Table 5.

A comparison of the pharmacological responses of human adult and fetal CMs/myocardium and hPSC-CMs.

Drug Name	Target	Effect in Human Adult CMs/Myocardium	Effect in Human Fetal CMs/Myocardium	Effect in hPSC-CMs
Epinephrine (EPI) Norepinephrine (NOR) Isoproterenol (ISO)	β-adrenergic receptor agonist	Positive inotropic, chronotropic and lusitropic effects [1, 2] Right-shifted force-Ca2+ relationship (3μM ISO; RV trabecular skinned and intact muscle) [3] EC50 = 11–80nM (ISO; inotropic; LV muscle strips) [4, 8] EC50 = 1.21–2.43 μM (NOR; inotropic; LV papillary muscle strips) [8]	Positive isotropic effect (NOR, ISO; 12–22 week fetal atria) [9] Gestation-dependent ↑ in inotropic effects (0.1μM ISO; 20% at week 12 to 150% at week 22; fetal atria) [9] ↑peak Ca2+ transient and Ca2+ transient decay (ISO; monolayer) [10] Positive chronotropic effect (EPI, NOR, ISO; 5–24 week fetal heart) [11]	Positive chronotropic effect (ISO; hESC-CMs) [12–14] EC50 = 12.9nM (ISO; chronotropic; hESC EBs) [15]
Carbachol	Cholinergic agonist	Negative inotropic, chronotropic and dromotropic effects [16–18] EC50 = 140nM (inotropic; LV papillary muscle strips) [19]	Negative inotropic effect (0.1–10μM; 12–20 week fetal hearts) [20] No chronotropic effect (100μM; 16–17 week ventricular CMs) [14] Gestation-dependent ↓ in repolarization time (10μM, no effect in 12–13 week hearts; 10μM, 21% ↓ in 14 week hearts; 1–10μM, 26–50% ↓ in 16–20 week hearts)	Negative chronotropic (hESC-CMs) [14]
Verapamil	KV11.1 (hERG) & CaV1.2 channel antagonist	Negative inotropic, chronotropic and dromotropic IC50 = 143nM (KV11.1; transfected cell line) [21, 22] IC50 = 0.24–4.3μM (CaV1.2; transfected cell line) [23, 25] IC50 = 0.32–1.21μM (inotropic; LV papillary muscle strips) [26] IC50 = 89–170nM (inotropic; RA trabeculae muscle strips) [27]	Inhibition of AP propagation (5μM; 16–17 week ventricular CMs) [14]	Inhibition of AP propagation (5μM; hESC-CMs) [14] Negative inotropic, positive chronotropic and ↓FPD (0.01–0.3μM; hiPSC-CM monolayer) [22, 28] Negative chronotropic and ↓FPD (1–5μM; hiPSC-CM clusters) [29] IC50 = 62–80nM (L-type Ca2+ channel; hiPSC-CM monolayer) [30] IC50 = 73–120nM (L-type Ca2+ channel; hESC-CM monolayer) [30]
Nifedipine	L-type Ca2+ channel antagonist	Negative inotropic effect [26, 27,31] IC50 = 16–24nM (CaV1.2; transfected cell line) [24] IC50 = 50–200nM (inotropic; ventricular muscle) [26, 31] IC50 = 76–166nM (inotropic; RA trabeculae muscle strips) [27]	Negative inotropic effect (10–20μM; 7–9 week beating clusters) [32] Blocked L-type Ca2+ current (10μM; 20 week CMs) [33]	Negative inotropic, positive chronotropic and ↓FPD (0.003–1μM; hiPSC-CM monolayer) [22, 28] ↓APD (1μM; hESC-CMs, hiPSC-CMs) [34] Blocked AP propagation (10μM; hESC-CMs, hiPSC-CMs) [34] IC50 = 39nM (Ca2+ current; hiPSC-CMs) [35] IC50 = 2–4nM (L-type Ca2+ channel; hiPSC-CM monolayer) [30] IC50 = 5–7nM (L-type Ca2+ channel; hESC-CM monolayer) [30]
Nisoldipine	CaV1.2 channel antagonist	Negative inotropic effect (ventricular muscle) [31] IC50 = 67–81nM (CaV1.2; transfected cell line) [36] IC50 = 200–400nM (inotropic; ventricular muscle) [31]	Blocked L-type Ca2+ current (1–2μM; 13–24 week CMs) [37, 38]	Inhibition of AP propagation and contraction (1μM; hESC-CM EBs) [39]
Thapsigargin	SERCA antagonist	Negative inotropic effect [40] ↑TTP and RT90 (1μM; LV CMs) [41] Negative inotropic effect at high frequency, resulting in flattened FFR (1μM; LV CMs) [41]		↓ Ca2+ transient amplitude (1–20μM; hiPSC-CMs) [42] ↓ Ca2+ transient amplitude in subset of cells (0.5μM; 35–40%; hESC-CMs) [43] ↓maximal Ca2+ decay velocity (0.5μM; hESC-CMs) [43]
Caffeine	Ryanodine receptor agonist	Positive inotropic and chronotropic effect [44] Left-shifted force-Ca2+ relationship (10mM; RV trabecular skinned fiber and intact muscle) [3] Positive inotropic effect (>0.5mM) and ↑+dF/dt (20mM; RV skinned fibers) [45]	↑Ca2+ transient amplitude in subset of cells (65%; 10mM; 16–18 week LV CMs) [43]	↑Ca2+ transient amplitude (10–40mM; hiPSC-CMs) [42] ↑Ca2+ transient amplitude in subset of cells (35–40%; 10mM; hESC-CMs) [43]
E-4031	KV11.1 (hERG) channel antagonist	↑APD [46, 47] ↓IK current amplitude (5μM; RV CMs) [47] IC50 = 7–32nM (KV11.1; transfected cell line) [22, 25]	Gestation-dependent effect on AP propagation (1μM; no effect on APD in week 5 CMs; ↑APD in week 7.5–9.5 CMs) [48] Irregular AP pattern (1μM; week 5–9.5 CMs) [48] ↓AP amplitude and ↑inter AP interval (1μM; week 5–7 fetal CMs) [48]	↑APD, EADs and ↑short-term variability in APD (1μM; hESC-CMs) [49] ↑APD and EADs (12nM; hiPSC-CM clusters) [50]
Terfenadine	K+, Na+, and Ca2+ cardiac ion channel antagonist	↓IK current, ↑rate of current decay and ↓current amplitude (3μM; KV1.5; transfected cell line, whole cell) [51] IC50 = 367nM (KV1.5; transfected cell line, cell patch) [51] IC50 = 56 nM (KV11.1; transfected cell line) [52] IC50 = 26nM (KV11.1; atrial CMs) [53] Blocked IKr and Ito currents (atrial CMs and KV1.5 transfected cell line) [54] Frequency-dependent inhibition of L-type calcium current (IC50 = 185nM at 1Hz; IC50 = 750nM at 0.2Hz; RA CMs) [55] ↑Na+/Ca2+-exchange current (INCX) frequency (1μM; atrial CMs) [55] IC50 = 1.7–8.1μM (NaV1.5; atrial CMs) [53]		↑APD (30nM; hiPSC-CMs) [35] ↑FPD (100nM; hiPSC-CM monolayer) [22] ↓AP amplitude with (1μM; hiPSC-CM monolayer) [22] Negative chronotropic effect (0.01–0.3μM; hiPSC-CM monolayer) [28] Time-and dose-dependent irregular AP pattern (0.3μM; hiPSC-CM monolayer) [28] Blocked AP propagation (1μM; hiPSC-CM monolayer) [28]
Tetrodotoxin	NaV1.5 channel antagonist	Negative chronotropic effect [56, 57] ↑APD, ↓Vmax (2μM; papillary muscle) [58] IC50 ≥ 1μM [59, 60]	Insensitive to TTX (10μM; 10 week ventricular CMs) [61] Cessation of contraction (0.63μM; 13–15 week left atria) [62]	Blocked AP propagation in a subset of cells (100μM; hiPSC-CMs) [34] Blocked AP propagation in most cells (10μM; hESC-CMs) [34]
Lidocaine	Na+ channel antagonist	↑APD, ↓Vmax (ventricular muscle) [63] IC50 = 34–38μM (Na+ current; transfected cell line) [64]		Blocked Na+ influx, ↓conduction velocity, no effect on APD (hiPSC-CMs) [29] Blocked AP propagation (50μM hiPSC-CMs) [34] Blocked AP propagation (1mM; hESC-CMs) [34] ↓Vmax, ↑APD and caused MDP depolarization (500μM; hESC-CMs) [34]

LV = left ventricle; RV = right ventricle; RA = right atria; AP = action potential; APD = action potential duration; FPD = field potential duration; FFR = force-frequency relationship; +dF/dt = maximal rate of force increase; EAD = early afterdepolarization; Vmax = depolarization velocity; MDP = maximum diastolic potential

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