title: Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload.
abstract: OBJECTIVE
  Left ventricular hypertrophy is a risk factor for heart failure. However, it also is a compensatory response to pressure overload, accommodating for increased workload. We tested whether the changes in energy substrate metabolism may be predictive for the development of contractile dysfunction.
  
  
  RESULTS
  Chronic pressure overload was induced in Sprague-Dawley rats by aortic arch constriction for 2, 6, 10, or 20 weeks. Contractile function in vivo was assessed by echocardiography and by invasive pressure measurement. Glucose and fatty acid oxidation as well as contractile function ex vivo were assessed in the isolated working heart, and respiratory capacity was measured in isolated cardiac mitochondria. Pressure overload caused progressive hypertrophy with normal ejection fraction (EF) at 2, 6, and 10 weeks, and hypertrophy with dilation and impaired EF at 20 weeks. The lung-to-body weight ratio, as marker for pulmonary congestion, was normal at 2 weeks (indicative of compensated hypertrophy) but significantly increased already after 6 and up to 20 weeks, suggesting the presence of heart failure with normal EF at 6 and 10 weeks and impaired EF at 20 weeks. Invasive pressure measurements showed evidence for contractile dysfunction already after 6 weeks and ex vivo cardiac power was reduced even at 2 weeks. Importantly, there was impairment in fatty acid oxidation beginning at 2 weeks, which was associated with a progressive decrease in glucose oxidation. In contrast, respiratory capacity of isolated mitochondria was normal until 10 weeks and decreased only in hearts with impaired EF.
  
  
  CONCLUSIONS
  Pressure overload-induced impairment in fatty acid oxidation precedes the onset of congestive heart failure but mitochondrial respiratory capacity is maintained until the EF decreases in vivo. These temporal relations suggest a tight link between impaired substrate oxidation capacity in the development of heart failure and contractile dysfunction and may imply therapeutic and prognostic value.
authors.affiliation: Department of Cardiac Surgery, University of Leipzig, Heart Center Leipzig, Strümpellstr. 39, 04289 Leipzig, Germany. torsten.doenst@med.uni-leipzig.de
authors.forename: Torsten
authors.initials: T
authors.lastname: Doenst
authors.forename: Gracjan
authors.initials: G
authors.lastname: Pytel
authors.forename: Andrea
authors.initials: A
authors.lastname: Schrepper
authors.forename: Paulo
authors.initials: P
authors.lastname: Amorim
authors.forename: Gloria
authors.initials: G
authors.lastname: Färber
authors.forename: Yasushige
authors.initials: Y
authors.lastname: Shingu
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Mohr
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarzer
mesh_terms: D000818:Animals; D001794:Blood Pressure; D019069:Cell Respiration; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000150:complications* / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D011654:Pulmonary Edema / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D005227:Fatty Acids; D005947:Glucose