The Effects of Mechanical Load on Transmural Differences in Mechano-Electric Feedback in Single Cardiomyocytes

Abstract

We have shown previously that subendocardial (ENDO) and subepicardial (EPI) cardiomyocytes isolated from the mouse left ventricle (LV) have different mechanical responses to changes in preload (stretch) to the cells (Khokhlova et al., 2018). However, the main limitation of previous study was small amount of stretch (about 3.5%) applied. Here we resolved the limitation applying up to 20% of stretch and used our new electromechanical ENDO and EPI mathematical models to predict effects of mechanical load on electrophysiological function of ENDO and EPI cells. Various preloads imposed via axial stretch were applied to the mouse LV cells using carbon fiber technique for single myocytes (Iribe et al., 2014). To simulate experimentally obtained results and to predict mechanisms underlying the cellular response to change in preload we developed mathematical models of the mouse ENDO and EPI cells. In consistency with the previous results, under auxotonic contractions at low preload (unstretched cells), time to peak contraction (Tmax) was significantly longer in ENDO cells than in EPI cells. An increase in preload (stretch) prolonged Tmax in both cell types, however, the slope of “Tmax - sarcomere stretch” relationship was significantly higher in EPI cells, demonstrating greater contraction sensitivity of EPI cells to the stretch. Our mathematical cellular models reproduced the experimental results when we accounted for the ENDO/EPI differences in the parameters of cooperativity of calcium activation of myofilaments. The models predicted greater prolongation of action potential in EPI cells under high preload. Our results suggest that mechanical load changes transmural gradient in contraction of ENDO and EPI cardiomyocytes that in turn affect the gradient in electrophysiological function via mechano-calcium-electric feedback. Supported by The Russian Science Foundation (#18-74-10059) and JSPS KAKENHI (#16K12878).