Birgit C. Donner

Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation

Background— Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K2P3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K+ channel–related acid-sensitive K+ channel-1]) 2-pore-domain K+ (K2P) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Methods and Results— Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K2P3.1 subunits exhibited predominantly atrial expression, and atrial K2P3.1 transcript levels were highest among functional K2P channels. K2P3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared with patients in sinus rhythm. In contrast, K2P3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K2P3.1 inhibition prolonged APD90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions— Enhancement of atrium-selective K2P3.1 currents contributes to APD shortening in patients with chronic AF, and K2P3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K2P3.1 as a novel drug target for mechanism-based AF therapy.

In vivo electrophysiological characterization of TASK-1 deficient mice

Background/Aims: TASK-1 is a potassium channel predominantly expressed in heart and brain. We have previously shown that anesthetized TASK-1-/-mice have prolonged QT intervals in surface electrocardiograms (ECGs). In addition, heart rate variability quantified by time and frequency domain parameters was significantly altered in TASK-1-/-mice with a sympathetic preponderance. Aims of the present study were the analysis of QT intervals by telemetric ECGs, to determine potential influences of anesthesia and β-adrenergic stimulation on repolarization in surface ECGs, to investigate in vivo electrophysiological parameters by intracardiac electrical stimulation and to quantify heart rate turbulence after ischemia/reperfusion or ventricular pacing in TASK-1+/+ and TASK-1-/-mice. Methods: Rate corrected QT intervals (QTc) were recorded in conscious mice by telemetry and in surface ECGs following administration of various anesthetics (tribromoethanol (Avertin®), pentobarbital and isoflurane). TASK-1+/+ and TASK-1-/mice were characterized by programmed electrical stimulation using an intracardiac octapolar catheter. The baroreceptor reflex was analyzed by heart rate turbulence (turbulence onset and slope) after ischemia/reperfusion and by stimulated premature ventricular contractions. Results: Telemetric and surface ECGs in mice sedated with Avertin®and pentobarbital, showed a significantly lengthened rate corrected QT interval in TASK-1-/-mice (telemetry: TASK-1+/+ 43±3ms vs. TASK-1-/-49±5ms, n=6, p<0.05; Avertin®: TASK-1+/+ 36±8ms vs. TASK-1-/-48±4ms, n=13/16, p<0.0001). The prolongation of the QT interval was most pronounced at lower heart rates. Isoflurane, known for its stimulatory effects on the TASK channel family, attenuated the rate corrected QT interval prolongation in TASK-1-/-mice. Intracardiac electrical stimulation revealed normal values for electrical conduction and refractoriness. No significant arrhythmias after atrial and ventricular burst stimulation were induced before and after adrenergic challenge in both genotypes. Turbulence onset after premature ventricular contraction was significantly altered in TASK-1-/-mice. Conclusion: TASK-1-/-mice exhibit a phenotype of QT prolongation, which distinct relation to heart rate. TASK-1 deficiency does neither alter key electrophysiological parameters nor increases atrial/ventricular vulnerability after electrical stimulation. The heart rate response after premature ventricular contractions is significantly abolished indicating a diminished baroreceptor reflex in TASK-1-/-mice.

D-Transposition of the Great Arteries in a Case of Microduplication 22q11.2

The 22q11.2 deletion syndrome is one of the most frequent genetic syndromes, mainly characterized by cleft palate, facial dysmorphism, conotruncal heart malformations and immune deficiencies. Microduplication of the 22q11.2 region is a quite recently characterized genetic entity comprising a variable phenotype including some overlapping features with the 22q11.2 deletion syndrome. So far only few reports of patients with this microduplication and heart defects have been published. To our knowledge this is the first description of a patient with genetically confirmed duplication of the 22q11.2 region and d-transposition of the great arteries (d-TGA) as well as Ebstein’s anomaly.

Pannexin-1 Deficient Mice Have an Increased Susceptibility for Atrial Fibrillation and Show a QT-Prolongation Phenotype

Background/Aims: Pannexin-1 (Panx1) is an ATP release channel that is ubiquitously expressed and coupled to several ligand-gated receptors. In isolated cardiac myocytes, Panx1 forms large conductance channels that can be activated by Ca2+ release from the sarcoplasmic reticulum. Here we characterized the electrophysiological function of these channels in the heart in vivo, taking recourse to mice with Panx1 ablation. Methods: Cardiac phenotyping of Panx1 knock-out mice (Panx1-/-) was performed by employing a molecular, cellular and functional approach, including echocardiography, surface and telemetric ECG recordings with QT analysis, physical stress testing and quantification of heart rate variability. In addition, an in vivo electrophysiological study entailed programmed electrical stimulation using an intracardiac octapolar catheter. Results: Panx1 deficiency results in a higher incidence of AV-block, delayed ventricular depolarisation, significant prolongation of QT- and rate corrected QT-interval and a higher incidence of atrial fibrillation after intraatrial burst stimulation. Conclusion: Panx1 seems to play an important role in murine cardiac electrophysiology and warrants further consideration in the context of hereditary forms of atrial fibrillation.

A presumably benign human ether-a-go-go-related gene mutation (R176W) with a malignant primary manifestation of long QT syndrome.

A 12-year-old girl presented with a first prolonged syncope. She was successfully resuscitated by external defibrillation after recording torsade de pointes tachycardia. Repeated electrocardiograms and a 12-channel Holter monitoring showed an intermittent prolongation of the QT interval. Genetic analysis identified a heterozygous point mutation in the KCNH2 gene, which is thought to be associated with a rather mild clinical phenotype of the long QT syndrome.

A modified approach for programmed electrical stimulation in mice: Inducibility of ventricular arrhythmias

Background Electrophysiological studies in mice, the prevailing model organism in the field of basic cardiovascular research, are impeded by the low yield of programmed electrical stimulation (PES). Objective To investigate a modified approach for ventricular arrhythmia (VA) induction and a novel scoring system in mice. Method A systematic review of literature on current methods for PES in mice searching the PubMed database revealed that VA inducibility was low and ranged widely (4.6 ± 10.7%). Based on this literature review, a modified PES protocol with 3 to 10 extrastimuli was developed and tested in comparison to the conventional PES protocol using up to 3 extrastimuli in anesthetized wildtype mice (C57BL/6J, n = 12). Induced VA, classified according to the Lambeth Convention, were assessed by established arrhythmia scores as well as a novel arrhythmia score based on VA duration. Results PES with the modified approach raised both the occurrence and the duration of VA compared to conventional PES (0% vs 50%; novel VA score p = 0.0002). Particularly, coupling of >6 extrastimuli raised the induction of VA. Predominantly, premature ventricular complexes (n = 6) and ventricular tachycardia <1s (n = 4) were observed. Repeated PES after adrenergic stimulation using isoprenaline resulted in enhanced induction of ventricular tachycardia <1s in both protocols. Conclusion Our findings suggest that the presented approach of modified PES enables effective induction and quantification of VA in wildtype mice and may well be suited to document and evaluate detailed VA characteristics in mice.

Complicated Postoperative Course after Pulmonary Artery Sling Repair and Slide Tracheoplasty

Pulmonary artery sling (PAS) is a rare congenital condition in which the left pulmonary artery (LPA) arises from the right pulmonary artery, and then passes between the trachea and the esophagus to reach the left lung, thereby forming a sling around the airway. It is often associated with intrinsic tracheal stenosis due to complete cartilaginous rings. Therapeutic management nowadays consists of one-stage reimplantation of the LPA and tracheoplasty with cardiopulmonary bypass support. Here, we present a 7-week-old boy with PAS and long-segment tracheal stenosis (LSTS) who underwent surgical intervention consisting of reimplantation of the LPA and slide tracheoplasty. Multiple respiratory and cardiovascular complications marked the postoperative course. They consisted of recurrent failed attempts in weaning off mechanical ventilation due to bronchomalacia, left vocal cord paralysis, development of granulation tissue at the anastomosis and restenosis of the trachea, and the main stem bronchi requiring balloon dilatation. The patient also developed bilateral pulmonary artery thrombosis and stenosis of the LPA. After a prolonged hospitalization, the patient is doing well without any respiratory symptoms and has a good result on follow-up bronchoscopy 1 year after the initial surgery. The stenosis of the LPA responded well to percutaneous balloon dilatation 12 months after the primary surgery. The case illustrates that even though surgical techniques are improving and are in general associated with a low morbidity and mortality, management of PAS and tracheal stenosis can still be challenging. However, good long-term outcome can be achieved if the initial postoperative phase is overcome.

Response to Letter Regarding Article, “Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation”

We thank Dr Olschewski and colleagues for their interest in our article,1 and we appreciate their recapitulation of 2 key findings of our work: (1) the identification of increased atrial K2P3.1 (TASK-1) K+ channel expression, I K2P3.1 upregulation, and action potential shortening as substrate in patients with chronic atrial fibrillation (AF); and (2) the presentation of K2P3.1 current inhibition and resulting action potential prolongation as mechanism-based therapeutic paradigm in this subentity of the arrhythmia. Our study focused on the mechanistic contribution of K2P3.1 channels to human atrial electrophysiology and action potential regulation, with particular emphasis on pathophysiological dysregulation in AF. Based on mechanistic data presented in the study, functional correction of atrial ionic remodeling through the suppression of atrial K2P3.1 current emerged as a novel antiarrhythmic option for AF management. We agree with Olschewski et al that efficacy and safety require in-depth preclinical evaluation before transfer of novel therapeutic principles into human application. In their letter, the authors highlight their findings of K2P3.1 expression and functional …