Utilizing human induced pluripotent stem cells to study atrial arrhythmias in the short QT syndrome

Assad Shiti; Gil Arbil; Naim Shaheen; Irit Huber; Noga Setter; Lior Gepstein

doi:10.1016/j.yjmcc.2023.08.003

Utilizing human induced pluripotent stem cells to study atrial arrhythmias in the short QT syndrome

J Mol Cell Cardiol. 2023 Oct:183:42-53. doi: 10.1016/j.yjmcc.2023.08.003. Epub 2023 Aug 12.

Authors

Assad Shiti¹, Gil Arbil¹, Naim Shaheen¹, Irit Huber¹, Noga Setter¹, Lior Gepstein²

Affiliations

¹ Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel.
² Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel; Cardiolology Department, Rambam Health Care Campus, Haifa, Israel. Electronic address: mdlior@technion.ac.il.

Abstract

Background: Among the monogenic inherited causes of atrial fibrillation is the short QT syndrome (SQTS), a rare channelopathy causing atrial and ventricular arrhythmias. One of the limitations in studying the mechanisms and optimizing treatment of SQTS-related atrial arrhythmias has been the lack of relevant human atrial tissues models.

Objective: To generate a unique model to study SQTS-related atrial arrhythmias by combining the use of patient-specific human induced pluripotent stem cells (hiPSCs), atrial-specific differentiation schemes, two-dimensional tissue modeling, optical mapping, and drug testing.

Methods and results: SQTS (N588K KCNH2 mutation), isogenic-control, and healthy-control hiPSCs were coaxed to differentiate into atrial cardiomyocytes using a retinoic-acid based differentiation protocol. The atrial identity of the cells was confirmed by a distinctive pattern of MLC2v downregulation, connexin 40 upregulation, shorter and triangular-shaped action potentials (APs), and expression of the atrial-specific acetylcholine-sensitive potassium current. In comparison to the healthy- and isogenic control cells, the SQTS-hiPSC atrial cardiomyocytes displayed abbreviated APs and refractory periods along with an augmented rapidly activating delayed-rectifier potassium current (I_Kr). Optical mapping of a hiPSC-based atrial tissue model of the SQTS displayed shortened APD and altered biophysical properties of spiral waves induced in this model, manifested by accelerated spiral-wave frequency and increased rotor curvature. Both AP shortening and arrhythmia irregularities were reversed by quinidine and vernakalant treatment, but not by sotalol.

Conclusions: Patient-specific hiPSC-based atrial cellular and tissue models of the SQTS were established, which provide examples on how this type of modeling can shed light on the pathogenesis and pharmacological treatment of inherited atrial arrhythmias.

Keywords: Atrial arrhythmias; Optical mapping; Short QT syndrome; hiPSC-CMs modeling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / genetics
Atrial Fibrillation* / genetics
Atrial Fibrillation* / metabolism
Humans
Induced Pluripotent Stem Cells*
Myocytes, Cardiac / metabolism
Potassium / metabolism

Substances

Potassium

Supplementary concepts

Short Qt Syndrome