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World J Stem Cells. May 26, 2026; 18(5): 117584
Published online May 26, 2026. doi: 10.4252/wjsc.v18.i5.117584
Published online May 26, 2026. doi: 10.4252/wjsc.v18.i5.117584
Calcium dysregulation underlies phenotypic diversity in LQT2: Insights from induced pluripotent stem cell-derived cardiomyocytes of a KCNH2 p.Y427H family trio
Qing Li, Yi-Fei Wang, Qiu-Yu Wang, Qing Liu, School of Clinical Medicine, Tsinghua University, Beijing 100084, China
Cong-Ting Guo, Jia-Cheng Ren, Zi-Juan Zhao, Chang-Hua Lv, Kun Li, Jing Yang, Rong He, Fu-Lan Liu, Ting-Ting Lv, Ping Zhang, Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
Co-first authors: Qing Li and Cong-Ting Guo.
Co-corresponding authors: Ting-Ting Lv and Ping Zhang.
Author contributions: Li Q and Guo CT were responsible for performing experiments and drafting the manuscript, they contributed equally to this work and are co-first authors; Ren JC and Wang YF conducted statistical analysis; Zhao ZJ performed data analysis; Lv CH managed the lab; Wang QY and Liu Q collected data; Li K and Yang J contributed to pedigree analysis and clinical data; He R performed subcutaneous implantable cardioverter defibrillator surgery; Liu FL managed case data; Lv TT and Zhang P supervised the project and revised the manuscript, they contributed equally to this manuscript and are co-corresponding authors. All authors approved the final version of the manuscript.
Supported by Beijing Hospitals Authority Clinical Medicine Development Special Funding, No. ZLRK202518.
Institutional review board statement: The study was approved by the Institutional Review Board of Beijing Tsinghua Changgung Hospital (Approval No. 24472-4-01).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at zhpdoc@126.com.
Corresponding author: Ting-Ting Lv, Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 174 Litang Road, Changping District, Beijing 102218, China. lvtingting0616@163.com
Received: December 11, 2025
Revised: January 17, 2026
Accepted: March 17, 2026
Published online: May 26, 2026
Processing time: 166 Days and 0.1 Hours
Revised: January 17, 2026
Accepted: March 17, 2026
Published online: May 26, 2026
Processing time: 166 Days and 0.1 Hours
Core Tip
Core Tip: Using induced pluripotent stem cell-derived cardiomyocytes, we modeled a family with congenital long QT syndrome type 2 caused by a KCNH2 variant to explain why clinical severity differs among carriers. Although both affected individuals showed a reduced rapid delayed rectifier potassium current, only the symptomatic proband exhibited calcium handling abnormalities, increased L-type calcium current, and spontaneous arrhythmias. Pharmacological correction with nifedipine suppressed these arrhythmias. This work highlights calcium dysregulation as a key modifier of disease severity and supports the use of patient-specific induced pluripotent stem cell-derived cardiomyocytes for personalized risk assessment and therapy selection.