Caroline Rolfes

TASK-1 Channels May Modulate Action Potential Duration of Human Atrial Cardiomyocytes

Background/Aims: Atrial fibrillation is the most common arrhythmia in the elderly, and potassium channels with atrium-specific expression have been discussed as targets to treat atrial fibrillation. Our aim was to characterize TASK-1 channels in human heart and to functionally describe the role of the atrial whole cell current ITASK-1. Methods and Results: Using quantitative PCR, we show that TASK-1 is predominantly expressed in the atria, auricles and atrio-ventricular node of the human heart. Single channel recordings show the functional expression of TASK-1 in right human auricles. In addition, we describe for the first time the whole cell current carried by TASK-1 channels (ITASK-1) in human atrial tissue. We show that ITASK-1 contributes to the sustained outward current IKsus and that ITASK-1 is a major component of the background conductance in human atrial cardiomyocytes. Using patch clamp recordings and mathematical modeling of action potentials, we demonstrate that modulation of ITASK-1 can alter human atrial action potential duration. Conclusion: Due to the lack of ventricular expression and the ability to alter human atrial action potential duration, TASK-1 might be a drug target for the treatment of atrial fibrillation.

Kv1.5 blockers preferentially inhibit TASK-1 channels: TASK-1 as a target against atrial fibrillation and obstructive sleep apnea?

Atrial fibrillation and obstructive sleep apnea are responsible for significant morbidity and mortality in the industrialized world. There is a high medical need for novel drugs against both diseases, and here, Kv1.5 channels have emerged as promising drug targets. In humans, TASK-1 has an atrium-specific expression and TASK-1 is also abundantly expressed in the hypoglossal motor nucleus. We asked whether known Kv1.5 channel blockers, effective against atrial fibrillation and/or obstructive sleep apnea, modulate TASK-1 channels. Therefore, we tested Kv1.5 blockers with different chemical structures for their TASK-1 affinity, utilizing two-electrode voltage clamp (TEVC) recordings in Xenopus oocytes. Despite the low structural conservation of Kv1.5 and TASK-1 channels, we found all Kv1.5 blockers analyzed to be even more effective on TASK-1 than on Kv1.5. For instance, the half-maximal inhibitory concentration (IC50) values of AVE0118 and AVE1231 (A293) were 10- and 43-fold lower on TASK-1. Also for MSD-D, ICAGEN-4, S20951 (A1899), and S9947, the IC50 values were 1.4- to 70-fold lower than for Kv1.5. To describe this phenomenon on a molecular level, we used in silico models and identified unexpected structural similarities between the two drug binding sites. Kv1.5 blockers, like AVE0118 and AVE1231, which are promising drugs against atrial fibrillation or obstructive sleep apnea, are in fact potent TASK-1 blockers. Accordingly, block of TASK-1 channels by these compounds might contribute to the clinical effectiveness of these drugs. The higher affinity of these blockers for TASK-1 channels suggests that TASK-1 might be an unrecognized molecular target of Kv1.5 blockers effective in atrial fibrillation or obstructive sleep apnea.

TASK-1 and TASK-3 may form heterodimers in human atrial cardiomyocytes

TASK-1 channels have emerged as promising drug targets against atrial fibrillation, the most common arrhythmia in the elderly. While TASK-3, the closest relative of TASK-1, was previously not described in cardiac tissue, we found a very prominent expression of TASK-3 in right human auricles. Immunocytochemistry experiments of human right auricular cardiomyocytes showed that TASK-3 is primarily localized at the plasma membrane. Single-channel recordings of right human auricles in the cell-attached mode, using divalent-cation-free solutions, revealed a TASK-1-like channel with a single-channel conductance of about 30pS. While homomeric TASK-3 channels were not found, we observed an intermediate single-channel conductance of about 55pS, possibly reflecting the heteromeric channel formed by TASK-1 and TASK-3. Subsequent experiments with TASK-1/TASK-3 tandem channels or with co-expressed TASK-1 and TASK-3 channels in HEK293 cells or Xenopus oocytes, supported that the 55pS channels observed in right auricles have electrophysiological characteristics of TASK-1/TASK-3 heteromers. In addition, co-expression experiments and single-channel recordings suggest that heteromeric TASK-1/TASK-3 channels have a predominant surface expression and a reduced affinity for TASK-1 blockers. In summary, the evidence for heteromeric TASK-1/TASK-3 channel complexes together with an altered pharmacologic response to TASK-1 blockers in vitro is likely to have further impact for studies isolating ITASK-1 from cardiomyocytes and for the development of drugs specifically targeting TASK-1 in atrial fibrillation treatment.

The role of acid-sensitive two-pore domain potassium channels in cardiac electrophysiology: focus on arrhythmias.

The current kinetics of two-pore domain potassium (K2P) channels resemble those of the steady-state K+ currents being active during the plateau phase of cardiac action potentials. Recent studies support that K2P channels contribute to these cardiac currents and thereby influence action potential duration in the heart. Ten of the 15 K2P channels present in the human genome are sensitive to variations of the extracellular and/or intracellular pH value. This review focuses on a set of K2P channels which are inhibited by extracellular protons, including the subgroup of tandem of P domains in a weak inward-rectifying K+ (TWIK)-related acid-sensitive potassium (TASK) and TWIK-related alkaline-activated K+ (TALK) channels. The role of TWIK-1 in the heart is also discussed since, after successful expression, an extracellular pH dependence, similar to that of TASK-1, was described as a hallmark of TWIK-1. The expression profile in cardiac tissue of different species and the functional data in the heart are summarized. The distinct role of the different acid-sensitive K2P channels in cardiac electrophysiology, inherited forms of arrhythmias and pharmacology, and their role as drug targets is currently emerging and is the subject of this review.

Neue Verfahren der Regionalanästhesie – Zervikalblockaden für die Karotischirurgie

Cervical plexus blocks have been established as safe and feasible procedures for carotid endarterectomy. Comparable perioperative complication rates have been reported for plexus techniques and general anaesthesia. The results of the GALA trial support the theory that the indication for insertion of intraluminal shunts was significantly reduced by regional procedures (14 % vs. 43 %) in consequence of the more reliable diagnosis of neurological complications. However, it has not been identified yet which technique (superficial, deep or a combination) offers the highest effectiveness.

Der perioperative Myokardinfarkt - Eine interdisziplinäre Aufgabe

Perioperative kardiovaskulare Komplikationen gehoren zu den haufigsten und schwerwiegendsten perioperativen Risiken und beeinflussen masgebend die perioperative Morbiditat und Mortalitat nach nicht-kardiochirurgischen Operationen. Insbesondere der perioperative Myokardinfarkt (PMI) ist mit einer erhohten Mortalitat assoziiert und stellt eine grose Herausforderung fur alle begleitenden Disziplinen dar. Der PMI entsteht bei ca. 60% der Falle aufgrund einer Koronarplaqueverletzung mit resultierenden intraluminalem Thrombus und bei ca. 40% Falle aufgrund eines Missverhaltnisses zwischen myokardialen Sauerstoffbedarf und –angebot. Die Besonderheiten des PMI und der perioperativen Phase fuhren haufig dazu, dass der PMI asymptomatisch und ohne EKG Veranderungen verlauft und somit haufig nicht oder zu spat diagnostiziert wird. Die meisten PMI ereignen sich in intraoperativ oder in der fruhen postoperativen Phase (d.h. in den ersten 48-72 Std), so dass sich in diesen Zeitraum die Notwendigkeit einer engmaschigen klinischen Uberwachung, insbesondere bei Risikopatienten, ergibt. Die Diagnostik umfasst primar die Registrierung eines 12-Kanal EKG und die Bestimmung der Herzenzyme. Die Therapie des PMI ist eine interdisziplinare Aufgabe die eine enge Zusammenarbeit zwischen Chirurgen, Anasthesisten und Kardiologen erfordert. Standardisierte Ablaufe sind fur die Einleitung einer raschen zielgerichteten Diagnostik und Therapie dabei besonders wichtig.

Successful Treatment of Severe Pneumonia Caused by Burkholderia cenocepacia With Intravenous Antibiotics and Immunosuppression Under Extracorporal Membrane Oxygenation

Purulent destruction–complicated pneumonia is a rare and serious disease of multifactorial genesis. In many cases, the diagnosis cannot be established by microbiological analysis of bronchial aspirates or transbronchial biopsies. In our present case, isolation of the pathogen was only possible by collecting specimens via open surgical lung biopsy. A 57-year-old otherwise healthy man was transferred to our department from another hospital. He presented with progressive respiratory failure while computed tomographic scan showed severe bilateral necrotising pneumonia. With open surgical lung biopsy, we could prove evidence of Burkholderia cenocepacia as causative pathogen. As the patients pulmonary condition deteriorated and he developed septic multiorgan failure, we initiated extracorporeal membrane oxygenation (ECMO) and commenced aggressive treatment with 4 intravenous antibiotics, cyclosporine, and corticosteroids. With this therapy, the patients situation rapidly improved; and he was successfully weaned from ECMO andmechanical ventilation. Pneumonia caused by B cenocepaciawithout underlying pulmonary disease such as cystic fibrosis is an absolute rarity. According to the severity of cepacia syndrome, an interdisciplinary approach including ECMO aggressive antibiotic treatment and immunosuppression was decisive for a successful therapy.