Elsevier

International Journal of Cardiology

Volume 203, 15 January 2016, Pages 909-915
International Journal of Cardiology

Review
Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure

https://doi.org/10.1016/j.ijcard.2015.11.060Get rights and content

Highlights

  • Heart failure is currently one of the leading causes of death and disability worldwide.

  • Heart failure is associated with alterations in cardiac energy metabolism that leads to an energy deficit.

  • Inhibiting fatty acid oxidation and stimulating glucose oxidation improves cardiac efficiency and function in heart failure.

  • Optimizing energy metabolism is a novel approach to treat heart failure.

Abstract

Heart failure is a systemic and multiorgan syndrome with metabolic failure as a fundamental mechanism. As a consequence of its impaired metabolism, other processes are activated in the failing heart, further exacerbating the progression of heart failure.

Recent evidence suggests that modulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation represents a promising approach to the treatment of patients with heart failure.

Clinical trials have demonstrated that the adjunct of trimetazidine to the conventional medical therapy improves symptoms, cardiac function and prognosis in patients with heart failure without exerting negative hemodynamic effects.

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 readiness of this agent to be included in all the major guidelines dealing with 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.

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