Cardiomyocyte apoptosis is associated with increased wall stress in chronic failing left ventricle

Eur Heart J. 2003 Apr;24(8):742-51. doi: 10.1016/s0195-668x(02)00655-3.

Abstract

Aims: We examined cardiomyocyte apoptosis in chronic heart failure (HF) and its possible link to elevated wall stress.

Methods and results: Moderate HF was produced in sheep by sequential coronary microembolization. Six months later, the animals remained in a stable compensated haemodynamic state of HF. Apoptosis of cardiomyocytes in left ventricles was verified using Western blotting based on increased expression of: the apoptosis-associated death receptor Fas (1.5-fold); its ligand (FasL, 2.0-fold); and an upstream protease caspase-8 (2.7-fold) as well as its active cleavage peptide, p20 (5.6-fold). Previously we have reported the elevated expression of caspase-3 in the same animal model. The occurrence of apoptotic cardiomyocytes (0.3%) was quantified by TUNEL assays. Haemodynamic analysis indicated that ventricular dilatation, without wall thickening, caused a 2-fold increase in LV wall stress which, together with LV end-diastolic pressure, was linearly correlated with expression of Fas/FasL. Immunohistochemical studies localized FasL and caspase-8 to intercalated discs, suggesting that wall stress may play a role in initiating cardiomyocyte apoptosis.

Conclusion: Apoptosis of cardiomyocytes in chronic HF is associated with increased wall stress, which may be responsible for the activation of a Fas/FasL and caspase-8 interaction in the region of intercalated discs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cardiac Output, Low / pathology
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Chronic Disease
  • Fas Ligand Protein
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Membrane Glycoproteins / metabolism
  • Myocytes, Cardiac / pathology*
  • Sheep
  • Stress, Physiological / pathology*
  • Ventricular Dysfunction, Left / pathology*
  • fas Receptor / metabolism

Substances

  • Fas Ligand Protein
  • Membrane Glycoproteins
  • fas Receptor
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases