title: A pressure overload model to track the molecular biology of heart failure.
abstract: OBJECTIVE
  Pressure overload plays an important role in left ventricular remodelling and the development of heart failure. The underlying molecular mechanisms behind these processes are poorly understood at the myocyte level. To investigate this, we developed an ovine model of pressure overload-induced heart failure, in which serial left ventricular biopsies were obtained.
  
  
  METHODS
  Adult male sheep were chronically banded with a novel variable aortic constriction device. This was progressively inflated via a subcutaneous port to increase left ventricular afterload. The animals were monitored clinically and echocardiographically. Serial left ventricular endomyocardial biopsies were obtained via the right external carotid artery under fluoroscopic guidance. They were used to measure mRNA expression of the genetic regulators of apoptosis by reverse transcription polymerase chain reaction. In a subset of the animals, once left ventricular failure had been established, the constriction device was deflated to produce unloading of the left ventricle.
  
  
  RESULTS
  Ten of the 17 sheep banded developed left ventricular failure. Over the first 3-4 weeks, left ventricular mass index increased acutely (88+/-18 vs. 44+/-10 g/m(2), P<0.01) followed by gradual left ventricular dilatation (diastolic left ventricular internal diameter 4.1+/-0.7 vs. 3.2+/-0.3 cm, P<0.01). Ventricular function remained stable until 7-8 weeks postoperatively, when there was significant deterioration (fractional shortening 17+/-8 vs. 40+/-8%, P<0.01) associated with clinical heart failure. Expression of the pro-apoptotic genes (bax and Fas) increased significantly following inflation of the constriction device and persisted through the transition to left ventricular failure. Following deflation of the constriction device, myocardial contractility gradually improved over a 3 week period (fractional shortening 32+/-1 vs. 17+/-8%).
  
  
  CONCLUSIONS
  Progressively increasing the afterload on the left ventricle produces a clinical and echocardiographical picture of chronic heart failure. Obtaining myocardial tissue during this transition will allow the molecular correlates of pressure overload-induced heart failure and potential myocardial recovery to be investigated.
authors.affiliation: Department of Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DY, UK. narain.moorjani@doctors.org.uk
authors.forename: Narain
authors.initials: N
authors.lastname: Moorjani
authors.forename: Pedro
authors.initials: P
authors.lastname: Catarino
authors.forename: Raafat
authors.initials: R
authors.lastname: El-Sayed
authors.forename: Samaher
authors.initials: S
authors.lastname: Al-Ahmed
authors.forename: Brian
authors.initials: B
authors.lastname: Meyer
authors.forename: Futwan
authors.initials: F
authors.lastname: Al-Mohanna
authors.forename: Stephen
authors.initials: S
authors.lastname: Westaby
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D015150:Echocardiography, Doppler; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D012333:RNA, Messenger