Background
Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in KCNH2. LQT2 may manifest as QT prolongation on an electrocardiogram and present with arrhythmic
syncope/seizures and sudden cardiac arrest/death. Progestin-based oral contraceptives
may increase the risk of LQT2-triggered cardiac events in women. We previously reported
on a woman with LQT2 and recurrent cardiac events temporally related and attributed
to the progestin-based contraceptive medroxyprogesterone acetate (“Depo-Provera” [Depo]).
Objective
The purpose of this study was to evaluate the arrhythmic risk of Depo in a patient-specific
induced pluripotent stem cell–derived cardiomyocyte (iPSC-CM) model of LQT2.
Methods
An iPSC-CM line was generated from a 40-year-old woman with p.G1006Afs∗49-KCNH2. A
CRISPR/Cas9 gene-edited/variant-corrected isogenic control iPSC-CM line was generated.
FluoVolt was used to measure the action potential duration after treatment with 10
μM Depo. Erratic beating patterns characterized as alternating spike amplitudes, alternans,
or early afterdepolarization–like phenomena were assessed using a multielectrode array
after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment.
Results
Depo treatment shortened the APD90 of G1006Afs∗49 iPSC-CMs from 394 ± 10 to 303 ± 10 ms (P < .0001). Combined Depo + ISO treatment increased the percentage of electrodes displaying
erratic beating in G1006Afs∗49 iPSC-CMs (baseline: 18% ± 5% vs Depo + ISO: 54% ± 5%;
P < .0001) but not in isogenic control iPSC-CMs (baseline: 0% ± 0% vs Depo + ISO: 10%
± 3%; P = .9659).
Conclusion
This cell study provides a potential mechanism for the patient’s clinically documented
Depo-associated episodes of recurrent ventricular fibrillation. This in vitro data
should prompt a large-scale clinical assessment of Depo’s potential proarrhythmic
effect in women with LQT2.
Keywords
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Article info
Publication history
Published online: March 06, 2023
Publication stage
In Press Journal Pre-ProofFootnotes
Funding Sources: This work was supported by the Windland Smith Rice Comprehensive Sudden Cardiac Death Program, Rochester, Minnesota (Dr Ackerman).
Disclosures: Dr Pinsky received the Sarnoff Cardiovascular Research Foundation Fellowship as a medical student to support her time while performing this research. Dr Ackerman is a consultant for Abbott, Boston Scientific, Daiichi Sankyo, InVitae, Medtronic, and Thryv Therapeutics. Dr Ackerman and Mayo Clinic are involved in an equity/intellectual property/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Pfizer, and UpToDate. However, none of these entities were involved in this study in any manner. The rest of the authors have no conflicts of interest to disclose.
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