Reversal of impaired myocardial β-adrenergic receptor signaling by continuous-flow left ventricular assist device support

Background: Myocardial β-adrenergic receptor (β-AR) signaling is severely impaired in chronic heart failure (HF). This study was conducted to determine if left ventricular (LV) β-AR signaling could be restored after continuous-flow LV assist device (LVAD) support. Methods: Twelve patients received LVADs as a bridge to transplant. Paired LV biopsy specimens were obtained at the time of LVAD implant (HF group) and transplant (LVAD group). The mean duration of LVAD support was 152 ± 34 days. Myocardial β-AR signaling was assessed by measuring adenylyl cyclase (AC) activity, total β-AR density (B_max), and G protein-coupled receptor kinase-2 (GRK2) expression and activity. LV specimens from 8 non-failing hearts (NF) were used as controls. Results: Basal and isoproterenol-stimulated AC activity was significantly lower in HF vs NF, indicative of β-AR uncoupling. Continuous-flow LVAD support restored basal and isoproterenol-stimulated AC activity to levels similar to NF. B_max was decreased in HF vs NF and increased to nearly normal in the LVAD group. GRK2 expression was increased 2.6-fold in HF vs NF and was similar to NF after LVAD support. GRK2 activity was 3.2-fold greater in HF vs NF and decreased to NF levels in the LVAD group. Conclusions: Myocardial β-AR signaling can be restored to nearly normal after continuous-flow LVAD support. This is similar to previous data for volume-displacement pulsatile LVADs. Decreased GRK2 activity is an important mechanism and indicates that normalization of the neurohormonal milieu associated with HF is similar between continuous-flow and pulsatile LVADs. This may have important implications for myocardial recovery.