Abstract 1468: Opposite Effects Of Chronic Beta-blocker Therapy On Myofilament Function In Heart Failure With Reduced Or Normal Left Ventricular Ejection Fraction
Large clinical trials have shown that β-blockers reduce morbidity and mortality in patients with reduced left ventricular ejection fraction (LVEF), while the effectiveness of β-blockers in patients with normal LVEF is not known. Improved myofilament function may be part of the beneficial effects of β-blocker therapy. We investigated if cardiomyocyte contractility is altered in patients with normal and reduced LVEF treated with β-blockers. Isometric force was measured in single permeabilized cardiomyocytes isolated from LV catheter biopsies from heart failure patients free of coronary artery disease with normal LVEF (55±3%; HFNEF) and reduced LVEF (33±2%; HFREF). Patients were treated with β-blockers (HFNEF+β, n=14/HFREF+β, n=13) or received no β-blockers (HFNEF-β, n=14/HFREF-β, n=12). Active (Fact) and passive (Fpas) force were measured at baseline and saturated β-adrenergic stimulation, mimicked by application of the active subunit of protein kinase A (PKA). At baseline, Fact and Fpas were higher in HFNEF+β than in HFNEF-β (both P<0.05), while no differences were observed between the HFREF groups (Table⇓). PKA increased Fact in both patient groups without β-blockers and decreased Fpas in all groups (all P<0.05). However, after PKA Fpas remained higher in HFNEF+βcompared to HFNEF-β (P<0.05). Electron microscopy revealed that cardiomyocyte myofibrillar density was not different in patients with reduced LVEF, while it was significantly higher in HFNEF patients treated with β-blockers (HFNEF+β, 49.5±1.8 vs. HFNEF-β, 44.0±1.3; P<0.05). Paradoxically our data show that β-blockers increase the maximal force generating capacity of myoflaments in patients with normal LVEF, but not in patients with reduced LVEF. Moreover, in HFNEF β-blockers may increase passive cardiomyocyte stiffness, which is no longer corrected to normal values upon PKA treatment. The increased Fact and Fpas in HFNEF+β may be explained by increased myofibrillar density.