Abstract
SummaryCardiomyocytes (CMs) generated from human induced pluripotent stem cells (hiPSCs) are under investigation for their suitability as human models in preclinical drug development. Antiarrhythmic drug development focuses on atrial biology for the treatment of atrial fibrillation. Here we used recent retinoic acid-based protocols to generate atrial CMs from hiPSCs and establish right atrial engineered heart tissue (RA-EHT) as a 3D model of human atrium. EHT from standard protocol-derived hiPSC-CMs (Ctrl-EHT) and intact human muscle strips served as comparators. RA-EHT exhibited higher mRNA and protein concentrations of atrial-selective markers, faster contraction kinetics, lower force generation, shorter action potential duration, and higher repolarization fraction than Ctrl-EHTs. In addition, RA-EHTs but not Ctrl-EHTs responded to pharmacological manipulation of atrial-selective potassium currents. RA- and Ctrl-EHTs’ behavior reflected differences between human atrial and ventricular muscle preparations. Taken together, RA-EHT is a model of human atrium that may be useful in preclinical drug screening.
Highlights
More than 33 million people worldwide suffer from atrial fibrillation (AF), with increasing prevalence (Chugh et al, 2014)
Antiarrhythmic drug development focuses on atrial biology for the treatment of atrial fibrillation
engineered heart tissue (EHT) from standard protocol-derived human induced pluripotent stem cells (hiPSCs)-CMs (Ctrl-EHT) and intact human muscle strips served as comparators
Summary
More than 33 million people worldwide suffer from atrial fibrillation (AF), with increasing prevalence (Chugh et al, 2014). Pulmonary vein isolation by catheter ablation and antiarrhythmic drugs represent two treatment options. While ablation is not always effective, in advanced forms of the disease, the available antiarrhythmic drugs have limited efficacy and cause adverse effects (Schotten et al, 2011). Drug development is hampered by the difficulty in isolating and maintaining human atrial cardiomyocytes (CMs). Animal models do not accurately represent the physiology of human CMs, limiting their predictive power (Denayer et al, 2014). CMs generated from human induced pluripotent stem cells (hiPSCs) may offer a platform to study disease mechanism and evaluate novel drugs. Recent developments aim at establishing hiPSC-derived models of predominantly atrial-like myocytes
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