Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2

Alexa M. Pinsky; Xiaozhi Gao; Sahej Bains; Changsung John Kim; Julien Louradour; Katja E. Odening; David J. Tester; John R. Giudicessi; Michael J. Ackerman

doi:10.1016/j.hrthm.2023.03.002

Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2

Alexa M. Pinsky, Xiaozhi Gao, Sahej Bains, Changsung John Kim, Julien Louradour, Katja E. Odening, David J. Tester, John R. Giudicessi, Michael J. Ackerman

Cardiovascular Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

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] MilliporeSigma, Catalog# 1378001, St. Louis, MO). 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 (Invitrogen, F10488, Waltham, MA) 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 multielectrode array (MEA) after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment. Results: Depo treatment shortened the action potential duration at 90% repolarization 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.

Original language	English (US)
Pages (from-to)	910-917
Number of pages	8
Journal	Heart rhythm
Volume	20
Issue number	6
DOIs	https://doi.org/10.1016/j.hrthm.2023.03.002
State	Published - Jun 2023

Keywords

Arrhythmia
Cardiomyocytes
Depo-Provera
Long QT syndrome type 2
iPSC

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1016/j.hrthm.2023.03.002

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Pinsky, A. M., Gao, X., Bains, S., Kim, C. J., Louradour, J., Odening, K. E., Tester, D. J., Giudicessi, J. R., & Ackerman, M. J. (2023). Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2. Heart rhythm, 20(6), 910-917. https://doi.org/10.1016/j.hrthm.2023.03.002

Pinsky, AM, Gao, X, Bains, S, Kim, CJ, Louradour, J, Odening, KE, Tester, DJ, Giudicessi, JR & Ackerman, MJ 2023, 'Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2', Heart rhythm, vol. 20, no. 6, pp. 910-917. https://doi.org/10.1016/j.hrthm.2023.03.002

@article{1eb5c66607e54856863ffe26c8246823,

title = "Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2",

abstract = "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] MilliporeSigma, Catalog# 1378001, St. Louis, MO). 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 (Invitrogen, F10488, Waltham, MA) 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 multielectrode array (MEA) after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment. Results: Depo treatment shortened the action potential duration at 90% repolarization 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 = "Arrhythmia, Cardiomyocytes, Depo-Provera, Long QT syndrome type 2, iPSC",

author = "Pinsky, {Alexa M.} and Xiaozhi Gao and Sahej Bains and Kim, {Changsung John} and Julien Louradour and Odening, {Katja E.} and Tester, {David J.} and Giudicessi, {John R.} and Ackerman, {Michael J.}",

note = "Publisher Copyright: {\textcopyright} 2023 Heart Rhythm Society",

year = "2023",

month = jun,

doi = "10.1016/j.hrthm.2023.03.002",

language = "English (US)",

volume = "20",

pages = "910--917",

journal = "Heart rhythm",

issn = "1547-5271",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2

AU - Pinsky, Alexa M.

AU - Gao, Xiaozhi

AU - Bains, Sahej

AU - Kim, Changsung John

AU - Louradour, Julien

AU - Odening, Katja E.

AU - Tester, David J.

AU - Giudicessi, John R.

AU - Ackerman, Michael J.

PY - 2023/6

Y1 - 2023/6

N2 - 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] MilliporeSigma, Catalog# 1378001, St. Louis, MO). 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 (Invitrogen, F10488, Waltham, MA) 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 multielectrode array (MEA) after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment. Results: Depo treatment shortened the action potential duration at 90% repolarization 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.

AB - 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] MilliporeSigma, Catalog# 1378001, St. Louis, MO). 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 (Invitrogen, F10488, Waltham, MA) 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 multielectrode array (MEA) after 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment. Results: Depo treatment shortened the action potential duration at 90% repolarization 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.

KW - Arrhythmia

KW - Cardiomyocytes

KW - Depo-Provera

KW - Long QT syndrome type 2

KW - iPSC

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SN - 1547-5271

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Injectable contraceptive Depo-Provera induces erratic beating patterns in patient-specific induced pluripotent stem cell–derived cardiomyocytes with long QT syndrome type 2

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