Abstract 11931: Clenbuterol and its (d)-isomer Induce Physiological Cardiac Hypertrophy in Both Normal and Failing Rat Hearts, but Do Not Prevent Myocardial Atrophy Associated with Prolonged Mechanical Unloading
Clenbuterol (CL) a β2-AR agonist has been used to enhance explantation rates in patients receiving left ventricular assist device (LVAD) for treatment of severe heart failure (HF). CL causes physiological cardiac hypertrophy but whether CL prevents mechanical unloading (MU) induced myocardial atrophy is still debated. CL is a chiral structure of D and L isomers shown to have different effects in smooth and skeletal muscle, but their effects on normal, failing myocardium, and during mechanical unloading (MU) are unknown. We compared the chronic effects (4 wks) of CL and its isomers (2mg/kg/day) in normal hearts, and in failing hearts either alone or in combination with MU (heterotopic abdominal transplantation) on heart/cardiomyocyte (CM) size and function in a rat model of HF (LAD ligation). CL and D-CL caused hypertrophy of normal hearts and L-CL did not (heart weight: tibial length ratio p<0.01 vs control (C), (all n=8). CL and D-CL alone improved ejection fraction (EF) equally ((%): C 78.9 ± 1.9, CL 86 ± 2.2, D-CL 83.9 ± 2.7 (both n=8) p<0.01 vs C. CM hypertrophy was seen in CL and D-CL groups and not L-CL group (cell volume measured by di-8-ANNEPS staining and confocal microscopy (µm3)): C 32461 ± 10291 p<0.001 vs CL 47988 ± 11486, D-CL 48312 ± 12452 p<0.001 vs C, and L-CL 38940 ± 12092, (all n=50). Similarly, CL and D-CL caused hypertrophy of failing hearts and L-CL did not (heart weight:body weight ratio (g/g x 1000)): HF 3.6 ± 0.28, CL 4.2 ± 0.38, D-CL 4.3 ± 0.39, (both n=8) p <0.05 vs HF. However CL, D-CL and L-CL all showed similar improvement in EF (p<0.01 vs HF). CM volumes were found to be greater in CL and D-CL groups compared with L-CL (p<0.01). Failing hearts underwent MU. MU-induced myocyte atrophy was not prevented by CL or its isomers but CM size was greater in CL and D-CL groups compared with L-CL (cell volume (µm3)): MU+ CL 30025 ± 8562, MU + D-CL 29927 ± 8916, both p <0.01 vs MU+ L-CL 24257 ± 7932, (all n=50) We show that CL and D-CL, but not L-CL cause physiological hypertrophy in normal and failing hearts, but do not prevent MU-induced atrophy. These results suggest that mechanisms other than clenbuterol-induced prevention of myocardial atrophy play a role in enhancing recovery rates in HF patients receiving combined pharmacological and LVAD therapy, and requires further study.
- Ventricular assist devices
- Beta-adrenergic receptor agonists
- Cardiac hypertrophy
- Ventricular function
- © 2011 by American Heart Association, Inc.