The Effects of Mechanical Preload on Transmural Differences in Mechano-Calcium-Electric Feedback in Single Cardiomyocytes: Experiments and Mathematical Models.

Anastasia Khokhlova,Gentaro Iribe,Pavel Konovalov,Olga Solovyova,Leonid Katsnelson

doi:10.3389/fphys.2020.00171

Abstract

Transmural differences in ventricular myocardium are maintained by electromechanical coupling and mechano-calcium/mechano-electric feedback. In the present study, we experimentally investigated the influence of preload on the force characteristics of subendocardial (Endo) and subepicardial (Epi) single ventricular cardiomyocytes stretched by up to 20% from slack sarcomere length (SL) and analyzed the results with the help of mathematical modeling. Mathematical models of Endo and Epi cells, which accounted for regional heterogeneity in ionic currents, Ca2+ handling, and myofilament contractile mechanisms, showed that a greater slope of the active tension–length relationship observed experimentally in Endo cardiomyocytes could be explained by greater length-dependent Ca2+ activation in Endo cells compared with Epi ones. The models also predicted that greater length dependence of Ca2+ activation in Endo cells compared to Epi ones underlies, via mechano-calcium-electric feedback, the reduction in the transmural gradient in action potential duration (APD) at a higher preload. However, the models were unable to reproduce the experimental data on a decrease of the transmural gradient in the time to peak contraction between Endo and Epi cells at longer end-diastolic SL. We hypothesize that preload-dependent changes in viscosity should be involved alongside the Frank–Starling effects to regulate the transmural gradient in length-dependent changes in the time course of contraction of Endo and Epi cardiomyocytes. Our experimental data and their analysis based on mathematical modeling give reason to believe that mechano-calcium-electric feedback plays a critical role in the modulation of electrophysiological and contractile properties of myocytes across the ventricular wall.

Highlights

Over the past 30 years, the main concept of the studies on regional heterogeneity in the healthy heart has maintained that transmural differences are required in the myocyte function to effectively optimize the ejection of blood by the heart (Katz and Katz, 1989; Solovyova et al, 2016)
Comparing the parameters of cell contractions at slack end-diastolic SL (EDSL), we found the amplitude of auxotonic tension to be higher and the time to peak contraction (Tmax) to be greater in Endocardial and subendocardial (Endo) cells compared with epicardial and subepicardial (Epi) ones (Figures 2, 3)
This study was designed to examine the effects of mechanical preload on mechano-calcium-electric feedback in single cardiomyocytes isolated from the Endo and Epi layers of the central region of mouse free left ventricular (LV) wall

Summary

Introduction

Over the past 30 years, the main concept of the studies on regional heterogeneity in the healthy heart has maintained that transmural differences are required in the myocyte function to effectively optimize the ejection of blood by the heart (Katz and Katz, 1989; Solovyova et al, 2016). A larger Na+ current, INa, in the subendocardium underlies the higher AP upstroke velocity in Endo cells, whereas a greater transient outward current, Ito, and a smaller L-type Ca2+ current, ICaL, and Na+–Ca2+ exchanger current, IN aCa, both (Wan et al, 2005; Xu et al, 2012) underlie the higher repolarization rate and shorter APD in Epi cells (Veerman et al, 2017). These differences in repolarization duration lead to EndoEpi differences in the Ca2+ transient and force developed. There are several cross-links, electromechanical, mechanocalcium, and mechano-electric, that underlie the manifestation of transmural heterogeneity in the cellular function

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