Table 1.
Overview of published 2D iPSC-CM cardiac arrhythmia disease models.
| Syndrome | Causal Gene Variant |
Experimental Approach |
Cellular Phenotype | Ref. |
|---|---|---|---|---|
| LQTS |
KCNQ1 p.(Arg190Gln) |
PC, IF | Prolonged AP, reduced IKs current, ER retention, increased susceptibility to catecholamine-induced tachyarrhythmia, attenuation of this phenotype with beta blockade | [6] |
| KCNH2 p.(Thr983Ile) | PC, MEA, WB, CI | Prolonged APD50 and APD90, beat irregularity, EAD, decreased IKr density, reduced channel surface expression, higher diastolic Ca2+ | [11] | |
| CACNA1C p.(Asn639Thr) | CardioExcyte 96, PC | Prolonged Maximum Field Potential Duration and APD, slower CaV1.2 voltage-dependent inactivation | [12] | |
| BrS/LQT |
SCN5A p.(1798insAsp) |
PC | Reduced INa peak current, persistent INa, reduced Vmax, prolonged APD90 | [13] |
| BrS |
SCN5A p.(Arg620His)+ p.(Arg811His) SCN5A (c. 4190delA) |
PC, CI | Reductions in INa and Vmax of AP, increased burden of triggered activity, abnormal calcium transients and beating interval variation | [14] |
|
CACNB2 p.(Ser142Phe) |
PC, CI | Reduction in peak ICa-L, acceleration recovery of inactivation and altered voltage dependent inactivation, reduced APA and Vmax, reduced protein expression of the CACNB2 gene, increased arrhythmia-like events, suppression of arrhythmic events by quinidine and bisoprolol | [15] | |
|
SCN5A p.(Val1405Met) SCNB1 p.(Ala197Val) |
PC, CI | Reduction in peak INa density, reduced APA and Vmax, prolonged AP, more proarrhythmic events (EAD, DAD-like events), reduced Nav1.5 protein expression | [16] | |
|
SCN5A p.(Ser1812X) |
PC, IF, MEA | Reduced INa and a delayed sodium channel activation, slowed AP upstroke velocity, reduced FP and CV, enhanced Ito and an augmented ICa-L window current, reduced NaV1.5 protein expression | [17] | |
| SQTS |
KCNH2 p.(Asn588Lys) |
PC, IF, CI | Shortening APD, Increased IKr tail current, arrhythmic events, increased hERG expression, re-entrant arrhythmias | [18,19] |
|
KCNH2 p.(Thr618Ile) |
PC, WB | Increased Ikr, shortened APD, beat-to-beat variability, increased membrane expression | [20] | |
| CPVT |
RYR2 p.(Phe2483Ileu) |
PC, MEA, CI | Arrhythmias, DAD, forskolin can rescue these phenotypes | [21] |
|
RYR2 p.(Phe2483Ile) |
CI | Longer Ca2+ sparks, higher diastolic Ca2+ levels, irregular beating, SR calcium leak and lower load levels | [22] | |
|
RYR2 p.(Asp3638Ala) |
AFM, CI, PC, | Higher beat rate, diastolic SR Ca2+ leak, weaker force contraction during stress, APD, Vmax and APA decreased during stress | [23] | |
|
RYR2 p.(Arg176Gln) |
CI | Aberrant diastolic SR Ca2+ release, EAD | [24] | |
|
RYR2 p.(Gln4201Arg) p.(Arg420Gln) p.(Phe2483Ile) |
PC, CI, qPCR, WB | p.(Gln4201Arg): decrease mRNA levels RYR2, protein similar, All mutants: longer sparks p.(Arg420Gln): lower spark frequency | [25] | |
|
RYR2 p.(Phe13Leu) p.(Leu14Pro) p.(Arg15Pro) p.(Arg176Gln) |
CI, WB, qPCR, MEA LEAP | Increased Ca2+ amplitude and upstroke velocity, decrease in calcium transient duration, irregular beating, decreased beat rate | [26] | |
|
CASQ2 p.(Asp307His) |
PC, CI, EM | DADs, oscillatory arrhythmic, after-contractions and diastolic [Ca2+]i rise, less organised myofibrils, enlarged SR cisternae and reduced number of caveolae | [27] | |
| ACM |
PKP2 p.(Leu614Pro) |
PC, CI, qPCR, IF | Reduction in rate of spontaneous cell contraction and amplitude under nifedipine, reduced expression plakophilin2 and plakoglobin | [28] |
|
DSG2 p.(Gly638Arg) |
IF, PC, CI, qPCR | Lower APA and Vmax, decreased peak INa, INCX, Ito, ISK, and IKATP, increased IKr, more arrhythmogenic events | [29] | |
|
DSG2 p.(Gly638Arg) |
PC, WB, qPCR | Upregulation of SK4 and NDPK-B, enhanced SK4 channel currents, pacemaker activity and more arrhythmic events | [30] |
Adapted and updated from Garg et al. (2018) and Pan et al. (2021) [9,10]. PC: patch clamp; IF: immunofluorescence; MEA: Multi electrode array; WB: Western Blot; CI: Calcium imaging; AFM: atomic force microscopy; AP: action potential; IKs: slow delayed rectifier K+ current; ER: endoplasmic reticulum; APD50-90: Action potential duration at 50–90% of repolarisation; EAD: early after depolarisation; IKr: rapid delayed rectifier K+ current; ICa-L: L-type calcium current; APA: action potential amplitude; Vmax: maximum rate of rise of the action potential; INa: sodium current; DAD: delayed after repolarisation; FP: field potential; CV: conduction velocity; Ito: transient outward current; SR: sarcoplasmic reticulum; EM: electron microscope.