The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity
Abstract
:1. Introduction
2. The Potential of hiPSC-CMs and the Substantial Issues with Maturation
2.1. Standardisation Procedures
2.2. The Need for Co-Cultures and Subtype-Specific Cultures
2.3. The Benefits of Gene-Editing Technology
3. In Vitro Cardiotoxicity
Cardiotoxic Effects and Their Detection
4. Scaffolds in Cardiac Applications
5. Heart-on-a-Chip Platforms
6. In Silico Models
7. Disease Modelling
7.1. Atrial Fibrillation
7.2. Hypertrophy
7.3. Channelopathies
7.4. Ischaemia/Hypoxia
8. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AF | atrial fibrillation |
AI | artificial intelligence |
AP | action potential |
APA | action potential amplitude |
APD | action potential duration |
BPA | bisphenol A |
BPAF | bisphenol F |
BPM | beats per minute |
BR | beat rate |
CAST | Cardiac Arrhythmia Suppression Trial |
CF | cardiac fibroblast |
CiPA | Comprehensive in vitro Proarrhythmia Assay |
CL | cycle length |
CM | cardiomyocyte |
cTnT | cardiac troponin T |
CVD | cardiovascular disease |
DAPI | 4′,6-diamidino-2-phenylindole |
DL | deep learning |
ECG | electrocardiogram |
ECM | extracellular matrix |
ECT | engineered cardiac tissues |
EHT | engineered heart tissue |
EMV | endothelial cell-derived microvesicle |
ESC | embryonic stem cell |
FDA | US Food and Drug Administration |
FPD | field potential duration |
GATA4 | GATA binding protein 4 |
hESC-CM | human embryonic stem cell-derived cardiomyocyte |
hiPSC | human induced pluripotent stem cell |
hiPSC-CM | human induced pluripotent stem cell-derived cardiomyocyte |
hiPSC-aCMs | human induced pluripotent stem cell-derived atrial cardiomyocyte |
HOC | heart-on-a-chip |
HUVEC | human umbilical vein endothelial cells |
IDE | interdigitated electrodes |
LDH | lactate dehydrogenase |
LQTS | long QT syndrome |
MCS | maximum contraction speed |
MEA | multielectrode array |
ML | machine learning |
MRS | maximum relaxation speed |
NFAT | nuclear factor of activated T-cells |
NGS | next-generation sequencing |
Nkx2.5 | homeobox protein Nkx2.5 |
OAP | optical action potential |
PKC | protein kinase C |
RMP | resting membrane potential |
ROS | reactive oxygen species |
SERCA | sarcopendoplasmic reticulum calcium-ATPase |
SK | small conductance calcium-activated potassium channel |
SNP | single nucleotide polymorphism |
SQTS | short QT syndrome |
SR | sarcoplasmic reticulum |
SWORD | Survival with oral d-sotalol Trial |
TdP | torsade de pointes type polymorphic ventricular tachyarrhythmia |
VEGF | vascular endothelial growth factor |
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Assay | Method | Measured Parameters | Possible Applications | References |
---|---|---|---|---|
Field potential measurement | Multielectrode array systems | stand-alone FPD sodium spike amplitude RR-interval (beat-to-beat interval) spontaneous BR network analysis (syncytium) | direction and magnitude of depolarisation QT interval, beat-to-beat variability heart rate propagation and contractility | [92,93] |
CardioExcyte 96 | FPD, impedance | QT interval on ECG, prediction of TdP risk | [94] | |
Action potential measurement | CellOPTIQ | depolarisation time and APD by voltage sensitive dye, spontaneous activity | assessing hiPSC-CM function on hydrogels, drug evaluation | [95] |
CardioExcyte 96 | myocardial cell activity, BPM, FPD | risk prediction model for TdP in hiPSC-CMs, tool for compound-induced arrhythmias | [94] | |
Patch-clamp/ Sharp microelectrode | APD, APA, Vmax, ion currents, RMP | electrophysiological characterisation, drug-induced arrhythmias, sequential pharmacological dissection | [96,97,98] | |
µGMEA | APD, APA, Vmax, FPD, RR-interval | long-term electrophysiological recordings, dynamic changes in transmembrane potential of hiPSC-CMs in network, spatial heterogeneity | [99] | |
Optical mapping | OAP, CL, d (−F)/dtmax, APD | detection of propensities for drug-induced tachyarrhythmias | [100] | |
Calcium measurement | CellOPTIQ | intracellular Ca concentration, Ca transient amplitude, Tau | assessing hiPSC-CM function on hydrogels, drug evaluation | [95] |
Epifluorescence with simultaneous electrophysiology | intracellular Ca concentration, Ca transient amplitude, contractility, Tau, SR content, release kinetics, systolic and diastolic calcium levels | characterisation and drug-induced arrhythmias, Ca flux balance | [101,102,103] | |
FLIPR Tetra system | Ca transient peak frequency, amplitude, rise time and decay time | cardiotoxicity assessment of a compound (contractility and arrhythmogenic potential) | [104] | |
Contractile function | CellOPTIQ | contraction amplitude, duration, relaxation duration | assessing hiPSC-CM function on hydrogels, drug evaluation | [95] |
Cell motion analysis | MCS, MRS, contraction-relaxation duration, BR | detection of drug-induced changes in contractility | [105] | |
Single cell contraction measurement | single cell shortening, BR | assessing drug effects | [96] | |
Video-based analysis | BR, beating velocity, maximum contraction and relaxation | detection of dysfunctional CM contractility | [106] |
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Kistamás, K.; Lamberto, F.; Vaiciuleviciute, R.; Leal, F.; Muenthaisong, S.; Marte, L.; Subías-Beltrán, P.; Alaburda, A.; Arvanitis, D.N.; Zana, M.; et al. The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity. Int. J. Mol. Sci. 2024, 25, 9186. https://doi.org/10.3390/ijms25179186
Kistamás K, Lamberto F, Vaiciuleviciute R, Leal F, Muenthaisong S, Marte L, Subías-Beltrán P, Alaburda A, Arvanitis DN, Zana M, et al. The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity. International Journal of Molecular Sciences. 2024; 25(17):9186. https://doi.org/10.3390/ijms25179186
Chicago/Turabian StyleKistamás, Kornél, Federica Lamberto, Raminta Vaiciuleviciute, Filipa Leal, Suchitra Muenthaisong, Luis Marte, Paula Subías-Beltrán, Aidas Alaburda, Dina N. Arvanitis, Melinda Zana, and et al. 2024. "The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity" International Journal of Molecular Sciences 25, no. 17: 9186. https://doi.org/10.3390/ijms25179186