Background: Arrhythmogenic Cardiomyopathy (AC) is a genetic
cardiac disease resulting from different mutations within proteins
constituting the intercalated disc, including desmosomal and nondesmosomal proteins. Recent studies have revealed that mutations in
filamin-C (FLNC) may lead to AC. The arrhythmogenesis and
electrophysiological effects of FLNC-related AC are incompletely
understood. Therefore, the aim of this study is to assess the potential
electrophysiological consequences of FLNC loss as occurs in AC in
human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs). Specifically, I aimed to characterise abnormal electrical activity
and the expression and function of key proteins in cardiac electrical
activity such as gap junction protein connexin 43 (Cx43).//
Methods: hiPSC-CMs were differentiated and observed by
immunofluorescence microscopy. Small interfering RNA (siRNA)
transfection was utilised to knockdown the expression of FLNC in
hiPSC-CMs. Protein analysis was performed using western blotting to
confirm the knockdown efficiency. Electrophysiological properties were
recorded using a multielectrode array and manual patch clamping.
Optical recording of membrane potential and calcium activity from
hiPSC-CMs were also carried out using parameter sensitive dyes.//

Results: Silencing of FLNC led to markedly decreased
immunofluorescence signals of FLNC, Cx43, desmoplakin, and
junctional plakoglobin. No significant reductions were noted in the immunofluorescence signals of voltage-gated sodium channel (Nav1.5) and plakophilin-2 compared with control hiPSC-CMs. Western blotting showed the reduction of FLNC and Cx43 expression following silencing
of FLNC. Knockdown of FLNC resulted in disturbances to the recorded
action and field potential signals of hiPSC-CMs and arrhythmic likeevents. Transfected hiPSC-CMs with siRNA-FLNC were associated
with prolongation of calcium transient durations, optical action potential
duration, and action potentials measured with patch clamping.//
Conclusion: The current findings indicated that loss of FLNC resulted in a complex arrhythmogenic phenotype in hiPSC-CMs