Recapitulation of dyssynchrony-associated contractile impairment in asymmetrically paced engineered heart tissue. (February 2022)

• Record Type: Journal Article
• Authors: Stenzig, Justus; Lemoine, Marc D.; Stoter, Aaltje M.S.; Wrona, Kinga M.; Lemme, Marta; Mulla, Wesam; Etzion, Yoram; Eschenhagen, Thomas; Hirt, Marc N.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 163(2022)
• Page Start: 97
• Page End: 105
• Publication Date: 2022-02
• Subjects: Cardiac dyssynchrony -- Tissue engineering -- Engineered heart tissue -- Pacing -- Resynchronization; AE Afterload enhancement or afterload enhanced -- CRT Cardiac resynchronization therapy -- DHF Dyssynchrony associated heart failure -- EHT Engineered heart tissue -- fps Frames per second -- hEHT Human engineered heart tissue -- HF Heart failure -- HiPSC Human induced pluripotent stem cell -- LBBB Left bundle branch block -- LV Left ventricular -- MOI Multiplicity of infection -- rEHT Rat engineered heart tissue -- RV Right ventricular; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.10.001
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: One 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. Methods: Cardiomyocytes 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. Results: Asymmetrical pacing led to a depolarization wave from one end to the other end, which was visualized in human EHT transduced with a fast genetic Ca 2+ -sensor (GCaMP6f) arguing for dyssynchronous excitation. Symmetrical pacing in contrast led to an instantaneous (synchronized) Ca 2+ -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. Conclusions: This 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. Graphical abstract: Unlabelled Image Highlights: Cardiac electrical dyssynchrony can be modeled in vitro in engineered heart tissue. Asymmetrically paced engineered heart tissue recapitulates important protein markers of cardiac dyssynchrony. Asymmetrical vs. symmetrical pacing in vitro allows for studying synchrony in cardiomyocytes in an isolated manner.