Abstract 1876: Beta-blocker Therapy alters Myofilament Function in Patients with Congestive Heart Failure
Large randomised multi-center trials have shown that treatment of patients with congestive heart failure (CHF) with beta-adrenergic receptor blockers reduces both morbidity and mortality. To reveal if beta-blocker therapy induces structural and functional alterations at the cellular level, histological and cardiomyocyte force characteristics were analyzed in left ventricular biopsies obtained during cardiac catheterization from CHF patients treated with (CHF+, n=11) and without beta-blockers (CHF−, n=10). LV ejection fraction amounted to 32±3% and 31±3% in CHF+ and CHF−, respectively. Light and electron microscopy was performed to determine cardiomyocyte diameter, collagen volume fraction (CVF) and myofi-brillar density (FibD). Isometric force was measured in mechanically isolated single perme-abilized cardiomyocytes at various calcium concentrations at baseline and saturated beta-adrenergic stimulation, mimicked by application of the active subunit of protein kinase A (PKA). Beta-blocker therapy had no effect on cardiomyocyte diameter (15.2±0.3 μm in CHF+ vs.16.1±0.3 μm in CHF−), CVF, FibD, active (Fact) and passive force (Fpas). Myofilament calcium sensitivity (pCa50) was larger in CHF+ compared to CHF− patients (ΔpCa50=0.07; P<0.05). PKA treatment significantly increased Fact in CHF− but not in CHF+ patients and reduced Fpas and pCa50 in both groups. The PKA-induced shift in pCa50 was larger in CHF+ compared to CHF− (0.32±0.01 and 0.27±0.01; P<0.05) abolishing the initial difference in myofilament Ca2+-sensitivity.
Conclusions: Our data indicate that beta-blocker therapy alters PKA-mediated responses at the myofilament level but has no effect on the histological parameters studied. Beta-blocker therapy may exert a beneficial effect on cardiac function by enhancing the PKA-mediated shift in Ca2+-responsiveness in CHF.