Abstract 9970: Combined Clenbuterol and Metoprolol Therapy Improves Cardiac Function and Calcium Handling in a Rodent Model of Heart Failure, but Does Not Prevent Myocardial Atrophy or Enhance Myocyte Recovery Associated with Mechanical Unloading

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Clenbuterol (CL) a β 2 -AR agonist has been successfully employed alongside β 1 -AR blockade in combination with left ventricular assist devices (LVAD) to prevent myocardial atrophy, and promote myocardial recovery in patients with severe heart failure (HF). CL is known to have beneficial effects on excitation contraction (EC) coupling in HF and during mechanical unloading (MU) in animal models. However, CL-induced cardiac hypertrophy and tachycardia have discouraged its use in clinical HF therapy. We compared the chronic effects (4 wks) of CL (2mg/kg/day) and metoprolol (M) (200mg/kg/day) alone and in combination with MU (heterotopic abdominal transplantation) on heart/cardiomyocyte size, function and cellular EC coupling in a rat model of HF (LAD ligation). CL improved ejection fraction compared to untreated HF group, an effect further augmented by M (EF (%): HF 36.2 ± 2.3, p<0.01 vs CL 40.78 ± 2.1, p<0.001 vs M+CL 44.3 ± 2.3 (all groups n=8). CL caused a rise in heart rate (HR) but, when combined with M, HR was reduced (both groups p<0.01 vs HF). CL caused cardiac hypertrophy whereas combined M+CL did not (heart weight:body weight ratio (g/g x 1000)): HF 3.6 ± 0.28, p< 0.05 vs CL 4.2 ± 0.38, Μ+CL 3.6 ± 0.24, p>0.05 vs HF (all groups n=8). Both groups failed to prevent MU-induced myocyte atrophy, but myocyte size was greater in MU+CL group compared with MU+M+CL (cell volume measured by di-8-ANNEPS staining and confocal microscopy (µm3)): MU+ CL 30025 ± 8562, p<0.001 vs MU + M+CL 18750 ± 7500, (both groups n= 50). Myocyte Ca 2+ cycling was studied using the fluorescent dye Indo-1 AM. Ca 2+ transient amplitude was elevated in M+CL group but was not affected by CL (ratio units): HF 0.14 ± 0.06, p<0.001 vs M+CL 0.19 ± 0.09 (both groups n=26). CL alone and M + CL augmented sarcoplasmic reticulum Ca2 + content equally (ratio units): CL 0.20 ± 0.04, M + CL 0.22 ± 0.06, both groups p<0.01 vs HF, (all groups n=20). MU alone normalised HF cardiomyocyte EC parameters with no additional benefit derived by M+CL therapy. We show that combination of CL and M enhances whole heart function and cellular EC coupling in HF without increase in heart size or HR, but does not affect the consequences of MU on cell size and function. Whether such effects can be exploited in the treatment of HF patients requires further studies.