American Heart Association, Circulation: Heart Failure, 3(2), p. 233-242, 2009
DOI: 10.1161/circheartfailure.108.806125
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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 (F max ) was lower, whereas Ca 2+ sensitivity was higher in untreated MI compared with sham (both P <0.05). The difference in Ca 2+ sensitivity was abolished by treatment of cells with the β-adrenergic kinase, protein kinase A. β-blocker therapy partially reversed F max and Ca 2+ sensitivity to sham values and significantly reduced passive force. Despite the lower myofilament Ca 2+ sensitivity in MI+β compared with untreated myocardium, the protein kinase A induced reduction in Ca 2+ 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.