Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure.
OBJECTIVE
Experimental evidence suggests that modulation of myocardial substrate metabolism can markedly affect the progression of chronic heart failure (HF). We tested whether the inhibition of carnitine palmitoyl transferase-I (CPT-I), the enzyme regulating mitochondrial fatty acid oxidation, slows left ventricular remodeling and deterioration of function in pacing-induced HF.


METHODS
Normal dogs (n=9) were compared to untreated dogs with pacing-induced HF (n=9) and HF dogs treated with 65 mg/kg/day of oxfenicine (HF+Oxf, n=9), a CPT-I inhibitor.


RESULTS
HF+Oxf reached terminal failure (LV end-diastolic pressure=25 mm Hg) 6 days later than untreated HF (P<0.05). At 28 days of pacing, hemodynamic alterations and LV dilation were significantly attenuated and the 25% decrease in LV wall thickness was completely prevented in HF+Oxf vs. untreated HF, as was the activation of matrix metalloproteinase-2 and -9, markers of tissue remodeling. Oxfenicine also prevented HF-induced transcriptional down-regulation of CPT-I, medium chain acyl-CoA dehydrogenase, GAPDH and citrate synthase, key enzymes of cardiac energy metabolism. In addition, mRNA, but not protein levels of the nuclear receptor peroxisome proliferator-activated receptor-alpha were reduced in untreated HF, while they did not change significantly in HF+Oxf, as compared to control.


CONCLUSIONS
CPT-I inhibition early in the development of HF prevented LV wall thinning and delayed the time to end-stage failure. While these results are limited to an experimental model of disease, they nevertheless suggest that CPT-I inhibition might be effective for slowing the progression of clinical HF.
Lionetti
Vincenzo
V
Department of Physiology, BSB 622, New York Medical College, Valhalla, 10595, USA.
Linke
Axel
A
Chandler
Margaret P
MP
Young
Martin E
ME
Penn
Marc S
MS
Gupte
Sachin
S
d'Agostino
Chiara
C
Hintze
Thomas H
TH
Stanley
William C
WC
Recchia
Fabio A
FA
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002304:Cardiac Pacing, Artificial; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects*
D004791:Enzyme Inhibitors; D005227:Fatty Acids; D047492:Peroxisome Proliferator-Activated Receptors; C023010:4-hydroxyphenylglycine; D002334:Carnitine O-Palmitoyltransferase; D005998:Glycine