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(Circulation. 2008;118:1250-1258.)
© 2008 American Heart Association, Inc.

Heart Failure

Trimetazidine, a Metabolic Modulator, Has Cardiac and Extracardiac Benefits in Idiopathic Dilated Cardiomyopathy

Helena Tuunanen, MD; Erik Engblom, MD; Alexandru Naum, MD; Kjell Någren, PhD; Mika Scheinin, MD; Birger Hesse, MD; K.E. Juhani Airaksinen, MD; Pirjo Nuutila, MD; Patricia Iozzo, MD; Heikki Ukkonen, MD; Lionel H. Opie, MD; Juhani Knuuti, MD

From the Turku PET Centre (H.T., A.N., K.N., P.N., P.I., H.U., J.K.), Department of Medicine, Turku University Central Hospital (H.T., E.E., K.E.J.A., P.N., H.U.), Department of Pharmacology, Drug Development and Therapeutics, University of Turku (M.S.), and Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland (M.S.), Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (B.H.); Institute of Clinical Physiology, National Research Council, Pisa, Italy (P.I.); and Hatter Cardiovascular Research Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa (L.H.O.).

Correspondence to Professor Juhani Knuuti, MD, Turku PET Centre, PO BOX 52, FI-20521 Turku, Finland. E-mail juhani.knuuti{at}utu.fi

Received July 24, 2007; accepted June 23, 2008.

Background— The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that is hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. We investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy.

Methods and Results— Nineteen nondiabetic patients with idiopathic dilated cardiomyopathy on standard medication were randomized to single-blind trimetazidine (n=12) or placebo (n=7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [¹⁵O]H₂O, [¹¹C]acetate, and [¹¹C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9±8.5% to 34.8±12% (P=0.027 versus placebo). Myocardial FFA uptake was unchanged, and β-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9±0.7 versus 5.5±0.6 mmol/L, P=0.047; insulin: 10±6.9 versus 7.6±3.6 mU/L, P=0.031; homeostasis model assessment index: 2.75±2.28 versus 1.89±1.06, P=0.027). The degree of β-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11% (P<0.001).

Conclusions— In idiopathic dilated cardiomyopathy with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant idiopathic dilated cardiomyopathy patients, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater β1-adrenoceptor occupancy, suggesting a synergistic mechanism.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 1217-1218. [Extract] [Full Text]