Journal
CARDIOVASCULAR RESEARCH
Volume 116, Issue 8, Pages 1487-1499Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvz245
Keywords
Optogenetics; Chronic pacing; Tachypacing; hiPSC-CMs; Tachycardia; Channelrhodopsin-2; Tissue engineering; Action potential
Categories
Funding
- European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant (AFibTrainNet) [675351]
- German Ministry of Education and Research
- German Centre for Cardiovascular Research [81Z0710101]
- European Research Council (ERC AG IndivuHeart)
- Deutsche Forschungsgemeinschaft [HA 3423-5-1]
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Aims Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart tissue (EHT) was used to investigate the effect of chronic tachypacing on hiPSC-cardiomyocytes (hiPSC-CMs). Methods and results To avoid cell toxicity by electrical pacing, we developed an optogenetic approach. EHTs were transduced with lentivirus expressing channelrhodopsin-2 (H134R) and stimulated by 15s bursts of blue light pulses (0.3mW/mm(2), 30ms, 3Hz) separated by 15s without pacing for 3weeks. Chronic optical tachypacing did not affect contractile peak force, but induced faster contraction kinetics, shorter action potentials, and shorter effective refractory periods. This electrical remodelling increased vulnerability to tachycardia episodes upon electrical burst pacing. Lower calsequestrin 2 protein levels, faster diastolic depolarization (DD) and efficacy of JTV-519 (46% at 1 mu mol/L) to terminate tachycardia indicate alterations of Ca2+ handling being part of the underlying mechanism. However, other antiarrhythmic compounds like flecainide (69% at 1 mu mol/L) and E-4031 (100% at 1 mu mol/L) were also effective, but not ivabradine (1 mu mol/L) or SEA0400 (10 mu mol/L). Conclusion We demonstrated a high vulnerability to tachycardia of optically tachypaced hiPSC-CMs in EHT and the effective termination by ryanodine receptor stabilization, sodium or hERG potassium channel inhibition. This new model might serve as a preclinical tool to test antiarrhythmic drugs increasing the insight in treating ventricular tachycardia.
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