ReviewRationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure
Introduction
Despite advances in the treatment of heart failure, the disease continues to remain a costly and deadly condition, the management of which requires a lot of human and economic resources [1], [2]. Heart failure is a complex syndrome with several features, including abnormal myocardial structure and function and neurohumoral activation. Therefore, pharmacological treatment of heart failure has focused on the suppression of neurohumoral activation, as well as regulation of the fluid volume overload, hemodynamics and optimization of heart rate control [3]. However, the growing understanding of the role of other mechanisms in the pathogenesis of heart failure, such as inflammatory activation and metabolic impairment, determined the search for new therapeutic approaches in addition to the therapy recommended by the guidelines.
Currently, multiple myocardial metabolic abnormalities have been revealed in heart failure. Moreover, beyond myocardial metabolic failure, systemic (peripheral) metabolic regulation has been found to contribute both to major symptoms (muscle weakness, fatigue, exercise limitation, and dyspnea) and to disease progression [4]. As a consequence, heart failure is conceived as a systemic and multi-organ syndrome with metabolic failure as the basic mechanism. Recently, impaired mitochondrial oxidative metabolism in heart failure, defined with the term “metabolic remodeling”, was described as a component of a broader and more general concept of remodeling covering hemodynamic, neurohumoral, metabolic, and inflammatory processes, causing changes in cardiomyocytes, endothelium, vascular smooth muscle cells as well as interstitial cells and matrix [5]. This concept allows considering therapies targeting the cardiac metabolism along with conventional treatment of heart failure.
The list of new therapies targeting heart metabolism is constantly expanding, but most of them are not available in clinical practice yet. Trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine dihydrochloride) is an anti-ischemic metabolic modulator, which has been approved in more than 80 countries worldwide for the symptomatic treatment of chronic stable angina. Furthermore, there has been growing evidence that trimetazidine reduces ischemia-reperfusion injury after myocardial revascularization procedures [6], [7], [8] and improves cardiac function in heart failure [9], [10], [11]. There are now more than 100 articles available on PubMed that report on experimental or clinical trials proving the beneficial efficacy of trimetazidine in heart failure.
This review focuses on the rationale and clinical benefits of trimetazidine by acting on cardiac metabolism in heart failure, and aims to draw attention to the additional advantages that might be obtained by adding this agent to the standard therapy of heart failure.
Section snippets
Metabolic processes in the normal and failing heart
Due to its continuous contractile activity, the heart has a very high energy demand. About 95% of this energy is normally obtained by the production of ATP from mitochondrial oxidative metabolism, while the remaining 5% originate from glycolytic ATP production (Fig. 1A). The source of fuel for mitochondrial oxidative metabolism normally originates from a balance between fatty acids and carbohydrates (glucose and lactate), and to a lesser degree ketones and amino acids [12]. Dramatic alterations
Mechanisms of action of trimetazidine in heart failure
Trimetazidine is a partial fatty acid oxidation inhibitor that inhibits 3-ketoacyl CoA thiolase, one of the enzymes of fatty acid β-oxidation [39], [40]. This results in an increase in glucose oxidation [39], [40]. In pressure overload-induced hypertrophied rat hearts, trimetazidine reduces glycolysis, enhances glucose oxidation, and improves post-ischemic recovery [41]. The beneficial effect of trimetazidine on left ventricular function has been attributed to the preservation of intracellular
Clinical benefits of trimetazidine in heart failure
Small randomized clinical trials (RCTs) have demonstrated the efficacy of trimetazidine in improving New York Heart Association (NYHA) functional class, exercise tolerance, quality of life, left ventricular ejection fraction and cardiac volumes in patients with systolic chronic heart failure [9], [10], [50], [51], [52], [53], [54], [55], [56], [57]. Table 1 summarizes the characteristics and the key results of the principal clinical trials of trimetazidine in patients with systolic heart
Trimetazidine effects on preventing cardiovascular events and hospitalizations
The first observation that trimetazidine could reduce the risk of cardiovascular events in heart failure patients came from the single-center, open-label, randomized trial by El-Kady et al. [61]. In this study, 200 patients with ischemic cardiomyopathy and multivessel coronary artery disease were randomized to receive trimetazidine or placebo on top of optimal medical therapy including β-blockers (in 69 to 75% patients) and ACE inhibitors (in 89 to 94% patients). After 2 years of follow-up,
Discussion
According to the current ESC guidelines, the major aims of the medical management of patients with established heart failure are alleviation of symptoms and signs, reduction of re-hospitalizations, and decrease of mortality [3]. Increase in physical performance and improvement of quality of life are also important targets of treatment. Effective pharmacological treatment is able to slow or prevent progressive worsening of heart failure due to the reverse left ventricular remodeling and a
Conclusion
Heart failure is associated with alterations in cardiac energy metabolism that leads to an energy deficit. In heart failure, there is a switch from oxidative metabolism to greater reliance on glycolysis. Specifically, increase in fatty acid and decrease of glucose oxidation result in energy deficit that is inadequately compensated for by an increase in glycolysis. Increased glycolysis and decreased glucose oxidation result in lactate and proton build up in the myocardium that compromises
Conflict of interest
YL, GF, DV and PJ have received speaker fees, research or travel grants from Servier, manufacturer of trimetazidine. GR, GL, PS, LHG, MAH and PP report no relationships that could be construed as a conflict of interest.
References (79)
- et al.
Metabolic impairment in heart failure: the myocardial and systemic perspective
J. Am. Coll. Cardiol.
(2014) - et al.
Cardiovascular remodelling in coronary artery disease and heart failure
Lancet
(2014) - 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) - et al.
Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)p-sloop magnetic resonance spectroscopy
J. Am. Coll. Cardiol.
(2002) - et al.
Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31p magnetic resonance spectroscopy
Lancet
(1991) - et al.
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) - et al.
Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate
J. Am. Coll. Cardiol.
(1994) - et al.
The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus
Lancet
(1963) - et al.
Effects of trimetazidine on endothelial dysfunction after sheath injury of radial artery
Am. J. Cardiol.
(2010) - et al.
Free fatty acid kinetics and oxidation in congestive heart failure
Am. J. Cardiol.
(1998)
Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease
Am. J. Cardiol.
The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated cardiomyopathy
Life Sci.
Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicenter retrospective cohort study
Int. J. Cardiol.
Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis
J. Am. Coll. Cardiol.
Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan heart failure trial)
J. Am. Coll. Cardiol.
Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study
J. Am. Coll. Cardiol.
Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study
J. Am. Coll. Cardiol.
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study
Lancet
Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial
Lancet
Neurohormones and oxidative stress in nonischemic cardiomyopathy: relationship to survival and the effect of treatment with amlodipine
Am. Heart J.
Epidemiology and risk profile of heart failure
Nat. Rev. Cardiol.
Heart disease and stroke statistics—2010 update: a report from the American Heart Association
Circulation
Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012
Eur. Heart J.
Metabolic cardiac protection is beneficial in patients undergoing coronary revascularization: is it necessary afterwards?
Heart Metab.
Effects of trimetazidine therapy on left ventricular function after percutaneous coronary intervention
Chin. J. Cardiol.
The effectiveness of preoperative trimetazidine on myocardial preservation in coronary artery bypass graft patients: a systematic review and meta-analysis
Cardiology
Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy
Heart
Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy
Circulation
Myocardial fatty acid metabolism in health and disease
Physiol. Rev.
The failing heart—an engine out of fuel
N. Engl. J. Med.
Is the failing heart energy starved? On using chemical energy to support cardiac function
Circ. Res.
Preischemic glycogen reduction or glycolytic inhibition improves postischemic recovery of hypertrophied rat hearts
Am. J. Physiol.
Return to the fetal gene program protects the stressed heart: a strong hypothesis
Heart Fail. Rev.
Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure
Circ. Heart Fail.
Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts
Am. J. Physiol.
Contribution of glycogen to aerobic myocardial glucose utilization
Circulation
Hyperpolarized (13)c magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart
Eur. J. Heart Fail.
Cardiac insulin resistance and decreased mitochondrial energy production precede the development of systolic heart failure following pressure overload hypertrophy
Circulation: Heart Fail.
Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload
Cardiovasc. Res.
Cited by (72)
Glycometabolism reprogramming: Implications for cardiovascular diseases
2023, Progress in Biophysics and Molecular BiologyTraditional Chinese medicine enhances myocardial metabolism during heart failure
2022, Biomedicine and PharmacotherapyMyocardial Metabolism in Heart Failure with Preserved Ejection Fraction
2024, Journal of Clinical MedicineAnimal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery
2024, Acta Pharmacologica Sinica
- 1
The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.