Number 27, 2005
Metabolic approach in heart failure

Evidence of efficacy of metabolic agents

Back to the Summary

Mario Marzilli, Silvia Affinito
Policlinico Le Scotte, Viale Bracci, Siena, Italy
Correspondence: Mario Marzilli, Head, Division of Cardiology, Policlinico Le Scotte, Viale Bracco, 53100, Siena, Italy.
Tel: +39 0577 585374, fax: +39 0577 233112, e-mail: marzilli@unisi.it

Cardiac energy metabolism in heart failure
Abnormalities of cardiac energy metabolism may contribute to the progressive worsening of left ventricular contractile function. Many investigators have reported a reduced ATP content and dysfunctional mitochondria, increased fatty acid oxidation, and decreased carbohydrate oxidation in failing hearts as compared with normal hearts [1–3]. Reduced rates of carbohydrate oxidation and increased rates of fatty acid oxidation contribute to the progression of myocardial dysfunction in heart failure: the contractile performance of the heart is improved when the heart uses more glucose and lactate rather than fatty acids [4,5]. Furthermore, increased plasma concentrations of free fatty acids can be harmful to the ischemic myocardium, especially in the presence of increased catecholamine concentrations [6]. The rate of fatty acid oxidation is regulated by the plasma concentration of free fatty acids, by the activity of carnitine palmitoyl transferase-1 and by a series of enzymes that catalyze the several steps of fatty acid oxidation [7]. In individuals with failing hearts, the utilization of noncarbohydrate substrates for energy production is increased. In fact, blood concentrations of ketone bodies [8], in addition to fat oxidation during exercise [9] are increased in these patients. Insulin resistance has been found in this condition [10], and the consequent impaired suppression of lipolysis could contribute to the development of ketosis.
Many different approaches have been proposed to manipulate energy metabolism in the ischemic heart [11], including increasing glucose oxidation and decreasing fatty acid metabolism by glucose–insulin solutions or nicotinic acid, by ß-adrenergic blockade, or by drugs that inhibit key enzymes in the fatty acid oxidation chain. Agents such as trimetazidine shift substrate utilization from fatty acid to glucose, by inhibiting a key enzyme in the ß-oxidation chain, 3-ketoacyl coenzyme A thiolase (“3-KAT“).
Trimetazidine improves ventricular function in patients with coronary artery disease and various degrees of contractile dysfunction, preventing or delaying regional myocardial dysfunction during ischemia, and improving the contractile response to inotropic stimulation.

Metabolic approach to heart failure
The first evidence of the efficacy of trimetazidine in heart failure was reported by Brottier et al in 1990 [12]. In patients with ischemic cardiomyopathy and severely depressed ventricular ejection fraction, these investigators completed a double-blind placebo-controlled study assessing the effect of trimetazidine 60mg in addition to standard treatment. After 6 months of treatment, patients receiving trimetazidine were more free from angina, dyspnea was improved, the ejection fraction increased, and cardiac volume decreased.

Ischemic cardiomyopathy
In 1998, Lu et al [13] demonstrated that trimetazidine can delay the onset of ischemic myocardial dysfunction and reduce its severity. In a double-blind, randomized placebo-controlled study, they applied dobutamine testing in patients with coronary artery disease to demonstrate that trimetazidine improved resting left ventricular function and reduced the severity of dobutamine-induced dysfunction.
Belardinelli and Purcaro [14], in a more recent study, showed that trimetazidine improves the mechanical efficiency of chronically dysfunctioning myocardium. Low-dose dobutamine echocardiographic testing was performed in a double-blind, randomized placebo-controlled fashion in 38 patients with ischemic cardiomyopathy treated with trimetazidine for 2 months. Trimetazidine improved the contractile response of chronically dysfunctioning myocardium to dobutamine without associated hemodynamic changes. This effect was associated with an improvement of left ventricular function and peak oxygen consumption (VO₂).
The importance of fatty acid inhibition in the improvement of left ventricular function has been confirmed recently by Sabbah's group [15,16], who found that ranolazine, a drug with a mechanism of action similar to that of trimetazidine, also increased the ejection fraction without increasing myocardial oxygen demand in a dog model of chronic ischemia. The absence of any hemodynamic effects of either ranolazine or trimetazidine confirms that these drugs have no direct inotropic effect and act primarily by optimizing cardiac metabolism.

Diabetes and the metabolic approach
Fragasso et al [17] have reported findings similar to the above in patients with diabetes and postischemic cardiomyopathy: trimetazidine consistently improved patients' tolerance to exercise, and their left ventricular function. In addition, for the first time, the beneficial effects of trimetazidine have been associated with improved endothelial function. These results support the hypothesis that shifting energy substrate preference from fatty acid toward glucose utilization is an effective treatment in patients with diabetes and postischemic cardiomyopathy.
Rosano et al [18] confirmed the beneficial effects of trimetazidine in diabetes: the addition of trimetazidine to standard treatment in 32 patients with type 2 diabetes mellitus and ischemic cardiomyopathy was associated with a significant reduction in left ventricular diameter and volume index. An improvement in ejection fraction and a significant decrease in wall motion score index were also reported.

Metabolic treatment in elderly patients
Vitale et al [19] confirmed the beneficial effects of trimetazidine on left ventricular function in elderly patients with ischemic heart disease and reduced left ventricular function. Forty-seven elderly patients were allocated randomly to groups to receive, in addition to standard treatment, either trimetazidine or placebo, and were evaluated by echocardiography at baseline and after 6 months. The adjunct of trimetazidine to standard treatment prevented or limited reverse remodeling of chronically dysfunctioning myocardium, attenuated cardiac symptoms, and improved the quality of life in these elderly patients with coronary artery disease.

Anti-inflammatory effect
The cardioprotective action of trimetazidine has recently been associated with a possible anti-inflammatory effect in patients with ischemic dilated cardiomyopathy [20]. Sixty-one patients were randomly assigned to receive trimetazidine in addition to their conventional treatment for 18 months. Trimetazidine improved the patients' functional class, increased the ejection fraction, with a significant effect on ventricular remodeling, and limited the inflammatory response.

Metabolic treatment in nonischemic cardiomyopathy
The findings of several studies suggest that an effect on cellular lipid metabolism may contribute to the cytoprotective properties of trimetazidine. Sentex et al [21] demonstrated that a significant increase in membrane phospholipid synthesis was a major effect of the administration of trimetazidine. This beneficial effect on membrane homeostasis induced a significant increase in the incorporation of long-chain polyunsaturated fatty acids into membrane structures.
More recently, this effect on lipid metabolism was reported to occur in vitro in addition to in vivo. Tabbi-Anneni et al [22] tested the hypothesis that, through the acceleration of phospholipid turnover, treatment with trimetazidine would result in a delayed development of heart failure in the rat. In that species, chronic pressure overload secondary to aortic banding results in physiological and morphological signs of heart failure, including acceleration of breathing, hydrothorax and ascites, liver congestion, renal hypotrophy, and possible renal failure. In this model of heart failure, trimetazidine treatment results in a significant decrease in cardiac hypertrophy and an increase in plasma concentrations of brain natriuretic peptide. The morphological alterations associated with heart failure were also less severe in the trimetazidine-treated rats. In addition, ß-adrenergic receptor density was also significantly limited by the trimetazidine treatment during the progression from hypertrophy to failure.

Conclusion
Agents, such as trimetazidine, that decrease free fatty acid concentrations or inhibit myocardial oxidation of free fatty acids improve the contractile performance of failing hearts and offer a promising alternative to the clinical management of heart failure. ?

Back to the Summary

REFERENCES

Back to the Summary