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Hundahl L.A.,Copenhagen University | Sattler S.M.,Copenhagen University | Skibsbye L.,Copenhagen University | Diness J.G.,Acesion Pharma | And 2 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2017

Acute myocardial infarction (AMI) with development of ventricular fibrillation (VF) is a common cause of sudden cardiac death (SCD). At present, no pharmacological treatment has successfully been able to prevent VF in the acute stage of AMI. This study investigates the antiarrhythmic effect of inhibiting small conductance Ca2+-activated K+ (SK) channels using the pore blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) in AMI rats. Acute coronary ligation was performed in 26 anesthetized rats, and ECG, monophasic action potentials (MAPs), and ventricular effective refractory period (vERP) were recorded. Rats were randomized into four groups: (i) 3 mg/kg i.v. ICA with AMI (AMI-ICA-group, n = 9), (ii) vehicle with AMI (AMI-vehicle-group, n = 9), (iii) vehicle with sham operation (sham-vehicle-group, n = 8), and (iv) 3 mg/kg i.v. ICA with sham operation (sham-ICA-group, n = 6). At the end of experiments, hearts were stained for the non-perfused area at risk (AAR). AMI resulted in the development of ventricular tachycardia (VT) in all AMI-vehicle and AMI-ICA rats; however, ICA significantly decreased VT duration. VF occurred in 44% of AMI-vehicle rats but not in AMI-ICA rats. Monophasic action potential duration at 80% repolarization (MAPD80) in the ischemic area decreased rapidly in both AMI-vehicle and AMI-ICA rats. However, 5 min after occlusion, MAPD80 returned to baseline in AMI-ICA rats but not in AMI-vehicle rats. The vERP was prolonged in the AMI-ICA group compared to AMI-vehicle after ligation. AAR was similar between the AMI-vehicle group and the AMI-ICA group. In rats with AMI, ICA reduces the burden of arrhythmia. © 2017 Springer-Verlag Berlin Heidelberg


Qi X.-Y.,Montreal Heart Institute | Diness J.G.,Acesion Pharma | Brundel B.J.J.M.,University of Groningen | Zhou X.-B.,University of Heidelberg | And 10 more authors.
Circulation | Year: 2014

BACKGROUND - : Recent evidence points to functional Ca-dependent K (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model. METHODS AND RESULTS - : Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single-channel properties were measured in isolated canine atrial cardiomyocytes by patch clamp. NS8593, a putative selective SK blocker, suppressed SK current with an IC50 of ≈5 μmol/L, without affecting Na, Ca, or other K currents. Whole-cell SK current sensitive to NS8593 was significantly larger in pulmonary vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open probability (Po), whereas AT-P enhanced both whole-cell SK currents and single-channel Po. SK-current block increased action potential duration in both PV and LA cells after AT-P; but only in PV cells in absence of AT-P. SK2 expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF duration without affecting the Wenckebach cycle length, left ventricular refractoriness, or blood pressure. CONCLUSIONS - : SK currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF maintenance. These results are relevant to the potential mechanisms underlying the association between SK single-nucleotide polymorphisms and AF and suggest SK blockers as potentially interesting anti-AF drugs. © 2013 American Heart Association, Inc.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2015-ETN | Award Amount: 4.10M | Year: 2015

The AFib-TrainNet consortium will enable promising young scientists to become excellent research leaders of the future, capable of fighting the challenges that Atrial Fibrillation (AF) presents to the European population. AF is the most common sustained cardiac arrhythmia, occurring in between 1-2% of the general population. More than 6 million Europeans suffer from this arrhythmia and its prevalence is expected to increase by more than two-fold during the next 40 years due to increased life expectancy. Thus, AF is said to assume epidemic proportions. Current options for pharmacological therapy are limited by both low efficacy and side effects, including lifethreatening ventricular arrhythmias and severe extra-cardiac toxicities. A very limited number of novel AF drug therapies have been introduced in the last 20 years. This imbalance reflects a gap in understanding in both how AF develops and how it can be treated, which thereby limits the development of new medicines. Our ambition with the AFib-TrainNet is to fill this gap by producing new knowledge, leading to critical insight into origins and mechanisms of sustenance of atrial fibrillation. We will accomplish this by developing novel experimental and computational models recapitulating human AF, and employing these models on two very promising atrial biological targets. Experimental models will be instrumental in improving the understanding AFs underlying mechanisms, and will, along with clinical data, inform state-of-the-art computational models of human atrial electrophysiology. These new tools will permit fresh insight into the molecular, cellular and electrical mechanisms involved in the progression of healthy atria into an AF state. Our endeavor will deliver results which can be leveraged by the pharmaceutical industry to target AF drug development, and the work accomplished in AFib-TrainNet will thus constitute a beacon in the search for new AF medicine.


Skibsbye L.,Copenhagen University | Poulet C.,TU Dresden | Diness J.G.,Copenhagen University | Diness J.G.,Acesion Pharma | And 11 more authors.
Cardiovascular Research | Year: 2014

Aims Small-conductance calcium-activated potassium (SK) channels are expressed in the heart of various species, including humans. The aim of the present study was to address whether SK channels play a functional role in human atria. Methods and results Quantitative real-time PCR analyses showed higher transcript levels of SK2 and SK3 than that of the SK1 subtype in human atrial tissue. SK2 and SK3 were reduced in chronic atrial fibrillation (AF) compared with sinus rhythm (SR) patients. Immunohistochemistry using confocal microscopy revealed widespread expression of SK2 in atrial myocytes. Two SK channel inhibitors (NS8593 and ICAGEN) were tested in heterologous expression systems revealing ICAGEN as being highly selective for SK channels, while NS8593 showed less selectivity for these channels. In isolated atrial myocytes from SR patients, both inhibitors decreased inwardly rectifying K+ currents by ∼15% and prolonged action potential duration (APD), but no effect was observed in myocytes from AF patients. In trabeculae muscle strips from right atrial appendages of SR patients, both compounds increased APD and effective refractory period, and depolarized the resting membrane potential, while only NS8593 induced these effects in tissue from AF patients. SK channel inhibition did not alter any electrophysiological parameter in human interventricular septum tissue. Conclusions SK channels are present in human atria where they participate in repolarization. SK2 and SK3 were down-regulated and had reduced functional importance in chronic AF. As SK current was not found to contribute substantially to the ventricular AP, pharmacological inhibition of SK channels may be a putative atrial-selective target for future antiarrhythmic drug therapy. © 2014 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014.


Schmitt N.,Copenhagen University | Schmitt N.,Acesion Pharma | Schmitt N.,Lundbeck | Grunnet M.,Copenhagen University | And 5 more authors.
Physiological Reviews | Year: 2014

About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia. © 2014 the American Physiological Society.


Bentzen B.H.,Copenhagen University | Bentzen B.H.,Acesion Pharma | Olesen S.-P.,Copenhagen University | Ronn L.C.B.,Lundbeck | And 2 more authors.
Frontiers in Physiology | Year: 2014

The large conductance calcium- and voltage-activated K+ channel (KCa1.1, BK, MaxiK) is ubiquitously expressed in the body, and holds the ability to integrate changes in intracellular calcium and membrane potential. This makes the BK channel an important negative feedback system linking increases in intracellular calcium to outward hyperpolarizing potassium currents. Consequently, the channel has many important physiological roles including regulation of smooth muscle tone, neurotransmitter release and neuronal excitability. Additionally, cardioprotective roles have been revealed in recent years. After a short introduction to the structure, function and regulation of BK channels, we review the small organic molecules activating BK channels and how these tool compounds have helped delineate the roles of BK channels in health and disease. © 2014 Bentzen, Olesen, Rønn and Grunnet.


Kirchhoff J.E.,Copenhagen University | Goldin Diness J.,Copenhagen University | Goldin Diness J.,Acesion Pharma | Sheykhzade M.,Copenhagen University | And 4 more authors.
Heart Rhythm | Year: 2015

Background Application of antiarrhythmic compounds is limited by both proarrhythmic and extracardiac toxicities, as well as incomplete antiarrhythmic efficacy. An improved antiarrhythmic potential may be obtained by combining antiarrhythmic drugs with different modes of action, and a reduction of the adverse effect profile could be an additional advantage if compound concentrations could be reduced. Objective The purpose of this study was to test the hypothesis that combined inhibition of Ca2+-activated K+ channels (SK channels) and voltage-gated Na+ channels, in concentrations that would be subefficacious as monotherapy, may prevent atrial fibrillation (AF) and have reduced proarrhythmic potential in the ventricles. Methods Subefficacious concentrations of ranolazine, flecainide, and lidocaine were tested alone or in combination with the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) in a Langendorff-perfused guinea pig heart model in which AF was induced after acetylcholine application and burst pacing. Results AF duration was reduced when both flecainide and ranolazine were combined with ICA in doses that did not reduce AF as monotherapy. At higher concentrations, both flecainide and ranolazine revealed proarrhythmic properties. Conclusion A synergistic effect in AF treatment was obtained by combining low concentrations of SK and Na+ channel blockers. © 2015 Published by Elsevier Inc.


Haugaard M.M.,Copenhagen University | Hesselkilde E.Z.,Copenhagen University | Pehrson S.,Copenhagen University | Carstensen H.,Copenhagen University | And 7 more authors.
Heart Rhythm | Year: 2015

Background Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF). Objective The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart. Methods Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times. Results Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment. Conclusion SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses. © 2015 Heart Rhythm Society.


Patent
Acesion Pharma | Date: 2013-06-13

This invention relates to the use of pharmaceutical compositions comprising a therapeutically effective amount of a sodium channel inhibitor, in a combination with a small-conductance calcium-activated potassium (SK) channel inhibitor, for the treatment of cardiac arrhythmias.


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