Anesthesia & Analgesia:
Technology, Computing, and Simulation: Special Article
Reduction of Myocardial Infarct Size with Ischemic “Conditioning”: Physiologic and Technical Considerations
Przyklenk, Karin PhD
From the Cardiovascular Research Institute and Departments of Physiology and Emergency Medicine, Wayne State University School of Medicine, Detroit, Michigan.
Accepted for publication March 20, 2013.
Published ahead of print August 19, 2013
The author declares no conflicts of interest.
Reprints will not be available from the author.
Address correspondence to Karin Przyklenk, PhD, Cardiovascular Research Institute, Wayne State University School of Medicine, Elliman Bldg., Room 1107, 421 E Canfield, Detroit, MI 48201. Address e-mail to email@example.com.
A wealth of evidence has revealed that the heart can be “conditioned” and rendered less vulnerable to ischemia–reperfusion injury via the upregulation of endogenous protective signaling pathways. Three distinct conditioning strategies have been identified: (1) preconditioning, the phenomenon where brief episodes of myocardial ischemia (too brief to cause cardiomyocyte death) limit necrosis caused by a subsequent sustained ischemic insult; (2) postconditioning, the concept that relief of myocardial ischemia in a staged or stuttered manner attenuates lethal ischemia–reperfusion injury; and (3) remote conditioning, or upregulation of a cardioprotective phenotype initiated by ischemia in a remote organ or tissue and “transported” to the heart. Progress has been made in defining the technical requirements and limitations of each of the 3 ischemic conditioning models (including the timing and severity of the protective stimulus), as well as elucidating the molecular mechanisms (in particular, the receptor-mediated signaling pathways) responsible for conditioning-induced myocardial protection. Moreover, phase III clinical trials are in progress, seeking to capitalize on the protection that can be achieved by postconditioning and remote conditioning, and applying these strategies in patients undergoing cardiac surgery or angioplasty for the treatment of acute myocardial infarction. There is, however, a potentially important caveat to the clinical translation of myocardial conditioning: emerging data suggest that the efficacy of ischemic conditioning is compromised in aging, diabetic, and hypertensive cohorts, the specific populations in which myocardial protection is most relevant. Successful clinical application of myocardial conditioning will therefore require an understanding of the potential confounding consequences of these comorbidities on the “conditioned” phenotype.
THE QUEST FOR MYOCARDIAL PROTECTION
Cardiovascular disease remains the leading global cause of death and disability, and, in the United States, accounts for approximately 32% of all deaths.1–3 Included in this spectrum of cardiovascular disease is acute myocardial infarction (MI): the estimated incidence of new and recurrent MI among Americans is 935,000 per annum, 15% of which will be fatal.1,3
Acute MI occurs when blood flow to a region of the heart is obstructed, thereby rendering myocardium distal to the occlusion ischemic. The current and only established and approved treatment to limit infarct size and improve outcome post-MI is prompt restoration of coronary flow to the ischemic territory. Restoration of coronary perfusion can, however, paradoxically exacerbate cell injury and death (rather than initiate salvage) in populations of ischemic myocytes, a phenomenon termed “lethal reperfusion injury.”3–7 Thus, not surprisingly, substantial effort has been devoted to identifying the mechanisms responsible for ischemia–reperfusion-induced necrosis and apoptosis and developing new strategies to minimize ischemia–reperfusion injury and maximize the benefits of timely reflow.3,5,6,8
ISCHEMIC “CONDITIONING”: THE CONCEPT OF ENDOGENOUS MYOCARDIAL PROTECTION
The first studies seeking to modulate the outcome of MI were initiated more than 4 decades ago,9 and focused largely on administration of drugs in an effort to reduce infarct size. A diverse array of drugs have been evaluated (including oxygen radical scavengers and antioxidants, calcium channel antagonists, sodium–hydrogen exchange inhibitors, adenosine, and many others) with the goal of reducing ischemia-induced cardiomyocyte death or the continuum of ischemia–reperfusion injury.8 However, despite the promise shown in preclinical studies, the outcomes of subsequent clinical trials were largely disappointing and none of the pharmacologic strategies have been adopted into clinical practice.3,8,10,11
In 1986, Murry et al.12 made a seminal observation that revolutionized and reinvigorated the field of myocardial protection. Using the anesthetized canine model, the authors reported that repeated episodes of brief (5 minutes) myocardial ischemia, too brief in themselves to cause cardiomyocyte death, had a paradoxical, protective effect and rendered the myocardium less vulnerable to a subsequent sustained ischemic insult.12 This phenomenon was termed “preconditioning with ischemia,” and triggered the onset of the era of intense investigation into the broad concept of endogenous myocardial protection encompassing ischemic preconditioning (PC), postconditioning (PostC), and remote conditioning. Indeed, as of March 2013, the triad of PC, PostC, and remote conditioning has been the focus of >5000 publications indexed in PubMed. Moreover, interest in ischemic conditioning has extended beyond the heart and been applied to multiple organs and tissues including brain, kidney, liver, and skeletal muscle.13–19
Confirmation and Documentation
The first report of infarct size reduction with PC12 precipitated a logical sequence of subsequent studies seeking, first and foremost, to document and confirm this arguably surprising observation. In this regard, in a field often fraught with controversy, PC-induced myocardial protection has the distinction of being one of the few concepts that has been recapitulated by countless investigators in all models and species that have been evaluated, ranging from isolated cardiomyocytes to isolated buffer-perfused hearts to multiple in vivo preparations (including mouse, rat, rabbit, dog, and pig).11,20–22
The primary end point in this first report, and in early confirmatory studies, was infarct size: that is, the volume of necrotic tissue, typically expressed as a percentage of the volume of at-risk myocardium (i.e., the extent of the ischemic territory) in PC versus control cohorts. Accordingly, a second priority was to determine: does PC have other benefits beyond reduction of infarct size? Multiple end points have been evaluated, and PC has been reported, in some (but not all) studies and models, to have a spectrum of favorable effects including a reduction in the incidence of ischemia- and reperfusion-induced arrhythmias, improvement in postischemic recovery of myocardial contractile function, and preservation of coronary vasodilator reserve.5,20,22 In addition, there is evidence that brief PC ischemia significantly inhibits platelet activation/aggregation, and thus may amplify the infarct-sparing benefits of PC in instances of thrombotic coronary occlusion by favoring the preservation of coronary patency.23–27 However, with the exception of the antiplatelet effect of PC, these are secondary consequences of infarct size reduction rather than an independent beneficial effect of PC per se. The “gold standard” of PC is, without question, its infarct-sparing effect.20,21
The Biology of Preconditioning
The third priority has been to address the more complex question: how does PC work? This question encompasses both the characterization of the temporal and physiological requirements required to evoke PC-induced myocardial protection (the primary focus of this review), as well as the elucidation of the cellular mechanisms that play a role in rendering the heart less vulnerable to ischemia.
Temporal and Physiologic Characterization
PC is, by definition, a pretreatment. In a typical PC protocol, subjects are assigned to undergo 1 or more cycles of brief ischemia–reperfusion (the PC stimulus) or a time-matched period of uninterrupted perfusion. After the treatment phase, both groups are subjected to an identical period of sustained coronary artery occlusion, and the extent of myocardial necrosis is delineated by tetrazolium staining or other standard techniques (Fig. 1). The key components of the PC protocol, and the temporal and physiologic characteristics of each component that determine the efficacy of PC, are well-characterized and include:
1. The number and duration of the brief ischemic episodes. Typically 2 to 4 cycles of ischemia are applied, each with a duration in the order of 2 to 5 minutes and interspersed with a similar 2 to 5 minutes period of reperfusion.20–22 However, a single 1½- to 2½-minute period of coronary artery occlusion has been reported as sufficient to serve as a PC stimulus, while, perhaps not surprisingly, prolongation of the brief ischemic episode to 15 to 20 minutes failed to evoke protection and exacerbated infarct size.20–22,28,29 Complete coronary artery occlusion is not a prerequisite for PC-induced protection; short (15 minutes) periods of coronary stenosis, as well as transient pacing–induced ischemia have been shown to render the heart less vulnerable to infarction.20,30 However, the precise threshold of ischemia (or combination of severity and duration of ischemia) that must be achieved during the PC stimulus to trigger the protective effect has not been established.
2. The interval between the PC stimulus and the onset of sustained ischemia. The standard duration of intervening reperfusion is on the order of 5 to 15 minutes, and, if prolonged to approximately 2 hours (with the precise timing dependent on the model and species), the favorable effects of PC begin to wane.20–22 Interestingly, if a second PC stimulus is applied after 2 to 6 hours of reperfusion, the efficacy of PC is reestablished.20,22,31,32 Moreover, if the period of intervening reperfusion is extended to 24 to 72 hours, a so-called “second window of protection” emerges, the mechanisms of which differ from those of classic (or “first window”) PC.20,21,33–35
3. The duration of sustained occlusion. A critical feature of PC revealed by Murry et al.12 in their seminal paper is that brief antecedent ischemia delays, but does not prevent, myocyte death. Accordingly, in models of permanent coronary artery occlusion, or in models where the period of sustained occlusion is prolonged to >2 to 3 hours (precise timing dependent on the model and species), PC fails to limit infarct size.12,20–22
There has been an exhaustive effort to elucidate the cellular mechanisms by which brief antecedent ischemia renders the myocardium less vulnerable to infarction and, although gaps remain, a general paradigm has emerged..5–7,11,20,21,36–38 In brief, there is no question that PC is a receptor-mediated phenomenon. The PC stimulus initiates the release of 1 or more triggers from the ischemic-reperfused myocardium including, most notably, adenosine, bradykinin, and opioids. These triggers bind to their respective G-protein–coupled receptors on the cardiomyocyte membranes and activate multiple, complex (and possibly redundant) signaling pathways. Of note, this upregulation in signaling is biphasic: i.e., involves kinase activation: (1) at the onset of the sustained ischemic insult (including the ε-isoform of protein kinase C, nitric oxide–mediated activation of protein kinase G, and others); as well as (2) repopulation of receptors and kinase activation during the early seconds-minutes after relief of ischemia, including, most notably, phosphatidylinositol 3 [PI3] kinase/Akt and extracellular regulated kinase [ERK] (components of the so-called “RISK” [reperfusion injury salvage kinase] pathway). Finally, this constellation of receptor-mediated signals is proposed to converge on the mitochondria and confer myocardial protection by stabilizing the mitochondrial membranes, inhibiting the opening of large-diameter conductance channels (mitochondrial permeability transition pores) and thereby attenuating the swelling and rupture of mitochondria (Fig. 2).5–7,11,20,21,36–38
Although the discovery of ischemic PC was a milestone in the field of myocardial protection, the practical significance of PC is limited by the fact that it is a pretreatment. However, in 2003, Zhao et al.39 demonstrated, using the anesthetized canine model, that a simple mechanical strategy applied at the time of reperfusion evoked a significant reduction in infarct size that was comparable in magnitude with that achieved with PC. The crux of the strategy was relief of ischemia in a staccato or stuttered manner (rather than the standard approach of abrupt and complete restoration of blood flow) and was termed “postconditioning.”39
The Biology of Postconditioning: Comparisons with Preconditioning
Subsequent investigation of PostC followed a similar course to that of PC. Initial studies provided the requisite confirmation of the phenomenon in multiple models ranging from isolated buffer-perfused heart to all standard in vivo preparations (including rat, rabbit, and pig); infarct size was smaller in groups that received stuttered reflow when compared with controls that received full and abrupt reperfusion. Moreover, as with PC, the benefits of PostC reportedly encompass multiple end points, but the gold standard is reduction of infarct size.40,41
The typical PostC protocol uses 3 to 6 cycles of stuttered reflow applied at the time of reperfusion. Accordingly, the obvious and intrinsic difference between PostC and PC is the time at which the protective stimulus is applied (Fig. 3). A second distinction is the shortened timescale of the stimulus. For PostC, each brief cycle of reperfusion–reocclusion is in the order of approximately 10 to 60 seconds (rather than approximately 5 minutes), and the first episode of reocclusion must be applied rapidly (within seconds) after initial reperfusion;7,40,41 if there is a delay of only approximately 1 minute, PostC fails to limit infarct size.42 Of note, all of these temporal variables are empirical, the optimal PostC algorithm has not been established, and in all likelihood the optimal stimulus will be model-dependent. Moreover, the relative contribution and importance of the reperfusion component(s) versus the reocclusion phase(s) of the PostC cycles remain unknown.41
Finally, as with PC, the third component of a typical PostC protocol is the sustained ischemic insult. There is undoubtedly an upper limit in the duration of sustained ischemia, beyond which PostC will be ineffective in attenuating ischemia–reperfusion injury, and logic would suggest that the time frame for loss of protection is similar to that of PC (i.e., >2–3 hours, depending on the model and species). However, in contrast to PC, this time frame has not been meticulously investigated and characterized.
Not surprisingly, efforts to elucidate the mechanisms of PostC have been guided and influenced by insights gained from the investigation of PC. Both forms of myocardial protection reportedly follow the same general paradigm, i.e., stimulation of G-protein–coupled receptors (including adenosine, bradykinin, and opioid receptors), followed by activation of 1 or more signaling pathways.7,37,40,41 However, in the case of PostC, both receptor stimulation and postreceptor signaling obviously occur during and after the PostC stimulus and, thus, during the first minutes after relief of ischemia. With regard to postreceptor signaling, the greatest attention has focused on the roles of: (1) the RISK pathway (including the classic “survival” kinases, ERK, and PI3 kinase/Akt); (2) the so-called “SAFE” (survival activating factor enhancement) pathway (triggered by tumor necrosis factor-α and involving janus-activated kinase and signal transducer and activator of transcription 3[STAT3]); and (3) activation of a nitric oxide and protein kinase G-dependent pathway.7,37,40,43–47 The relative importance of the 3 pathways appear to be model-dependent,46,48–50 and, as with PC, all pathways appear to converge on the mitochondria with enhanced mitochondrial stability serving as the final requisite step in achieving myocardial protection (Fig. 2).7,40,41,46,47,51,52
Anesthesia and Myocardial Conditioning
It is important to emphasize that the overwhelming majority of in vivo experiments investigating the biology and mechanisms of PC and PostC have been conducted using anesthetized (rather than conscious) animals. Although it was rapidly confirmed that infarct size reduction with PC and PostC is manifest in conscious models53–55 (i.e., is not an artifact associated with anesthesia), there is no question that the choice of anesthetic drug influences myocardial infarct size. For example, in our laboratory, area of necrosis in anesthetized open-chest pigs subjected to 45 minutes of coronary artery occlusion averages approximately 55% of the myocardium at risk in animals anesthetized with sodium pentobarbital56 versus <5% of the risk region in pigs sedated with ketamine + midazolam and anesthetized with isoflurane (Fig. 4A).
These differences in infarct size are likely due, in part, to the higher heart rate and arterial blood pressure (and thus higher myocardial oxygen demand) associated with pentobarbital anesthesia. However, this is not the sole explanation. It is well established that: (1) inhaled volatile anesthetics (isoflurane, enflurane, sevoflurane) protect the heart against ischemia–reperfusion injury, an effect that is independent of their anesthetic effects; (2) anesthetic conditioning is effective when administered as a pretreatment or at the time of reperfusion (mimicking PC and PostC); and (3) the signal transduction cascades that are upregulated by and reportedly contribute to anesthetic conditioning are similar to those identified to play a role in ischemic conditioning.57–64 Despite these common mechanistic themes, it is important to note that the infarct-sparing effect of ischemic conditioning is not precluded by the use of inhaled anesthetics. For example, in isoflurane-anesthetized pigs subjected to a prolonged, 75-minute period of sustained coronary artery occlusion, we found that myocardial infarct size was on the order of 35% of the risk region in animals that received PC ischemia vs 65% in controls (Fig. 4B). This apparent additive effect suggests that the benefits of anesthetic conditioning may wane or be suboptimal with longer periods of sustained ischemia, and/or the signaling mechanisms contributing to ischemic and anesthetic conditioning are not fully redundant.
Pre- and Postconditioning: Bench to Bedside?
The wealth of data obtained from multiple experimental models documenting infarct size reduction with PC and PostC raise the obvious question: is ischemic conditioning simply a laboratory curiosity, or do these concepts extend to the human heart? There are 2 facets to this question: the first issue is whether PC and PostC are clinically relevant, and the second is whether PC and PostC can be applied to achieve clinically meaningful benefit.
The hallmark of PC is its infarct-sparing effect, presumably a consequence of an adaptation of the heart to sequential episodes of ischemia. Clinical evidence consistent with the concept of myocardial adaptation to ischemia is provided by: (1) the significant reductions in ST segment elevation and lactate release seen in patients undergoing repeated balloon inflations during angioplasty; (2) the increased threshold for anginal pain in patients performing repeated bouts of exercise (the so-called “walk-through” or “warm-up” phenomenon); and (3) perhaps most notably, the improved in-hospital outcome (lower incidence of death, heart failure, and/or shock) seen in patients with versus without preinfarct angina.8,20,21,65,66 These data are not proof of PC-induced myocardial protection, as the adaptation to ischemia may reflect recruitment of collateral blood flow rather than upregulation of endogenous protective signaling. Evidence that is more directly comparable with infarct size reduction with PC has been reported in patients undergoing cardiac surgery involving ischemic cardiac arrest: in the majority of small phase II studies conducted to date, brief ischemia intentionally imposed on the heart before coronary artery bypass grafting or value surgery has been associated with a significant attenuation in the release of biomarkers indicative of cardiac injury.67 Taken together, these studies suggest that, as in animal models, the human heart is amenable to PC-induced protection. However, as PC is a pretreatment, and MI is unpredictable, its application is limited to planned ischemic events. For this reason, PC has little scope for clinical translation and clinical benefit.
In contrast to the inherent temporal limitations of PC, relief of ischemia in a stuttered manner may hold greater promise for clinical application, particularly in ST segment elevation MI (STEMI) patients in whom coronary flow is reestablished via percutaneous coronary intervention. Indeed, in 2005 (only 2 years after the first description of PostC in the canine model),39 Staat et al.68 reported a significant reduction in creatine kinase release (a clinical surrogate for infarct size) in STEMI patients who were postconditioned with 4 supplemental cycles of brief angioplasty balloon inflation–deflation after initial restoration of flow when compared with controls who underwent standard angioplasty with no subsequent intervention. Among the 11 subsequent phase II studies conducted to date, 9 have confirmed this initial observation (i.e., reported a significant attenuation in creatine kinase or troponin release in patients assigned to receive PostC via angioplasty balloon inflation/deflation versus controls),67,69 with 1 study documenting sustained benefit with PostC at 6 months after MI.70 The outcomes of the small studies, with total n values ranging from 25 to 118 patients, suggest that infarct size reduction with PostC is clinically feasible. However, at present, no conclusions can be drawn regarding the ability of PostC to yield a clinically meaningful benefit. It is anticipated that results of the ongoing phase III DANAMI-3 trial (“DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction”; ClinicalTrials.gov Identifier: NCT01435408) will provide critical insight into this issue.
Despite the clinical feasibility of PostC, restoration of blood flow in a stuttered manner is invasive, involves manipulation of the culprit coronary artery, and subjects the ischemic-reperfused myocardium to an additional ischemic burden. However, in 1993, our laboratory made a third observation that precludes this concern:71,72 we found that reversible ischemia, applied at a remote site, protected the heart against infarction. Specifically, anesthetized dogs underwent a 1 hour period of sustained ischemia in the left anterior descending coronary artery bed; this was preceded by either four 5-minute episodes of brief ischemia applied in the remote circumflex bed or a matched no-intervention control period. Infarct size in the left anterior descending bed was significantly reduced in the cohort that received remote circumflex conditioning versus controls, with a magnitude of protection that appeared as robust as that achieved with classic PC.72–74
The Biology of Remote Conditioning
Protection at a Distance: Expanding the Concept
Our initial report of intracardiac PC (with the protective stimulus applied in a remote coronary bed) was expanded to encompass other remote triggers including: (1) the transfer of coronary effluent collected after brief ischemia–reperfusion to naïve acceptor hearts; (2) brief ischemia imposed in remote organs (including kidney, mesentery, and skeletal muscle) before the onset of coronary occlusion; and, most recently (3) a remote nociceptive (nonischemic) stimulus applied before coronary occlusion (termed “remote PC of trauma”).18,75–80 Moreover, prophylaxis is not a requirement for remote conditioning: the concept has been expanded beyond remote PC to include remote PostC (with the remote stimulus applied on relief of coronary occlusion) and perconditioning (with the remote stimulus applied during the sustained ischemic insult).41
The Push to Clinical Application
The concept that brief ischemia applied in a remote tissue or organ can protect the heart against infarction is, without question, intriguing. However, interest in remote conditioning increased exponentially after an observation made in the pig model that a noninvasive approach (brief skeletal muscle ischemia, achieved by simple inflation of a blood pressure cuff on an arm or leg) was capable of initiating myocardial protection.78 This finding provided the impetus for efforts to implement a rapid translation of remote conditioning from the laboratory to clinical application. The emphasis has been on remote arm or leg ischemia applied before a planned ischemic event (including, in particular, coronary artery bypass surgery)18,19,81–87 and limb ischemia used as a perconditioning stimulus during ambulance transport in patients with acute MI.88 However, despite the need for new cardioprotective strategies, this push to clinical application has come at a price; in contrast to PC and PostC, minimal effort has been devoted to the systematic characterization of remote conditioning, and, as a result, our understanding of the biology and mechanisms of this phenomenon is limited.
Myocardial protection via remote conditioning is a broad concept, and the optimal algorithm needed to achieve an infarct-sparing effect will presumably be determined at least, in part, by the site and timing of the protective stimulus. Focusing on remote PC with brief skeletal muscle ischemia (the stimulus that, because of its potential for clinical application, has generated the greatest interest) the typical protocol uses 3 to 4 repeated 5-minute episodes of arm and/or leg ischemia interspersed with comparable 5-minute periods of reperfusion (Fig. 5).78,85,86,88–93 These choices are, however, empiric: the optimal algorithm, in terms of the site of remote ischemia (arm[s]) versus leg[s]), the number and duration of the remote ischemic episodes, and the threshold of ischemia required to evoke myocardial protection are unknown.41,73,74,85 Requirements for PC, PostC, and perconditioning, initiated at other remote sites, are even less well defined.
The time frame of the second component, i.e., the interval between the remote stimulus and the onset of sustained myocardial ischemia, is equally ambiguous. In experimental studies using skeletal muscle ischemia as the remote PC stimulus, the interval is on the order of approximately 5 to 15 minutes.78,89–93 In contrast, in clinical protocols conducted on patients undergoing coronary artery bypass surgery, the timing is more prolonged (on the order of approximately 2–3 hours) and variable; i.e., in some instances, initiated at or after the first surgical incision.85,94 In either case, the interval beyond which remote PC fails to limit infarct size has not been established. Similarly, the optimal time frames for application of remote perconditioning or PostC stimuli have not been delineated.
As might be expected, the common mechanistic themes identified for PC and PostC, including stimulation of G-protein–coupled receptors, cardiac upregulation of kinases in the RISK and/or SAFE pathways, and stabilization of mitochondria, appear to extend to remote conditioning (Fig. 2).19,73,74,81,95 However, the unique and as-yet poorly understood facet of remote conditioning is communication; i.e., transfer of the protective signal from the remote tissue or organ to the heart. Three hypotheses have been proposed: communication via one or more blood- or perfusate-borne humoral factors, communication via neuronal stimulation and transmission, and communication via systemic modification of circulating immune cells.19,73,75,76,81,83,86,96,97 Compelling evidence has been provided in support of each of these theories, with the mode of communication in all likelihood dependent on the model under investigation.73,74 For example, the infarct-sparing effect achieved by transfer of coronary effluent from PC donor hearts to naïve acceptor hearts is presumably explained by a perfusate-borne factor. Potential candidates include adenosine, bradykinin, and opioids,75,97,98 as well as an as-yet unidentified, small hydrophobic molecule (approximately 3.5–15.0 kDa) isolated from the perfusate and implicated in several studies to evoke myocardial protection.97,99,100 In in vivo models, communication between remote tissues and the heart may be more complex and multifactorial, possibly involving both neuronal and/or humoral transport of protective stimuli.73,74,93,101
Remote Conditioning: Potential for Clinical Translation?
As noted previously, investigation into remote conditioning has largely been driven by its translational appeal, with noninvasive inflation of a blood pressure cuff on an arm and/or leg engendering the greatest interest. Indeed, successes have been achieved in phase II studies, most notably with application of remote conditioning during ambulance transport in patient with STEMI and as a pretreatment in patients undergoing coronary artery bypass surgery and other cardiac surgical procedures.18,19,67,69,81–87 It is, however, important to acknowledge that not all studies have been positive: among the 25 published studies, 13 reported statistically significant myocardial protection, 5 showed a positive trend that did not achieve significance, whereas the remaining 7 concluded that remote conditioning had no benefit or exacerbated myocardial injury.67,69
Of the 7 studies reporting negative outcomes, 6 were conducted in the setting of cardiac surgery (reviewed in Refs. 67,69). Reasons for these discrepancies are speculative, but may reflect: (1) heterogeneity both within and among protocols (including differences in the specific surgical procedures that were performed, the choice of anesthetic and cardioplegic drugs, temporal differences in the remote conditioning algorithm, and differences in the proportion of high-risk patients enrolled in each study), together with (2) our lack of understanding of the biology of remote conditioning and, thus, the consequences of these variations.67,69,74,85,94,102 Recent evidence suggests that the choice of anesthesia may be particularly critical, with the use of propofol in the anesthetic regimen emerging as a consistent theme among studies in which remote conditioning failed to protect the heart.67,69,85,103,104 The mechanisms by which propofol abrogates the favorable effects of remote conditioning are unknown, but may involve the reported absence of myocardial STAT5 phosphorylation, implicated as a key molecular event in human hearts protected by remote limb ischemia.103,104
Thus, as with PostC, the outcome of the small studies conducted to date suggest that, under appropriate but as-yet poorly defined conditions, remote conditioning can render the human heart less vulnerable to ischemia–reperfusion injury. Two ongoing phase III protocols, the ERICCA trial (“Effect of Remote Ischemic Preconditioning on Clinical Outcomes in CABG Surgery”; ClinicalTrials.gov: NCT01247545) and the RIPHeart-Study (“Remote Ischemic Preconditioning for Heart Surgery”; ClinicalTrials.gov: NCT01067703) are scheduled for completion within the next 2 years,105,106 and the results will yield highly anticipated information on the potential clinical benefit of this phenomenon.
THE ELEPHANT IN THE ROOM: CONFOUNDING EFFECT OF COMORBIDITIES?
The implicit goal of all studies that have interrogated the biology of ischemic conditioning is clinical application. There is, however, a critical caveat that may limit the clinical translation of conditioning strategies; our current understanding of the temporal, physiologic, and mechanistic aspects of ischemic conditioning is based almost exclusively on studies conducted in healthy, adult cohorts. This issue is problematic for 2 reasons. First, these models do not reflect the multiple risk factors and comorbidities (such as aging, diabetes, hypertension, and hyperlipidemia) associated with cardiovascular disease and acute MI. Second, and of greater concern, there is a growing consensus that these comorbidities (in particular, aging and diabetes) are associated with unfavorable alterations in the expression and phosphorylation of a host of cardioprotective mediators, including the classic survival kinases identified to play a role in PC, PostC, and remote conditioning.40,107 Indeed, data from our laboratory and others have revealed a loss in the infarct-sparing effect of ischemic conditioning in diabetic, aging, and hypertensive models.40,107–111
How can this impaired responsiveness of comorbid models to ischemic conditioning be reconciled with the encouraging (albeit not definitive) reports of improved outcomes with myocardial conditioning in patients undergoing cardiac surgery or angioplasty for the treatment of acute MI? One potential explanation is that the experimental models are overly simplistic and, thus, not clinically relevant: i.e., the standard mouse and rat models typically involve a single comorbid condition, the comorbidities are comparatively acute (manifest for weeks, rather than years), and the experimental protocols do not usually incorporate the pharmacologic therapies administered to patients as standard clinical care.40,107 There is, however, a second possible interpretation: results obtained from the preclinical models may predict an attenuation or abrogation of the favorable effects of ischemic conditioning in subpopulations of diabetic and elderly patients. In this regard, post hoc analysis of a clinical study conducted by our group112 appears to provide support for this concept: we found that PostC was ineffective in limiting creatine kinase release (a biomarker of cardiac injury) in patients >65 years of age.40,107 The outcome of this and similar post hoc analyses107 does not provide definitive proof for a loss in efficacy of ischemic conditioning in these subpopulations, but, rather, underscores the need to design phase III trials with adequate statistical power to discern the effects of myocardial conditioning in aging and diabetic subsets. If the data reveal that myocardial protection is, indeed, compromised in the face of comorbidities, the challenge will be to determine whether protection can be reestablished in these cohorts via rational and targeted, mechanisms-based modification of the current conditioning algorithms.
SUMMARY AND CONCLUSIONS
Overwhelming evidence amassed throughout the past 2½ decades has demonstrated that ischemic conditioning, including PC, PostC, and remote conditioning, provides endogenous myocardial protection and renders the heart less vulnerable to ischemia–reperfusion injury. Moreover, PostC and remote conditioning may be poised for clinical translation. However, successful clinical application of ischemic conditioning will depend on enhancing our understanding of: (1) the technical, physiologic, and mechanistic components of conditioning-induced myocardial protection and (2) the potentially confounding effects of clinically relevant comorbidities on the conditioned phenotype.
Name: Karin Przyklenk, PhD.
Contribution: This author conducted the PubMed-based literature search and was responsible for preparation of the manuscript.
This manuscript was handled by: Dwayne R. Westenskow, PhD.
1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MBAmerican Heart Association Statistics Committee and Stroke Statistics Subcommittee. . Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–245
2. Hausenloy DJ, Baxter G, Bell R, Bøtker HE, Davidson SM, Downey J, Heusch G, Kitakaze M, Lecour S, Mentzer R, Mocanu MM, Ovize M, Schulz R, Shannon R, Walker M, Walkinshaw G, Yellon DM. Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations. Basic Res Cardiol. 2010;105:677–86
3. Schwartz Longacre L, Kloner RA, Arai AE, Baines CP, Bolli R, Braunwald E, Downey J, Gibbons RJ, Gottlieb RA, Heusch G, Jennings RB, Lefer DJ, Mentzer RM, Murphy E, Ovize M, Ping P, Przyklenk K, Sack MN, Vander Heide RS, Vinten-Johansen J, Yellon DMNational Heart, Lung, and Blood Institute, National Institutes of Health. . New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation. 2011;124:1172–9
4. Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest. 1985;76:1713–9
5. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–35
6. Bell RM, Yellon DM. There is more to life than revascularization: therapeutic targeting of myocardial ischemia/reperfusion injury. Cardiovasc Ther. 2011;29:e67–79
7. Sanada S, Komuro I, Kitakaze M. Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. Am J Physiol Heart Circ Physiol. 2011;301:H1723–41
8. Kloner RA, Schwartz Longacre L. State of the science of cardioprotection: challenges and opportunities—proceedings of the 2010 NHLBI workshop on cardioprotection. J Cardiovasc Pharmacol Ther. 2011;16:223–32
9. Maroko PR, Kjekshus JK, Sobel BE, Watanabe T, Covell JW, Ross J Jr, Braunwald E. Factors influencing infarct size following experimental coronary artery occlusions. Circulation. 1971;43:67–82
10. Braunwald E. Clinical efforts to reduce myocardial infarct size–the next step. J Cardiovasc Pharmacol Ther. 2011;16:349–53
11. Cohen MV, Downey JM. Is it time to translate ischemic preconditioning’s mechanism of cardioprotection into clinical practice? J Cardiovasc Pharmacol Ther. 2011;16:273–80
12. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–36
13. Mergenthaler P, Dirnagl U. Protective conditioning of the brain: expressway or roadblock? J Physiol. 2011;589:4147–55
14. Wever KE, Menting TP, Rovers M, van der Vliet JA, Rongen GA, Masereeuw R, Ritskes-Hoitinga M, Hooijmans CR, Warlé M. Ischemic preconditioning in the animal kidney, a systematic review and meta-analysis. PLoS One. 2012;7:e32296
15. Whittaker P, Przyklenk K. Remote-conditioning ischemia provides a potential approach to mitigate contrast medium-induced reduction in kidney function: a retrospective observational cohort study. Cardiology. 2011;119:145–50
16. Wang WZ, Baynosa RC, Zamboni WA. Update on ischemia-reperfusion injury for the plastic surgeon: 2011. Plast Reconstr Surg. 2011;128:685e–92e
17. Selzner N, Boehnert M, Selzner M. Preconditioning, postconditioning, and remote conditioning in solid organ transplantation: basic mechanisms and translational applications. Transplant Rev (Orlando). 2012;26:115–24
18. Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury–a review. J Surg Res. 2008;150:304–30
19. Lim SY, Hausenloy DJ. Remote ischemic conditioning: from bench to bedside. Front Physiol. 2012;3:27
20. Przyklenk K, Kloner RA. Ischemic preconditioning: exploring the paradox. Prog Cardiovasc Dis. 1998;40:517–47
21. Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev. 2003;83:1113–51
22. Vander Heide R. Clinically useful cardioprotection: ischemic preconditioning then and now. J Cardiovasc Pharmacol Ther. 2011;16:251–4
23. Hata K, Whittaker P, Kloner RA, Przyklenk K. Brief antecedent ischemia attenuates platelet-mediated thrombosis in damaged and stenotic canine coronary arteries: role of adenosine. Circulation. 1998;97:692–702
24. Przyklenk K, Whittaker P. Brief antecedent ischemia enhances recombinant tissue plasminogen activator-induced coronary thrombolysis by adenosine-mediated mechanism. Circulation. 2000;102:88–95
25. Linden MD, Whittaker P, Frelinger AL 3rd, Barnard MR, Michelson AD, Przyklenk K. Preconditioning ischemia attenuates molecular indices of platelet activation-aggregation. J Thromb Haemost. 2006;4:2670–7
26. Linden MD, Barnard MR, Frelinger AL, Michelson AD, Przyklenk K. Effect of adenosine A2 receptor stimulation on platelet activation-aggregation: differences between canine and human models. Thromb Res. 2008;121:689–98
27. Andreotti F, Pasceri V, Hackett DR, Davies GJ, Haider AW, Maseri A. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med. 1996;334:7–12
28. Cokkinos AD, Tzeis S, Moraitis P, Pantos C, Carageorgiou H, Panousopoulos D, Varonos DD, Cokkinos DV. Loss of cardioprotection induced by ischemic preconditioning after an initial ischemic period in isolated rat hearts. Exp Clin Cardiol. 2003;8:5–9
29. Yamasaki K, Fujiwara H, Tanaka M, Yokota R, Miyamae M, Ogawa J, Fujiwara T, Sasayama S. Preconditioning with 15-minute ischemia extends myocardial infarct size after subsequent 30-minute ischemia in rabbits. Jpn Circ J. 1997;61:344–52
30. Ovize M, Przyklenk K, Kloner RA. Partial coronary stenosis is sufficient and complete reperfusion is mandatory for preconditioning the canine heart. Circ Res. 1992;71:1165–73
31. Li YW, Whittaker P, Kloner RA. The transient nature of the effect of ischemic preconditioning on myocardial infarct size and ventricular arrhythmia. Am Heart J. 1992;123:346–53
32. Li Y, Kloner RA. Cardioprotective effects of ischemic preconditioning can be recaptured after they are lost. J Am Coll Cardiol. 1994;23:470–4
33. Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res. 1993;72:1293–9
34. Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation. 1993;88:1264–72
35. Hausenloy DJ, Yellon DM. The second window of preconditioning (SWOP) where are we now? Cardiovasc Drugs Ther. 2010;24:235–54
36. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004;61:448–60
37. Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation. 2008;118:1915–9
38. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88:581–609
39. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285:H579–88
40. Vinten-Johansen J, Granfeldt A, Mykytenko J, Undyala VV, Dong Y, Przyklenk K. The multidimensional physiological responses to postconditioning. Antioxid Redox Signal. 2011;14:791–810
41. Vinten-Johansen J, Shi W. Perconditioning and postconditioning: current knowledge, knowledge gaps, barriers to adoption, and future directions. J Cardiovasc Pharmacol Ther. 2011;16:260–6
42. Alker KJ, Bellows SD, Kloner RA. Stuttering reperfusion of ischemic myocardium does not exacerbate myocardial infarction: evidence against lethal cell reperfusion injury in the rabbit. J Thromb Thrombolysis. 1996;3:185–8
43. Darling CE, Jiang R, Maynard M, Whittaker P, Vinten-Johansen J, Przyklenk K. Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2. Am J Physiol Heart Circ Physiol. 2005;289:H1618–26
44. Lacerda L, Somers S, Opie LH, Lecour S. Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res. 2009;84:201–8
45. Lecour S. Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway? J Mol Cell Cardiol. 2009;47:32–40
46. Heusch G, Musiolik J, Gedik N, Skyschally A. Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res. 2011;109:1302–8
47. Hausenloy DJ, Lecour S, Yellon DM. Reperfusion injury salvage kinase and survivor activating factor enhancement prosurvival signaling pathways in ischemic postconditioning: two sides of the same coin. Antioxid Redox Signal. 2011;14:893–907
48. Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G. Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res. 2009;104:15–8
49. Heusch G. No risk, no. cardioprotection? A critical perspective. Cardiovasc Res. 2009;84:173–5
50. Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M. STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res. 2012;110:111–5
51. Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation. 2005;111:194–7
52. Boengler K, Heusch G, Schulz R. Mitochondria in postconditioning. Antioxid Redox Signal. 2011;14:863–80
53. Cohen MV, Yang XM, Downey JM. Conscious rabbits become tolerant to multiple episodes of ischemic preconditioning. Circ Res. 1994;74:998–1004
54. Ping P, Zhang J, Qiu Y, Tang XL, Manchikalapudi S, Cao X, Bolli R. Ischemic preconditioning induces selective translocation of protein kinase C isoforms epsilon and eta in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. Circ Res. 1997;81:404–14
55. Tang XL, Sato H, Tiwari S, Dawn B, Bi Q, Li Q, Shirk G, Bolli R. Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min. Am J Physiol Heart Circ Physiol. 2006;291:H2308–17
56. Sala-Mercado JA, Wider J, Undyala VV, Jahania S, Yoo W, Mentzer RM Jr, Gottlieb RA, Przyklenk K. Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation. 2010;122:S179–84
57. Zaugg M, Lucchinetti E, Uecker M, Pasch T, Schaub MC. Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms. Br J Anaesth. 2003;91:551–65
58. Zaugg M, Schaub MC, Foëx P. Myocardial injury and its prevention in the perioperative setting. Br J Anaesth. 2004;93:21–33
59. Tanaka K, Ludwig LM, Kersten JR, Pagel PS, Warltier DC. Mechanisms of cardioprotection by volatile anesthetics. Anesthesiology. 2004;100:707–21
60. Pratt PF Jr, Wang C, Weihrauch D, Bienengraeber MW, Kersten JR, Pagel PS, Warltier DC. Cardioprotection by volatile anesthetics: new applications for old drugs? Curr Opin Anaesthesiol. 2006;19:397–403
61. Shim YH, Kersten JR. Preconditioning, anesthetics, and perioperative medication. Best Pract Res Clin Anaesthesiol. 2008;22:151–65
62. Huffmyer J, Raphael J. Physiology and pharmacology of myocardial preconditioning and postconditioning. Semin Cardiothorac Vasc Anesth. 2009;13:5–18
63. Ge ZD, Pravdic D, Bienengraeber M, Pratt PF Jr, Auchampach JA, Gross GJ, Kersten JR, Warltier DC. Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism. Anesthesiology. 2010;112:73–85
64. Lotz C, Kehl F. Translating volatile anesthetic-induced cardioprotection into systems biology. Anesthesiology. 2012;116:238–9
65. Kloner RA, Yellon D. Does ischemic preconditioning occur in patients? J Am Coll Cardiol. 1994;24:1133–42
66. Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S, Gibson M, Poole WK, Cannon CP. Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation. 1995;91:37–45
67. Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet. 2013;381:166–75
68. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart. Circulation. 2005;112:2143–8
69. Ovize M, Thibault H, Przyklenk K. Myocardial conditioning: opportunities for clinical translation. Circ Res. 2013;113:439–50
70. Thibault H, Piot C, Staat P, Bontemps L, Sportouch C, Rioufol G, Cung TT, Bonnefoy E, Angoulvant D, Aupetit JF, Finet G, André-Fouët X, Macia JC, Raczka F, Rossi R, Itti R, Kirkorian G, Derumeaux G, Ovize M. Long-term benefit of postconditioning. Circulation. 2008;117:1037–44
71. Whittaker P, Przyklenk K. Reduction of infarct size in vivo
with ischemic preconditioning: mathematical evidence for protection via non-ischemic tissue. Basic Res Cardiol. 1994;89:6–15
72. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87:893–9
73. Przyklenk K, Whittaker P. Remote ischemic preconditioning: current knowledge, unresolved questions, and future priorities. J Cardiovasc Pharmacol Ther. 2011;16:255–9
74. Przyklenk K, Whittaker P. Genesis of remote conditioning: action at a distance—‘hypotheses non fingo’? J Cardiovasc Med (Hagerstown). 2013;14:180–6
75. Dickson EW, Lorbar M, Porcaro WA, Fenton RA, Reinhardt CP, Gysembergh A, Przyklenk K. Rabbit heart can be “preconditioned” via transfer of coronary effluent. Am J Physiol. 1999;277:H2451–7
76. Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996;94:2193–200
77. Pell TJ, Baxter GF, Yellon DM, Drew GM. Renal ischemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels. Am J Physiol. 1998;275:H1542–7
78. Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106:2881–3
79. Jones WK, Fan GC, Liao S, Zhang JM, Wang Y, Weintraub NL, Kranias EG, Schultz JE, Lorenz J, Ren X. Peripheral nociception associated with surgical incision elicits remote nonischemic cardioprotection via neurogenic activation of protein kinase C signaling. Circulation. 2009;120:S1–9
80. Gross GJ, Baker JE, Moore J, Falck JR, Nithipatikom K. Abdominal surgical incision induces remote preconditioning of trauma (RPCT) via activation of bradykinin receptors (BK2R) and the cytochrome P450 epoxygenase pathway in canine hearts. Cardiovasc Drugs Ther. 2011;25:517–22
81. Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res. 2008;79:377–86
82. Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol. 2011;8:619–29
83. Saxena P, Newman MA, Shehatha JS, Redington AN, Konstantinov IE. Remote ischemic conditioning: evolution of the concept, mechanisms, and clinical application. J Card Surg. 2010;25:127–34
84. Candilio L, Hausenloy DJ, Yellon DM. Remote ischemic conditioning: a clinical trial’s update. J Cardiovasc Pharmacol Ther. 2011;16:304–12
85. Hausenloy DJ, Yellon DM. “Conditional Conditioning” in cardiac bypass surgery. Basic Res Cardiol. 2012;107:258
86. Veighey K, Macallister RJ. Clinical applications of remote ischemic preconditioning. Cardiol Res Pract. 2012;2012:620681
87. D’Ascenzo F, Cavallero E, Moretti C, Omedè P, Sciuto F, Rahman IA, Bonser RS, Yunseok J, Wagner R, Freiberger T, Kunst G, Marber MS, Thielmann M, Ji B, Amr YM, Modena MG, Zoccai GB, Sheiban I, Gaita F. Remote ischaemic preconditioning in coronary artery bypass surgery: a meta-analysis. Heart. 2012;98:1267–71
88. Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sørensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375:727–34
89. Cao Y, Zhang SZ, Zhao SQ, Bruce IC. The mitochondrial Ca(2+)-activated K(+) channel contributes to cardioprotection by limb remote ischemic preconditioning in rat. Life Sci. 2011;88:1026–30
90. Heinen NM, Pütz VE, Görgens JI, Huhn R, Grüber Y, Barthuber C, Preckel B, Pannen BH, Bauer I. Cardioprotection by remote ischemic preconditioning exhibits a signaling pattern different from local ischemic preconditioning. Shock. 2011;36:45–53
91. Li J, Xuan W, Yan R, Tropak MB, Jean-St-Michel E, Liang W, Gladstone R, Backx PH, Kharbanda RK, Redington AN. Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of β-catenin. Clin Sci (Lond). 2011;120:451–62
92. Lim SY, Yellon DM, Hausenloy DJ. The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol. 2010;105:651–5
93. Mastitskaya S, Marina N, Gourine A, Gilbey MP, Spyer KM, Teschemacher AG, Kasparov S, Trapp S, Ackland GL, Gourine AV. Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones. Cardiovasc Res. 2012;95:487–94
94. Thielmann M. Remote ischemic preconditioning in cardiac surgery: caught between clinical relevance and statistical significance? Basic Res Cardiol. 2012;107:259
95. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: underlying mechanisms and clinical application. Atherosclerosis. 2009;204:334–41
96. Weber C. Far from the heart: receptor cross-talk in remote conditioning. Nat Med. 2010;16:760–2
97. Dickson EW, Blehar DJ, Carraway RE, Heard SO, Steinberg G, Przyklenk K. Naloxone blocks transferred preconditioning in isolated rabbit hearts. J Mol Cell Cardiol. 2001;33:1751–6
98. Schoemaker RG, van Heijningen CL. Bradykinin mediates cardiac preconditioning at a distance. Am J Physiol Heart Circ Physiol. 2000;278:H1571–6
99. Serejo FC, Rodrigues LF Jr, da Silva Tavares KC, de Carvalho AC, Nascimento JH. Cardioprotective properties of humoral factors released from rat hearts subject to ischemic preconditioning. J Cardiovasc Pharmacol. 2007;49:214–20
100. Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, Li J, Gross G, Wilson GJ, Callahan J, Redington AN. Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond). 2009;117:191–200
101. Basalay M, Barsukevich V, Mastitskaya S, Mrochek A, Pernow J, Sjöquist PO, Ackland GL, Gourine AV, Gourine A. Remote ischaemic pre- and delayed postconditioning—similar degree of cardioprotection but distinct mechanisms. Exp Physiol. 2012;97:908–17
102. Peters J. Remote ischaemic preconditioning of the heart: remote questions, remote importance, or remote preconditions? Basic Res Cardiol. 2011;106:507–9
103. Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J. Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol - a clinical trial. Acta Anaesthesiol Scand. 2012;56:30–8
104. Kottenberg E, Musiolik J, Thielmann M, Jakob H, Peters J, Heusch G. Interference of propofol with signal transducer and activator of transcription 5 activation and cardioprotection by remote ischemic preconditioning during coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2013 Mar 1 [Epub ahead of print]
105. Hausenloy DJ, Candilio L, Laing C, Kunst G, Pepper J, Kolvekar S, Evans R, Robertson S, Knight R, Ariti C, Clayton T, Yellon DMERICCA Trial Investigators. . Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi-centre randomized double-blinded controlled clinical trial. Clin Res Cardiol. 2012;101:339–48
106. Meybohm P, Zacharowski K, Cremer J, Roesner J, Kletzin F, Schaelte G, Felzen M, Strouhal U, Reyher C, Heringlake M, Schön J, Brandes I, Bauer M, Knuefermann P, Wittmann M, Hachenberg T, Schilling T, Smul T, Maisch S, Sander M, Moormann T, Boening A, Weigand MA, Laufenberg R, Werner C, Winterhalter M, Treschan T, Stehr SN, Reinhart K, Hasenclever D, Brosteanu O, Bein BRIP Heart-Study Investigator Group. . Remote ischaemic preconditioning for heart surgery. The study design for a multi-center randomized double-blinded controlled clinical trial–the RIPHeart-Study. Eur Heart J. 2012;33:1423–6
107. Przyklenk K. Efficacy of cardioprotective ‘conditioning’ strategies in aging and diabetic cohorts: the co-morbidity conundrum. Drugs Aging. 2011;28:331–43
108. Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev. 2007;59:418–58
109. Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol. 2008;51:1393–8
110. Przyklenk K, Maynard M, Greiner DL, Whittaker P. Cardioprotection with postconditioning: loss of efficacy in murine models of type-2 and type-1 diabetes. Antioxid Redox Signal. 2011;14:781–90
111. Jensen RV, Støttrup NB, Kristiansen SB, Bøtker HE. Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients. Basic Res Cardiol. 2012;107:285
112. Darling CE, Solari PB, Smith CS, Furman MI, Przyklenk K. ‘Postconditioning’ the human heart: multiple balloon inflations during primary angioplasty may confer cardioprotection. Basic Res Cardiol. 2007;102:274–8
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