Copyright © 2003 by the European Society of Cardiology.
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Cardiomyocyte apoptosis is associated with increased wall stress in chronic failing left ventricle
a Department of Cardiology, Cardiac Technology Centre, Royal North Shore Hospital, St. Leonards, NSW, Australia
b Department of Anatomy and Histology, Institute for Biomedical Research, University of Sydney, NSW, Australia
* Corresponding author. Department of Physiology (F13), Institute for Biomedical Research, The University of Sydney, NSW 2006, Australia. Tel.: +61-2-93514526; fax: +61-2-93512058
E-mail address: lelej{at}physiol.usyd.edu.au
Received 22 July 2002; revised 6 September 2002; accepted 11 September 2002
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.
Key Words: Apoptosis • Fas/Fas ligand • Caspase • Chronic heart failure • Wall stress • Intercalated disc
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