gathered the most recent data regarding the main mechanisms related with myocardial protection.
Cell Damage Secondary to Ischemia and Reperfusion
The interruption or decrease in blood flow to the myocardium reduces the delivery of oxygen and metabolic substrates to the myocytes, causing functional, structural, and metabolic changes in the cardiac muscle. This is followed by an accumulation of ions and metabolites, changing the metabolism from aerobic to anaerobic. The interruption in blood flow results in fast depletion of the cellular reserves of adenosine triphosphate (ATP) and creatine phosphate (high-energy phosphates). As a consequence, contractility and ATP-dependent ion pumps (calcium ATPase, in the sarcoplasmatic reticulum and sarcolema, and Na+/K+ pump) are depressed 9. The accumulation of Ca++ and Na+ in the citosol, along with the loss of intracellular K+, affects the membrane potential and the transmembrane ion gradient. Those changes lead to the accumulation of byproducts and metabolites, cellular acidosis, increase in osmotic load, and formation of reactive oxygen species (ROS) and finally to the activation of Ca++-sensitive enzymes. From this moment on, morphologic changes start to develop. Proteases activated especially by the sudden increase in calcium and ROS concentration start to degrade myofibrillar proteins of the cytoskeleton while lipases affect membranes causing their rupture and consequent cellular death 18.
Recovery of the production of energy by cardiomyocytes that did not undergo apoptosis during the ischemic period would be expected after perfusion is reinstituted. However, reperfusion generates greater pressure on the cardiac cell. The return of oxygen and nutrients increases the already elevated cytosolic Ca++ levels due to the entry of additional calcium through voltage-dependent Ca++ channels (L-type Ca++ channel). Those channels are located in the sarcolema and they are regulated by the Na/Ca exchange protein and also by the release of Ca++ from the sarcoplasmatic reticulum 11,12. Therefore, the loss of the rigid control on coordination of intracellular mechanisms lead to the development of reperfusion arrhythmias, whose mechanism is related with the transient oscillation of cytosolic Ca++ and hyperstimulation of the tricarboxylic acid cycle 13,14. Finally, due to the mitochondrial overload of Ca++, the generation of ROS increases dramatically.
Therefore, during I/R, cardiomyocytes are exposed to a sequence of harmful and adaptive events that should be divided in two components: during ischemia (ischemic damage) and during reperfusion (reperfusion damage). Experimental data indicate that the damage caused by reperfusion is proportional to the degree of damage caused by ischemia. Therefore, treatment protocols that are aimed at alleviating the ischemic component of damage (adenosine, Ca++ channel blockers, and agonists of KATP-dependent channels) will reduce, indirectly, the unavoidable damage caused by reperfusion. Besides, different areas of the myocardium can be more or less severely affected, depending on the duration and degree of blood flow restriction. Thus, cardiomyocytes can present different states of reversible and irreversible damages 15.
During ischemia, the contractile effort of cardiomyocytes is decreased within a few seconds, with interruption of the contractile mechanisms in the first minutes. If ischemia lasts more than 15 minutes, cellular necrosis begins, resulting in reduction of the contractile function even if the blood flow to the myocardium is restored. In addition to necrosis, apoptosis, or programmed cell death, occurs after the beginning of reperfusion 16.
On the other hand, in 1986 Murray et al. 17 described a phenomenon in which dogs submitted to four 5-minute periods of cardiac ischemia before and after a period of 40 minutes of ischemia developed a smaller area of infarction when compared with the control group. This phenomenon was called ischemic preconditioning (IPC). Several researchers continue investigating the mechanisms of IPC; however a few steps still need to be explained.
The ischemic stimulus causes the release of stress mediators from the heart, including adenosine, bradykinin, catecholamines, opioids, and ROS 18-20. Those mediators bind to specific receptors in the cell membrane (protein G), which amplifies the initial stimulus for phospholipase C (PLC). Activation of PLC leads to the formation of inositol triphosphate (IP3), which promotes the release of Ca++ from the sarcoplasmatic reticulum, and production of diacylglycerol (DAG). Diacylglycerol activates different isoforms of protein kinase C (PKC). Besides DAG, PKC can be activated by protein G, increased intracellular levels of Ca++, nitric oxide (NO), and ROS can also activate PKC. Finally, PKC induces the phosphorylation and activation of ATP-dependent potassium channels (KATP dependent) in the sarcolema and mitochondria, the most likely effectors of ICP due to the control of the intracellular concentration of Ca++ 15.
Note that ICP is a treatment that should be instituted before the ischemic event, while the I/R lesion occurs after ischemia. It also should be mentioned that ICP alone does not prevent the death of myocytes but delays significantly its occurrence during the first two to three hours of sustained ischemia (classical or early preconditioning) 21. After this period, the protection provided by the initial ischemic stimulus disappears, returning after 12 to 24 hours, and it can last up to 72 hours, which is known as late preconditioning or second window of protection 22 (Figure 1).
Three classes of anesthetics including opioids, volatile anesthetics, and ethanol hypnotics (chloral hydrate and a-chloralose) have properties of cardiac preconditioning 23. Clinically, opioids and volatile anesthetics are used more often, presenting a great potential to prevent or attenuate perioperative myocardial ischemic events 21.
Since it was demonstrated that volatile anesthetics can also protect the endothelium and smooth muscle cells 24 by preconditioning, the use of those agents in organic protection can be potentially important. This concept is in agreement with the findings of the first double-blind study on preconditioning (SEVO) in patients undergoing myocardial revascularization 25. Using biochemical markers, this study demonstrated significant postoperative improvement in renal and cardiac function in patients undergoing preconditioning with sevoflurane.
Anesthetic preconditioning and IPC share most of the steps involved in establishing the state of preconditioning, including the activation of protein G binding receptors in the cell membrane 26,27, interaction of several types of protein kinases 28-30, ROS 31, and KATP dependent channels in the sarcolema and mitochondria, as final effectors of cardioprotection by regulating the ion Ca++. Recent studies demonstrated differences in the cardioprotective phenotype between ACP and ICP. One of them is related with the translocation and phosphorylation of protein kinase C isoforms, as well as the distinct activation of mitosis-activated protein kinases (MAPKs).
Initially, opening of KATP-dependent sarcolemmal channels were implicated in IPC and APC, by shortening the duration of the action potential 32,33, and, therefore, reducing the intracellular overload of Ca++ during ischemia 32. However, further studies that led to the discovery of KATP mitochondrial channels 34, demonstrated that the anti-ischemic actions of KATP channels were independent of the duration of the action potential 35-37. However, ICP did not occur in Kir6.2-deficient mice (gene that expresses sulphonylurea receptors and K+-entry rectifying channels in the molecular complex of KATP channels 38 suggesting that the presence of sarcolemmal KATP-dependent channels would still be necessary for cardioprotection 39. Despite these last data most results indicate that the preservation of mitochondrial bioenergetic function, which is a consequence of the opening of mitochondrial KATP channels, seems to be fundamentally important to promote protection against ischemia 40-43. Drugs that promote the opening of KATP-dependent mitochondrial channels (e.g., diazoxide) maintain mitochondrial Ca++ homeosthasis and inhibit the overload of this ion inside the organelle 42,43. The change in mitochondrial balance in oxy-reduction reactions caused by opening of mitochondrial KATP-dependent channels can also promote cellular protection 43,44. Membrane depolarization, matrix edema, and inhibition of ATP synthesis occur as a result of the opening of mitochondrial KATP-dependent channels, guaranteeing cellular viability during IPC 44. The opening of mitochondrial KATP-dependent channels causes depolarization of the internal mitochondrial membrane and transitory matrix edema 45, resulting in the change in ion balance 46. These events initially reduce the production of ATP 43, but they promote a compensatory increase in respiratory chain that optimizes the efficacy of oxidative phosphorylation, partly by regulating the volume of the mitochondrial matrix 47. Thus, moderate disruption in mitochondrial homeosthasis caused by the opening of KATP-dependent mitochondrial channels can provide more tolerance to the ischemic lesion due to the reduction in Ca++ overload 42,43, prevention of reactions that result in necrosis and apoptosis 48,49, or attenuation of the oxidative stress 50.
It has also been demonstrated that the mitochondrial synthesis of ATP would be preserved after a prolonged period of I/R, as well as after a short period of I/R 51. This beneficial effect was abolished by 5-hydroxidecanoate (a selective blocker of mitochondrial KATP-dependent channels), suggesting that the activation of those channels improves energy production 52. It has been hypothesized that the opening of mitochondrial KATP-dependent channels preserves the permeability of the external mitochondrial membrane to ATP precursors (adenosine and adenosine diphosphate-ADP) and cytochrome c. The structure of the intermembrane space can also be preserved as a consequence of the activation of mitochondrial KATP-dependent channels, even in the presence of matrix edema 40. The preservation of ATP substrates and mitochondrial structure can facilitate more efficient energy transfer between the mitochondria and the cytosol immediately after ischemia. It has been demonstrated recently that sevoflurane preserved ATP synthesis in mitochondria isolated from cardiomyocytes obtained during the initial stages of reperfusion in vivo, and this benefit was abolished by the pre-treatment with free radical scavengers 53. Preconditioning induced by sevoflurane improved mitochondrial bioenergetics by activating mitochondrial KATP-dependent channels in isolated guinea-pig hearts 54. Thus, one can infer that the opening of KATP-dependent channels by volatile anesthetics can be associated with the preservation of mitochondrial function during reperfusion, and the preservation of mitochondrial performance can also contribute for cardioprotection. Studies in isolated mitochondria demonstrated that the amount of ROS that overshoots the critical threshold results in transient permeability of the internal mitochondrial membrane and the subsequent release of large amounts of ROS 55. This transitory mitochondrial permeability (TMP) precedes cell death by necrosis or apoptosis 56 and glutathione is the primary defense against this event 55,57. Those data suggest that volatile anesthetics and other mitochondrial KATP-dependent channels can prevent TMP in an oxidative-sensitive medium, but this hypothesis has not been tested yet. Opening of TMP by the agonist atractyloside during reperfusion abolished the preconditioning induced by ICP and diazoxide in isolated mice hearts 58. Those results suggest that inhibition of the opening of TPM pores may represent the last effector responsible for the preconditioning, where the activation of mitochondrial KATP-dependent channels would work as a mediator or inductor. More recently, rabbit hearts treated with desflurane before ischemia and reperfusion, showed resistance to the opening of TMP pores 59. Further studies are needed to delineate the exact role of TMP during anesthetic preconditioning.
The cytosolic and mitochondrial Ca++ overload during prolonged I/R has been associated with mitochondrial damage and the death of myocytes 60-62. Ischemic preconditioning and sevoflurane-induced preconditioning reduced the cytosolic Ca++ overload and myocardial damage 64 and improved the recovery of the contractile strength during reperfusion 63. Ischemic preconditioning and APC attenuated the Ca++ overload during ischemia in mice and guinea pigs hearts 65,66, effects that were abolished by 5-hydroxidecanoate. Thus, it is possible that the protection against I/R-induced damage by volatile anesthetics can be partly due to the attenuation of cytosolic and mitochondrial Ca++ overload through a mechanism dependent of mitochondrial KATP-dependent channels. Volatile anesthetics also suppressed the release of Ca++ from the sarcoplasmatic reticulum 67,68 and the sensitivity of the monofilament to Ca++ 68. Therefore, the modulation of the sarcoplasmatic reticulum reduces cellular Ca++ overload and the changes in the sensitivity of the monofilaments under conditions of Ca++ excess have also been considered as cardioprotective 69,70.
The Importance of Reactive Oxygen Species (ROS)
Several experimental evidences indicate that ROS play an important role in APC. Free radicals scavengers administered during treatment with isoflurane abolished the protective effects against the I/R damage 71,72. A study of isoflurane in isolated guinea pigs hearts used dihydroethidium to observe the generation of ROS through a spectrophotometer, in which a fiberoptic probe was placed against the wall of the left ventricle 73. The administration of isoflurane caused an immediate and reversible increase in ethidium bromide fluorescence, which is consistent with the production of small amounts of signaling ROS. Volatile anesthetics are small hydrophobic molecules that readily cross cell membranes, causing depression of mitochondrial respiration in some oxidative phosphorylation complexes 74. Attenuation of respiration can cause the loss of electrons in the internal membrane of the mitochondrial matrix and increase the generation of ROS. The effects of volatile anesthetics on electron transport in submitochondrial particles were investigated 75. Isoflurane and sevoflurane inhibited the activity of the NADH-ubiquinone oxireductase, suggesting that complex I would be the probable target of anesthetics. On the other hand, oxidation of succinate was not affected, indicating that those agents do not affect complexes II and IV. Those results are in agreement with another study in which the administration of sevoflurane increased the concentration of NADH in isolated guinea pigs hearts 76. The attenuation of respiration in complex I induced by sevoflurane in isolated mitochondria of guinea pigs was abolished by free radicals scanvengers 77. The last data suggest that formation of ROS induced by volatile anesthetics can contribute for the mechanism of positive response by attenuating the activity of complex I, contributing even more for the amplification and signaling of ROS to initiate APC. Mixothiazol, a complex III inhibitor, abolished the generation of ROS by sevoflurane and the size of the infarct area, which did not happen with diphenyleneidonium, a complex I inhibitor 78. This indicates that the generation of ROS by the mitochondrial electron transport chain is a fundamental component of cellular protection during APC.
In contrast with the small amounts of ROS necessary to initiate APC, large amounts of ROS have an important role on the pathophysiology of reperfusion damage. Volatile anesthetics also protect the myocardium by attenuating the consequences of ROS burst during reperfusion. The protective effect of APC associated with a markedly reduction in the formation of ROS during I/R is an example 73. The increased production of ROS during reperfusion increases the influx of Ca++ into the mitochondria, opening TMP pores, resulting in cell death by apoptosis. Desflurane increased the resistance to the opening of those pores induced by the overload of Ca++ after I/R 79. Analysis of those data supports the hypothesis that the preservation of myocardial availability during reperfusion is partly due to the attenuation of the serious consequences of large amounts of ROS produced in the mitochondria.
Post-Conditioning: New Perspectives
Although it is clear that APC provides a powerful means of reducing myocardial damage, the clinical applicability of APC might be limited to Cardiac Surgeries because preconditioning should be instituted before the ischemic event, which is difficult to predict in other types of surgeries. Reperfusion is necessary for maintenance of the ischemic myocardium, but paradoxically it contributes for the lesion 80,81. Thus, one intervention at the time of reperfusion could be more clinically advantageous by attenuating the reperfusion damage and, therefore, inhibiting myocardial necrosis. Recently, Vinten-Johansen et al. 2,83 demonstrated that short periods of ischemia during the early minutes of reperfusion after prolonged arterial occlusion reduced the size of the infarct, endothelial dysfunction, accumulation of neutrophils, and inhibited partially the generation of large amounts of ROS. It has also been demonstrated that post-ischemic conditioning was mediated by the activation of ERK1/2 (extracellular signal regulated kinase) and P13K-Akt (phosphatydilinositol-3-kinase), besides the production of nitric oxide.
Volatile anesthetics have protective effects against myocardial damage when administered for short periods of time during reperfusion. Halothane protected the myocardium against the hypercontractility induced by reoxygenation by preventing the oscillations of intracellular Ca++ during the early stages of reperfusion 85. Administration of volatile anesthetics in isolated hearts during the first 15 minutes of reperfusion protected the myocardium against reperfusion damage 86. Sevoflurane and desflurane, but not isoflurane, reduced the size of the infarcted area when administered in the first 15 minutes of reperfusion in rabbits 87. The dose-dependent cardioprotective effect of sevoflurane was confirmed, posteriorly, in mice in vivo 88. More recently, it has been demonstrated that isoflurane reduced the area of infarction when administered three minutes before and two minutes after the beginning of reperfusion 89. A selective P13K inhibitor abolished the protective effect of the short exposure to sevoflurane during the beginning of reperfusion, indicating that this protein participates in post-anesthetic conditioning. Activation of P13K contributed for the recruitment of several endogenous signaling mechanisms and pathways to reduce reperfusion damage. Phosphorylation of Akt (pro-survival kinase), stimulation of endothelial nitric oxide synthase (eNOS), and activation of PKC were demonstrated to be protective mechanisms of P13K, as well as other drugs, such as insulin 90, bradykinin 91, and opioids 92 during reperfusion. Those data suggest that post-anesthetic conditioning seems to be mediated by the P13K cascade and signaling. Isoflurane and sevoflurane also reduced reperfusion damage by decreasing the post-ischemic adhesion of polymorphonuclear leukocytes, which are known mediators of the post-ischemic lesion and represent an important source of ROS 93,94. So far, modulation of the oxygen supply and oxygen consumption index of the myocardium contributed for the protective effects of volatile anesthetics during the early stages of reperfusion. The role of the P13K/Akt enzymes in preconditioning should be established to differentiate the mechanisms involved in pre- and post-conditioning.
A large volume of evidence on the cardioprotective actions of anesthetics when administered before myocardial ischemia or in the early phases of reperfusion has been accumulated over the last decades. Pre- and post-anesthetic conditioning can become powerful tools in the management of patients with ischemic coronariopathy undergoing cardiac and non-cardiac surgeries. Signaling events in APC are present not only in myocytes, but also in other cell types. Therefore, anesthetics can reduce the damage of other organs, which is called remote preconditioning. Several events that occur in APC have been identified; however, further studies demonstrating its importance, activation time, and interconnections are necessary.
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Correspondence to: Submitted em 18
de abril de 2007 *
Received from Programa Pós-Graduação - Disciplina de Anestesiologia
da Faculdade de Medicina da Universidade de São Paulo (FMUSP), Laboratório
de Investigação Médica/Anestesiologia (LIM-8), São
Dr. José Otávio Costa Auler Junior
Serviço de Anestesia Incor HC-FMUSP 2° andar
Avenida Enéas de Carvalho Aguiar 44 - Cerqueira César
05401-900 São Paulo, SP
Accepted para publicação em 19 de junho de 2008
Submitted em 18
de abril de 2007
* Received from Programa Pós-Graduação - Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), Laboratório de Investigação Médica/Anestesiologia (LIM-8), São Paulo, SP