Abstract
Heart failure (HF) often includes changes in myocardial contractile function. This study addressed the myofibrillar basis for contractile dysfunction in failing human myocardium. Regulation of contractile properties was measured in cardiac myocyte preparations isolated from frozen, left ventricular mid-wall biopsies of donor (n = 7) and failing human hearts (n = 8). Permeabilized cardiac myocyte preparations were attached between a force transducer and a position motor, and both the Ca2+ dependence and sarcomere length (SL) dependence of force, rate of force, loaded shortening, and power output were measured at 15 ± 1°C. The myocyte preparation size was similar between groups (donor: length 148 ± 10 μm, width 21 ± 2 μm, n = 13; HF: length 131 ± 9 μm, width 23 ± 1 μm, n = 16). The maximal Ca2+-activated isometric force was also similar between groups (donor: 47 ± 4 kN⋅m-2; HF: 44 ± 5 kN⋅m-2), which implicates that previously reported force declines in multi-cellular preparations reflect, at least in part, tissue remodeling. Maximal force development rates were also similar between groups (donor: k tr = 0.60 ± 0.05 s-1; HF: k tr = 0.55 ± 0.04 s-1), and both groups exhibited similar Ca2+ activation dependence of k tr values. Human cardiac myocyte preparations exhibited a Ca2+ activation dependence of loaded shortening and power output. The peak power output normalized to isometric force (PNPO) decreased by ∼12% from maximal Ca2+ to half-maximal Ca2+ activations in both groups. Interestingly, the SL dependence of PNPO was diminished in failing myocyte preparations. During sub-maximal Ca2+ activation, a reduction in SL from ∼2.25 to ∼1.95 μm caused a ∼26% decline in PNPO in donor myocytes but only an ∼11% change in failing myocytes. These results suggest that altered length-dependent regulation of myofilament function impairs ventricular performance in failing human hearts.
Highlights
Measurements of twitch kinetics or action potentials and recording of X-Y-coordinates of the individual plated hESC-CMs was followed by fluorescence-insitu-hybridization against MYH6 and MYH7-mRNAs, and by immunofluorescent staining of a and b-myosin heavy chain (MyHC) proteins
582-Pos In Human Embryonic Stem Cell-Derived Cardiomyocytes Twitch Kinetics, Action Potential Parameters and MyH-mRNA Fractions Are Independent of the Expressed Myosin Heavy Chain Isoform Natalie Weber1, Kathrin Kowalski1, Tim Holler1, Ante Radocaj1, Martin Fischer2, Jeanne de la Roche2, Stefan Thiemann2, Kristin Schwanke3, Alexander Lingk1, Uwe Krumm1, Birgit Piep1, Ullrich Martin3, Robert Zweigerdt3, Bernhard Brenner1, Theresia Kraft1. 1Institute of Molecular & Cell Physiology, Hannover Medical School, Hannover, Germany, 2Institute of Neurophysiology, Hannover Medical School, Hannover, Germany, 3Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Hannover, Germany
We found that the majority of single hESC-CMs, though expressing pure bMyHC, had still detectable variable fractions of MYH6-mRNA
Summary
Measurements of twitch kinetics or action potentials and recording of X-Y-coordinates of the individual plated hESC-CMs was followed by fluorescence-insitu-hybridization against MYH6 and MYH7-mRNAs, and by immunofluorescent staining of a and b-MyHC proteins. Binding of cMyBP-C’s C0C3 N-terminal domains to regulated actin enhanced myosin association at low calcium levels. 581-Pos Regulation of Myofilament Contractile Function in Human Donor and Failing Hearts Kerry S.
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