Injectable Contraceptive, Depo-Provera, Produces Erratic Beating Patterns in Patient-Specific Induced Pluripotent Stem Cell-derived Cardiomyocytes with Type 2 Long QT Syndrome.

Pinsky, Alexa M; Gao, Xiaozhi; Bains, Sahej; Kim, Cs John; Louradour, Julien; Odening, Katja E; Tester, David J; Giudicessi, John R; Ackerman, Michael J (2023). Injectable Contraceptive, Depo-Provera, Produces Erratic Beating Patterns in Patient-Specific Induced Pluripotent Stem Cell-derived Cardiomyocytes with Type 2 Long QT Syndrome. Heart rhythm, 20(6), pp. 910-917. Elsevier 10.1016/j.hrthm.2023.03.002

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BACKGROUND

Long QT syndrome type 2 (LQT2) is caused by pathogenic variants in KCNH2. LQT2 may manifest as QT prolongation on an ECG and present with arrhythmic syncope/seizures, sudden cardiac arrest/death. Oral progestin-based contraceptives may increase the risk of LQT2-triggered cardiac events in women. We previously reported on a LQT2 woman with recurrent cardiac events temporally related and attributed to the progestin-based contraceptive, medroxyprogesterone acetate ("Depo-Provera", Depo).

OBJECTIVE

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 female with p.G1006Afs*49-KCNH2. A CRISPR/Cas9 gene-edited/variant-corrected, isogenic control (IC) iPSC-CM line was generated. FluoVolt was used to measure the action potential duration (APD) following treatment with 10 μM Depo. Erratic beating patterns characterized as alternating spike amplitudes, alternans, or early after depolarization-like phenomena were assessed using multi-electrode array (MEA) following 10 μM Depo, 1 μM isoproterenol (ISO), or combined Depo + ISO treatment.

RESULTS

Depo treatment shortened the APD-90 of the G1006Afs*49 iPSC-CMs from 394±10 ms to 303±10 ms (p<0.0001). Combined Depo and ISO treatment increased the percent of electrodes displaying erratic beating in G1006Afs*49 iPSC-CMs [baseline 18±5% vs. Depo + ISO 54±5% (p<0.0001)] but not in IC iPSC-CMs [baseline 0±0% vs. Depo + ISO 10±3% (p=0.9659)].

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 pro-arrhythmic effect in women with LQT2.

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