Atrial fibrillation (AF) is a condition in which the electrical signals in the upper heart chambers (atria) are rapid and disorganized, producing an irregular and chaotical heartbeat. AF is the most common arrhythmia linked to noteworthy mortality and morbidity [1]. The sinus rhythm should be between 60 to 100 bpm at rest, while the heart rhythm in AF patients may be over 140 bpm [2]. The most dramatic cardiovascular outcomes of AF are stroke and heart failure (HF) [3]. AF affects over 33 million people worldwide with increasing prevalence because of aging and obesity population [4]. Men are 1.5 times more likely to develop AF compared with women. In addition to age, race and sex, risk factors for developing AF include intrinsic cardiovascular diseases and modifiable noncardiac risk factors, including smoking, alcohol or drug use, caffeine, lack of physical activity, overweight, diabetes, high blood pressure or obstructive sleep apnea (OSA) [5]. The symptoms of AF include rapid and irregular pulse, palpitations, weakness, fatigue, chest pain, dizziness and shortness of breath, considerably affecting the quality of life [6]. However, for many people AF may have no symptoms. AF is classified based on aetiology or degree of persistence. In terms of aetiology, AF can be classified as environmental factor induced-, congenital or genetic [3]. A strong genetic component underlies the disease, since variants in 160 genes associated with AF have been detected. Cardiac ion channel gene variants are a underlying risk factor to AF development [7]. In terms of persistence, AF can be paroxysmal, persistent (over 7 days), long-standing persistent (over 1 year) or permanent.

The pathophysiology of AF is complex as described Fig. 1. Either structural and electro-mechanical remodeling of the atrial tissue underlies the perpetuation and evolution of AF from the paroxysmal to permanent forms [8]. AF genesis initiates with well-established ectopic firings that initiate reentrant wave propagation under a vulnerable atrial substrate [9]. Both trigger factors and a vulnerable atrial substrate are critical for AF onset [9]. An important substrate for FA may be conduction and refractoriness abnormalities, an inflammatory or fibrotic background. Ectopic atrial foci are thought caused by an enhanced automaticity, delayed afterdepolarizations (DADs) and/or early afterdepolarizations (EADs) [10]. There is no doubt that the autonomic nervous system (ANS) also cooperates in the triggers, substrate and perpetuators of AF [11].

Fig. 1.

Pathophysiology of Atrial Fibrillation. AF, Atrial Fibrillation; OSA, Obstructive Sleep Apnea; BMI, Body Mass Index; bpm, Beats per minute; ERP, Effective Refractory Period; EAD, Early afterdepolarizations; DAD, Delayed afterdepolarizations.

Electrical remodeling is caused by a dysfunction of the atrial ion channels that essentially increasing outward K${}^{+}$ currents and/or decreasing inward L-type Ca${}^{2+}$ current, accelerating repolarization which accelerates atrial repolarization lead to a short atrial action potential (AP) duration and refractoriness, and thus favoring reentry [12]. All these changes have a strong impact not only on the atria electrophysiology but also on atria structure [13]. The disruption of Ca${}^{2+}$ handling, secondary to electrical remodeling, cause the alteration of sarcomere proteins promoting the contractile remodeling which induce atrium dilatation and blood clot formation perpetuating AF [9]. The structural remodeling particularly atrial enlargement, fibrosis and cellular/molecular changes causing localized conduction slowing and enhance re-entry [14]. Electrophysiological, structural, and mechanical irregularities also encourage AF perpetuation by stabilizing unidirectional block and re-entry [12]. Brief refractoriness, slow conduction and conduction barriers favor the induction and maintenance of reentry [15].

The main goal of AF treatment is relief of symptoms and prevention of stroke. Pharmacological treatment mainly includes anticoagulation, heart rate or rhythm control, and non-arrhythmic supportive pharmacological therapy. A variety of medicines are available to convert and maintain the patient in a normal sinus rhythm such as atenolol or bisoprolol (beta-blockers) or diltiazem or verapamil (Ca${}^{2+}$ channel blockers) could be prescribed. These medications can be combined with digoxin, which helps controlling the heart rate and preventing the rapid ventricular response [16]. Electrical cardioversion and interventional ablation procedures can also help for correcting abnormal heart rhythms. These pharmacological strategies often fail with the progression of AF to the persistent or permanent forms; even ablation procedures have poor success [16]. Consequently, it is necessary to find new therapeutic targets for the relief of persistent or chronic AF forms, as well as the development of new and more effective pharmacological tools.

The cardiac PA reflects the integrated conductance of numerous individual ionic currents, largely dominated by the movement of Na${}^{+}$, Ca${}^{2+}$ and K${}^{+}$ ions, which change the membrane potential (Vm) as a function of time. Cardiac ion channel function is highly regulated and orchestrated, being influenced by multiple factors, such as voltage, ligand binding, second messengers such as cyclic adenosine monophosphate, and post-translational modification. The summarized input and output of all ionic currents expressed in a specific cardiac cell determines the duration and the cardiac AP shape [17]. Consequently pacemaker, atrial, and ventricular cells possess heterogeneous morphology and AP duration due to cardiac ion channel differences which confers distinctive electrophysiological properties [17]. In atrial and ventricular cardiomyocytes, most of the ion channels responsible for determining the AP are essentially the same; however, the expression patterns, biophysical properties, and regulatory pathways may differ. The atrial and ventricular AP are described in 5 main phases (0–4), with different duration and morphology as described Fig. 2.

Fig. 2.

Schematic illustration of cardiac ion channels, currents and proteins implicated in action potential (AP) morphology of ventricular, atria, and AF-atrial cardiomyocytes.

The ventricular AP exhibits a peak-and-dome morphology with a prominent plateau phase; conversely, the human atrial AP usually has a triangular morphology compared to its ventricular homologue (Fig. 2). Moreover, electrophysiological heterogeneity is included in AP in different zones of the atria. The atrial resting membrane potential (Vrest) varies between -65 and -80 mV and is more depolarized than that in the ventricle mainly due to the differences in the expression density of the inward rectifier K${}^{+}$ current (Fig. 2) [17, 18]. The human atrial AP duration at 90% repolarization (APD90) and the atrial maximum upstroke velocities (Vmax) have been reported between 150–500 ms and $\sim$150 and 300 V/s, respectively; while for ventricular cells the APD90 and Vmax ranging 200–450 ms and 300–400 V/s [17, 18]. Atrial APs lose acquire a more triangular shape in AF, the APD is significantly shortened and shows a decreased APD rate with poor adaptation and abrupt changes (Fig. 2) [19]. The atrial AP depends on three prime time- and voltage-dependent currents: I${}_{\text{Na}}$, I${}_{\text{K}}$, and I${}_{\text{Ca}}$. Alterations in atrial ion currents due to AF pathogenesis have a strong impact on the shape of atrial AP. I${}_{\text{Na}}$ current density or biophysical properties remain unaltered in patients with chronic AF. I${}_{\text{CaL}}$ current density is decreased by $\sim$60–75% in chronic AF; whereas it appears to be unaltered in AF. I${}_{\text{to}}$ and I${}_{\text{Kur}}$ currents are also downregulated in atrial cardiomyocytes from AF patients. Conversely, the inwardly rectifying potassium current (I${}_{\text{K1}}$) and acetylcholine-activated inward rectifier (I${}_{\text{KACh}}$), essential currents in the late phase repolarization, are increased in AF. The excessive activity of I${}_{\text{K1}}$ and I${}_{\text{KACh}}$ currents could accelerate repolarization shortening the atrial AP and encouraging AF [17, 18]. Not much information is available on the role of the rapid (I${}_{\text{Kr}}$) and slow (I${}_{\text{Ks}}$) components in FA [12, 15, 18, 19].

Some K${}^{+}$ channels may be distinctively or predominantly expressed in atria compared with ventricles or/and possess distinctive biophysical properties that differentiate them from their counterparts in the ventricles, making them ideal drug targets for AF. So far, the ultrafast activation delayed rectifier voltage-dependent Kv1.5 current (I${}_{\text{Kur}}$), the I${}_{\text{KACh}}$ current, and the TWIK-related acid-sensitive K${}^{+}$ channel type 1 (TASK1) conducting I${}_{\text{TASK1}}$ current have been best validated atrial-specific ionic currents [20]. The atrial- and ventricular-K${}^{+}$-currents could be formed by the participation of several $\alpha$-subunits as well as $\beta$-regulatory subunits as is described in Fig. 2.

Numerous variants in K${}^{+}$ channel encoding genes are associated with rare forms of genetic AF, such as Kv1.5, Kv4.2, Kv4.3, Kir2.1, Kir3.4, and K${}_2$P${}_{3.1}$ (TASK-1) [11], these last two specific to atria cells. So far, many previous studies have demonstrated that the dysregulation of the cardiac ion channel conducting I${}_{\text{to}}$, I${}_{\text{Kur}}$, I${}_{\text{CaL}}$, I${}_{\text{SK}}$, I${}_{\text{K1}}$, I${}_{\text{KACh}}$, and I${}_{\text{K2P}}$ currents is critical in the electrophysiological remodeling of AF (Fig. 2). Hence, it has highlighted that targeting these atrial-specific K${}^{+}$ channel as a promising therapeutic principle for AF. K${}_2$P channels are fascinating ion channel group since are responsible of the leak or conductance voltage-independent K${}^{+}$ current and appear to have functionality for most of the duration of the atrial AP [21, 22]. In addition, knowledge of the regulation and physiological role of K${}_2$P channels is not yet fully understood. Therefore, throughout this review we will mainly emphasize the role of K${}_2$P channels in AF and their therapeutic potential.

K${}_2$P channels are formed by a structure of two pore-forming loop domains in each alpha subunit; two of these alpha subunits assemble into a dimer to form the channel [23]. I${}_{\text{K2P}}$ currents are involved in background K${}^{+}$ conductance, stabilizing the Vrest and the repolarization in atrial cells. K${}_2$P channels have been considered voltage-independent ion channels, since there is no voltage-sensing domain (VSD) in their structure, where their strong outward rectification arises from the asymmetric K${}^{+}$ gradient across the membrane following the Goldman-Hodgkin-Katz equation. K${}_2$P channels produce basically instantaneous and non-inactivatable currents an extensive range of the membrane potential (Vm) [24].

Due to these characteristic biophysical properties K${}_2$P channels are also known as background or “leak” K${}^{+}$ channels with important implications in stabilizing Vrest and contributing to repolarization. Whereas the TASK1 currents conform to the Goldman-Hodgkin-Katz equation, other K${}_2$P channels may exhibit variations: i.e., TREK1 have a slight outward; TWIK1/TWIK2 channels have inward rectification; there is a slow inactivation component that represents for approximately 50% of TWIK2 current; and TRESK shows asymmetric gating behavior [24, 25, 26]. Interestingly a noteworthy voltage-dependent activation has been found in some K${}_2$P channels, nevertheless the exact mechanism remains uncertain due to the lack of a canonical voltage-sensing domain in channel structure [27].

Then, the modulation of K${}_2$P currents provides a mechanism for regulating cellular excitability [27]. K${}_2$P channels can be modulated by several physiological and chemical factors such as temperature, pH, lipids, stretch, kinases, neurotransmitters, unsaturated fatty acids, antidepressants and anesthetics [28]. The K${}_2$P channels is categorized into six groups: Two pore-domain weakly inward rectifying K${}^{+}$ channel (TWIK), TWIK-related alkaline-sensitive K${}^{+}$ channel (TALK), TWIK-related acid-sensitive K${}^{+}$ channel (TASK), TWIK-related spinal cord K${}^{+}$ channel (TRESK), TWIK-related K${}^{+}$ channel (TREK) and tandem pore domain halothane-inhibited K${}^{+}$ channel (THIK) [25]. To date, only TWIK-1, TREK-1, TASK-1, TASK-2 and TASK-3 channel have been identified as responsible for background I${}_{\text{K2P}}$ current in atrial cells [21, 22]. The I${}_{\text{K2P}}$ current persists throughout all phases of the atrial AP, stabilizing the membrane potential toward Vrest (Fig. 2), prevent EADs, and could be involved in adjusting the availability of the Na${}^{+}$ channel for depolarization (phase 0) [29]. Patch clamp recordings have indicated that alteration in I${}_{\text{K2P}}$ current can alter the shape and the duration of action potentials in human atrial cells [30]. Then, the alteration of I${}_{\text{K2P}}$ current either by changes in channel expression, trafficking or activity, can contribute to changes that can affects the processes involved in the generation of pro-arrhythmic phenomena as development of EADs or DADs and enhancing the automaticity, constituting a trigger for the development and maintenance of AF.

However, it is not excluded that other K${}_2$P${}_{\text{X}}$ subunits or subfamilies have physiological roles in atria. New research in this area may improve our knowledge about K${}_2$P channel function. K${}_2$P channel family is really fascinating since several studies have demonstrated that the expression of TWIK-1, TREK-1, TASK-1, TASK-2 and TASK-3 are dysregulated in AF [6, 11, 23, 24, 31, 32, 33]. Moreover, the loss of function (LoF) mutations on TASK1-enconding gene have been reported in patients with familiar AF [34].

K${}_2$P channel modulators could have enormous therapeutic potential in AF and, luckily, they are known to be very good “druggable” targets [28]. As most studies have focused on elucidating the physiological role of these channels in cardiomyocytes, the pharmacological profiles developed so far have not been very satisfactory. Many studies have shown that several of the medications used to control heart rate and heart rhythm in AF exert their mechanism of action in part by modulation of K${}_2$P channels. To date, many marketed and non-marketed compounds capable of targeting K${}_2$P channels direct or indirectly have been identified. However, many of these drugs are not selective for a unique K${}^{+}$ channel subfamily or subtype, but rather target several ion channels. Although the exact pharmacology of TWIK channels is not yet known, many potent activators/blockers for TASK and TREK have been identified. Our recent advances in the physiology and pharmacology of K${}_2$P channels have helped us to better understand many of the intricate mechanisms that can modulate the K${}_2$P activity or expression.

Here we will review the information on K${}_2$P channels expressed in atria and review available drugs to modulate potentially the activity of specific K${}_2$P channels and their possible use for AF treatment.

3.1 TWIK-1

TWIK-1 or K${}_2$P${}_{1.1}$ channels are encoded by KCNK1 gene and expressed robustly in atria; however, is still a matter of ongoing debate its physiological significance. The TWIK-1 channel appears to have a well-conserved role in cardiac function. A study in zebrafish embryos demonstrated TWIK-1 channel is needed for a normal atrial morphology and heart rate. The TWIK-1 knockdown results in bradycardia and atrial dilatation [28]. However, despite its functional importance in atria, genetic variation in KCNK1 has not been revealed to be a common direct cause of AF. Gaborit N and colleagues [35] also showed that TWIK-1 is upregulated in AF associated to valvular heart disease. Therefore, TWIK-1 inhibitors may be useful for AF treatment. Another study also demonstrated that the TWIK-1 channel could change its permeability to Na${}^{+}$ by promoting membrane depolarization under conditions of hypokalemia and acidosis. The changes in TWIK-1 ion selectivity could increase excitability of atrial cardiomyocytes resulting in enhanced automaticity under these conditions predisposing to tachycardia and AF development [24]. In this case, where the selectivity of K${}^{+}$ is replaced by Na${}^{+}$ will be also effective TWIK-1 blockers to preventing AF.

As stated above, the TWIK channels-related pharmacology is still very lacking. To date, it has not been identified any TWIK-1 channels activators or enhancers and any TWIK-1 inhibitor/blockers reported are not useful in the submicromolar range. Bupivacaine, a local anesthetic, showed a low potency block effect on TWIK subfamily [36]. Antiarrhythmic such as quinidine, useful for controlling heart rhythm in AF, and Ibutilide, useful for the cardioversion of recent AF or flutter, have a blocker effect on TWIK-1 channels [37, 38, 39]. Quinine, a antimalaria treatment, also have been demonstrated that can inhibit these channels [37] (Fig. 3). It should be noted that TWIK-1 is also expressed in brain, kidney, and pancreatic cells; therefore, drugs targeting these channels for the treatment of AF could have side effects on these tissues. In brain, TWIK-1 channels contribute to the regulation of AP firing and excitability in dentate gyrus granule cells. TWIK-1 channel also participates in the ion and water transport in kidney and in the regulation of Vrest on pancreatic beta cells [25, 28, 40].

Fig. 3.

K${}_{\mathrm{2}}$P channels in the pathogenesis of atrial fibrillation and available drug therapy.

Remarkable efforts over several years have been made to define and improve the molecular, structural and electrophysiological processes underlying the induction and perpetuation of AF. Our mechanistic and biological understanding of AF is incomplete and current therapeutic options have limited efficacy and are often fraught with risk and side effects. There is a primordial need to explore and propose new therapeutic approaches. Understanding the pathological mechanisms involved in atrial tissue remodeling and arrhythmogenesis in AF is essential for developing targeted approaches. Understanding the pathological pathways linked to atrial arrhythmogenesis and remodeling in AF is crucial for developing new targeted approaches. Atrial-specific K${}_2$P channels constitute the background current in atrial cardiomyocytes and modulate cell excitability emerging as novel targets in this disease. This family was one of the last K${}^{+}$ channels to be cloned, which makes them relatively unknown compared to other channels. By advancing crystal structures, in silico experiments with molecular dynamics simulations, mathematical models, docking studies and electrophysiological studies have greatly helped to reveal the physiological role of these channels and improve the drug design [101, 102, 103, 104]. Molecular dynamics simulations provide information at molecular level that can be contrasted with functional studies [101, 102, 103, 104]. These simulations are used for the study of conductance, ion selectivity and ion channel opening where the channel is usually embedded in a membrane patch model that allows following ion movements with a high spatial-temporal resolution [30, 105]. Knowing in more detail the ion channel structure allows to perform docking studies between the channel and candidate drugs, to investigate the points of highest affinity for modulation and to propose new modulatory structures. For instance, Xin Tan and colleges investigated how Quercetin alleviate AF explored by network pharmacology combined with molecular docking and experimental validation [106]. Limberg SH et al. [30], demonstrated that TASK1 channel modulate atrial AP shape and duration and shape of human atrial cells using mathematical modeling and patch-clamp technique.

Given the recent advances related to their physiological importance in different cellular, k2p channels have emerged as relevant pharmacological targets against a wide variety of diseases, including AF. So far, TWIK-1, TREK-1, TASK-1, TASK-2 and TASK-3 channel have been identified as responsible for background currents I${}_{\text{K2P}}$ current in atrial cells [21, 22]. However, it is not excluded that other groups or subunits have physiological roles. To date, a great diversity openers, activators and blockers of K${}_2$P channel have been identified, particularly those targeting TASK and TREK channels. However, a major limitation is that many of these TASK modulators are not selective for TASK-1, TASK-2, or TASK-3 members, but have affinity for all subunits due to their high homology. The main goal of this review is to outline the pathways of K${}_2$P channel modulation in AF and how correct their dysfunction using different pharmacological K${}_2$P modulators. Interestingly, many of heart rate and rhythm controlling medications used as current therapy in AF patients have a multichannel blocking profile, among them K${}_2$P channels. Blockade of K${}_2$P channels in the heart causes AP prolongation and may provide antiarrhythmic action in AF [72]. Here, it has been summarized as several antiarrhythmic drugs exert their mechanism of action in part by modulation of K${}_2$P channels. Despite the multitude of known K${}_2$P channel modulators, more selective and potent compounds with adequate pharmacokinetics are needed to avoid side effects on other tissues. There are two TASK-1 channel blockers under clinical investigation against and AF (DOCTOS Clinical Trial) and OSA (SANDMAN Clinical Trial) [77, 107]. The future therapeutic applications of these two compounds for AF are a compelling incentive for further study of the pharmacology of K${}_2$P channels. However, a serious complication of the use of TASK1 blockers for the treatment of AF may be their effect on the pulmonary vasculature. For example, Wiedmann and colleagues [63] found that in vivo TASK-1 channel inhibition in pigs with persistent AF was associated with an increase in pulmonary arterial pressure (PAP), confirming that TASK-1 plays a role in the homeostasis of the pulmonary vasculature. One way to overcome this could be to encourage a more cardiac-targeted drug delivery procedure, cardiac cell therapy or regulation of the expression of this ion channel by an upstream component, i.e., using oligonucleotide therapeutics. For example, one study showed that microRNA-34a might regulate the expression of atrial TASK-1 channels and modulation of this miR-34a can help alleviating AF [108]. Up to now, many studies have highlighted the pathological role and pharmacology of TWIK-1, TREK-1, TASK-1, TASK-1, TASK-2 and TASK-3 channels in AF and, undoubtedly, future research study in this field will provide more detailed mechanistic knowledge about K${}_2$P channels allowing the development of new drugs modulation of these channels to alleviate AF.

GMP wrote, edited and approved the final version of the manuscript.

Not applicable.

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This research was funded by American Heart Association (AHA) Postdoc Award #872244 (GMP).

The author declares no conflict of interest.