Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age

Pecha, Simon; Ismaili, Djemail; Geelhoed, Bastiaan; Knaut, Michael; Reichenspurner, Hermann; Eschenhagen, Thomas; Schnabel, Renate B.; Christ, Torsten; Ravens, Ursula

doi:10.1016/j.yjmcc.2023.01.006

Cited by 5 publications

(6 citation statements)

References 58 publications

(73 reference statements)

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“…Next, we simulated I Ks contribution to repolarization in AF. Our computer model nicely reproduced the higher plateau potential in AF than in SR 10 under basal conditions ( Figure 5A vs. 6A ), leading to a stronger activation of both I Ks and I Kr compared with SR (four-fold vs. two-fold; Figure 5B and C , left, vs. Figure 6B and C , left).…”

Section: Resultsmentioning

confidence: 58%

“…While patch clamp data were not used before from human atrial cardiomyocytes, basal AP data (before adding potassium channel blockers) were used for a larger retrospective analysis focusing on impact of sex and age on AP characteristics. 10 Patients in AF were older than in SR, and ejection fraction was not reduced in both groups (57 and 51% in SR and AF, respectively). The majority of patients was treated with β-blockers, diuretics, and angiotensin-converting enzyme-inhibitors (for details, see Table 1 ).…”

Section: Methodsmentioning

confidence: 76%

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Human induced pluripotent stem cell–derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium

Sönmez,

Goldack,

Nurkkala

et al. 2024

Europace

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Background Human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCM) could be a helpful tool to study the physiology and diseases of the human atrium. To fulfill this expectation, the electrophysiology of hiPSC-aCM should closely resemble the situation in human atrium. Data on the contribution of the slowly activating delayed rectifier currents (IKs) to repolarization are lacking for both human atrium and hiPSC-aCM. Methods Human atrial tissues were obtained from patients with sinus rhythm (SR) or atrial fibrillation (AF). Currents were measured in human atrial cardiomyocytes (aCM) and compared with hiPSC-aCM and used to model IKs contribution to action potential (AP) shape. AP were recorded by sharp microelectrodes. HMR-1556 (1 µM) was used to identify IKs and to estimate IKs contribution to repolarization. Results Less than 50% of hiPSC-aCM and aCM possessed IKs. Frequency of occurrence, current densities, activation/deactivation kinetics and voltage-dependency of IKs did not differ significantly between hiPSC-aCM and aCM, neither in SR nor AF. β-adrenoceptor stimulation with isoprenaline did not increase IKs neither in aCM nor in hiPSC-aCM. In tissue from SR block of IKs with HMR-1556 did not lengthen the action potential duration, even when repolarization reserve was reduced by block of the ultrarapid repolarizing current with 4-aminopyridine or the rapidly activating delayed rectifier potassium outward current with E-4031. Conclusions IKs exists in hiPSC-aCM with biophysics not different from aCM. As in adult human atrium (SR and AF), IKs does not appear to relevantly contribute to repolarization in hiPSC-aCM.

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Section: Resultsmentioning

confidence: 58%

Section: Methodsmentioning

confidence: 76%

Human induced pluripotent stem cell–derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium

Sönmez,

Goldack,

Nurkkala

et al. 2024

Europace

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“…Interestingly, recent characterization of atrial APs from male and female patients revealed some sex-dependent differences in AP duration and resting membrane potential; however, these differences were only present in nSR conditions and were diminished in AF. 43 Additionally, previous expression profiling of human hearts identified several ion channels that were sex-differentially expressed or modified. 30,63 Therefore, future studies should integrate additional sex-dependent differences in electrophysiology to extend our sex-specific models to investigate the sex-specific interactive role of AP and Ca 2+ processes in promoting AF and as therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

“…As such, we next sought to determine the arrhythmogenic propensity of atrial cardiomyocytes using a pacing-pause protocol. Because experimental characterization of sex differences in atrial electrophysiology is lacking, and a recent study reported no difference between male and female AP characteristics in AF at 1 Hz, 43 we applied an AP-clamp protocol to provoke SCRs using the same AP configuration for both sexes. This allowed studying the effects of sex differences in Ca 2+ handling independent of possible sex differences in atrial electrophysiology.…”

Section: Fast Atrial Rate-induced Scr Events Are More Frequent In Fem...mentioning

confidence: 99%

Enhanced Ca²⁺-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

Zhang,

Wu,

Smith

et al. 2024

Preprint

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Background and AimsSubstantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca2+dysregulation, whereby female cardiomyocytes more frequently exhibit potentially proarrhythmic Ca2+-driven instabilities compared to male cardiomyocytes. In this study, we aim to gain a mechanistic understanding of the Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in males vs females and establish their responses to Ca2+-targeted interventions.Methods and ResultsWe incorporated known sex differences and AF-associated changes in the expression and phosphorylation of key Ca2+-handling proteins and in ultrastructural properties and dimensions of atrial cardiomyocytes into our recently developed 3D atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca2+-handling processes. Our simulations of quiescent cardiomyocytes show increased incidence of Ca2+sparks in female vs male myocytes in AF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to develop pacing-induced spontaneous Ca2+releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca2+transients compared with the male model. Parameter sensitivity analysis uncovered precise arrhythmogenic contributions of each component that was implicated in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation in female AF cardiomyocytes emerged as the major SCR contributor, while reduced L-type Ca2+current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulations of tentative Ca2+-targeted interventions identified potential strategies to attenuate Ca2+-driven arrhythmogenic events in female atria (e.g., t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase), and revealed enhanced efficacy when applied in combination.ConclusionsOur sex-specific computational models of human atrial cardiomyocytes uncover increased propensity to Ca2+-driven arrhythmogenic events in female compared to male atrial cardiomyocytes in AF, and point to combined Ca2+-targeted interventions as promising approaches to treat AF in female patients. Our study establishes that AF treatment may benefit from sex-dependent strategies informed by sex-specific mechanisms.Translational perspectiveAccumulating evidence demonstrates substantial sex-related differences in atrial fibrillation (AF), which is the most common arrhythmia, with female patients faring worse with the condition. By integrating known sex-differential components into our computational atrial cardiomyocyte model we found that female atrial cardiomyocytes in AF exhibit greater propensity to develop Ca2+-driven arrhythmia than male cardiomyocytes. Model analyses provided novel mechanistic insights and suggested strategies such as t-tubule restoration, correction of Ca2+-handling disturbances, and the combination of both, as promising approaches to treat AF in female patients. Our study uncovers and validate sex-specific AF mechanisms and inform the development of targeted anti-AF strategies.Graphical abstractSex-specific 3D spatiotemporal models of human atrial cardiomyocyte Ca2+signaling reveal a greater propensity to develop Ca2+-driven arrhythmic events in female vs male atrial cardiomyocytes in AF. Model analysis links sex-specific AF remodeling to arrhythmogenic mechanisms. AF, atrial fibrillation; SCR, spontaneous Ca2+release; CaT, cytosolic Ca2+transient; RyR2-P, phosphorylated ryanodine receptor type 2 (RyR2); CSQ, calsequestrin; LTCC, L-type Ca2+channel; PLB, phospholamban; SERCA, sarcoendoplasmic reticulum Ca2+ATPase.

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“…Furthermore, some studies have shown modulatory effects of sex-steroids on mRNA levels of ion channels [ 20 , 23 ]. One study has recently shown that there is a significant difference in the resting membrane potential (RMP) between men and women, possibly due to fewer inward rectifier channels in women, thus resulting in a slower conduction in the atria of women [ 24 ]. This could also be a potential mechanistic explanation for the lower incidence of AF in women [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Sex on the Susceptibility for Atrial Fibrillation in Pigs with Ischemic Heart Failure

Pauly

Vlcek

Zhang

et al. 2023

Cells

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Atrial fibrillation (AF) is the most prevalent arrhythmia, often caused by myocardial ischemia/infarction (MI). Men have a 1.5× higher prevalence of AF, whereas women show a higher risk for new onset AF after MI. However, the underlying mechanisms of how sex affects AF pathophysiology are largely unknown. In 72 pigs with/without ischemic heart failure (IHF) we investigated the impact of sex on ischemia-induced proarrhythmic atrial remodeling and the susceptibility for AF. Electrocardiogram (ECG) and electrophysiological studies were conducted to assess electrical remodeling; histological analyses were performed to assess atrial fibrosis in male and female pigs. IHF pigs of both sexes showed a significantly increased vulnerability for AF, but in male pigs more and longer episodes were observed. Unchanged conduction properties but enhanced left atrial fibrosis indicated structural rather than electrical remodeling underlying AF susceptibility. Sex differences were only observed in controls with female pigs showing an increased intrinsic heart rate, a prolonged QRS interval and a prolonged sinus node recovery time. In sum, susceptibility for AF is significantly increased both in male and female pigs with ischemic heart failure. Differences between males and females are moderate, including more and longer AF episodes in male pigs and sinus node dysfunction in female pigs.

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Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age

Cited by 5 publications

References 58 publications

Human induced pluripotent stem cell–derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium

Human induced pluripotent stem cell–derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium

Enhanced Ca²⁺-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

Effects of Sex on the Susceptibility for Atrial Fibrillation in Pigs with Ischemic Heart Failure

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Resting membrane potential is less negative in trabeculae from right atrial appendages of women, but action potential duration does not shorten with age

Cited by 5 publications

References 58 publications

Human induced pluripotent stem cell–derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium

Human induced pluripotent stem cell–derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium

Enhanced Ca2+-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

Effects of Sex on the Susceptibility for Atrial Fibrillation in Pigs with Ischemic Heart Failure

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Resources

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Enhanced Ca²⁺-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling