Mechanisms of enhanced beta-adrenergic reserve from cardiac resynchronization therapy.
BACKGROUND
Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown.


RESULTS
We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, beta(1) and beta(2) stimulation was enhanced, coupled to increased beta(1) receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Galpha(i)) suppression of beta-adrenergic stimulation was greater in DHF and reversed by CRT. Galpha(i) expression itself was unaltered; however, expression of negative regulators of Galpha(i) signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control.


CONCLUSIONS
CRT improves rest and beta-adrenergic-stimulated myocyte function and calcium handling, upregulating beta(1) receptors and adenylate cyclase activity and suppressing G(i)-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.
Chakir
Khalid
K
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Daya
Samantapudi K
SK
Aiba
Takeshi
T
Tunin
Richard S
RS
Dimaano
Veronica L
VL
Abraham
Theodore P
TP
Jaques-Robinson
Kathryn M
KM
Jacques
Kathryn
K
Lai
Edwin W
EW
Pacak
Karel
K
Zhu
Wei-Zhong
WZ
Xiao
Rui-ping
RP
Tomaselli
Gordon F
GF
Kass
David A
DA
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D004285:Dogs; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010138:Pacemaker, Artificial; D020710:RGS Proteins / Q000502:physiology; D011869:Radioligand Assay; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D012518:Sarcomeres / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D002395:Catecholamines; D020710:RGS Proteins; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases