Revascularization in angina patients: addressing cardiac metabolism challenges



by G. D. Lopaschuk, Canada

Gary D. LOPASCHUK, PhD, MSc, BSc Cardiovascular Research Centre Mazankowski Alberta Heart Institute University of Alberta, Edmonton CANADA

The onset of an angina pectoris attack is associated with dramatic alterations in cardiac energy metabolism. A mismatch between oxygen (O2) demand and O2 supply to the heart muscle results in a decrease in mitochondrial oxidative metabolism, leading to an energy-deficient state in the heart. In addition, changes in the source of substrates for cardiac mitochondrial energy metabolism contribute to contractile dysfunction and to a decrease in cardiac efficiency. These changes include an increase in the contribution of cardiac fatty acid (FA) oxidation to residual mitochondrial oxidative metabolism and an uncoupling of glycolysis from glucose oxidation. Revascularization can lessen angina symptoms predominantly by lessening the mismatch between O2 demand and O2 supply to the heart muscle. However, while revascularization can improve O2 supply, some of the switches in cardiac metabolism persist after revascularization. In particular, the muscle becomes overly reliant on FA oxidation as a source of energy, primarily at the expense of glucose oxidation. This can continue to uncouple glycolysis from glucose oxidation, resulting in a continued decrease in cardiac efficiency. As a result, a challenge in revascularized angina patients is to normalize cardiac energy metabolism and improve cardiac efficiency. Recent evidence suggests that therapeutically regulating cardiac energy metabolism by reducing FA oxidation —which increases glucose oxidation—can improve cardiac efficiency and cardiac function and lessen the symptoms of angina, even in revascularized patients. In this article, we review the cardiac mitochondrial energy metabolic changes that occur in the heart in angina patients, and the changes that occur during revascularization, as well as the potential for targeting FA oxidation to treat angina, both in the presence or absence of revascularization.

Angina pectoris due to coronary artery disease (CAD) is a major health problem in the world. Revascularization of angina patients, either by percutaneous coronary interventions (PCI) or by coronary artery bypass graft (CABG) surgery, can substantially improve angina symptoms for most patients. However, symptoms of angina can persist and may return over time, even when taking optimal antianginal medications.1 As a result, it is imperative to identify new approaches to treat angina, even in the revascularized patient. One potentially promising approach to treating angina is to optimize cardiac energy metabolism.2 This would appear to be a logical approach, as a decrease in oxygen availability and alterations in cardiac energy metabolism are prominent changes in the angina patient. However, in order to fully exploit the potential of optimizing cardiac energy metabolism in angina patients, it is first important to understand how cardiac energy metabolism is regulated in the normal patient, in the angina patient, and after revascularization of the angina patient. This paper reviews the cardiac metabolic changes that occur in the angina patient, and how optimizing cardiac energy metabolism can be used as an approach to treat such patients, both those with or without revascularization.

Cardiac energy metabolism in the normal heart

The heart has a very high energy demand, due to the need to produce large amounts of adenosine triphosphate (ATP) to support the continuous contractile function of the heart. There are no significant energy reserves in the heart, and there is a near complete turnover of the myocardial ATP pool every 5 to 10 seconds.2,3 To meet these high energy demands, the heart generates ATP by metabolizing a variety of energy substrates, including fatty acids, glucose, lactate, ketone bodies, and amino acids (Figure 1). The contributions of each of these energy substrates to ATP generation are tightly regulated, and there is a significant degree of plasticity and interdependence in the use of these energy substrates. Under normal, physiological conditions, fatty acids and carbohydrates (ie, glucose and lactate) represent the primary metabolic fuels that sustain cardiac function, and upwards of 95% of ATP production is attributable to mitochondrial oxidative phosphorylation.2,3 The remainder of this ATP production primarily originates from glycolysis, which has the benefit of producing ATP without the need for oxygen (Figure 1). The trade off of this anaerobic ATP production is that lactate and protons (H+’s) are two of the metabolic byproducts of glycolysis if the pyruvate produced from glycolysis is not subsequently subjected to mitochondrial oxidative metabolism.2

The heart normally displays substantial metabolic flexibility, with fatty acid and glucose metabolism having a considerable degree of interdependence, a process referred to as the Randle Cycle or the glucose/fatty acid cycle.4 Increasing fatty acid oxidation in the heart decreases glucose oxidation, whereas increasing glucose oxidation inhibits fatty acid oxidation. A key site at which fatty acid oxidation decreases glucose metabolism is at the level of pyruvate dehydrogenase (PDH), the rate-limiting enzyme for glucose oxidation. High rates of fatty acid oxidation inhibit PDH, secondary to activating a PDH kinase that phosphorylates and inhibits PDH.

Figure 1. Overview of energy metabolism in the heart. Abbreviations: I-IV, complexes I to IV in the electron transport chain; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT, carnitine palmitoyl transferase; H+, proton; H2O, water; LDH, lactate dehydrogenase; MPC, mitochondrial pyruvate carrier; O2, oxygen; PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid.

Cardiac energy metabolism in angina

Various cardiac pathophysiological states cause perturbations of the tightly regulated pathways of myocardial energy substrate metabolism, and these perturbations contribute to the progression of myocardial injury. In CAD, repeated oxygen (O2) supply and demand mismatches results in downregulation of mitochondrial oxidative metabolism, and an increase in glucose uptake and glycolysis.5 During an angina attack, where O2 availability is not sufficient to meet the O2 requirements of the heart, impaired mitochondrial oxidative metabolism results in a rapid decline in ATP production from fatty acid oxidation and glucose oxidation that is proportional to the degree of ischemia (Figure 2A). Glycolysis becomes a very important source of energy during ischemia due to its ability to generate ATP in the absence of O2. During periods of mild-to-moderate ischemia, glucose uptake and the mobilization of endogenous glucose from stored glycogen contribute to increased flux through the glycolytic pathway.2

Despite the presence of ischemia, mitochondrial fatty acid oxidation remains the predominant source of residual oxidative metabolism.6 This is due to a number of ischemia-induced changes, which include the following: (i) an increase in circulating fatty acids to which the heart is exposed; (ii) an increase in myocardial fatty acid uptake; and (iii) an increase in mitochondrial fatty acid uptake (see Lopaschuk et al2 for review). The increase in the relative contribution of fatty acid oxidation to mitochondrial oxidative metabolism results in a parallel decrease in glucose oxidation during ischemia. Since glycolysis is accelerated during ischemia, the hydrolysis of glycolytically derived ATP uncoupled from subsequent pyruvate oxidation leads to an increased generation of lactate and H+ (Figure 2A). In severely ischemic hearts, this can result in a decrease in pH in the myocardium, which can lead to cell death. In milder ischemia (such as seen during angina), the production of H+ from glycolysis leads to disturbances in ionic homeostasis, which leads to a decrease in cardiac efficiency, as ATP is required to restore these ionic imbalances.

Cardiac energy metabolism after revascularization

Revascularization is an important approach to reducing the myocardial O2 supply and demand mismatch that can occur in the CAD patient. However, during revascularization, the short complete interruptions of blood flow produce a profound ischemia, which are accompanied by dramatic alterations in cardiac energy metabolism. During reperfusion of the ischemic heart, overall cardiac fatty acid oxidation rates are elevated, due, at least partially, to elevated levels of circulating fatty acids (Figure 2B).5,7 In addition, the subcellular control of fatty acid oxidation is altered, such that fatty acid oxidation becomes deregulated. Elevated levels of circulating fatty acids combined with an increase in mitochondria fatty acid uptake results in an increase in fatty acid oxidation rates during reperfusion, with a concomitant marked decrease in glucose oxidation rates (Figure 2B).2,6-8 This elevation in circulating fatty acids and cardiac fatty acid oxidation after restoration of blood flow can impair cardiac function and cardiac efficiency (Figure 2B).6,7 The decrease in glucose oxidation after revascularization can result in increased uncoupling of glycolysis from glucose oxidation and a subsequent increase in production of lactate and H+, which can decrease cardiac efficiency and impair heart function.2,6,7 As a result, a challenge in the revascularized angina patient is to normalize cardiac energy metabolism, particularly by increasing glucose oxidation rates.

While revascularization can improve cardiac function and decrease mortality risk, alterations in cardiac energetics can persist in the heart after revascularization. This includes persistent abnormalities in mitochondrial oxidative metabolism,5 as well as alterations in energy substrate preference by the heart. In particular, a continued increased reliance on fatty acid oxidation at the expense of glucose oxidation can occur after reperfusion,6-9 providing a challenge in the revascularized patient to restore normal cardiac energy metabolism.

Figure 2. Alterations in myocardial energy metabolism during ischemia and reperfusion. During ischemia (A), glycolysis becomes the main source of energy production in the absence of or a decreased supply of oxygen. Fatty acids dominate as the substrate for residual oxidative metabolism due to increased plasma levels of fatty acids, as well as alterations in the subcellular control of fatty acid oxidation. During reperfusion (B), glycolytic rates remain high, while fatty acid oxidation dominates over glucose oxidation as the main source of oxidative metabolism. The dominant fatty acid oxidation rates during reperfusion inhibit glucose oxidation. The uncoupling of glycolysis from glucose oxidation leads to an increase in proton production, which ultimately leads to myocardial acidosis and calcium overload. Abbreviations: I-IV, complexes I to IV in the electron transport chain; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT, carnitine palmitoyl transferase; H+, proton; H2O, water; LDH, lactate dehydrogenase; MPC, mitochondrial pyruvate carrier; O2, oxygen; PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid.

Targeting fatty acid oxidation to treat angina

Classically, the pharmacological treatment of angina patients has focused on the use of agents that alter systemic and/or cardiac hemodynamics. With increasing knowledge of the mechanisms regulating cardiac energy substrate metabolism, and with the understanding that alterations in such metabolism contribute to the severity of angina symptoms, the modulation and optimization of energy substrate metabolism represents a novel and promising area for therapeutic intervention in angina patients. In this regard, pharmacological agents that shift the balance between the oxidative utilization of fatty acid and glucose toward glucose oxidation have been an area of intense research activity.2,3 In particular, pharmacological agents that either inhibit fatty acid oxidation and/or stimulate glucose oxidation are promising anti-ischemic interventions (Figure 3).2,3,8-18

Fatty acid oxidation can be inhibited directly by decreasing fatty acid uptake into the mitochondria or by inhibiting mitochondrial fatty acid oxidation. Fatty acid oxidation can also be inhibited indirectly by increasing glucose oxidation. Pharmacological inhibition of fatty acid oxidation with drugs that lower fatty acid levels, block mitochondrial fatty acid uptake, or directly inhibit fatty acid oxidation all have potential benefit in the setting of angina.

One drug that directly targets mitochondrial fatty acid oxidation is trimetazidine.8-15 Trimetazidine is a partial fatty acid oxidation inhibitor that competitively inhibits the fatty acid oxidation enzyme, long chain 3-ketoacyl coenzyme A thiolase. 8-10 The inhibition of fatty acid oxidation is accompanied by an increase in glucose oxidation. This is beneficial in both ischemic myocardium during restoration of blood flow or in already revascularized myocardium, as the increased glucose oxidation decreases the production of H+’s arising from the uncoupling of glycolysis from glucose oxidation.

Figure 3. Diagrams for pharmacological targets that decrease fatty acid oxidation and/or increase glucose oxidation in the heart. Abbreviations: I-IV, complexes I to IV in the electron transport chain; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT, carnitine palmitoyl transferase; DCA, dichloroacetate; H+, proton; H2O, water; LDH, lactate dehydrogenase; MPC, mitochondrial pyruvate carrier; O2, oxygen; PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid.

Results from clinical studies have confirmed the effectiveness of trimetazidine as an anti-ischemic agent. Treatment of angina with trimetazidine increases time to 1-mm ST segment depression as well as weekly nitrate consumption.11,12 Trimetazidine has been shown to have comparable effectiveness to propranolol in treating stable angina.11-14 Combination therapy with standard antianginal therapy reduces the number of symptomatic episodes of angina and improves time to ischemia- related electrocardiogram changes on exercise testing. 13 As discussed, many revascularized angina patients still require antianginal therapy.14,15 The use of metabolic agents during and after revascularization has been shown to provide myocardial protection.15,16 Angina patients with previous PCI or CABG show significant improvement in time to 1-mm STsegment depression, exercise test duration, total workload, time to onset of angina, and weekly angina attacks and nitrate consumption.15 Trimetazidine is cardioprotective in patients undergoing CABG and PCI procedures, evidenced by its ability to decrease the release of troponin T and decrease ST-segment elevation, respectively, during balloon inflation.17,18 Arecent meta-analysisof patients undergoing PCI also showed that the use of trimetazidine during the PCI procedure resulted in a significant reduction in myocardial injury and in improved cardiac function,18 effects that would be expected by inhibiting fatty acid oxidation in the myocardium.

Although classified as a late sodium current inhibitor, ranolazine is also a partial fatty acid oxidation inhibitor, which has been shown to inhibit fatty acid oxidation and reciprocally increase glucose oxidation and PDH activity.19 In experimental studies, ranolazine attenuates myocardial stunning, reduces infarct size, increases cardiac ejection fraction, increases stroke volume, and increases mechanical efficiency without increasing oxygen consumption.19,20 Clinically, ranolazine, as an anti-ischemic agent, has been shown to increase exercise capacity and time to 1-mm ST-segment depression, and reduce the number of weekly angina attacks and nitroglycerin consumption as a monotherapy or combined therapy. 21 However, a recent study showed that ranolazine had no incremental benefit in angina or quality of life in patients with incomplete revascularization after PCI.22 b-Adrenoceptor antagonists (b-blockers) are classic drugs used in the setting of angina. This class of drug is believed to exert an oxygensparing effect by a reduction in inotropic and chronotropic effects, thus reducing cardiac workload. However, blockade of b-adrenoceptors decreases catecholamine-induced lipolysis and therefore decreases plasma fatty acid availability and extraction. As a result, part of the benefit of b-blockade in the setting of angina may occur secondary to decreased myocardial fatty acid oxidation. Indeed, carvedilol has been shown to reduce myocardial free fatty acid uptake by 57% in patients with heart failure.23

In addition to inhibiting fatty acid oxidation, directly increasing myocardial glucose oxidation may be another approach to optimizing energy metabolism in angina. Dichloroacetate (DCA) acts via direct stimulation of the mitochondrial PDH complex via the inhibition of the activity of PDH kinase. The improved coupling between glycolysis and glucose oxidation is believed to be the mechanism by which DCA exerts its cardioprotective effects.7,24 Experimental studies show that DCA is cardioprotective in the setting of ischemia and reperfusion (see Lopaschuk et al2 for review). However, clinical data on the use of DCA is scarce. In a small clinical study, where DCA was given to patients with CAD via intravenous infusion, improvements in left ventricular stroke volume were observed in the absence of changes in heart rate, left ventricular end diastolic pressure, or myocardial oxygen consumption.25 The poor potency and pharmacokinetic profile of DCA make it unlikely that this drug will ever be used clinically.

Conclusion

Alterations in cardiac energy metabolism are an important factor in the severity of angina in both the revascularized and nonrevascularized patient. Significant metabolic changes result in an increase in the contribution of fatty acid oxidation compared with glucose oxidation to cardiac energy production, that leads to a decrease in cardiac efficiency. A challenge in the revascularized angina patient is to normalize cardiac energy metabolism and to improve cardiac efficiency. Therapeutic strategies aimed at inhibiting fatty acid oxidation are one potential approach to optimizing energy metabolism in the angina patient. One such approach is to directly inhibit fatty acid oxidation with trimetazidine, which leads to an indirect increase in glucose oxidation in the heart. The subsequent improvement in cardiac efficiency is associated with beneficial effects of trimetazidine in decreasing angina symptoms, even in the revascularized patient.

References

1. Weintraub WS, Spertus JA, Kolm P, et al; COURAGE Trial Research Group. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med. 2008;359:677-687. 
2. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207-258. 
3. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. 2007;356: 1140-1151. 
4. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1:785-789. 
5. Holley CT, Long EK, Lindsey ME, McFall EO, Kelly RF. Recovery of hibernating myocardium: what is the role of surgical revascularization? J Card Surg. 2015;30:224-231. 
6. Folmes CD, Sowah D, Clanachan AS, Lopaschuk GD. High rates of residual fatty acid oxidation during mild ischemia decrease cardiac work and efficiency. J Mol Cell Cardiol. 2009;47:142-148. 
7. Liu Q, Docherty JC, Rendell JC, Clanachan AS, Lopaschuk GD. High levels of fatty acids delay the recovery of intracellular pH and cardiac efficiency in post-ischemic hearts by inhibiting glucose oxidation. J Am Coll Cardiol. 2002; 39:718-725. 
8. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86:580-588. 
9. Lopaschuk GD, Barr R, Thomas PD, Dyck JR. Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2003;93:e33-37. 
10. Saeedi R, Grist M, Wambolt RB, Bescond-Jacquet A, Lucien A, Allard MF. Trimetazidine normalizes postischemic function of hypertrophied rat hearts. J Pharmacol. Exp Ther. 2005;314:446-454. 
11. Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database Syst Rev. 2005;(4):CD003614. 
12. Marzilli M, Klein WW. Efficacy and tolerability of trimetazidine in stable angina: a meta-analysis of randomized, double-blind, controlled trials. Coron Artery Dis. 2003;14(2):171-179. 
13. Ruzyllo W, Szwed H, Sadowski Z, et al. Efficacy of trimetazidine in patients with recurrent angina: a subgroup analysis of the TRIMPOL II study. Curr Med Res Opin. 2004;20(9):1447-1454. 
14. Szwed H, Sadowski Z, Pachocki R, et al. The antiischemic effects and tolerability of trimetazidine in coronary diabetic patients. A substudy from TRIMPOL- 1. Cardiovasc Drugs Ther. 1999;13(3):217-222. 
15. Danchin N. Clinical benefits of a metabolic approach with trimetazidine in revascularized patients with angina. Am J Cardiol. 2006;98(5A):8J-13J. 
16. Zhang Y, Ma XJ, Shi D-Z. Effect of trimetazidine in patients undergoing percutaneous coronary intervention: a meta-analysis. PLoS ONE. 2015;10(9): e0137775. 
17. Tunerir B, Colak O, Alatas O, Besogul Y, Kural T, Aslan R. Measurement of troponin T to detect cardioprotective effect of trimetazidine during coronary artery bypass grafting. Ann Thorac Surg. 1999;68(6):2173-2176. 
18. Polonski L, Dec I, Wojnar R, Wilczek K. Trimetazidine limits the effects of myocardial ischaemia during percutaneous coronary angioplasty. Curr Med Res Opin. 2002;18(7):389-396. 
19. McCormack JG, Barr RL, Wolff AA, Lopaschuk GD. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation. 1996;93:135-142. 
20. Clarke B, Spedding M, Patmore L, McCormack JG. Protective effects of ranolazine in guinea-pig hearts during low-flow ischaemia and their association with increases in active pyruvate dehydrogenase. Br J Pharmacol.1993;109: 748-750. 
21. Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291: 309-316. 
22. Alexander KP, Weisz G, Prather K, et al. Effects of ranolazine on angina and quality of life after percutaneous coronary intervention with incomplete revascularization: results from the Ranolazine for Incomplete VEssel Revascularization (RIVER-PCI) Trial. Circulation. 2016;133(1):39-47. 
23. Al-Hesayen A, Azevedo ER, Floras JS, Hollingshead S, Lopaschuk GD, Parker JD. Selective versus nonselective b-adrenergic receptor blockade in chronic heart failure: differential effects on myocardial energy substrate utilization. Eur J Heart Fail. 2005;7:618-623. 
24. Liu B, Clanachan AS, Schulz R, Lopaschuk GD. Cardiac efficiency is improved after ischemia by altering both the source and fate of protons. Circ Res. 1996; 79:940-948. 
25. Wargovich TJ, MacDonald RG, Hill JA, Feldman RL, Stacpoole PW, Pepine CJ. Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol. 1988;6:65-70.