Impaired Myofilament Contractility in Post-infarct Remodeled Myocardium is Restored upon β-Adrenergic Stimulation

Abstract

Previously we have shown that in vivo cardiac responsiveness to exercise-induced increases in noradrenaline was blunted in pigs with a myocardial infarction (MI), consistent with defects in β-adrenergic signaling. Here we tested the hypothesis that the blunted increase in pump function with exercise after MI is due to reduced myofilament responsiveness, and is prevented by β-blocker therapy. 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. Myofilament force measurements and protein analysis were performed in left ventricular subendocardial biopsies taken at baseline, and upon dobutamine stimulation 3 weeks after MI or sham (n=6). Isometric force was measured in single permeabilized cardiomyocytes. At baseline, maximal force (Fmax) was lower in MI compared to sham, while Ca2+-sensitivity (pCa50) was higher (both P<0.05). Passive force (Fpas) did not differ. Fmax did not change upon dobutamine in sham, while it markedly increased in MI. Moreover, the dobutamine-induced decrease in pCa50 was larger in MI than in sham. Beta-blockers prevented baseline myofilament dysfunction, reduced Fpas and enhanced the responsiveness to β-AR stimulation illustrated by a large change in pCa50 upon dobutamine. Baseline phosphorylation of β-adrenergic target proteins (myosin binding protein C and troponin I) was not altered in MI, while the dobutamine-induced increase in troponin I phosphorylation was less in MI compared to sham and MI+β. Dobutamine enhanced myosin light chain 2 phosphorylation solely in sham. In conclusion, acute β-adrenoceptor stimulation largely restores baseline myofilament dysfunction despite attenuation of β-adrenergic-mediated troponin I phosphorylation. Myofilament dysfunction in remodelled myocardium and its reversal by β-blockers is not a direct consequence of reduced PKA-mediated phosphorylation, and does not contribute to the blunted in vivo response to β-adrenoceptor stimulation.