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

• Published in: Circulation (New York, N.Y.) Vol. 104; no. 8; pp. 881 - 886
• Main Authors: OGLETREE-HUGHES, Monique L, STULL, Linda B, SWEET, Wendy E, SMEDIRA, Nicholas G, MCCARTHY, Patrick M, MORAVEC, Christine Schomisch
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 21.08.2001
• Subjects: Adult; Aged; Binding, Competitive; Biological and medical sciences; Cardiology. Vascular system; Disease Progression; Down-Regulation; Female; Heart; Heart - drug effects; Heart - innervation; Heart - physiopathology; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Heart Ventricles - drug effects; Heart Ventricles - innervation; Heart Ventricles - physiopathology; Heart-Assist Devices; Humans; In Vitro Techniques; Isoproterenol - pharmacology; Male; Medical sciences; Middle Aged; Myocardial Contraction - drug effects; Myocardium - metabolism; Myocardium - pathology; Receptors, Adrenergic, beta - metabolism; Recovery of Function; Sympathetic Nervous System; Human; Heart failure; Pathogenesis; Heart disease; Cardiocirculatory support; Cardiovascular disease; Instrumentation; Sympathetic nervous system; Left ventricle; β-Adrenergic receptor
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/hc3301.094911

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 beta-adrenergic receptors. 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 beta-adrenergic agonist were measured in isolated trabecular muscles. beta-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to beta-adrenergic stimulation 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 beta-adrenergic receptors (58.7+/-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. Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of beta-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.