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. Author manuscript; available in PMC: 2019 Jul 6.
Published in final edited form as: Circ Res. 2018 Jul 6;123(2):224–243. doi: 10.1161/CIRCRESAHA.118.311209

Table 2.

hiPSC-CM Models of Inherited Arrhythmia Syndromes

Syndro
me		 Causal gene Effect on ion
channel		 Experimental
approach		 Cellular phenotype Ref
LQTS1 KCNQ1
(R190Q)
  Trafficking
defect, altered
channel activation
and deactivation
properties		 Patch clamp Reduced IKs, APD prolongation, increased
susceptibility to catecholamine-induced
tachyarrhythmia, attenuation of this
phenotype with beta blockade		 58
KCNQ1 exon7
deletion		 Possible
Haploinsufficiency
and trafficking
defect of KCNQ1		 Patch clamp Reduced IKs, APD prolongation, reduced
wild type KCNQ1 mRNA and protein,
small molecule ML277 partially restored
APD and reversed the decreased IKs.
141
KCNQ1
(R594Q
R190Q)		 Trafficking defect Patch clamp,
MEA,		 Prolonged APD, reduced IKs activation that
was reversed by hERG allosteric modulator
LUF7346		 142
LQTS2 KCNH2
(A614V)		 Trafficking defect Patch clamp,
MEA		 Reduced IKr, APD prolongation, induction
of EADs and triggered activity, potential
improvement with pinacidil		 86
KCNH2
(G1681A)		 Trafficking defect Patch clamp APD prolongation and EADs 57
KCNH2
(R176W)		 Trafficking defect Patch clamp,
MEA		 Reduced IKr, APD prolongation, mild
incidence of EADs		 59
KCNH2
(N006I)		 Trafficking defect Patch clamp,
MEA		 Prolonged APD, reduced IKr activation that
was reversed by hERG allosteric modulator
LUF7346		 142
LQTS3 SCN5A
(V1763M)		 Gating defect-
inactivation of
sodium channel		 Patch-clamp Enhanced INaL, APD prolongation,
phenotype reversed by Nav1.5 blockade by
mexiletine		 91
SCN5A
(F1473C)		 Gating defect-
deficiency in
sodium channel
inactivation		 Patch clamp Delayed repolarization, arrhythmia,
prolonged QT interval with increase in
pacing improving the phenotype		 92
SCN5A
(V240M
R535Q)		 Gating defect-
deficiency in
sodium channel
inactivation		 Patch clamp Insignificant increase in APD, delayed time
to peak INa inactivation		 90
SCN5A
(R1644H)		 Gating defect-
deficiency in
sodium channel
inactivation		 Patch clamp,
MEA		 Prolonged APD, high EADs, and
accelerated recovery from inactivation of
Na+ currents. Rescue of abnormal
phenotypeby mexiletine and ranolazine		 143
LQTS7 KCNJ2
(R218W),
(R67W),
(R218Q)		 Trafficking defect MEA, calcium
imaging		 Strong arrhythmic events, higher incidence
of irregular Ca2+ release. Flecainide, but not
pilsicainide, suppressed irregular Ca2+
release and arrhythmic events		 97
LQTS8 CACNA1C
(G1216A)		 Gating defect- loss
of voltage-
dependent channel
inactivation		 Patch clamp,
calcium imaging		 APD prolongation and DADs, abnormal
calcium handling, irregular and slow
contraction. Roscovitine rescued abnormal
cellular phenotype		 60
LQTS14 CALM1
(F142L)		 Gating defect-
impaired Ca2+-
dependent
inactivation		 Patch clamp,
MEA, calcium
imaging		 Prolonged APD, defective ICaL inactivation,
altered rate-dependency and response to
isoproterenol. Repolarization abnormalities
reversed by verapamil		 144
LQTS15 CALM2 (N98S) Gating defect-
suppression of L-
type Ca2+ channel
(LTCC)
inactivation		 Patch clamp Lower beating rate, prolonged APD, and
impaired ICaL inactivation, correction of the
mutant allele rescued abnormal phenotype		 145
CALM2
(D130G)		 Gating defect-
disruption of
Ca2+/CaM-
Dependent
inactivation of
LTCC		 Patch clamp,
Fluorescence
imaging		 Prolonged APD, disrupted Ca2+ cycling
properties, and diminished Ca2+/CaM-
dependent inactivation of ICaL. Suppressing
the mutant gene rescued abnormal
phenotype		 146
BrS SCN5A
(R620H),
(R811H		 Trafficking defect Patch clamp,
calcium imaging		 Reduced INa and maximal upstroke velocity
of AP, abnormal Ca2+ transients, and
variation in beating interval		 81
PKP2
(c.2484C>T)		 Trafficking defect Patch clamp,
MEA, calcium
imaging		 Reduced INa, deficit restored by transfection
of WT gene 		147
CPVT1 RYR2
(M4109R)		 Patch clamp,
calcium
imaging, MEA		 DADs, isoproterenol enhanced DADs and
developed triggered activity. Flecainide and
thapsigargin eliminated DADs. Ca2+
transient irregularities that worsened with
adrenergic stimulation and Ca2+ overload
and improved with β-blockers		 106
RYR2 (F2483I) Patch clamp,
calcium imaging		 Longer duration of Ca2+ release from SR
long after repolarization, arrhythmias and
DADs with adrenergic stimulation		 107
RYR2 (S406L) Patch clamp,
Calcium
imaging		 Elevated diastolic Ca2+ concentrations,
reduced SR Ca2+ content, and arrhythmias.
Dantrolene ameliorated arrhythmia and
restored normal Ca2+ 		108
RYR2 (P2328S) Patch clamp,
Calcium
imaging		 Increased non-alternating variability of
Ca2+ transients in response to isoproterenol
and β-agonists decreased AP upslope
velocity		 108
RYR2 (R420Q) Calcium
imaging		 Less developed ultrastructure, isoproterenol
either ineffective, caused arrhythmias, or
markedly increased diastolic Ca2 		148
RYR2 (L3741P) Calcium
imaging, MEA		 Altered intracellular Ca2+ homeostasis, β-
adrenergic stimulation potentiated
spontaneous Ca2+ waves and prolonged
Ca2+ sparks. Flecainide ameliorated disease
phenotype		 149
RYR2 (I4587V) Patch clamp,
Calcium
imaging		 Increased diastolic Ca2+ waves and DADs
with pacing, while S107 suppressed the
DADs		 150
CPVT2 CASQ2
(D307H)		 Patch clamp,
Calcium
imaging		 β-adrenergic agonist caused DADs,
oscillatory arrhythmic pre-potentials, and
diastolic [Ca2+]i rise		 108,
148,
151
CASQ2
(D307H)		 Patch clamp,
Calcium
imaging		 Ca2+-transient irregularities, EADs, and
reduced threshold for store overload-
induced Ca2+-release, β-blockers prevented
arrhythmia		 152

APD, action potential duration; EAD, early after depolarization; DAD, delayed after depolarization; CALM1, Calmodulin 1; CALM2, Calmodulin 2; PKP2, Plakophilin-2.