Abstract 17118: Direct Cardiac Myosin Activation Augments Force Production in isolated Cardiomyocytes but might Impair Diastolic Functions
Omecamtiv mecarbil (OM) a novel cardiac myosin activator drug may provide inotropic support for weakened cardiac contractions in systolic HF. The aim of this study was to assess the mechanical effects of OM on the contractile machinery and to analyze those influence on diastolic ventricular functions.
Force measurements were performed in skinned myocyte-sized preparations from LV tissue samples of Wistar rats exposed to test solutions with increasing concentrations of OM to test its concentration dependence on mechanical contractile parameters. Active (Fact) and passive (Fpass) forces, Ca2+ sensitivity of force production (pCa50), cooperativity of the myofilaments (nHill), rate constant of force development and re-development (ktr) were then determined.
In the presence of 0.1 μM OM the Ca2+ sensitivity of force production of cardiomyocytes increased significantly (ΔpCa50: 0.10; n=8; P<0.05) while the Hill-coefficient decreased (nHill in drug free: 2.39±0. 2 and at 0.1 μM: 1.52±0.08; mean±SEM; n=10; P<0.05). OM significantly increased Fpass at 0.3 μM concentration and higher (Fpass in drug free: 1.4±0.14 kN/m2 and at 0.3 μM OM concentration: 2.24±0.31 kN/m2; n=16). Surprisingly, active force development was noticed at drug concentrations of 1 μM and higher in virtually Ca2+-free relaxing solutions as well (Fact in drug free: 0.02±0.01 kN/m2 and at 1 μM drug concentration: 1.11±0.22 kN/m2; pCa 9.0; n=6; P<0.05), whereas OM decreased Fact at the same concentration in activating solution (Factive in drug free: 13.67±1.01 kN/m2 and at 1 μM OM concentration: 8.69±1.00 kN/m2; pCa 4.75; n=8; P<0.05). OM slowed down the kinetics of force development and ktr (rate of force development in drug free: 1.57±0.24 and at 30 nM OM concentration: 1.09±0.12, relative units; n=8; P<0.05). OM application prolonged duration of contraction (t1/2max in drug free 0.89±0.11 s and at 0.3 μM OM concentration: 2.11±0.61 s; n=9; P<0.05).
Our data firstly illustrated OM as a Ca2+-sensitizer using a downstream Ca2+-sensitizing mechanism. As its potential clinical limitation, the drug might impair diastolic function due to Ca2+-sensitization at diastolic Ca2+ concentration, by increasing cardiomyocyte passive forces and by prolongation of duration of contraction.
Author Disclosures: L. Nagy: None. A. Kovacs: None. A. Toth: None. B. Bodi: None. G. Fulop: None. Z. Papp: None.
- © 2014 by American Heart Association, Inc.