title: Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy.
abstract: 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.
  
  
  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 [(15)O]H(2)O, [(11)C]acetate, and [(11)C]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 beta-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 beta-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 beta1-adrenoceptor occupancy, suggesting a synergistic mechanism.
authors.affiliation: Turku PET Centre, PO BOX 52, FI-20521 Turku, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Tuunanen
authors.forename: Erik
authors.initials: E
authors.lastname: Engblom
authors.forename: Alexandru
authors.initials: A
authors.lastname: Naum
authors.forename: Kjell
authors.initials: K
authors.lastname: Någren
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Birger
authors.initials: B
authors.lastname: Hesse
authors.forename: K E
authors.initials: KE
authors.lastname: Juhani Airaksinen
authors.forename: Pirjo
authors.initials: P
authors.lastname: Nuutila
authors.forename: Patricia
authors.initials: P
authors.lastname: Iozzo
authors.forename: Heikki
authors.initials: H
authors.lastname: Ukkonen
authors.forename: Lionel H
authors.initials: LH
authors.lastname: Opie
authors.forename: Juhani
authors.initials: J
authors.lastname: Knuuti