Biology subjects

Herrera, N. T.

Publications and source records attributed to Herrera, N. T..

3 recordsLinked to original sources

bioRxiv2026

Predicting Sex-Specific Antiarrhythmic Strategies for Atrial Fibrillation through a Regression-Guided Computational Modeling Pipeline

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a major contributor to stroke, heart failure, and mortality worldwide. Although AF affects both men and women at a similar rate, accumulating experimental and clinical evidence indicates that its underlying mechanisms, disease progression, and treatment responses differ by sex. However, current antiarrhythmic drug development and clinical management of AF remains largely sex neutral, likely contributing to limited efficacy and increased adverse effects. To address this gap, we developed a computational drug-screening pipeline based on experimentally constrained, sex-specific human atrial cardiomyocyte models to predict and evaluate sex-specific pharmacological strategies for AF. The pipeline integrates multivariable regression with mechanistic modeling to systematically test multi-target combinations of ion channel inhibitors and Ca2+ handling modulators and identify interventions that reduce arrhythmia vulnerability by restoring sex-specific electrophysiological and Ca2+ handling properties toward normal sinus rhythm (nSR). Application of this approach revealed a greater number of successful inhibitory drug combinations in males than in females. In males, optimal recovery to nSR primarily required inhibition of Na+ and K+ channels to prolong repolarization and refractoriness, increase Ca2+ transient amplitude (CaTAmp), and reduce susceptibility to action potential duration (APD) alternans. In females, modulation of Ca2+-related pathways was additionally required to suppress delayed afterdepolarizations (DADs). Forward single-cell simulations confirmed the predictions of the drug-analysis pipeline, demonstrating recovery of APD, CaTAmp, and arrhythmia vulnerability indices without introducing instabilities. Importantly, extension of these interventions to two-dimensional atrial tissue simulations demonstrated that sex-specific drug strategies reduce vulnerability to triggered activity, while suppression of reentry was most effective when combined with partial recovery of cell-cell coupling. Our results establish a multiscale computational pipeline for identifying sex-informed, multi-target antiarrhythmic therapies, amenable to experimental validation and translation to the clinic. Clinical PerspectiveO_ST_ABSWhat is KnownC_ST_ABSO_LIAtrial fibrillation arises from multiple interacting multiscale mechanisms, which limit the effectiveness of single-target therapies. C_LIO_LICurrent single-target antiarrhythmic drugs for atrial fibrillation show more limited efficacy and higher adverse event rates in women than in men C_LI What the Study AddsO_LIThis study demonstrates that effective pharmacologic strategies require different combinations of ion channel and calcium handling modulation in males versus females with persistent (chronic) atrial fibrillation. C_LIO_LIIn males, coordinated Na+ and K+ channel inhibition most effectively improves electrical stability, whereas in females additional targeting of Ca2+ handling is required to suppress triggered activity. C_LIO_LISex-specific multi-target drug strategies including partial recovery of intercellular coupling suppress triggered activity and reentry in atrial tissue while preserving conduction. C_LI

pharmacology and toxicology↗

bioRxiv2025

Mechanistic Insights into Sex Differences in Atrial Electrophysiology and Arrhythmia Vulnerability through Sex-specific Computational Models.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is characterized by notable sex differences in clinical presentation, treatment response, and outcomes. Although prevalence is similar between sexes, women often experience more severe symptoms, higher rates of adverse drug effects, and reduced treatment efficacy. To investigate the underlying sex-specific AF mechanisms, we developed and validated male and female human atrial cardiomyocyte models that integrate known sex-based differences in electrophysiology and calcium (Ca2+) handling under normal sinus rhythm (nSR) and chronic AF (cAF) conditions. While the model parameterizations were based on limited human data, and the assumptions may not capture the full spectrum of clinical variability, the models reproduced key reported sex-dependent differences in human atrial cardiomyocyte action potential (AP) and Ca2+ transient (CaT) dynamics. Simulations revealed that both sexes exhibited shortened effective refractory periods and wavelengths in cAF vs. nSR. However, females were more prone to delayed afterdepolarizations (DADs), while males were more susceptible to AP duration (APD) and CaT amplitude (CaTAmp) alternans. Population-based modeling identified distinct parameter associations with arrhythmia mechanisms, whereby DAD vulnerability was associated with enhanced ryanodine receptor sensitivity to Ca2+ (in females), and alternans in males correlated with reduced L-type Ca2+ current maximal conductance. Pharmacological simulations revealed sex-specific responses to antiarrhythmic therapies. In males, multiple drug combinations proved effective in restoring APD at 90% repolarization (APD90), CaTAmp, and reducing alternans susceptibility, whereas females responded to only one combination improving APD90 and CaTAmp but with minimal impact on DAD risk. These findings underscore the need for sex-specific therapeutic strategies and support the use of computational modeling in guiding precision medicine approaches against AF. Key pointsO_LIAtrial fibrillation (AF) is a common heart rhythm disorder that presents differently in males and females, but how the underlying mechanisms differ in males and females is not fully understood. C_LIO_LIWe developed and validated computer models of male and female human atrial cardiomyocytes that incorporate known sex differences in ion channels and calcium handling under normal sinus rhythm and AF conditions. C_LIO_LIUnder normal rhythm, males and females showed distinct electrical activity, which became less pronounced in AF. In AF, both sexes showed reduced effective refractory period and wavelength and depressed calcium transients. Males were more susceptible to electrical alternans, while females showed a greater tendency for calcium-driven delayed afterdepolarizations. C_LIO_LISimulated drug treatments showed greater benefit in male models, particularly with combinations targeting multiple potassium channels, while female models showed limited response. These results highlight the need for sex-specific approaches to treating AF and may help guide future drug development. C_LI

physiology↗

bioRxiv2023

Dual effects of the small-conductance Ca2+-activated K+ current on human atrial electrophysiology and Ca2+-driven arrhythmogenesis: an in silico study

By sensing changes in intracellular Ca2+, small-conductance Ca2+-activated K+ (SK) channels dynamically regulate the dynamics of the cardiac action potential (AP) on a beat-to-beat basis. Given their predominance in atria vs. ventricles, SK channels are considered a promising atrial-selective pharmacological target against atrial fibrillation (AF), the most common cardiac arrhythmia. However, the precise contribution of SK current (ISK) to atrial arrhythmogenesis is poorly understood, and may potentially involve different mechanisms that depend on species, heart rates, and degree of AF-induced atrial remodeling. Both reduced and enhanced ISK have been linked to AF. Similarly, both SK channel up- and downregulation have been reported in chronic AF (cAF) vs. normal sinus rhythm (nSR) patient samples. Here, we use our multi-scale modeling framework to obtain mechanistic insights into the contribution of ISK in human atrial myocyte electrophysiology. We simulate several protocols to quantify how ISK modulation affects the regulation of AP duration (APD), Ca2+ transient, refractoriness, and occurrence of alternans and delayed afterdepolarizations (DADs). Our simulations show that ISK activation shortens the APD and atrial effective refractory period, limits Ca2+ cycling, and slightly increases the propensity for alternans in both nSR and cAF conditions. We also show that increasing ISK counteracts DAD development by reducing the coupling between transmembrane potential and intracellular Ca2+. Taken together, our results suggest that increasing ISK in human atrial myocytes could promote reentry, while protecting against triggered activity. Depending on the leading arrhythmogenic mechanism, ISK inhibition may thus be a beneficial or detrimental anti-AF strategy.

physiology↗