Recapitulation of dyssynchrony-associated contractile impairment in asymmetrically paced engineered heart tissue

Justus Stenzig,Marc D Lemoine,Aaltje M.S Stoter,Kinga M Wrona,Marta Lemme,Wesam Mulla,Yoram Etzion,Thomas Eschenhagen,Marc N Hirt

doi:10.1016/j.yjmcc.2021.10.001

Abstract

BackgroundOne third of heart failure patients exhibit dyssynchronized electromechanical activity of the heart (evidenced by a broad QRS-complex). Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. Technically demanding and laborious large animal models have been developed to better predict responders of CRT and to investigate molecular mechanisms of dyssynchrony and CRT. The aim of this study was to establish a first humanized in vitro model of dyssynchrony and CRT. MethodsCardiomyocytes were differentiated from human induced pluripotent stem cells and cast into a fibrin matrix to produce engineered heart tissue (EHT). EHTs were either field stimulated in their entirety (symmetrically) or excited locally from one end (asymmetrically) or they were allowed to beat spontaneously. ResultsAsymmetrical pacing led to a depolarization wave from one end to the other end, which was visualized in human EHT transduced with a fast genetic Ca2+-sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca2+-signal throughout the EHT. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5–0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Contractile dysfunction that can be evoked by an increased afterload was aggravated in the asymmetrically paced group. Consistent with reports from paced dogs, p38MAPK and CaMKII-abundance was higher under asymmetrical than under symmetrical pacing while pAKT was considerably lower. ConclusionsThis model allows for long-term pacing experiments mimicking electrical dyssynchrony vs. synchrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT.

Highlights

The prevalence of heart failure (HF) is rising worldwide
Asymmetrical pacing leads to dyssynchronous excitation of engineered heart tissue (EHT)
Different pacing units were tested for dyssynchronous pacing

Summary

Introduction

The prevalence of heart failure (HF) is rising worldwide. Main rea sons are aging of the population and the improved treatment of hyper tension, valvular disease and coronary disease, which allows patients to survive these conditions longer, though often at the expense of a later development of HF [1]. About one third of heart failure patients exhibit electrical dyssynchrony (evidenced by a QRS-complex >120 ms in the surface ECG), which leads to ventricular mechanical dyssynchrony and worsens clinical outcome [2]. Cardiac resynchronization therapy (CRT) in the form of biventricular pacing improves cardiac output and clinical outcome of responding patients. To investigate acute and long-term functional effects, spontaneously beating human EHTs (0.5–0.8 Hz) were divided into a non-paced control group, a symmetrically and an asymmetrically paced group, each stimulated at 1 Hz. Symmetrical pacing was clearly superior to asymmetrical pacing or no pacing regarding contractile force both acutely and even more pronounced after weeks of continuous stimulation. Conclusions: This model allows for long-term pacing experiments mimicking electrical dyssynchrony vs syn chrony in vitro. Combined with force measurement and afterload stimulus manipulation, it provides a robust new tool to gain insight into the biology of dyssynchrony and CRT

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