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Ann Thorac Surg 1999;68:1988-1994
© 1999 The Society of Thoracic Surgeons
a Department of Cardiovascular Surgery and INSERM Unité 127, Hôpital Lariboisière, Paris, France
b Research Center and Department of Surgery, Montreal Heart Institute, Montreal, Quebec, Canada
Address reprint requests to Dr Menasché, Department of Cardiovascular Surgery, Hôpital Bichat, 46 rue Henri Huchard, 75018 Paris, France
Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sep 21–24, 1997.
Abstract
Endogenous myocardial protection refers to the natural defense mechanisms available to the heart to withstand an ischemic injury. So far, these mechanisms have been shown to encompass two phenomena most likely interrelated: ischemic preconditioning and stress protein synthesis. Ischemic preconditioning can be defined as the adaptive mechanism induced by a brief period of reversible ischemia increasing the heart’s resistance to a subsequent longer period of ischemia. The therapeutic exploitation of these natural adaptive mechanisms in cardiac surgery is an appealing prospect, as preconditioning could be used before aortic cross-clamping to enhance the current methods of myocardial protection. Two major conclusions emerge from the bulk of experimental data on preconditioning: First, the adaptive phenomenon reduces infarct size after regional ischemia in animal preparations across a wide variety of species but its effects on arrhythmias and on preservation of function after global ischemia are less consistent. This is relevant to cardiac surgery where postbypass pump failure is more often due to stunning than to discrete necrosis. Second, regardless of the various components of the intracellular signaling pathway elicited by the preconditioning stimulus, it seems that the major mechanisms by which this pathway leads to a cardioprotective effect are a slowing of adenosine triphosphate depletion and a limitation of acidosis during the protracted period of ischemia. If the latter is true, then it can reasonably be predicted that these energy-sparing and acidosis-limiting effects may become redundant to those of cardioplegia. From these observations, it can be inferred that preconditioning may find an elective indication in situations where the potential for suboptimal protection increases the risk of necrosis (extensive coronary artery disease, severe left ventricular hypertrophy, long ischemic time, and beating heart operations where occlusion of the target vessels leads to unprotected distal ischemia). Since an ischemic preconditioning stimulus could be clinically undesirable, it is critically important to identify the endogenous mediators of the phenomenon in order to use them therapeutically. One of the most important of these mediators seems to be the adenosine triphosphate-dependent potassium channel. Currently, however, the clinical application of these drugs is hampered by their poor cardioselectivity which could result in untoward systemic vasodilatory effects before cardioprotection becomes manifest. Thus, although the modalities of pharmacologically induced preconditioning still remain to be determined, the concept of therapeutic exploitation of the endogenous adaptive mechanisms of the heart could potentially represent an important adjunct to our current techniques of myocardial protection.
Endogenous myocardial protection refers to the natural defense mechanisms available to the heart to withstand an ischemic injury. So far, these mechanisms have been shown to encompass two phenomena most likely interrelated: ischemic preconditioning and stress protein synthesis. Ischemic preconditioning can be defined as an adaptive mechanism by which a brief period of reversible ischemia increases the heart’s tolerance to a subsequent longer period of ischemia. Two different time frames are defined for preconditioning, one early (or "classical" preconditioning) which involves activation of various membrane receptors and one late (termed the "second window" of protection) which is related to changes in gene expression leading to an increased synthesis of cardioprotective stress proteins [1, 2]. The therapeutic exploitation of these natural adaptive mechanisms in cardiac surgery is an appealing prospect because the possibility of planning the onset of the cross-clamping period could allow the timely appropriate implementation of preconditioning interventions targeted at enhancing the efficacy of current methods of myocardial protection. In this review, only those interventions that afford early protection (classical preconditioning) will be considered. Before they can be used in patients undergoing heart surgery, at least two major questions have to be answered: Are these endogenous protective mechanisms relevant to surgically induced myocardial ischemia? And, if so, how can they be applied practically during open-heart procedures?
Relevance of preconditioning to cardiac surgery
Clinical trials: an apparent discrepancy
Clinically, the first use of preconditioning has been reported by Alkhulaifi and coworkers [3] using conservation of adenosine triphosphate (ATP) as the major end point. Twenty patients were randomized to either preconditioning by two 3-minute periods of cross-clamping separated by 2 minutes of reperfusion prior to 10 minutes of normothermic ventricular fibrillation, or to a control, nonpreconditioned group receiving only the 10-minute ischemic stimulus. The major finding of this study was that preconditioning slowed the rate of ATP depletion to such an extent that at the end of the 10-minute period, the preconditioned group had a significantly higher ATP content than the controls. The authors should certainly be credited for having demonstrated the reality of an adaptive response of the human heart to an ischemic stress. However, a major limitation of this study was that normothermic ventricular fibrillation is uncommonly used (this technique is routinely employed with a moderate degree of hypothermia) which likely resulted in such extensive myocardial injury that it provided some room for improvement from preconditioning.
Thus, to assess whether this type of cardioprotective intervention would still be relevant to the more common practice of cardioplegic arrest, we [4] assessed the effects of ischemic preconditioning (achieved with 3 minutes of aortic cross-clamping and 2 minutes of reperfusion under cardiopulmonary bypass support) before continuous retrograde warm blood cardioplegia in 10 patients undergoing coronary artery bypass operations. Ten case-matched patients in whom an equivalent period (5 minutes) of bypass was used before arrest served as controls. At the end of arrest, the release of creatine kinase (CK)-MB isoenzymes (CK-MB) from the myocardium (calculated as the difference between coronary sinus and radial artery values) of preconditioned patients was markedly greater than in controls (5.7 ± 1.7 ng/ml versus 1.9 ± 1.1 ng/ml, p = 0.05). The transmyocardial lactate gradient was shifted toward production in the preconditioned group (+0.22 ± 0.13 mmol/L) and toward extraction in the control group (-0.06 ± 0.21 mmol/L). The lack of additional protection conferred by ischemic preconditioning was further confirmed by the absence of difference in postarrest myocardial levels of ribonucleic acid messengers coding for the cardioprotective heat shock proteins (HSP) 70 between the two groups. Although there were no preconditioning-related adverse clinical events, the trend toward an increased ischemic insult cannot be dismissed, thereby suggesting that the detrimental effects of a brief prearrest period of aortic occlusion largely offset its putative cardioprotective action. Since then, similarly negative results have been reported by Kaukoranta and associates [5]. In keeping with our data, their patients were preconditioned by 5 minutes of global ischemia before warm aerobic arrest and tended to have higher postoperative serum levels of CK-MB and troponin T indicative of greater tissue injury than nonpreconditioned control patients.
The reconciliating hypothesis
The apparently discrepant results obtained with noncardioplegic and cardioplegic techniques can be reconciliated if one takes into account the two following observations: (1) Preconditioning reduces infarct size, not stunning, and (2) its salutary effects are only manifest in situations of unprotected ischemia.
To date, there is convincing evidence that preconditioning improves function by reducing infarct size, not by decreasing stunning of periinfarct viable myocardium. Only those few studies that have concomitantly assessed function and infarct size can shed some light on this problem [6]. Indeed, their findings conclusively demonstrate that preconditioning improves postischemic function only by reducing infarct size, not by relieving stunning of reversibly injured myocardium. Importantly, this conclusion applies both to regionally ischemic preparations which have been preconditioned by a transient coronary artery occlusion and to models of global ischemia where preconditioning has been induced by a transient period of aortic cross-clamping [7, 8]. For example, Qiu and associates [9] have recently reported, in a conscious pig model, that preconditioning dramatically reduced the size of the infarction resulting from a 40-minute occlusion produced 25 minutes later, which was paralleled by a marked functional benefit; however, when the sustained occlusion was produced 24 hours later, the same preconditioning protocol failed to reduce infarct size and regional function was no longer preserved. These data are further supported by a recent study from our laboratory [10] in which isolated buffer-perfused rabbit hearts were subjected to 60 minutes of normothermic potassium arrest. This ischemic insult caused only minimal necrosis (< 10% of the left ventricle), as assessed by triphenyltetrazolium chloride staining at the end of the 60-minute reperfusion period. In this situation, preconditioning, achieved with 5 minutes of total (zero-flow) ischemia followed by 5 minutes of reperfusion before arrest, failed to improve recovery of function or coronary flow over that seen in nonpreconditioned hearts. Conversely, Hendricx and coworkers [11] have reported that a similar protocol of preconditioning improved functional recovery of rabbit hearts subjected to 45 minutes of unprotected global ischemia. However, in this study, infarct size was not measured. We then duplicated these experiments and found that the type of injury used by Hendricx and his coauthors caused a massive infarction of the left ventricle, thereby offering some room for preconditioning to reduce the extent of necrosis and confirming that the functional benefits of this phenomenon were achieved through its infarct size-limiting capacity. Taken together, these data indicate that the relevance of preconditioning to routine cardiac surgery may be limited in that postbypass pump failure is more often due to global reversible contractile dysfunction rather than to discrete necrosis [12].
A second important observation is that virtually all experimental studies that have documented the salutary effects of preconditioning have used models of unprotected ischemia, with these effects being no longer apparent when protective measures like hypothermia and/or cardioplegia are implemented [13]. This is clearly demonstrated in the recent study of Cleveland and coworkers [14] showing that preconditioning effectively improved mechanical recovery of human right atrial trabeculae exposed to warm hypoxia, whereas this protection was lost as soon as the trabeculae were cooled. This can be explained by the fact that regardless of the precise mechanism(s) by which preconditioning is cardioprotective, slowing of the decay of high energy phosphates during the early phase of the prolonged period of ischemia appears to be an important phenomenon [15]. It is therefore plausible that this energy-sparing effect may become redundant to that of cardioplegia. Likewise, the preconditioning episodes result in glycogen depletion so that lactate accumulation is slowed when the glycogen-depleted myocardium is subsequently exposed to the sustained period of ischemia [16]. Again, it seems that the slower rate of development of intracellular acidosis associated with preconditioning is redundant to the buffering capacity of appropriately formulated cardioplegic solutions. This hypothesis is indeed confirmed by the observation, made in isolated rat hearts subjected to 35 minutes of global ischemia, that both ischemic preconditioning and cardioplegia independently improve the recovery of function over that seen in control unprotected hearts, but without additive effects [17]. Likewise, preconditioning combined with magnesium-based cardioplegia fails to ameliorate the recovery of hearts compared with cardioplegia alone [18]. Conversely, it is conceivable that preconditioning may enhance the effects of a technique like normothermic ventricular fibrillation—the one used in Alkhulaifi and coworkers’ study [3]—which is expected to cause a major decline in ATP levels and intracellular pH leaving room for cardioprotective interventions like preconditioning to provide some improvement. From this standpoint, it is noteworthy that the same group of investigators who reported a metabolic benefit of preconditioning in clinical cardiac surgery performed in the setting of normothermic ventricular fibrillation, failed to show any benefit when fibrillation occurring after preconditioning was induced at lower temperatures [19]. Along this line of reasoning, the favorable outcomes of patients undergoing coronary artery bypass operations under intermittent aortic cross-clamping and fibrillation might be explained by the fact that the cumulative injury caused by the successive no-flow periods is limited by the initial episode of aortic occlusion acting as a preconditioning stimulus [20].
Possible clinical indications of preconditioning in cardiac surgery
From the above considerations, it results that preconditioning may find an elective indication in settings where a potential for suboptimal myocardial protection increases the risk of perioperative infarction as it can then be anticipated that the extent of this infarction will be reduced by the preconditioning intervention with an attendant preservation of function. Indeed, experimentally, the only situations in which preconditioning has been shown to confer additional protection to that of hypothermia and cardioplegia are long ischemic times [21–23], and inhomogenous delivery of cardioplegia due to proximal coronary artery blockade [24]. It is likely that in these two settings, the beneficial effects of preconditioning are due to a reduction in the amount of necrosis resulting from suboptimal cardioplegic protection (and, in fact, in the studies documenting an added benefit of preconditioning, the early postischemic leakage of creatine kinase was consistently greater in control than in preconditioned hearts). Thus, in clinical practice, high-risk situations that could benefit from preconditioning may include: (1) extensive coronary artery disease with poor collaterals that increases the risk of cardioplegia maldistribution even with the use of combined antegrade/retrograde perfusion; (2) severe left ventricular hypertrophy (where subendocardial perfusion is problematic); (3) anticipated long ischemic times including those incurred by cardiac allografts during cold storage; (4) the senescent myocardium, more prone to develop tissue-damaging calcium overload [25], although the ability of the aged heart to respond to preconditioning remains controversial [26, 27]; and (5) beating heart minimally invasive coronary artery bypass operations where local occlusion of the target vessel results in an unprotected distal ischemia that closely mimicks the experimental models of regional ischemia where the infarct-limiting effect of preconditioning has been the most clearly demonstrated. In all these cases, the clinical use of an ischemic stimulus for inducing preconditioning is unappealing, hence the importance of identifying the endogenous mediators of this adaptative phenomenon with the goal of therapeutically exploiting their cardioprotective effects.
Pharmacological preconditioning
According to a commonly accepted scheme, the preconditioning ischemia activates various membrane receptors, including those for adenosine, catecholamines, acetylcholine, bradykinin, and opioids. The involvement of each of these receptors varies among species (adenosine, for example, mediates preconditioning in rabbit, dog, pig, and man, but not in rats) and an additive activation of preconditioning triggers could be required to reach a certain threshold beyond which cardioprotection becomes manifest [28]. Activated receptors then initiate an intracellular signaling pathway leading to the activation of protein kinase C (PKC) although the pivotal role of the latter remains questionable as other kinases (in particular the mitogen-activated protein kinase) might also be involved [29]. According to the "PKC hypothesis," activation of the enzyme leads to its translocation from the cytosol to the membrane where it phosphorylates substrate protein(s) that confer an increased resistance to ischemia. These end-effectors of the pathway are not completely characterized but the most likely candidate is the ATP-dependent potassium channel and, from a mechanistic standpoint, it is of interest that PKC can activate rabbit potassium channels at near physiological levels of ATP [30]. It has usually been considered that opening of the sarcolemmal potassium channels shortens the duration of the action potential, thereby reducing calcium influx and related tissue damage. This hypothesis has been, however, challenged by the observation that the potassium channel opener bimakalin induces cardioprotection without affecting the duration of action potential [31], which raises the possibility that mitochondrial potassium channels could rather play a predominant role in mediating the cardioprotective effects of ischemic preconditioning [32]. Another potential end-effector is the sodium–proton exchanger which normally extrudes hydrogen ions in exchange for an influx of sodium ions but can paradoxically contribute to ischemia-reperfusion-induced myocardial damage by increasing intracellular sodium producing a calcium overload through the sodium–calcium exchange. Thus, by reducing acidosis during ischemia, preconditioning could decrease the sodium–proton exchange [18]; the resulting attenuation in the rise of intracellular sodium would, in turn, reduce the rise in intracellular calcium via the sodium–calcium exchange, thereby accounting for the cardioprotective effects of preconditioning. In line with this hypothesis, it has been recently reported that these effects are achieved through the preservation of sarcolemmal sodium–potassium ATPase [33] resulting in prevention of sodium, and ultimately, calcium overload. Thus, it is noteworthy that all end-effectors under consideration share in common the property of reducing the intracellular accumulation of calcium, which is consistent with the ability of preconditioning to preserve tissue viability.
This paradigm provides a convenient framework for classifying interventions targeted at pharmacologically preconditioning the myocardium.
Interventions targeted at the triggers
Among these triggers, the most widely used has been adenosine. Experimentally, strategies designed to stimulate adenosine A1 receptors have been successful (except in rats) in duplicating the cardioprotective effects of ischemic preconditioning [34]. Data supporting a role of adenosine in preconditioning human myocardium have been more limited and, until recently was primarily based on isolated, in vitro preparations of human atrial trabeculae or cultured ventricular myocytes. Of greater clinical relevance is the report by Lee and coworkers [35] that infusion of adenosine prior to bypass in patients undergoing coronary artery operations improved postoperative ventricular function. This issue has also been addressed in a more convincing study recently published by Leesar and coworkers [36] in which the intracoronary infusion of adenosine 10 minutes before percutaneous transluminal coronary angioplasty rendered the myocardium markedly more resistant to subsequent ischemia induced by successive balloon inflations. In surgical practice, however, the use of adenosine can be fraught with several problems including down-regulation of the receptors with uncoupling from the intracellular signaling pathway and, in addition, systemic vasodilation and subsequent hypotension. It remains to be determined whether these issues will be successfully addressed by more selective A1 agonists currently under development.
Induction of preconditioning by activation of 
1-adrenergic receptors [37] is another interesting possibility since agonists of these receptors, such as phenylephrine, are available for human use. The clinical applicability of this approach remains, however, to be determined. The same holds true for stimulation of bradykinin receptors whose nitric oxide-mediated cardioprotective properties seem to mediate the antiarrhythmic effects of preconditioning [38].
Interventions targeted at the mediator(s)
These have been focused on the use of PKC agonists. However, because these activators have tumor-promoting effects, they remain useful mechanistic tools (their ability to reproduce the cardioprotective effects of ischemic preconditioning has been a major argument in favor of the role of PKC) rather than drugs for potential human use. This view could now change since calcium chloride appears to effectively precondition the heart through a PKC-dependent mechanism [39]. Although this observation is attractive because calcium can be used readily in cardiac surgical patients, it is noteworthy that it is usually given at the end of cardiopulmonary bypass or shortly thereafter. Whether an intentional calcium-induced increase in inotropism is beneficial before going on bypass remains to be established.
Interventions targeted at the end-effectors
As previously mentioned, the ATP-dependent potassium channel is currently considered one of the major effectors of the signaling pathway that leads to preconditioning-induced cardioprotective effects. This hypothesis is largely based on the observations that potassium channel openers duplicate these effects whereas they are abolished by potassium channel blockers [40]. Indeed, pharmacological opening of potassium channels has turned out to be a very successful cardioprotective strategy in a wide variety of species, including man, as demonstrated by the finding that human right atrial trabeculae can be equally protected against hypoxia by hypoxic preconditioning or prehypoxic exposure to the potassium channel opener cromakalin [41], and the more recent concordant observations that trabeculae can no longer be hypoxically preconditioned when they are harvested from diabetic patients who were on potassium channel-blocking hypoglycemic drug therapy preoperatively [42].
In the surgically relevant setting of global ischemia and cardioplegia, several reports [43–45] have documented the ability of potassium channel openers, given before standard depolarized arrest induced with potassium, to enhance functional recovery during reperfusion. In these studies, however, the drug was infused as a pretreatment until the onset of cardioplegia. Using an isolated rat heart model of 45-minute normothermic potassium arrest, we [46] have shown that the protective effects of ischemic preconditioning (achieved by 5 minutes of zero-flow ischemia followed by 5 minutes of reperfusion before arrest) on postcardioplegia systolic and diastolic function could be duplicated by nicorandil (10 µM/L), given according to a true preconditioning regimen, ie, the 5-minute drug infusion was followed by 5 additional minutes of drug-free buffer perfusion before arrest. Also, both forms of preconditioning similarly lengthened the time to peak contracture during arrest as well as the magnitude of this peak. The potassium channel blocker glibenclamide completely abolished the cardioprotective effects of nicorandil preconditioning, thereby confirming that the drug acts through modulation of potassium channel activation, whereas it only partially blunted those of ischemic preconditioning, which suggests that, at least in rat heart, other end-effectors may be involved. These normothermic experiments have been subsequently duplicated with similar results under the more commonly used conditions of hypothermic cardioplegic arrest [47]. The mechanism by which myocardial cells keep the "memory" of their transient exposure to potassium channel openers before arrest remains unclear. One possibility is that the lasting effect of the drug occurs through a lowering of the threshold beyond which potassium channels open so that they might be more readily activated during the subsequent period of global ischemia [48]. Unfortunately, the clinical administration of these drugs during cardiac operations is currently hampered by the fact that only one (nicorandil, which also has nitrate-like properties) is available for human use and can only be given orally. Furthermore, because of its poor cardiac selectivity, the antiischemic effects related to opening of potassium channels in the myocardium can only be obtained at much higher doses than those required for relaxation of smooth muscle, so that it is a concern that important hemodynamic changes due to vasodilation occur before the cardioprotective effects become apparent [49].
As one of the consequences of preconditioning is to limit acidosis during ischemia and, consequently, to reduce sodium–proton exchange, the hypothesis has been raised that inhibitors of this exchange could reproduce the cardioprotective effects of preconditioning. In support of this hypothesis is the finding that the effects of ischemic preconditioning on intracellular calcium, sodium, and ATP during ischemia are similar to those yielded by pretreatment with the antiport inhibitor amiloride [18]. However, in a rat model of regional ischemia, it has been shown that the reduction of infarct size afforded by ischemic preconditioning was additive to that of pharmacological inhibition of the sodium–proton exchange, thereby suggesting that these two protective strategies act through different mechanisms [50]. Thus, although antiport inhibitors are, by themselves, extremely effective in improving recovery following global ischemia and cardioplegia [51], there is no current evidence that the cardioprotective effects of preconditioning can be reproduced by their sole use.
Confounding factors in cardiac surgery
During cardiac operations, numerous pre- and intraoperative confounding factors may skew the preconditioning effect and should be controlled for in both experimental and clinical studies. These include, in particular, the use of opioids agonists, aprotinin, and cardiopulmonary bypass itself, which all may have preconditioning effects.
In the rat heart, opioid receptor stimulation by morphine results in a reduction in infarct size similar to that produced by ischemic preconditioning, an effect which is most likely mediated by opening of potassium channels since it is abolished by glibenclamide [52]. Recent studies from our laboratory, performed in a rat model of prolonged cold storage, have more specifically identified the 
-opioid receptor as an target for pharmacological interventions intended to electively duplicate the cardioprotective effects of preconditioning [53].
In a sheep model of regional ischemia, aprotinin has been shown to increase infarct size, an effect that was partially lessened by preconditioning [54]. Should these observations be confirmed, additional support would be provided for the use of preconditioning interventions in patients who require aprotinin therapy.
Finally, the same group of investigators [55] has also shown that cardiopulmonary bypass, by itself, could act as a preconditioning stimulus, possibly through the release of membrane-activating mediators like adenosine or catecholamines. This hypothesis is based on the observation that the reduction in infarct size achieved by short bursts of preconditioning ischemia could be duplicated by a period of cardiopulmonary bypass, whereas this cardioprotective effect of bypass was abolished by antagonists of adenosine A1 and 1 adrenoreceptors. If this hypothesis is correct, it would imply that, in any clinical study of preconditioning, "control" patients might be already preconditioned to the point that it would lessen the likelihood of demonstrating an added benefit from a superimposed intraoperative preconditioning intervention.
In conclusion, preconditioning is an extremely effective mechanism for limiting ischemia-induced cell necrosis and, consequently, preserving myocardial function. As none of our current methods of cardioplegia is perfect, improved protection could result in select cases, from the use of preconditioning. This, in turn, requires the characterization of the endogenous mediators of this phenomenon to develop pharmacologic agents that can duplicate their cardioprotective effects. At that point, the clinical evaluation of these agents will be plagued with the methodological difficulties inherent to this type of study. Nevertheless, this should not discourage us from continued efforts to better understand and therapeutically exploit this adaptive defense system which has proven to be one of the most effective infarct-limiting strategies reported so far.
Acknowledgments
This work was supported by a grant from the European Commission, Biomed-2 Concerted Action 95-0838, "The New Ischemic Syndromes." Dr Perrault is supported by the Clinician-Scientist program of the Medical Research Council of Canada.
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