Published Online
on March 25, 2009

A more recent version of this article appeared on May 1, 2009

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Original Article

Prevention of Myofilament Dysfunction by Beta-blocker Therapy in Post-infarct Remodeling

Dirk J. Duncker¹; Nicky M. Boontje²; Daphne Merkus¹; Amanda Versteilen²; Judith Krysiak³; Giulia Mearini⁴; Ali El-Armouche⁴; Vincent J. de Beer¹; Jos M.J. Lamers¹; Lucie Carrier⁵; Lori A. Walker⁶; Wolfgang A. Linke³; Ger J.M. Stienen² and Jolanda van der Velden^2,7

¹ Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;
² VU Medical Center, Amsterdam, the Netherlands;
³ University of Muenster, Germany;
⁴ University Medical Center Hamburg-Eppendorf, Germany;
⁵ University Medical Center Hamburg-Eppendorf, Germany; INSERM, University of Paris, France;
⁶ University of Colorado, Health Sciences Center, Denver

⁷ E-mail: j.vandervelden{at}vumc.nl

Background—Myofilament contractility of individual cardiomyocytes is depressed in remote non-infarcted myocardium and contributes to global left ventricular (LV) pump dysfunction after myocardial infarction (MI). Here we investigated whether β-blocker therapy could restore myofilament contractility.

Methods and Results—In pigs with a MI induced by ligation of the left circumflex coronary artery, β-blocker therapy (bisoprolol, MI+β) was initiated on the first day after MI. Remote LV subendocardial biopsies were taken 3 weeks after sham or MI surgery. Isometric force was measured in single permeabilized cardiomyocytes. Maximal force (F_max) was lower, while Ca²⁺-sensitivity was higher in untreated MI compared to sham (both P<0.05). The difference in Ca²⁺-sensitivity was abolished by treatment of cells with the β-adrenergic kinase, protein kinase A (PKA). Beta-blocker therapy partially reversed basal F_max and Ca²⁺-sensitivity to sham values and significantly reduced passive force. Despite the lower myofilament Ca²⁺-sensitivity in MI+β compared to untreated myocardium, the PKA-induced reduction in Ca²⁺-sensitivity was largest in cardiomyocytes from myocardium treated with β-blockers. Phosphorylation of β-adrenergic target proteins (myosin binding protein C and troponin I) did not differ among groups, whereas myosin light chain 2 phosphorylation was reduced in MI, which coincided with increased expression of protein phosphatase 1. Beta-blockade fully restored the latter alterations and significantly reduced expression of protein phosphatase 2a.

Conclusions—Beta-blockade reversed basal myofilament dysfunction and enhanced myofilament responsiveness to PKA in remote myocardium after MI. These beneficial effects likely contribute to the beneficial effects of β-blockade on global LV function after myocardial infarction.

Key Words: contractility • myocardial infarction • beta-blockers • myofilament proteins • phosphatases