Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy

Khalid Chakir, Samantapudi K. Daya, Takeshi Aiba, Richard S. Tunin, Veronica L. Dimaano, Theodore P. Abraham, Kathryn Jacques, Edwin W. Lai, Karel Pacak, Wei Zhong Zhu, Rui Ping Xiao, Gordon F. Tomaselli, David A. Kass

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

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, β 1 and β 2 stimulation was enhanced, coupled to increased β 1 receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Galpha; 1) suppression of β-adrenergic stimulation was greater in DHF and reversed by CRT. Galpha; 1 expression itself was unaltered; however, expression of negative regulators of Galpha; 1 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 beta; 1 receptors and adenylate cyclase activity and suppressing Galpha; 1coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.

Original languageEnglish (US)
Pages (from-to)1231-1240
Number of pages10
JournalCirculation
Volume119
Issue number9
DOIs
StatePublished - Mar 10 2009
Externally publishedYes

Fingerprint

Cardiac Resynchronization Therapy
Adrenergic Agents
Muscle Cells
Adenylyl Cyclases
Heart Failure
Calcium
Sarcomeres
Isoproterenol
GTP-Binding Proteins
Catecholamines
Canidae
Up-Regulation

Keywords

  • Adenylate cyclase
  • Adrenergic
  • Beta
  • Heart failure
  • Myocytes
  • Pacing
  • Receptors
  • Rgs proteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Chakir, K., Daya, S. K., Aiba, T., Tunin, R. S., Dimaano, V. L., Abraham, T. P., ... Kass, D. A. (2009). Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy. Circulation, 119(9), 1231-1240. https://doi.org/10.1161/CIRCULATIONAHA.108.774752

Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy. / Chakir, Khalid; Daya, Samantapudi K.; Aiba, Takeshi; Tunin, Richard S.; Dimaano, Veronica L.; Abraham, Theodore P.; Jacques, Kathryn; Lai, Edwin W.; Pacak, Karel; Zhu, Wei Zhong; Xiao, Rui Ping; Tomaselli, Gordon F.; Kass, David A.

In: Circulation, Vol. 119, No. 9, 10.03.2009, p. 1231-1240.

Research output: Contribution to journalArticle

Chakir, K, Daya, SK, Aiba, T, Tunin, RS, Dimaano, VL, Abraham, TP, Jacques, K, Lai, EW, Pacak, K, Zhu, WZ, Xiao, RP, Tomaselli, GF & Kass, DA 2009, 'Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy', Circulation, vol. 119, no. 9, pp. 1231-1240. https://doi.org/10.1161/CIRCULATIONAHA.108.774752
Chakir K, Daya SK, Aiba T, Tunin RS, Dimaano VL, Abraham TP et al. Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy. Circulation. 2009 Mar 10;119(9):1231-1240. https://doi.org/10.1161/CIRCULATIONAHA.108.774752
Chakir, Khalid ; Daya, Samantapudi K. ; Aiba, Takeshi ; Tunin, Richard S. ; Dimaano, Veronica L. ; Abraham, Theodore P. ; Jacques, Kathryn ; Lai, Edwin W. ; Pacak, Karel ; Zhu, Wei Zhong ; Xiao, Rui Ping ; Tomaselli, Gordon F. ; Kass, David A. / Mechanisms of enhanced β-adrenergic reserve from cardiac resynchronization therapy. In: Circulation. 2009 ; Vol. 119, No. 9. pp. 1231-1240.
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abstract = "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, β 1 and β 2 stimulation was enhanced, coupled to increased β 1 receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (Galpha; 1) suppression of β-adrenergic stimulation was greater in DHF and reversed by CRT. Galpha; 1 expression itself was unaltered; however, expression of negative regulators of Galpha; 1 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 beta; 1 receptors and adenylate cyclase activity and suppressing Galpha; 1coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.",
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AU - Dimaano, Veronica L.

AU - Abraham, Theodore P.

AU - Jacques, Kathryn

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KW - Myocytes

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KW - Receptors

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