. 2019 Oct 28;8(11):1331. doi: 10.3390/cells8111331

Table 3.

MEA based safety testing of drugs without cardiac indication using human induced pluripotent stem cell cardiomyocyte (hiPSC-CM).

Substance	(Site of) Action	Effect	Min. Effective Conc.	Cell Type/ Subtype	Differentiation Protocol	Age/ Maturation State	Platform	Reference
Alfuzosin	Treatment of benign prostatic enlargement, a hERG-channel blocker	Clinical QT prolongation	30 nM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days	MEA	[87,88]
Astemizole	Antihistaminergic drug, H1 receptor antagonist, multi-channel block	Repolarization prolongation/arrhythmogenic effects, hERG channel blockade	3–10 nM	hiPSC-CM iCell™/iCell²™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation (+15–26 days) n/a	MEA	[87,88,93]
BaCl₂	Digitalis like activity, stimulation tonic contraction in muscle, used as contrast agent	Chronotropic effect K⁺ and Ca²⁺ modulation	-	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days	MEA	[87]
Blebbistatin	Myosin II ATPase inhibitor	Increase in beating frequency, beating arrest (30 µM)	1–30 µM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	Min. 32 days of differentiation	MEA	[88]
Carbachol	Parasympathomimetic drug cholinergic agonist K_Ach- channel, glaucoma treatment	Negative chronotropic effects, FPDc prolongation, decrease in beating frequency	10 µM	Double reporter cell line, subtypes: ventricular, atrial, nodal, TBX5 Nkx2.5/hiPSC-CM (iCell™ mixture of ventricular, atrial, nodal cells)	2D n/a	35-40 day of differentiation 32 days of differentiation	Patch clamp, MEA	[21,88]
Chlorpromazine	Anti-psychotic drug, multi-channel block	Early afterdepolarization, beating arrest	10 µM	hiPSC-CM iCell™ mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation	MEA	[88]
Chromanol 293B	IKv7.1 channel Blocker	Prolong FPD in control cells,		LQTS cells and control (patient- derived cells) n/a	3D	30-60 days of differentiation +50 days	MEA	[97]
Cisapride	Prokinetic gastrointestinal drug, multi-channel block	Prolongation of FPD, Repolarization delays/arrhythmogenic effects Prolongation of QT from patients with long QT syndrome	100 nM	hiPSC-CM Cor4U^® and iCell™ mixture of ventricular, atrial, nodal cells Wt iPSC, and from patient with LQTS (n/a)	n/a 3D	10 days after differentiation, min. 32 days of differentiation n/a	MEA, automated patch clamp	[26,87,88,93,98,99]
Clarithromycin	Antibiotic drug	Repolarization prolongation, arrhythmogenic effects	-	hiPSC-CM iCell²™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation n/a	MEA/VSO	[93]
Clozapine	Anti-psychotic drug, multi-channel block	Shortening of FPDc, increase in beat frequency	0.3–1 µM	hiPSC-CM iCell™ mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation	MEA	[88]
Domperidone	Dopamine-antagonist, anti-nausea drug hERG- channel blocker	Repolarization prolongation, arrhythmogenic effects	10 nM	hiPSC-CM iCell™/iCell²™/Cor4U^® mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation n/a	MEA/VSO	[88,93]
Doxorubicin	anthracycline chemotherapy agent	Decrease in FPD, beat frequency and spike amplitude	1 µM	hiPSC-CMs iCell™ 50% ventricular, 10% atrial cells patient derived cells (n/a)	n/a 2D	32 days of differentiation 20–30 days of differentiation	MEA	[100,101]
Droperidol	Neuroleptic drug	Repolarization prolongation, arrhythmogenic effects	-	hiPSC-CM iCell²™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation n/a	MEA/VSO	[93]
Fluoxetine	Anti-depressant drug	Clinical QT prolongation	-	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days	MEA	[87]
Isoproterenol	Bronchodilator	Chronotropic effect, K⁺ and Ca²⁺ Modulation, FPDc shortening, increasing beating frequency	3–100 nM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days	MEA	[87,88]
Loratadine	Anti- histaminergic drug, H1 receptor block, multi-channel block	Increase in beating frequency	0.1–3 µM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation	MEA	[88]
Moxifloxacin	Anti-biotic drug, multi-channel block	Repolarization delay	10 µM	hiPSC-CM iCell™/Cor4U^® (mixture of ventricular, atrial, nodal cells) GE Healthcare (Cytiva™), Stanford Cardiac Institute	n/a	32 days of differentiation +14–24 days n/a	MEA	[85]
Ondansetron	Antiemetic drug, serotonin-receptor block	Repolarization prolongation, arrhythmogenic effects	30 nM	hiPSC-CM iCell² ™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation n/a	MEA/VSO	[93]
Pimozide	Anti-psychotic drug, multi-channel block	Repolarization prolongation/arrhythmogenic effects	3–10 nM	hiPSC-CM iCell™/iCell² ™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days n/a	MEA	[87,93]
Risperidon	Anti-psychotic drug, serotonin-receptor block	Repolarization prolongation	3–30 nM	hiPSC-CM iCell²™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation n/a	MEA	[93]
Sunitinib	Anti-cancer drug, tyrosine kinase inhibitor	FPDc prolongation, early afterdepolarization	0.3–10 µM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation	MEA	[88]
Terfenadine	Anti-histaminergic drug, H1 receptor block	FPDc prolongation, decrease in spike amplitude, repolarization prolongation	100–1000 nM	hiPSC-CM iCell™/iCell²™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation n/a	MEA	[93,98]
Tetrodotoxin (TTX)	Neurotoxic drug, (voltage sensitive) Na_v (1.1, 1.7, 1.5)- channel block	Decrease in slope, depolarization potential and action potential duration	10 µM	hiPSC-CM Cor4U^® mixture of ventricular, atrial, nodal cells	n/a	10 days after differentiation	Automated patch clamp	[26]
Thioridazine	Sedative, anti- psychotic drug, multi-channel block	Repolarization delays/arrhythmogenic effects	100 nM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days	MEA	[87,88]
Tolterodine	Treatment of urinary incontinence, muscarinic receptor antagonist	clinical QT prolongation, early afterdepolarization	100–300 nM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days	MEA	[87]
Vanoxerine	Serotonin-dopamine reuptake inhibitor	Clinical QT prolongation, multiple ion-channel effects, early afterdepolarizations	100 nM	hiPSC-CM iCell™ (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation +15–26 days	MEA	[87]
Vandetanib	Anti-cancer drug for thyroid gland, kinase inhibitor	Repolarization prolongation, arrhythmia like events	0.1–1 µM	hiPSC-CM iCell²™/Cor4U^® (mixture of ventricular, atrial, nodal cells)	n/a	32 days of differentiation n/a	MEA/VSO	[93]