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 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.


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 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.


CONCLUSIONS
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.
Ogletree-Hughes
M L
ML
Center for Anesthesiology Research, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Stull
L B
LB
Sweet
W E
WE
Smedira
N G
NG
McCarthy
P M
PM
Moravec
C S
CS
D000328:Adult; D000368:Aged; D001667:Binding, Competitive; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006321:Heart / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000294:innervation / Q000503:physiopathology; D006353:Heart-Assist Devices; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D020127:Recovery of Function; D013564:Sympathetic Nervous System
D011943:Receptors, Adrenergic, beta; D007545:Isoproterenol