This Article Full Text Full Text (PDF) Data Supplement Correction Correction (v119,pe533) All Versions of this Article: 119/9/1231    most recent CIRCULATIONAHA.108.774752v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chakir, K. Articles by Kass, D. A. Search for Related Content PubMed PubMed Citation Articles by Chakir, K. Articles by Kass, D. A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure Pacemakers and Implantable Defibrillators Related Collections Contractile function Congestive Pacemaker Animal models of human disease Heart failure - basic studies Receptor pharmacology Related Article

(Circulation. 2009;119:1231-1240.)
© 2009 American Heart Association, Inc.

Heart Failure

Mechanisms of Enhanced β-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 Jaques, BA; Edwin W. Lai, PhD; Karel Pacak, MD; Wei-Zhong Zhu, MD, PhD; Rui-ping Xiao, PhD; Gordon F. Tomaselli, MD, PhD; 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 (E.W.L., K.P.); and Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore (W.-Z.Z., R.-p.X.), Md.

Correspondence to David A. Kass, MD, 720 Rutland Ave, Ross Bldg 835, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205. E-mail dkass{at}jhmi.edu

Received February 21, 2008; accepted November 24, 2008.

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, β₁ and β₂ stimulation was enhanced, coupled to increased β₁ receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (G_i) suppression of β-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 β-adrenergic–stimulated myocyte function and calcium handling, upregulating β₁ 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.

---

 

CLINICAL PERSPECTIVE

Related Article:

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

This article has been cited by other articles:

				A. S. Barth, T. Aiba, V. Halperin, D. DiSilvestre, K. Chakir, C. Colantuoni, R. S. Tunin, V. L. Dimaano, W. Yu, T. P. Abraham, et al. Cardiac Resynchronization Therapy Corrects Dyssynchrony-Induced Regional Gene Expression Changes on a Genomic Level Circ Cardiovasc Genet, August 1, 2009; 2(4): 371 - 378. [Abstract] [Full Text] [PDF]

				M. Vanderheyden and J. Bartunek Cardiac Resynchronization Therapy in Dyssynchronous Heart Failure: Zooming in on Cellular and Molecular Mechanisms Circulation, March 10, 2009; 119(9): 1192 - 1194. [Full Text] [PDF]