Reversal of impaired myocardial beta-adrenergic receptor signaling by continuous-flow left ventricular assist device support.
BACKGROUND
Myocardial beta-adrenergic receptor (beta-AR) signaling is severely impaired in chronic heart failure (HF). This study was conducted to determine if left ventricular (LV) beta-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 beta-AR signaling was assessed by measuring adenylyl cyclase (AC) activity, total beta-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 beta-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 beta-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.
Akhter
Shahab A
SA
Department of Surgery, Section of Cardiac and Thoracic Surgery, University of Chicago Medical Center, Chicago, Illinois 60637, USA. sakhter@surgery.bsd.uchicago.edu
D'Souza
Karen M
KM
Malhotra
Ricky
R
Staron
Michelle L
ML
Valeroso
Tracy B
TB
Fedson
Savitri E
SE
Anderson
Allen S
AS
Raman
Jai
J
Jeevanandam
Valluvan
V
D000328:Adult; D002908:Chronic Disease; D015536:Down-Regulation; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D020127:Recovery of Function; D015398:Signal Transduction; D013997:Time Factors
D011943:Receptors, Adrenergic, beta; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2