Isabella Doherty, Roshni Shetty, Haibo Ni, Stefano Morotti, Eleonora Grandi
{"title":"Exploring the mechanisms of sex-specific proarrhythmia in long QT syndrome through computational modeling.","authors":"Isabella Doherty, Roshni Shetty, Haibo Ni, Stefano Morotti, Eleonora Grandi","doi":"10.1152/ajpheart.00792.2024","DOIUrl":null,"url":null,"abstract":"<p><p>Females exhibit longer QT intervals and a higher risk of long QT syndrome (LQTS) associated arrhythmogenesis compared with males. Although several studies suggest these sex disparities result from the effect of sex hormones on cardiac ion channels, the underlying mechanisms remain incompletely understood. This research investigates the arrhythmogenic effects, sex-specific risk, and mechanisms associated with LQTS linked to either to loss-of-function of the rapidly activating delayed rectifier K<sup>+</sup> current (<i>I</i><sub>Kr</sub>), or gain-of-function of the L-type Ca<sup>2+</sup> current (<i>I</i><sub>CaL</sub>). We primarily used the Tomek-Rodriguez (ToR-ORd) model of human ventricular cardiomyocytes and incorporated sex-specific parameterizations based on previous studies. The O'Hara-Rudy and Grandi-Bers models were used to demonstrate model-independence of the findings. We used a populations-of-models approach to assess early afterdepolarization (EAD) susceptibility in control and LQTS male and female groups. All female models had consistently longer action potentials and were more prone to EADs than male models. In the ToR-ORd model, <i>I</i><sub>Kr</sub> loss-of-function led to EADs in 65.8% of females versus 22.8% of males. <i>I</i><sub>CaL</sub> gain-of-function led to EADs in 66.2% of females but only 3.6% of males. Using logistic regression analysis, we identified key ionic predictors of EAD susceptibility, with maximal conductance of the L-type Ca<sup>2+</sup> current (<i>G</i><sub>CaL</sub>) and maximal transport rate of the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger (<i>G</i><sub>NCX</sub>) consistently emerging as positively and maximal conductance of the rapidly activating delayed rectifier K<sup>+</sup> current (<i>G</i><sub>Kr</sub>) as negatively associated to EADs across both sexes and LQTS types. Notably, higher <i>G</i><sub>NCX</sub> but lower <i>G</i><sub>Kr</sub> in female versus male cardiomyocytes could explain heightened female EAD risk. Our studies explore the ionic traits that favor (or confer resilience against) EADs with potential implications for personalized treatments. <b>NEW & NOTEWORTHY</b> We explored sex disparities in long QT syndrome (LQTS) using sex-specific human ventricular cardiomyocyte models. We showed that females exhibit greater susceptibility to early afterdepolarizations (EADs) than males, and identified key ionic predictors of EAD risk, including increases in the voltage-gated L-type Ca<sup>2+</sup> current and electrogenic Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, and downregulation of the rapidly activating delayed rectifier K<sup>+</sup> current. These findings offer new insights into sex-specific mechanisms underlying arrhythmogenesis in LQTS, with potential implications for personalized treatments.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H963-H972"},"PeriodicalIF":4.1000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Heart and circulatory physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpheart.00792.2024","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/13 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
Females exhibit longer QT intervals and a higher risk of long QT syndrome (LQTS) associated arrhythmogenesis compared with males. Although several studies suggest these sex disparities result from the effect of sex hormones on cardiac ion channels, the underlying mechanisms remain incompletely understood. This research investigates the arrhythmogenic effects, sex-specific risk, and mechanisms associated with LQTS linked to either to loss-of-function of the rapidly activating delayed rectifier K+ current (IKr), or gain-of-function of the L-type Ca2+ current (ICaL). We primarily used the Tomek-Rodriguez (ToR-ORd) model of human ventricular cardiomyocytes and incorporated sex-specific parameterizations based on previous studies. The O'Hara-Rudy and Grandi-Bers models were used to demonstrate model-independence of the findings. We used a populations-of-models approach to assess early afterdepolarization (EAD) susceptibility in control and LQTS male and female groups. All female models had consistently longer action potentials and were more prone to EADs than male models. In the ToR-ORd model, IKr loss-of-function led to EADs in 65.8% of females versus 22.8% of males. ICaL gain-of-function led to EADs in 66.2% of females but only 3.6% of males. Using logistic regression analysis, we identified key ionic predictors of EAD susceptibility, with maximal conductance of the L-type Ca2+ current (GCaL) and maximal transport rate of the Na+/Ca2+ exchanger (GNCX) consistently emerging as positively and maximal conductance of the rapidly activating delayed rectifier K+ current (GKr) as negatively associated to EADs across both sexes and LQTS types. Notably, higher GNCX but lower GKr in female versus male cardiomyocytes could explain heightened female EAD risk. Our studies explore the ionic traits that favor (or confer resilience against) EADs with potential implications for personalized treatments. NEW & NOTEWORTHY We explored sex disparities in long QT syndrome (LQTS) using sex-specific human ventricular cardiomyocyte models. We showed that females exhibit greater susceptibility to early afterdepolarizations (EADs) than males, and identified key ionic predictors of EAD risk, including increases in the voltage-gated L-type Ca2+ current and electrogenic Na+/Ca2+ exchanger, and downregulation of the rapidly activating delayed rectifier K+ current. These findings offer new insights into sex-specific mechanisms underlying arrhythmogenesis in LQTS, with potential implications for personalized treatments.
期刊介绍:
The American Journal of Physiology-Heart and Circulatory Physiology publishes original investigations, reviews and perspectives on the physiology of the heart, vasculature, and lymphatics. These articles include experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the intact and integrative animal and organ function to the cellular, subcellular, and molecular levels. The journal embraces new descriptions of these functions and their control systems, as well as their basis in biochemistry, biophysics, genetics, and cell biology. Preference is given to research that provides significant new mechanistic physiological insights that determine the performance of the normal and abnormal heart and circulation.