Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment.
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.


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 (VO2max), 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 VO2max (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 VO2max, 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.
Lee
Leong
L
Department of Cardiology, University of Nottingham, Queens Medical Centre, Nottingham, England.
Campbell
Ross
R
Scheuermann-Freestone
Michaela
M
Taylor
Rachel
R
Gunaruwan
Prasad
P
Williams
Lynne
L
Ashrafian
Houman
H
Horowitz
John
J
Fraser
Alan G
AG
Clarke
Kieran
K
Frenneaux
Michael
M
D000368:Aged; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002908:Chronic Disease; D025401:Echocardiography, Stress; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010480:Perhexiline / Q000008:administration & dosage* / Q000009:adverse effects; D011788:Quality of Life; D013318:Stroke Volume / Q000187:drug effects; D016896:Treatment Outcome
D002317:Cardiovascular Agents; D005227:Fatty Acids; D005947:Glucose; D010480:Perhexiline