title: Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure.
abstract: 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.
authors.affiliation: Department of Physiology, BSB 622, New York Medical College, Valhalla, 10595, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Axel
authors.initials: A
authors.lastname: Linke
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
authors.forename: Sachin
authors.initials: S
authors.lastname: Gupte
authors.forename: Chiara
authors.initials: C
authors.lastname: d'Agostino
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
authors.forename: William C
authors.initials: WC
authors.lastname: Stanley
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
mesh_terms: 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*
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; D047492:Peroxisome Proliferator-Activated Receptors; C023010:4-hydroxyphenylglycine; D002334:Carnitine O-Palmitoyltransferase; D005998:Glycine