Abstract
Improvements in Ca2+ handling, and sarcoplasmic reticulum (SR) Ca2+ regulation in particular, are associated with myocardial recovery in patients with end stage heart failure (HF) treated with left ventricular assist devices (LVAD). Ivabradine (IV), a novel heart rate reducing agent has been shown to have positive Ca2+ regulatory effects in rodent HF, and is used in human HF therapy; however, the effects of IV during LVAD treatment have not been studied.We studied the chronic effects of IV on cellular Ca2+ handling during mechanical unloading (MU) of HF hearts. HF was induced by left coronary artery ligation and was characterized by reduced ejection fraction (EF), smaller Ca2+ transient amplitude (CaT) and reduced SR Ca2+ content compared to age matched sham operated animals (SH). MU (4 weeks) was achieved by heterotopic abdominal heart transplantation and IV (10mg/kg/day) was administered for 4 weeks. Isolated ventricular myocytes were loaded with Indo-1 AM and field stimulated at 1 Hz.CaT was significantly elevated in the MU+IV group (indo-1 ratio units): MU+IV: 0.25 ± 0.06 (n=45) p< 0.001 vs MU: 0.18 ± 0.05 (n=40), and p<0.001 vs SH: 0.17 ± 0.05 (n=45)). IV augmented SR Ca2+ content in combination with MU compared with MU alone and to a level even greater than SH: SR Ca2+ content (indo-1 ratio units): MU+IV: 0.27 ± 0.07 (n=45) p< 0.05 vs MU: 0.24 ± 0.05 (n=40), and p<0.001 vs SH: 0.22 ± 0.07 (n=45))Our results show that IV treatment combined with mechanical unloading induces a larger increase of Ca2+ transient amplitude and SR Ca2+ content compared with mechanical unloading alone. These effects may be exploited to enhance myocardial recovery in patients receiving LVAD therapy for HF.
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