Prevention of myofilament dysfunction by β-blocker therapy in postinfarct remodeling
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 Fmaxand 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.
|Keywords||Contractility, Myocardial infarction, Myofilament proteins, Phosphatases, β-blockers|
|Persistent URL||dx.doi.org/10.1161/CIRCHEARTFAILURE.108.806125, hdl.handle.net/1765/25277|
|Journal||Circulation. Heart Failure|
Duncker, D.J.G.M, Boontje, N.M, Merkus, D, Versteilen, A, Krysiak, J, Mearini, G, … van der Velden, J. (2009). Prevention of myofilament dysfunction by β-blocker therapy in postinfarct remodeling. Circulation. Heart Failure, 2(3), 233–242. doi:10.1161/CIRCHEARTFAILURE.108.806125