Abstract 18765: Cardiac Resynchronization Therapy Upregulates Beta Reserve Through RGS and β-arrestin2 Proteins Only in Previously Dyssynchronous Hearts
Bacgkground: Cardiac resynchronization therapy (CRT) reduces symptoms and mortality in patients with left bundle branch block and heart failure by reversing basal and beta-adrenergic receptor (?-AR) stimulated myocyte contractile dysfunctions associated with dyssynchronous heart failure (DHF). Here, we tested the mechanism and prerequisite conditions for CRT to improve beta-adrenergic receptor signaling in isolated myocytes in an animal model.
Methods: Adult dogs (n=10) underwent LBB radio-frequency ablation; half were subjected to right atrial tachypacing-induced DHF for 6 weeks, while in the other half, 3 weeks DHF was followed by 3 weeks of bi-ventricular tachypacing (CRT). 5 other dogs were subjected to LV tachypacing for 3 weeks (dyssynchrony) followed by 3 weeks resynchronization by a right atrial tachypacing (V3A3). 5 more dogs were subjected to synchronous heart failure by a right atrial tachypacing for 6 weeks (A6). An additional 5 non-paced dogs served as controls. Myocytes were enzymatically isolated from the LV free wall and field stimulated in a perfusion chamber. Sarcomere shortening and calcium transient were determined with and without 10–7 M isoproterenol.
Results: DHF, V3A3, A6 and CRT hearts had similar global failure, with dP/dtmax 1190.2±139.8 vs. 1111.8±131.6 vs. 1333.0±205.2 vs. 1195.3±137.6 mmHg/s, respectively (1900.3±176.8 in control). However, there were marked differences in basal and β-stimulated myocyte calcium transient and sarcomere shortening (n=8–30 cells/group). DHF and A6 myocytes showed depressed basal and β-AR stimulated sarcomere shortening and Ca transient versus control, V3A3 and CRT. In contrast, myocytes from V3A3 and CRT hearts had similarly enhanced basal and β-AR stimulated functions. Both Atrial- and BiV-resynchronizations enhance the expression of regulator of G protein signaling 2 and 3 proteins (RGS2, RGS3) to inactivate Gαi signaling and downregulate β-arrestin2 to promote re-sensitization of β-ARs.
Conclusions: Both Atrial- (His-Purkinje) and BiV-pacing improve cardiac dyssynchrony and up-regulate β-signaling through RGS proteins upregulation and β-arrestin2 downregulation mechanism. Dyssynchrony is necessary for the CRT to improve basal and β-AR-reserve myocyte function.
- © 2010 by American Heart Association, Inc.