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Right arrow Myocardial protection

Ann Thorac Surg 2003;75:S661-S666
© 2003 The Society of Thoracic Surgeons

I: Pathophysiology of ischemic-reperfusion injury

Mechanisms and alternative methods of achieving cardiac arrest

David J. Chambers, PhDa*

a Cardiac Surgical Research/Cardiothoracic Surgery, The Rayne Institute, Guy’s and St Thomas’ NHS Hospital Trust, St Thomas’ Campus, London SE1 7EH, United Kingdom

* Address reprint requests to Dr Chambers, Cardiac Surgical Research, Cardiothoracic Surgery, The Rayne Institute, Guy’s and St Thomas’ NHS Hospital Trust, St Thomas’ Campus, London SE1 7EH, UK.
e-mail: david.chambers{at}kcl.ac.uk

Presented at the 3rd International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002.

Abstract

Elective cardiac arrest during surgery can be achieved by inducing depolarization, polarization, or influencing calcium mechanisms. Depolarized arrest, induced by elevating the extracellular potassium concentration, is currently the most commonly used technique. However, injury associated with ionic imbalance involving sodium and calcium overload, together with maintained metabolic processes aimed at correcting these imbalances, have lead to alternatives being sought. "Polarized" arrest, induced by sodium-channel blockers or by agents that activate potassium channels, has been shown to exert equal or superior protection. Similarly, agents that induce calcium desensitization may also prove to enhance protection. These alternative techniques, however, require extensive characterization before introduction into routine clinical use can be recommended.

Providing the cardiac surgeon with a relaxed and still operating field, which allows technically demanding or delicate manipulations to be optimally conducted during cardiac surgery, requires cardiac arrest in a flaccid diastolic state (with reduction in myocardial oxygen consumption as an important consequence). Elective cardiac arrest is achieved by targeting various points in the excitation-contraction coupling pathway by a variety of arresting agents (Fig 1). These agents induce either a depolarized arrest, a "polarized" arrest, or an arrest by influencing calcium mechanisms.



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  		Fig 1. Excitation-contraction coupling and the targets within this pathway that are inhibited or activated by agents that induce depolarized arrest, polarized arrest, or arrest by influencing calcium mechanisms. BDM = 2,3-butanedione monoxime; SR = sarcoplasmic reticulum; TTX = tetrodotoxin (modified from reference 4).

 
Depolarized arrest

Hyperkalemia
The most commonly used method for inducing rapid diastolic arrest during cardiac surgery is moderate elevation of the extracellular potassium (K+) concentration (usually within the range of 15 to 40 mmol/L). As the extracellular K+ concentration increases, the resting membrane potential (Em) becomes progressively more depolarized [1] and, at each K+ concentration, a new resting Em is established. As the resting Em depolarizes to approximately -65 mV (at K+ concentrations around 10 mmol/L) the voltage-dependent fast sodium (Na+) channel is inactivated [2], preventing the rapid Na+-induced spike of the action potential and arresting the heart in diastole. Further increases in extracellular K+ will further depolarize resting Em; at a resting Em of about -40 mV (extracellular K+ around 30 mmol/L or higher), the slow calcium (Ca2+) channel will be activated [2], promotingCa2+ overload. Thus, any beneficial effects of elevated extracellular K+ are restricted to a relatively narrow concentration window (about 10 to 30 mmol/L), emphasizing the importance of dose-response studies for K+ in relation to the other ionic constituents of the cardioplegic solution, especially Ca2+ and Na+. The St Thomas’ Hospital cardioplegic solution has an optimal extracellular K+ concentration for myocardial protection between 15 and 20 mmol/L [3]; thus, the depolarized Em falls approximately in the middle of the protective Em window [4]. At these levels of depolarization, however, other ionic currents remain active; it is thought [5] that the voltage-dependent activation and inactivation "gates" of the Na+ channel operate at different rates and lead to a Na+ "window" current. This results from a noninactivating current that will tend to increase the intracellular Na+ concentration, and this, in turn, will increase the Ca2+ "window" current [6], causing contracture even in the arrested condition, and contribute to Ca2+ overload and reperfusion injury. Energy-dependent transmembrane pumps remain active in an attempt to correct these abnormal ionic gradients, depleting critical energy supplies [7, 8]; hyperkalemic arrest has been shown to be associated with decreased myocardial ATP levels compared with arrest with magnesium [9].

Alternative techniques that avoid the problems associated with depolarized arrest (such as ionic imbalance, maintained metabolism, potassium-induced endothelial injury [10, 11], and arrhythmias [11]) may provide superior protection. An increasing number of studies have investigated the potential of polarized arrest, or arrest through mechanisms involving inhibition of calcium interaction within the excitation-contraction coupling pathway.

Polarized arrest

An alternative to inducing arrest by depolarization (with elevated K+ concentrations) is to maintain polarization of the Em, close to the resting Em. Polarized arrest should have a number of advantages; ionic movement (particularly Na+ and Ca2+ ions) should be reduced, because the threshold potential for activation of the ion channels will not be reached and window currents will not be activated. This reduction in ionic imbalance should, in turn, reduce myocardial energy utilization for ion movements and attempts to maintain ionic gradients. Polarized arrest can be achieved in a number of ways.

Sodium-channel blockade
Sodium-channel blockade can effectively arrest the heart by preventing the rapid, Na+-induced depolarisation of the action potential [12]. Local anesthetic agents, such as procaine and lignocaine (lidocaine), have been widely used, either as cardioplegic agents or in combination with other agents, to induce cardiac arrest [3]. Procaine (1 mmol/L) is a constituent of the St Thomas’ Hospital cardioplegic solution No. 1 for membrane stabilization and has been shown to control postoperative rhythm disturbances [13]. There is, however, a small risk of toxicity and seizures with these agents [14, 15].

Tetrodotoxin (TTX), which is a highly toxic but potent and rapidly reversible Na+-channel blocker, is an effective cardioplegic and protective agent [16], and has been shown to reduce myocardial oxygen consumption in comparison with hyperkalemic arrest [7]. Recently, we [17] used TTX (at an optimal concentration of 22 µmol/L) to arrest rat hearts before long-term hypothermic storage preservation and demonstrated significantly improved protection compared with a hyperkalemic (16 mmol/L K+) buffer solution. Measurements of Em during storage showed that TTX maintained Em at around -70 mV (polarized arrest) compared with around -50 mV in the depolarized (hyperkalemically arrested) hearts. In addition, high-energy phosphate levels (ATP and phosphocreatine) measured at the end of the storage ischemia were significantly higher in the TTX-arrested hearts. We have also demonstrated reduced ionic changes (indirectly measured as a smaller increase in extracellular K+) during polarized arrest [18]. The importance of Na+ and Ca2+ in the development of injury was demonstrated [19] by the sequential addition of optimal concentrations of drugs that prevent Na+ influx (a Na/H exchange inhibitor [HOE 694] and a Na/K/2Cl cotransport inhibitor [furosemide]) as well as influencing Ca2+ desensitization (2,3-butanedione monoxime [BDM]; see also later) lead to a significant improvement in protection (Fig 2).



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  		Fig 2. Post-ischemic recovery of aortic flow in hearts arrested and stored in Krebs Henseleit buffer (KH) containing TTX (22 µmol/L) (Control), control plus HOE 694 (10 µmol/L), control plus HOE 694 plus furosemide (1 µmol/L), control plus HOE 694 plus furosemide plus BDM (30 mmol/L), or STH2. Columns represent mean ± SEM; n = 6 hearts/group. *p less than 0.05 versus control; §p less than 0.05 versus STH2. BDM = 2,3-butanedione monoxime; STH2 = St Thomas’ Hospital cardioplegic solution No. 2; TTX = tetrodotoxin (redrawn from reference 19).

 
ATP-sensitive potassium-channel activation
At high concentrations, KATP-channel openers (KCOs) have cardioplegic effects, thought to be by induction of membrane hyperpolarization [20–22]. The myocardial resting Em (around -80 mV) is close to the equilibrium potential of K+ (about -94 mV), because the relative membrane conductance to K+ is much greater than the relative membrane conductance to Na+. KCO-induced activation of ATP-sensitive potassium channels increases the difference between these conductances, causing Em to be shifted towards the K+ equilibrium potential (hence, a hyperpolarization from the previous Em). If Em remains more negative than -65 mV, initiation of the fast voltage-dependent Na-channel that triggers the action potential will not occur, and the heart will arrest in diastole. Em hyperpolarization with KCOs has been demonstrated in isolated guinea pig and human ventricular myocytes [23], but only if the K+ concentration in the solution remains low. We [24] have recently shown that the KCO pinacidil, when used alone, is unable to induce complete arrest, even at very high concentrations and prolonged exposure. Measurements of Em during ischemia show that it is not maintained below the threshold of Na+ activation with pinacidil alone. For complete arrest together with maintenance of a more polarized Em and improved protection, a combination of optimal concentrations of a KCO (0.3 mmol/L pinacidil) and a Na-channel blocker (1.0 mmol/L procaine) was required [25]. These results were similar to the additional protection seen with this same combination (0.5 mmol/L pinacidil and 5.0 mmol/L procaine) in a study by Hoenicke and colleagues [26].

KCOs have also been used as additives to hyperkalemic cardioplegic solutions and have been shown to enhance postischemic recovery of function [27, 28], but this remains controversial [29]. Potentially, addition of these drugs to hyperkalemic cardioplegia may reduce K+-induced influx of Ca2+ [30]. Any effect may also be related to the location of the KATP-channel, with beneficial effects being observed with mitochondrial-specific drugs [31].

Adenosine
Adenosine can also induce arrest through a hyperpolarization effect, particularly on myocardial conductive tissue [32], and was shown to provide good myocardial protection when used alone (at a concentration of 10 mmol/L) as a cardioplegic agent [33, 34] or as an additive (1 mmol/L) to K+ cardioplegia [35]. It was shown to reduce the time to arrest and to be at least as effective as hyperkalemic arrest. Interestingly, adenosine (1 mmol/L) has been shown to reduce K+-induced Ca2+ overload in isolated myocytes [36], suggesting a mechanism for its benefit as an adjunct to hyperkalemic solutions. More recently, the additive beneficial effect of adenosine (to K+-based cardioplegia) has been tested clinically and shown to be safe and to reduce postoperative complications [37], although again this remains controversial [38]. Interestingly, at this symposium, a combination of adenosine and lignocaine (which should induce a polarized arrest) was shown to be an effective protective combination over ischemic periods up to 4 hours [39].

Influence of calcium mechanisms

Hypocalcemia
The absence of extracellular Ca2+ induces cardiac arrest in diastole by inhibiting excitation-contraction coupling [40]. This characteristic was used in early cardioplegic solutions (predominantly from Germany), although accompanying low extracellular Na+ also attenuated the Na+-channel current, thereby maintaining Em close to the resting Em. However, the absence of Ca2+ increased the risk of inducing a "calcium paradox" [41], although traces of contaminant Ca2+, hypothermia and low Na+, or high Mg2+ counteracted this risk; the relationships between low Ca2+, low Na+, and high Mg2+ are highly complex [3]. An alternative approach to blocking calcium-mediated contractile activity is to use drugs that influence calcium movements.

Calcium antagonists
High concentrations of calcium antagonists prevent Ca2+-induced Ca2+ release and induce arrest by inhibiting excitation-contraction coupling. Calcium antagonists have been suggested as cardioplegic agents per se [42], potentially exerting comparable protection to hyperkalemic arrest, but the delayed reversal of activity (membrane binding) of these drugs may result in slow recovery. Calcium antagonists have also been used as additives to K+ cardioplegia, but their effects are temperature dependent, with little additional protection during hypothermia [43]. Thus, although calcium antagonists have antiischemic properties, any benefits appear to be outweighed by disadvantages relating to their dose-dependent, temperature-dependent, and time-related effects.

Hypermagnesemia
Elevated extracellular Mg2+ can arrest the heart, possibly by displacing Ca2+ from the rapidly exchangeable sarcolemmal binding sites involved in excitation-contraction coupling [44]; however, it is less effective than K+ and requires higher concentrations [3]. As with calcium antagonists, Mg2+ is more usually employed as an effective additive protective agent [45], and (at a concentration of 16 mmol/L) is a standard component of the St Thomas’ Hospital cardioplegic solutions.

2,3-Butanedione monoxime
2,3-Butanedione monoxime (BDM) was developed as an antidote to sarin poisoning, having apparent "chemical phosphatase" activity. In the heart, BDM uncouples myofilament excitation-contraction by inhibition of cross-bridge formation [46]. It is a small, uncharged lipophilic molecule, and hence, can rapidly interchange with the intracellular milieu, allowing rapid reversibility. Many studies [19, 47, 48] have documented the protective effect of BDM as a beneficial additive to hyperkalemic preservation solutions. It has been shown [48] to induce reversible desensitization of the contractile apparatus for Ca2+; a 30-mmol/L BDM solution abolished contractile force despite maintenance of the Ca2+ transient. More recently [49], BDM has been examined as a cardioplegic agent and shown to exert comparable protective effects to St Thomas’ cardioplegia, as well as displaying beneficial reductions in postischemic myocardial edema. To my knowledge, BDM has not been used clinically as an additive to cardioplegia during cardiac surgery. It is known to have significant Ca2+-chelating properties at the millimolar concentrations shown to be effective [19], and this may have restricted its use.

Esmolol
Esmolol, an ultra-short–acting ß-blocker with a half-life of around 10 minutes, has recently been used during cardiac surgery to induce "minimal myocardial contraction" while maintaining continuous normothermic perfusion to avoid ischemia, and has been shown to give myocardial protection equivalent to cardioplegia [50]. At high concentrations (approximately 1.0 mmol/L), esmolol induces cardiac arrest [51, 52], and we [52, 53] have shown that multidose infusions (for 2 minutes every 15 minutes at 45 mm Hg) of a 1.0 mmol/L esmolol solution can completely protect isolated crystalloid-perfused rat hearts for extended periods (up to 90 minutes) of normothermic global ischemia (Fig 3). We also have very preliminary unpublished data suggesting that esmolol acts by inducing Ca2+ desensitization (in a similar way to that of BDM); this property was not demonstrated by equivalent concentrations of atenolol.



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  		Fig 3. Recovery of left ventricular developed pressure (LVDP) with increasing durations of ischemia in control hearts intermittently infused (2 minutes every 15 minutes at 45 mm Hg) with Krebs Henseleit buffer (KH) (open squares) or hearts intermittently infused (2 minutes every 15 minutes at 45 mm Hg) with KH containing 1 mmol/L esmolol (closed squares). Values are mean ± SEM; n = 6 hearts/group. *p less than 0.05 versus control value.

 
Comment

The induction of rapid depolarized arrest of the heart in diastole by moderately elevated concentrations of K+ is by far the most widely used technique (possibly because it is the simplest to apply and to remove) for cardiac arrest during cardiac surgery; however, it cannot be used haphazardly, has a number of disadvantages, and is not necessarily the best and most optimally protective. The concept of maintaining arrest by induction of polarization (or hyperpolarization) compared with depolarization (induced by hyperkalemia) may have significant advantages; reduction in ionic imbalance and metabolism should improve myocardial protection. Arrest by inhibiting Ca2+ influx, whereas effective, is potentially damaging to the myocardium. Alternatively, prevention of Ca2+ interaction with the myofilaments may be a promising technique for inducing arrest and enhancing myocardial protection.

Despite the theoretical disadvantages of elevated K+, it has proven to be an extremely effective protective agent for over a quarter of a century, particularly during the relatively short ischemic durations used in modern cardiac surgery. It is unlikely that any of the alternative techniques will completely replace the use of elevated K+ solutions, although some may be used in combination (such as adenosine and lignocaine [see above], or esmolol with hyperkalemia) to achieve superior protection. A more promising arena for some of these alternative strategies may be in long-term preservation of hearts for transplantation, where elevated K+ solutions (either with an extracellular or intracellular type formulation) are relatively ineffective. However, considerably more characterization and research are required before these techniques could be considered for routine use in cardiac surgical patients.

Acknowledgments

Some of the studies conducted in the author’s laboratory were funded by the British Heart Foundation.

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Replacing potassium with nicorandil in cold St. Thomas' Hospital cardioplegia improves preservation of energetics and function in pig hearts
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D. J. Chambers
Nicorandil cardioplegia or procaine cardioplegia?
Eur. J. Cardiothorac. Surg., October 1, 2003; 24(4): 670 - 670.
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