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Ann Thorac Surg 1996;61:760-768
© 1996 The Society of Thoracic Surgeons

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Current Review

Optimal Myocardial Preservation: Cooling, Cardioplegia, and Conditioning

Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado

	Abstract

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Myocardial preservation techniques have evolved in conjunction with cardiac surgery and currently offer substantial protection against myocardial injury. We propose that cardiac preconditioning, a robust, endogenous mechanism of cardioprotection, is emerging as an important adjunct to current cardioplegic techniques. By reviewing the physiologic basis for current cardioplegic strategies, and understanding the cardioprotective benefits of preconditioning, we postulate that cardiac preconditioning may represent an important, clinically accessible component of myocardial protection.

	Introduction

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Myocardial preservation techniques have revolutionized cardiac surgery, but continued refinements in our practice of myocardial protection are necessary to optimize postsurgical cardiac function. The purposes of this review are to examine the components of current myocardial preservation and to introduce cardiac preconditioning as a synergistic adjunct to current strategies. We will build upon the physiologic basis of cardioplegic solutions and assess the complementary benefits of myocardial preconditioning to achieve an enhanced postoperative cardiac contractile state.

	Brief Historical Perspective (Reversible Versus Irreversible Mechanical Dysfunction)

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
In designing an optimal surgical cardiac protection strategy, it is useful to assess sequentially the progress that has already been made. Normothermic ischemic arrest provided the basis for myocardial management before the acceptance of cardioplegic solutions. Cooley and associates' report [1] of ischemic contracture of the heart (``stone heart''), however, illustrated the shortcomings of this technique. In that report, ventricular hypertrophy was identified in all of the 13 hearts in which this irreversible systolic contracture developed, thus revealing the inadequacy of unprotected myocardial ischemia especially in the setting of altered left ventricular oxygen requirements. Laboratory investigations examining the duration of ischemia suggested that the duration of normothermic ischemia required to produce injury, although somewhat species dependent, was brief (30 to 60 minutes). Jennings and associates [2] noted that 20 minutes of normothermic ischemia is completely reversible in the working canine heart; after 40 minutes half the cells are necrotic, and 1 hour of ischemia is lethal for all cells. Extrapolation of these animal investigations to humans can only be presumptive; thus the clinical lethal ischemic limit is and probably will always remain unknown. Most cardiac surgeons, however, would probably agree that irreversible ventricular muscle injury occurs with normothermic ischemia of approximately 30 minutes. The observation that the subendocardium [3] and hypertrophied ventricles [4] appear more susceptible to ischemic injury suggested that the imbalance of myocardial energy/oxygen supply relative to myocellular energy/oxygen utilization was the sole mechanism of postischemic cardiac dysfunction. Initial protection strategies logically turned to modes of decreasing myocardial oxygen demand.

	Reduction of Myocardial Oxygen Demand

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Hypothermia
Cardiac hypothermia as a method for limiting myocardial energy utilization and therefore ischemic injury originated with Bigelow and colleagues [5] and Shumway and Lower [6]. Hypothermia reduces the energy requirements of the heart by depressing all nine of Sonnenblick and associates' separate determinants of myocardial oxygen consumption [7]:

• Intramyocardial tension
  

• Ventricular pressure
  
• Ventricular volume
  
• Myocardial mass
  

• Heart rate
  
• Contractile state
  

• Force-velocity relation
  
• Maximal velocity of contraction
  

• Basal metabolism
  
• Energy associated with shortening against a load
  

• External work (load and fiber shortening)
  
• Internal work (series elastic component shortening)
  

By decreasing the three dominant modes of myocellular oxygen utilization—tension development, heart rate, and contractility—myocardial oxygen utilization plummets asymptotically to a level that Sonnenblick and associates termed ``basal.'' In the absence of myocellular contraction, the myocyte still requires oxygen for basic ``housekeeping'' functions, but even this basal cost can be further reduced with hypothermia. As shown by Buckberg and co-workers [8], normothermic arrest (37°C) decreases the oxygen demands of the heart by 90% to 1 mL O₂100 g^-1min^-1. At 22°C, oxygen requirements drop to 0.3 mL•100 g^-1min^-1 in an arrested heart. Although further reduction in oxygen consumption does occur at temperatures less than 22°C, the effects of reducing myocardial oxygen consumption below this temperature plateau such that further benefits are nominal. It soon became apparent that although hypothermia was an efficacious myocardial protectant against ischemia, reliance on hypothermia alone was not sufficient surgical protection.

Potassium Depolarization Arrest
With the addition of cold, hyperkalemic crystalloid cardioplegia to myocardial hypothermia, Conti and colleagues [9] uncovered an incremental advantage of cardioplegia plus hypothermia during cardiac operations in comparison with hypothermia alone. Although the most notable change in the cold potassium cardioplegia group was limited to lessened creatine kinase MB release, protected hearts maintained a postoperative cardiac index that was independent of aortic cross-clamp time. The conduct of routine cardiac operation had been refined to the point that it did not represent a rigorous test of myocardial preservation.

Although potassium depolarization has been a fundamental component of modern cardioplegia [10], the merits of depolarization arrest versus hyperpolarization arrest deserve consideration. Depolarizing the cardiomyocyte membrane with hyperkalemia reduces the metabolic energy demands of the myocyte; however, certain energy-dependent processes—such as membrane ion pumps—are still operative during depolarization arrest. Of these pumps, the sarcolemmal and sarcoplasmic reticular Ca⁺² adenosine triphosphatases continue functioning, as does the Na⁺K⁺ adenosine triphosphatase. Cohen and colleagues [11] argue that the energy requirements of these pumps and their movement of ions may actually contribute to ischemic injury during potassium depolarization arrest through energy depletion and the generation of ionic imbalances. They argue in favor of hyperpolarization of the membrane during ischemic arrest, as the hyperpolarized membrane exists closer to its true ``resting potential.'' They compared hyperpolarized cardioplegic arrest with a potassium adenosine triphosphate (ATP) channel agent versus traditional potassium depolarization arrest in rabbits and found improved functional outcome in the hyperpolarized group. This study is intriguing as it challenges K⁺ depolarization arrest, which has traditionally been a cornerstone of myocardial protection. The combination of hypothermia and depolarization arrest has proved vastly beneficial in comparison with warm ischemia; however, it is likely that postischemic contractile dysfunction is not exclusively an energy/oxygen supply demand imbalance, and thus other modalities of protection merit attention.

	Resuscitation of Energy-Depleted Myocardium

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
It became apparent that a particular subset of patients—those with severe left ventricular dysfunction, or those who came to operation in cardiogenic shock—manifested a reduced tolerance to aortic clamping, presumably due to preischemic depletion of their myocardial energy stores [12, 13]. Rosenkranz and colleagues [14] investigated this hypothesis by depleting the myocardial energy charge of dogs with 45 minutes of ischemia. The dogs were then randomized to receive either warm or cold induction of cardioplegia before 2 hours of continuous aortic clamping with intermittent cold blood cardioplegia. The dogs that received warm induction showed improved aerobic metabolism and improved ventricular function. The benefit of warm induction was explored further by this group in a similar study involving dogs that were subjected to brain death [15]. These animals displayed progressive hemodynamic deterioration, which was reversed by the initiation of warm induction of cardioplegia. Thus, warm induction added a new facet of myocardial protection: resuscitating the energy stores of previously abnormal hearts during cardiopulmonary bypass. The benefits of warm cardioplegic induction, however, still remain putative in clinical use.

	Continuous Warm Cardioplegia

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
The proponents of continuous warm cardioplegia cite its theoretical basis as the avoidance of direct myocellular injury inflicted by any cold solution or environment [16]. In addition, warm induction of cardioplegia allows for metabolic reparative processes [14], and a terminal ``hot shot'' of cardioplegia before removal of the cross-clamp attenuates reperfusion injury [17]. Lichtenstein and colleagues [16] thus proposed that the ideal temperature of cardioplegic delivery was warm (37°C), and that delivery of cardioplegia should be (and could be) continuous.

Early retrospective studies by Lichtenstein and colleagues [16] indicated that continuous warm blood cardioplegia was at least as effective as cold intermittent blood cardioplegia in myocardial protection. These early studies actually showed fewer perioperative myocardial infarcts (MIs), a greater postoperative cardiac output, and a reduction in low cardiac output syndrome in patients who received warm blood cardioplegia when compared with historical controls [16]. Implementing therapy based on retrospective data is difficult, however, and therefore two randomized clinical trials were performed.

The first of these randomized studies conducted by Martin and colleagues [18] randomized 1,001 patients to receive either 35°C warm cardioplegic induction with retrograde, continuous warm cardioplegia or the same induction with intermittent cold 8°C crystalloid cardioplegia. Of note, systemic body temperature was actively maintained greater than 35°C in the warm group. The data showed no difference in the postoperative rates of MI, death, or need for intraaortic balloon counterpulsation. Of substantial concern was an unexpected increased rate of perioperative stroke and overall neurologic events in the warm cardioplegic group. The second randomized, multicenter trial [19] compared continuous warm blood cardioplegia with intermittent cold blood cardioplegia and found that myocardial preservation appeared similar between these two strategies. The death rate, postoperative MI incidence, and need for intraaortic balloon counterpulsation were similar between the two groups. Further, this study did not demonstrate a greater incidence of stroke in the warm cardioplegic group, possibly because systemic temperature was cooler.

Although warm, continuous cardioplegia offers the theoretical benefits of uninterrupted, aerobic metabolism for the myocardium, and it avoids the potential detriments of direct cold injury to myocytes, several questions about this mode of myocardial protection need to be resolved. Buckberg [20] has logically expressed these concerns. To paraphrase Buckberg's conclusions, warm cardioplegia has still left unanswered (1) the flow rate of cardioplegia necessary for adequate myocardial protection, (2) the duration of interruption in flow allowable, (3) the ideal composition of the warm cardioplegic solution, (4) whether cerebral complications will be more frequent, and (5) whether more fatal perfusion accidents will occur because of the vulnerability of the brain to cessation of flow under normothermic conditions. Normothermia would theoretically appear to escalate the risk of myocardium vulnerable to inadvertent ischemic injury, as this mode of protection is based on a homogenous delivery of cardioplegia. This uniform distribution of warm cardioplegia is yet to be established, but adequate distribution of infused solutions is a critical determinate of the efficacy of cardioplegia-based myocardial preservation strategies.

	Attenuation of Intracellular Ionic Dyshomeostasis

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Intracellular Acidosis
The processes responsible for generating H⁺ ions during ischemia principally include anaerobic glycolysis with resultant lactate production [21] and hydrolysis of ATP [22]. Of fundamental concern to cardiac surgeons, acidosis possesses a profoundly negative inotropic effect in myocardium [23]. Glycolysis, which becomes the dominant metabolic pathway responsible for generating ATP during ischemia, is inhibited by acidosis [24], and the function of myocardial contractile proteins are depressed [25]. Animal studies have suggested that a relationship does exist between myocardial pH and recovery [26], but this relationship has been less well characterized in clinical studies.

The proteins in blood—particularly the imidazole group of histidine residues—provide efficacious buffering of H⁺ ions in the physiologic range [27]. In addition, histidine-buffered crystalloid cardioplegic solutions maintain similar levels of myocardial tissue pH when compared with a blood-based solution [28]. Tromethamine and bicarbonate have been examined as additives in blood cardioplegia with the intent of normalizing intracellular pH: although tromethamine-supplemented blood cardioplegia preserved myocardial pH, bicarbonate supplementation did not [29]. Studies documenting the efficacy of pH control during cardiac operations have predominantly focused on pH from the coronary effluent, or myocardial tissue pH as an end point. Although animal models suggest a relationship between pH and recovery of function, the clinical advantages of modifying intracellular pH need further investigation.

Intracellular Calcium Homeostasis
The association of increased intracellular Ca⁺² and irreversible myocellular injury was first demonstrated by Shen and Jennings [30]. Subsequently, altered Ca⁺² modulation has been suggested as the potential mediator of myocardial stunning [31, 32]. Indeed, the increase in postischemic cytosolic calcium retards actin-myosin filament disengagement, leading to the loss of diastolic compliance (increased stiffness) that is characteristic of post–cardiopulmonary bypass cardiac function. As calcium flux across the sarcolemmal membrane mediates myocardial contractile function, a substantial effort has been undertaken to attenuate the increased intracellular Ca⁺² after ischemia. The L-type Ca⁺² channel has been targeted as the source of increased Ca⁺² after ischemia, and thus most efforts at reducing Ca⁺² overload have focused on the use of L-type Ca⁺²-channel blockers. In a canine study of regional ischemia-reperfusion, it was demonstrated that preischemic treatment with verapamil reduced infarct size; however, if infusion of verapamil was delayed until reperfusion, this effect was lost [33]. Christakis and colleagues [34] subsequently studied the use of diltiazem with cardioplegia in a randomized fashion. Although this group demonstrated enhanced metabolic indices of myocardial recovery with diltiazem, the negative dromotropic effects, specifically the occurrence of atrioventricular blockade, and the negative inotropic effects of diltiazem outweighed any of the metabolic benefits. Presently, the clinical evidence concerning calcium-channel blockers in cardioplegic solutions does not support their use due to these side effects.

Recently, attempts to restore Ca⁺² homeostasis independent of Ca⁺² channels have also been undertaken. Kitakaze and colleagues [35] have proposed that acidotic reperfusion (pH = 6.6 during minutes 0 to 3, and pH = 7.0 during minutes 4 to 6 of early reperfusion) attenuated myocardial stunning in ferret hearts. This study inferred that the improved postischemic recovery of function was because acidosis mitigated Ca⁺² overload, although intracellular Ca⁺² levels were not measured to confirm this proposed mechanism. Magnesium supplementation represents another method to attenuate ischemia-reperfusion–induced changes in contractile function that has recently been employed. Brown and colleagues [36] studied the effects of Mg⁺² in relation to concentrations in cardioplegia and found that cardioplegia with high levels of Mg⁺² and low levels of Ca⁺² improved postischemic ventricular function in rat hearts. Caspi and colleagues [37] explored this experimental work clinically, when they randomized patients to receive systemic magnesium supplementation before aortic cross-clamping or a non–magnesium-supplemented infusion. They found improved postoperative mechanical function and an attenuation of arrhythmias in the Mg⁺²-treated group. Currently, although it is conceptually appealing to implicate improved postischemic function with an improvement in Ca⁺² handling by the myocyte, this fundamental concept has been difficult to prove clinically.

	Scavenging of Toxic Oxygen Metabolites (Blood Cardioplegia)

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Investigations into the physiology of myocardial ischemia-reperfusion indicate that reperfusion by itself is a separate insult associated with an early burst of toxic oxygen metabolites [38]. Although blood was initially added to crystalloid cardioplegia as a source of oxygen, it soon became apparent that the delivered oxygen (especially hyperoxia) was a two-edged sword. Animal investigations have revealed that reperfusion of ischemic hearts results in an explosive release of oxygen free radicals, which have the capacity to damage myocardial membranes through lipid peroxidation. Attempts to modify this oxidant stress emphasized one of the salutary features of blood cardioplegia: its role as a toxic oxygen metabolite scavenger [39]. Work in our laboratory assessing blood cardioplegia with a hematocrit as low as 0.5% (or pretreated with carbon monoxide) revealed that red blood cells were uniquely protective of ventricular function [38]. Augmentation of oxygen delivery was clearly not the mode of protection. Conversely, red blood cells depleted of catalase and glutathione (oxygen radical scavengers) lost their protective ability, suggesting that the functional protection was conferred by these agents. It is also important, however, to note that red cells confer salutary benefits in cardioplegia that are separate from their antioxidant role [40].

Reduction of oxidant stress during reoxygenation injury has also been attempted by administering antioxidants and iron chelators in cardioplegic solutions [41]. Allopurinol-supplemented blood cardioplegia has been examined in dogs exposed to 30 minutes of normothermic ischemia followed by hypothermic blood cardioplegia with or without allopurinol. Postischemic left ventricular performance was enhanced in the allopurinol group. Iron chelators, particularly deferoxamine, also have been employed on the basis that hydroxyl radicals are known to be catalyzed by iron. Improved postischemic ventricular function in animal models with deferoxamine has been reported as well [42]. Deferoxamine has also been shown to reduce free radical formation during cardiopulmonary bypass in human myocardium, but the issue of whether this inhibition of free radical formation correlated with improved function was not addressed by this study [43]. Overall, although inhibition of radical-induced injury with free radical scavengers is attractive from a theoretical standpoint, like with other cardioplegic additives, benefit in humans subjected to bypass with these agents has been difficult to demonstrate convincingly.

Others have focused on limiting reoxygenation injury by introducing the concept of ``controlled cardiac reoxygenation'' [44]. This group demonstrated a reoxygenation injury in hypoxic piglets that were subjected to cardiopulmonary bypass with conventional normoxic oxygen tension (400 mm Hg). Conversely, piglets that were delivered an oxygen tension of 25 mm Hg until cardiopulmonary bypass was instituted with blood cardioplegia did not sustain this reoxygenation injury. Morita and associates [44] note that this ``unintentional'' reoxygenation injury nullifies the protective effects of blood cardioplegia, thus describing the potential role for controlled reoxygenation to limit postischemic contractile dysfunction. The alternative strategy of scavenging the toxic oxygen metabolites associated with reoxygenation may prove more practical.

	Substrate Enhancement

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Once we have reached the apparent limit in our capacity to further reduce cardiac energy-oxygen demand and oxidant-mediated damage, the next logical strategy is to enhance energy production during ischemia in an oxygen-independent fashion. Attempts to improve myocardial mechanical function after global ischemia include the generation of ATP from pathways other than aerobic and anaerobic glycolysis. Rau and colleagues [45] investigated amino acid utilization through anaerobic pathways to provide ATP synthesis during ischemia. Infusion of three amino acids—glutamate, aspartate, and ornithine—during ischemia provided for augmented recovery of contractile function in isolated rabbit septa. The mechanistic basis for this improved recovery is that glutamate is transaminated to -ketoglutarate, which directly enters into the tricarboxylic acid cycle and provides for nonglycolytic generation of ATP. Aspartate uses the malate-aspartate shuttle. Aspartate is converted to oxaloacetate, which subsequently picks up cytosolic reducing equivalents as the reduced form of nicotinamide adenine dinucleotide is oxidized in the conversion of oxaloacetate to malate. Malate transports into the mitochondria, where it donates the reducing equivalents when malate is converted back to oxaloacetate, which liberates the reducing equivalents for ATP synthesis. These tricarboxylic acid cycle intermediates provide for ATP generation by replenishing substrates lost during ischemia. In pioneering work, Buckberg's group [46] established improved mechanical function and metabolic profiles in adult dogs with glutamate supplemented cardioplegia. Specifically, these investigators found increased rates of contraction and relaxation, improved stroke work index, and improved recovery of ATP with glutamate-enhanced cardioplegia. Engleman's group [47] showed a reduction in infarct size in a swine model of regional ischemia-reperfusion injury using glutamate and aspartate during reperfusion. They also demonstrated improved levels of ATP and acetyl coenzyme A in animals receiving glutamate and aspartate, which again confirms that these amino acids exert their salutary effects through the malate-aspartate shuttle and tricarboxylic acid cycle intermediates [47].

A clinical report described the use of warm glutamate/aspartate-enriched cardioplegia in 14 patients after witnessed perioperative arrest [48]. Remarkably, 13 of the 14 patients had enhanced recovery of their ejection fraction when compared with preoperative levels, and 11 of 14 patients survived to discharge. It is uniquely difficult to control the multitude of variables in any clinical study; however, this study was conducted in patients on cardiopulmonary bypass, and thus it provides important circumstantial evidence supporting the use of glutamate and aspartate, although the survival benefit in this study cannot be definitively linked to their presence in the cardioplegic solutions.

Recently, novel agents that could impart a therapeutic benefit against ischemic injury, although their administration was delayed until after ischemic injury has occurred, have been described by Abd-Elfattah and colleagues [49]. They reported full recovery of left ventricular contractile function after 30 minutes of normothermic, global ischemia in dogs given erythro-9-(2-hydroxy-3-nonyl)adenine (an adenosine deaminase inhibitor) and p-nitrobenzyl-thioinosine (a nucleoside transport blocker) both before ischemia and after ischemia. Interestingly, although left ventricular function recovered in the group receiving these agents after ischemic injury, the myocardial adenosine and ATP levels were not augmented in this group. These findings that imply that recovery of contractile function can occur with these agents, despite depletion of the nucleoside and ATP pools. Although these observations are intriguing, the clinical benefits of these agents are still unknown.

	Antidysrhythmic Agents

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Reperfusion associated dysrhythmias represent a potential for morbidity and mortality postoperatively and may also exacerbate myocellular energy imbalance. Lidocaine is proposed to control post–cardiopulmonary bypass dysrhythmias [27]. In a study by Fiore and associates [50] in which lidocaine was administered with blood cardioplegia, fewer patients experienced ventricular fibrillation compared with controls. Additionally, the lidocaine group required fewer cardioversion attempts to defibrillate the heart after cardiopulmonary bypass. The putative mechanisms of lidocaine's protection were not elucidated in this study, but it was speculated that lidocaine stabilized membranes [50]. Similarly, procaine has been employed in cardioplegic solutions and has been advocated as a membrane stabilizer in addition to its antidysrhythmic effects [51].

	Preischemic Endogenous Myocellular Protection: Cardiac Preconditioning

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Cardiac preconditioning has emerged as a powerful, endogenous mechanism whereby tolerance to myocardial ischemia can be enhanced. Cardiac preconditioning, induced by antecedent ischemia, was first reported by Murry and co-workers [52], who originally described protection against infarction. In this intriguing study, they noted that dogs subjected to four brief 5-minute coronary artery occlusions interspersed with reperfusion paradoxically sustained smaller infarcts when subsequently subjected to 3 hours of coronary occlusion than dogs not given this ``ischemic preconditioning'' stimulus. This endogenous protection has now been reported in a variety of animal species, including rabbits [53], swine [54], and rats [55]; most importantly, evidence is now emerging to suggest that preconditioning extends to humans [56–58]. In addition, the benefits of preconditioning now extend beyond that of infarct size limitation: preconditioning has been shown to prevent arrhythmias [59], reduce myocellular acidosis [60], and attenuate postischemic contractile dysfunction [55]. Whether preconditioning attenuates postischemic contractile dysfunction solely through infarct size reduction or whether it also attenuates stunning is a controversial and currently unresolved issue.

Insights into the existence of human cardiac preconditioning can be gleaned from clinical reports that infer that preconditioning mediates a beneficial role in modifying ischemia/reperfusion injury in humans. Deutsch and colleagues [61] examined 12 patients undergoing percutaneous transluminal coronary angioplasty and reported functional and metabolic adaptation during serial balloon inflations. This group compared the sensation of chest discomfort, the mean pulmonary artery pressure, ST elevation, and myocardial lactate production after two 90-second balloon inflations. All of the parameters examined were lessened after the second balloon inflation when compared with after the first balloon inflation. They inferred from these data that adaptation to the second period of ischemia had been conferred by the preceding period of transient ischemia.

Two recent clinical reports also offer insights into the occurrence of preconditioning in humans. Kloner and colleagues [62] retrospectively analyzed patients in the Thrombolysis in Myocardial Infarction 4 study and found that the subset of patients who experienced angina 48 hours before their infarct had smaller infarcts and a more favorable outcome compared with patients who did not have angina before their MI. Ottani and his group [63] independently reported a retrospective analysis of 25 patients who presented with their first MI. They also noted that angina within 24 hours before the MI conferred benefit in reduction of infarct size. Together, these reports suggest a protective role for prodromal angina that is mediated by ischemic preconditioning. Although clinical studies are valuable, it is difficult to control the vast number of variables that could confound these conclusions.

A limited number of preliminary reports suggest that human myocardium can be preconditioned. Yellon and colleagues [58] conducted a study in 14 patients undergoing cardiopulmonary bypass during coronary artery bypass grafting. The preconditioned group had an ischemic stimulus delivered by two 3-minute cycles of aortic cross-clamping while the heart was paced at 90 beats/min. When myocardial ATP levels were compared with controls at the end of a subsequent 10 minutes of aortic cross-clamping with mildly hypothermic ventricular fibrillation, the preconditioned group had higher levels of tissue ATP [58]. This study, however, did not address the potential of using preconditioning as an adjunct to cardioplegia, and the results cannot be extrapolated to current cardioplegic techniques, as both cardioplegia and preconditioning may share an ATP-sparing effect. These investigators have also recently reported that human atrial tissue obtained from patients undergoing cardiac operations can be preconditioned in vitro with ischemia. They examined the contractile responses of human atrial tissue and found that tissue treated with ischemia before prolonged ischemia/reperfusion had preserved contractile function when compared with controls [57]. Ikonomidis and colleagues [56] have also reported that isolated cardiomyocytes from human ventricle can be preconditioned. Although these insightful studies imply that human myocardium can be preconditioned, only Walker and associates' [57] study of human atrial tissue offered mechanistic insights, as they gave an adenosine agonist that reproduced the protection conferred by ischemia, and they blocked the protection of ischemia with an adenosine antagonist, thus implicating a role for adenosine's involvement in human myocardial preconditioning. In the context of this study, however, it must be appreciated that adenosine was evaluated in an isolated tissue bath system, where side effects such as conduction delays and hypotension, which are common in vivo, did not occur. Because of these undesirable effects of adenosine and its short half-life, analogues of adenosine or agents that pharmacologically enhance adenosine's local action may be clinically more relevant to the cardiac surgeon who wishes to employ preconditioning using adenosine-receptor–based signaling.

The importance of understanding the mechanism(s) underlying cardiac preconditioning lies in the clinical applicability and accessibility of this potent protection; it is unlikely that clinicians will deliberately subject their patients to intentional (even transient) ischemia. Thus, the signaling mechanisms that are triggered by the first brief ischemic episode that confers protection are an active area of investigation. A variety of agents have been proposed to mediate the protection of preconditioning; however, two signaling pathways have emerged in animal models: adenosine activation [53] and ₁-adrenergic activation [55].

The hypothesis that the transient episode of ischemia releases adenosine, which then mediates the protection against the subsequent ischemic injury, is attractive. Adenosine is released by ischemic myocytes and has protective effects when infused before ischemia [64]. In addition, Liu and associates [53] implicated adenosine as a mediator of ischemic preconditioning in a rabbit infarct model. The ₁-adrenergic pathway has also emerged as a clinically accessible mediator of ischemic preconditioning. Noradrenergic nerve termini are present in the mammalian heart, and norepinephrine release from these termini occurs in response to ischemia [65]. Work from our laboratory indicates that nonselective -adrenoceptor stimulation (norepinephrine), as well as ₁-adrenoceptor stimulation (phenylephrine), could confer protection against ischemia/reperfusion in an isolated perfused rat heart [55].

Although the emergence of these two seemingly unrelated receptor pathways as mechanistic explanations for ischemic preconditioning was initially somewhat confusing, further work reveals that both of these receptor-based pathways are capable of activating protein kinase C. This finding has illuminated the signal transduction of ischemic preconditioning [66–68]. In fact it now seems that the activation of protein kinase C is an obligatory event in mediating the protection of cardiac preconditioning (Fig 1). Intracellular protein kinase C activation can be accessed by either ₁-adrenergic or adenosine receptors located in the sarcolemma. Subsequently, diacylglycerol and inositol triphosphate are released, with both agents independently activating protein kinase C. This working hypothesis is intuitively appealing, as protein kinase C–mediated phosphorylation of target proteins [69], ion channels [70], and the myofilaments [71] occurs rapidly and is plausible in explaining the protection of cardiac preconditioning.

View larger version (31K): [in this window] [in a new window]   Fig 1. . Convergence of both 1-adrenergic and adenosine receptor pathways upon activation of protein kinase C (PKC), which appears obligate in providing cardioprotection against ischemia-reperfusion injury in the cardiomyocyte. (Ado = adenosine; ATP = adenosine triphosphate; DAG = diacylglycerol; G = G protein; IP3 = inositol triphosphate; NE = norepinephrine; PL = phospholipase.)

View larger version (15K): [in this window] [in a new window]   Fig 2. . Incremental beneficial effects of the various components of current cardioplegia. This is an attractive working hypothesis, based on the interpretation of multiple studies, to conceptually understand the basis for current cardioplegia. The top staircase line represents the amount of protection, expressed as percent normal ventricular function, that is cumulatively added by each component. The bottom solid bars represent the individual protection of each component. It is our hypothesis that preconditioning (PC) will add an incremental benefit to current cardioplegic techniques.

	Recommendations

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

	Acknowledgments

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Supported by National Institutes of Health grants HL-43696, HL-44186, and GM 08315.

	Footnotes

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 
Address reprint requests to Dr Cleveland, Department of Surgery, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Box C-305, Denver, CO 80262.

	References

Top Footnotes Abstract Introduction Brief Historical Perspective... Reduction of Myocardial Oxygen... Resuscitation of Energy-Depleted... Continuous Warm Cardioplegia Attenuation of Intracellular... Scavenging of Toxic Oxygen... Substrate Enhancement Antidysrhythmic Agents Preischemic Endogenous... Recommendations Acknowledgments References

 

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