title: Activation of apoptotic pathways in experimental acute afterload-induced right ventricular failure.
abstract: OBJECTIVE
  The pathobiology of persistent right ventricular failure observed after an acute increase in right ventricular afterload remains incompletely understood. We hypothesized that persistent right ventricular dysfunction might be related to activation of apoptotic pathways.
  
  
  METHODS
  Prospective, randomized, controlled animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Mongrel dogs.
  
  
  METHODS
  Fourteen anesthetized dogs were randomized to a transient 90-min pulmonary artery constriction operation to induce persistent right ventricular failure or to a sham operation followed 30 mins later by hemodynamic measurements and sampling of cardiac tissue.
  
  
  RESULTS
  We evaluated effective arterial elastance to estimate right ventricular afterload and end-systolic elastance to estimate right ventricular contractility. Transient increase in pulmonary artery pressure persistently increased effective arterial elastance from 0.75 +/- 0.08 to 1.37 +/- 0.18 mm Hg/mL and decreased end-systolic elastance from 1.06 +/- 0.09 to 0.49 +/- 0.09 mm Hg/mL, end-systolic elastance/effective arterial elastance from 1.44 +/- 0.06 to 0.34 +/- 0.03, and cardiac output from 3.78 +/- 0.16 to 1.46 +/- 0.10 L/min, indicating right ventricular failure. At the pathobiologic level, we assessed apoptosis by real-time quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. As compared with the sham-operated group, and with the left ventricle in animals with persistent right ventricular failure, there were decreased right ventricular and septal expressions of Bcl-2 with no changes in expressions of Bax, resulting in an increased Bax/Bcl-2 ratio. Right ventricular and septal Bcl-XL, and right ventricular Bcl-w gene expressions were decreased as compared with the sham-operated group, whereas Bak gene expression did not change. There were activations of right ventricular caspases-8 and -9 and of right ventricular and septal caspase-3. Diffuse right ventricular and septal apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. There were also increased right ventricular and septal protein expressions of tumor necrosis factor-alpha.
  
  
  CONCLUSIONS
  Acute afterload-induced persistent right ventricular failure appears to be related to an early activation of apoptotic pathways and to a local overexpression of tumor necrosis factor-alpha, a proinflammatory cytokine.
authors.affiliation: Laboratory of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium. cdewacht@ulb.ac.be
authors.forename: Céline
authors.initials: C
authors.lastname: Dewachter
authors.forename: Laurence
authors.initials: L
authors.lastname: Dewachter
authors.forename: Benoît
authors.initials: B
authors.lastname: Rondelet
authors.forename: Pierre
authors.initials: P
authors.lastname: Fesler
authors.forename: Serge
authors.initials: S
authors.lastname: Brimioulle
authors.forename: François
authors.initials: F
authors.lastname: Kerbaul
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001794:Blood Pressure; D002302:Cardiac Output / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D051793:Hypoxia-Inducible Factor 1; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases