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Ischemic preconditioning

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ischemic preconditioning
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Ischemic preconditioning
Remote ischaemic preconditioning
Remote ischemic preconditioning underlying mechanisms
Humoral pathway
Neural pathway
Systemic pathway
Summary

Ischemic preconditioning

Ischemic preconditioning refers to the ability of short periods of ischemia to make the heart muscle (myocardium) more resistant to a subsequent ischemic insult 1. The term ischemic preconditioning was introduced for the first time in 1986 by Murry et al 2, who found in a canine model that 4 consecutive periods of coronary occlusion of 5 minutes were able to reduce the myocardial infarct size caused by a subsequent period of occlusion of 40 minutes by as much as 75%. In other word, if the blood supply to an organ or a tissue is halted for a short time (usually less than five minutes) and then restored two or more times so that blood flow is resumed the downstream cells of the tissue or the organ are robustly protected from a final ischemic insult when the blood supply is cut off entirely and permanently. In an experimental setting if the left anterior descending coronary artery of the animal is ligated the downstream cardiac cellular mass is infarcted and will be injured and then die. If, on the other hand the tissue is subjected to ischemic preconditioning the downstream cellular mass will sustain only minimal to modest damage. Ischemic preconditioning protects the tissue by initiating a cascade of biochemical events that allows for an up-regulation of the energetics of the tissue. Ischemic postconditioning, where a non-lethal ischemia-reperfusion is performed to the heart by interrupting the percutaneous coronary intervention (PCI)-induced reperfusion, delivers a similar outcome to ischemic preconditioning making it a better strategy to treat patients with acute myocardial infarction 3. Both ischemic preconditioning and ischemic postconditioning require interventional approaches, which limit application in clinical settings.

Ischemic preconditioning has been well studied and found to reduce ischemia-reperfusion associated damage to other organs including the lung 4, kidney 5, liver 6, skeletal muscle 7, intestine 8, brain 9 and improve post-operative recovery from cardiac surgeries 10. The potential clinical application of ischemic preconditioning is restricted to elective cardiac surgeries, where the timing of ischemic insult is well controlled. However, patients with acute myocardial infarction presented with blocked coronary arteries, making it impossible to precondition the heart 3.

Although ischemic preconditioning initially referred to the ability of short periods of ischemia to limit infarct size 2, some investigators extended this definition to include a beneficial effect on ischemia- and reperfusion-induced arrhythmias 11 and on myocardial stunning 12. It is questionable, however, whether the reduction in the incidence of arrhythmias by ischemic preconditioning is a result of a direct antiarrhythmic effect or a mere consequence of the delay of ischemic cell death 13. Regarding the beneficial effects of ischemic preconditioning on post-ischemic contractile dysfunction, Cohen et al 12 showed that preconditioning in rabbits can lead to enhanced recovery of contractile function of the myocardial region at risk. Also, in this case, the beneficial effects of preconditioning on acute recovery of contractile function might be a consequence of the delay of ischemic cell death; indeed, parameters of necrosis extent, ie, infarct size and enzyme leakage, correlate with the enhancement of functional recovery 12.

The chain of events which confers resistance to ischemia is only partially understood. Recently, Downey and coworkers 14 have developed the hypothesis that stimulation of a variety of G protein-coupled receptors results in the activation of protein kinase C. This, in turn, leads to the translocation of protein kinase C from the cytoplasm to the sarcolemma, where it phosphorylates a substrate protein (possibly the ATP-sensitive K+[KATP] channel), which confers resistance to ischemia.

It is now well established that the protective effects of ischemic preconditioning are transient and last for <2 hours 14. However, a so-called second window of protection or delayed ischemic preconditioning has been shown in different species, occurring 24 hours after the preconditioning stimulus and lasting for about 48 hours 15. This time course is consistent with the concept that the second window of protection is mediated by the activation of genes encoding for cytoprotective proteins, such as heat shock proteins or antioxidant enzymes 15. Similar to the early phase of ischemic preconditioning, aside from a delayed anti-infarct effect, a delayed anti-arrhythmic effect following preconditioning has been reported 16. Furthermore, Bolli’s group 17 has recently described a preconditioning against myocardial stunning, independent of ischemic necrosis because the ischemic challenge used was insufficient to induce infarction.

Remote ischaemic preconditioning

In contrast to directly preconditioning the target organ, Przyklenk and Whittaker 18 in 1993 made the intriguing discovery that preconditioning the heart does not limit its efficacy to the perfused area of the coronary artery, but was extended to remote myocardial tissue. Similarly, Liauw et al 19. showed that skeletal muscle can be protected against ischemia-reperfusion injury by preconditioning the contralateral skeletal muscle. This discovery facilitated the extension of ischemic preconditioning techniques to protect other organs beyond the heart. This approach of remotely protecting a target organ through ischemic preconditioning is known as remote ischemic preconditioning 3. A major advance in myocardial remote ischemic preconditioning came with the use of skeletal muscle as the origin of remote ischemic preconditioning stimulus and brief ischemia-reperfusion injury produced with a tourniquet applied to one of the hind limbs of pig 20. This lead to a blood pressure measuring cuff around the arm to achieve the remote ischemic preconditioning stimulus making it possible to accommodate most of the clinical settings of acute ischemia-reperfusion injury. In a non-invasive approach, remote ischemic preconditioning has the capacity to protect the organ or tissue whether applied prior to ischemia-reperfusion (remote ischemic preconditioning), after ischemia but prior to reperfusion 21 or during reperfusion (remote ischemic postconditioning) 22. Pryds and colleagues 23 demonstrated the long term effect of remote ischemic preconditioning on heart failure patients and reported that though remote ischemic preconditioning does not improve left ventricular ejection fraction (LVEF) but reduces blood pressure and NT-proBNP in patients with compensated chronic ischemic heart failure and may reduce the risk of thrombosis by stimulating fibrinolysis 24. Table ​1 summarizes the key clinical trials on the effect of remote ischemic preconditioning prior to coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI). Previous review papers by Hausenloy and Yellon in 2008 25 and Costa et al. in 2013 26 discussed the cardioprotective pathways induced by remote ischemic preconditioning.

The effect of remote ischemic preconditioning is not confined to one organ but impacts multiple organs. Similarly, different organs can be used as the remote ischemic preconditioning site. Table ​2 summarizes the key findings on inter-organ preconditioning studies. Briefly, applying remote ischemic preconditioning stimulus to different organs has been shown to protect various target organs from ischemia-reperfusion injury. These protective effects include reduced infarct size, decrease arrhythmia, improved lung and liver function (Table 1).

Figure 1. Remote ischemic preconditioning

Remote ischemic preconditioning

Footnote: Signaling mechanisms underpinning remote ischemic preconditioning-induced cardioprotection. Intermittent limb ischemia and reperfusion confers cardioprotection through neuronal, systemic and humoral mechanism.

[Source 3 ]

Table 1. Key clinical trials of remote ischemic preconditioning

First authorNature of trialNumber of participants analyzed (Remote ischemic preconditioning / Control)Remote ischemic preconditioning protocolCardioprotection
Coronary artery bypass graft
Hong et al. 27Randomized control trial35/354 cycles of 5 min I/R on lower limbYes
Lucchinetti et al. 28Randomized control trial27/284 cycles of 5 min I/R of legNo
Hausenloy et al. 29Randomized control trial27:303 cycles of 5 min I/R of right upper limbYes
Candilio et al. 30Randomized control trial89/892 cycles of simultaneous 5 min I/R on upper arm and upper thighYes
Venugopal et al. 31Randomized control trial23/223 cycles of 5 min I/R of right forearmYes
Hausenloy et al. 32Multicenter randomized control trial801/8114 cycles of 5 min I/R of upper armNo
Krogstad et al. 33Randomized control trial45/473 cycles of 5 min I/R of upper armNo
Hong et al. 34Randomized control trial644/6364 cycles of 5 min I/R of upper limb as RIPC and 4 cycles of 5 min I/R of upper limb as RIPostNo
Meybohm et al. 35Multicenter randomized control trial692/6934 cycles of 5 min I/R of upper armNo
Percutaneous coronary intervention (PCI)
Pryds et al.36Post-hoc analysis of randomized control trial166:1674 cycles of 5 min I/R of upper armYes
Sloth et al. 37Post-hoc analysis of randomized control trial71:684 cycles of 5 min I/R of upper armYes
Pryds et al. 38Post-hoc analysis of randomized control trial71:684 cycles of 5 min I/R of upper armYes
Botker et al. 39Randomized control trial126: 1254 cycles of 5 min I/R of upper armYes
Prasad et al. 40Randomized control trial47:483 cycles of 3 min I/R of upper armNo
Verouhis et al. 41Randomized control trial60:551 cycle of 5 min I/R of left thigh before PCI and 4 cycles of 5 min I/R of left thigh post reperfusionNeutral

Table 2. Key studies on inter-organ ischemic preconditioning

Study (remote ischemic preconditioning site)SpeciesTarget organResult
Renal
McClanahan et al. 42RabbitHeart↓Infarct size
Gho et al. 43RatHeart↓Infarct size
Verdouw et al. 44PigHeart↓Infarct size
Pell et al. 45RabbitHeart↓Infarct size
Takaoka et al. 46RabbitHeart↓Infarct size and improved myocardial energy metabolism
Diwan et al. 47RatHeartConferred cardioprotection by NFkB activation followed by opening of K(ATP) channels
Lang et al. 48RatHeart↓Infarct size
Singh et al. 49RatHeart↓Infarct size and proposed the involvement of angiotensin AT(1) receptors in renal preconditioning
Kant et al. 50RatHeartReduced myocardial injury through inhibition of hypoxia inducible factor-prolyl 4-hydroxylases
Small Intestine
Gho et al. 43RatHeart↓Infarct size
Verdouw et al. 51PigHeart↓Infarct size
Patel et al. 52RatHeart↓Infarct size
Heidbreder et al. 53RatHeart↓Infarct size and activated p38 MAPK, ERK ½ and JNK ½ selectively in the intestine but not in the heart
Liver
Ates et al. 54RatKidneyImproved creatine clearance and improvement in hepatic histopathologic parameters
Brzozowski et al. 55RatGutReduced gastric mucosa lesion
Brain
Tapuria et al. 56RatLiverImproved hepatic microcirculation and reduced hepatic ischemia-reperfusion injury.
Hind Limb
Oxman et al. 57RatHeartDecreased arrhythmias
Birnbaum et al. 58RabbitHeartReduced myocardial infarct size
Liauw et al. 19RatThigh muscleReduced muscle necrosis
Kharbanda et al. 20PigHeartReduced MI size
Gunaydin et al. 59HumanHeartEnhanced anaerobic glycolysis to protect heart
Xia et al. 60SheepLungProtected lung from repeated coronary artery occlusion (CAO) and reperfusion mimicking multi-vessel off-pump coronary artery bypass (OPCAB) revascularization and decreased pulmonary vascular resistance
Addison et al. 61PigSkeletal muscleProtected global skeletal muscle against infarction
Kuntscher et al. 62RatAdipocutaneous flapsDecreased flap necrosis
Kuntscher et al. 63RatCremasteric muscle flapsDecreased flap necrosis
Kuntscher et al. 64RatEpigastric adipocutaneous flapsDecreased flap necrosis
Moses et al. 65PigLatissimus dorsi (LD) muscle flapsDecreased flap infarction
Wang et al. 66RatCremaster flapDecreased flap necrosis
Harkin et al. 67PigLungReduced acute remote lung damage against systemic inflammatory response from limb ischemia-reperfusion injury
Li et al. 68MiceHeartProtected LV function and reduced infarction size
Konstantinov et al. 69PigHeartReduced ischemia-reperfusion injury in the brain-dead donor heart following orthotopic heart transplantation.
Chen et al. 70RatHeartReduced infarction size
Chen et al. 71RatHeartReduced infarction size through free radical pathway
Luokogeorgakis et al. 72HumanForearmPreserved endothelial function in the forearm
Waldow et al. 73PigLungProtected lung function and reduced the plasma interleukin-1beta level
Kristiansen et al. 74RatHeartReduced myocardial infarction size through a mechanism involving mitochondrial K(ATP) channels and improved LV function during reperfusion
Zhang et al. 75RatHeartReduced infarction size and ischemia-reperfusion-induced plasma lactate dehydrogenase level
Dave et al. 76RatHeartIncreased neuroprotection from asphyxial cardiac arrest
Kanoria et al. 77RabbitLiverReduced liver ischemia-reperfusion injury and improved liver function
Lai et al. 78RatLiverRemote ischemic preconditioning stimulated heme oxygenase-1 expression in liver tissue and associated with liver protection from ischemia-reperfusion injury
Cheung et al. 79HumanHeartPostoperative improvement in lung function and reduction in plasma troponin-I level
Mudaliar et al. 80RatHeart↓ Infarct size through JAK-STAT pathway upregulation

Abbreviations: CAO = coronary artery occlusion, OCABG = off-pump coronary artery bypass, LV = left ventricular

Remote ischemic preconditioning underlying mechanisms

The underlying mechanisms through which brief episodes of ischemia-reperfusion in an organ or tissue transduces a protective signal to a distant organ and renders it resistant to sustained ischemia-reperfusion injury is not fully understood. Some studies suggest there is similarity in the mechanistic process of direct preconditioning and remote ischemic preconditioning. Based on current knowledge, this can be divided into three major parts: (i) the humoral (ii) the neuronal pathway, and (iii) the systemic pathway (Figure 1). However, whether these pathways independently exert protective effect on the target organ or that crosstalk is involved is not well understood.

Humoral pathway

Multiple studies support the theory of blood borne mediators as a signal transduction mechanism and the requirement for a period of reperfusion to washout humoral factors generated by remote ischemic preconditioning 81. These protective substances circulate via the bloodstream and upon reaching the target organ bind to respective receptors and activate intracellular signaling pathways. Humoral pathway involvement in remote ischemic preconditioning was demonstrated by Konstantinov and colleagues 69. Denervated donor heart recipient pigs that underwent remote limb preconditioning showed significant reduction of myocardial infarction size, which provides evidence for the concept of humoral-mediated cardioprotection by remote ischemic preconditioning. Dickson and colleagues showed for the first time that remote ischemic preconditioning could elicit cross species protection 82. These studies explored transfusing blood from preconditioned rabbit hearts and kidneys to a non-preconditioned isolated rabbit heart and showed recovery of the heart from myocardial ischemia-reperfusion injury by reducing the infarct size. These authors also showed that coronary effluent from a preconditioned ex-vivo rabbit heart could potentiate the similar infarction limiting effect and improve left ventricle function 83. Shimizu et al. 84 reported similar cross species protection after using plasma dialysate from remote preconditioned rabbit and human blood to protect ex vivo rabbit heart from ischemia-reperfusion injury. These authors also confirmed that the transferrable factors are hydrophobic in nature and <15 kDa in size. Serejo et al. 85 provided evidence that the humoral factors released from the ischemic preconditioned heart were thermolabile, hydrophobic, >3.5 kDa and conferred cardioprotection via the activation of protein kinase C (PKC). Breivik et al. 86 also reported the presence of <30 kDa hydrophobic factors in the coronary ischemic preconditioning effluent, which can confer cardioprotection via the PI3K/AKT pathway. Interestingly, proteomic analysis of renal remote ischemic preconditioning conducted by Lang and colleagues 48 could not detect any cytoprotective factors larger than 8 kDa. The humoral factors responsible for the remote ischemic preconditioning effect on the target organs still remain unclear and investigation into the factors responsible continues. Identifying the potential humoral mediators of remote ischemic preconditioning could assist in confirming that the threshold for a remote ischemic preconditioning response has been achieved 87.

Neural pathway

A neural pathway is one that connects one part of the nervous system with another by way of axons. Evidence suggests that intact neural pathway is essential for the remote organ or tissue to convey protective signal to the target organ during the process of remote ischemic preconditioning. Denervation of the neural pathway in the remote organ abolishes remote ischemic preconditioning protection 88. In contrast Konstantinov and colleagues 69 show that denervation of the recipient donor heart does not eliminate the remote ischemic preconditioning-induced myocardial infarction size reduction effect. However, the exact role of the afferent and efferent component of the neural pathway is unclear. The involvement of the neural pathway in remote ischemic preconditioning-mediated cardioprotection was explored by Gho et al. 43 who demonstrated that transient occlusion of the anterior mesenteric artery can mediate cardioprotection, which can be abrogated by ganglionic blockers. This finding was supported with the proposition that remote ischemic preconditioning propels the production of autacoids such as adenosine, bradykinin, CGRP in the remote preconditioned organ, which stimulates afferent nerves and relays the neural signal to the myocardium via the efferent nerve fibers. Furthermore, Ding et al. 89 explored the role of renal nerve-mediated cardioprotection. They confirmed that renal nerve resection abolished renal preconditioning-induced cardioprotection. Liem et al. 90 provided confirmatory evidence implicating adenosine in a neural pathway of cardioprotection. They reported that adenosine released by the mesenteric artery during preconditioning reduced myocardial infarct size from 68% to 48%, a protective effect that was reversed by the ganglionic blocker hexamethonium. In addition, intramesenteric artery infusion of adenosine mimicked similar cardioprotection as mesenteric artery-induced preconditioning, which could be abolished by hexamethonium. From these findings, the investigators concluded that locally released adenosine during mesenteric artery preconditioning stimulates afferent nerves in the mesenteric bed which helps activate myocardial adenosine receptors. Dong et al. 91 demonstrated that dissecting the femoral nerve prior remote ischemic preconditioning does not protect the myocardium against ischemia-reperfusion injury and suggested that an intact neural pathway was required for the sensory afferent neural signaling from the preconditioned limb. A study carried out by Jones and colleagues 92 showed that instead of ischemic preconditioning, abdominal slit in mice activates the cardiac sensory and sympathetic nerves. This procedure elicits cardioprotection via bradykinin (a known hormone and neurotransmitter) release in the heart by the sympathetic nerves and bradykinin dependent activation of PKC-ε.

Systemic pathway

Remote ischemic conditioning has been shown to provoke a systemic response by modulating inflammatory cells either post-transcriptionally or through transcriptional regulation 93. In contrast to the humoral pathway, the systemic pathway involves the inflammatory cells and provokes an inflammatory response to confer the remote ischemic preconditioning signal. Kharbanda et al. 94 previously showed that remote ischemic preconditioning reduced expression of neutrophil CD11b and platelet-neutrophil complexes in humans. In 2004, Konstantinov et al. 95 used microarray analysis of blood samples from healthy human volunteers subjected to forearm preconditioning to reveal that preconditioning suppressed genes regulating cytokine production, leukocyte chemotaxis, adhesion and migration, exocytosis, innate immunity, signaling pathways, and apoptosis, while up-regulating anti-inflammatory genes such as HSP-70 and calpastatin. Later, the same group provided evidence to show that remote ischemic preconditioning upregulated genes associated with growth and metabolism, DNA repair and redox regulation. ischemic preconditioning attenuated P-selectin expression in liver and prevented neutrophil infiltration in lung, stomach, pancreas, small intestine and colon via inhibition of systemic TNF-α production 96. In another study, Albrecht et al. 97 reported similar findings in human, showing that within the early phase of remote ischemic preconditioning, serum cytokines were upregulated. It may be that, cytokines function as both pro- and anti-inflammatory mediators in ischemic conditioning to prepare the target organ to mitigate the tissue damage. This group’s findings showed concurrent increase of IL-8, IL-1β, TNF-α and concurrent cardioprotection due to increased neutrophil infiltration after right atrial bypass surgery 97.

Summary

Remote ischemic preconditioning has provided an innovative non-invasive therapeutic strategy to prevent acute ischemia-reperfusion injury in susceptible organs and tissues with some variability. Non-invasive procedures such as using a blood pressure measuring cuff around the arm to achieve protection against ischemia-reperfusion injury has facilitated its translation from bench to bedside. Though there are several clinical trials that did not show beneficial effects of remote ischemic preconditioning, further mechanistic studies will help us understand the underlying cause of the failure of these studies. Optimal modality, site and duration of remote ischemic preconditioning remains unclear. remote ischemic preconditioning may nonetheless benefit children and adults undergoing certain elective surgeries where there is potential to improve clinical outcomes. Future insights into the control of circulating mediators of remote ischemic preconditioning, including transcriptional regulation and secretion into the bloodstream will assist the development of pharmacologic approaches stimulating protective signaling pathways in target organs.

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