Published online before print March 25, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.806125
Original Articles |
Prevention of Myofilament Dysfunction by β-Blocker Therapy in Postinfarct Remodeling
From the Experimental Cardiology (D.J.D., D.M., V.J.B.), Thoraxcenter, and Department of Biochemistry (J.M.J.L.), Cardiovascular Research School COEUR, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Laboratory for Physiology (N.M.B., A.V., G.J.M.S. J.V.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Physiology and Biophysics Unit (J.K., W.A.L.), University of Muenster, Muenster, Germany; Institute of Experimental and Clinical Pharmacology and Toxicology (G.M., A.E.A., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Inserm U582 (L.C.), Inserm U974-CNRS UMR 7215, UPMC University of Paris, Paris, France; and Department of Medicine (L.A.W.), Section of Cardiology, University of Colorado, Health Sciences Center, Denver, Colo.
Correspondence to Jolanda van der Velden, PhD, Laboratory for Physiology, VUmc, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail j.vandervelden{at}vumc.nl
Received July 10, 2008; accepted February 23, 2009.
Background— Myofilament contractility of individual cardiomyocytes is depressed in remote noninfarcted myocardium and contributes to global left ventricular 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 left ventricular subendocardial biopsies were taken 3 weeks after sham or MI surgery. Isometric force was measured in single permeabilized cardiomyocytes. Maximal force (Fmax) was lower, whereas Ca2+ sensitivity was higher in untreated MI compared with sham (both P<0.05). The difference in Ca2+ sensitivity was abolished by treatment of cells with the β-adrenergic kinase, protein kinase A. β-blocker therapy partially reversed Fmax and Ca2+ sensitivity to sham values and significantly reduced passive force. Despite the lower myofilament Ca2+ sensitivity in MI+β compared with untreated myocardium, the protein kinase A 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. β-blockade fully restored the latter alterations and significantly reduced expression of protein phosphatase 2a.
Conclusions— β-blockade reversed myofilament dysfunction and enhanced myofilament responsiveness to protein kinase A in remote myocardium after MI. These effects likely contribute to the beneficial effects of β-blockade on global left ventricular function after MI.
Key Words: myocardial infarction • β-blockers • contractility • myofilament proteins • phosphatases