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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The human body is able to recruit various protective mechanisms in order to maintain homeostasis in response to a variety of aggressions&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">When the coronary circulation is interrupted&#44; the size of the resulting infarct is proportional to the duration of ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Paradoxically&#44; even early revascularization leads to tissue damage&#44; a phenomenon known as ischemia-reperfusion injury&#44;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> which is estimated to be responsible for up to 30&#37; of infarct size&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> This has prompted a search for cytoprotective mechanisms that make the myocardium less vulnerable to such damage&#44; not only in acute settings &#40;as in revascularization in the context of acute coronary syndrome &#91;ACS&#93;&#41; but also following surgical procedures that entail temporary interruption of the coronary circulation&#44; particularly cardiac surgery with aortic clamping and heart transplantation&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In 1986&#44; Murry et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> observed that in animals subjected to short episodes of coronary ischemia before prolonged occlusion of the same artery&#44; infarct size was 25&#37; of that seen in the control group&#46; The authors proposed that short periods of non-lethal myocardial ischemia&#44; followed by reperfusion&#44; could protect the myocardium from subsequent prolonged ischemia&#44; a phenomenon known as myocardial ischemic preconditioning&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Subsequent research into the mechanisms of ischemic preconditioning revealed two other phenomena&#58; ischemic perconditioning<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and ischemic postconditioning&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> in which the cardioprotective stimulus is applied during and after prolonged coronary occlusion&#44; respectively&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Przyklenk et al&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> extended the concept of ischemic preconditioning by showing that repeated brief occlusions of a coronary artery protect not only that artery&#39;s territory&#44; as suggested by Murry&#44; but also other parts of the myocardium&#46; They called this intracardiac protection &#8216;regional ischemic preconditioning&#8217;&#46; This opened up the possibility that such cytoprotective mechanisms could be induced by ischemia in remote organs&#44; which was confirmed by reports of myocardial remote ischemic preconditioning &#40;RIPC&#41;&#44; initially induced by renal and mesenteric ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Although this discovery was experimentally interesting&#44; the kidney and&#44; to a lesser extent&#44; the intestine are vulnerable to damage from even brief periods of ischemia<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> and are thus not suitable for clinical application in this context&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">A major advance in myocardial RIPC came with the use of skeletal muscle as the ischemic stimulus&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> A tourniquet or inflatable cuff applied to a limb can induce RIPC without the need for invasive procedures or interruption of the blood supply to vital organs&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Myocardial RIPC is thus a mechanism through which transient ischemia of distant vascular territories increases the resistance of cardiomyocytes to prolonged coronary ischemia and ischemia-reperfusion injury&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">This article sets out to describe the pathophysiological mechanisms responsible for myocardial RIPC and to provide examples of possible clinical applications&#44; examining the main clinical trials assessing its effectiveness&#46; Inducing ischemia in a limb has greater clinical potential&#44; since skeletal muscle is easily accessible and has high resistance to ischemia&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and so this review of the literature will focus on induced by ischemia of skeletal muscle&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methodology</span><p id="par0045" class="elsevierStylePara elsevierViewall">We searched PubMed for articles published between 1986 &#40;when ischemic preconditioning was first described<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#41; and December 2012 containing the terms &#8220;remote ischemic preconditioning&#8221; or &#8220;ischemic preconditioning at a distance&#8221;&#46; Additional searches were performed in the Scopus and Cochrane databases&#46; All articles considered relevant to the subject were included&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathophysiological mechanisms involved in remote ischemic preconditioning</span><p id="par0050" class="elsevierStylePara elsevierViewall">Like local preconditioning&#44;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> the myocardial protection induced by RIPC occurs in two phases&#46; The early phase or &#8220;first window&#8221; lasts around four hours&#44; while the delayed phase &#40;the &#8220;second window&#8221; of protection&#41; begins &#62;24 hours after the induction of ischemia and is sustained for at least 48 hours&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In the early phase there are immediate alterations in the myocardium and coronary circulation&#44; with increased diastolic flow<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and coronary vasodilation&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> which reduce infarct size and the risk of reperfusion arrhythmias<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;17</span></a> &#40;particularly extrasystoles and ventricular fibrillation and tachycardia<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#41; and help preserve left ventricular function&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The second window of cardioprotection depends on protein synthesis&#44; which is consistent with the changes in gene expression seen in cardiomyocytes<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and leukocytes<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> in the period following myocardial ischemia&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The pathophysiological mechanisms involved in RIPC are still not fully understood&#44; but can be divided into three components&#58; &#40;i&#41; the production or release of the effector&#40;s&#41; in the ischemic tissue&#59; &#40;ii&#41; the mechanisms of communication between the distant territory and the myocardium&#59; and &#40;iii&#41; the induction of a cardioprotective response &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">The early phase of ischemic preconditioning</span><p id="par0070" class="elsevierStylePara elsevierViewall">Transient periods of ischemia-reperfusion trigger the production and&#47;or release of various substances by the ischemic tissue &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; but there is as yet no agreement as to their relative importance&#46; Depending on the site of the stimulus &#40;renal&#44; mesenteric or skeletal muscle&#41;&#44; different protective substances and mechanisms may be involved&#44; which prevents extrapolation of data from one experimental protocol to others&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> For example&#44; hexamethonium&#44; a cholinergic antagonist&#44; abolishes protection induced by mesenteric ischemia but not that induced by renal<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> or skeletal muscle ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The cardioprotection afforded by these mediators occurs through neural and&#47;or humoral mechanisms&#44; and there is evidence for both&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The neural hypothesis postulates that substances produced in the remote ischemic territory act locally via afferent neural pathways&#44; activating various efferent pathways that induce cardioprotection&#46; In favor of this hypothesis is the fact that a limb used for preconditioning must be enervated&#44; since cutting the femoral nerve abolishes or weakens the protection conferred by transient ischemia of a lower limb&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> Nicotinic receptor antagonists and reserpine&#44; which inhibits uptake of neurotransmitters by synaptic vesicles&#44; also weaken RIPC&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;14</span></a> Neurons of the dorsal motor nucleus of the vagus nerve appear to play a crucial role in cardioprotective RIPC&#44; and activating these neurons even in the absence of muscle ischemia is sufficient to reproduce the effect of remote preconditioning&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The humoral hypothesis&#44; on the other hand&#44; posits that the ischemic stimulus leads to the production of substances that enter the circulation and reach the myocardium&#44; where they have a protective effect&#46; Support for this view comes from the fact that the remote organ must be reperfused before the onset of coronary ischemia for the protective effect to be produced&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;28</span></a> This suggests that substances must be &#8216;washed out&#8217; and reach the heart via the circulation before the ischemic event occurs&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Studies of heart transplantation in animal models also support the humoral hypothesis&#46; In pigs undergoing RIPC before transplantation&#44; infarct area following myocardial infarction &#40;MI&#41; was reduced in the donor heart&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Since in this case the heart has no extrinsic innervation&#44; it is likely that a humoral factor in the circulation is acting on the transplanted heart&#46; Furthermore&#44; in isolated rabbit hearts perfused with plasma from donor animals subjected to RIPC&#44; a cardioprotective effect is seen with significantly reduced infarct size&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> which supports the idea that the plasma contains a cytoprotective substance&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Whatever mechanism is responsible&#44; a kind of memory is involved&#44; since the explanted heart retains the effect of RIPC to which it was subjected in vivo&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p></span></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Subcellular mechanisms</span><p id="par0100" class="elsevierStylePara elsevierViewall">Although the substances that induce cardioprotection have not been identified&#44; more is understood of the effects on cardiomyocytes at the subcellular level&#46; The initial step appears to involve the activation of myocardial protein kinase C &#40;PKC&#41;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Mitochondrial ATP-sensitive potassium &#40;K<span class="elsevierStyleInf">ATP</span>&#41; channels open during transient ischemia of skeletal muscle&#46; These are downstream of PKC in RIPC<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> and depend on it for their activation&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> It is thus likely that protein G agonists trigger a cardioprotective signaling cascade that activates PKC and opens mitochondrial K<span class="elsevierStyleInf">APT</span> channels&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In pathophysiological terms&#44; as ATP is depleted during ischemia&#44; ion channels lose function&#44; leading to intracellular Ca<span class="elsevierStyleSup">2&#43;</span> accumulation&#44; which further reduces ATP&#46; Mitochondrial Ca<span class="elsevierStyleSup">2&#43;</span> overload mainly occurs when ischemia is followed by reperfusion&#59; although reintroduction of oxygen enables ATP production to resume&#44; ischemia-reperfusion injury alters the mitochondrial electron transport chain&#44; resulting in the production of reactive oxygen species &#40;ROS&#41;&#46; Increases in ROS and mitochondrial Ca<span class="elsevierStyleSup">2&#43;</span> and falls in the mitochondrial membrane potential following ischemia-reperfusion result in opening of the mitochondrial permeability transition pore &#40;MPTP&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> a polyprotein mitochondrial transmembrane channel that is absent or closed in physiological conditions&#46; Opening of the MPTP in response to ischemia leads to the release of mitochondrial proteins&#44; including cytochrome C&#44; into the cytoplasm&#44; which activate the caspase cascade&#46; This&#44; in conjunction with low ATP levels and changes in ion homeostasis&#44; results in rupture of the plasma membrane and cell death&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">These mechanisms are counteracted by the opening of mitochondrial K<span class="elsevierStyleInf">APT</span> channels via PKC activation&#44; which depolarizes the mitochondrial membrane&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> thereby reducing Ca<span class="elsevierStyleSup">2&#43;</span> uptake and concentrations during reperfusion and maintaining mitochondrial integrity&#44; and thus has a cardioprotective effect&#46; It also reduces the activity of voltage-dependent ion channels and preserves ATP by reducing hydrolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a> ROS production increases during preconditioning&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> which as well as possibly reducing their concentrations during subsequent ischemia&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> increases the production of antioxidant enzymes that preserve mitochondrial function and reduce apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">The importance of PKC is not limited to its effect on mitochondrial K<span class="elsevierStyleInf">APT</span> channels&#59; it also acts on the MPTP&#46; During preconditioning&#44; PKC forms a complex with the MPTP&#44; preventing the latter from opening and thus inhibiting cardiomyocyte apoptosis during ischemia-reperfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Although the above subcellular sequence is the dominant theory&#44; it is only one of several that seek to explain the mechanisms of preconditioning&#46; The large number of substances involved in RIPC make it difficult to produce a single theory&#44; since they may have synergistic effects&#44; or there may be redundancy in the subcellular pathways involved in cardioprotection&#44; which makes it difficult to determine their relative importance&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">The delayed phase of ischemic preconditioning</span><p id="par0130" class="elsevierStylePara elsevierViewall">The second window of protection is apparently triggered by changes in the expression of genes involved in the myocardium&#39;s response to oxidative and inflammatory injury &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Inflammatory reactions are heightened during reperfusion&#44; with polymorphonuclear leukocytes accumulating in the myocardium and contributing to cardiac damage by release of ROS&#44; proteases and leukotrienes&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> In humans&#44; RIPC leads to anti-inflammatory changes in circulating leukocytes&#44; suppressing genes encoding proteins involved in chemotaxis&#44; adhesion and migration&#44; exocytosis&#44; apoptosis and innate immunity within 15 minutes of the RIPC stimulus and more so after 24 hours &#40;second window RIPC&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Besides its role in modulating mitochondrial function&#44; PKC is also involved in regulating gene expression&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> and may be responsible for the changes that occur in the delayed phase of preconditioning&#46; Unlike in cardiomyocytes 15 minutes after RIPC&#44; after 24 hours genes involved in cytoprotection &#40;<span class="elsevierStyleItalic">Hsp73</span>&#41; and protection against oxidative stress &#40;including <span class="elsevierStyleItalic">Hadhsc</span>&#44; <span class="elsevierStyleItalic">Prdx4</span>&#44; and <span class="elsevierStyleItalic">Fabp4</span>&#41; are upregulated&#44; whereas many proinflammatory genes &#40;e&#46;g&#46; <span class="elsevierStyleItalic">Egr-1</span> and <span class="elsevierStyleItalic">Dusp 1</span> and <span class="elsevierStyleItalic">6</span>&#41; are suppressed&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Li et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> showed that nuclear factor kappa-B &#40;NF-&#954;B&#41;&#44; a redox-sensitive transcription factor that regulates various inflammatory genes including those coding for inducible nitric oxide &#40;NO&#41; synthase &#40;iNOS&#41; and inducible cyclooxygenase&#44; is involved in RIPC&#46; Although NF-&#954;B during ischemia-reperfusion is detrimental through production of leukocyte adhesion molecules&#44; cytokines and chemokines and increased infarct size&#44; when activated following RIPC it has an adaptive effect on the heart within 24 hours&#46; This is because there is a parallel increase in its own inhibitor&#44; I&#954;B&#44; which reduces NF-&#954;B activation following reperfusion&#44; reducing infarct size and protecting left ventricular function&#46; Following preconditioning a gradual increase in iNOS mRNA is also seen&#44; reaching a peak at 24 hours&#46; Knockout mice for the NF-&#954;B and iNOS genes do not exhibit adaptation to ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">It thus appears that preconditioning reduces the inflammatory response during reperfusion by inducing NF-&#954;B&#44; which increases production of its own inhibitor&#44; leading to iNOS transcription&#44; which in turn increases NO production&#46; The latter&#39;s role in the delayed phase is not known&#44; but it probably has antiapoptotic and anti-inflammatory effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Clinical applications of remote ischemic preconditioning</span><p id="par0155" class="elsevierStylePara elsevierViewall">Cardioprotection through RIPC is a highly promising therapy and there are currently over a hundred clinical trials registered on the clinicaltrials&#46;gov website&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">If experimental results can be reproduced in clinical practice&#44; RIPC could be induced by&#44; for example&#44; cycles of inflation and deflation of a cuff on a limb&#46; This would be a simple&#44; rapid&#44; extremely inexpensive&#44; noninvasive and nonpharmacological method that could be applied before percutaneous or surgical interventions in which coronary blood flow is to be interrupted&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Remote ischemic preconditioning as adjuvant therapy in cardiac surgery or percutaneous coronary intervention</span><p id="par0165" class="elsevierStylePara elsevierViewall">The first clinical trial using RIPC was in children undergoing surgical correction of congenital heart defects&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> in which four cycles of 5-min lower limb ischemia using a blood-pressure cuff followed by 5-min reperfusion reduced postoperative troponin I levels&#44; inotropic requirement and airway resistance&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">A subsequent randomized trial using a similar RIPC protocol in 57 individuals undergoing elective coronary artery bypass grafting &#40;CABG&#41; produced similar results&#44; with a reduction in troponin T levels in the first 72 hours after surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Since then&#44; there have been several clinical trials of RIPC in CABG surgery &#40;with and without extracorporeal circulation&#41;&#44; surgical repair of abdominal aortic aneurysms&#44; valve replacement surgery and percutaneous coronary intervention &#40;PCI&#41;&#46; The main trials are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; The primary endpoint in most cases was release of troponins after surgery&#44; which is associated with worse short- and long-term prognosis<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a> and is related to infarct area&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">52&#44;53</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0180" class="elsevierStylePara elsevierViewall">However&#44; the results of trials on RIPC are not consistent&#44; which may be due to differences in study protocols &#40;such as the site for the preconditioning stimulus and number and duration of ischemia-reperfusion cycles&#41;&#44; age&#44; comorbidities&#44; medication and anesthetic protocol during surgery&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Differences in preconditioning protocols and in study populations make it difficult to compare trials&#44; which hampers attempts to establish a protocol that will afford maximum cardioprotection&#46; In one study&#44; on patients with stable angina and single-vessel disease undergoing elective PCI&#44; RIPC induced by ischemia-reperfusion of both upper limbs actually led to increases in CK-MB and troponin I levels&#44; particularly in those not taking statins&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> This may have been due to an increased inflammatory state following ischemia of skeletal muscle&#44; which&#44; in the absence of statins&#44; worsened myocardial ischemia-reperfusion injury&#44; rather than protecting against it&#46; Furthermore&#44; application of ischemia to both upper limbs simultaneously may be an excessive stimulus that does not confer benefit&#59; most other trials have used ischemia of only one limb&#46; It is also likely that the strength of the stimulus would differ between upper and lower limbs&#44; due to their differing muscle mass&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The patient&#39;s age may impose limitations to RIPC&#46; Ageing leads to changes in cardiomyocytes&#44; including reduced contractile function and weakened cardioprotective mechanisms&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> and the heart loses its sensitivity to preconditioning&#44;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;57</span></a> which may limit its application in patients aged over 65&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Comorbidities can also influence the effectiveness of preconditioning&#46; For example&#44; in a patient with stable angina&#44; transient ischemia triggered by exertion have a natural preconditioning effect on the heart&#59; several studies have shown that patients with angina in the 48 hours before MI have a better prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a> Thus&#44; in theory&#44; patients with stable angina may not gain additional benefit from RIPC&#59; nor would those with peripheral arterial disease&#44; which simulates remote preconditioning&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Type 2 diabetes induces a state of chronic resistance to ischemia-reperfusion injury due to increases in levels of glycosylated proteins which&#44; among other effects&#44; alter mitochondrial function&#46; One consequence is suppression of the MPTP&#44; which&#44; as mentioned above&#44; is also an effect of RIPC&#46; However&#44; the additional cardioprotection induced by preconditioning is weakened in diabetic patients&#44; since the same subcellular mechanisms are involved&#44; and so RIPC does not appear to provide additional protection in these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">The effect of RIPC is also influenced by patients&#8217; medication&#44; such as sulfonylureas&#44; oral hypoglycemic agents that inhibit mitochondrial K<span class="elsevierStyleInf">ATP</span> channels&#46; These drugs are associated with higher mortality following MI&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> which may be due to the fact that they prevent RIPC&#44; which involves opening these channels&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Chronic exposure to these agents thus makes the myocardium insensitive to RIPC&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> New sulfonylureas such as gliclazide&#44; which are more specific to pancreatic beta cells&#44; do not appear to increase cardiovascular mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Another factor influencing RIPC is the anesthetic protocol used during surgery&#46; Kottenberg et al&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> compared different anesthetic regimens in patients undergoing RIPC during CABG with extracorporeal circulation&#46; They found no differences when the anesthetic used was propofol&#44; but lower troponin I levels were seen with isoflurane&#44; which is consistent with data suggesting that volatile anesthetic agents have intrinsic preconditioning effects&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> It is thus possible that certain anesthetics provide cardioprotection when combined with skeletal muscle preconditioning through an additive or synergistic effect&#44; but that other agents&#44; such as propofol&#44; do not&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">A recent meta-analysis on RIPC in cardiac surgery confirmed a reduction in troponin levels after surgery&#44; although there was considerable heterogeneity in the results&#44; possibly due to the degree of blinding&#59; studies with double blinding showed less marked reductions in cardiac necrosis markers postoperatively&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> Another meta-analysis&#44; including nine studies with 704 patients&#44; showed a statistically significant reduction in troponin release&#44; even after excluding confounding factors such as the use of volatile anesthetic agents&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Various aspects of RIPC need to be clarified in future studies&#44; particularly the preconditioning protocol &#40;duration&#44; number of cycles and stimulus site&#41;&#46; In addition&#44; so far only the benefits of the early phase of RIPC have been tested&#44; not the delayed phase&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">On the basis of the different clinical trials analyzed&#44; we propose a model for the application of RIPC in individuals about to undergo cardiac surgery &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0230" class="elsevierStylePara elsevierViewall">A randomized double-blinded multicenter clinical trial&#44; RIPHeart&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> designed to determine the benefits of RIPC is currently under way&#46; It aims to recruit over 2000 patients undergoing cardiac surgery and its primary endpoint is a composite of all-cause mortality&#44; non-fatal myocardial infarction&#44; any new stroke&#44; and&#47;or acute renal failure&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Pharmacological ischemic preconditioning</span><p id="par0235" class="elsevierStylePara elsevierViewall">Knowledge of the pathophysiological mechanisms involved in RIPC may lead to the development of drugs that reproduce its effects&#44; and hence new therapeutic strategies for preserving cardiac tissue subjected to ischemia&#46; One drug currently under investigation is diazoxide&#44; an activator of mitochondrial K<span class="elsevierStyleInf">APT</span> channels&#44; administration of which before an episode of ischemia has been shown in experimental models to delay cardiomyocyte death and thus reduce infarct size&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> Only one clinical trial of use of this drug for preconditioning has been published to date&#59; this showed that administration of diazoxide in cardioplegic solution during cardiac surgery is safe and improves mitochondrial function&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">However&#44; some drugs already on the market owe some of their effects to activation of subcellular ischemic preconditioning mechanisms&#46; One example is nicorandil&#44; used in clinical practice as an antianginal agent&#44; which has a dual action&#58; as an NO donor it induces vasodilation of the epicardial coronary arteries&#44; as well as opening mitochondrial K<span class="elsevierStyleInf">APT</span> channels&#44; dilating coronary resistance vessels&#46; In the IONA trial&#44; treating stable angina with nicorandil reduced the combined endpoint of cardiovascular mortality&#44; MI and hospitalization&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> which does not appear to be explained by its vasodilator effect alone&#46; It is likely that by opening mitochondrial K<span class="elsevierStyleInf">APT</span> channels&#44; nicorandil has a preconditioning effect on the myocardium&#44; reducing ischemia-reperfusion injury&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Ischemic preconditioning in organ transplantation</span><p id="par0245" class="elsevierStylePara elsevierViewall">An area in which RIPC may be particularly valuable is heart transplantation&#46; Before being transplanted&#44; the organ is subjected to varying periods of ischemia&#44; and ischemia-perfusion injury also occurs in the recipient&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> Preclinical trials show that if RIPC is induced in the recipient before transplantation&#44; the cardioprotective effect is transferred to the donor heart&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">Although known pathophysiological mechanisms suggest that RIPC should be feasible before transplantation&#44; no clinical trials have examined the possibility&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Clinical applications of other forms of remote ischemic conditioning</span><p id="par0255" class="elsevierStylePara elsevierViewall">Two new forms of ischemic conditioning have been described in the last decade&#58; perconditioning and postconditioning&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Remote ischemic postconditioning consists of cycles of limb ischemia-perfusion after myocardial reperfusion&#44; such as immediately following primary PCI in patients with ST-elevation ACS&#46; Pre-clinical trials have shown a cytoprotective effect similar to that of RIPC&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">Remote ischemic perconditioning involves the administration of the stimulus during myocardial ischemia&#44; before reperfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> It is an attractive clinical option since ischemic events cannot be predicted and perconditioning can be applied in acute situations such as MI&#46; A clinical trial published in 2010 in the <span class="elsevierStyleItalic">Lancet</span><a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> assessed 330 patients with ST-elevation ACS about to undergo PCI randomized during transport to hospital to standard therapy or remote conditioning by arm ischemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff&#46; Thirty days after PCI&#44; the volume of viable myocardium compared to the area at risk was greater in the group who had undergone remote ischemic perconditioning&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Finally&#44; protection against ischemia-reperfusion injury by preconditioning is not limited to the myocardium&#46; Recent years have seen an exponential growth in research into this phenomenon&#44; and there are reports of liver preconditioning by skeletal muscle ischemia<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> and lung preconditioning by intestinal ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conclusion</span><p id="par0275" class="elsevierStylePara elsevierViewall">Myocardial RIPC is part of a complex web of interactions between and within organs through which the organism generates cytoprotective stimuli that increase its resistance to ischemia&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">It is hoped that in the near future the application of this technique in various clinical contexts&#44; including prior to cardiac surgery&#44; following reperfusion therapy&#44; and for heart transplantation&#44; will help reduce ischemia-reperfusion injury and infarct area&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical disclosures</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Protection of human and animal subjects</span><p id="par0285" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Confidentiality of data</span><p id="par0290" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Right to privacy and informed consent</span><p id="par0295" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Funding</span><p id="par0300" class="elsevierStylePara elsevierViewall">This work was funded by the <span class="elsevierStyleGrantSponsor" id="gs0005">Portuguese Foundation for Science and Technology</span> &#40;Projects PEst-C&#47;SAU&#47;UI0051&#47;2011 and EXCL&#47;BIM-MEC&#47;0055&#47;2012&#41; through the Cardiovascular Research and Development Unit&#44; and by European Commission Grant FP7-Health-2010 &#40;MEDIA-261409&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0305" class="elsevierStylePara elsevierViewall">This work was funded by the <span class="elsevierStyleGrantSponsor" id="gs0015">Portuguese Foundation for Science and Technology</span> &#40;Projects PEst-C&#47;SAU&#47;UI0051&#47;2011 and EXCL&#47;BIM-MEC&#47;0055&#47;2012&#41; through the Cardiovascular Research and Development Unit&#44; and by European Commission Grant FP7-Health-2010 &#40;MEDIA-261409&#41;&#46;</p></span></span>"
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              "titulo" => "Pathophysiological mechanisms involved in remote ischemic preconditioning"
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                  "titulo" => "The early phase of ischemic preconditioning"
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          "titulo" => "Subcellular mechanisms"
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              "titulo" => "The delayed phase of ischemic preconditioning"
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                  "titulo" => "Remote ischemic preconditioning as adjuvant therapy in cardiac surgery or percutaneous coronary intervention"
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                  "titulo" => "Pharmacological ischemic preconditioning"
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                  "titulo" => "Ischemic preconditioning in organ transplantation"
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              "titulo" => "Clinical applications of other forms of remote ischemic conditioning"
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    "fechaRecibido" => "2013-02-20"
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            0 => "Myocardial ischemic preconditioning"
            1 => "Myocardial ischemia"
            2 => "Myocardial reperfusion injury"
            3 => "Myocardial infarction"
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            0 => "Pr&#233;-condicionamento isqu&#233;mico do mioc&#225;rdio"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Short periods of myocardial ischemia followed by reperfusion induce a cardioprotective mechanism when the myocardium is subsequently subjected to a prolonged period of ischemia&#44; a phenomenon known as ischemic preconditioning&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">As well as its application in the myocardium&#44; ischemic preconditioning can also be induced by brief interruptions of blood flow to other organs&#44; particularly skeletal muscle&#46; Transient ischemia induced noninvasively by inflating a cuff on a limb&#44; followed by reperfusion&#44; helps reduce the damage caused to the myocardium by interruption of the coronary circulation&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Remote ischemic preconditioning involves activation of humoral and&#47;or neural pathways that open mitochondrial ATP-sensitive potassium channels in the myocardium and close mitochondrial permeability transition pores&#44; making cardiomyocytes less vulnerable to ischemia-induced cell death&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This cardioprotective mechanism is now being translated into clinical practice&#44; with positive results in several clinical trials in coronary artery bypass surgery&#44; surgical repair of abdominal aortic aneurysms&#44; valve replacement surgery and percutaneous coronary intervention&#46; However&#44; certain factors weaken the subcellular mechanisms of preconditioning &#8211; age&#44; comorbidities&#44; medication&#44; anesthetic protocol &#8211; and appear to explain the heterogeneity of results in some studies&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Detailed understanding of the pathways involved in cardioprotection induced by ischemic preconditioning is expected to lead to the development of new drugs to reduce the consequences of prolonged ischemia&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Curtos per&#237;odos de isquemia do mioc&#225;rdio seguida de reperfus&#227;o induzem um mecanismo de cardioprote&#231;&#227;o quando este &#233; depois submetido a um per&#237;odo de isquemia prolongada&#44; um fen&#243;meno designado pr&#233;-condicionamento isqu&#233;mico&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Al&#233;m da sua aplica&#231;&#227;o local no mioc&#225;rdio&#44; o pr&#233;-condicionamento isqu&#233;mico tamb&#233;m pode ser induzido por breves interrup&#231;&#245;es da circula&#231;&#227;o sangu&#237;nea em outros &#243;rg&#227;os&#44; nomeadamente no m&#250;sculo esquel&#233;tico&#46; De uma forma n&#227;o invasiva&#44; a indu&#231;&#227;o de isquemia transit&#243;ria atrav&#233;s da insufla&#231;&#227;o de um bra&#231;al num dos membros&#44; seguida de reperfus&#227;o&#44; leva &#224; diminui&#231;&#227;o dos danos causados no mioc&#225;rdio pela interrup&#231;&#227;o da circula&#231;&#227;o coron&#225;ria&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">O pr&#233;-condicionamento isqu&#233;mico remoto envolve a ativa&#231;&#227;o de vias humorais e&#47;ou neuronais que&#44; atuando no mioc&#225;rdio&#44; provocam a abertura de canais de pot&#225;ssio mitocondriais sens&#237;veis ao ATP e o encerramento do poro de transi&#231;&#227;o de permeabilidade mitocondrial&#44; tornando os cardiomi&#243;citos menos sens&#237;veis &#224; morte celular causada pela isquemia&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Este mecanismo cardioprotetor pode j&#225; ser transposto para a pr&#225;tica cl&#237;nica&#44; havendo resultados positivos em v&#225;rios estudos cl&#237;nicos realizados na cirurgia coron&#225;ria&#44; cirurgia de repara&#231;&#227;o de aneurismas da aorta abdominal&#44; cirurgia de substitui&#231;&#227;o valvular e interven&#231;&#227;o coron&#225;ria percut&#226;nea&#46; Contudo&#44; existem alguns fatores que atenuando os mecanismos subcelulares do pr&#233;-condicionamento &#8211; idade&#44; comorbilidades&#44; medica&#231;&#227;o&#44; protocolo anest&#233;sico &#8211; parecem explicar a heterogeneidade de resultados nalguns estudos&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Finalmente&#44; &#233; de esperar que a compreens&#227;o detalhada das vias envolvidas na cardioprote&#231;&#227;o induzida pelo pr&#233;-condicionamento isqu&#233;mico possam permitir o desenvolvimento de novos f&#225;rmacos que permitam reduzir as consequ&#234;ncias da isquemia prolongada&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Costa JF&#44; Fontes-Carvalho R&#44; Leite-Moreira AF&#46; Pr&#233;-condicionamento isqu&#233;mico remoto do mioc&#225;rdio&#58; dos mecanismos fisiopatol&#243;gicos &#224; aplica&#231;&#227;o na pr&#225;tica cl&#237;nica&#46; Rev Port Cardiol&#46; 2013&#46; <a class="elsevierStyleInterRef" id="intr0005" href="doi:10.1016/j.repc.2013.02.012">http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;1016&#47;j&#46;repc&#46;2013&#46;02&#46;012</a></p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Diagram of the different phases and respective pathophysiological mechanisms involved in myocardial remote ischemic preconditioning&#46; Figure produced using Servier Medical Art&#46; MPTP&#58; mitochondrial permeability transition pore&#59; PKC&#58; protein kinase C&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Proposed protocol for application of remote ischemic preconditioning&#46; Figure produced using Servier Medical Art&#46; I&#58; ischemia&#59; R&#58; reperfusion&#59; SBP&#58; systolic blood pressure&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">CGRP&#58; calcitonin gene-related peptide&#59; NO&#58; nitric oxide&#59; ROS&#58; reactive oxygen species&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Renal ischemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Mesenteric ischemia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Skeletal muscle ischemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adenosine<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">76&#8211;79</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bradykinin<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">80&#44;81</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Opioids<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;87&#8211;89</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cannabinoids<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NO<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;31</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CGRP<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">82&#8211;84</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Noradrenaline<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Opioids<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">85&#44;86</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">ROS<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;40&#44;88</span></a>&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Substances implicated in the development of myocardial remote ischemic preconditioning&#46;</p>"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">AUC&#58; area under the curve&#59; BNP&#58; brain natriuretic peptide&#59; CIA&#59; common iliac artery&#59; CK-MB&#58; creatine kinase MB&#59; cTnI&#58; cardiac troponin I&#59; ECC&#58; extracorporeal circulation&#59; EPCs&#58; endothelial progenitor cells&#59; hs-CPR&#58; high-sensitivity C-reactive protein&#59; I&#58; ischemia &#40;duration in min&#41;&#59; ICU&#58; intensive care unit&#59; MI&#58; myocardial infarction&#59; PCI&#58; percutaneous coronary intervention&#59; R&#58; reperfusion &#40;duration in min&#41;&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Trial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Surgical procedure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Ischemic stimulus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Anesthetic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cheung et al&#46; &#40;2006&#41;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Repair of congenital cardiac defects in children under ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leg&#44; 4 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with sevoflurane&#44; maintained with fentanyl and isoflurane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower cTnI&#44; lower inotropic requirement at 3 and 6 hours postoperatively and lower airway resistance at 6 hours&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ali et al&#46; &#40;2007&#41;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">90</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Open abdominal aortic aneurysm repair&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 cycles &#40;10I&#43;10R&#41;&#44; 1st cycle in the right CIA and 2nd in the left CIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with propofol and remifentanil&#44; maintained with desflurane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower cTnI and serum creatinine&#59; lower incidence of MI and shorter ICU stay&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hausenloy et al&#46; &#40;2007&#41;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery under ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Right arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with midazolam&#44; propofol and etomidate or fentanyl&#44; maintained with propofol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower troponin T at 6&#44; 12&#44; 24 and 48 hours after surgery&#59; 43&#37; reduction of the AUC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hoole et al&#46; &#40;2009&#41;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">91</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective PCI in adults with coronary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not applicable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower cTnI and improvement in ST-segment alterations&#59; lower incidence of postoperative chest discomfort and cardiac&#47;cerebral events at 6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hong et al&#46; &#40;2010&#41;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery without ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arm&#44; 4 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with midazolam e sufentanil&#44; maintained with sevoflurane and remifentanyl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reduction &#40;not statistically significant&#41; in cTnI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Li et al&#46; &#40;2010&#41;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">92</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Valve replacement for rheumatic valve disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Right leg&#44; 3 cycles &#40;4I&#43;4R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with midazolam&#44; maintained with fentanyl and isoflurane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower cTnI and lower incidence of ventricular fibrillation after surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thielmann et al&#46; &#40;2010&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">93</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery under ECC in adults with 3-vessel coronary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Left arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with sufentanil and etomidate&#44; maintained with isoflurane or propofol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower cTnI &#40;peak&#44; total and AUC&#41; after surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rahman et al&#46; &#40;2010&#41;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">94</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective or urgent coronary surgery under ECC in adults with multivessel coronary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with etomidate and fentanyl&#44; maintained with propofol and alfentanyl&#44; supplemented with enflurane or sevoflurane during ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No differences between the groups&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kottenberg et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery under ECC in adults with 3-vessel coronary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Left arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with sufentanyl and etomidate&#44; maintained with isoflorane or propofol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower cTnI &#40;peak&#44; total and AUC&#41; with isoflurane but not with propofol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Karuppasamy et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">95</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery under ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Left arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with remifentanyl and propofol&#44; maintained with isoflurane before ECC and propofol during and after ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No differences in cTnI&#44; BNP&#44; CK-MB&#44; or central venous concentrations of cytokines or growth factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Venugopal et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">96</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery under ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Right arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with midazolam and etomidate or propofol&#44; maintained with propofol or volatile agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower absolute troponin T at 72 hours after surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ghaemian et al&#46; &#40;2012&#41;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">97</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective PCI in adults with coronary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Leg&#44; 2 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not applicable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reduced intra-procedural chest pain and ST-segment deviation&#59; lower troponin T at 24 hours&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prasad et al&#46; &#40;2012&#41;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">98</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective PCI in adults with coronary disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arm&#44; 3 cycles &#40;3I&#43;3R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not applicable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No differences in cTnT&#44; hs-CPR or EPCs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lomivorotov et al&#46; &#40;2012&#41;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">99</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery under ECC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with fentanyl and propofol&#44; maintained with isoflurane and fentanyl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reduced mean arterial pressure and vascular resistance&#59; increased stroke volume&#59; no differences in cardiac necrosis markers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Young et al&#46; &#40;2012&#41;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">100</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective coronary surgery under ECC in high-risk patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arm&#44; 3 cycles &#40;5I&#43;5R&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Induced with midazolam and fentanyl&#44; maintained with propofol and isoflurane&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No differences in cTnT&#44; markers of acute renal injury or postoperative support requirements&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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