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Cardiovascular Research 2006 70(2):174-180; doi:10.1016/j.cardiores.2006.01.020
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Copyright © 2006, European Society of Cardiology

Clinical applicability of preconditioning and postconditioning: The cardiothoracic surgeons's view

Danny Ramzy, Vivek Rao* and Richard D. Weisel

Toronto General Hospital, University Health Network, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada

* Corresponding author. Alfredo and Teresa DeGasperis Chair in Heart Failure Surgery, Surgical Director, Heart Transplant Program, 4N464, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, Canada M5G 2C4. Tel.: +1 416 340 3562; fax: +1 416 340 3337. Email address: vivek.rao{at}uhn.on.ca

Received 5 December 2005; revised 21 January 2006; accepted 26 January 2006


   1. Introduction
Top
 1. Introduction
2. Ischemic preconditioning
 3. Pharmacological...
 4. Remote preconditioning and...
 5. Conclusions
 References
 

"Any surgeon who operates upon the heart should lose the respect of his colleagues." Theodor Billroth

The field of cardiac surgery has progressed significantly since this 19th century quote from Dr Billroth. The ability to perform cardiac procedures was limited by the inability to support the circulation and to offer adequate myocardial protection. Cardiac surgery as a profession was made possible by our ability to translate experimental research into the clinical arena. Two major concepts allowed the feasibility of open-heart surgery: 1) the development of mechanical circulatory support and 2) our understanding of myocardial protection. Myocardial protection refers to all strategies that increase the myocardium's ability to withstand an ischemic insult. Ischemic and reperfusion injuries are principally responsible for cardiac failure, morbidity and mortality following cardiac surgery. Bigelow et al.'s original work on hypothermia, driven by the desire to protect the brain from ischemic insult, led to the discovery that the myocardium also benefited from hypothermia during cardiac surgery [1]. The next development in the field of myocardial protection was the use of cardioplegia. Melrose et al. first used their solution to initiate cardiac arrest as well as to cool the heart [2,3]. Their strategy combined two methods of myocardial protection: hypothermia and cardiac standstill. Both strategies reduce myocardial oxygen demand and therefore decreased ischemic injury.

The field of myocardial protection then shifted to providing oxygen to the myocardium while arrested. The use of blood was introduced as a method to increase myocardial oxygen delivery [4]. Cardiac surgeons quickly adopted blood cardioplegia as their myocardial protective strategy of choice. This strategy remains the mainstay of myocardial protection. Cardioplegia protects the myocardium by providing continuous or intermittent oxygen while simultaneously reducing cardiomyocyte oxygen demand through both hypothermia and cardiac arrest. Although an effective strategy, cardioplegia does not inherently increase the ischemic tolerance of the myocyte.


   2. Ischemic preconditioning
Top
 1. Introduction
 2. Ischemic preconditioning
3. Pharmacological...
 4. Remote preconditioning and...
 5. Conclusions
 References
 
In 1986, Murry et al. demonstrated a new concept in myocardial protection, ischemic preconditioning (IPC) [5]. IPC refers to the phenomenon of inducing tolerance to ischemia–reperfusion injury by controlled brief periods of ischemia prior to a prolonged ischemic insult. This landmark study exposed dog hearts to four short periods of ischemia and reperfusion resulting in a 75% reduction in infarct size after a subsequent 40-min ischemic insult. They also demonstrated that IPC was not a result of opening of collaterals. Murry's observations further revealed that the protective effects of IPC are overwhelmed by a prolonged and sustained ischemic insult lasting 3 h. Their findings indicated that IPC delays rather that completely prevents cell death. Following this discovery, IPC has been demonstrated in several different animal species as well as in humans.

IPC has two phases: an early phase lasting from a few minutes to several hours and a late phase that starts after 12 h and lasts up to 3 days. IPC as described by Murry et al. is referred to as classic or early preconditioning, and the late phase is referred to as delayed preconditioning [5–7].

2.1 Clinical benefits of IPC
Preconditioning offers the cardiac surgeon the promise of rendering the myocardium resistant to future ischemic insults seen during coronary artery bypass surgery (CABG), valvular surgery or following cardiac allograft storage and transplantation. Since its original description, over 3000 articles have described this phenomenon. Despite this enormous body of work, IPC has yet to be adopted by the cardiac surgical community as readily as hypothermia and cardioplegia. Several reasons may explain the reluctance of cardiac surgeons to adopt IPC as their method of myocardial protection. Although the majority of clinical studies on IPC demonstrated benefit, some demonstrated no benefit and a small number even showed harm [8–14]. The first clinical study analyzing IPC in the setting of CABG was described by Yellon et al. [11]. In this small study, patients undergoing CABG (n=14) were randomized to a 10-min insult of cross-clamp fibrillation or two 3-min periods of cross-clamping followed by a 2-min period of reperfusion [11]. They observed a significant 76% increase in the ATP concentration in myocardial biopsies from the IPC group following the ischemic insult [11]. Baldwin et al. confirmed Yellon's observation in a dog model of IPC [8]. Myocardial ATP levels were higher in the IPC region compared to the non-IPC region. In addition, they showed significant improvement in myocardial glucose uptake as well as cardiomyocyte contractile function [8]. Illes et al. demonstrated in a larger study that IPC improved cardiac function. Induction of IPC was achieved with a 1-min period of aortic cross-clamping followed by a 5-min period of reperfusion before the initiation of blood cardioplegic arrest [14]. Although IPC resulted in a 32% improvement in cardiac index 12 h following bypass with no requirement for inotropic support, no significant differences were seen in creatine kinase-MB (CK-MB), morbidity or mortality between groups [14]. However, Jenkings et al. did observe a significant 80% reduction in troponin T levels 72 h following CABG in the IPC group [9]. In contrast, Pego-Fernandes et al. showed no significant differences in CK-MB, troponin T, adenosine, and lactate levels between control and the IPC group [12]. Cremer et al. demonstrated that patients undergoing two 5-min cycles of ischemia followed by 10 min of reperfusion prior to CABG had no benefit over blood cardioplegia and may have been harmed as seen by impairment in myocardial contractility [10,15]. In their studies, no differences in mortality were seen between treatment groups [10,15]. Perrault et al. also showed no IPC-enhanced protection over warm retrograde cardioplegia. They concluded that IPC may be detrimental to the myocardium as assessed by increased CK-MB in the IPC group and that pharmacological preconditioning may be a better strategy. However, Teoh et al. demonstrated in two studies that IPC is superior to intermittent cross-clamp fibrillation, cold crystalloid cardioplegia, and pharmacological preconditioning [16,17]. In their first study, they compared IPC to pharmacological preconditioning [16]. Thirty patients were randomly assigned to one of three groups. Groups consisted of intermittent cross-clamp fibrillation alone, a GR79236X (selective adenosine A1 receptor agonist) group, and an IPC group. IPC was achieved by two 3-min periods of ischemia followed each by a 2-min period of reperfusion. They demonstrated that IPC results in a 56% and 52% reduction in troponin T release compared to fibrillatory cross-clamp alone and GR79236X, respectively. Their second study showed that IPC results in a 71% and 54% reduction in troponin T levels compared to fibrillatory cross-clamp alone and cold crystalloid cardioplegia [17]. In this study, the IPC group did not receive cardioplegia. Whether cardioplegia would have enhanced or negated the protective effects of IPC remains unknown. In both of their manuscripts, no significant differences in myocardial function were seen between groups.

2.2 Strategies for inducing IPC
IPC is achieved in the operating room by intermittent aortic cross-clamping. This technique has several drawbacks including an increased stroke rate as a result of manipulation of the atherosclerotic aorta. The clinical significance of a potentially increased stoke rate from the atherosclerotic aorta is of such concern that clinical trials exclude patients with high risk of embolization from their studies. Illes et al. only included primary cardiac cases and excluded reoperations due to increased risk of embolization [14]. Although cross-clamping the aorta is a relatively simple process several issues remain such as 1) number of ischemia reperfusion cycles, 2) length of cross-clamp and 3) time period between cycles [18]. Several investigators have found that too few or too many cycles of ischemia–reperfusion had no effect on the degree of protection afforded by IPC, whereas others have found that the level of myocardial protection varied directly with the intensity of the IPC stimulus [19–21]. Alkulaifi et al. demonstrated that the time period between ischemia reperfusion cycles was critical [18]. In a rodent model, they showed that when the interval between IPC episodes are reduced to 30 s from 1 min, the protective effects of IPC were lost [18]. In a swine model, Schulz et al. observed that IPC was a graded phenomenon [20]. They showed that 2 min of preconditioning ischemia was insufficient to trigger the protective effects of IPC, whereas 3 and 10 min of preconditioning ischemia resulted in a significant reduction in myocardial infarct size. They also observed that 10 min of ischemia was superior to 3 min. Barbosa et al. confirmed in a rodent model that increasing preconditioning ischemia time enhanced the myocardial protective effects of IPC [21]. Although animal studies indicate that longer preconditioning ischemia and greater cycle interval time results in superior protection, the optimal strategy to induce IPC in the clinical setting remains unclear [18,20,21].

Whether IPC offers increased myocardial protection in addition to cardioplegia is another important issue requiring study [13,17,22]. Faris et al. demonstrated using rabbit hearts that IPC failed to improve on cardioplegic myocardial preservation [22]. They examined myocardial function using a Langendorff apparatus in order to assess the more clinically relevant end-point of stunning [22]. They observed that in the absence of significant injury, IPC did not improve on cardioplegic protection [22]. The same group demonstrated in a clinical trial that IPC did not improve upon the protective effect of cardioplegia [13]. Teoh et al. demonstrated that IPC was beneficial and offered superior protection than cardioplegia alone. However, they did not analyze the effect of IPC combined with cardioplegia.

2.3 Clinical applicability of IPC
The applicability of IPC may be limited to situations were the myocardium is not protected by intermittent cardioplegia or in patients with no coronary or aortic disease requiring valvular repair/replacement or in cardiac transplantation [23]. These patients are at lower risk of stroke with intermittent cross-clamping. In clinical cardiac transplantation, the mainstay of myocardial protection remains cold hypothermic arrest and storage. The allograft does not receive cardioplegia until its arrival at the recipient table or following implantation. In this setting, IPC may confer myocardial protection to the allograft. In several animal studies of cardiac transplantation IPC demonstrated benefit [24–28]. Karck et al. revealed that IPC improved myocardial protection following hypothermic storage [25]. They also showed that IPC enhanced myocardial preservation even in groups that received various preservation solutions. Kevelaitis et al. demonstrated in a rodent model that IPC protected the allograft from ischemic injury following cardiac transplantation [27]. They also observed that cariporide (Na+/H+ exchange inhibitor) offered preconditioning-like effects, however, to a lesser extent than IPC [27]. When they combined IPC with cariporide, it resulted in superior myocardial preservation than IPC alone as measured by systolic and diastolic function, CK leakage, coronary blow flow, and myocardial water content [27]. Their study indicated that pharmacological preconditioning could offer protection in addition to IPC. We have recently demonstrated that intermittent donor blood perfusion enhanced myocardial protection following cardiac transplantation, suggesting that intermittent blood perfusion has a preconditioning-like effect [29]. We hypothesized that intermittent cardioplegia mimics IPC or offered significant protection that overshadows the potential benefit of IPC.

A further concern with IPC is whether the already damaged myocardium (from previous myocardial infarctions) can be protected or rendered more dysfunctional by intermittent cross-clamping. It is important to mention that all the above studies were performed in either animals with normal myocardium/coronaries or in patients with near normal ejection fraction. Although several clinical studies focused on patients with normal or near-normal ejection fractions, there are a paucity of experimental investigations that observed the effects of IPC in the diseased heart [30–32]. Li et al. demonstrated in an atherosclerotic model that IPC can be induced [30]. This provides some evidence that IPC may be achieved in the clinical arena. Further studies are required to assess the potential advantages of IPC in the damaged or severely diseased heart.


   3. Pharmacological preconditioning
Top
 1. Introduction
 2. Ischemic preconditioning
 3. Pharmacological...
4. Remote preconditioning and...
 5. Conclusions
 References
 
Since the description of IPC by Murry et al., several studies investigated the mechanisms behind its protective effects. Determining the mechanisms by which IPC confers myocardial preservation may eventually lead to the development of therapies to reduce cardiomyocyte injury following cardiopulmonary bypass. These studies led to the discovery that preconditioning can be induced by pharmacological means [16,17,20,27,33–39]. The protective effects of pharmacological preconditioning (66–85% reduction in infarct size) are similar to that observed in Murry's original study (75% reduction in infarct size) [16,17,20,27,33–39]. However, the clinical benefit of pharmacological preconditioning has yet to be as convincing. In addition, which agent or combination of agents is required to elicit optimal preservation has yet to be elucidated. Pharmacological preconditioning offers the benefit of IPC without the drawback of intermittent cross-clamping. In addition, the cardiac surgeon can utilize pharmacological preconditioning readily through direct access via the cardioplegic cannulae. Pharmacological preconditioning offers the promise of an easy and effective way to mimic preconditioning without ischemia and may provide additional benefit to cardioplegic protection. The theoretic enhanced protection of pharmacological preconditioning over IPC may occur through the simultaneous effects of cardioplegia (hypothermia and cardiac standstill) and the preconditioning mimetic versus the protective effect of IPC followed by the protective effect of cardioplegia as seen with current IPC strategies. However, clinical studies demonstrate conflicting results. Teoh et al. demonstrated the IPC was superior to both cardioplegia and pharmacological preconditioning, whereas Kevelaitis et al. showed that pharmacological preconditioning did offer myocardial preservation and that it enhanced the protective effects of IPC [16,17,27,39]. Further clinical studies are needed to determine if pharmacological preconditioning provides the same benefit as IPC and whether it can enhance IPC-mediated myocardial preservation.


   4. Remote preconditioning and postconditioning
Top
 1. Introduction
 2. Ischemic preconditioning
 3. Pharmacological...
 4. Remote preconditioning and...
5. Conclusions
 References
 
Two novel strategies have recently been described: 1) remote preconditioning [40–48] and 2) postconditioning [49–56]. These two strategies offer the best potential of becoming the new mainstay of myocardial protection. Remote preconditioning is the phenomenon that occurs when an organ is submitted to sublethal periods of ischemia and reperfusion to confer protection to another organ. For the cardiac surgeon, it refers to submitting a non-cardiac organ to periods of ischemia and reperfusion to achieve myocardial preservation. Postconditioning is the event that renders myocardial protection following the ischemic insult either pharmacologically or by intermittent cross-clamping.

4.1 Remote preconditioning
Remote preconditioning has several desirable aspects: 1) confers to the heart the same benefit of IPC, 2) avoids intermittent cross-clamping of the potentially atherosclerotic aorta, 3) avoids ischemic insult to the diseased heart (ischemic due to coronary artery disease), and 4) relatively easy to perform. Remote preconditioning can be initiated for example by intermittent cross-clamping of the renal artery, mesenteric artery (MA), infrarenal aorta or iliac artery. Wolfrum et al. demonstrated that MA occlusion achieved preconditioning protection [42]. In their rodent model, they occluded the MA for 15 min and reperfused for 15 min prior to the ischemic insult. Infarct size was reduced by 48% compared to their control group. A 48% reduction in infarct size is significant; however, it is lower than the 66–85% reduction seen with IPC. This study did not compare whether IPC and remote preconditioning offer the same degree of protection. Weinbrenner et al. utilized an infrarenal aortic occlusion technique and achieved remote preconditioning in their rodent model [43]. They observed that remote preconditioning significantly reduced infarct size by 71% compared to control. Comparison of the classical IPC group to remote preconditioning demonstrated no significant differences (81% vs. 71% infarct reduction) [43]. Similar to IPC, remote preconditioning demonstrated a dependency on preconditioning ischemia time [43]. Infrarenal occlusion of less than 15 min conferred inferior protection to the myocardium (32–40% infarct reduction) [43]. The same group confirmed their results in another study demonstrating remote preconditioning protective effects through infrarenal aortic occlusion [46]. Clinically remote preconditioning has the drawback of requiring opening of the abdomen with its potential complications. Furthermore, the cardiac patient often has renal impairment or peripheral vascular disease that makes intermittent renal ischemia a hazard to renal function. Even transient lower leg ischemia may not be tolerated in the vasculopath. Remote preconditioning can also be induced by intermittent upper limb ischemia. Upper limb ischemia can be achieved by intermittent inflation of the blood pressure cuff or with the use of a tourniquet [41]. This method has the advantages of being facile and potentially offers the same protection as other forms of remote preconditioning. This method of remote preconditioning can provide either early preconditioning protection if done just prior to the operative procedure or late preconditioning if done 1 to 3 days before the cardiac procedure. Gunaydin et al. demonstrated the feasibility of an upper limb remote preconditioning protocol [41]. In a small study (n=8), they used a tourniquet around the right upper extremity of the patient and inflated and deflated twice to perform a 3-min period of ischemia separated by a 2-min period of reperfusion in the preconditioning group [41]. Although they observed no differences in CK levels, they did show that LDH levels were significantly lower in the remote preconditioning group. Their data indicated that remote preconditioning appeared to enhance anaerobic glycolysis and improve myocardial protection. A larger study is required to determine the potential benefit of this strategy in the clinical setting. The combination of remote preconditioning and cardioplegic protection may offer the best strategy for myocardial protection during cardiac surgery.

4.2 Postconditioning
Postconditioning, brief periods of ischemia performed just at the time of reperfusion, can be easily performed at the end of a prolonged ischemic insult. Zhao et al. first described this phenomenon [57]. Using a canine LAD ligation model, they compared the protective effects of IPC to that of postconditioning. Their control groups received an LAD occlusion for 60 min and reperfused for 3 h, the IPC group had the LAD occluded for 5 min followed by 10 min of reperfusion before regional ischemia and the postconditioning group had reperfusion initiated for 30 s followed by 30 s of reocclusion which was repeated for three cycles after LAD occlusion. Their study showed that postconditioning reduced infarct size by 44% compared to control, while no differences were seen compared to IPC [57]. Zhao's observations indicated that postconditioning preserved the myocardium to the same extant as IPC [57]. They further demonstrated that the beneficial effect of IPC and postconditioning was not related to improved collateral flow [57]. In addition, they showed that plasma CK and tissue myeloperoxidase activity were lower in the IPC and postconditioning groups [57]. One of the most important findings of their study was that postconditioning offered the same protection as IPC. Following this manuscript, Kin et al. demonstrated the benefit of postconditioning in a rodent model [49]. They showed a 23% reduction in infarct size; however, this benefit was significantly lower than IPC which resulted in a 56% reduction [49]. These studies indicate that there may be species variability in the effectiveness of postconditioning. Tsang et al. observed the myocardial protective effects of postconditioning with a 38% infarct size reduction [50]. They showed similar benefit in infarct size reduction between IPC and postconditioning [50]. Their study also addressed the issue of combining IPC with postconditioning and showed no added benefit [50]. Halkos et al., in a canine model, confirmed Tsang's findings that IPC had no additive effect on postconditioning protection [58]. The only clinical study on postconditioning is that of Staat et al. [55]. Their study was performed in patients undergoing angioplasty for ongoing acute myocardial infarction [55]. After stenting, the postconditioning group had four episodes of 1-min inflation and 1-min deflation of the angioplasty balloon. This protocol had a 36% reduction in serum CK levels compared to the control group [55]. Their data showed that postconditioning could be applied clinically. This study demonstrated one of the advantages of postconditioning over IPC in that it can be initiated after the ischemic insult has occurred. Cardiac surgeons can also exploit this benefit. Postconditioning as with IPC has the drawback of intermittent cross-clamping. Unlike preconditioning, postconditioning does not require initiation prior to the ischemic event. This aspect offers several interesting opportunities to the cardiac surgeon. Postconditioning can be used in situations where preconditioning is difficult or impossible to achieve. In patients with severe aortic disease where cross-clamping may be harmful, postconditioning can be used following replacement of the aorta. The cardiac transplant surgeon can also benefit from postconditioning. The storage time of the cardiac allograft can often exceed the protective effects of early preconditioning and therefore, postconditioning may play an important role for allograft protection following storage and transplantation. Remote postconditioning has also been demonstrated in an animal model [47]. Kerendi et al. demonstrated in a rodent model that remote postconditioning using renal artery occlusion reduced infarct size by 50% [47]. Ischemic postconditioning requires intermittent cross-clamping of another organ to protect the myocardium which may be associated with morbidity or increased complexity and length of the operative procedure. The optimal postconditioning strategy would be pharmacologic. Pharmacological postconditioning would avoid the adverse consequences associated with intermittent cross-clamping and provide a simple method of myocardial protection following all cardiac procedures. A potential drawback of postconditioning is that it offers protection after the ischemic insult has occurred and by then, the myocardial injury may be so extensive that postconditioning is of little benefit.


   5. Conclusions
Top
 1. Introduction
 2. Ischemic preconditioning
 3. Pharmacological...
 4. Remote preconditioning and...
 5. Conclusions
References
 
Preconditioning has greatly evolved since its first description by Murry et al. IPC has beneficial effects (protection before the ischemic insult) but is also associated with negative aspects (intermittent cross-clamping, ischemia to the vulnerable myocardium) and may have no additive protection to cardioplegia. Postconditioning also has desirable aspects (myocardial protection in clinical situations where pretreatment is not feasible such as dissection, transplantation and the severely diseased aorta); however, it is also associated with negative effects (intermittent cross-clamping and its protective effects may be ineffective following a severe ischemic insult). Remote preconditioning results in myocardial protection while avoiding ascending aortic cross-clamping; however, MA, renal artery and infrarenal aortic cross-clamping are associated with their own risks and increased time and complexity of the surgical case. Remote preconditioning with upper limb ischemia may be the best alternative. Ischemic conditioning, whether pre or post, has been successfully applied clinically; however, each strategy has its advantages and disadvantages. The decision to use one method over another depends on the patient and type of cardiac surgical procedure being performed. In addition, both ischemic pre- and postconditioning may not be suitable for all patients and great care must be taken before implementing such strategies on our patients.

The future of myocardial protection rests in our understanding of the mechanisms behind preconditioning. Our understanding of the mechanisms underlying preconditioning will lead to the development of pharmacological preconditioning mimetics that may then be used routinely in the setting of cardiac surgery to offer superior myocardial protection than our current strategies. The ultimate myocardial protective strategy may involve a combination of both pre- and postconditioning in addition to cardioplegic arrest. Cardiac surgery was made possible by advances in myocardial protection and pre(post)conditioning may be the future of cardiac protection. Finally, the cardiac surgeon of the 21st century may say "any surgeon who operates upon the heart without pre(post)conditioning should lose the respect of his colleagues."


   Notes
 
* DR is a Research Fellow of the Thoracic Surgery Foundation for Research and Education and VR is a CIHR New Investigator.


   References
Top
 1. Introduction
 2. Ischemic preconditioning
 3. Pharmacological...
 4. Remote preconditioning and...
 5. Conclusions
 References
 

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