Metabolic Modulators in Cardioprotection: A Focus on Trimetazidine

  • Qingyou Du University of Dundee, School of Medicine, Molecular and Clinical Medicine
Keywords: cardioprotection, trimetazidine

Abstract


Cardiovascular diseases remain a significant health burden worldwide, necessitating the development of effective cardioprotective strategies. Central to this pursuit is the recognition of metabolic dysregulation as a key contributor to the pathogenesis of cardiovascular diseases, particularly in the context of aging and modern lifestyle factors. Metabolic modulators, such as trimetazidine, have emerged as promising therapeutic agents by optimizing cardiac energy substrate utilization and enhancing metabolic efficiency. Trimetazidine demonstrates cardioprotective properties by inhibiting fatty acid oxidation and promoting glucose oxidation, especially under ischemic conditions where oxygen supply is limited. This metabolic shift enhances myocardial efficiency, reduces the likelihood of acidosis, and mitigates the accumulation of toxic fatty acid metabolites. Pre-clinical studies and clinical trials have demonstrated the efficacy of trimetazidine in a range of cardiac conditions, including chronic stable angina, heart failure, and diabetic cardiomyopathy, resulting in improvements in symptoms, exercise capacity, and cardiac function. Through its ability to address underlying metabolic inefficiencies, trimetazidine offers a promising adjunct therapy for patients with cardiovascular diseases, particularly those inadequately controlled by first-line treatments. This manuscript underscores the important role of metabolic modulation in the management of cardiovascular diseases and highlights trimetazidine as a valuable therapeutic option in the armamentarium against cardiac diseases.

References

Zeng Y, Li Y, Jiang W, Hou N. Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy. Front Cardiovasc Med. 2024;11:1375400.

Marzilli M, Vinereanu D, Lopaschuk G, Chen Y, Dalal JJ, Danchin N, et al. Trimetazidine in cardiovascular medicine. Int J Cardiol. 2019;293:39-44.

Pușcaș A, Ștefănescu R, Vari CE, Ősz BE, Filip C, Bitzan JK, et al. Biochemical aspects that lead to abusive use of trimetazidine in performance athletes: A Mini-Review. Int J Mol Sci. 2024;25:1605.

Wang H, Shen M, Shu X, Guo B, Jia T, Feng J, et al. Cardiac metabolism, reprogramming, and diseases. J Cardiovasc Transl Res. 2024;17:71-84.

Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circ Res. 2021;128:1487-1513.

Varma U, Koutsifeli P, Benson VL, Mellor KM, Delbridge LMD. Molecular mechanisms of cardiac pathology in diabetes - Experimental insights. Biochim Biophys Acta Mol Basis Dis. 2018;1864:1949-1959.

Liu Z, Chen JM, Huang H, Kuznicki M, Zheng S, Sun W, et al. The protective effect of trimetazidine on myocardial ischemia/reperfusion injury through activating AMPK and ERK signalling pathway. Metabolism. 2016;65:122-130.

Jovanović A. Cardioprotective signalling: Past, present and future. Eur J Pharmacol. 2018;833:314-319.

Xiao Z, Guan L, Shi H, Yu Y, Yu Z, Qin S, et al. Trimetazidine affects mitochondrial calcium uniporter expression to restore ischemic heart function via reactive oxygen species/NFκB pathway inhibition. J Cardiovasc Pharmacol. 2023;82:104-116.

Farzaei MH, Ramezani-Aliakbari F, Ramezani-Aliakbari M, Zarei M, Komaki A, Shahidi S, et al. Regulatory effects of trimetazidine in cardiac ischemia/reperfusion injury. Naunyn Schmiedebergs Arch Pharmacol. 2023;396:1633-1646.

Tang SG, Liu XY, Wang SP, Wang HH, Jovanović A, Tan W. Trimetazidine prevents diabetic cardiomyopathy by inhibiting Nox2/TRPC3-induced oxidative stress. J Pharmacol Sci. 2019;139:311-318.

Zhao D, Ma J, Sun Y, Huang W, Fan J, Ye M, et al. Influence of trimetazidine on myocardial injury in mice with diabetic cardiomyopathy. J Diabetes Complications. 2024;38:108744.

Glezer MG, Vygodin VA; ODA investigators. Effectiveness of trimetazidine in patients with stable angina pectoris of various durations: results from ODA. Cardiol Ther. 2020;9:395-408.

Lopatin Y, Petrova P; MODUS VIVENDI investigators. Effectiveness and tolerability of trimetazidine 80 Mg once daily in patients with stable angina uncontrolled with bisoprolol-based therapy: The Modus Vivendi Observational Study. Cardiol Ther. 2022;11:93-111.

Min Z, Xuelu L, Ran Z, Qiuhong S, Yong M. Effectiveness of trimetazidine in patients with chronic heart failure Stratified by the expression of soluble suppression of tumorigenicity-2 (sST2): A Prospective Cohort Study. Adv Ther. 2022;39:5514-5529.

van de Bovenkamp AA, Geurkink KTJ, Oosterveer FTP, de Man FS, Kok WEM, Bronzwaer PNA, et al. Trimetazidine in heart failure with preserved ejection fraction: a randomized controlled cross-over trial. ESC Heart Fail. 2023;10:2998-3010.

Zou H, Zhu XX, Ding YH, Jin QY, Qian LY, Huang DS, Cen XJ. Trimetazidine in conditions other than coronary disease, old drug, new tricks? Int J Cardiol. 2017;234:1-6.

Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, et al. 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.

Ruzyllo W, Szwed H, Sadowski Z, Elikowski W, Grzelak-Szafranska H, Orszulak W, et al. Efficacy of trimetazidine in patients with recurrent angina: a subgroup analysis of the TRIMPOL II study. Curr Med Res Opin. 2004;20:1447-1454.

Danchin N. Clinical benefits of a metabolic approach with trimetazidine in revascularized patients with angina. Am J Cardiol. 2006;98(5A):8J-13J.

Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol. 2006:48:992-998.

Belardinelli R, Cianci G, Gigli M, Mazzanti M, Lacalaprice F. Effects of trimetazidine on myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy. J Cardiovasc Pharmacol. 2008;51:611-615.

Ye P, Ye P, He J. [Effect of trimetazidine on cardiac function and exercise tolerance in hypertension patients with diabetes]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019;48:282-288.

Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024 Aug 30:ehae177. doi: 10.1093/eurheartj/ehae177. Epub ahead of print. PMID: 39210710.

European Medicines agency [Internet]. Trimetazidine Art 31 [cited 2024 Oct 10]. Available from: https://www.ema.europa.eu/en/documents/referral/trimetazidine-article-31-annex-iii_en.pdf.

Published
2024/10/27
Section
Review articles