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.
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. Source
Agency: Cordis | 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.
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.
Skibsbye L.,Copenhagen University |
Poulet C.,TU Dresden |
Diness J.G.,Copenhagen University |
Diness J.G.,Acesion Pharma |
And 11 more authors.
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. Source
Diness J.G.,Acesion Pharma |
Bentzen B.H.,Acesion Pharma |
Bentzen B.H.,Copenhagen University |
Sorensen U.S.,Acesion Pharma |
And 2 more authors.
Journal of Cardiovascular Pharmacology
Small-conductance Ca2+-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti-atrial fibrillation principle. © 2015 Wolters Kluwer Health, Inc. All rights reserved. Source