Table 3.
Overview of published drug testing in iPSC-CM arrhythmia models.
| Drug | Mode of Action | Disease Gene Mutation |
Effect on Phenotype | Ref. |
|---|---|---|---|---|
| Mexiletine analogues | Class 1B antiarrhythmic drug, inhibits INa | LQT SCN5A p.(Phe1473Cys), p.(Asn406Lys) |
Mexiletine: INaL inhibition and APD shortening at lower dose but modest prolongation at higher dose and proarrhythmic response Analogues ‘MexA2′ and ‘MexA5′: more potent and selective for INaL over INaP and IKr, Shortening of APD and suppression of arrhythmia Analogues ’13, 14, 25′: shortening of APD and no EADs |
[76,77] |
| Verapamil, Lidocaine |
Calcium channel blocker Sodium channel blocker |
LQT KCNQ1 p.(Gly219Glu)/ TRPM4 p.(Thr160Met) |
Reduction in APD | [78] |
| Telmisartan, GW0742 | Agonists of the PPARδ pathway, stabilise the active PKA-phosphorylated state of hERG | LQT KCNH2 p.(Ala561Thr) |
Reduction in APD50, APD90 and triangularisation | [79] |
| NS1643 | Change the voltage dependence of inactivation of hERG | LQT KCNH2 p.(Ala561Thr) |
Reductions in APD50, APD90 and triangularisation | [79] |
| Lumacaftor | Trafficking chaperone during protein folding | LQT KCNH2 Trafficking p.(Ala561Val), (IVS9-28A/G), p.(Asn633Ser), p.(Arg685Pro), p.(Gly604Ser) Synthesis p.(Ser428X), p.(Arg366X) |
Trafficking variants Increased membrane localisation, reduced cFPD and APD90, increase in IKr current densities, reduced calcium transient irregularities and frequency p.(Gly604Ser): increased membrane expression, no effect on APD90 Other variants Reduced calcium transient irregularities and frequency, no effect on cFPD |
[80,81] |
| ICA-105574 | Type II IKr activator (impairs transition to the inactivated state) | LQT KCNH2 p.(Thr983Ile), p.( Ala422Thr) |
Increased IKr, shortening APD/cFPD in patient and control, shortened calcium transient, at higher concentrations (10–30 µM): cessation of the spontaneous calcium transients | [11,82] |
| Ajmaline | Class IA anti-arrhythmic drug inhibits INa, Ito or IKr | BrS Unknown mutation |
No difference between patient and control | [83] |
| BrS SCN10A p.(Arg1268Gln)/p.(Arg1250Gln) |
Prolonged APD50 and APD90, reduced APA and Vmax | [84] | ||
| BrS SCN1B p.(Leu210Pro)/ p.(Pro213Thr) |
Reduced APA and Vmax | [85] | ||
| Cilostazol, Milrinone | Phosphodiesterase III inhibitors, increase ICa and suppress Ito | BrS SCN5A p.(Ser1812X) |
Reduction in Ito, decreased arrhythmic beating, no EAD- or EAD-triggered activities | [17] |
| Bisoprolol | Beta blocker | BrS CACNB2 p.(Ser142Phe) |
Reduced arrhythmic events and reduced variation in the beat-to-beat interval time at 30 nM | [15] |
| Quinidine | Class I antiarrhythmic agent, blocking Ito | BrS CACNB2 p.(Ser142Phe) |
Reduced arrhythmic events | [15] |
| BrS SCN5A p.(Val1405Met) SCN1B p.(Ala197Val) |
Elimination of arrhythmic events (EAD, DAD), Vmax, APA, and RMP reduced in control and patients’ groups | [16] | ||
| SQT KCNH2 p.(Thr618Ile) |
Prolonged APD | [20] | ||
| SQT KCNH2 p.(Asn588Lys) |
Reduced Vmax, prolonged APD, elimination of arrhythmic events | [18] | ||
| Toxin BmKKx2 | Selective IKr blocker | SQT KCNH2 p.(Thr618Ile) |
Prolonged APD | [20] |
| Ivabradine, Ajmaline, Mexiletine |
Inhibitor of the pacemaker funny current Class IA anti-arrhythmic drug, inhibits INa, Ito or IKr Class 1B antiarrhythmic drug |
SQT KCNH2 p.(Asn588Lys) |
Prolonged APD90, reduced number of arrhythmic events | [86] |
| MiCUps (efsevin, kaempferol, ezetimibe, disulfiram) |
Mitochondrial Ca2+ uptake enhancers | CPVT RYR2 p.(Ser406Leu) |
Reduced number of cells displaying Ca2+ waves and reduced frequency of Ca2+ waves | [87] |
| CPVT unknown mutation |
Reduced Ca2+ waves | [88] | ||
| Autocamtide-2-related inhibitory peptide (AIP) | Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitory peptide | CPVT RYR2 p.(Ser404Arg)/p.(Asn658Ser), p.(Gly3946Ser)/p.(Gly1885Glu) |
Reduced abnormal Ca2+ transients, reduced frequency of Ca2+ sparks, restored regular and spontaneous Ca2+ transients | [89] |
| Tetracaine derivative EL20 | Targeted inhibition of RyR2 | CPVT RYR2 p.(Arg176Gln) |
Reduced the Ca2+ spark frequency, prevented pacing-evoked Ca2+ oscillations | [24] |
| Nadolol, Flecainide |
Non-selective beta blocker Class IC anti-arrhythmic agent inhibits INa and IKr |
CPVT RYR2 p.(Phe13Leu), p.(Leu14Pro), p.(Arg15Pro), p.(Arg176Gln) |
Reduced Ca2+ transient amplitude, reduced spontaneous Ca2+ release, reduced Ca2+ sparking activity, decreased irregularities in beat period and spontaneous beat rate | [26] |