Number 29, 2006
Bypass surgery for coronary artery disease: a vanishing treatment?

Mechanism of cardiac damage associated with cardiac surgery

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David J. Chambers
Cardiac Surgical Research/Cardiac Surgery, The Rayne Institute, Guy's and St Thomas’ NHS Foundation Hospital, London, UK
Correspondence: Dr David J. Chambers, Cardiac Surgical Research/Cardiac Surgery, The Rayne Institute, Guy's and St Thomas’ NHS Foundation Hospital, St Thomas’ Campus, London SE1 7EH, UK.
Tel: +44 (0)20 7188 0958; fax: +44 020 7188 3902; e-mail: david.chambers@kcl.ac.uk or david.chambers@gstt.nhs.uk

Introduction
Patients requiring cardiac surgery will have experienced some form of myocardial injury, be it ischemic heart disease requiring revascularization or the influence of diseased heart valves on the myocardium. The surgical process is likely to exacerbate any injury as a result of a number of factors associated with the procedure. The cardiac surgeon requires a relaxed, still, and blood-free operating field for optimal application of the technically demanding and delicate manipulations involved in the surgery; this can be achieved most easily by inducing a period of global ischemia in the heart, and during this time the systemic circulation is supported by a heart–lung machine for cardiopulmonary bypass.
The survival of any ischemic myocardium is absolutely dependent on reperfusion, which should be initiated at the earliest opportunity to avoid ischemic injury; however, when a period of extended elective ischemia is imposed (such as during cardiac surgery), protective measures designed to delay the rate of development of ischemic injury are necessary. Thus damage to the heart during cardiac surgery can occur from ischemic injury, from reperfusion injury, and from the activation of the inflammatory response involved in blood (which becomes significantly diluted) circulating through nonbiological tubing of the cardiopulmonary bypass system, which can lead to exacerbation of the ischemia and reperfusion injury by infiltration of the heart and lungs by activated leukocytes and platelets [1], and by activation of the complement system and the coagulation and fibrinolytic systems [2].
Despite the many advances that have been made in cardiac surgery since the first cardiac surgical operations in the mid-1950s, the operative mortality is 1–3%; up to 10% of patients will experience new myocardial dysfunction, and around 24% of high-risk patients will die within 3 years [3]. Thus it is important to understand the nature of the damage to the myocardium that can occur during cardiac surgery and to continue to explore new ways of attenuating that damage during the surgical process. One of the most important factors involved in cardiac surgery is the induction of elective global ischemia and the consequent arrest of the heart that occurs; the way in which arrest is induced can have a significant impact on the outcome of the surgery.
The induction of ischemia is convenient for the surgeon, but it has potentially serious consequences for the heart (particularly when considering the underlying heart disease). The damage could rapidly progress from a reversible injury (after only a relatively short period of ischemia) to an irreversible injury. Considerable research has been conducted to render surgically induced ischemia less damaging, and to develop protective measures designed to reduce (or, ideally, prevent) this irreversible damage. Over the past 30 years of cardiac surgery, this has routinely involved the use of a “cardioplegic” solution [4] to induce rapid elective myocardial arrest of the heart (in contrast to the arrest after metabolic collapse that is associated with ischemia), thereby significantly reducing myocardial oxygen consumption [5] by approximately 6-fold (at various temperatures) and consequently slowing the utilization of myocardial high-energy phosphates. Such elective cardiac arrest induced during surgery can be achieved in a number of ways, by targeting various points in the excitation–contraction coupling pathway, using various arresting agents (Figure 1).

Mechanisms of arrest

Depolarized arrest
The method most commonly used to induce cardiac arrest during cardiac surgery involves a cardioplegic solution containing a concentration of potassium that is moderately increased (usually 15–40 mmol/L), compared with that of the extracellular milieu to induce a depolarization of the membrane. Increasing the extracellular potassium concentration of the solution causes the resting membrane potential (E_m) to depolarize; at each new potassium concentration, a new resting E_m equilibrium is established. Depolarization to approximately −65 mV (corresponding to the inactivation threshold of the fast sodium channel) at a potassium concentration of approximately 10 mmol/L prevents the rapid sodium influx of the action potential and maintains diastole of the myocardium [6]. As the potassium concentration increases, E_m becomes more depolarized, but at approximately −40 mV (corresponding to a potassium concentration of about 30 mmol/L) the calcium channel will be activated, promoting calcium overload, which can lead to myocardial damage [6]. Thus there is a relatively narrow window of potassium concentration for “safe” myocardial arrest with increased potassium; most hyperkalemic solutions use a potassium concentration around 16–20 mmol/L (such as the St Thomas’ Hospital solution) and arrest at a membrane potential around −50 mV (Figure 2). However, at the levels of depolarization induced by these potassium concentrations, other noninactivating currents remain active.

Polarized arrest
Polarized arrest involves maintaining the membrane potential of the arrested heart at or near the resting value. This should provide a number of advantages: maintained ionic balance (particularly of sodium and calcium) and reduced energy requirements. Polarized arrest can be achieved by either sodium channel blockade or potassium channel activation (Figure 1).
Blocking the sodium channel directly prevents the rapid, sodium-induced depolarization of the action potential, and many agents (such as procaine and lidocaine) have previously been used as cardioplegic agents or as additives. Tetrodotoxin, a toxic but potent sodium channel blocker, is an effective and protective cardioplegic agent [10,13]. Recent studies using this agent have demonstrated the benefit of polarized arrest over depolarized arrest for myocardial protection, with E_m during ischemia being maintained around −70 mV (Figure 2) and a reduced ionic imbalance, particularly when it is used in conjunction with agents inhibiting sodium influx (a sodium–hydrogen exchange inhibitor and a sodium–potassium–chloride cotransport inhibitor) [14,15].
Potassium channel openers (such as aprikalim, pinacidil, and nicorandil) activate the ATP-dependent potassium channel (K_ATP channel). Because the relative membrane conductance of the myocardium to potassium is much greater than that to sodium, the myocardial resting E_m (approximately −85 mV) is close to the equilibration potential of potassium (E_k of approximately −94 mV). Opening K_ATP channels increases the difference between these conductances, shifting E_m towards E_k and thereby inducing a hyperpolarization relative to the previous E_m [16], but this only applies if the extracellular potassium concentration remains low. When used at high concentrations, K_ATP channel openers are believed to exert a cardioprotective effect by inducing membrane hyperpolarization that results in diastolic arrest, and they have been shown to improve protection compared with that achieved with hyperkalemic solutions [17,18]. However, more recent studies have shown that pinacidil (even at concentrations as high as 1 mmol/L) is unable to induce arrest per se, requiring the addition of a sodium channel blocker for complete arrest occurring at E_m values around −70 mV [19,20].
Adenosine has also been shown to act as a hyperpolarizing agent [21], and has been used to induce cardioplegic arrest, with mixed results [22–24]. More recently, a combination of lidocaine, a sodium channel blocker, and adenosine has demonstrated effective myocardial protection compared with a hyperkalemic cardioplegic solution [25]; similarly, other studies have demonstrated effective combinations of arresting agents [26].

Influencing calcium mechanisms
Solutions with a zero, or very low, extracellular calcium concentration rapidly arrest the heart in diastole by inhibiting excitation–contraction coupling [27]. This is the basis of some “intracellular type” cardioplegic solutions (particularly the original Bretschneider solution [28] and the subsequent Histidine-Tryptophan-Ketoglutarate [HTK] [Custodiol] solution [29]), although combination with a sodium channel blocker (procaine) and a low sodium concentration would also tend to induce a polarized arrest. The HTK solution has shown particular application for long-term preservation of hearts, in addition to other organs (kidney, liver, pancreas), before transplantation.
An alternative approach is to influence the affinity of calcium for intracellular components, and there is current interest in agents that lead to reversible desensitization of the contractile apparatus for calcium. The most widely used is 2,3-butanedione monoxime (BDM), which uncouples myofilament excitation–contraction coupling by inhibiting the formation of crossbridges [30]. BDM has recently been used as a cardioplegic agent [31], demonstrating effective protective properties when compared with conventional depolarizing cardioplegia. Another agent with potential to improve myocardial protection by reducing the damaging effects of depolarized arrest is esmolol, an ultra-short-acting β-blocker with a half-life of only 9 min. The efficacy of using esmolol during cardiac surgery as an alternative to depolarizing cardioplegia has been demonstrated [32], and recent experimental studies [33,34] have shown that the use of multidose infusions of an esmolol cardioplegia solution (at a concentration of 1 mmol/L) provides significantly improved protection during normothermic global ischemia compared with that obtained with a depolarizing cardioplegic solution. Preliminary studies indicate the possibility that esmolol is acting via a calcium desensitization mechanism, but this remains under investigation.

Conclusion
Damage to the myocardium during cardiac surgery is associated with a number of factors, the most important being the induction of elective global ischemic arrest. It is necessary to protect the myocardium against the damaging effects of ischemia; since the mid-1970s, the most widely used protective technique has been to infuse a solution containing a moderately increased concentration of potassium, which leads to a rapid and “safe” diastolic arrest by depolarization of the membrane potential. This is simple to apply and to remove; however, it does not necessarily provide the optimal protection against cardiac damage, particularly in the context of the increasing number of high-risk patients who are older and have more diffuse and severe ischemic heart disease and who undergo cardiac surgery nowadays. Other techniques of arrest, such as inducing a polarized ischemic arrest or arresting the heart by influencing calcium mechanisms may be more suited to preventing the damaging effects of elective ischemia in present-day cardiac surgical patients. In addition, improvements in preventing ischemic damage to the heart will reduce the associated reperfusion injury, and may also mean that any inflammatory response is similarly reduced. However, more characterization and research are required before these alternative techniques can be considered for routine use during cardiac surgery.

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