Two-pore-domain potassium (K
-) channels conduct outward K
currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K
channel family are ...widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K
-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K
3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K
3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K
2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K
channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K
channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K
channels.
In search of more efficacious and safe pharmacological treatments for atrial fibrillation (AF), atria-selective antiarrhythmic agents have been promoted that target ion channels principally expressed ...in the atria. This concept allows one to engage antiarrhythmic effects in atria, but spares the ventricles from potentially proarrhythmic side effects. It has been suggested that cardiac small conductance Ca
2+
-activated K
+
(SK) channels may represent an atria-selective target in mammals including humans. However, there are conflicting data concerning the expression of SK channels in different stages of AF, and recent findings suggest that SK channels are upregulated in ventricular myocardium when patients develop heart failure. To address this issue, RNA-sequencing was performed to compare expression levels of three SK channels (
KCNN1
,
KCNN2
, and
KCNN3
) in human atrial and ventricular tissue samples from transplant donor hearts (no cardiac disease), and patients with cardiac disease in sinus rhythm or with AF. In addition, for control purposes expression levels of several genes known to be either chamber-selective or differentially expressed in AF and heart failure were determined. In atria, as compared to ventricle from transplant donor hearts, we confirmed higher expression of
KCNN1
and
KCNA5
, and lower expression of
KCNJ2
, whereas
KCNN2
and
KCNN3
were statistically not differentially expressed. Overall expression of
KCNN1
was low compared to
KCNN2
and
KCNN3
. Comparing atrial tissue from patients with AF to sinus rhythm samples we saw downregulation of
KCNN2
in AF, as previously reported. When comparing ventricular tissue from heart failure patients to non-diseased samples, we found significantly increased ventricular expression of
KCNN3
in heart failure, as previously published. The other channels showed no significant difference in expression in either disease. Our results add weight to the view that SK channels are not likely to be an atria-selective target, especially in failing human hearts, and modulators of these channels may prove to have less utility in treating AF than hoped. Whether targeting SK1 holds potential remains to be elucidated.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and one of the major causes of cardiovascular morbidity and mortality. Despite good progress within the past years, safe and ...effective treatment of AF remains an unmet clinical need. The anti-anginal agent ranolazine has been shown to exhibit antiarrhythmic properties
mainly late I
and I
blockade. This results in prolongation of the atrial action potential duration (APD) and effective refractory period (ERP) with lower effect on ventricular electrophysiology. Furthermore, ranolazine has been shown to be effective in the treatment of AF. TASK-1 is a two-pore domain potassium (K
) channel that shows nearly atrial specific expression within the human heart and has been found to be upregulated in AF, resulting in shortening the atrial APD in patients suffering from AF. We hypothesized that inhibition TASK-1 contributes to the observed electrophysiological and clinical effects of ranolazine.
We used
oocytes and CHO-cells as heterologous expression systems for the study of TASK-1 inhibition by ranolazine and molecular drug docking simulations to investigate the ranolazine binding site and binding characteristics.
Ranolazine acts as an inhibitor of TASK-1 potassium channels that inhibits TASK-1 currents with an IC
of 30.6 ± 3.7 µM in mammalian cells and 198.4 ± 1.1 µM in
oocytes. TASK-1 inhibition by ranolazine is not frequency dependent but shows voltage dependency with a higher inhibitory potency at more depolarized membrane potentials. Ranolazine binds within the central cavity of the TASK-1 inner pore, at the bottom of the selectivity filter.
In this study, we show that ranolazine inhibits TASK-1 channels. We suggest that inhibition of TASK-1 may contribute to the observed antiarrhythmic effects of Ranolazine. This puts forward ranolazine as a prototype drug for the treatment of atrial arrhythmia because of its combined efficacy on atrial electrophysiology and lower risk for ventricular side effects.
Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. However, underlying molecular mechanisms are insufficiently understood. Previous studies suggested that microRNA ...(miRNA) dependent gene regulation plays an important role in the initiation and maintenance of AF. The 2-pore-domain potassium channel TASK-1 (tandem of P domains in a weak inward rectifying K
channel-related acid sensitive K
channel 1) is an atrial-specific ion channel that is upregulated in AF. Inhibition of TASK-1 current prolongs the atrial action potential duration to similar levels as in patients with sinus rhythm. Here, we hypothesize that miRNAs might be responsible for the regulation of
that encodes for TASK-1. Methods and Results We selected miRNAs potentially regulating
and studied their expression in atrial tissue samples obtained from patients with sinus rhythm, paroxysmal AF, or permanent/chronic AF. MiRNAs differentially expressed in AF were further investigated for their ability to regulate
mRNA and TASK-1 protein expression in human induced pluripotent stem cells, transfected with miRNA mimics or inhibitors. Thereby, we observed that miR-34a increases TASK-1 expression and current and further decreases the resting membrane potential of
oocytes, heterologously expressing hTASK-1. Finally, we investigated associations between miRNA expression in atrial tissues and clinical parameters of our patient cohort. A cluster containing AF stage, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left atrial diameter, atrial COL1A2 (collagen alpha-2(I) chain), and TASK-1 protein level was associated with increased expression of miR-25, miR-21, miR-34a, miR-23a, miR-124, miR-1, and miR-29b as well as decreased expression of miR-9 and miR-485. Conclusions These results suggest an important pathophysiological involvement of miRNAs in the regulation of atrial expression of the TASK-1 potassium channel in patients with atrial cardiomyopathy.
Electrocardiographic (ECG) features of left bundle branch (LBB) block (LBBB) can be observed in up to 20%-30% of patients suffering from heart failure with reduced ejection fraction. However, ...predicting which LBBB patients will benefit from cardiac resynchronization therapy (CRT) or conduction system pacing remains challenging. This study aimed to establish a translational model of LBBB to enhance our understanding of its pathophysiology and improve therapeutic approaches.
Fourteen male pigs underwent radiofrequency catheter ablation of the proximal LBB under fluoroscopy and ECG guidance. Comprehensive clinical assessments (12-lead ECG, bloodsampling, echocardiography, electroanatomical mapping) were conducted before LBBB induction, after 7, and 21 days. Three pigs received CRT pacemakers 7 days after LBB ablation to assess resynchronization feasibility.
Following proximal LBB ablation, ECGs displayed characteristic LBBB features, including QRS widening, slurring in left lateral leads, and QRS axis changes. QRS duration increased from 64.2 ± 4.2 ms to 86.6 ± 12.1 ms, and R wave peak time in V6 extended from 21.3 ± 3.6 ms to 45.7 ± 12.6 ms. Echocardiography confirmed cardiac electromechanical dyssynchrony, with septal flash appearance, prolonged septal-to-posterior-wall motion delay, and extended ventricular electromechanical delays. Electroanatomical mapping revealed a left ventricular breakthrough site shift and significantly prolonged left ventricular activation times. RF-induced LBBB persisted for 3 weeks. CRT reduced QRS duration to 75.9 ± 8.6 ms, demonstrating successful resynchronization.
This porcine model accurately replicates the electrical and electromechanical characteristics of LBBB observed in patients. It provides a practical, cost-effective, and reproducible platform to investigate molecular and translational aspects of cardiac electromechanical dyssynchrony in a controlled and clinically relevant setting.
Understanding molecular mechanisms involved in atrial tissue remodeling and arrhythmogenesis in atrial fibrillation (AF) is essential for developing specific therapeutic approaches. Two-pore-domain ...potassium (K
2P
) channels modulate cellular excitability, and TASK-1 (K
2P
3.1) currents were recently shown to alter atrial action potential duration in AF and heart failure (HF). Finding animal models of AF that closely resemble pathophysiological alterations in human is a challenging task. This study aimed to analyze murine cardiac expression patterns of K
2P
channels and to assess modulation of K
2P
channel expression in murine models of AF and HF. Expression of cardiac K
2P
channels was quantified by real-time qPCR and immunoblot in mouse models of AF cAMP-response element modulator (CREM)-IbΔC-X transgenic animals or HF (cardiac dysfunction induced by transverse aortic constriction, TAC). Cloned murine, human, and porcine TASK-1 channels were heterologously expressed in
Xenopus laevis
oocytes. Two-electrode voltage clamp experiments were used for functional characterization. In murine models, among members of the K
2P
channel family, TASK-1 expression displayed highest levels in both atrial and ventricular tissue samples. Furthermore, K
2P
2.1, K
2P
5.1, and K
2P
6.1 showed significant expression levels. In CREM-transgenic mice, atrial expression of TASK-1 was significantly reduced in comparison with wild-type animals. In a murine model of TAC-induced pressure overload, ventricular TASK-1 expression remained unchanged, while atrial TASK-1 levels were significantly downregulated. When heterologously expressed in
Xenopus oocytes
, currents of murine, porcine, and human TASK-1 displayed similar characteristics. TASK-1 channels display robust cardiac expression in mice. Murine, porcine, and human TASK-1 channels share functional similarities. Dysregulation of atrial TASK-1 expression in murine AF and HF models suggests a mechanistic contribution to arrhythmogenesis.
Effective and safe pharmacological management of cardiac arrhythmia still constitutes a major clinical challenge. Outward potassium currents mediated by two-pore-domain potassium (K2P) channels ...promote repolarization of excitable cells. In the heart, inhibition or genetic inactivation of K2P currents results in action potential prolongation. Human K2P3.1 (TASK-1) channels are predominantly expressed in the atria and represent targets for the treatment of atrial fibrillation. In addition, stretch-sensitive K2P2.1 (TREK-1) channels are implicated in mechanoelectrical feedback and arrhythmogenesis in atrial and ventricular tissue. K2P current inhibition by clinically used antiarrhythmic drugs indicates a role of the channels as potential drug targets. This work summarizes the current knowledge on function, pharmacology, and significance of cardiac K2P channels. Therapeutic implications with emphasis on atrial fibrillation are highlighted.
Upregulation of the two-pore-domain potassium channel TASK-1 (hK
3.1) was recently described in patients suffering from atrial fibrillation (AF) and resulted in shortening of the atrial action ...potential. In the human heart, TASK-1 channels facilitate repolarization and are specifically expressed in the atria. In the present study, we tested the antiarrhythmic effects of the experimental ion channel inhibitor A293 that is highly affine for TASK-1 in a porcine large animal model of persistent AF.
Persistent AF was induced in German landrace pigs by right atrial burst stimulation via implanted pacemakers using a biofeedback algorithm over 14 days. Electrophysiological and echocardiographic investigations were performed before and after the pharmacological treatment period. A293 was intravenously administered once per day. After a treatment period of 14 days, atrial cardiomyocytes were isolated for patch clamp measurements of currents and atrial action potentials. Hemodynamic consequences of TASK-1 inhibition were measured upon acute A293 treatment.
In animals with persistent AF, the A293 treatment significantly reduced the AF burden (6.5% vs. 95%;
< 0.001). Intracardiac electrophysiological investigations showed that the atrial effective refractory period was prolonged in A293 treated study animals, whereas, the QRS width, QT interval, and ventricular effective refractory periods remained unchanged. A293 treatment reduced the upregulation of the TASK-1 current as well as the shortening of the action potential duration caused by AF. No central nervous side effects were observed. A mild but significant increase in pulmonary artery pressure was observed upon acute TASK-1 inhibition.
Pharmacological inhibition of atrial TASK-1 currents exerts
antiarrhythmic effects that can be employed for rhythm control in a porcine model of persistent AF. Care has to be taken as TASK-1 inhibition may increase pulmonary artery pressure levels.
Atrial fibrillation (AF) is the most common sustained arrhythmia with a prevalence of up to 4% and an upwards trend due to demographic changes. It is associated with an increase in mortality and ...stroke incidences. While stroke risk can be significantly reduced through anticoagulant therapy, adequate treatment of other AF related symptoms remains an unmet medical need in many cases. Two main treatment strategies are available: rate control that modulates ventricular heart rate and prevents tachymyopathy as well as rhythm control that aims to restore and sustain sinus rhythm. Rate control can be achieved through drugs or ablation of the atrioventricular node, rendering the patient pacemaker-dependent. For rhythm control electrical cardioversion and pharmacological cardioversion can be used. While electrical cardioversion requires fasting and sedation of the patient, antiarrhythmic drugs have other limitations. Most antiarrhythmic drugs carry a risk for pro-arrhythmic effects and are contraindicated in patients with structural heart diseases. Furthermore, catheter ablation of pulmonary veins can be performed with its risk of intraprocedural complications and varying success. In recent years TASK-1 has been introduced as a new target for AF therapy. Upregulation of TASK-1 in AF patients contributes to prolongation of the action potential duration. In a porcine model of AF, TASK-1 inhibition by gene therapy or pharmacological compounds induced cardioversion to sinus rhythm. The DOxapram Conversion TO Sinus rhythm (DOCTOS)-Trial will reveal whether doxapram, a potent TASK-1 inhibitor, can be used for acute cardioversion of persistent and paroxysmal AF in patients, potentially leading to a new treatment option for AF.
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