Open access peer-reviewed chapter - ONLINE FIRST
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia with potentially severe consequences that include stroke and sudden death. A high prevalence in the general population, combined with severe morbidity and mortality, make AF a major public health concern. Factors that predispose to AF are numerous and complex and include electrical, structural, neurohumoral, immunological and inflammatory remodeling of the heart. This chapter provides a review of animal and computational models of AF that have provided insights into this complex arrhythmia. These models bridge the gap between nonclinical and clinical research, and have been indispensable for expanding our understanding of the many factors that contribute to progression of this arrhythmia. Using a wide variety of investigational approaches and scientific models, researchers gain insights into mechanisms that affect the onset and progression of AF, as well as test novel treatments and therapeutic strategies.
Keywords
- atrial fibrillation
- experimental animal models
- computational models
- arrhythmia
- cardiac electrophysiology
1. Introduction
Atrial Fibrillation (AF) is the most common sustained arrhythmia that is linked with negative health outcomes [1]. The Global Burden project estimated that in 2016, about 46.3 million people globally were affected by AF [2]. In 2004, the lifetime risk of developing AF for white men and women over 40 years was about 1 in 4 [3]. However, a decade later, this risk increased to approximately 1 in 3 for white individuals and 1 in 5 for Black individuals [4]. In the United States, between 3 and 6 million individuals currently suffer from AF, and predictions suggest this could rise to approximately 6 to 16 million by 2050 [5, 6]. Meanwhile, in Europe there were about 9 million cases of AF in 2010 among those aged 55 and older. This number is anticipated to grow to 14 million by 2060 [7, 8]. Projections for Asia suggest that by 2050, AF will be diagnosed in roughly 72 million people, with almost 3 million of those experiencing AF-related strokes [9, 10]. The clinical risk factors for AF include advancing age, diabetes, hypertension, congestive heart failure, rheumatic and nonrheumatic valve disease, and myocardial infarction [11].
This chapter reviews different types of large and small animal models of AF that have been developed as investigational tools for the study of mechanisms and treatments of AF. This review includes the development of computational models that have provided further insights that are often untestable in animal model experimentation.
2. Sterile pericarditis-induced AF
Sterile pericarditis emerged as an early, valuable approach for inducing AF in animal models. This model involves the introduction of irritants into the pericardial space, triggering a localized inflammatory response that alters atrial conduction and refractoriness, favoring a substrate for AF initiation and persistence. Several techniques have been utilized to induce sterile pericarditis, each having distinct aspects of the inflammatory response and overall development of AF.
2.1 Techniques to elicit sterile pericarditis
Mineral Oil Injection: The injection of sterile mineral oil into the pericardial space serves as an effective technique to induce sterile pericarditis. This method triggers an inflammatory response characterized by immune cell infiltration and cytokine release, resulting in an environment conducive to AF-associated inflammation.
Talc Administration: Intrapericardial talc injection induces inflammation via pleuropericardial irritation, leading to fibrinous pericarditis. The resulting inflammatory cascade extends to the atrial myocardium, promoting electrophysiological changes comparable of those seen in clinical AF.
Lipopolysaccharide (LPS) Administration: LPS is a component of Gram-negative bacterial cell walls. When it is introduced intrapericardially, it elicits an immune response similar to infection-induced pericarditis. This approach demonstrates the role of immune activation in AF pathogenesis, offering insights into the connection between inflammation and arrhythmogenesis.
When creating an animal model of AF, there are a variety of techniques employed to create a suitable inflammatory response that is conducive to formation of a pro-fibrillatory substrate. Sterile pericarditis created in a swine model has been achieved by placing double-layer gauze on the surface of the left and right atrial walls, combined with spreading talcum powder on the exterior of atrial surfaces [12]. A similar approach for inducing AF in a canine model using sterile pericarditis employed talcum powder coating, followed by single-layer gauze placement on the right and left atrial free walls, which was adequate for creating an atrial substrate prone to AF [13]. Another approach employing sterile pericarditis in canines used arachidonic acid applied to atrial appendages to trigger an acute inflammatory response promoting AF, where treatment with anti-inflammatory drugs attenuated arrhythmogenic effects [14]. Furthermore, simple pericardiotomies, involving a cutdown of the pericardium, have been performed on rabbits to induce AF. Here, histone deacetylase (HDAC), an epigenetic regulator of cardiac remodeling during cardiovascular disease, was inhibited to reduce instances of AF in rabbits [15]. Within these models, researchers have observed increased frequency of premature atrial contractions, shortened atrial refractory periods, cardiac hypertrophy and elevated fibrosis that is commonly observed in clinical cases of AF [12, 13, 15].
2.2 Large animal models utilizing sterile pericarditis
Sterile pericarditis-induced AF has been primarily explored in larger animal models like dogs, pigs and goats, as they share a comparable atrial anatomy and size to humans. Large animal models allow for the introduction of catheter-based electrophysiological mapping and monitoring, making them suitable for studying mechanisms of AF [16, 17]. This feature of large animal models makes them useful for studying the spatiotemporal dynamics of AF [14], and offers insights into AF progression from paroxysmal to persistent [18], allowing researchers to investigate mechanisms of reentrant circuits and rotor formation [19, 20, 21] that are hallmarks of AF. The utility of the large animal AF model lies in its similarity to human clinical AF, including the ability to maintain high-frequency atrial activation, electrophysiological heterogeneity, electrical remodeling, and reentrant circuit establishment as the principal driver of AF.
Sterile pericarditis as a method for AF induction gives rise to structural and electrical remodeling that is similar to that observed in clinical AF. Characteristics of cardiac remodeling that favor an atrial substrate conducive to AF include persistence of atrial flutter, altered gap junction connexin 40 and 43 distribution, unstable re-entrant circuits near and around the pulmonary veins and atrial septum, presence of short-lived rotors, and a dysregulated inflammatory response [14, 22, 23, 24, 25, 26]. These characteristics provide researchers with a reliable and robust environment to study the onset and progression of AF as well as novel treatments that may reduce re-entrant events or mitigate progression of the arrhythmia.
2.3 Insights and implications
Researchers employing sterile pericarditis-induced AF models have investigated the relationship between inflammation, structural remodeling, and electrophysiological changes in the pathogenesis of AF [12, 13, 15, 23, 27]. Through these models, researchers have been able to understand the contributions of pro-inflammatory cytokines, immune cell infiltration, and fibrotic changes to atrial electrical remodeling [15, 23]. These models confirm that inflammation plays a crucial role in creating an arrhythmogenic substrate, and that atrial fibrosis is a critical factor contributing to AF maintenance [15, 27, 28]. Insights from sterile pericarditis models have shaped the development of anti-inflammatory and antifibrotic therapeutic strategies that address underlying mechanisms that drive AF [15].
The use of sterile pericarditis in animal models allows researchers to study the effects of post-operative atrial fibrillation (POAF), a condition that occurs in 30–50% of patients several days following open heart surgery who have no prior medical history of AF [29, 30]. Other studies have claimed these occurrences for POAF to range from 10 to 65% of patients, where onset of AF occurred around 2–3 days following surgery [31]. Observing and studying inflammatory mechanisms in controlled instances of POAF has been done through inducing sterile pericarditis in canine and swine models as they share comparative structural anatomies and electrophysiological properties to that of a human heart [12, 13, 27]. Open heart surgery leading to AF can lead to a multitude of complications that compromise cardiac functionality. Heightened risk of myocardial ischemia, decreased diastolic filling and cardiac output, loss of optimal atrial contraction leading to increased pulmonary arterial pressure make up several of these complications [32]. As a result, POAF is associated with increased stroke risk, mortality, and hospital stays [31, 33]. Developing novel treatments to reduce the risks exacerbated by AF drives much of the current research, making animal models an indispensable research approach. Sterile pericarditis provides a reliable and replicable model to assess onset, progression, maintenance, and treatment of AF.
3. Canine models of AF
3.1 Inducing AF in canine models
The research behind canine models of AF unravels a range of techniques designed to replicate the intricate arrhythmic behavior that can be observed in humans. These methods provide insights into distinct features of AF pathophysiology. One of the most common and efficacious techniques in inducing AF in canine models involves rapid atrial pacing (tachypacing), a technique that simulates the electrophysiological dynamics of AF through sustained high-frequency stimulation, commonly induced from pacemaker leads extending into the walls of the atrium [34, 35, 36, 37, 38, 39, 40, 41, 42]. By subjecting the atria to prolonged episodes of rapid pacing, researchers simulate the conditions that induce atrial electrical and structural remodeling similar to the AF substrate. This approach provides a model that recapitulates irregular atrial activation observed in clinical AF, but also shows conduction pathways and refractory period alterations associated with AF onset and stabilization.
In addition to rapid atrial pacing, atrial remodeling induced by heart failure serves as an avenue to understand the relationship between structural and electrical changes leading to AF. Studies have revealed that heart failure triggers substantial atrial remodeling, involving changes in ion channel expression, action potential characteristics, and conduction properties [41, 43]. These changes set the stage for the initiation and perpetuation of AF, further emphasizing how the nature of AF arrhythmogenesis may not all be entirely the same.
3.2 Electrophysiological insights and mapping
Electrophysiological exploration in canine models has ushered in an increased understanding of the mechanisms at play that govern induction and persistence of atrial fibrillation. By carefully mapping and monitoring the electrical landscape of the atria in these models, researchers have expanded their understanding of the initiation and maintenance of AF. Among these insights, atrial refractoriness dispersion takes center stage, demonstrating the critical role it plays in creating a conducive substrate for rotors and reentrant circuits, the hallmark of AF. The canine model’s fidelity to human atrial physiology allows researchers to uncover variations in refractoriness across different atrial regions, providing a greater understanding of the arrhythmia’s onset and persistence.
Conduction velocity alterations also emerge as a key characteristic in AF, clarifying how variations in atrial conduction contribute to the irregular rhythm. Canine AF models have shed light on the regional disparities in conduction velocity, depicting the complex conduction pathways that facilitate the chaotic activation patterns characteristic of AF. These observations not only deepen our understanding of AF but also give rise to potential targets for therapeutics aimed at normalizing conduction velocity and restoring atrial rhythm within patients experiencing AF.
The current understanding of electrophysiological remodeling has been advanced with application of high-resolution electrophysiological mapping techniques, such as the use of catheter-based mapping, in canine models. By employing these techniques, researchers can visualize activation patterns during AF, and further understand the spatial heterogeneity of atrial activation. The atrial dimensions in dogs, similar to those in humans, allow for accurate representation of conduction pathways and provide for the identification of regions prone to reentry. This approach enables scientists to precisely map the pathways through which AF perpetuates, guiding the development of therapeutic strategies that target specific regions of interest.
3.3 Translational implications of canine AF models
Translational implications of canine models in AF research extend far beyond the laboratory, holding promise in shaping clinical interventions and management strategies for individuals experiencing more severe cases of AF. These models not only unveil the dynamic mechanisms underlying onset and persistence of AF, but also serve as testing grounds for novel therapeutic interventions. Using canine models in AF exploration can pave the way for innovative strategies that have a meaningful and effective impact on clinical care. Insights from canine models have been instrumental in refining catheter ablation techniques, which serves as a popular and common practice in treating AF and in AF management. Through accurately mapping conduction pathways and visualizing reentrant circuits [21], these models contribute to the advancement of ablation strategies, leading to improved success rates and patient outcomes.
Furthermore, canine models facilitate the evaluation of antiarrhythmic drugs, bridging the gap between experimental findings and clinical translation. Through these models, researchers can assess the efficacy and safety of potential therapeutic agents, steering drug development towards more targeted and effective treatments for AF [35, 43]. The canine model’s ability to simulate the dynamic environment of AF enhances the predictive value of preclinical trials, ensuring that only the most promising candidates proceed to human trials, thus expediting the drug discovery process. By serving as a bridge for translational research, canine models ultimately increase the tools available for clinicians to combat this arrhythmia in patient settings.
Spontaneous AF is a condition that has been observed to naturally occur in dogs and has been shown to have linkage to certain heart diseases, such as myxomatous mitral valve disease. This dysfunction can lead to enlargement of the left atrium and overall, heart failure, a prognosis commonly seen in clinical cases, increasing mortality [44, 45]. Canine models have seen high use in studying electrophysiological implications of AF. In canine models of AF, action potential durations in pulmonary veins are notably shorter than the surrounding left atrium, having an altered resting membrane potential and lower inward rectifier (IK1) current density [46, 47, 48]. Induction of AF in dogs has been mostly achieved by atrial tachypacing [34, 35, 36, 37, 38, 39, 40, 41, 42], sometimes following catheter-induced atrioventricular node ablation to separate the electrical connection between the atria and ventricles [49]. Notably, atrial tachypacing does not always lead to sustained episodes of AF in dogs: one study found that to achieve sustained AF (AF episodes lasting >15 minutes), atrial tachypacing at a rate of 400 bpm was needed over a 6-week time period [42]. In this model, the resultant decreased atrial refractory period and slowed conduction velocity was directly correlated with how long animal subjects were exposed to atrial tachypacing [42]. Additionally, inflammatory models, such as sterile pericarditis-induced AF, has emerged as a widely used model in studying AF, as outlined above. These models helped reveal the presence of short-lived rotors during episodes of AF as well as demonstrating a correlation between post operative AF and heterogenous atrial conduction [14, 26, 27].
Canine models of AF have shed light on the relationship between the autonomic nervous system and induction of AF. Canine models experiencing atrial tachypacing showed inducibility of AF to be significantly decreased by sympathovagal denervation, indicating that the triggering and modulation of AF episodes lasting at least 1 hour could be related to sympathovagal stimulation [50, 51]. One study found both isoproterenol and acetylcholine were useful in inducing AF and prolonging AF duration [52]. Indeed, combining autonomic stimulation with atrial tachypacing has been proven a reliable trigger for AF in canine models, with acute episodes lasting more than 1 hour [53].
Atrial remodeling in humans, to a degree that is conducive to AF, can occur secondarily to ventricular remodeling [54]. Ventricular tachypacing models of heart failure in canines have been used to study atrial remodeling, where alterations of connexins, reduced expression of ionic currents including ICaL, Ito, and IKs, and increased expression of Na-Ca exchanger activity (INCX), has been observed [41, 55]. These changes parallel various types of cellular remodeling observed in human cardiomyocytes, allowing ventricular tachypacing in canine models to serve as a suitable example for studying AF [56].
Canine models have provided a fruitful platform to study mechanisms, progression, and treatments for various arrhythmias, AF in particular. Nevertheless, canine models do come with limitations. Genetic heterogeneity, stemming from the use of different dog breeds, poses challenges to assessing and studying genetic differences between healthy and AF states in dogs as well as comparing them to human cases. Dog breeds need to be selected and monitored when choosing how the model will be created. Additionally, there are differences in coronary collateralization, heart weight-to-body weight ratio, and ECG metrics (P waves, QRS complexes, and QT intervals) compared to humans [57]. Nonetheless, canines have provided a fruitful model for studying AF.
4. Goat models of AF
In the realm of atrial fibrillation research, the goat model stands out as particularly insightful. Goats can sustain AF for extended periods, up to several weeks. This longitudinal property renders them invaluable in observing long-term structural and electrical modifications that persistent AF induces. However, no model is without its limitations. In the case of goats, researchers must grapple with issues like pronounced ECG variability, characteristically shorter action potentials, a predominance of the left-sided coronary system, and a scarcity of detailed cellular electrophysiological data.
4.1 Atrial tachypaced goat model
Most goat models of AF have employed an atrial tachypacing (ATP) approach that was pioneered by Wijffels [58, 59, 60, 61]. The model design involved surgical thoracotomy, where electrodes were meticulously placed on atrial epicardial surfaces. Goats were treated with a regimen of ampicillin to ward off infections and buprenorphine to manage pain. After recovery, goats were instrumented with an external fibrillation pacemaker. This was achieved using a suspended cable connected to an electrode positioned on the goat’s neck, which interfaced with a multi-channel monitoring apparatus. This design ensured goats retained their full range of movement. Pacemaker operations were managed automatically by computer software, designed to distinguish sinus rhythms from atrial fibrillation. Any detection of regular sinus rhythm immediately triggered the software to deliver biphasic stimuli, thus re-inducing AF.
4.2 Properties of atrial tachypacing goat AF models
Observations from the tachypaced Goat Models unveiled intriguing patterns. The onset of AF initiated a period of electrical remodeling within the first 24 hours. Tachypacing had a pronounced impact on repolarization and atrial excitability. Initial AF episodes were fleeting, often concluding within seconds. But over time, these episodes began to prolong in duration—lasting roughly 20 seconds after a day and then extending into chronic episodes in the weeks that followed. These observations gave rise to the expression, “Atrial Fibrillation Begets Atrial Fibrillation” [60]. As these episodes extended, there was a distinct rise in the fibrillation rate, accompanied by a decrease in the prominence of high-amplitude deflections, making way for more fragmented electrograms.
4.3 Atrial fibrillation begets atrial fibrillation
The concept that AF begets AF was conceived in these early observations [60]. The continual occurrence of AF instigates transformative changes in the heart’s structural anatomy and its electrical properties, thereby predisposing it to further AF episodes. In other words, the more frequently, or the longer one experiences AF, the higher the chances of its recurrence and the longer its duration in subsequent events. This cyclical nature of AF poses two primary challenges:
Electrical Remodeling: Prolonged AF episodes instigate modifications in ion channel expression in atrial cells. This remodeling can drastically alter a fibrillating heart’s response to antiarrhythmic medications, potentially undermining the effectiveness of chemical cardioversion.
Rate Adaptation: When transitioning from AF back to sinus rhythm, there’s a marked shift in atrial interbeat intervals. An inappropriately adjusted, or even counteractive adaptation of the atrial refractory period can leave the atria vulnerable, escalating the risk of a rapid return to AF.
5. Sheep chronic and acute models of AF
Sheep, as experimental subjects, have proven to be instrumental in the elucidation of AF mechanics. While naturally occurring, AF in sheep is elusive, and multiple ovine model systems have been tailored to mimic the various elements of human AF. These intricate models dive deep, shedding light on the structural, metabolic, and cellular metamorphoses that herald the advent of AF.
5.1 Sheep AF induction by rapid pacing and acetylcholine
Utilizing an
5.2 Sheep AF modulation by interatrial pressure
In this method, the heart is Langendorff perfused with Tyrode’s solution. Increasing interatrial pressure by elevating perfusion pressure renders the hearts more susceptible to AF, creating stretch-related AF in sheep hearts [19, 20, 62, 63, 64]. The interatrial septum is perforated to equilibrate left and right interatrial pressures (IAP) and venous orifices are ligated to maintain a closed pressure system. Changes in IAP are controlled by adjusting the height of pressure relief outflow tubing with respect to height of the perfused heart. Enhanced inducibility of AF with stretch is reversible, returning to sinus rhythm when IAP is returned to normal physiologic pressures. This stretch-related sheep AF model has been used to explore atrial regions of high rate activity [62, 63, 64], differences between acute stretch AF and persistent AF [20], and mechanisms of AF rate acceleration [19].
5.3 Sheep AF induction by intermittent tachypacing
The tachypaced sheep model has offered significant insights into mechanisms of AF. In the intermittent right atrial tachypacing model, sheep are instrumented with a modified pacemaker to deliver a short burst of high frequency (20 Hz) atrial stimulation whenever sinus rhythm is detected [18, 20, 66, 67, 68, 69]. In this model, AF progresses from brief runs of AF to long-standing persistent AF which remains self-sustained (in the absence of device tachypacing) for periods as long as 1 year [18]. This progression of AF is characterized by hallmark electrical remodeling, including altered current densities of calcium, sodium and potassium currents; as well as features of structural remodeling including increased fibrosis, cellular hypertrophy, and atrial chamber dilation [18, 67, 68, 69]. The dynamic and biophysical properties of AF induced by tachypacing varies with the duration of arrhythmia burden [18], and are distinct from those induced acutely by increased chamber pressure and stretch [20]. This indicates that AF likely represents a broad spectrum of arrhythmia substrates that might not benefit from a single therapeutic approach.
In similar studies, sheep were implanted with dual pacemakers that affected both atrial and ventricular functions using a transvenous approach. A neurostimulator was embedded subcutaneously in the neck region, ensuring rapid atrial pacing capabilities. After post-operative recovery, atrial pacing was initiated at 15 Hz, laying a foundation for persistent AF, with occasional pauses in pacing to ensure accurate rhythm evaluations. The key indicator for the establishment of persistent AF was when sinus rhythm was consistently absent over consecutive assessments [70]. Electrical remodeling, was evidenced by shortened atrial refractory periods and wavelengths
6. Rodent models of AF
When diving into the field of AF, murine models stand as key players in providing genetic insights, wide ranges of induction strategies, molecular pathways, cellular remodeling, and targeted interventions. Despite their distinct atrial characteristics compared to humans, mice and rats serve as more-than suitable organisms for understanding the complexities of AF initiation and progression. Central to this exploration is the creation of AF models, a process with an array of techniques that mirror the genetic and structural alterations seen in clinical AF cases. These models allow researchers to investigate intricacies of genetic predispositions, molecular pathways, and electrophysiological changes that culminate in AF.
The use of small animals, such as mice and rats have provided a model for studying AF that is generally both time- and cost-efficient. Given that rodents have smaller hearts compared to humans and other large animal model counterparts, these hearts are more prone to recovering from cases of induced and spontaneous AF. Early on, this observation gave rise to the “critical mass” hypothesis, suggesting smaller animals with smaller hearts were not capable of sustaining a fibrillatory rhythm [71, 72]. This was mainly due to re-entrant circuits not having a large-enough pathway to travel within smaller hearts to sustain fibrillation, as the depolarizing wavefront of the re-entrant circuit would likely collide with the repolarizing tail, stopping fibrillation and restoring homeostatic rhythm. Small animal models require genetic manipulation or programmed electrical stimulation to induce AF, which in some cases only lasts for seconds at a time [57]. Although spontaneous AF is not commonly seen in rodent models, mouse models offer a good platform for studying the AF substrate, rather than the triggers that elicit AF [73]. Nonetheless, there have been several rodent models employed to study characteristics of structural and electrical remodeling seen in clinical AF.
Transesophageal Atrial Pacing Model: Due to low cost and utility of genetic manipulation, rodent models have become the most used animal models in biomedical research. To overcome a lack of spontaneously occurring AF, transesophageal atrial pacing has been used to initiate AF in closed-chest mice and rats [74, 75, 76, 77, 78, 79]. A pacing lead is advanced down the esophagus and positioned to capture and stimulate the adjacent atria with burst pacing (as fast as 100 Hz) or programmed premature stimulation. Prolonged transesophageal atrial stimulation increases inducibility of atrial tachyarrhythmias in anesthetized mice, especially in the presence of diminished cell coupling [79], with high reproducibility [78], and particularly in male mice [75]. The summed duration of AF episodes can add up on the order of several minutes for an experimental protocol; however, effects of rapid atrial pacing using a transesophageal approach can be confounded by activation of neighboring nerves and parasympathetic ganglia [75]. Transesophageal atrial pacing has also been used in rat models, where rapid pacing at 83 Hz for 30 seconds induces runs of AF lasting around 10 seconds [74].
Glycolytic Inhibition Model: Rat hearts with glycolytic inhibition display vulnerability to AF in older rats due to Ca2+ handling abnormalities. This model underscores the role that glycolysis can play in the development of AF and its relationship with intracellular calcium levels, as the uptake of intracellular Ca2+ into the sarcoplasmic reticulum is ATP-dependent. Glycolytic inhibition was induced by adding sodium pyruvate to glucose-free perfusate in isolated rat hearts [80].
Asphyxia Model: This involves burst-pacing and asphyxia in rat models to induce AF. Asphyxia can be induced through clamping of the tracheal tube at the end of an inspiratory cycle. A study researching asphyxia-induced AF in rats found that clamping of the tracheal tube for 35 seconds posed the best time course for inducing AF. Asphyxiation for shorter periods were associated with lowered AF inducibility while longer time periods were associated with prolonged atrioventricular block and severe cases of hypotension [81].
Myocardial Infarction Model: Rats with induced myocardial infarction (MI) through coronary artery ligation can be used to study mechanisms of AF. Although post-infarction rats exhibit remodeling of the extracellular matrix and increased matrix metalloproteinase activity, AF may not always be observable through ECG recordings [82, 83]. These models experience collagen and fibrotic accumulation between atrial cardiomyocytes, conducive to an AF substrate [82, 84].
Spontaneous Hypertension Model: Rats in this model are genetically predisposed to systemic hypertension, displaying increased fibrosis of the left atrium. Activation of the renin-angiotensin system, as a result of hypertension, contributes to progression of a fibrotic substrate. In this model, effective refractory period is unchanged; however, increased fibrosis predisposes to an AF substrate [85, 86].
Dilated Cardiomyopathy Model: Transgenic mice with overexpressed GTPase RhoA, muscle-restricted putative coiled-coil (MURC) protein, and/or tumor necrosis factor-α, replicate aspects of dilated cardiomyopathy. These models display substrates related to AF through increased fibrosis (induced by GTPase RhoA and further stimulated with MURC protein) and downregulated connexin40, revealing a connection between structural changes and onset and progression of AF [87, 88, 89, 90].
Hypertrophic Cardiomyopathy Model: Mouse models with accelerated atrial repolarization replicate aspects of hypertrophic cardiomyopathy. Inducing AF in these models has been done through overexpression of junctin, a calsequestrin-binding protein; junctate, a calcium-binding protein associated with the calcium storage capacity within the sarcoplasmic reticulum; GTPase, and Rac1, both regulators of NADPH oxidase activity [91, 92, 93]. Prolonged episodes of AF have been observed in rodent models showing overexpression of cardiac Gαq, a mediator of alpha-adrenoceptor, angiotensin II, and endothelin, a protein involved in blood pressure regulation and blood vessel constriction [94]. These models create a substrate for development of AF, drawing a relationship between electrophysiological changes and arrhythmogenesis similar to clinical AF.
In rodents, various models have been employed to induce AF that provide insight into arrhythmia mechanisms. These models capture diverse aspects of the development of AF, highlighting structural changes and electrophysiological abnormalities that contribute to the AF substrate. However, rodent models also come with their own limitations as there are substantial differences in heart scale and electrophysiology between humans and rodents that pose translational research challenges. Rodents have varied action potential morphology and duration attributed to higher resting heart rates, ion channel expression, and current densities [95]. Because of this, tools used to induce AF in large animals, such as catheter-ablations and pacemaker-induced tachycardias have proved difficult to replicate in small animal counterparts [96]. Regardless of these drawbacks, rodent models offer avenues with high potential and value in researching therapeutic interventions.
6.1 Genetic mapping: genetic attributes of AF
Mice and rats serve as laboratories for genetic exploration, enabling us to better understand the genetic landscape of AF. Through genetic manipulations, researchers have a better understanding of how AF originates and persists. Genetic modifications targeting ion channels such as KCNA5, KCNH2, and KCNJ2, as well as calcium handling proteins, such as RyR2 and SERCA2a, offer insights into molecular pathways underlying AF [97, 98]. These genetic manipulations replicate mutations seen clinically, bridging genetic anomalies with molecular conditions that promote arrhythmogenesis.
6.2 Induction of AF in murine models
The induction of AF in murine models has been attributed to diverse strategies, echoing the multitudes of causes that drive the arrhythmogenesis of the clinical condition. While rapid atrial pacing emerges as a prominent approach, simulating the rapid firing characteristic of AF, it’s only one technique employed within murine models [99]. Techniques like transesophageal atrial burst pacing over a short period and surgical interventions introduce different AF triggers, providing the arrhythmia’s varied nature [75]. Each induction strategy reflects distinct characteristics of AF causation, reflecting the relationship between genetics and triggers that promote its onset.
6.3 Insights from murine models: cellular remodeling
Murine models of AF not only offer insight into genetic and molecular events, but also bring to light the wide array of cellular remodeling that can be observed. These models reflect differences in remodeling patterns encompassing action potential duration changes, altered calcium dynamics, and fibrosis development [100]. Through these changes in cellular remodeling, as a result of variance in gene expression, researchers have been able to better map the pathway of cellular transformations, furthering the understanding underlying molecular cues and genetic predispositions that bring about these changes. By unveiling these patterns, we uncover the pathways in which genetic expression influences cellular remodeling, paving the way for targeted interventions.
6.4 Translational implications of murine models
The murine models’ ability to provide insights into AF initiation and persistence extends to targeted interventions, paving the way for laboratory research to guide and influence clinical applications. The combination of genetic manipulation, a wide range of induction strategies, and diverse cellular remodeling helps researchers gain knowledge and direction in the development of interventions and therapeutics that address the diverse characteristics that cause AF. Pharmacological regulation and modulation of ion channels, calcium handling, and anti-inflammatory pathways emerge as promising frontiers in better understanding and treating AF [97, 100]. By targeting specific remodeling pathways, these interventions hold the potential to prevent, or at the least lessen AF progression, ultimately allowing for murine discoveries to translate into practical clinical treatments.
7. Computational models of AF
Atrial fibrillation stands as the most frequently diagnosed cardiac arrhythmia, ensnaring millions globally [1, 2]. The mystique surrounding AF is not merely a product of its prevalence, but stems from a wide variety of causes and mechanisms that drive it. These mechanisms, sprawling across scales from minute molecular interactions to overarching organ dynamics, necessitate an arsenal of sophisticated tools for comprehension. Herein enters the computational model, a digital crucible wherein AF’s enigmatic dance can be dissected, offering researchers a panoramic view of its initiation, maintenance, and progression. Insights gleaned from these models not only further the scientific discourse, but also funnel directly into clinical interventions, bridging the chasm between theory and therapeutic application.
Modeling atrial electrical activity and AF, at the theoretical level, involves simulating the spread of an electrical impulse (atrial cell action potential) through a network of connected cells. Most AF models incorporate detailed biophysical properties of membrane protein kinetics, such as ionic channels, pumps, and exchangers. The mathematical foundation of these models is largely built on the formalism developed by Hodgkin and Huxley [101]. In computational AF research, cells are typically arranged in a regular 2- or 3-dimensional network, or in a volumetric model that reflects the geometry and structure of the atria.
7.1 Computational electrophysiological cell models
Early atrial action potential models focused on single cell electrophysiology based on biophysical properties of ion channels, pumps and exchangers [102, 103, 104]. These models were used to examine implications of electrical remodeling on potential therapeutic approaches to AF medical management [105]. In more recent computational studies, cellular action potential models have been integrated into structurally realistic cell-coupled models incorporating cardiomechanics [106], regional heterogeneity [107], muscle fiber orientation [108], and patient-specific individualization [109, 110] to develop novel approaches for understanding AF mechanisms and treatment [20, 111].
Peering into the cellular theater of AF, these models render the molecular intricacies of ion movements - the symphony of influxes and effluxes through channels, pumps, and exchangers. As with any scientific tool, the magnifying lens on these models has sharpened over time, adapting to the influx of newer data, particularly human-centric. Not all models are cast in the same mold. While some models sketch the broad contours of AF, others zoom in on the mutations birthed by chronic AF, or explore regions of scientific inquiry that are not readily amenable to in vivo examination, such as effects of fibrillatory substrate size and acetylcholine conditions on rotor maintenance [112].
7.2 Computational models of AF-induced structural remodeling
AF, the ever-evolving maelstrom, often triggers a series of structural shifts in the heart, with fibrosis taking center stage. This scarring of the atrial tissue forms the bedrock of AF’s resilience. Computational models, sensing the gravity of fibrosis, have delved deep, by either painting it as non-conductive barricades or by tweaking conduction attributes. The revelations from these models are striking. They spotlight fibrosis as both the anchor for reentrant circuits and the architect of conduction barriers—with either role amplifying AF’s stronghold. While lab-based experimental endeavors often grapple with the challenge of segregating the multifaceted roles of fibrosis, computational models allow for explicit investigation of cause and effect. High-definition imagery of atrial fibrosis has infused these models with a granular understanding, empowering them to traverse the fibrotic landscape with unmatched precision and predictive power [113, 114, 115].
8. Conclusions
Large and small animal models as well as computational approaches serve as invaluable tools in advancing our understanding of atrial fibrillation. Animal models offer biological context and empirical data, while computational models provide a flexible platform for hypothesis testing and data analysis. The synergistic application of these two methods allows for a more comprehensive understanding of AF. As technology and methodologies evolve, the combined use of these experimental and theoretical approaches will become increasingly crucial for developing effective therapies and achieving a holistic understanding of atrial fibrillation.
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