Abstract 2358: Chronic Clenbuterol Treatment Improves Heart and Myocyte Function in Heart Failure, with and without Mechanical Unloading.
Combined LVAD and pharmacological therapy has been proposed to favour myocardial recovery in patients with end -stage heart failure (HF). Clenbuterol (Clen), a β2 adrenoceptor agonist has been used as a part of this strategy, but its effects on unloaded myocardium in heart failure are unknown. Left coronary artery ligation or sham operation was performed in male Lewis rats. After 4 – 6 weeks, mean LV ejection fraction (EF) % was 34.8±1.2  (Mean±SEM [n]), measured by echocardiography. Heterotopic abdominal transplantation of the failing hearts into normal recipients was performed to induce LV unloading (UN). Recipient rats were treated with saline (Sal) or Clen (2mg/kg/day) via osmotic minipumps (HF+UN+Sal or HF+UN+Clen) for 7 days. Non-transplanted HF animals were also treated with Sal (Sham+Sal, HF+Sal) or Clen (HF+Clen). Clen improved LV function in HF (HF+Clen, mean EF %: 33.8 ±8 to 52±7; p<0.001) Ex-vivo LV pressure-volume relationship was assessed in all hearts during Langendorff perfusion. Clen in UN increased dP/dTmax ((mm Hg/s) at 150 μl LV volume: HF+UN+Clen 2623±349 ; HF+UN+Sal 1605±419 ; p<0.05). LV myocytes were isolated from all hearts by enzymatic digestion. Sarcomere length (SL) was measured by Fourier analysis of digitised myocyte images, at 1Hz field-stimulation. HF caused impaired sarcomere shortening (SL amplitude (μm): Sham+Sal 0.08 ±0.01 [46 myocytes]; HF+Sal 0.07±0.004 ; p< 0.05[CT2] ) and relaxation (time-to-50% relaxation (ms): Sham+Sal 71±6 ; HF+Sal 91±6 ; p<0.05). Clen treatment in HF increased sarcomere shortening (SL amplitude (μm): HF+Clen 0.1 ±0.01 ; vs HF+Sal; p<0.001) and relaxation (time-to-50% relaxation (ms): HF+Clen 54±2  vs HF+Sal; p<0.001). Clen treatment in UN also increased sarcomere shortening (SL amplitude (μm): HF+UN+Clen 0.1 ±0.01 ; HF+UN+Sal 0.07±0.01 ; p<0.001) and relaxation (time-to-50% relaxation (ms): HF+UN+Clen 46±2 ; HF+UN+Sal 90±6 ; p<0.001). We conclude that Clen treatment improves whole heart and myocyte function in HF with and without mechanical unloading.