Mechanical Unloading Restores β-Adrenergic Responsiveness and Reverses Receptor Downregulation in the Failing Human Heart

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Abstract
Background— Mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in clinically documented reversal of chamber dilation and improvement of cardiac function. We tested the hypothesis that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of β-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, with or without LVAD. Baseline contractile parameters and inotropic response to a β-adrenergic agonist were measured in isolated trabecular muscles. β-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to β-adrenergic stimulation after LVAD (developed tension increased by 0.76±0.09 g/mm2 in nonfailing, 0.38±0.07 in failing, and 0.68±0.10 in failing+LVAD; PPConclusions— Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of β-adrenergic receptors and restore the ability of cardiac muscle to respond to inotropic stimulation by the sympathetic nervous system. This indicates that functional impairment of cardiac muscle in human heart failure is reversible.

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