Mechanical unloading restores beta-adrenergic responsiveness and reverses receptor downregulation in the failing human heart

Background-Mechanical unloading of the failing human heart with a left vent ricular assist device (LVAD) results in clinically documented reversal of c hamber dilation and improvement of cardiac function. We tested the hypothes is that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of beta -adrenergic receptors. Methods and Results-Human LV tissue was obtained from nonfailing hearts of unmatched organ donors and failing hearts at the time of transplantation, w ith or without LVAD. Baseline contractile parameters and inotropic response to a beta -adrenergic agonist were measured in isolated trabecular muscles . P-Adrenergic receptor density was quantified by radioligand binding. Resu lts showed a significant increase in the response to beta -adrenergic stimu lation after LVAD (developed tension increased by 0.76 +/- 0.09 g/mm(2) in nonfailing, 0.38 +/- 0.07 in failing, and 0.68 +/- 0.10 in failing + LVAD; P < 0.01), accompanied by an increased density of P-adrenergic receptors (5 8.7 +/- 9.6 fmol/mg protein in nonfailing, 26.2 +/- 3.8 in failing, and 63. 0 +/- 8.3 in failing + LVAD; P < 0.05). These changes were unrelated to the duration of support. Conclusions-Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of P-adrenergic receptor s and restore the ability of cardiac muscle to respond to inotropic stimula tion by the sympathetic nervous system. This indicates that functional impa irment of cardiac muscle in human heart failure is reversible.