Myosin Heavy Chain Isoform Expression and Contractile Function in Mechanically Unloaded Left Ventricles Following Left Ventricular Assist Device (LVAD) Implantation

Abstract

The ventricles of human myocardium normally express low levels of α myosin heavy chain (MHC) on a predominately β MHC background. However, in heart failure the distribution changes to ∼100% β MHC with virtually undetectable levels of α MHC, a change that has been associated with contractile dysfunction. In cases of severe failure, surgical implantation of a left ventricular assist device (LVAD) may be used as destination therapy and has been previously associated with improvements in contractile function in single myocytes. Here, we used post-LVAD myocardium in which the heart has been explanted for transplantation to test the hypothesis that mechanical unloading of ventricular myocardium increases contraction kinetics, possibly through the re-expression of α MHC. Measurements of the maximal rate of ATP utilization and isometric force in permeabilized multicellular preparations revealed no significant difference between failing myocardium prior to LVAD implantation (pre-LVAD) and post-LVAD myocardium. Tension cost, which is calculated as the rate of ATP utilization divided by the isometric force, was also similar between groups. For comparison, normal myocardium displayed maximal rates of ATP turnover that were approximately 2.5-fold greater than in pre- and post-LVAD myocardium. SDS-PAGE indicated virtually undetectable levels of α MHC in pre- and post-LVAD myocardium, while protein phosphorylation gels revealed significant differences in the basal level of phosphorylation of myosin binding protein-C, TnT, and TnI between both groups. These results suggest that while mechanical unloading of failing myocardium may not cause a re-expression of α MHC, improvements in contractile function following LVAD implantation may be associated in part with alterations in the phosphorylation status of key regulatory proteins. This work supported by NIH RO1-HL61635 (RLM).