Mechanisms of Enhanced (cid:1) -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. Methods and 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, (cid:1) 1 and (cid:1) 2 stimulation was enhanced, coupled to increased (cid:1) 1 receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (G (cid:2) i ) suppression of (cid:1) -adrenergic stimulation was greater in DHF and reversed by CRT. G (cid:2) i expression itself was unaltered; however, expression of negative regulators of G (cid:2) 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 (cid:1) -adrenergic–stimulated myocyte function and calcium handling, upregulating (cid:1) 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. ( Circulation . 2009;119:1231-1240.) 0.4 mol/L perchloric acid containing 0.5 mmol/L EDTA and centri- fuged at 5000 rpm at 4°C. Catecholamines were extracted from the supernatant with an alumina extraction procedure and quantified by liquid chromatography with electrochemical detection as described. 24 Concentration was normalized to tissue weight. signaling. Accompa-nying this adrenergic upregulation was a decline in myocardial catecholamines from the higher levels observed in dyssynchronous heart failure hearts. Thus, CRT effectively restored a more normal balance of greater cellular adrenergic responsiveness with reduced chronic sympathetic stimulation. This may play an important role in the long-term efficacy of CRT on clinical symptoms and survival and its interaction with concurrent pharmacological neuroblockade treatment.