Scholarly article on topic 'Myocardial ischemic conditioning: Physiological aspects and clinical applications in cardiac surgery'

Myocardial ischemic conditioning: Physiological aspects and clinical applications in cardiac surgery Academic research paper on "Basic medicine"

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{"Ischemia–reperfusion injury" / "Ischemic preconditioning" / "Ischemic postconditioning" / "Remote ischemic preconditioning" / "Cardiac surgery"}

Abstract of research paper on Basic medicine, author of scientific article — Radhouane Bousselmi, Mohamed Anis Lebbi, Mustapha Ferjani

Abstract Ischemia–reperfusion is a major determinant of myocardial impairment in patients undergoing cardiac surgery. The main goal of research in cardioprotection is to develop effective techniques to avoid ischemia–reperfusion lesions. Myocardial ischemic conditioning is a powerful endogenous cardioprotective phenomenon. First described in animals in 1986, myocardial ischemic conditioning consists of applying increased tolerance of the myocardium to sustained ischemia by exposing it to brief episodes of ischemia–reperfusion. Several studies have sought to demonstrate its effective cardioprotective action in humans and to understand its underlying mechanisms. Myocardial ischemic conditioning has two forms: ischemic preconditioning (IPC) when the conditioning stimulus is applied before the index ischemia and ischemic postconditioning when the conditioning stimulus is applied after it. The cardioprotective action of ischemic conditioning was reproduced by applying the ischemia–reperfusion stimulus to organs remote from the heart. This non-invasive manner of applying ischemic conditioning has led to its application in clinical settings. Clinical trials for the different forms of ischemic conditioning were mainly developed in cardiac surgery. Many studies suggest that this phenomenon can represent an interesting adjuvant to classical cardioprotection during on-pump cardiac surgery. Ischemic conditioning was also tested in interventional cardiology with interesting results. Finally, advances made in the understanding of mechanisms that underlie the cardioprotective action of ischemic conditioning have paved the way to a new form of myocardial conditioning which is pharmacological conditioning.

Academic research paper on topic "Myocardial ischemic conditioning: Physiological aspects and clinical applications in cardiac surgery"

Myocardial ischemic conditioning: c^Ma*

Physiological aspects and clinical applications in cardiac surgery

Radhouane Bousselmia,b'*, Mohamed Anis Lebbia,b, Mustapha Ferjania,b

a Department of Cardiovascular Anaesthesia and Critical Care, Military Hospital of Tunis b Faculty of Medicine, University of Tunis, El Manar

a,b Tunisia

Ischemia-reperfusion is a major determinant of myocardial impairment in patients undergoing cardiac surgery. The main goal of research in cardioprotection is to develop effective techniques to avoid ischemia-reperfusion lesions. Myocardial ischemic conditioning is a powerful endogenous cardioprotective phenomenon. First described in animals in 1986, myocardial ischemic conditioning consists of applying increased tolerance of the myocardium to sustained ischemia by exposing it to brief episodes of ischemia-reperfusion. Several studies have sought to demonstrate its effective cardioprotective action in humans and to understand its underlying mechanisms. Myocardial ischemic conditioning has two forms: ischemic preconditioning (IPC) when the conditioning stimulus is applied before the index ischemia and ischemic postconditioning when the conditioning stimulus is applied after it. The cardioprotective action of ischemic conditioning was reproduced by applying the ischemia-reperfusion stimulus to organs remote from the heart. This non-invasive manner of applying ischemic conditioning has led to its application in clinical settings. Clinical trials for the different forms of ischemic conditioning were mainly developed in cardiac surgery. Many studies suggest that this phenomenon can represent an interesting adjuvant to classical cardioprotection during on-pump cardiac surgery. Ischemic conditioning was also tested in interventional cardiology with interesting results. Finally, advances made in the understanding of mechanisms that underlie the cardioprotective action of ischemic conditioning have paved the way to a new form of myocardial conditioning which is pharmacological conditioning.

© 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

Keywords: Ischemia-reperfusion injury, Ischemic preconditioning, Ischemic postconditioning, Remote ischemic preconditioning, Cardiac surgery

Disclosure: Authors have nothing to disclose with regard to commercial support.

Received 28 August 2013; revised 3 October 2013; accepted 3 November 2013.

Available online 13 November 2013

* Corresponding author. Tel.: +216 22 622 495.

E-mail address: rdh.bousselmi@gmail.com (R. Bousselmi).

P.O. Box 2925 Riyadh - 11461KSA Tel: +966 1 2520088 ext 40151 Fax: +966 1 2520718 Email: sha@sha.org.sa URL: www.sha.org.sa

1016-7315 © 2013 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

Peer review under responsibility of King Saud University. URL: www.ksu.edu.sa http://dx.doi.org/10.1016/j.jsha.2013.11.001

Contents

Introduction....................................................................................................................................................................................................94

Physiological aspects of ischemic conditioning..............................................................................................................................................94

Ischemic preconditioning (IPC)..............................................................................................................................................................94

Remote ischemic preconditioning (RIPC)..............................................................................................................................................95

Ischemic postconditioning - remote ischemic postconditioning............................................................................................................95

Clinical applications of myocardial ischemic conditioning............................................................................................................................96

Ischemic preconditioning (IPC) in cardiac surgery................................................................................................................................96

Remote ischemic preconditioning (RIPC) in cardiac surgery................................................................................................................96

Ischemic postconditioning in cardiac surgery........................................................................................................................................96

Other clinical applications of myocardial ischemic conditioning..........................................................................................................97

From ischemic conditioning to pharmacological conditioning......................................................................................................................97

Conclusion......................................................................................................................................................................................................97

Conflict of interest statement........................................................................................................................................................................97

References....................................................................................................................................................................................................97

Introduction

Postoperative myocardial dysfunction is still common in patients undergoing cardiac surgery [1,2]. It is one of the leading causes of postoperative morbidity and mortality. Ischemia-reperfusion injury is the most decisive factor in myocardial impairment in such patients. Developing new strategies to reduce ischemia-reperfusion injury is currently one of the main goals of research in cardioprotection. In this context, myo-cardial ischemic conditioning has recently been proposed as an interesting adjuvant to classical cardioprotection during cardiac surgery. Myocar-dial ischemic conditioning is a powerful endogenous cardioprotective phenomenon. It was first described in animals in 1986 [3]. During the last thirty years, myocardial ischemic conditioning has been the subject of much research concerning both its underlying mechanisms and its clinical applications. Several clinical trials in cardiac surgery and interventional cardiology have therefore sought to demonstrate its effectiveness in clinical settings.

The aim of this article is to review the different types of myocardial ischemic conditioning, its underlying mechanisms, and its clinical applications in cardiac surgery.

Physiological aspects of ischemic conditioning

Ischemic preconditioning (IPC)

In 1986, Murry et al. [3]. discovered that by applying 40 min of occlusion of the circumflex coronary artery in dogs, the myocardial infarct size resulting from this sustained ischemia was reduced by 75% if the dogs were previously exposed to brief episodes of ischemia-reperfusion. Ischemia-reperfusion

Abbreviations

IPC ischemic preconditioning RIPC remote ischemic preconditioning mPTP mitochondrial permeability transition pore mKATP mitochondrial ATP-dependent potassium channels

consisted of four five-minute cycles of intermittent occlusion of this same coronary artery. This ability of the myocardium to tolerate sustained ischemia after short episodes of ischemia-reperfusion was named ischemic preconditioning (IPC). This powerful cardioprotective phenomenon was found thereafter in all species including humans [4]. During IPC, protection occurs in two phases. An early phase of protection, known as classical ische-mic preconditioning, begins immediately after the preconditioning stimulus and lasts for 2-4 h. A delayed phase of protection begins after 12-24 h, lasts 2-3 days, and is known as the second window of protection [5]. The classical ischemic preconditioning likely involves preformed factors. It has a powerful protective effect against myocardial necrosis but does not protect against stunning [6]. The second window of protection is likely related to the synthesis of neoformed factors. It protects against myocardial stunning but is less effective against necrosis [6].

Ischemic preconditioning involves several factors that are usually divided into three groups: triggers, mediators, and effectors. The signaling pathways are complex and not yet fully understood. Brief episodes of ischemia result in the release of initiating factors such as adenosine, bradykinin, and endorphins [7].

During the early phase, these initiators bind to their specific receptors coupled to G proteins resulting in message transduction. Two signaling

pathways have been identified. The RISK pathway (Reperfusion-Induced Salvage Kinase) [8], involves the Phosphatidylinositol 3-Kinase (PI3-Ki-nase) [9,10], the protein kinase Akt [11], and the extracellular signal-regulated kinase xh (ERK %) [12]. These kinases activate glycogen synthetase kinase 3 b (GSK-3P), which leads to inhibiting the opening of the mitochondrial permeability transition pore (mPTP) [13]. The survivor activating factor enhancement (SAFE) pathway which involves the TNFa and the signal transducer and activator of transcription-3 (STAT-3) [14], also leads to inhibition of the mPTP opening. The mPTP is the main effector of preconditioning. Its opening causes the shutdown of ATP production, mitochondrial swelling, and likely cell-membrane rupture [15]. Other kinases are activated such as the protein kinase C [16] and the protein kinase G [17], and are responsible for the activation of mitochondrial ATP-dependent potassium channels (mKATP) which are also likely effectors of ischemic preconditioning [18,19].

During the second window of protection, mechanisms are different from those of the early phase [20]. After the initial stages of receptor activation coupled to G proteins and various signaling pathways (protein kinase C, protein kinase G, mKATP), the activation of transcription factors occurs: specifically, the nuclear factor kb (NF-kb) [21]. This induces the expression of several proteins that provide myocardial protection such as NO syn-thase (iNOS) [22], cyclooxygenase 2 (COX-2) [23], and anti-apoptotic proteins [24].

Remote ischemic preconditioning (RIPC)

In 1993, Przyklenk et al. discovered a new form of myocardial ischemic conditioning in dogs. They demonstrated that prior application of four five-minute cycles of ischemia-reperfusion on the circumflex coronary artery is able to significantly reduce the infarct size caused by sustained occlusion of the left anterior descending coronary artery [25]. It was subsequently shown that this cardioprotective phenomenon is universal, and can be provided by applying ischemia-reperfu-sion episodes in organs remote from the heart such as the kidney [26], or the mesentery [27]. This new form of myocardial ischemic conditioning was called remote ischemic preconditioning (RIPC). Applying this phenomenon to humans was possible after discovering that the RIPC effect is reproducible after inflating-deflating a cuff placed around the limbs; in this case, a non-invasive method to trigger ischemia-reperfusion episodes in remote organs and muscles [28,29].

The mechanisms underlying cardioprotection induced by remote ischemic preconditioning are similar to those described for classical ischemic preconditioning [30]. But the pathway that links remote organs, on which the preconditioning stimulus is applied, to the heart remains unclear. Three theories were advanced. The first one involves humoral factors, the second one involves a neural pathway, and the third one a systemic response. The humoral theory is supported by a study that found that the blood taken from a previously preconditioned rabbit can reduce the myocardial infarct size when it is transferred to a non-preconditioned rabbit [31]. Another experimental study showed that remote ischemic preconditioning applied to pigs with a denervated transplanted heart can reduce myocardial infarct size [32]. The neural theory was advanced after finding that hexametho-nium, which is a ganglionic blocker, can cancel the cardioprotective effect of ischemia-reperfusion applied to the mesenteric artery [27]. Finally, the systemic response theory is supported by studies suggesting that RIPC promotes the transcription of the anti-inflammatory gene [33].

Ischemic postconditioning - remote ischemic postconditioning

In 2003, Zhao et al. found that applying brief episodes of ischemia-reperfusion immediately after a sustained occlusion of a coronary artery in dogs is as cardioprotective as ischemic preconditioning [34]. The authors showed that the interruption of reperfusion for three 90-s cycles immediately after a sustained occlusion of a coronary artery reduces myocardial infarct size by 50%. This phenomenon became known as ische-mic postconditioning and was later found to occur in all animal species [35-39]. Two years later, Kerendi et al. demonstrated that ischemic post-conditioning is reproducible by applying the post-conditioning stimulus on organs remote from the heart [40]. They were able to reduce the myocar-dial infarct size by nearly 50% in rats after a sustained occlusion of a coronary artery when 5 min of ischemia-reperfusion was applied to the renal artery at the time of reperfusion. This was called remote ischemic postconditioning, and its repro-ducibility - by simple inflation-deflation of a cuff placed around the limb - has been demonstrated [41]. This paved the way for its non-invasive application in humans. The underlying mechanisms of ischemic postconditioning are very similar to those described for ischemic preconditioning. After a sustained ischemia, sudden reperfusion causes myocardial injuries by multiple mecha-

nisms: generation of reactive oxygen species, endothelium dysfunction, neutrophil accumulation, and loss of calcium homeostasis. Ischemic postconditioning contributes to reducing these injuries. It involves initiators (adenosine, bradyki-nin, opioids) and their receptors coupled to G proteins. Signaling pathways are complex and involve at least the reperfusion-induced salvage kinase pathway, protein kinase C and the JAK-STAT pathway (Janus kinase-signal transducer and activator of transcription). Effectors are mainly represented by the mPTP (mitochondrial permeability transition pore), the mKATP (mitochondrial ATP-dependent potassium channel) and ROS (reactive oxygen species) [42].

Clinical applications of myocardial ischemic conditioning

Ischemic preconditioning (IPC) in cardiac surgery

Yellon et al. were the first to find a cardioprotec-tive effect of IPC in humans [4]. In a randomized controlled trial, they demonstrated that the application of two three-minute episodes of clamping the ascending aorta, followed each time by 2 min of declamping improves ATP levels in the myocardium after on-pump coronary artery bypass grafting. Many clinical trials were subsequently performed in coronary artery bypass grafting and valvular surgery. The preconditioning stimulus was almost the same, consisting of brief episodes of clamping-declamping the ascending aorta after starting cardiopulmonary bypass and before any other cardioprotection. The primary endpoint was variable across studies, ranging between myocar-dial ATP levels [4,43], blood markers of myocardial necrosis (CK-MB and troponin) [44-47], ventricular arrhythmias [48] and the left ventricular contractile function [49,50]. In 2008, a meta-analysis compiled 22 randomized controlled trials including 933 patients over 10 years. The conclusion was that ische-mic preconditioning applied to cardiac surgery significantly reduces postoperative ventricular arrhythmias, the inotropic support, and the intensive care unit stay when it is associated with intraoperative myocardial protection by cardioplegia [51]. But these studies were heterogeneous in relation to their endpoints, and most of them were made to demonstrate the phenomenon of ischemic preconditioning in humans and not to evaluate its effects on prognosis. The high rate of neurologic complications resulting from a risk increase in embolic accidents during the manipulation of the ascending aorta [52], and the emergence of RIPC,

which is much less invasive than IPC, led to the surrender of this technique.

Remote ischemic preconditioning (RIPC) in cardiac surgery

The discovery that RIPC is reproducible after application of ischemia-reperfusion by simple inflation-deflation of a cuff placed around the limbs was a turning point in the clinical application of this cardioprotective phenomenon [29]. The first clinical trial in humans was negative. In 2000, Gunaydin et al. found no difference in the CK-MB levels between two groups of patients undergoing CABG of which one was preconditioned with two cycles of ischemia-reperfusion in the upper limb [53]. However, the size of groups was very small (four patients in each group), and ischemia-reperfusion cycles were very short (only two episodes of three-minute ischemia followed each time by 2 min of reperfusion). Thereafter, it took 6 years for clinical trials to reappear with Cheung et al. [54]. The authors randomized 37 children scheduled for surgical repair of congenital heart defects. Seventeen children were included in the RIPC group and received four five-minute cycles of ischemia-reperfusion achieved by inflation-deflation of a cuff placed on the lower limb. Twenty children were included in the control group. The postoperative levels of troponin I and the postoperative inotropic requirement were significantly higher in the control group. It was the first study to demonstrate the cardioprotective effect of RIPC in humans. RIPC has subsequently been the subject of several clinical trials in cardiac surgery. In 2011, a meta-analysis compiled nine randomized controlled trials including 482 patients [55]. The conclusions were that RIPC reduces postoperative myocardial injury, but is not associated with either a reduction in early postoperative mortality or with a reduction in the incidence of postoperative myocardial infarction. However, large multicentre studies are needed to determine the benefit of RIPC in clinical settings.

Ischemic postconditioning in cardiac surgery

The possibility of administering the conditioning stimulus after the onset of index ischemia has aroused a lot of interest, especially in inter-ventional cardiology where the sudden installation of acute coronary syndromes leaves no time to prior preconditioning. Ischemic postcondition-ing has therefore been more developed in inter-ventional cardiology. In cardiac surgery, only three clinical trials from the same team evaluated

the interest of ischemic postconditioning on myocardial protection against ischemia-reperfusion injury [56-58]. The first clinical trial was performed on children scheduled for surgical repair of Tetralogy of Fallot [56]. The postconditioning stimulus consisted of two 30-s cycles of clamping the ascending aorta, followed each time by 30 s of declamping it just before the cessation of cardiopulmonary bypass. The results were positive. In fact, the levels of troponin I and CK-MB and the postoperative inotropic requirement were significantly lower in the group that had postcondi-tioning stimulus compared to the control group. This was confirmed by a clinical trial performed on adults undergoing valve replacement [57], and also in another clinical trial on children undergoing congenital heart disease repair [58]. But clamping-declamping the ascending aorta was associated with a high risk of embolic accidents especially in adults with atherosclerotic lesions of the aortic wall. This partly explains the paucity of clinical trials in cardiac surgery.

Other clinical applications of myocardial ischemic conditioning

In some clinical trials, remote ischemic preconditioning was applied in interventional cardiology. It was done in patients scheduled for elective percutaneous coronary intervention. Their results were interesting [59,60]. Ischemic postcondition-ing, however, seems more suitable to interven-tional cardiology since it can be done without predicting the occurrence of ischemia. Postconditioning stimulus consists of short cycles of inflation-deflation of a balloon in the occluded coronary artery before removal of occlusion. In 2010, a meta-analysis compiled six randomized controlled trials that evaluated the effect of ische-mic postconditioning on 244 patients with ST-ele-vation acute coronary syndrome treated with percutaneous coronary intervention [61]. The results demonstrated an effective cardioprotective effect of ischemic postconditioning. The rates of CK-MB were significantly lower and the left ventricular ejection fraction was significantly better in patients who underwent postconditioning compared to control patients. The effect on prognosis requires larger trials.

From ischemic conditioning to pharmacological conditioning

Advances in the understanding of the physiological mechanisms underlying the cardioprotec-tive action of different forms of myocardial

ischemic conditioning have led to numerous studies that seek to develop pharmacological agents able to reproduce this action. Several animal studies have demonstrated the ability to mimic the effects of ischemic preconditioning by agonists of A1 and A3 adenosine receptors [62,63]. Other studies were able to reproduce the cardioprotective action by d opioids [64,65]. In humans, it has been demonstrated that nicorandil, acting on mitochondrial KATP channel, is able to provide a cardioprotective effect in patients with coronary artery disease [66,67]. Also, several clinical trials in cardiac surgery showed that volatile anesthetics have a preconditioning effect on the myocardium [68-75]. A recent meta-analysis compiled 22 clinical trials in cardiac surgery including 1922 patients randomized into two groups, one receiving total intravenous anesthesia (TIVA) and the other volatile anesthetics (sevoflurane or desflurane) [76]. The use of volatile anesthetics resulted in a significant reduction in the incidence of postoperative myo-cardial infarction and a significant reduction in in-hospital mortality. Similarly, the troponin levels, the postoperative inotropic requirements, the intensive care unit stay, and the duration of mechanical ventilation were significantly lower with volatile anesthetics.

Despite the existence of clinical trials that demonstrate the cardioprotective effect of several molecules, the adoption of pharmacological conditioning in clinical practice requires larger studies to better understand its underlying mechanisms and validate its daily use.

Conclusion

Since its discovery in 1986, myocardial ischemic conditioning has attracted much interest. Despite the large number of studies related to this phenomenon, its underlying mechanisms remain incompletely understood. Also, clinical trials in humans are mostly proof-of-concept studies. Large multicenter studies evaluating prognostic data are necessary to validate the use of this car-dioprotective method in clinical settings.

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