Mouse models of spontaneous atrial fibrillation

Keefe, Joshua; Hulsurkar, Mohit; Reilly, Svetlana; Wehrens, Xander H.T.

doi:10.1007/s00335-022-09964-x

Cited by 6 publications

(9 citation statements)

References 98 publications

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“…Our main finding was that the combination of both conditions was necessary to induce spontaneous atrial tachyarrhythmias in aged C57BL/6 mouse hearts. As discussed in recent comprehensive reviews, murine models offer unique opportunities to investigate atrial tachyarrhythmias including AF (Keefe et al, 2022; Riley et al, 2012; Schuttler et al, 2020). However, very few mouse models exhibit spontaneous tachyarrhythmias and the majority require supraphysiological stimuli to induce arrhythmogenesis (Keefe et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…As discussed in recent comprehensive reviews, murine models offer unique opportunities to investigate atrial tachyarrhythmias including AF (Keefe et al, 2022; Riley et al, 2012; Schuttler et al, 2020). However, very few mouse models exhibit spontaneous tachyarrhythmias and the majority require supraphysiological stimuli to induce arrhythmogenesis (Keefe et al, 2022). Atrial tachyarrhythmias are often intermittent in nature which hinders detection in vivo, particularly without concomitant triggering factors.…”

Section: Discussionmentioning

confidence: 99%

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Atrial arrhythmogenesis in ex vivo aged mouse hearts with hypokalemia and right atrial stretch

Cayton,

Nourian,

Lambert

et al. 2023

Preprint

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Introduction: Atrial Fibrillation (AF) and atrial flutter (AFL) are the two most common cardiac arrhythmias in the United States. While advanced age has been correlated to AF/AFL, the lack of an appropriate animal model has hindered progress on better understanding the pathophysiology of atrial arrhythmogenesis. Both hypokalemic conditions and hemodynamic stretch have been associated with atrial tachyarrhythmias in patient populations. The purpose of this study was to examine the incidence of atrial tachyarrhythmias in an ex vivo aging C57BL/6 mouse model following hypokalemia and stretch challenges. Methods: Hearts were isolated with combined cannulation of the aorta and superior vena cava in a modified right-sided working heart perfusion technique. Isolated hearts of Aged (26-29 month) male (n=14) and female (n=14) mice were subjected to normokalemic and hypokalemic conditions +/- atrial preload elevation to 12 cmH20 to induce atrial stretch. Heart rate, right ventricular (RV) pressure development, and incidence of atrial tachyarrhythmias were monitored using a pressure catheter and intracardiac electrocardiogram. Results: In response to hypokalemia, there were no changes in mean heart rate, RV pressure development, or RV Rate-Pressure Product (Rate x RV peak pressure). Atrial tachyarrhythmias were not observed under baseline conditions, and only 1 of 8 hearts exhibited atrial tachycardia following the hypokalemia challenge. In response to atrial preload elevation, there was an increase in heart rate (P=0.0006 versus baseline) with no change in RV pressure development. RV Rate-Pressure Product was significantly elevated (P=0.013 versus baseline) with atrial preload due to the increase in heart rate. Atrial tachyarrhythmias were not observed under both baseline conditions and following atrial preload elevation. In response to the combined hypokalemia and preload challenges, there was an increase in heart rate (P=0.008 versus baseline) with no change in RV pressure development or RV Rate Pressure product. Atrial tachyarrhythmias were not observed under baseline conditions, yet after the combined challenges 50% of aged hearts exhibited atrial tachycardia or AF/AFL. During bouts of AF/AFL, the AF/AFL led to a variable ventricular response and concomitant contractile dysfunction in the form of variable RV pressure development. Conclusion: Ex vivo aged mouse hearts exhibit atrial tachyarrhythmias in response to combined hypokalemia and right atrial stretch conditions. The aged C57BL/6 mouse model is therefore useful for pre-clinical studies of atrial arrhythmogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Atrial arrhythmogenesis in ex vivo aged mouse hearts with hypokalemia and right atrial stretch

Cayton,

Nourian,

Lambert

et al. 2023

Preprint

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“…When using transesophageal PES, several factors can influence AF inducibility, including age, sex, and the pacing protocol employed. AF susceptibility increases as mice age ( Luo et al, 2013 ; Jansen et al, 2017 ), and determining an age window when AF is inducible in the model under study but not in control mice is essential ( Keefe et al, 2022b ). In addition, only one sex may demonstrate an AF phenotype ( Keefe et al, 2022b ; Murphy et al, 2022b ).…”

Section: Protocol Optimization For Transesophageal Pesmentioning

confidence: 99%

“…While mouse models of AF risk factors Frontiers in Physiology frontiersin.org are not without limitations (e.g., differences in ion channel expression and shorter action potential durations), they do address a number of limitations encountered with large animals and are often quite similar to human disease (Fukui et al, 2013;Guasch et al, 2013). However, few mouse models develop spontaneous AF (Keefe et al, 2022a) and, as a result, most require programmed electrical stimulation (PES) to assess AF susceptibility (Figure 1). Atrial pacing can be performed by either intracardiac stimulation of the right atrium using a multipolar catheter placed into the heart via an internal jugular vein, or by transesophageal pacing, given the close proximity of the esophagus to the posterior left atrium (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice

2023

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Atrial fibrillation (AF) is the most common human arrhythmia and is associated with increased risk of stroke, dementia, heart failure, and death. Among several animal models that have been used to investigate the molecular determinants of AF, mouse models have become the most prevalent due to low cost, ease of genetic manipulation, and similarity to human disease. Programmed electrical stimulation (PES) using intracardiac or transesophageal atrial pacing is used to induce AF as most mouse models do not develop spontaneous AF. However, there is a lack of standardized methodology resulting in numerous PES protocols in the literature that differ with respect to multiple parameters, including pacing protocol and duration, stimulus amplitude, pulse width, and even the definition of AF. Given this complexity, the selection of the appropriate atrial pacing protocol for a specific model has been arbitrary. Herein we review the development of intracardiac and transesophageal PES, including commonly used protocols, selected experimental models, and advantages and disadvantages of both techniques. We also emphasize detection of artifactual AF induction due to unintended parasympathetic stimulation, which should be excluded from results. We recommend that the optimal pacing protocol to elicit an AF phenotype should be individualized to the specific model of genetic or acquired risk factors, with an analysis using several definitions of AF as an endpoint.

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“…Animal models can be used to gain novel insight into the molecular and cellular mechanisms underlying cardiac arrhythmia formation (Wehrens et al., 2000). Mouse models are particularly suitable to uncover the causal relationship between specific genes and inherited arrhythmia syndromes (Dobrev & Wehrens, 2018; Keefe et al., 2023). Mouse models of arrhythmias can also be used to validate new drugs or therapeutic modalities at the preclinical stage.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Cardiac Electrophysiology in Mice: Determination of Atrial and Ventricular Arrhythmic Substrates

Navarro‐Garcia,

Bruns,

Moore

et al. 2024

Current Protocols

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Cardiac arrhythmias are a common cardiac condition that might lead to fatal outcomes. A better understanding of the molecular and cellular basis of arrhythmia mechanisms is necessary for the development of better treatment modalities. To aid these efforts, various mouse models have been developed for studying cardiac arrhythmias. Both genetic and surgical mouse models are commonly used to assess the incidence and mechanisms of arrhythmias. Since spontaneous arrhythmias are uncommon in healthy young mice, intracardiac programmed electrical stimulation (PES) can be performed to assess the susceptibility to pacing‐induced arrhythmias and uncover the possible presence of a proarrhythmogenic substrate. This procedure is performed by positioning an octopolar catheter inside the right atrium and ventricle of the heart through the right jugular vein. PES can provide insights into atrial and ventricular electrical activity and reveal whether atrial and/or ventricular arrhythmias are present or can be induced. Here, we explain detailed procedures used to perform this technique, possible troubleshooting scenarios, and methods to interpret the results obtained. © 2024 Wiley Periodicals LLC.Basic Protocol: Programmed electrical stimulation in mice

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Mouse models of spontaneous atrial fibrillation

Cited by 6 publications

References 98 publications

Atrial arrhythmogenesis in ex vivo aged mouse hearts with hypokalemia and right atrial stretch

Atrial arrhythmogenesis in ex vivo aged mouse hearts with hypokalemia and right atrial stretch

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice

In Vivo Cardiac Electrophysiology in Mice: Determination of Atrial and Ventricular Arrhythmic Substrates

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