doi: 10.1161/CIRCULATIONAHA.105.551457
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(Circulation. 2005;112:3280-3288.)
© 2005 American Heart Association, Inc.
Heart Failure |
Metabolic Modulation With Perhexiline in Chronic Heart Failure
A Randomized, Controlled Trial of Short-Term Use of a Novel Treatment
From the Department of Cardiology (L.L.), University of Nottingham, Queens Medical Centre, Nottingham, England; Department of Cardiology (R.C., R.T., P.G., L.W., M.F.), University of Birmingham, Queen Elizabeth Medical Centre, Birmingham, England; University Laboratory of Physiology (M.S.-F., K.C.), University of Oxford, Oxford, England; Department of Cardiology (H.A.), Ealing Hospital, London, England; Queen Elizabeth Hospital (J.H.), University of Adelaide, Adelaide, Australia; and University of Wales College of Medicine (A.G.F.), Wales Heart Research Institute, Cardiff, Wales.
Correspondence to Prof Michael Frenneaux, Department of Cardiology, University of Birmingham, Birmingham, B15 2TH UK. E-mail M.P.Frenneaux{at}bham.ac.uk
Received March 28, 2005; revision received July 26, 2005; accepted August 1, 2005.
Background— Chronic heart failure (CHF) is a major cause of morbidity and mortality that requires a novel approach to therapy. Perhexiline is an antianginal drug that augments glucose metabolism by blocking muscle mitochondrial free fatty acid uptake, thereby increasing metabolic efficiency. We assessed the effects of perhexiline treatment in CHF patients.
Methods and Results— In a double-blind fashion, we randomly assigned patients with optimally medicated CHF to either perhexiline (n=28) or placebo (n=28). The primary end point was peak exercise oxygen consumption (
O2max), an important prognostic marker. In addition, the effect of perhexiline on myocardial function and quality of life was assessed. Quantitative stress echocardiography with tissue Doppler measurements was used to assess regional myocardial function in patients with ischemic CHF. 31P magnetic resonance spectroscopy was used to assess the effect of perhexiline on skeletal muscle energetics in patients with nonischemic CHF. Treatment with perhexiline led to significant improvements in O2max (16.1±0.6 to 18.8±1.1 mL · kg–1 · min–1; P<0.001), quality of life (Minnesota score reduction from 45±5 to 34±5; P=0.04), and left ventricular ejection fraction (24±1% to 34±2%; P<0.001). Perhexiline treatment also increased resting and peak dobutamine stress regional myocardial function (by 15% and 24%, respectively) and normalized skeletal muscle phosphocreatine recovery after exercise. There were no adverse effects during the treatment period.
Conclusions— In patients with CHF, metabolic modulation with perhexiline improved O2max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Perhexiline may therefore represent a novel treatment for CHF with a good safety profile, provided that the dosage is adjusted according to plasma levels.
Key Words: heart failure • metabolism • exercise • fatty acids • glucose
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