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Cardiovascular Research 1997 33(2):243-257; doi:10.1016/S0008-6363(96)00245-3
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions

Potential for pharmacological interventions

William C. Stanleya,*, Gary D. Lopaschukb, Jennifer L. Hallc and James G. McCormackd

aCV Therapeutics, 3172 Porter Drive, Palo Alto, CA 94304, USA
bCardiovascular Disease Research Group and Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
cDepartment of Medicine, Stanford University, Stanford, CA, USA
dDepartment of Diabetes Biology, Novo Nordisk, DK-2880 Bagsvaerd, Denmark

Received 22 May 1996; accepted 25 October 1996

KEYWORDS G 6-P, glucose 6-phosphate; TCA, tricarboxylic acid; GT, GLUT 1 and GLUT 4 glucose transporters; LT, lactate transporter; HK, hexokinase; PDHa, active dephosphorylated pyruvate dehydrogenase; ETC, electron transport chain.


   1. Introduction
Top
 1. Introduction
2. Overview
 3. Effects of plasma...
 4. Effects of ischaemia
 5. Effects of reperfusion
 6. Pharmacological effectors of...
 7. Summary and conclusions
 References
 
The regulation of mammalian myocardial carbohydrate metabolism is complex in that it is linked to arterial substrate and hormone levels, coronary flow, inotropic state and the nutritional status of the tissue. Optimal cardiac function under normal and pathological conditions is dependent upon glycolysis and pyruvate oxidation. The purpose of this review is to examine the regulation of myocardial carbohydrate metabolism under physiological conditions, and during myocardial ischaemia and reperfusion. The therapeutic potential of a variety of pharmacological interventions affecting myocardial carbohydrate metabolism will then be discussed.


   2. Overview
Top
 1. Introduction
 2. Overview
3. Effects of plasma...
 4. Effects of ischaemia
 5. Effects of reperfusion
 6. Pharmacological effectors of...
 7. Summary and conclusions
 References
 
The tricarboxylic acid cycle (TCA cycle) provides reducing equivalents for mitochondrial oxidative phosphorylation, resulting in the condensation of ADP and inorganic phosphate to regenerate ATP, and is fueled by acetyl-CoA formed primarily from oxidation of pyruvate and fatty acids (Fig. 1). Cardiomyocytes oxidise fatty acids derived from both the plasma and the breakdown of intracellular triacylglycerol stores, while pyruvate is derived from either lactate dehydrogenase or glycolysis. The rates of these metabolic pathways are tightly coupled to the rate of contractile work, and conversely, contractile work is coupled to the supply of oxygen and the rate of oxidative phosphorylation (Fig. 1). Early studies in animals [1] and human [2, 3] showed that after an overnight fast the heart extracts free fatty acids (FFA), lactate and glucose from the blood, and that if one assumes complete oxidation of extracted substrates, fatty acids are the major oxidative fuel for the heart (60–100% of the oxygen consumption), with a lesser contribution from lactate and glucose (0–20% from each) [2, 3]. Subsequent studies by others using a variety of experimental approaches have confirmed these early results (see [4–7] for reviews).


Figure 1
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  		Fig. 1 Schematic depiction of myocardial substrate metabolism. Abbreviations: G 6-P, glucose 6-phosphate; TCA, tricarboxylic acid; GT, GLUT 1 and GLUT 4 glucose transporters; LT, lactate transporter; HK, hexokinase; PDHa, active dephosphorylated pyruvate dehydrogenase; ETC, electron transport chain.

 
2.1. Regulation of glycolysis and glycogen metabolism
The uptake of extracellular glucose is regulated by the transmembrane glucose gradient and the concentration and activity of glucose transporters (Fig. 1) in the plasma membrane. Two isoforms from the glucose transporter family have been identified in the myocardium, GLUT 1 and GLUT 4 [8, 9]; both are located in the sarcolemmal membrane and in intracellular microsomal vesicles [10–14]. Insulin and ischaemia result in a translocation of GLUT 1 and GLUT 4 from the intracellular site into the plasma membrane, which results in an increase in the membrane capacitance for glucose transport [12, 13, 15]. The transmembrane glucose gradient is determined by the interstitial glucose and intracellular free glucose concentrations. The interstitial glucose concentration is a function of the arterial glucose concentration and blood flow, thus interstitial glucose levels and the transmembrane glucose gradient are decreased during ischaemia [16], and are increased by hyperglycemia [17].

Upon entering the cell, free glucose is rapidly phosphorylated by hexokinase to form glucose 6-phosphate, thus rendering glucose impermeable to the cell membrane (Fig. 1). Insulin activates hexokinase in isolated rat hearts, and causes the release of hexokinase from the outer mitochondrial membrane, thus increasing the uptake and phosphorylation of glucose [7, 18]. Studies in isolated quiescent cultured cardiomyocytes suggest that glucose phosphorylation by hexokinase, rather than transport across the sarcolemmal membrane, is the rate limiting step in insulin-stimulated glucose utilization [19]. G 6-P can be used for either glycogen synthesis or it can proceed down the glycolytic pathway to form pyruvate (Fig. 1). The rate of glycogen synthesis is regulated by the concentration of G 6-P and the activity of glycogen synthase. Glycogen synthetase activity and glycogen storage are increased by insulin [20–23]. Glycogenolysis results in the formation of G 6-P, and is regulated by the activity of glycogen phosphorylase. Glycogen phosphorylase is activated when phosphorylated by phosphorylase kinase, which is activated by Ca2+. The activity of phosphorylase kinase is regulated by protein kinase a, and thus is activated by cAMP [20]. Thus glycogen phosphorylase activity is controlled by both hormonal stimulation (e.g. β-adrenergic receptor stimulation resulting in increased cAMP and Ca2+), and metabolic feedback (AMP, Pi, and Ca2+). Animal and human studies indicate that there is simultaneous synthetase and phosphorylase activities in vivo [22–26]. The content of glycogen in the heart is highly dependent on diet and feeding state, and is quite variable between species, being lower in rodent (10–30 µmol glycosyl units/g wet weight) than in humans (40–60 µmol glycosyl units/g wet weight) [24]. Studies in cardiac surgery patients show that acute hyperglycemia and hyperinsulinemia prior to surgery will result in significant increases in myocardial glycogen concentration [27–29]. Studies in rats have shown that high plasma FFA concentration and a greater reliance on β-oxidation, such as occurs with fasting [6, 7] or during the recovery from exhaustive exercise [30], will result in elevated myocardial glycogen levels. On the other hand, myocardial ischaemia or an increase in cardiac work results in a fall in glycogen concentration [4, 5, 30, 31].

The overall rates of glucose uptake, glycogen synthesis and breakdown, and the rate of glycolysis are controlled by multiple steps distributed along these pathways, and not subject to control at discrete points [32]. Given a constant supply of G 6-P, the primary regulators of glycolytic rate are the activity of phosphofructokinase (PFK), and the ability to form reduced NADH [32–37]. There are two isoforms of PFK, denoted PFK1 and PFK2. PFK1 phosphorylates fructose 6-phosphate (F 6-P) to form fructose 1,6-diphosphate [33, 34]. The activity of PFK1 is inhibited by H+, citrate and ATP, and stimulated by ADP, Ca2+, and fructose 2,6-diphosphate. PFK2 forms fructose 2,6-diphosphate from F 6-P, and thus activates PFK1. NAD+ is reduced to NADH by the conversion of glyceraldehyde 3-phosphate to 3-phosphoglycerol phosphate by the enzyme glyceraldehyde 3-phosphate dehydrogenase. Cytosolic NADH can be converted back to NAD+ through the conversion of pyruvate to lactate by lactate dehydrogenase, or the reducing equivalents can be shuttled into the mitochondria via the malate-aspartate shuttle. The glyceraldehyde 3-phosphate dehydrogenase appears to be a rate-limiting step for glycolysis with high rates of contractile work [35], or during myocardial ischaemia [37].

It has been proposed that glycolytically derived ATP is preferentially used for Ca2+ re-uptake into the sarcoplasmic reticulum, and that it is essential for optimal diastolic relaxation [38–40]. Evidence for this concept comes from studies in isolated tissues that demonstrated that inhibition of glycolysis resulted in impaired relaxation, especially in ischaemic or reperfused myocardium [38–40]. Activity of key enzymes for glycogenolysis [41] and glycolysis [42, 43] are found associated with the sarcoplasmic reticulum, suggesting that glycolytically derived ATP is spatially located at the site of the Ca2+ pump. It has also been demonstrated that key glycolytical enzymes are associated with the cardiac ATP-sensitive K+ channels and that glycolytically derived ATP preferentially inhibits these channels [44]. Glycolysis is also important for optimal function of the Na+/K+ ATPase and prevention of intracellular Na+ accumulation during ischaemia [45].

2.2. Regulation of pyruvate and lactate oxidation
Lactate is a major source of pyruvate formation under well-perfused conditions in vivo, and under some conditions lactate uptake can exceed glycolysis as a source of pyruvate [46, 47]. Studies with carbon-labeled lactate tracers in humans show that 80–100% of the lactate taken up by the healthy human heart is immediately released as labeled CO2 into the coronary effluent [46, 48], suggesting that extracted lactate is rapidly oxidised by lactate dehydrogenase, decarboxylated by pyruvate dehydrogenase (PDH) and oxidized to CO2 in the TCA cycle. Lactate transport across the sarcolemmal membrane is mediated by at least one inhibitable, stereoselective transport protein. A 45 kDa lactate transporter protein has recently been cloned, and is referred to as the monocarboxylate transporter-1 (MCT1) [49]. Studies on isolated myocytes suggests that the rate of lactate efflux during ischaemia is limited by the capacity of the carrier [50]. At present, it is unclear if MCT1 is responsible for lactate efflux, influx or both.

Pyruvate decarboxylation is the key irreversible step in carbohydrate oxidation and is catalysed by pyruvate dehydrogenase (PDH) [51]. PDH is a multi-enzyme complex located on the inside of the inner mitochondrial membrane. The activity of PDH is regulated by a variety of mechanisms: in particular, it is inactivated by phosphorylation by a specific PDH kinase, and is activated by dephosphorylation by a specific PDH phosphatase [52–56] (Fig. 2). The rate of pyruvate oxidation is strongly dependent on the degree of phosphorylation of PDH, and also on the concentrations of its substrates and products in the mitochondria as these control flux through the active dephosphorylated form of the enzyme [51, 57]. The activity of PDH phosphatase is increased by Ca2+ and Mg2+ [58], while PDH kinase is inhibited by pyruvate and ADP, and activated by increases in acetyl CoA/CoA and NADH/NAD+ [51, 57]. Pyruvate oxidation and the activity of PDH in the heart are decreased by elevated rates of fatty acid oxidation caused by increased plasma levels of FFA, and are enhanced by suppression of FFA oxidation induced by a decrease in plasma FFA levels [51], or by inhibition of carnitine palmitoyl transferase I (CPT-I), a key enzyme in the oxidation of fatty acids [59–62] (Fig. 3). Positive inotropic agents increase the amount of active enzyme by a Ca2+-dependent activation of PDH phosphatase, whereas PDH kinase activity is increased and the enzyme is more inactivated when carbohydrate reserves are low as in starvation or diabetes [63].


Figure 2
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  		Fig. 2 Regulation of pyruvate dehydrogenase (PDH). Abbreviation: DCA, dichloroacetate; PDH, pyruvate dehydrogenase.

 

Figure 3
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  		Fig. 3 Inter-regulation of fatty acid and pyruvate oxidation. The dotted lines denote inhibition of enzymatic activity. Abbreviations: ACC, acetyl CoA carboxylase; AMPK, 5'' AMP-activated protein kinase; CPT-I, carnitine palmitoyl transferase I; CPT-II, carnitine palmitoyl transferase II; CAT, carnitine acetyl transferase; PDHa, active dephosphorylated pyruvate dehydrogenase.

 
2.3. Inter-relation between fatty acid and carbohydrate metabolism
High rates of fatty acid oxidation feed back to inhibit glucose uptake [53, 64], lactate uptake [65], and glucose oxidation [6, 24, 66] by a variety of mechanisms. First, high levels of cytosolic citrate, which could occur when rates of fatty acid oxidation are high, can inhibit PFK activity and decrease the rate of glycolysis [67]. It is unclear, however, if citrate regulates PFK activity in vivo. Rat heart mitochondria, unlike liver mitochondria, have a very low activity of the tricarboxylate carrier [68], thus it is difficult to implicate changes in citrate concentration in the mitochondrial matrix with the regulation of PFK in the cytosol. High rates of fatty acid oxidation have been shown to inhibit PDH activity via elevated mitochondrial levels of acetyl CoA and NADH, which activates PDH kinase that then phosphorylates and inhibits PDH [51, 69]. In addition, in isolated heart mitochondria it has been shown that elevated rates of fatty acid oxidation inhibit flux through PDH for any given PDH phosphorylation state [57]. Pharmacological inhibition of CPT I with etomoxir or oxfenicine inhibits fatty-acyl CoA transport into the mitochondria and thus its subsequent oxidation, and results in greater glucose oxidation by lowering acetyl CoA levels and relieving tonic inhibition of PDH [59, 60, 62].

Recent evidence suggests that reciprocal regulation of myocardial pyruvate and FFA metabolism are linked through changes in cytosolic malonyl CoA concentration, as malonyl CoA is a potent physiological inhibitor of CPT-I [70–73] (Fig. 3). Malonyl CoA is produced in the cytosol by the carboxylation of acetyl CoA by acetyl CoA carboxylase (ACC) [61, 70–75]. Treatment of hearts with dichloroacetate (DCA), an inhibitor of PDH kinase (Fig. 2), increases the amount of active PDH [76] and the levels of acetyl CoA and malonyl CoA, and inhibits fatty acid oxidation [71, 72]. Mitochondrial acetyl-CoA can be transferred to the cytosol by the formation of acetylcarnitine via carnitine acetyl transferase (CAT), transported into the cytosol by carnitine acetyltranslocase [71, 77–79], and converted back to acetyl CoA by cytosolic CAT (Fig. 3). As a result, an increase in intramitochondrial acetyl-CoA production due to DCA stimulation of PDH can result in an increase in cytosolic levels of acetyl-CoA, an increase in malonyl CoA production by ACC, and subsequent inhibition of CPT I and fatty acid oxidation.

Inhibition of pyruvate oxidation can also stimulate myocardial glycogen storage. Providing an alternative source for acetyl CoA production (e.g. fatty acid β-oxidation or ketone bodies) inhibits flux through PDH, resulting in a build-up of cytosolic pyruvate. Since pyruvate is a product of glycolysis, glycolytic flux is inhibited and a greater fraction of the glucose uptake and G 6-P is directed towards glycogen synthesis. Studies in rats have shown that increasing FFA levels with triacylglycerol emulsion and heparin in conscious rats results in inhibition of PDH and an increase in myocardial glycogen stores [69]; similar results are found with short-term fasting [7, 36, 80] and during the recovery from exhaustive exercise [29]. Similarly, there is a rapid 6-fold increase in the rate of glycogen synthesis in dogs infused with β-hydroxybutyrate or lactate [81]; this increase occurred without stimulation of glucose uptake. Thus G 6-P is re-routed toward glycogen when either an alternative source of pyruvate is provided, or flux through PDH is inhibited by increasing intramitochondrial acetyl CoA.


   3. Effects of plasma substrate and insulin levels
Top
 1. Introduction
 2. Overview
 3. Effects of plasma...
4. Effects of ischaemia
 5. Effects of reperfusion
 6. Pharmacological effectors of...
 7. Summary and conclusions
 References
 
Under most conditions, plasma FFA levels are the primary regulator of myocardial glucose and lactate oxidation. High plasma FFA levels (>0.8 mM) inhibit both the uptake and oxidation of glucose and lactate in human myocardium [24, 48, 65], while pharmacologically lowering plasma FFA levels (<0.3 mM) results in an increase in myocardial glucose and lactate uptake [82–84]. This is primarily related to the release of product inhibition on PDH and glycolysis as FFA concentration decreases [51]. Arterial lactate concentration is not a key regulator of lactate uptake and oxidation under normal resting conditions in humans, when levels are rather constant at about 0.6–1.2 mM [65]. However, during and after exercise arterial lactate levels increase as an exponential function of exercise intensity, reaching values in excess of 8 mM. With heavy, short duration exercise, arterial lactate concentration becomes the major regulator of lactate oxidation [46, 47, 85]. Plasma glucose concentration is not a major determinant of glucose uptake and oxidation under well-perfused conditions where plasma insulin and FFA are held constant [24, 86].

Plasma insulin levels directly regulate myocardial carbohydrate metabolism by stimulating glucose transport into cardiomyocytes, and indirectly by inhibiting lipolysis in adipocytes and thus lowering plasma FFA levels. The direct action of insulin on glucose uptake occurs by increasing the incorporation of GLUT 4 and GLUT 1 into the sarcolemmal membrane [12–15, 87]. Insulin also results in stimulation of hexokinase and glycogen synthetase activities [18, 20], resulting in increased glucose phosphorylation and glycogen synthesis; the mechanism for this effect in heart is unclear, but could be at least partially due to the increase in glucose and glucose 6-phosphate that occurs secondary to insulin-stimulated glucose transport. In addition, recent studies in isolated rat hearts have demonstrated that insulin also decreases the activity of 5' AMP-activated protein kinase (J Gamble and GD Lopaschuk, unpublished observation). This may result in decreased phosphorylation and hence activation of ACC, leading to increases in cytosolic malonyl CoA levels and decreased fatty acid oxidation due to CPT I inhibition [61, 71]. In addition to these direct effects, insulin indirectly increases flux through glycolysis and PDH by decreasing plasma FFA levels and thereby releasing fatty acid inhibition on PDH, causing an increase in glucose and lactate uptake and oxidation [25].


   4. Effects of ischaemia
Top
 1. Introduction
 2. Overview
 3. Effects of plasma...
 4. Effects of ischaemia
5. Effects of reperfusion
 6. Pharmacological effectors of...
 7. Summary and conclusions
 References
 
Myocardial substrate metabolism during ischaemia is highly dependent upon the severity of ischaemia [5, 36, 88–90]. Complete elimination of flow quickly results in depletion of high energy phosphates, lactate accumulation, and contractile akinesis, which over time evolves into tissue necrosis and myocardial infarction. On the other hand, a more modest reduction in flow (20–60%) causes a decrease in myocardial oxygen consumption (~10–50%), a transient increased dependence on anaerobic glycolysis (glycogen depletion and lactate production), oxidation of FFA at a reduced rate, and modest to more severe contractile dysfunction. Depending on the metabolic demand, these modest reductions in flow do not necessarily lead to irreversible tissue damage.

4.1. Mild to moderate ischaemia
Studies in large animals (dogs and swine) have shown that a ~20–30% reduction in coronary blood flow results in a rapid reduction in mechanical work, a decrease in ATP and creatine phosphate concentrations, and a transient net output of lactate by the myocardium. Over the course of 30–90 min lactate output decreases [91] and there is a partial restoration of myocardial ATP levels [92], but contractile work does not return back to normal. Restoration of flow back to normal levels in these mildly ischaemic hearts results in a return to normal contractile function. This modest level of ischaemia and contractile dysfunction has been termed myocardial ‘hibernation’ [93], and acts to preserve the viability of the myocardium in the face of moderately subnormal myocardial blood flow by resetting the rate of mechanical work to match the rate of oxygen delivery. Studies in swine have shown that contractile work can be abruptly increased in hibernating myocardium by pacing or β-adrenergic receptor stimulation, resulting in a flow-demand mismatch and a switch back to lactate output and a decrease in creatine phosphate levels [94, 95]. The cellular mechanisms responsible for the resetting of mechanical work are not clear. The pronounced decrease in contractile work during short-term myocardial hibernation does not appear to be due to anaerobic glycolysis. When the rate of lactate production is pharmacologically reduced by activating PDH with dichloroacetate (DCA) there is no improvement in mechanical function, suggesting that the reduction in mechanical function is not caused by accelerated non-oxidative glycolysis during the initial hour of ischaemia [96].

Despite the contractile dysfunction and transient lactate production during moderate ischaemia, the primary oxidative fuel during mild to moderate ischaemia is fatty acids [5, 97, 98]. Studies in pigs with a 60% reduction in flow have shown that exogenous FFA oxidation supplies most of the energy for ATP synthesis during ischaemia even under conditions of severe contractile dysfunction, reduced myocardial oxygen consumption, and net lactate production [5, 88, 90, 97, 98]. Thus non-oxidative glycolysis and net lactate production occurs during moderate ischaemia even though the majority of the acetyl CoA is derived from fatty acid β-oxidation.

4.2. Severe ischaemia
More severe reductions in flow (>70%) result in greater rates of lactate accumulation and glycogen breakdown, severe or complete contractile dysfunction, and if the ischaemia is of sufficient duration, myocardial necrosis and infarction. As blood flow and oxygen delivery decrease, so does the rate of contractile work [99]. Glycogen depletion and lactate accumulation increase as a function of the severity of ischaemia [88–90, 100]. Sudden coronary occlusion in dogs results in a rapid transient decrease in glycogen content, which is reduced by β-adrenergic receptor blockade, suggesting that sympathetic discharge with the onset of ischaemia stimulates glycogen phosphorylase activity via increases in cytosolic cAMP and Ca2+ [101].

Complete elimination of flow differs from partial reductions in flow in that there is no residual resynthesis of ATP by oxidative phosphorylation, and thus there is total dependence on anaerobic metabolism with endogenous substrates. The sole source of glycolytic substrate under these conditions becomes glycogen, since there is no blood flow to deliver glucose to the tissue. There is no washout of lactate, intracellular pH decreases, and eventually a reduction in the rate of glycolysis occurs due to H+ inhibition of PFK. In addition, the flux through glyceraldehyde 3-phosphate dehydrogenase may also become rate limiting due to a low cytosolic NAD+/NADH ratio [37].

Myocardial ischaemia results in a decrease in flux through PDH, as seen in a decreased rate of glucose oxidation and a switch from net lactate uptake to net production. The mechanisms for the decreased flux through PDH with moderate to severe ischaemia could be: (1) an increased phosphorylation and inhibition of the enzyme, and/or (2) a build up of NADH and acetyl CoA in the mitochondria, resulting in inhibition of flux through PDH for a given phosphorylation state. The effects of ischaemia on the activation state of myocardial PDH have not been clearly elucidated. Work in isolated rat [57, 102, 103] or guinea pig [104] hearts has shown that PDH activity is either unchanged, increased, or decreased by ischaemia. Recent studies in vivo showed that a 60% reduction in coronary flow did not significantly affect PDH activation state in swine heart despite causing lactate production [72]. PDH inhibition by its products (NADH and acetyl CoA) [57], rather than phosphorylation inhibition, is thus likely to be more important in inhibiting flux through PDH in ischaemic myocardium in vivo.

Reductions in coronary artery blood flow in vivo results in a nonuniform distribution of blood flow across the left ventricular wall [100], with a relatively modest decrease in subepicardial blood flow, but more severe reductions in subendocardial blood flow [88, 90, 100]. Thus during ischaemia there are lower ATP, creatine phosphate and glycogen levels, and a higher lactate content in the subendocardium than in the subepicardium [90, 100]. Studies with radiolabeled 2-deoxyglucose suggest that subendocardial glucose uptake is not increased during ischaemia (~75–90% decrease in subendocardial flow) [90, 105]. The lack of an increase in glucose uptake in severely ischaemic myocardium appears to be the result of impaired glucose delivery and decreased interstitial glucose [16, 90]. Glucose uptake is maintained in severe but not complete subendocardial ischaemia by a large increase in the arterial-venous glucose difference [90, 105]. Some reports have shown a slight but significant increase in the capacity for glycolysis in the subendocardium relative to the subepicardium [106]. It has been hypothesized that the subendocardium might be inherently better suited to withstand ischaemia because of greater glycogen levels and a greater activity of key glycolytic enzymes. However, a critical review of this area demonstrates that there is not a consistent transmural gradient in these parameters [106]. Thus any transmural difference in metabolism appears to be due to differences in blood flow and contractile work, and not to the inherent capacity for glycolysis [90, 100, 106].

4.3. Demand-induced ischaemia
Almost all experimental studies investigating myocardial ischaemia create ischaemia by reducing coronary blood flow to the heart and comparing the subsequent response to a normal heart with normal blood flow. Clinically, however, myocardial ischaemia is often induced by an insufficient increase in myocardial blood flow in response to an increase in heart rate, inotropy, afterload, and/or preload that requires an increase in contractile work. The effects of this form of ischaemia on myocardial metabolism have not been extensively studied. Pacing-induced work in coronary artery disease patients results in an increase in glucose uptake and lactate output [107]. Dogs with partial coronary stenosis have a net lactate production during exercise instead of the normal large increase in lactate uptake [108]. It is likely that demand-induced ischaemia results in a decrease in myocardial glycogen concentration, however the effects of demand-induced ischaemia on glycogen levels have not been reported.


   5. Effects of reperfusion
Top
 1. Introduction
 2. Overview
 3. Effects of plasma...
 4. Effects of ischaemia
 5. Effects of reperfusion
6. Pharmacological effectors of...
 7. Summary and conclusions
 References
 
During ischaemia mitochondrial oxidative metabolism is suppressed and anaerobic glycolysis becomes an important source of ATP production [6]. In severely ischaemic myocardium, production of H+ from the hydrolysis of glycolytically derived ATP is a major contributor to the acidosis that occurs in the myocardium [109]. Upon reperfusion, mitochondrial oxidative phosphorylation returns to pre-ischaemic levels, however contractile power is transiently impaired, gradually recovering to pre-ischaemic values. This phenomenon is termed myocardial stunning. Stunned myocardium has a relative excess oxygen consumption for a given rate of contractile work, and thus has a decreased mechanical efficiency. Intracellular pH quickly recovers during reperfusion, although this can lead to significant increases in intracellular Na+ and Ca2+ that contribute to post-ischaemic contractile dysfunction [110–113]. A number of studies have now shown that intracellular acidosis during severe ischaemia increases sarcolemmal Na+-H+ exchange during reperfusion (see [114] and [115] for reviews). The resultant increase in intracellular Na+ in turn activates the sarcolemmal Na+-Ca2+ exchanger, resulting in exchange of intracellular Na+ with extracellular Ca2+. A high rate of Na+/Ca2+ exchange could lead to Ca2+ overload and cell death [114–117].

While accumulation of intracellular H+ during ischaemia is an important contributing factor to post-ischaemic Ca2+ overload, continued production of H+ during the critical early period of reperfusion has the potential to exacerbate injury [66, 118]. Studies in rat [119–121] and swine [122] hearts demonstrate that during myocardial reperfusion there is an overshoot in the rate of fatty acid oxidation [61, 118–123], and impaired pyruvate oxidation and accelerated nonoxidative glycolysis [124]. As discussed above, high rates of fatty acid β-oxidation dramatically inhibit glucose oxidation; this results in a marked imbalance between glycolysis and glucose oxidation [66, 125, 126]. Pyruvate oxidation is likely further inhibited in the clinical situation by the high plasma FFA concentration observed with acute myocardial infarction [61]. This uncoupling is a major source of the net H+ production in the heart. If glycolysis is coupled to glucose oxidation, H+ production from glycolysis is zero. However, if glycolysis is uncoupled from glucose oxidation, and pyruvate derived from glycolysis is converted to lactate, there is a net production of 2 H+ from each glucose molecule, which originates from the hydrolysis of glycolytically derived ATP [36]. Recently, it has been demonstrated that in isolated working rat hearts perfused with fatty acids, mitochondrial function and overall ATP production quickly recover following a 30 min period of severe ischaemia [118]. However, overall ATP production is not efficiently translated into mechanical work, which reflects a decrease in cardiac efficiency in the post-ischaemic heart [118, 122, 127]. DCA stimulates pyruvate dehydrogenase [128] and glucose oxidation during reperfusion of ischaemic hearts [66, 118]. DCA can also decrease the imbalance between glycolysis and glucose oxidation, resulting in a significant decrease in H+ production from glucose metabolism during reperfusion [66, 118]. Recent studies have demonstrated that by inhibiting the source and altering the fate of H+, a significant improvement in the recovery of mechanical function and cardiac efficiency is seen in the post-ischaemic heart [66, 118].

The reason for impaired pyruvate oxidation during post-ischaemic reperfusion is unclear, but may be due to low tissue malonyl CoA levels, resulting in less inhibition of CPT I and fatty acid oxidation. It was recently demonstrated that 30 min of total ischaemia in isolated rat hearts results in a 40% decrease in malonyl CoA concentration; this decreases to only 2% of aerobic control values after 30 min of reperfusion [129]. The fall in malonyl CoA levels corresponded to a fall in ACC activity (Fig. 3). This suggests that the overshoot in fatty acid oxidation and the inhibition of pyruvate oxidation during reperfusion are due to release of malonyl CoA inhibition on CPT I, resulting in a greater rate of β-oxidation and accumulation of acetyl CoA in the mitochondria and inhibition of flux through PDH.


   6. Pharmacological effectors of myocardial carbohydrate metabolism during ischaemia
Top
 1. Introduction
 2. Overview
 3. Effects of plasma...
 4. Effects of ischaemia
 5. Effects of reperfusion
 6. Pharmacological effectors of...
7. Summary and conclusions
 References
 
A variety of metabolic therapies have been proposed for the treatment of heart disease. Generally, they focus on either: (1) increasing myocardial glycolysis by increasing glucose uptake during ischaemia or by increasing glycogen levels prior to a surgical procedure known to result in ischaemia (e.g. coronary artery by-pass graft or heart transplantation), (2) inhibiting myocardial fatty acid oxidation and thus increasing carbohydrate oxidation and flux through PDH, or (3) directly activating PDH and increasing carbohydrate oxidation. Increased nonoxidative glycolysis results in a greater rate of anaerobic ATP regeneration, but also has the disadvantage of lactate and H+ accumulation and the accompanying negative effects described above. Therefore, in particular, increasing flux through PDH and carbohydrate oxidation during partial coronary ischaemia would theoretically have several therapeutic benefits. There would be a greater ATP yield for a given rate of oxygen consumption due to the greater ATP/oxygen ratio for carbohydrate compared to fatty acids (Table 1), as well as a greater rate of pyruvate oxidation and less lactate accumulation.


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  		Table 1 The theoretical ATP yield and oxygen consumption required for complete oxidation of glucose, lactate and palmitate

 
In general, pharmacological interventions affecting myocardial metabolism have been aimed at one of two therapeutic indications: (1) ischaemia associated with acute myocardial infarction or cardiac surgery, or (2) chronic stable angina. The treatment of acute myocardial infarction is usually with intravenous agents, and the therapeutic end-points are generally infarct size, recovery of myocardial function, the need for additional interventions, frequency of arrhythmias, and mortality and morbidity. On the other hand, chronic stable angina is treated using oral drugs, with the clinical end-points being the time to the onset of angina during a graded treadmill test, or the frequency of anginal attacks. Current therapies for chronic stable angina, such as calcium channel antagonists, nitrates, or β-adrenergic receptor antagonists, are aimed at increasing coronary blood flow and reducing arterial blood pressure and the after-load on the left ventricle. The advantage of metabolic therapies over traditional therapies is that they would potentially increase the mechanical efficiency of the left ventricle without adversely affecting hemodynamics. This would be particularly useful in patients already on maximal hemodynamically-oriented therapy (e.g. β-adrenergic receptor antagonist, calcium channel antagonist, and long acting nitrates).

Diabetes mellitus results in an elevation of plasma FFA levels, an increased rate of β-oxidation in the heart, inhibition of PDH activity and impaired glucose oxidation (see [130] for review). It has been hypothesize that diabetic patients in particular would benefit from therapies that suppressed fatty acid oxidation and increase pyruvate oxidation [130].

Treatment of myocardial ischaemia with metabolic therapies, such as PDH activators or fatty acid oxidation inhibitors, should work best under conditions where there is sufficient oxygen delivery to the myocardium to support pyruvate oxidation. In other words, it is important that there be a sufficient rate of TCA cycle activity and acetyl CoA oxidation so that increasing the rate of pyruvate oxidation has a meaningful effect on the rate of lactate production. Metabolic intervention should work best with demand-induced ischaemia (e.g. exercise-induced angina) or during post-ischaemic reperfusion, and less well or not at all in severely underperfused or completely anoxic tissue (e.g. during acute myocardial infarction due to a large thrombus).

6.1. Glycogen loading prior to ischaemic stress
Glucose and insulin infusions have been used to raise glycogen levels prior to cardiac surgery. In general, an infusion of glucose and insulin results in hyperglycemia (>10 mM), hyperinsulinemia (>80 µU/ml), and low plasma FFA levels (<0.3 mM) [26–28]. As discussed in Section 2above, hyperglycemia and hyperinsulinemia result in an increase in glycogen synthesis. Studies in patients have shown that infusing glucose and insulin overnight prior to cardiac surgery results in a 50–70% increase in cardiac glycogen concentration and improved clinical outcome from cardiac surgery [27, 28, 131]. Coronary-artery-bypass graft patients with elevated preoperative myocardial glycogen levels had reduced serum levels of myocardial enzymes during the post-operative period and a lower incidence of arrhythmias [27]. Glycogen-loaded patients undergoing mitral valve replacement had a lower incidence of postoperative hypotension, and fewer arrhythmias and serious complications during the postoperative period. These results demonstrate that overnight administration of glucose and insulin results in elevated myocardial glycogen content and improvement in patients undergoing cardioplegia. Substrate metabolism was not assessed in these studies, thus it is unclear if the improved outcome is due to a greater rate of carbohydrate oxidation due to lower FFA levels and higher rates of glycolysis and pyruvate oxidation, or rather to an increase in glycolytically derived ATP.

Studies in isolated rat hearts have found that myocardial glycogen loading can have either beneficial [80, 132] or detrimental [133] effects on post-ischaemic function. The results of these studies must be interpreted in the context of the perfusion conditions, with particular attention on the substrate composition of the perfusate and on the degree of residual flow during ischaemia and the subsequent wash-out of noxious metabolites, particularly H+ [113, 134].

6.2. Glucose and insulin
Glucose and insulin infusions have been shown to improve recovery from an acute myocardial infarction. The therapeutic concept that elevated glucose levels enhance cardiac performance during ischaemia dates back to the early part of the century [135, 136]. These early studies showed improvement in the symptoms of angina with glucose ingestion or infusion. In the 1960's Sodi-Pallares refined the treatment by adding insulin and potassium to the infusion, and demonstrated that the treatment was effective for the treatment of arrhythmias and angina [137, 138]. The beneficial effects of hyperglycemia and hyperinsulinemia could be due to a variety of factors, including (1) an increase glycolytically derived ATP, (2) an increase in PDH activity due to decreased plasma FFA concentration and elevated insulin levels, resulting in less lactate and H+ accumulation, and (3) less accumulation of noxious fatty-acyl CoAs due to lower FFA levels.

Glucose and insulin infusion was later shown to decrease infarct size and prevent the fall in creatine phosphate, ATP and pH in animal models of ischaemia/reperfusion injury [139, 140]. Clinical trials with glucose and insulin infusion following myocardial infarction [141, 142] or coronary artery by-pass surgery [143] have generally been favorable, although a fully powered multi-center trial has yet to be done. Clinical development and commercialization of glucose and insulin therapy is likely hampered by the lack of patent protection.

6.3. Dichloroacetate (DCA)
One strategy to stimulate carbohydrate oxidation is to directly activate the rate-limiting enzyme for pyruvate oxidation, PDH. An agent that effectively does this is DCA, which acts by inhibiting PDH kinase and preventing phosphorylation of PDH, thus maintaining PDH in the dephosphorylated active form and increasing the oxidation of pyruvate [76, 128]. In addition, DCA has been shown to bring about inhibition of fatty acid oxidation, presumably by shuttling acetyl CoA groups out of the mitochondria, which eventually can lead to an increase in malonyl CoA concentration and the inhibition of CPT I and mitochondrial fatty acid uptake [71, 72].

DCA has been studied in acute settings with intravenous administration. In clinical studies, DCA has been shown to increase left ventricular stroke volume in patients with coronary artery disease [144]. DCA has also been shown to stimulate glucose and lactate oxidation, and dramatically improve recovery of cardiac work following ischaemia [66, 118, 120, 145–147]. In a number of these studies, DCA was only present during the reperfusion period. While DCA is capable of stimulating both glycolysis and glucose oxidation in the aerobic heart, in the post-ischaemic period DCA selectively stimulates glucose oxidation [65]. Therefore, the beneficial effects of DCA appear to be directly due to stimulation of pyruvate oxidation, and not stimulation of glycolysis.

Unfortunately, while DCA is very effective as a stimulator of pyruvate oxidation, its use is limited by its low potency (blood levels need to approach millimolar levels) and short half-life [128]. Both of these limitations, and the fact that DCA is not under patent protection, suggests that this agent is unlikely to find widespread clinical use. However, it remains a very effective research tool for delineating the mechanisms as to why stimulation of pyruvate oxidation can benefit the ischaemic and reperfused ischaemic myocardium.

6.4. Carnitine palmitoyltransferase I (CPT I) inhibitors
An alternative approach to achieving the same desired switch in metabolic substrate utilization, via operation of the glucose-fatty acid cycle [51], is to inhibit fatty acid uptake by the mitochondria. The key enzyme involved in this process is CPT I (Fig. 3). Inhibition of CPT I reduces myocardial fatty acid oxidation, which relieves fatty acid inhibition of PDH, and increases the oxidation of glucose [59, 60, 148, 149] (Fig. 4) and lactate [150]. This has anti-ischaemic efficacy and improves cardiac function during the recovery from ischaemia. However, long-term administration of such agents has been found to be associated with toxicity problems, and in particular their causing cardiac hypertrophy [151]. It is interesting to note that etomoxir does not affect ventricular mass in rats with left ventricular hypertrophy following aortic banding, and actually prevents the impairment in contractile function in this model [152].


Figure 4
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  		Fig. 4 Effects of acute treatment with dichloroacetate [66], carnitine [77], etomoxir [184], or ranolazine [179] on glucose oxidation in isolated working rat hearts perfused with Krebs-Henseleit buffer containing 11 mM glucose, 1.2 mM palmitate, and 2.5 mM Ca2+ under nonischemic conditions. The ranolazine and DCA perfusion buffer contained insulin (100 µU/ml), while the buffer used in the etomoxir and carnitine studies was insulin free. * denotes statistically difference from respective control group (P<0.05).

 
6.5. L-Carnitine and propionyl L-carnitine
As already mentioned, an important step in the oxidation of fatty acids is the translocation of fatty acids into the inner mitochondrial space by L-carnitine-mediated transport [153]. In addition to this critical metabolic role, L-carnitine is also important in regulating pyruvate oxidation in the heart, and its administration has been shown to lead to increases in glucose oxidation [77, 78] (Fig. 4). This ability to increase glucose oxidation occurs secondary to an increase in PDH activity, due to a lowering of the intramitochondrial acetyl-CoA/CoA ratio (see Fig. 3). Propionyl L-carnitine is a L-carnitine analog that has similar effects on myocardial glucose oxidation [154]. This naturally occurring compound may also have beneficial effects on anaplerotic replenishing of intramitochondrial Krebs' cycle intermediates [155].

Anti-ischaemic effects of L-carnitine and propionyl L-carnitine have been shown in both experimental and clinical studies, and beneficial effects of these compounds have been seen on functional and hemodynamic parameters of failing hearts [156]. In experimental studies L-carnitine and propionyl L-carnitine have been demonstrated to be effective cardioprotective agents in a number of different models of experimental ischaemia (in vitro and in vivo) [157–160]. The supplementation of the myocardium with carnitine or propionyl L-carnitine results in an increased tissue carnitine content, a stimulation of pyruvate oxidation, lessening of the severity of ischaemic injury, and improvement in the recovery of heart function during reperfusion.

Clinically both L-carnitine and propionyl L-carnitine have been shown to have anti-ischaemic properties. Both compounds are effective anti-anginal agents that can reduce ST segment depression and left ventricular end-diastolic pressure during stress testing in patients with coronary artery disease [159]. In addition, cardioprotective effects of these compounds have been observed following aortocoronary bypass grafting and following acute myocardial infarction. In a recent multi-center trial, L-carnitine treatment initiated early after acute myocardial infarction and continued for 12 months was found to attenuate left ventricular dilation and result in smaller left ventricular volumes [156]. L-carnitine and propionyl L-carnitine have also been shown to benefit cardiac mechanics in clinical studies. For instance, in NYHA class II heart failure patients propionyl L-carnitine improves exercise capacity, from 1 month after starting treatment, and increased shortening fraction and ejection fraction [156].

In addition to direct cardiac effects, L-carnitine and propionyl L-carnitine also have the potential to alter skeletal muscle function. A recent multi-centered trial of patients with intermittent claudication showed that propionyl L-carnitine significantly improves maximal walking distance on treadmill performance tests [161]. Whether L-carnitine and propionyl L-carnitine increase glucose oxidation in skeletal muscle in a manner similar to the heart remains to be determined.

6.6. Trimetazidine
The oral antianginal trimetazidine ((1-[2,3,4-trimethoxibenzyl)]-piperazine) has anti-ischaemic actions without central hemodynamic effects in chronic stable anginal patients at rest or during exercise [162–165]. Studies in isolated perfused rodent hearts have demonstrated a similar effect. Trimetazidine has been shown to decrease the fall in pH during no-flow ischaemia in isolated rat hearts [166]. Trimetazidine does not affect the rate of glycolysis during reperfusion following 30 min of low-flow ischaemia in rat hearts [167], suggesting that it does not increase the rate of glycolytic ATP production. Studies in isolated mitochondria demonstrated that trimetazidine inhibits oxidative phosphorylation when palmitoyl carnitine is the substrate, but not with pyruvate, suggesting that trimetazidine may act as an inhibitor of β-oxidation, and thus stimulates flux through PDH in vivo [168]. Taken together, these results suggest that trimetazidine could exert its effects through inhibition of fatty acid oxidation and reciprocal activation of pyruvate oxidation, resulting in less production and accumulation of lactate and H+ during ischaemia. The effects of trimetazidine on fatty acid and glucose oxidation, and lactate production have not been reported.

6.7. Ranolazine
This is a novel oral anti-ischaemic agent which is also a piperazine derivative [RS-43285; (+)-N-(2,6-dimethyl-phenyl)-4[2-hydroxy-3(2-methoxy-phenoxy)propyl]-1-piperazine acetamide). It has shown efficacy in a number of in vivo [169–171] and in vitro [104, 172, 173] cardiac preparations from several different animal species, and as measured by a variety of different indices of ischaemic damage. It has also shown efficacy in the exercise treadmill tests in chronic stable angina patients in clinical trials at doses >267 mg t.i.d. [174, 175], but not at lower doses [176]. As with trimetazidine, ranolazine also appears to bring about these anti-ischaemic and anti-anginal effects without altering haemodynamics or baseline contactile parameters [171–178].

In animal studies where efficacy has been shown, the ischaemic insult has either been of short-term (up to 30 min) or of repetitive intermittent duration, or has involved a reduction, but not cessation, in flow [104, 169–175]. This would be consistent with a metabolic concept of action, as described above, where residual oxygen supply remains and there is then a potential to maximise its use [179]. In contrast, when flow is restricted totally and for longer terms or permanently, then the compound no longer appears to show any protective effects [180, 181].

The effects of ranolazine on metabolic substrate oxidation have been extensively investigated in both cardiac [179] and skeletal [182] muscle preparations. In hearts perfused with either 0.4 mM or 1.2 mM palmitate (plus 3% albumin), ranolazine consistently caused significant increases in glucose oxidation under a variety of different normoxic conditions (Fig. 4) and also during varied degrees of low-flow ischaemia, as well as during reperfusion following ischaemia [179]. Decreases in fatty acid oxidation were also observed under some conditions, although, no substantial or consistent effects on glycolysis were observed. The effective concentration range appears to be around 1–10 µM ranolazine, which is in a similar range to human plasma concentrations in studies where anti-anginal efficacy is observed [174, 175, 178]. In isolated rat epitrochlearis muscle, 10 µM ranolazine significantly increases glucose oxidation and decreases fatty acid oxidation, but, perhaps surprisingly, did not appear to affect lactate oxidation rates [182].

Ranolazine has been found to increase the amount of active PDH in isolated guinea pig hearts subjected to low-flow ischaemia [104], and also in normoxic rat hearts [183]. In the latter study, increases in active enzyme were only observed when fatty acid (palmitate) was present in the perfusate and the effects of ranolazine were also shown to be additive to those of dichloroacetate. Extensive investigation with extracted enzymes and isolated mitochondria, however, failed to find any direct effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity [183]; ranolazine is also known to have no effect on CPT-I or its inhibition by malonyl CoA [171].

Ranolazine caused a reduction in the acetyl CoA content of the palmitate-perfused rat hearts [183]. Moreover, in perfusions where the palmitate was replaced with octanoate (which does not require CPT-I to access the matrix for β-oxidation) ranolazine still caused reductions in acetyl CoA, but not in hearts where the palmitate was replaced by acetate [183]. Further analyses of the octanoate-perfused hearts revealed that in the presence of ranolazine there was a build up in the C8, C6 and C4 CoA esters coincident with the reduction in acetyl CoA, strongly suggesting that ranolazine causes an inhibition of fatty acid β-oxidation and thus leading to PDH activation (due to the decrease in acetyl CoA) and increased glucose oxidation in this manner. It should be emphasised that decreases in acetyl CoA may stimulate flux through active PDH as well as leading to increases in amount of active enzyme through reduction in PDH kinase activity (Fig. 2).


   7. Summary and conclusions
Top
 1. Introduction
 2. Overview
 3. Effects of plasma...
 4. Effects of ischaemia
 5. Effects of reperfusion
 6. Pharmacological effectors of...
 7. Summary and conclusions
References
 
It is now clear that the availability of different metabolic substrates can have a profound influence on the extent of damage incurred during episodes of cardiac ischaemia, and on cardiac functional recovery on reperfusion following ischaemia. In particular, increases in fatty acid availability and oxidation, compared to glucose oxidation, under such conditions leads to a worsening of outcome. Therefore metabolic interventions aimed at enhancing glucose utilisation and pyruvate oxidation at the expense of fatty acid oxidation is a valid therapeutic approach to the treatment of myocardial ischaemia. In particular, the development of agents which will promote full glucose oxidation as opposed to glycolysis alone, offer clear advantages. This can be accomplished by different means, including direct or indirect inhibition of CPT-I or inhibition of fatty acid β-oxidation, or by direct or indirect activation of PDH. It is not yet clear which of these approaches offers the best treatment of cardiac ischaemia. To date, trimetazidine and carnitine have received limited approval in Europe for the treatment of angina; large scale clinical trials with the other agents mentioned above have not been completed. The increasing availability of agents affecting these specific sites, and the increasingly sophisticated techniques for assessing myocardial metabolism, should allow elucidation of the optimum metabolic targets and development of novel pharmacological agents for the treatment of ischaemic heart disease.

Time for primary review 28 days.


   Notes
 
* Corresponding author. Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA. Tel.: (+1-216) 368-3400; fax: (+1-216) 368-5586; E-mail: wcs4@po.cwru.edu Back


   References
Top
 1. Introduction
 2. Overview
 3. Effects of plasma...
 4. Effects of ischaemia
 5. Effects of reperfusion
 6. Pharmacological effectors of...
 7. Summary and conclusions
 References
 

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Dichloroacetate improves postischemic function of hypertrophied rat hearts
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W. C Stanley and C. L Hoppel
Mitochondrial dysfunction in heart failure: potential for therapeutic interventions?
Cardiovasc Res, March 1, 2000; 45(4): 805 - 806.
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 J Am Coll CardiolHome page
J. Chen, T. A. Marciniak, M. J. Radford, Y. Wang, and H. M. Krumholz
Beta-blocker therapy for secondary prevention of myocardial infarction in elderly diabetic patients: Results from the national cooperative cardiovascular project
J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1388 - 1394.
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 Cardiovasc ResHome page
F. A. Recchia, P. I. McConnell, K. E. Loke, X. Xu, M. Ochoa, and T. H. Hintze
Nitric oxide controls cardiac substrate utilization in the conscious dog
Cardiovasc Res, November 1, 1999; 44(2): 325 - 332.
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 Eur Heart JHome page
R. Ferrari
Metabolic treatment of myocardial ischaemia
Eur. Heart J., August 2, 1999; 20(16): 1144 - 1145.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
P. Ferdinandy, D. Panas, and R. Schulz
Peroxynitrite contributes to spontaneous loss of cardiac efficiency in isolated working rat hearts
Am J Physiol Heart Circ Physiol, June 1, 1999; 276(6): H1861 - H1867.
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