Metabolic therapy for the treatment of ischemic heart disease: Reality and expectations

Expert Review of Cardiovascular Therapy

Volumn 5, Issue 6, 2007, Pages 1123-1134

  Wang, Wei ^a   Lopaschuk, Gary D ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

Author keywords

CPT1 inhibitors; Dichloroacetate; Fatty acid oxidation; Glucose oxidation; Insulin; Malonly CoA decarboxylase inhibitors; Trimetazidine

Indexed keywords

ACIPIMOX; ANTIANGINA PECTORIS AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CARNITINE PALMITOYLTRANSFERASE INHIBITOR; CARVEDILOL; DICHLOROACETIC ACID; ETOMOXIR; FATTY ACID; GLUCOSE; INSULIN; MALONYL COENZYME A DECARBOXYLASE; MALONYL COENZYME A DECARBOXYLASE INHIBITOR; METOPROLOL; MILDRONATE; NICOTINIC ACID; OXFENICINE; PERHEXILINE; PLACEBO; POTASSIUM; RANOLAZINE; TRIMETAZIDINE; UNCLASSIFIED DRUG; URIC ACID;

CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG EFFICACY; DRUG MEGADOSE; DRUG POTENCY; DRUG STRUCTURE; DRUG TOLERABILITY; ENERGY METABOLISM; FATTY ACID OXIDATION; FLUSHING; GLUCOSE OXIDATION; GLYCOLYSIS; HEART FAILURE; HEART MUSCLE ISCHEMIA; HEART MUSCLE METABOLISM; HEART PROTECTION; HUMAN; ISCHEMIC HEART DISEASE; LIPOLYSIS; LIVER TOXICITY; MONOTHERAPY; REPERFUSION INJURY; REVIEW; SIDE EFFECT; URIC ACID BLOOD LEVEL;

BLOOD GLUCOSE; CARBOHYDRATE METABOLISM; ENERGY METABOLISM; ENZYME INHIBITORS; FATTY ACIDS; FEMALE; HUMANS; MALE; MYOCARDIAL ISCHEMIA; MYOCARDIAL REPERFUSION INJURY; MYOCARDIUM; OXIDATION-REDUCTION; RISK ASSESSMENT; SENSITIVITY AND SPECIFICITY; SURVIVAL ANALYSIS;

EID: 37349129856     PISSN: 14779072     EISSN: 17448344     Source Type: Journal    
DOI: 10.1586/14779072.5.6.1123     Document Type: Review

References (102)

1. Taegtmeyer H. Metabolism - the lost child of cardiology. J. Am. Coll. Cardiol. 36(4), 1386-1388 (2000).
2. Stanley WC. Partial fatty acid oxidation inhibitors for stable angina. Expert Opin. Investig. Drugs 11 (5), 615-629 (2002).
3. 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. 86(5), 580-588 (2000).
4. van der Vusse GJ, Glatz JF, Stam HC, Reneman RS. Fatty acid homeostasis in the normoxic and ischernic heart. Physiol. Rev. 72(4), 881-940 (1992).
5. Gert EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in bumans. Dual carbon-labeled carbohydrate isotope experiments. J. Clin. Invest. 82(6), 2017-2025 (1988).
6. van der Vusse GJ, van Bilsen M, Glatz JF. Cardiac fatty acid uptake and transport in health and disease. Cardiovasc. Res. 45(2), 279-293 (2000).
7. Hamilton JA. Transport of fatty acids across membranes by the diffusion mechanism. Prostaglandins Leukot. Eisent. Fatty Acids 60(5-6), 291-297 (1999).
8. Veerkamp, JH, Maatman RG. Cytoplasmic fatty acid-binding proteins, their structure and genes. Prog. Lipid Res. 34(1), 17-52 (1995).
9. Glatz JF, van der Vusse GJ. Cellular fatty acid-binding proteins, their function and physiological significance. Prog. Lipid Res. 35(3), 243-282 (1996).
10. Koonen DP, Glatz JF, Bonen A, Luiken JJ. Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. Biochim. Biophys. Acta 1736(3), 163-180 (2005).
11. Chabowski A, Gorski J, Calles-Escandon J, Tandon NN, Bonen A. Hypoxia-induced fatty acid transporter translocation increases fatty acid transport and contributes to lipid accumulation in the heart. FEBS Lett. 580(15), 3617-3623 (2006).
12. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85(3), 1093-129 (2005).
13. Sambandam N, Lopaschuk GD. AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. Prog. Lipid Res. 42(3), 238-256 (2003).
14. Russell RR 3rd, Bergeron R, Shulman GI, Young LH. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am. J. Physiol. 277(2 Pt 2), H643-H649 (1999).
15. Kodde IF, van der Stok J, Smolenski RT, de Jong JW. Metabolic and genetic regulation of cardiac energy substrate preference. Comp. Biochem. Physiol., Part A Mol. Integr. Physiol. 146(1), 26-39 (2006).
16. Randle PJ. Fuel selection in animals. Biochem. Soc. Trans. 14(5), 799-806 (1986).
17. Stanley WC. Myocardial energy metabolism during ischemia and the mechanisms of metabolic therapies. J. Cardiovasc. Pharmacol. Ther. 9 (Suppl. 1), S31-S45 (2004).
18. Karmazyn M. The role of the myocardial sodium-hydrogen exchanger in mediating ischemic and reperfusion injury. From amiloride to cariporide. Ann. NY Acad. Sci. 874, 326-334 (1999).
19. Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischemic conditions. Potential for pharmacological interventions. Cardlovasc. Res. 33(2), 243-257 (1997).
20. Young LH, Russell RR 3rd, Yin R et al. Regulation of myocardial glucose uptake and transport during ischemia and energetic stress. Am. J. Cardiol. 83 (12A), 25H-30H (1999).
21. Lopaschuk GD, Stanley WC. Malonyi-CoA decarboxylase inhibition as a novel approach to treat ischemic heart disease. Cardiovasc. Drugs Ther. 20(6), 433-439 (2006).
22. Saddik M, Lopaschuk GD. Myocardial triglyceride turnover during reperfusion of isolated rat hearts subjected to a transient period of global ischemia. J. Biol. Chem. 267(6), 3825-3831(1992).
23. Lopaschuk GD, Collins-Nakai R, Olley PM et al. Plasma fatty acid levels in infants and adults after myocardial ischemia. Am. Heart J. 128(1), 61-67 (1994).
24. Dyck JR, Kudo N, Barr AJ, Davies SP, Hardie DG, Lopaschuk GD. Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5-AMP activated protein kinase. Eur. J. Biochem. 262(1), 184-190 (1999).
25. 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. 39(4), 718-725 (2002).
26. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ. Res. 68(5), 1250-1258 (1991).
27. Sodi-Pallares D, Testelli M, Fishelder F. Effects of an intravenous infusion of a potassium-insulin-glucose solution on the electrocardiographic signs of myocardial infarction. Am. J. Cardiol. 9, 166-181 (1962).
28. Gradinac S, Coleman GM, Taegtmeyer H, Sweeney MS, Frazier OH. Improved cardiac function with glucose-insulin-potassium after aortocoronary bypass grafting. Ann. Thorac. Surg. 48(4), 484-489 (1989).
29. van Wezel HB. Glucose - insulin-potassium techniques in cardiac surgery, historical overview and future perspectives. Semin. Cardiothorac. Vasc. Anesth. 10(3), 224-227 (2006).
30. Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction. An overview of randomized, placebo-controlled trials. Circulation 96, 1152-1156 (1997).
31. Diaz R, Paolasso EA, Piegas LS et al. Metabolic modulation of acute myocardial infarction. The ECLA glucose-insulin-potassium pilot trial. Circulation 98, 2227-2234 (1998).
32. Janiger JL, Cheng JW. Glucose-insulin-potassium solution for acute myocardial infarction. Ann. Pharmacother. 36(6), 1080-1084 (2002).
33. Jeschke MG, Klein D, Bolder U et al. Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinology 145, 4084-4093 (2004).
34. Mehta SR, Yusuf S, Diaz R et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction, the CREATE-ECLA randomized controlled trial. JAMA 293, 437-446 (2005).
35. Leos CL, Griego JE, Anderson JR. Glucose-insulin-potassium therapy in the era of coronary revascularization. Cardiol. Rev. 13(5), 266-270 (2005).
36. Apstein CS, Opie LH. Glucose-insulin-potassium (GIK) for acute myocardial infarction, a negative study with a positive value. Cardiovasc. Drugs Ther. 13(3), 185-189 (1999).
37. Janiger JL, Cheng JW. Glucose-insulin-potassium solution for acute myocardial infarction. Ann. Pharmacother. 36(6), 1080-1084 (2002).
38. Racey-Burns LA, Burns AH, Summer WR, Shepherd RE. The effect of dichloroacetate on the isolated no flow arrested rat heart. Life Sci. 44(26), 2015-2023 (1989).
39. Mazer CD, Cason BA, Stanley WC, Shnier CB, Wisneski JA, Hickey RF. Dichloroacetate stimulates carbohydrate metabolism but does not improve systolic function in ischemic pig heart. Am. J. Physiol. 268(2 Pt 2), H879-H885 (1995).
40. 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. 61, 65-70 (1988).
41. Lewis JF, DaCosta M, Wargowich T, Stacpoole P. Effects of dichloroacetate in patients with congestive heart failure. Clin. Cardiol. 21(12), 888-892 (1998).
42. Wang P, Lloyd SG, Chatham JC. Impact of high glucose/high insulin and dichloroacetate treatment on carbohydrate oxidation and functional recovery after low-flow ischemia and reperfusion in the isolated perfused rat heart. Circulation 111(16), 2066-2072 (2005).
43. Wolff AA, Rotmensch HH, Stanley WC, Ferrari R. Metabolic approaches to the treatment of ischemic heart disease, the clinicians' perspective. Heart Fail. Rev. 7, 187-203 (2002).
44. Tilley DG, Rockman HA. Role of β-adrenergic receptor signaling and desensitization in heart failure, new concepts and prospects for treatment. Expert Rev. Cardiovasc. Ther. 4(3), 417-432 (2006).
45. McNamara DM, MacGowan GA, London B. Clinical importance of β-adrenoceptor polymorphisms in cardiovascular disease. Am. J. Pharmacogenomics 2(2), 73-78 (2002).
46. Poole-Wilson PA, Swedberg K, Cleland JG et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the carvedilol or metoprolol european trial (COMET), randomised controlled trial. Lancet 362, 7-13 (2003).
47. Altschul R, Herman IH. Influence of oxygen inhalation on cholesterol metabolism. Arch. Biochem. 51, 308-309 (1954).
48. Carlson LA, Oro L. The effect of nicotinic acid on the plasma free fatty acids. Acta Med. Scand. 172, 641-645 (1962).
49. Tunaru S, Kero J, Schaub A et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat. Med. 9(3), 352-355 (2003).
50. Canner PL, Berge KG, Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients. Long-term benefits with niacin. J. Am. Coll. Cardiol. 81, 1245-1255 (1986).
51. Carlson LA. Nicotinic acid, the broad-spectrum lipid drug. A 50th anniversary review. J. Intern. Med. 258(2), 94-114 (2005).
52. O'Kane MJ, Trinick TR, Tynan MB, Trimble ER, Nicholls DP. A comparison of acipimox and nicotinic acid in type 2b hyperlipidaemia. Br. J. Clin. Pharmacol. 33(4), 451-453 (1992).
53. Stephens TW, Higgins AJ, Cook GA, Harris RA. Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem. J. 227, 651-660 (1995).
54. Drake-Holland AJ, Passingham JE. The effect of oxfenicine on cardiac carbohydrate metabolism in intact dogs. Basic Res. Cardiol. 78, 19-27 (1983).
55. Kahles H, Schafer W, Lick T, Junggeburth J, Kochsiek K. Changes in myocardial substrate and energy metabolism by S-(4)-hydroxyphenylglycine and an N-(6)-derivative of adenosine. Basic Res. Cardiol. 81, 258-266 (1986).
56. Higgins AJ, Morville M, Burges RA, Gardiner DG, Page MG, Blackburn KJ. Oxfenicine diverts rat muscle metabolism from fatty acid to carbohydrate oxidation and protects the ischemia rat heart. Life Sci. 27, 963-970 (1980).
57. Burges RA, Gardiner DG, Higgins AJ. Protection of the ischaemic dog heart by oxfenicine. Life Sci. 29, 1847-1853 (1981).
58. Chandler MP, Chavez PN, McElfresh TA, Huang H, Harmon CS, Stanley WC. Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia. Cardiovasc. Res. 59(1), 143-151 (2003).
59. Bergman G, Atkinson L, Metcalfe J, Jackson J, Jewitt DE. Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris. Eur. Heart J. 1, 247-253 (1980).
60. Vik-Mo H, Mjos OD, Neely JR, Maroko PR, Ribeiro LG. Limitation of myocardial infarct size by metabolic interventions that reduce accumulation of fatty acid metabolites in ischemic myocardium. Am. Heart J. 111, 1048-1054 (1986).
61. Hirshleifer I. Perhexiline maleate in the treatment of angina pectoris. Curr. Ther. Res. Clin. Exp. 11, 99-105 (1969).
62. Cho YW, Belej M, Aviado DM. Pharmacology of a new antianginal drug, perhexiline. I. Coronary circulation and myocardial metabolism. Chest 58(6), 577-581 (1970).
63. Morgan MY, Reshef R, Shah RR, Oates NS, Smith RL, Sherlock S. Impaired oxidation of debrisoquine in patients with perhexiline liver injury. Gut 25(10), 1057-1064 (1984).
64. Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JD. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br. Med. J. (Clin. Res. Ed.) 284 (6312), 295-299 (1982).
65. Cole PL, Beamer AD, McGowan N et al. Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Cirrulation 81(4), 1260-1270 (1990).
66. Kennedy JA, Unger SA, Horowitz JD. Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem. Pharmacol. 52(2), 273-280 (1996).
67. Lee L, Campbell R, Scheuermann-Freestone M et al. Metabolic modulation with perhexiline in chronic heart failure, a randomized, controlled trial of short-term use of a novel treatment. Circulation 112(21), 3280-3288 (2005).
68. Unger SA, Kennedy JA, McFadden-Lewis K, Minerds K, Murphy GA, Horowitz JD. Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium. J. Cardiovasc. Pharmacol. 46(6), 849-855 (2005).
69. Kennedy JA, Kiosoglous AJ, Murphy GA, Pelle MA, Horowitz JD. Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J. Cardiovasc. Pharmacol. 36(6), 794-801 (2000).
70. Lopaschuk GD, Wall SR, Olley PM, Davies NJ. Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ. Res. 63(6), 1036-1043 (1988).
71. Lopaschuk GD, McNeil GF, McVeigh JJ. Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. Mol. Cell Biochem. 88(1-2), 175-179 (1989).
72. Wall SR, Lopaschuk GD. Glucose oxidation rates in fatty acid-perfused isolated working hearts from diabetic rats. Biochim. Biophys. Acta 1006(1), 97-103 (1989).
73. Turcani M, Rupp H. Modification of left ventricular hypertrophy by chronic etomixir treatment. Br. J. Pharmacol. 126(2), 501-507 (1999).
74. Zarain-Herzberg A, Rupp H, Elimban V, Dhalla NS. Modification of sarcoplasmic reticulum gene expression in pressure overload cardiac hypertrophy by etomoxir. FASEB J. 10(11), 1303-1309 (1996).
75. Portilla D, Dai G, Peters JM, Gonzalez FJ, Crew MD, Proia AD. Etomoxic-induced PPARalpha-modulated enzymes protect during acute renal failure. Am. J. Physiol. Renal Physiol. 278, F667-F675 (2000).
76. Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin. Sci. (Lond.) 99(1), 27-35 (2000).
77. Stanley WC, Morgan EE, Huang H et al. Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia. Am. J. Physiol. Heart Circ. Physiol. 289(6), H2304-H2309 (2005).
78. Dyck JR, Hopkins TA, Bonnet S et al. Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation 114(16), 1721-1728 (2006).
79. Tang WH. Metabolic approach in heart failure, rethinking how we translate from theory to clinical practice. J. Am. Coll. Cardiol. 48(5), 999-1000 (2006).
80. Fantini E, Demaison L, Sentex E et al. Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation. J. Mol. Cell Cardiol. 26(8), 949-958 (1994).
81. Kennedy JA, Horowitz JD. Effect of trimetazidine on carnitine palmitoyltransferase-1 in the rat heart. Cardiovasc Drugs Ther 12(4), 359-363 (1998).
82. Lopaschuk GD, Barr R, Thomas PD et al. 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 thiclase. Circ. Res. 93(3), e33-e37 (2003).
83. Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine, a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Br. J. Clin. Pharmacol. 37, 279-288 (1994).
84. Marzilli M, Klein WW. Efficacy and tolerability of trimetazidine in stable angina, a meta-analysis of randomized, double-blind, controlled trials. Coron. Artery Dis. 14(2), 171-179 (2003).
85. Chazov EI. Lepakchin VK, Zharova EA et al. Trimetazidine in Angina Combination Therapy - the TACT study, trimetazidine versus conventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. Am. J. Ther. 12(1), 35-42 (2005).
86. Koylan N, Bilge AK, Adalet K, Mercanoglu F, Buyukozturk K, TTS Group. Comparison of the effects of trimetazidine and diltiazem on exercise performance in patients with coronary heart disease. The Turkish trimetazidine study (TTS). Acta Cardiol. 59(6), 644-650 (2004).
87. 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. 20(9), 1447-1454 (2004).
88. Sellier P, Broustet JP. Assessment of antiischemic and antianginal effect at trough plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris, a multicenter, double-blind, placebo-controlled study. Am. J. Cardiovasc. Drugs 3(5), 361-369 (2003).
89. Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database Syst. Rev. 19(4), CD003614 (2005).
90. Simkhovich BZ, Meirena DV, Khagi KhB, Kaivirish IIa, Lukevits Ela. Effect of a new structural analog of γ-butyrobetaine-3-(2,2,2-trimethylhydrazine) propionate (THP) on carnitine level, carnitine-dependent fatty acid oxidation and various indices of energy metabolism in the myricardium. Vopr. Med. Khim. 32(4), 72-76 (1986).
91. Simkhovich BZ, Shutenko ZV, Meirena DV et al. 3-(2,2,2-trimethylhydrazinium) propionate (THP) - a novel γ-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochem. Pharmacol. 37, 195-202 (1988).
92. Sesti C, Simkhovich BZ, Kalvinsh I, Kloner RA. Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. J. Cardiovasc. Pharmacol. 47(3), 493-499 (2006).
93. Liepinsh E, Vilskersts R, Loca D et al. Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in γ-butyrobetaine contents and cardioprotection in isolated rat heart infarction. J. Cardiovasc. Pharmacol. 48(6), 314-319 (2006).
94. Teplyakov AT, Sankevitch TV, Stepatcheva TA, Mamchur SE. The use of fatty acid β-oxidation inhibitor mildronate as monotherapy or in combination with atenolol in patients with left ventricular dysfunction after myocardial infarction. Kardiologiia 43(12), 15-18 (2003).
95. Semigolovskii NIu. Use of antihypoxants in the acute period of myocardial infarction. Anesteziol. Reanimatol. 2, 56-59 (1998).
96. McCormack JG, Barr RL, Wolff AA, Lopaschuk GD. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 93(1), 135-142 (1996).
97. MacInnes A, Fairman DA, Binding P et al. The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. 93(3), e26-e32 (2003).
98. Wang P, Fraser H, Lloyd SG, McVeigh JJ, Belardinelli L, Chatham JC. A comparison between rRanolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion. J. Pharmacol. Exp. Ther. 321(1), 213-220 (2007).
99. Antzelevitch C, Belardinelli L, Zygmunt AC et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 110(8), 904-910 (2004).
100. Zacharowski K, Blackburn B, Thiemermann C. Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat. Eur. J. Pharmacol. 418(1-2), 105-110 (2001).
101. Hale SL, Leeka JA, Kloner RA. Improved left ventricular function and reduced necrosis after myocardial ischemia/reperfusion in rabbits treated with ranolazine, an inhibitor of the late sodium channel. J. Pharmacol. Exp. Ther. 318(1), 418-423 (2006).
102. Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 113(20), 2462-2472 (2006).