Metabolic modulation for cardiac protection

Cardiac preservation during open heart surgery is key to optimizing postoperative cardiac performance. Methods to improve anaerobic tolerance and prolong the acceptable period of cardiac no-flow would greatly improve operative outcomes. A variety of strategies to protect the heart during and after ischemia have all aimed to improve either the balance between metabolic demand and oxygen supply, or to suppress free radical production. Metabolic modulation is an old strategy to improve cardiac function during ischemia that has received renewed interest for potential applications in treating heart failure and during open heart surgery [1]. Shifting cardiac metabolism from lipid to carbohydrate substrates is a powerful and effective tool in reducing the ill-effects of oxygen deprivation and ATP depletion [2]. Methodological innovations could further improve its efficacy and relevance to cardiac preservation.

Goal of metabolic modulation

The main goal of metabolic modulation is the overall reduced consumption of oxygen per mole of ATP synthesized, netting approximately 10–15% greater efficiency of oxygen utilization than lipid-based respiration [3]. The heart can, therefore, sustain a given level of work at lower levels of oxygen consumption – somewhat like shifting gears in a bicycle.

The earliest use of metabolic modulation was the infusion of glucose and insulin in the treatment of myocardial infarction (MI), first proposed by Sodi-Pallares in the early 1960s [4]. The rationale was to increase glycolysis, thereby increasing substrate level (i.e., anaerobic) ATP synthesis during ischemia. He reported that infusion of glucose–insulin improved electrocardiographic (ECG) changes during an acute MI. Studies of glucose and insulin in acute ischemia have continued to the present [5]. Recently, a study from Argentina of more than 400 patients with acute MI demonstrated a significant reduction of mortality among those receiving glucose–insulin, with the strongest effect occurring among those receiving reperfusion therapy (angioplasty, stenting or surgery) [6]. Survival was highest in the high glucose–insulin group, for which the benefit persisted for at least a year.

Metabolic modulation by inhibition of lipid oxidation

An alternative approach to shifting substrate preference to carbohydrates is to inhibit lipid metabolism. Drugs that inhibit specific enzymes required for lipid transport or β-oxidation have been shown in several studies to improve the clinical status in both acute myocardial ischemia and congestive heart failure. Studies in the 1990s demonstrated that ranolazine [7], a drug that inhibits fatty acid β-oxidation, improves exercise tolerance [8] or reduces diastolic dysfunction in patients with ischemic heart disease [9]. These results were confirmed by two more recent prospective studies [10,11]. Perhexiline, an inhibitor of carnitine palmitoyl transferase (CPT)-I, was shown to be highly effective at improving exercise tolerance in patients with coronary insufficiency, however, its popularity suffered a significant decline in the 1980s after evidence developed of hepatic- and neurotoxicity, particularly in the ‘slow-acetylator’ patients [12]. This toxicity is apparently secondary to intracellular phospholipid accumulation due to inhibition of the mitochondrial transport of lipid. Despite a study by Cole and colleagues indicating that perhexiline is safe and effective when administered at lower doses [13], the drug has not regained its former popularity. Trimetazidine is an established modulator drug and its clinical efficacy in treating angina has been well documented in many studies [14]. First thought to act by inhibiting CPT-1 and, possibly, 3-ketoacyl acetyl-CoA thiolase, its precise mechanism of action was called into question by MacInnes [15]. Nevertheless, trimetazidine has also been recently shown to improve contractility and diastolic function in diabetics with heart failure [16], and to improve the quality of life in elderly patients with heart failure [17]. More recently, Fragasso and colleagues demonstrated, in a well designed study, that trimetazidine improved functional capacity, ejection fraction and plasma natriuretic peptide levels in heart failure patients equally in both those with and without ischemia [18]. Although the clinical benefits of modulating drugs appear to be clear, can these benefits be extended to preserving cardiac function during open heart surgery?

Metabolic modulation of cardioplegia

Standard methods of cardioplegia and cardiac preservation aim to reduce cellular damage by minimizing oxidative metabolism, cellular acidosis and calcium loading. Typically, aerobic demands are minimized by the combination of mild hypothermia and electrical arrest induced by high concentrations of potassium [19] in the cardioplegia solution, often a mixture of crystalloid and blood, which is used for its oxygen carrying capacity and oncotic pressure to reduce cellular edema. Mannitol may also reduce cellular edema and, in theory, scavenge free radicals. The amino acids glutamate and aspartate are often added to replenish metabolic intermediates needed to sustain the ‘substrate-depleted’ Krebs cycle. Pharmacologic treatment, particularly with openers of the mitochondrial ATP-sensitive potassium channel, can mimic ischemic preconditioning. This effect reduces cardiac sensitivity to the cell damage caused by ischemia and can also be induced by volatile anesthetics (anesthetic preconditioning), which exert well established cardioprotective effects.

Glucose–insulin–potassium supplemented cardioplegia solutions have been studied a number of times, but with mixed results [20]. Lazar and colleagues demonstrated in small, prospective studies improved recovery of cardiac function after emergency coronary artery bypass surgery [21] and in diabetics [22] when the cardioplegia solution contained glucose–insulin–potassium. Rao and colleagues demonstrated improved functional outcomes after the use of a cardioplegia solution containing insulin for elective open heart surgery [23], but published a prospective study of more than 1100 patients and demonstrated no advantage of insulin-based cardioplegia in the rates of low output state, or MI after urgent coronary bypass surgery [24].

Studies of lipid inhibitors in cardioplegia have yielded similarly variable outcomes. Vedrinne and colleagues found no benefit in cardiac performance among patients administered trimetazidine systemically and in the cardioplegia solution for elective cardiopulmonary bypass surgery [25]. Tunerir and colleagues reported a prospective, double-blind, controlled study of 60 patients where treatment with trimetazidine significantly reduced patients’ serum troponin T levels compared with controls, but found no difference in postoperative hemodynamics [26]. More recently, Iskesen and colleagues demonstrated a more subtle benefit of systemic trimetazidine in a prospective study of cardiopulmonary bypass [27]. Treated patients demonstrated higher serum levels of superoxide dismutase and glutathione peroxidase, and lower malondialdehyde concentrations than controls, suggesting improved function of the most important endogenous antioxidant systems.

Pyruvate: a novel metabolic intervention in cardioplegia

Pyruvate is a key metabolic intermediary, as indicated by its central location in classic metabolic flow charts. It is at the crux of glycolysis and oxidative metabolism, gluconeogenesis, amino acid synthesis, fatty acid and cholesterol metabolism [28]. Pyruvate is also a potent antioxidant and free radical scavenger [29,30]. In addition it has well described salutary effects on myocardial performance [31,32]. Mitochondrial pyruvate uptake should also be protective because it places pyruvate’s potent metabolic and antioxidant activity at the center of oxidative metabolism and where reactive oxygen species are generated: the mitochondrial matrix. Woo and colleagues demonstrated that a soluble congener of pyruvate, ethylpyruvate prevents free radical damage and preserves function in a rat heart model of ischemia and reperfusion [33]. In a recent clinical study, Olivencia-Yurvati and colleagues demonstrated that a pyruvate fortified cardioplegia solution resulted in superior cardiac performance and less biochemical evidence of myocardial damage than control cardioplegia [34]. The pyruvate-treated patients also left the hospital sooner.

Bupivacaine-lipid rescue

Local anesthetics have been proposed for many years as a beneficial additive to cardioplegia solutions. Sodium channel blockers, such as tetrodotoxin, are cardioprotective and local anesthetics are classically viewed as ‘membrane stabilizers’, which are both cytoprotective and antiarrhythmic. More recently, Chambers has advocated the use of local anesthetics, along with adenosine and openers of the ATP-sensitive potassium channel, to provide myocardial quiescence without depolarization, the so-called hyperpolarized cardiac arrest [35]. He postulated that an important advantage of this method, compared with depolarizing cardioplegia, is the avoidance of intracellular derangements in sodium and calcium dynamics that must be corrected upon reperfusion at considerable energetic expense. Building on the work of Chambers, Dobson and colleagues demonstrated that combinations of adenosine and lidocaine protect isolated rat hearts from ischemia and reperfusion injury better than high potassium alone [36]. Corvera and colleagues extended this to a canine model of cardiopulmonary bypass and found that cardioplegia with lidocaine plus adenosine was as effective in preserving cardiac function as standard depolarizing cardioplegia [37].

Bupivacaine is a potent local anesthetic that we recently found has the unusual ability to significantly delay the onset and progression of myocardial tissue acidosis during a no-flow (anaerobic) state [38]. A contemporaneous and proportionate reduction in tissue pCO₂ content suggested significant reduction in cellular metabolism. We had reported previously that bupivacaine also potently inhibits lipid-supported respiration in cardiac mitochondrial and postulated that this contributed to the conservation of myocardial ATP and delayed cytoplasmic acidosis observed during anaerobic metabolism [39]. We wondered if this could possibly be useful for providing cardiac protection during ischemia.

Bupivacaine-induced asystole in the clinical setting is notoriously difficult to treat. However, the recent advent of lipid emulsion therapy has shown that even severe bupivacaine toxicity is entirely reversible [40,41]. This raises the paradoxical possibility that bupivacaine could be used intentionally during heart surgery to induce cardiac arrest that subsequently would be reversed with lipid infusion, a sequence we designate as bupivacaine-lipid rescue. We showed this to be highly effective in protecting function of rat isolated hearts after prolonged ischemia [42]. While there are several possible mechanisms for bupivacaine-induced cardiac protection, this observation lends support to a role for metabolic modulation, as predicted by bupivacaine’s potent inhibition of mitochondrial lipid metabolism and the reduction of tissue acidosis and CO₂ production during myocardial ischemia. Experiments are ongoing to determine the feasibility of adapting bupivacaine-lipid rescue to use as a method for cardioprotection during open heart surgery and cardiac allograft preservation for transplantation.

Clinical applications: a look ahead

Improved methods of protecting the heart from damage during ischemia and reperfusion would have widespread clinical applications. The concept of using metabolic modulation for intraoperative cardiac protection sits firmly within a well established clinical paradigm that supports the use of drugs that alter cardiac metabolism to treat both ischemia and heart failure. Improved methods of metabolic regulation and modulation could lead to longer cold storage times for the transplantable cardiac allograft and safer techniques of open heart surgery.