Published Online
on February 23, 2009

A more recent version of this article appeared on March 10, 2009

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Submitted on February 21, 2008
Accepted on November 24, 2008

Mechanisms of Enhanced -Adrenergic Reserve From Cardiac Resynchronization Therapy

Khalid Chakir PhD, Samantapudi K. Daya MD, Takeshi Aiba MD, PhD, Richard S. Tunin MS, Veronica L. Dimaano MD, Theodore P. Abraham MD, Kathryn Jacques BA, Edwin W. Lai PhD, Karel Pacak MD, Wei-Zhong Zhu MD, PhD, Rui-ping Xiao PhD, Gordon F. Tomaselli MD, PhD, and David A. Kass MD^*

From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore (K.C., S.K.D., T.A., R.S.T., V.L.D., T.P.A., K.J., G.F.T., D.A.K.); Reproductive Biology and Medicine Branch, Section on Medical Neuroendocrinology, National Institute of Child Health and Human Development, Bethesda (K.P.); and Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore (E.W.L., W.-Z.Z., R.-p.X.), Md.

^* To whom correspondence should be addressed. E-mail: dkass{at}jhmi.edu.

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, ₁ and ₂ stimulation was enhanced, coupled to increased ₁ receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (G_i) suppression of -adrenergic stimulation was greater in DHF and reversed by CRT. G_i expression itself was unaltered; however, expression of negative regulators of G_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 -adrenergic–stimulated myocyte function and calcium handling, upregulating 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.

Key words: adenylate cyclase • heart failure • myocytes • pacing • receptors, adrenergic, beta • RGS proteins

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Clinical Summaries
Circulation 2009 119: 1177-1179. [Extract] [Full Text]

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