Sex hormones and repolarization dynamics during the menstrual cycle in women with congenital long QT syndrome

Bjelic, Milica; Zaręba, Wojciech; Peterson, Derick R.; Younis, Arwa; Aktaş, Mehmet K.; Huang, David T.; Rosero, Spencer; Cutter, Kris; McNitt, Scott; Xia, Xiaojuan; MacKecknie, Bonnie D.; Horn, Rebecca; Sotoodehnia, Nona; Kudenchuk, Peter J.; Rea, Thomas D.; Arking, Dan E.; Wilde, Arthur A.M.; Shimizu, Wataru; Ackerman, Michael J.; Goldenberg, Ilan

doi:10.1016/j.hrthm.2022.04.029

Cited by 9 publications

(8 citation statements)

References 26 publications

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“…In addition, progesterone was found to show an inverse association with the corrected QT interval and with the ratio of progesterone to estradiol in women with LQTS2. This shortening of the QT interval was observed during the luteal phase, and was mainly attributed to increased progesterone levels in this phase (30). Such associations were not maintained in women with LQTS1, supporting that the observed differences in LQTS subtypes are due to different effects of hormones on the channels, with different sensitivity between genotypes.…”

Section: Role Of Hormones In Arrhythmogenic Riskmentioning

confidence: 89%

“…However, such effects have not been supported in human studies, in which a more complex interaction between estrogen and progesterone appears to exist ( 29 ). For example, a recent study in women with LQTS found an inverse relationship of RR interval with estradiol levels during the menstrual cycle ( 30 ). In addition, progesterone was found to show an inverse association with the corrected QT interval and with the ratio of progesterone to estradiol in women with LQTS2.…”

Section: Role Of Hormones In Arrhythmogenic Riskmentioning

confidence: 99%

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Sex differences in long QT syndrome

Díez-Escuté

Arbelo

Martínez-Barrios

et al. 2023

Front. Cardiovasc. Med.

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Long QT Syndrome (LQTS) is a rare, inherited channelopathy characterized by cardiac repolarization dysfunction, leading to a prolonged rate-corrected QT interval in patients who are at risk for malignant ventricular tachyarrhythmias, syncope, and even sudden cardiac death. A complex genetic origin, variable expressivity as well as incomplete penetrance make the diagnosis a clinical challenge. In the last 10 years, there has been a continuous improvement in diagnostic and personalized treatment options. Therefore, several factors such as sex, age diagnosis, QTc interval, and genetic background may contribute to risk stratification of patients, but it still currently remains as a main challenge in LQTS. It is widely accepted that sex is a risk factor itself for some arrhythmias. Female sex has been suggested as a risk factor in the development of malignant arrhythmias associated with LQTS. The existing differences between the sexes are only manifested after puberty, being the hormones the main inducers of arrhythmias. Despite the increased risk in females, no more than 10% of the available publications on LQTS include sex-related data concerning the risk of malignant arrhythmias in females. Therein, the relevance of our review data update concerning women and LQTS.

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Section: Role Of Hormones In Arrhythmogenic Riskmentioning

confidence: 89%

Section: Role Of Hormones In Arrhythmogenic Riskmentioning

confidence: 99%

Sex differences in long QT syndrome

Díez-Escuté

Arbelo

Martínez-Barrios

et al. 2023

Front. Cardiovasc. Med.

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“…31 The interaction with HSD17B12, which converts estrone to estradiol could be particularly significant given that female sex hormones increase the risk of LQTS related arrhythmias. 44,45 Several other 17-beta hydroxysteroid dehydrogenases localize in the ER membrane, and the catalytic site of HSD17B12 was found facing the ER lumen. 46 Thus this interaction could have early effects on K V 11.1 folding within the ER.…”

Section: Discussionmentioning

confidence: 99%

The proteostasis interactomes of trafficking-deficient K_V11.1 variants associated with Long QT Syndrome and pharmacological chaperone rescue

Egly,

Barny,

et al. 2024

Preprint

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Introduction: The voltage gated potassium ion channel KV11.1 plays a critical role in cardiac repolarization. Genetic variants that render Kv11.1 dysfunctional cause Long QT Syndrome (LQTS), which is associated with fatal arrhythmias. Approximately 90% of LQTS-associated variants cause intracellular protein transport (trafficking) dysfunction, which can be rescued by pharmacological chaperones like E-4031. Protein folding and trafficking decisions are regulated by chaperones, protein quality control factors, and trafficking machinery, comprising the cellular proteostasis network. Here, we test whether trafficking dysfunction is associated with alterations in the proteostasis network of pathogenic Kv11.1 variants, and whether pharmacological chaperones can normalize the proteostasis network of responsive variants. Methods: We used affinity-purification coupled with tandem mass tag-based quantitative mass spectrometry to assess protein interaction changes in human embryonic kidney (HEK293) cells expressing wild-type (WT) KV11.1 or trafficking-deficient channel variants in the presence or absence of E 4031. Results: We identified 573 core KV11.1 protein interactors. Both variants KV11.1-G601S and KV11.1-G601S-G965* had significantly increased interactions with proteins responsible for folding, trafficking, and degradation compared to WT. We found that proteasomal degradation is a key component for KV11.1 degradation and that the KV11.1-G601S-G965* variant was more responsive to E-4031 treatment. This suggests a role in the C-terminal domain and the ER retention motif of KV11.1 in regulating trafficking. Conclusion: Our report characterizes the proteostasis network of KV11.1, two trafficking deficient KV11.1 variants, and variants treated with a pharmacological chaperone. The identified protein interactions could be targeted therapeutically to improve KV11.1 trafficking and treat Long QT Syndrome.

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“… 9 These data are consistent with our recent report, showing that the effect of the estrogen to progesterone ratio on QTc duration is enhanced in women with LQT2 compared with LQT1. 22 …”

Section: Discussionmentioning

confidence: 99%

Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex‐Specific Risk Stratification in Potassium Channel‐Mediated Long QT Syndrome

Bjelic,

Goldenberg,

Younis

et al. 2024

JAHA

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Background Sex‐specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life‐threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel‐mediated LQTS. Methods and Results The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. Anderson‐Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow‐up. The genotype–phenotype risk prediction model identified low‐, intermediate‐, and high‐risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low‐risk group, high‐risk male subjects experienced a pronounced 5.2‐fold increased risk of recurrent CEs ( P <0.001), whereas intermediate‐risk patients had a 2.1‐fold ( P =0.004) increased risk . At age 20 years, the low‐, intermediate‐, and high‐risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10‐year adjusted probabilities for a first LTE were 2%, 6%, and 8%. Conclusions Personalized genotype–phenotype risk estimates can be used to guide sex‐specific management in male adolescents with potassium channel‐mediated LQTS.

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Sex hormones and repolarization dynamics during the menstrual cycle in women with congenital long QT syndrome

Cited by 9 publications

References 26 publications

Sex differences in long QT syndrome

Sex differences in long QT syndrome

The proteostasis interactomes of trafficking-deficient K_V11.1 variants associated with Long QT Syndrome and pharmacological chaperone rescue

Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex‐Specific Risk Stratification in Potassium Channel‐Mediated Long QT Syndrome

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Sex hormones and repolarization dynamics during the menstrual cycle in women with congenital long QT syndrome

Cited by 9 publications

References 26 publications

Sex differences in long QT syndrome

Sex differences in long QT syndrome

The proteostasis interactomes of trafficking-deficient KV11.1 variants associated with Long QT Syndrome and pharmacological chaperone rescue

Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex‐Specific Risk Stratification in Potassium Channel‐Mediated Long QT Syndrome

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The proteostasis interactomes of trafficking-deficient K_V11.1 variants associated with Long QT Syndrome and pharmacological chaperone rescue