Human-induced pluripotent stem cell-atrial-specific cardiomyocytes and atrial fibrillation

Table 1 The application of human induced pluripotent stem cells atrial cardiomyocytes and atrial fibrillation

Ref.	Specimens	Experiment	Results
AF disease modeling
Benzoni et al[63]	-2 untreatable persistent AF siblings (3 hiPSC clones)	-Differentiated 3 hiPSC clones’ cells towards the atrial cardiomyocytes (AF-aCMs)	-AF-aCMs had much longer action potentials, beat at a greater rate, and more ectopic beats than control-aCM cells. The patients' common genetic background causes functional changes in the If and ICa,L currents, resulting in a cardiac substrate that is more prone to arrhythmias under stressful situations
Argenziano et al[64]	-RA-derived hiPSC-aCMs	-Molecular, transcriptomic, and electrophysiological analysis of RA-derived hiPSC-aCMs	-RA causes differential expression of Ca2+ homeostasis genes that directly interact with the RA receptor via COUP-TFII
Nakanishi et al[65]	-2D monolayer of hiPSC-aCMs and atrial fibroblasts (aFbs)	-Conduction disruption influenced geometrical patterning and constituent cell heterogeneity under high frequency stimulation	-A higher frequency electrical stimulus preferentially caused poorer electrical conduction in hiPSC-aCMs monolayer preparations with an abrupt geometrical transition rather than those with uniform geometry. The addition of human aFbs tended to worsen the integrity of electrical conduction
Lemoine et al[66]	-hiPSC-aCMs cultured into atrial engineered heart tissue (aEHT)	- Optogenetic activation by blue light pulses after aEHTs were transduced with a lentiviral expression channel expressing rhodopsin-2	-The spontaneous beating rhythm of tachypaced aEHTs was more irregular; NT-proBNP and RNA levels were greater in the targeted group. Intermittent tachypacing in aEHTs causes some of the electrical changes seen in AF as well as an arrhythmic spontaneous beating pattern
Hong et al[67]	-hiPSC-aCMs from 2 relatives who carried SCN5A mutations (E428K and N470K)	-Characterize the pathogenesis of AF-linked SCN5A mutations compared with isogenic controls	- Mutant AF iPSC-aCMs demonstrated spontaneous arrhythmogenic activity with beat-to-beat irregularity, longer APD, and triggered-like beats. Single-cell recordings demonstrated that AF iPSC-aCMs had increased INa,L
Soepriatna et al[68]	-3D atrial microtissue from hiPSC-aCMs and hiPSC-vCMs	- AP responses to the atrial-specific potassium repolarizing current IKur-blocker 4-Aminopyridine and the funny current If-blocker Ivabradine were characterized in vitro	-An atrial microtissues having a quicker spontaneous beating rate, a slower AP rise time, and a shorter APD than ventricular microtissues
Drug screening platform for AF
Honda et al[69]	-hiPSCs with and without RA	-Gene expression and membrane potential analyses	-Pulse width duration 30cF lengthening was verified exclusively in hiPSC-aCMs using IKur channel inhibitor unique to aCMs. While hiPSC-vCMs displayed an early following depolarization by treatment with IKr channel inhibitor, which generates ventricular arrhythmia in clinical settings
Schmid et al[70]	-Nodal hiPSC-CMs, hiPSC-aCMs, and hiPSC-vCMs	-Assess the potential of drugs that cause chronotropic effects, AF, and ventricular arrhythmias	-Electrophysiological characteristics and ion channel expression differed across the three commercially available hiPSC-CM cultures. Whereas atrial/ventricular pluricytes demonstrate a tendency toward chamber specificity
Personalized regenerative medicine for AF
Wang et al[71]	- hiPSC-aCMs from patients with paroxysmal AF and healthy controls. A miR-155 transgenic (Tg) and knock-out mouse	-Expression of miR-155 and CACNA1C on the ICa,L	-The expression of miR-155 was elevated while the expression of CACNA1C was decreased in the hiPSC-aCMs of patients with AF. MiR-155/Tg mice exhibited a shorter action potential duration and increased susceptibility to AF, which was related to reduced ICa,L and was inhibited by a miR-155 inhibitor

aCMs: Atrial cardiomyocytes; aEHT: Atrial engineered heart tissue; AF: Atrial fibrillation; aFbs: Atrial fibroblasts; AP: Action potential; APD: Action potential duration; CACNA1C: Calcium voltage-gated channel subunit alpha1 C; COUP-TFII: Chicken ovalbumin upstream promoter-transcription factor 2; hiPSC: Human induced pluripotent stem cell; I_Ca,L: L-type calcium current; I_f: Pacemaker current; I_Kr: Rapidly activating delayed rectifier potassium current; I_Kur: Ultra-rapid activating delayed rectifier potassium current; I_Na,L: Late sodium current; miR-155: microrna-155; NT-pro-BNP: N-terminal pro B-type natriuretic peptide; RA: Retinoic acid; SCN5A: Sodium voltage-gated channel alpha subunit 5; Tg: Transgenic; vCMs: Ventricle cardiomyocytes.