Cardiovascular Drugs and Therapy

, Volume 30, Issue 4, pp 379–391 | Cite as

Pharmacological Agents Targeting Myocardial Metabolism for the Management of Chronic Stable Angina : an Update

  • Giacinta Guarini
  • Alda Huqi
  • Doralisa Morrone
  • Mario Marzilli
ORIGINAL ARTICLE

Abstract

Despite continuous advances in myocardial revascularization procedures and intracoronary devices, patients with ischemic heart disease (IHD) still experience worse prognosis and poor quality of life (QoL). Indeed, chronic stable angina (CSA) is a common disease with a large burden on healthcare costs. Traditionally, CSA is interpreted as episodes of reversible myocardial ischemia related to the presence of stable coronary artery plaque causing myocardial demand/supply mismatch when myocardial oxygen consumption increases. Accordingly, revascularization procedures are performed with the aim to remove the flow limiting stenosis, whereas traditional medical therapy (hemodynamic agents) aims at reducing myocardial oxygen demands. However, although effective, none of these treatment strategies or their combination is either able to confer symptomatic relief in all patients, nor to reduce mortality. Failure to significantly improve QoL and prognosis may be attributed at least in part to this “restrictive” understanding of IHD. Despite for many years myocardial metabolic derangement has been overlooked, recently it has gained increased attention with the development of new pharmacological agents (metabolic modulators) able to influence myocardial substrate selection and utilization thus improving cardiac efficiency. Shifting cardiac metabolism from free fatty acids (FA) towards glucose is a promising approach for the treatment of patients with stable angina, independently of the underling disease (macrovascular and/or microvascular disease). In this sense cardiac metabolic modulators open the way to a “revolutionary” understanding of ischemic heart disease and its common clinical manifestations, where myocardial ischemia is no longer considered as the mere oxygen and metabolites demand/supply unbalance, but as an energetic disorder. Keeping in mind such an alternative approach to the disease, development of new pharmacological agents directed toward multiple metabolic targets is mandatory.

Keywords

Chronic stable angina Myocardial ischemia Metabolic modulation therapy 

References

  1. 1.
    Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, Senior R, Taggart DP, van der Wall EE, Vrints CJ, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Knuuti J, Valgimigli M, Bueno H, Claeys MJ, Donner-Banzhoff N, Erol C, Frank H, Funck-Brentano C, Gaemperli O, Gonzalez-Juanatey JR, Hamilos M, Hasdai D, Husted S, James SK, Kervinen K, Kolh P, Kristensen SD, Lancellotti P, Maggioni AP, Piepoli MF, Pries AR, Romeo F, Ryden L, Simoons ML, Sirnes PA, Steg PG, Timmis A, Wijns W, Windecker S, Yildirir A, Zamorano JL. ESC guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003.PubMedCrossRefGoogle Scholar
  2. 2.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2014;131:e29–322.PubMedCrossRefGoogle Scholar
  3. 3.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB: Heart disease and stroke statistics--2013 update: a report from the American Heart Association. Circulation 2013;127:e6-e245.Google Scholar
  4. 4.
    Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, Daly C, De Backer G, Hjemdahl P, Lopez-Sendon J, Marco J, Morais J, Pepper J, Sechtem U, Simoons M, Thygesen K, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo J, Zamorano JL. Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006;27:1341–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Boden WE, O'Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356:1503–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Five-year clinical and functional outcome comparing bypass surgery and angioplasty in patients with multivessel coronary disease. A multicenter randomized trial. Writing Group for the Bypass Angioplasty Revascularization Investigation (BARI) Investigators. JAMA 1997;277:715–721.Google Scholar
  7. 7.
    Marzilli M, Huqi A, Morrone D. Persistent angina: the araba phoenix of cardiology. Am J Cardiovasc Drugs. 2010;10(Suppl 1):27–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Marzilli M, Merz CN, Boden WE, Bonow RO, Capozza PG, Chilian WM, DeMaria AN, Guarini G, Huqi A, Morrone D, Patel MR, Weintraub WS. Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol. 2012;60:951–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Pepine CJ, Douglas PS. Rethinking stable ischemic heart disease: is this the beginning of a new era? J Am Coll Cardiol. 2012;60:957–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ, Fonarow GC, Lange RA, Levine GN, Maddox TM, Naidu SS, Ohman EM, Smith PK. ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2014;130:1749–67.PubMedCrossRefGoogle Scholar
  11. 11.
    Marzilli M, Affinito S. Meeting the challenge of chronic ischaemic heart disease with trimetazidine. Coron Artery Dis. 2005;16(Suppl 1):S23–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Guarini G, Huqi A, Morrone D, Capozza P, Todiere G, Marzilli M. Pharmacological approaches to coronary microvascular dysfunction. Pharmacol Ther. 2014;144:283–302.PubMedCrossRefGoogle Scholar
  13. 13.
    Guarini G, Huqi A, Capozza P, Morrone D, Donati F, Marzilli M. Therapy against ischemic injury. Curr Pharm Des. 2013;19:4597–621.PubMedCrossRefGoogle Scholar
  14. 14.
    Wolff AA, Rotmensch HH, Stanley WC, Ferrari R. Metabolic approaches to the treatment of ischemic heart disease: the clinicians' perspective. Heart Fail Rev. 2002;7:187–203.PubMedCrossRefGoogle Scholar
  15. 15.
    Wimmer NJ, Stone PH. Anti-anginal and anti-ischemic effects of late sodium current inhibition. Cardiovasc Drugs Ther. 2013;27:69–77.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Stanley WC, Sabbah HN. Metabolic therapy for ischemic heart disease: the rationale for inhibition of fatty acid oxidation. Heart Fail Rev. 2005;10:275–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions. Cardiovasc Res. 1997;33:243–57.PubMedCrossRefGoogle Scholar
  18. 18.
    Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093–129.PubMedCrossRefGoogle Scholar
  19. 19.
    Jaswal JS, Keung W, Wang W, Ussher JR, Lopaschuk GD. Targeting fatty acid and carbohydrate oxidation--a novel therapeutic intervention in the ischemic and failing heart. Biochim Biophys Acta. 1813;2011:1333–50.Google Scholar
  20. 20.
    Rupp H, Zarain-Herzberg A, Maisch B. The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure. Herz. 2002;27:621–36.PubMedCrossRefGoogle Scholar
  21. 21.
    Stanley WC. Partial fatty acid oxidation inhibitors for stable angina. Expert Opin Investig Drugs. 2002;11:615–29.PubMedCrossRefGoogle Scholar
  22. 22.
    Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab. 2003;284:E855–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Spriet LL, Heigenhauser GJ. Regulation of pyruvate dehydrogenase (PDH) activity in human skeletal muscle during exercise. Exerc Sport Sci Rev. 2002;30:91–5.PubMedCrossRefGoogle Scholar
  24. 24.
    McVeigh JJ, Lopaschuk GD. Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. Am J Phys. 1990;259:H1079–85.Google Scholar
  25. 25.
    Bergman G, Atkinson L, Metcalfe J, Jackson N, Jewitt DE. Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris. Eur Heart J. 1980;1:247–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Cole PL, Beamer AD, McGowan N, Cantillon CO, Benfell K, Kelly RA, Hartley LH, Smith TW, Antman EM. Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation. 1990;81:1260–70.PubMedCrossRefGoogle Scholar
  27. 27.
    Klassen GA, Zborowska-Sluis DT, Wright GJ. Effects of oral perhexiline on canine myocardial flow distribution. Can J Physiol Pharmacol. 1980;58:543–9.PubMedCrossRefGoogle Scholar
  28. 28.
    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. 2005;46:849–55.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, Ashrafian H, Horowitz J, Fraser AG, Clarke K, Frenneaux M. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005;112:3280–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F, Yousef Z, Wagenmakers AJ, Thies F, Horowitz J, Frenneaux MP. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail. 2015;3:202–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Barclay ML, Sawyers SM, Begg EJ, Zhang M, Roberts RL, Kennedy MA, Elliott JM. Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status. Pharmacogenetics. 2003;13:627–32.PubMedCrossRefGoogle Scholar
  32. 32.
    Maarman G, Marais E, Lochner A, du Toit EF. Effect of chronic CPT-1 inhibition on myocardial ischemia-reperfusion injury (I/R) in a model of diet-induced obesity. Cardiovasc Drugs Ther. 2012;26:205–16.PubMedCrossRefGoogle Scholar
  33. 33.
    Lionetti V, Linke A, Chandler MP, Young ME, Penn MS, Gupte S, d'Agostino C, Hintze TH, Stanley WC, Recchia FA. Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure. Cardiovasc Res. 2005;66:454–61.PubMedCrossRefGoogle Scholar
  34. 34.
    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. 2003;59:143–51.PubMedCrossRefGoogle Scholar
  35. 35.
    Greaves P, Martin J, Michel MC, Mompon P. Cardiac hypertrophy in the dog and rat induced by oxfenicine, an agent which modifies muscle metabolism. Arch Toxicol Suppl. 1984;7:488–93.PubMedCrossRefGoogle Scholar
  36. 36.
    Bachmann E, Weber E. Biochemical mechanisms of oxfenicine cardiotoxicity. Pharmacology. 1988;36:238–48.PubMedCrossRefGoogle Scholar
  37. 37.
    Dyck JR, Cheng JF, Stanley WC, Barr R, Chandler MP, Brown S, Wallace D, Arrhenius T, Harmon C, Yang G, Nadzan AM, Lopaschuk GD. Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ Res. 2004;94:e78–84.PubMedCrossRefGoogle Scholar
  38. 38.
    McClellan KJ, Plosker GL. Trimetazidine. A review of its use in stable angina pectoris and other coronary conditions. Drugs. 1999;58:143–57.PubMedCrossRefGoogle Scholar
  39. 39.
    Bucci M, Borra R, Nagren K, Parkka JP, Del Ry S, Maggio R, Tuunanen H, Viljanen T, Cabiati M, Rigazio S, Taittonen M, Pagotto U, Parkkola R, Opie LH, Nuutila P, Knuuti J, Iozzo P. Trimetazidine reduces endogenous free fatty acid oxidation and improves myocardial efficiency in obese humans. Cardiovasc Ther. 2012;30:333–41.PubMedCrossRefGoogle Scholar
  40. 40.
    Vaillant F, Tsibiribi P, Bricca G, Bui-Xuan B, Bescond-Jacquet A, Tabib A, Descotes J, Timour Q. Trimetazidine protective effect against ischemia-induced susceptibility to ventricular fibrillation in pigs. Cardiovasc Drugs Ther. 2008;22:29–36.PubMedCrossRefGoogle Scholar
  41. 41.
    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;86:580–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Lopaschuk GD. Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Coron Artery Dis. 2001;12(Suppl 1):S8–11.PubMedGoogle Scholar
  43. 43.
    Blardi P, de Lalla A, Volpi L, Auteri A, Di Perri T. Increase of adenosine plasma levels after oral trimetazidine: a pharmacological preconditioning? Pharmacol Res. 2002;45:69–72.PubMedCrossRefGoogle Scholar
  44. 44.
    Polonski L, Dec I, Wojnar R, Wilczek K. Trimetazidine limits the effects of myocardial ischaemia during percutaneous coronary angioplasty. Curr Med Res Opin. 2002;18:389–96.PubMedCrossRefGoogle Scholar
  45. 45.
    Rebrova TY, Lasukova TV, Afanas'ev SA, Perchatkin VA, Maksimov IV, Markov VA. Cardioprotective effect of trimetazidine during thrombolytic therapy in patients with acute myocardial infarction. Bull Exp Biol Med. 2002;134:559–61.PubMedCrossRefGoogle Scholar
  46. 46.
    Levy S. Value of the combination of trimetazidine (Vastarel 20 mg) with diltiazem (Tildiem 60 mg) in stable effort angina. A double-blind versus placebo multicenter study. Ann Cardiol Angeiol (Paris). 1995;44:203–12.Google Scholar
  47. 47.
    Brochier M, Demange J, Ducloux G, Monpere C, Warin JF. [Value of the combination of trimetazidine and a calcium inhibitor in the treatment of chronic coronary insufficiency. Double-blind controlled study versus placebo]. Ann Cardiol Angeiol (Paris). 1986;35:49–56.Google Scholar
  48. 48.
    Deroux A, Brochier M, Demange J, Ducloux G, Monpere C. Warin JF: [therapeutic value of a combination of trimetazidine with a calcium inhibitor in the treatment of chronic coronary insufficiency]. Presse Med. 1986;15:1783–7.PubMedGoogle Scholar
  49. 49.
    Gallet M. Clinical effectiveness of trimetazidine in stable effort angina. A double-blind versus placebo controlled study. Presse Med. 1986;15:1779–82.PubMedGoogle Scholar
  50. 50.
    Manchanda SC, Krishnaswami S. Combination treatment with trimetazidine and diltiazem in stable angina pectoris. Heart. 1997;78:353–7.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Lu C, Dabrowski P, Fragasso G, Chierchia SL. Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Am J Cardiol. 1998;82:898–901.PubMedCrossRefGoogle Scholar
  52. 52.
    Bricaud H, Brottier L, Barat JL, Combe C, Boussens B, Bonnet J. Cardioprotective effect of trimetazidine in severe ischemic cardiomyopathy. Cardiovasc Drugs Ther. 1990;4(Suppl 4):861–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Szwed H, Hradec J, Preda I. Anti-ischaemic efficacy and tolerability of trimetazidine administered to patients with angina pectoris: results of three studies. Coron Artery Dis. 2001;12(Suppl 1):S25–8.PubMedGoogle Scholar
  54. 54.
    Passeron J. Effectiveness of trimetazidine in stable effort angina due to chronic coronary insufficiency. A double-blind versus placebo study. Presse Med. 1986;15:1775–8.PubMedGoogle Scholar
  55. 55.
    Hanania G, Haiat R, Olive T, Maalouf B, Michel D, Martelet M, Godard S. [Coronary artery disease observed in general hospitals: ETTIC study. Comparison between trimetazidine and mononitrate isosorbide for patients receiving betablockers]. Ann Cardiol Angeiol (Paris). 2002;51:268–74.CrossRefGoogle Scholar
  56. 56.
    Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, Skibinska E, Szymczak K, Swiatek J, Winter M. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand Eur Heart J. 2001;22:2267–74.PubMedCrossRefGoogle Scholar
  57. 57.
    Szwed H. Clinical benefits of trimetazidine in patients with recurrent angina. Coron Artery Dis. 2004;15(Suppl 1):S17–21.PubMedGoogle Scholar
  58. 58.
    Chazov EI, Lepakchin VK, Zharova EA, Fitilev SB, Levin AM, Rumiantzeva EG, Fitileva TB. 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. 2005;12:35–42.PubMedCrossRefGoogle Scholar
  59. 59.
    Michaelides A, Spiropoulos K, Dimopoulos K, Athanasiades D, Toutouzas P. Antianginal efficacy of the combination of trimetazidine-propranolol compared with isosorbide dinitrate-propranolol in patients with stable angina. Clinical Drug Investigation. 1997;13:8–14.CrossRefGoogle Scholar
  60. 60.
    Vitale C, Spoletini I, Malorni W, Perrone-Filardi P, Volterrani M, Rosano GM. Efficacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina - the VASCO-angina study. Int J Cardiol. 2013;168(2):1078–81.PubMedCrossRefGoogle Scholar
  61. 61.
    Grabczewska Z, Bialoszynski T, Szymanski P, Sukiennik A, Swiatkiewicz I, Kozinski M, Kochman W, Grzesk G, Kubica J. The effect of trimetazidine added to maximal anti-ischemic therapy in patients with advanced coronary artery disease. Cardiol J. 2008;15:344–50.PubMedGoogle Scholar
  62. 62.
    Marazzi G, Wajngarten M, Vitale C, Patrizi R, Pelliccia F, Gebara O, Pierri H, Ramires JA, Volterrani M, Fini M, Rosano GM. Effect of free fatty acid inhibition on silent and symptomatic myocardial ischemia in diabetic patients with coronary artery disease. Int J Cardiol. 2007;120:79–84.PubMedCrossRefGoogle Scholar
  63. 63.
    Peng S, Zhao M, Wan J, Fang Q, Fang D, Li K. The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials. Int J Cardiol. 2014;177:780–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Marzilli M. Cardioprotective effects of trimetazidine: a review. Curr Med Res Opin. 2003;19:661–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology. 2011;120:59–72.PubMedCrossRefGoogle Scholar
  66. 66.
    Marzilli M. Does trimetazidine prevent myocardial injury after percutaneous coronary intervention? Nat Clin Pract Cardiovasc Med. 2008;5:16–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Danchin N. Clinical benefits of a metabolic approach with trimetazidine in revascularized patients with angina. Am J Cardiol. 2006;98:8J–13J.PubMedCrossRefGoogle Scholar
  68. 68.
    Vasiuk Iu A, Shal'nova SA, Shkol'nik EL, Kulikov KG. [The (PRIMA) Study. Comparison of clinical effect of trimetazidine MR in men and women]. Kardiologiia. 2011;51:11–5.PubMedGoogle Scholar
  69. 69.
    Rodriguez Padial L, Maicas Bellido C, Velazquez Martin M, Gil Polo B. A prospective study on trimetazidine effectiveness and tolerability in diabetic patients in association to the previous treatment of their coronary disease. DIETRIC study. Rev Clin Esp. 2005;205:57–62.PubMedCrossRefGoogle Scholar
  70. 70.
    Ribeiro LW, Ribeiro JP, Stein R, Leitao C, Polanczyk CA. Trimetazidine added to combined hemodynamic antianginal therapy in patients with type 2 diabetes: a randomized crossover trial. Am Heart J. 2007;154(78):e71–7.Google Scholar
  71. 71.
    Sellier P, Audouin P, Payen B, Corona P, Duong TC, Ourbak P. Acute effects of trimetazidine evaluated by exercise testing. Eur J Clin Pharmacol. 1987;33:205–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol. 2006;48:992–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Zhao P, Zhang J, Yin XG, Maharaj P, Narraindoo S, Cui LQ, Tang YS. The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated cardiomyopathy. Life Sci. 2013;92:633–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Hu B, Li W, Xu T, Chen T, Guo J. Evaluation of trimetazidine in angina pectoris by echocardiography and radionuclide angiography: a meta-analysis of randomized, controlled trials. Clin Cardiol. 2011;34:395–400.PubMedCrossRefGoogle Scholar
  75. 75.
    Fragasso G, Piatti Md PM, Monti L, Palloshi A, Setola E, Puccetti P, Calori G, Lopaschuk GD, Margonato A. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am Heart J. 2003;146:E18.PubMedCrossRefGoogle Scholar
  76. 76.
    Fragasso G, Rosano G, Baek SH, Sisakian H, Di Napoli P, Alberti L, Calori G, Kang SM, Sahakyan L, Sanosyan A, Vitale C, Marazzi G, Margonato A, Belardinelli R. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol. 2013;163:320–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol. 2003;2:16.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Monti LD, Setola E, Fragasso G, Camisasca RP, Lucotti P, Galluccio E, Origgi A, Margonato A, Piatti P. Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy. Am J Physiol Endocrinol Metab. 2006;290:E54–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Gunes Y, Guntekin U, Tuncer M, Sahin M. Improved left and right ventricular functions with trimetazidine in patients with heart failure: a tissue Doppler study. Heart Vessel. 2009;24:277–82.CrossRefGoogle Scholar
  80. 80.
    Marazzi G, Gebara O, Vitale C, Caminiti G, Wajngarten M, Volterrani M, Ramires JA, Rosano G, Fini M. Effect of trimetazidine on quality of life in elderly patients with ischemic dilated cardiomyopathy. Adv Ther. 2009;26:455–61.PubMedCrossRefGoogle Scholar
  81. 81.
    Belardinelli R, Lacalaprice F, Faccenda E, Volpe L. Trimetazidine potentiates the effects of exercise training in patients with ischemic cardiomyopathy referred for cardiac rehabilitation. Eur J Cardiovasc Prev Rehabil. 2008;15:533–40.PubMedCrossRefGoogle Scholar
  82. 82.
    Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011;97:278–86.PubMedCrossRefGoogle Scholar
  83. 83.
    El-Kady T, El-Sabban K, Gabaly M, Sabry A, Abdel-Hady S. Effects of trimetazidine on myocardial perfusion and the contractile response of chronically dysfunctional myocardium in ischemic cardiomyopathy: a 24-month study. Am J Cardiovasc Drugs. 2005;5:271–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Tritto I, Wang P, Kuppusamy P, Giraldez R, Zweier JL, Ambrosio G. The anti-anginal drug trimetazidine reduces neutrophil-mediated cardiac reperfusion injury. J Cardiovasc Pharmacol. 2005;46:89–98.PubMedCrossRefGoogle Scholar
  85. 85.
    Williams FM, Tanda K, Kus M, Williams TJ. Trimetazidine inhibits neutrophil accumulation after myocardial ischaemia and reperfusion in rabbits. J Cardiovasc Pharmacol. 1993;22:828–33.PubMedCrossRefGoogle Scholar
  86. 86.
    Khan M, Meduru S, Mostafa M, Khan S, Hideg K, Kuppusamy P. Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. J Pharmacol Exp Ther. 2010;333:421–9.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Bonello L, Sbragia P, Amabile N, Com O, Pierre SV, Levy S, Paganelli F. Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention. Heart. 2007;93:703–7.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Fabiani JN, Ponzio O, Emerit I, Massonet-Castel S, Paris M, Chevalier P, Jebara V, Carpentier A. Cardioprotective effect of trimetazidine during coronary artery graft surgery. J Cardiovasc Surg. 1992;33:486–91.Google Scholar
  89. 89.
    Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA. 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;291:309–16.PubMedCrossRefGoogle Scholar
  90. 90.
    Rousseau MF, Pouleur H, Cocco G, Wolff AA. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. Am J Cardiol. 2005;95:311–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, Pepine CJ, Wang W, Nelson JJ, Hebert DA, Wolff AA. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–82.PubMedCrossRefGoogle Scholar
  92. 92.
    Zhang XQ, Yamada S, Barry WH. Ranolazine inhibits an oxidative stress-induced increase in myocyte sodium and calcium loading during simulated-demand ischemia. J Cardiovasc Pharmacol. 2008;51:443–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Maier LS. A novel mechanism for the treatment of angina, arrhythmias, and diastolic dysfunction: inhibition of late I(Na) using ranolazine. J Cardiovasc Pharmacol. 2009;54:279–86.PubMedCrossRefGoogle Scholar
  94. 94.
    Jerling M. Clinical Pharmacokinetics of ranolazine Clin Pharmacokinetic. 2006;45:469–91.Google Scholar
  95. 95.
    Kaliebe JW, Murdock DK. Suppression of non-sustained ventricular tachycardia with ranolazine: a case report. Wmj. 2009;108:373–5.PubMedGoogle Scholar
  96. 96.
    Belardinelli L, Liu G, Smith-Maxwell C, Wang WQ, El-Bizri N, Hirakawa R, Karpinski S, Li CH, Hu L, Li XJ, Crumb W, Wu L, Koltun D, Zablocki J, Yao L, Dhalla AK, Rajamani S, Shryock JC. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J Pharmacol Exp Ther. 2013;344:23–32.PubMedCrossRefGoogle Scholar
  97. 97.
    Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006;92(Suppl 4):iv6–iv14.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Antoons G, Oros A, Beekman JD, Engelen MA, Houtman MJ, Belardinelli L, Stengl M, Vos MA. Late na(+) current inhibition by ranolazine reduces torsades de pointes in the chronic atrioventricular block dog model. J Am Coll Cardiol. 2010;55:801–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Aidonidis I, Doulas K, Hatziefthimiou A, Tagarakis G, Simopoulos V, Rizos I, Tsilimingas N, Molyvdas PA. Ranolazine-induced postrepolarization refractoriness suppresses induction of atrial flutter and fibrillation in anesthetized rabbits. J Cardiovasc Pharmacol Ther. 2013;18:94–101.PubMedCrossRefGoogle Scholar
  100. 100.
    Coppini R, Ferrantini C, Yao L, Fan P, Del Lungo M, Stillitano F, Sartiani L, Tosi B, Suffredini S, Tesi C, Yacoub M, Olivotto I, Belardinelli L, Poggesi C, Cerbai E, Mugelli A. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy. Circulation. 2013;127:575–84.PubMedCrossRefGoogle Scholar
  101. 101.
    Burashnikov A, Antzelevitch C. Role of late sodium channel current block in the management of atrial fibrillation. Cardiovasc Drugs Ther. 2013;27:79–89.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Pelliccia F, Pasceri V, Marazzi G, Rosano G, Greco C, Gaudio C. A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention. Am Heart J. 2012;163:1019–23.PubMedCrossRefGoogle Scholar
  103. 103.
    Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y, Gill E, Minissian M, Shaw LJ, Slomka PJ, Slivka M, Berman DS, Bairey Merz CN. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imaging. 2011;4:514–22.PubMedCrossRefGoogle Scholar
  104. 104.
    Stone PH, Chaitman BR, Stocke K, Sano J, DeVault A, Koch GG. The anti-ischemic mechanism of action of ranolazine in stable ischemic heart disease. J Am Coll Cardiol. 2010;56:934–42.PubMedCrossRefGoogle Scholar
  105. 105.
    Chandler MP, Stanley WC, Morita H, Suzuki G, Roth BA, Blackburn B, Wolff A, Sabbah HN. Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure. Circ Res. 2002;91:278–80.PubMedCrossRefGoogle Scholar
  106. 106.
    Rastogi S, Sharov VG, Mishra S, Gupta RC, Blackburn B, Belardinelli L, Stanley WC, Sabbah HN. Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure. Am J Physiol Heart Circ Physiol. 2008;295:H2149–55.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Koren MJ, Crager MR, Sweeney M. Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the ranolazine open label experience (ROLE). J Am Coll Cardiol. 2007;49:1027–34.PubMedCrossRefGoogle Scholar
  108. 108.
    Rich MW, Crager M, McKay CR. Safety and efficacy of extended-release ranolazine in patients aged 70 years or older with chronic stable angina pectoris. Am J Geriatr Cardiol. 2007;16:216–21.PubMedCrossRefGoogle Scholar
  109. 109.
    Cocco G, Rousseau MF, Bouvy T, Cheron P, Williams G, Detry JM, Pouleur H. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta-blocker or diltiazem. J Cardiovasc Pharmacol. 1992;20:131–8.PubMedGoogle Scholar
  110. 110.
    Venkataraman R, Belardinelli L, Blackburn B, Heo J, Iskandrian AE. A study of the effects of ranolazine using automated quantitative analysis of serial myocardial perfusion images. JACC Cardiovasc Imaging. 2009;2:1301–9.PubMedCrossRefGoogle Scholar
  111. 111.
    Timmis AD, Chaitman BR, Crager M. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J. 2006;27:42–8.PubMedCrossRefGoogle Scholar
  112. 112.
    Arnold SV, McGuire DK, Spertus JA, Li Y, Yue P, Ben-Yehuda O, Belardinelli L, Jones PG, Olmsted A, Chaitman BR, Kosiborod M. Effectiveness of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina according to baseline hemoglobin A1c. Am Heart J. 2014;168:457–65 .e452PubMedCrossRefGoogle Scholar
  113. 113.
    Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, Ben-Yehuda O, Katz A, Jones PG, Olmsted A, Belardinelli L, Chaitman BR. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (type 2 diabetes evaluation of ranolazine in subjects with chronic stable angina). J Am Coll Cardiol. 2013;61:2038–45.PubMedCrossRefGoogle Scholar
  114. 114.
    Villano A, Di Franco A, Nerla R, Sestito A, Tarzia P, Lamendola P, Di Monaco A, Sarullo FM, Lanza GA, Crea F. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am J Cardiol. 2013;112:8–13.PubMedCrossRefGoogle Scholar
  115. 115.
    Tagliamonte E, Rigo F, Cirillo T, Astarita C, Quaranta G, Marinelli U, Caruso A, Romano C, Capuano N. Effects of ranolazine on noninvasive coronary flow Reserve in Patients with myocardial ischemia but without obstructive coronary artery disease. Echocardiography. 2015;32:516–21.PubMedCrossRefGoogle Scholar
  116. 116.
    Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007;297:1775–83.PubMedCrossRefGoogle Scholar
  117. 117.
    Melloni C, Newby LK. Metabolic efficiency with ranolazine for less ischemia in non-ST elevation acute coronary syndromes (MERLIN TIMI-36) study. Expert Rev Cardiovasc Ther. 2008;6:9–16.PubMedCrossRefGoogle Scholar
  118. 118.
    Mega JL, Hochman JS, Scirica BM, Murphy SA, Sloan S, McCabe CH, Merlini P, Morrow DA. Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36). Circulation. 2010;121:1809–17.PubMedCrossRefGoogle Scholar
  119. 119.
    Karwatowska-Prokopczuk E, Wang W, Cheng ML, Zeng D, Schwartz PJ, Belardinelli L. The risk of sudden cardiac death in patients with non-ST elevation acute coronary syndrome and prolonged QTc interval: effect of ranolazine. Europace. 2013;15:429–36.PubMedCrossRefGoogle Scholar
  120. 120.
    Morrow DA, Scirica BM, Sabatine MS, de Lemos JA, Murphy SA, Jarolim P, Theroux P, Bode C, Braunwald E. B-type natriuretic peptide and the effect of ranolazine in patients with non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 (metabolic efficiency with ranolazine for less ischemia in non-ST elevation acute coronary-thrombolysis in myocardial infarction 36) trial. J Am Coll Cardiol. 2010;55:1189–96.PubMedCrossRefGoogle Scholar
  121. 121.
    Chisholm JW, Goldfine AB, Dhalla AK, Braunwald E, Morrow DA, Karwatowska-Prokopczuk E, Belardinelli L. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non-ST elevation acute coronary syndrome. Diabetes Care. 2010;33:1163–8.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm. 2011;8:1281–90.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Bunch TJ, Mahapatra S, Murdock D, Molden J, Weiss JP, May HT, Bair TL, Mader KM, Crandall BG, Day JD, Osborn JS, Muhlestein JB, Lappe DL, Anderson JL. Ranolazine reduces ventricular tachycardia burden and ICD shocks in patients with drug-refractory ICD shocks. Pacing Clin Electrophysiol. 2011;34:1600–6.PubMedCrossRefGoogle Scholar
  124. 124.
    Frommeyer G, Rajamani S, Grundmann F, Stypmann J, Osada N, Breithardt G, Belardinelli L, Eckardt L, Milberg P. New insights into the beneficial electrophysiologic profile of ranolazine in heart failure: prevention of ventricular fibrillation with increased postrepolarization refractoriness and without drug-induced proarrhythmia. J Card Fail. 2012;18:939–49.PubMedCrossRefGoogle Scholar
  125. 125.
    Sabbah HN, Chandler MP, Mishima T, Suzuki G, Chaudhry P, Nass O, Biesiadecki BJ, Blackburn B, Wolff A, Stanley WC. Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail. 2002;8:416–22.PubMedCrossRefGoogle Scholar
  126. 126.
    Aaker A, McCormack JG, Hirai T, Musch TI. Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J Cardiovasc Pharmacol. 1996;28:353–62.PubMedCrossRefGoogle Scholar
  127. 127.
    Sossalla S, Wagner S, Rasenack EC, Ruff H, Weber SL, Schondube FA, Tirilomis T, Tenderich G, Hasenfuss G, Belardinelli L, Maier LS. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol. 2008;45:32–43.PubMedCrossRefGoogle Scholar
  128. 128.
    Hale SL, Shryock JC, Belardinelli L, Sweeney M, Kloner RA. Late sodium current inhibition as a new cardioprotective approach. J Mol Cell Cardiol. 2008;44:954–67.PubMedCrossRefGoogle Scholar
  129. 129.
    Wu Y, Song Y, Belardinelli L, Shryock JC. The late Na + current (INa) inhibitor ranolazine attenuates effects of palmitoyl-L-carnitine to increase late INa and cause ventricular diastolic dysfunction. J Pharmacol Exp Ther. 2009;330:550–7.PubMedCrossRefGoogle Scholar
  130. 130.
    Fragasso G, Spoladore R, Cuko A, Palloshi A. Modulation of fatty acids oxidation in heart failure by selective pharmacological inhibition of 3-ketoacyl coenzyme-a thiolase. Curr Clin Pharmacol. 2007;2:190–6.PubMedCrossRefGoogle Scholar
  131. 131.
    Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, Bugiardini R, Crea F, Cuisset T, Di Mario C, Ferreira JR, Gersh BJ, Gitt AK, Hulot JS, Marx N, Opie LH, Pfisterer M, Prescott E, Ruschitzka F, Sabate M, Senior R, Taggart DP, van der Wall EE, Vrints CJ, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Knuuti J, Valgimigli M, Bueno H, Claeys MJ, Donner-Banzhoff N, Erol C, Frank H, Funck-Brentano C, Gaemperli O, Gonzalez-Juanatey JR, Hamilos M, Hasdai D, Husted S, James SK, Kervinen K, Kolh P, Kristensen SD, Lancellotti P, Maggioni AP, Piepoli MF, Pries AR, Romeo F, Ryden L, Simoons ML, Sirnes PA, Steg PG, Timmis A, Wijns W, Windecker S, Yildirir A, Zamorano JL. 2013 ESC guidelines on the management of stable coronary artery disease: the task force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003.PubMedCrossRefGoogle Scholar
  132. 132.
    Ohman EM, Alexander KP. The challenges with chronic angina. N Engl J Med. 2014;371:1152–3.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Giacinta Guarini
    • 1
  • Alda Huqi
    • 1
  • Doralisa Morrone
    • 1
  • Mario Marzilli
    • 1
  1. 1.Cardiovascular Medicine Division, Cardio Thoracic and Vascular DepartmentUniversity of PisaPisaItaly

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