Table 2.

List of CPVT1 syndromes modeled using the hiPSC-CMs.

Localization	Mutations	Findings	Ref.
	D358N	CPVT tissues display re-entrant rhythms under stress that are prevented by CaMKII inhibition.	[60]
N-terminal domain	S406L	The β-adrenergic stimulation by isoproterenol induced DADs and diastolic Ca2+ leak, that were reduced with the Dantrolene treatment.	[61]
	E2311D/Q231D	Increased spontaneous calcium sparks and DADs, that were normalized by a CaMKII inhibition.	[62]
	R420Q	Non-ionotropic and lusitropic effects, increased arrhythmias and intracellular Ca2+ associated with immature ultrastructural features.	[63]
	ΔExon 3	Dantrolene treatment reduced the premature ventricular complexes and the abnormal Ca2+ release in 4 CPVT patients and CPVT hiPSC-CMs. However, Dantrolene was not effective to treat patients carrying mutations in or near the transmembrane domain of the RyR2.	[64]
Helical domain 1	F2483I	The reduction of Ca2+ stores induced by a higher CICR mechanism led to an abnormal Ca2+ homeostasis. These abnormalities were verified in 2018 in gene-edited CPVT hiPSC-CMs generated by the CRISPR/Cas9 technology.	[65–67]
	P2328S	The abnormal calcium homeostasis and the reduction of the SR Ca2+ load led to EADs and DADs at baseline and under isoproterenol stimulation. Another study found that the CPVT hiPSC-CMs exhibit increased non-alternating variability of Ca2+ transients and slow depolarization under isoproterenol stimulation.	[68, 69]
	P2328S, T2538R	See findings of the ΔExon 3 mutation.	[64]
	Y2476D	Arrhythmic events and impairment of the calcium handling and beating properties of CPVT hiPSC-CMs. These abnormalities were more pronounced under β-adrenergic stress.	[70]
Central domain	M4109R	The β-adrenergic stimulation induces DADs and irregular Ca2+ transients that were abolished with the Flecainide and Thapsigargin treatments.	[71]
	L4115F, Q4201R	See findings of the ΔExon 3 mutation.	[64]
	L3741P	The Flecainide treatment abolished the DADs and the spontaneous calcium sparks.	[72]
	D3638A	The RyR2 macromolecular complex remodeling, including FKBP12.6 depletion, SR Ca2+ leak and impaired contractile properties were observed in RyR2-D3638A hiPSC-CMs under stress conditions. Abnormal release of Ca2+ were prevented with the Flecainide and S107 treatments but not with the Metoprolol.	[73]
	R4651I	CPVT tissues display re-entrant rhythms under stress that are prevented by CaMKII inhibition.	[60]
Channel domain	V4653F	See findings of the P2328S mutation.	[64]
	I4587V	DADs and abnormal diastolic Ca2+ release were observed under β-adrenergic stress. The S107 treatment reduced the occurrence of DADs.	[74]
	R4959Q	See findings of the Y2476D mutation.	[70]