Subthreshold delayed afterdepolarizations provide an important arrhythmogenic substrate in the border zone of infarcted hearts

Campos, Fernanda; Shiferaw, Yohannes; Whitaker, John; Plank, Gernot; Bishop, Martin J.

doi:10.1016/j.hrthm.2022.10.026

Cited by 4 publications

(5 citation statements)

References 28 publications

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“…Indeed, triggered activity or automaticity can contribute to the initiation or sustained activity of a re-entry circuit. Additionally, it has been demonstrated that DADs may provide a substrate for the initiation of re-entry arrhythmias in the border zone of an infarcted area (54). In silico models suggest that when DADs occur below the threshold for action potential initiation, it may lead to inactivation of the late sodium current (INa) and impaired excitability.…”

Section: Ca 2+ Alternansmentioning

confidence: 99%

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CaMKII inhibition has dual effects on spontaneous Ca²⁺ release and Ca²⁺ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation

Sadredini

Hansen

Frisk

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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In conditions with abnormally increased activity of the cardiac ryanodine receptor (RyR2), Ca2+/calmodulin-dependent protein kinase II (CaMKII) can contribute to a further destabilization of RyR2 that results in triggered arrhythmias. Therefore, inhibition of CaMKII in such conditions has been suggested as a strategy to suppress RyR2 activity and arrhythmias. However, suppression of RyR2 activity can lead to the development of arrhythmogenic Ca2+ alternans. Aim: To test whether suppression of RyR2 activity caused by inhibition of CaMKII increases propensity for Ca2+ alternans. Methods and results: We studied spontaneous Ca2+-release events and Ca2+ alternans in isolated left ventricular cardiomyocytes from mice carrying the gain-of-function RyR2 mutation RyR2-R2474S and from wild-type mice. CaMKII inhibition by KN-93 effectively decreased the frequency of spontaneous Ca2+-release events in RyR2‑R2474S cardiomyocytes exposed to the β‑adrenoceptor agonist isoprenaline. However, KN-93-treated RyR2-R2474S cardiomyocytes also showed increased propensity for Ca2+ alternans and increased Ca2+ alternans ratio compared with both an inactive analog of KN‑93 and with vehicle-treated controls. This increased propensity for Ca2+ alternans was explained by prolongation of Ca2+-release refractoriness. Importantly, the increased propensity for Ca2+ alternans in KN‑93-treated RyR2-R2474S cardiomyocytes did not surpass that of wild-type. Conclusions: Inhibition of CaMKII efficiently reduces spontaneous Ca2+-release, but promotes Ca2+ alternans in RyR2-R2474S cardiomyocytes with a gain-of-function RyR2 mutation. The dominant effect in RyR2-R2474S is to reduce spontaneous Ca2+-release, which supports this intervention as a therapeutic strategy in this specific condition. However, future studies on CaMKII inhibition in conditions with increased propensity for Ca2+ alternans should include investigation of both phenomena.

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Section: Ca 2+ Alternansmentioning

confidence: 99%

“…In silico models suggest that when DADs occur below the threshold for action potential initiation, it may lead to inactivation of the late sodium current (INa) and impaired excitability. This substrate may contribute to increased risk of re-entry arrhythmias (54).…”

Section: Ca 2+ Alternansmentioning

confidence: 99%

CaMKII inhibition has dual effects on spontaneous Ca²⁺ release and Ca²⁺ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation

Sadredini

Hansen

Frisk

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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“…Recent studies have shown that DADs which inactivate I Na can simultaneously cause both focal excitations and conduction block, highlighting the importance of this novel mechanism (Campos et al., 2017, 2018, 2022; Liu et al., 2015). Our study adds further weight to the impact of subthreshold DADs, while also revealing a novel mechanism of non‐refractory induced unidirectional conduction block: the propagation of subthreshold DADs in one region that emerge as full excitations into another adjacent region.…”

Section: Discussionmentioning

confidence: 99%

Interactions between calcium‐induced arrhythmia triggers and the electrophysiological–anatomical substrate underlying the induction of atrial fibrillation

Colman,

Varela,

MacLeod

et al. 2024

The Journal of Physiology

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Atrial fibrillation (AF) is the most common cardiac arrhythmia and is sustained by spontaneous focal excitations and re‐entry. Spontaneous electrical firing in the pulmonary vein (PV) sleeves is implicated in AF generation. The aim of this simulation study was to identify the mechanisms determining the localisation of AF triggers in the PVs and their contribution to the genesis of AF. A novel biophysical model of the canine atria was used that integrates stochastic, spontaneous subcellular Ca2+ release events (SCRE) with regional electrophysiological heterogeneity in ionic properties and a detailed three‐dimensional model of atrial anatomy, microarchitecture and patchy fibrosis. Simulations highlighted the importance of the smaller inward rectifier potassium current (IK1) in PV cells compared to the surrounding atria, which enabled SCRE more readily to result in delayed‐afterdepolarisations that induced triggered activity. There was a leftward shift in the dependence of the probability of triggered activity on sarcoplasmic reticulum Ca2+ load. This feature was accentuated in 3D tissue compared to single cells (Δ half‐maximal [Ca2+]SR = 58 μM vs. 22 μM). In 3D atria incorporating electrical heterogeneity, excitations preferentially emerged from the PV region. These triggered focal excitations resulted in transient re‐entry in the left atrium. Addition of fibrotic patches promoted localised emergence of focal excitations and wavebreaks that had a more substantial impact on generating AF‐like patterns than the PVs. Thus, a reduced IK1, less negative resting membrane potential, and fibrosis‐induced changes of the electrotonic load all contribute to the emergence of complex excitation patterns from spontaneous focal triggers. imageKey points Focal excitations in the atria are most commonly associated with the pulmonary veins, but the mechanisms for this localisation are yet to be elucidated. We applied a multi‐scale computational modelling approach to elucidate the mechanisms underlying such localisations. Myocytes in the pulmonary vein region of the atria have a less negative resting membrane potential and reduced time‐independent potassium current; we demonstrate that both of these factors promote triggered activity in single cells and tissues. The less negative resting membrane potential also contributes to heterogeneous inactivation of the fast sodium current, which can enable re‐entrant‐like excitation patterns to emerge without traditional conduction block.

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“…In Campos et al . [42], it was demonstrated that subthreshold DADs in the isthmus within a scar could provide the necessary conditions for both conduction block of the incoming wavefront and the degeneration into re-entry.…”

Section: Discussionmentioning

confidence: 99%

“…demonstrated that DADs in one region of tissue could inactivate I Na and block the excitation wavefront emerging from another region of tissue, leading to both unidirectional conduction patterns and re-entry. In Campos et al [42], it was demonstrated that subthreshold DADs in the isthmus within a scar could provide the necessary conditions for both conduction block of the incoming wavefront and the degeneration into re-entry. This present study contributes to the growing understanding of these mechanisms by elucidating how triggers and substrates can interact to form complex excitation patterns.…”

Section: Mechanism Of Dad-mediated Focal Triggers In Fibrotic Tissuementioning

confidence: 99%

Patchy fibrosis promotes trigger–substrate interactions that both generate and maintain atrial fibrillation

Colman,

Sharma,

Aslanidi

et al. 2023

Interface Focus.

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Fibrosis has been mechanistically linked to arrhythmogenesis in multiple cardiovascular conditions, including atrial fibrillation (AF). Previous studies have demonstrated that fibrosis can create functional barriers to conduction which may promote excitation wavebreak and the generation of re-entry, while also acting to pin re-entrant excitation in stable rotors during AF. However, few studies have investigated the role of fibrosis in the generation of AF triggers in detail. We apply our in-house computational framework to study the impact of fibrosis on the generation of AF triggers and trigger–substrate interactions in two- and three-dimensional atrial tissue models. Our models include a reduced and efficient description of stochastic, spontaneous cellular triggers as well as a simple model of heterogeneous inter-cellular coupling. Our results demonstrate that fibrosis promotes the emergence of focal excitations, primarily through reducing the electrotonic load on individual fibre strands. This enables excitation to robustly initiate within these single strands before spreading to neighbouring strands and inducing a full tissue focal excitation. Enhanced conduction block can allow trigger–substrate interactions that result in the emergence of complex, re-entrant excitation patterns. This study provides new insight into the mechanisms by which fibrosis promotes the triggers and substrate necessary to induce and sustain arrhythmia.

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Subthreshold delayed afterdepolarizations provide an important arrhythmogenic substrate in the border zone of infarcted hearts

Cited by 4 publications

References 28 publications

CaMKII inhibition has dual effects on spontaneous Ca²⁺ release and Ca²⁺ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation

CaMKII inhibition has dual effects on spontaneous Ca²⁺ release and Ca²⁺ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation

Interactions between calcium‐induced arrhythmia triggers and the electrophysiological–anatomical substrate underlying the induction of atrial fibrillation

Patchy fibrosis promotes trigger–substrate interactions that both generate and maintain atrial fibrillation

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Subthreshold delayed afterdepolarizations provide an important arrhythmogenic substrate in the border zone of infarcted hearts

Cited by 4 publications

References 28 publications

CaMKII inhibition has dual effects on spontaneous Ca2+ release and Ca2+ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation

CaMKII inhibition has dual effects on spontaneous Ca2+ release and Ca2+ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation

Interactions between calcium‐induced arrhythmia triggers and the electrophysiological–anatomical substrate underlying the induction of atrial fibrillation

Patchy fibrosis promotes trigger–substrate interactions that both generate and maintain atrial fibrillation

Contact Info

Product

Resources

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CaMKII inhibition has dual effects on spontaneous Ca²⁺ release and Ca²⁺ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation

CaMKII inhibition has dual effects on spontaneous Ca²⁺ release and Ca²⁺ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation