Prolongation of the QT interval in the ECG is a critical finding that signifies an extended duration from the onset of ventricular depolarization to the end of ventricular repolarization. It can predispose patients to life-threatening arrhythmias, such as Torsades de Pointes (TdP). Long QT syndromes (LQTS) are defined by mutations in ion channel genes, particularly those encoding cardiac potassium and sodium channels and are characterized by a significant risk for sudden cardiac death if untreated. However, besides these clearly defined entities various medications have been implicated in causing QT interval prolongation. There is increasing evidence for a genetically determined risk for drug-induced QT prolongation. In addition, due to numerous clinical factors influencing the QT interval, QT prolongation increases the risk of TdP particularly in multi-morbid patients necessitating vigilant monitoring in at-risk populations. This review gives an overview of mechanisms and conditions which induce QT prolongation, the clinical assessment of QT interval duration, thereby highlighting quantitative variations in measurement techniques and heart-rate correction, as well as in demographic interpretation of normal values. The risk of cardiac arrhythmia is discussed, in both patients with congenital LQTS and acquired QT prolongation, along with influencing pharmacokinetic/pharmacodynamic, non-pharmacologic and genetic risk factors for TdP. Finally, clinical implications for individual patient management, including risk-adapted drug-prescription and use of ECG monitoring to mitigate the risks associated with QT prolongation, are summarized. Understanding the interplay between pharmacokinetics, pharmacodynamics, genetic predisposition and co-morbidities is essential for optimizing treatment in the context of prolonged QT intervals, preventing adverse cardiovascular events, and improving cardiac safety. Comprehensive drug labelling regarding exposure-QT relationships and available pharmacovigilance data are important sources of information enhancing patient safety.

There is an unmet medical need to treat patients with severe hypertrophic cardiomyopathy leading to heart failure and death in children carrying pathogenic activating variants in the RAS/mitogen-activated protein kinase pathway. A retrospective analysis of 61 patients provides evidence for decreased mortality and morbidity with improved cardiac status in patients with RASopathy with severe hypertrophic cardiomyopathy receiving mitogen-activated protein kinase kinase inhibition (n = 30) vs those with standard-of-care treatment (n = 31). Side effects were not life threatening and were manageable. The data presented suggest that personalized therapies targeting underlying signaling pathway abnormalities might be effective in critically ill patients with RASopathy warranting clinical investigation.

Abstract Aims Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5–19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator.

An association between QT prolongation (Bazett's corrected QT interval, QTcB) of 7 milliseconds and nocturnal hypoglycemia, compared with euglycemia, has been observed in children with type 1 diabetes (T1D). The objective of this pharmacometric analysis was to understand this association and other sources of QTc variability quantitatively. Data originate from a prospective observational study (25 cardiac healthy children with T1D, aged 8.1-17.6 years) with continuous subcutaneous glucose and electrocardiogram measurements for 5 consecutive nights. Mixed-effect modeling was used to compare QTcB with individual heart-rate correction (QTcI). Covariate models accounting for circadian variation, age, and sex were evaluated, followed by an investigation of glucose-QTc relationships (with univariable and combined adjusted analysis). Factors potentially modifying sensitivity to QTc lengthening were explored. Random inter-individual variability was reduced in the QTcI versus QTcB model (& PLUSMN;12.6 vs 14.1 milliseconds), and was further reduced in the adjusted covariate model (& PLUSMN;9.7 milliseconds), accounting for the significantly (P < .01) shortened QTc in adolescent boys (-14.6 milliseconds), circadian variation (amplitude, 19.2 milliseconds; shift, 2.9 hours), and linear glucose-QTc relationship (delay rate, 0.56(-h); slope, 0.76 milliseconds [95%CI 0.67- 0.85 milliseconds] per 1 mmol/L decrease in glucose). Differing sensitivity was suggested to depend upon hemoglobin A1c (HbA1c), T1D duration, and time spent in nocturnal hypoglycemia. In conclusion, a clinically mild association of QTc prolongation with nocturnal hypoglycemia was confirmed and quantified in this pharmacometric analysis, and the longest QTc interval was around 03:00 a.m. The characterized delayed association with glucose highlights the relevance of both the extent and the duration of hypoglycemia. Further clinical studies are warranted to investigate whether these factors contribute to increased risk of hypoglycemia-associated cardiac arrhythmia in children with T1D.

Background: RASopathies are a spectrum of pleomorphic syndromic disorders and caused by germline mutations in the RAS/mitogen-activated protein kinase (MAPK) pathway. They cause progressive RASopathy-associated cardiomyopathy (RAS-CM) for which no preventive or curative therapies exist. Young infants presenting with heart failure suffer from high mortality. RAS-CM presenting later in life is morbid with increased risk for sudden cardiac death or cardiac transplantation. Animal studies and limited case reports have suggested that small molecule inhibitors of target of rapamycin (mTOR) or mitogen-activated protein kinase kinase (MEK), pathways activated in certain RASopathies, are beneficial. The aim of this study is to report on 25 patients from Europe and North America with progressive and/or life-threatening RAS-CM in whom we initiated off-label or compassionate inhibition of mTOR or MEK after exhaustion of standard therapies.

Hypoglycemia is the most common complication in insulin treated diabetes. Though mostly mild, it can be fatal in rare cases: It is hypothesized that hypoglycemia related QTc prolongation contributes to cardiac arrhythmia.

Pregnant women with inherited long QT syndrome (iLQTS) are at an increased risk for preterm delivery and intrauterine growth retardation (IUGR) due to their underlying disease. Additionally, they are at a risk of arrhythmogenic events, particularly during the postpartum period because of physiological changes and increased emotional/physical stress. β-receptor blockers can effectively prevent life-threatening Torsades de Pointes ventricular tachycardia and they are the treatment of choice in iLQTS. Use of β-receptor blockers in pregnancy is recommended, although IUGR is commonly reported for prenatally exposed infants. IUGR, particularly in preterm infants, can result in adverse neonatal outcomes. This review was performed to support clinicians in their selection of β-receptor blocker treatment for their pregnant iLQTS women by (i) summarizing the available literature addressing the impact of different β-receptor blockers on IUGR and (ii) reporting additional aspects which might influence the β-receptor blocker selection. In general, experts recommend to use nonselective β-receptor blockers, such as nadolol and propranolol, for iLQTS management as these drugs seem to be superior in effectiveness. However, β-1-selective receptor blockers, such as bisoprolol or metoprolol, seem to affect less likely uterine contraction, peripheral vasodilation, and are associated with lower IUGR rates and fetal hypoglycemia. They are therefore recommended, except atenolol, as first-line therapy for pregnant women. Additionally, maternal factors such as iLQTS genotype, other underlying comorbidities (e.g., diabetes mellitus type 1, asthma bronchiale), and uteroplacental dysfunction or fetal factors have to be taken into account. Therefore, each woman with iLQTS who wants to become pregnant should be well-advised for a personalized β-receptor blocker therapy according to the individual risk-benefit evaluation by a multidisciplinary team of cardiologists, gynecologists, pediatric cardiologists, neonatologists, and clinical pharmacologists. During pregnancy, a close monitoring of IUGR and, after birth, monitoring of bradycardia, hypoglycemia, and respiratory depression in the neonate is mandatory. This review summarizes available data on β-receptor blocker-related risk for IUGR in prenatally exposed infants and illustrates which factors might influence β-receptor blocker selection with the aim to support clinicians in their pharmacological management of their pregnant iLQTS patients.

TWIK-related K+ channel (TREK-1) two-pore-domain potassium (K2P) channels mediate background potassium currents and regulate cellular excitability in many different types of cells. Their functional activity is controlled by a broad variety of different physiological stimuli, such as temperature, extracellular or intracellular pH, lipids and mechanical stress. By linking cellular excitability to mechanical stress, TREK-1 currents might be important to mediate parts of the mechanoelectrical feedback described in the heart. Furthermore, TREK-1 currents might contribute to the dysregulation of excitability in the heart in pathophysiological situations, such as those caused by abnormal stretch or ischaemia-associated cell swelling, thereby contributing to arrhythmogenesis. In this review, we focus on the functional role of TREK-1 in the heart and its putative contribution to cardiac mechanoelectrical coupling. Its cardiac expression among different species is discussed, alongside with functional evidence for TREK-1 currents in cardiomyocytes. In addition, evidence for the involvement of TREK-1 currents in different cardiac arrhythmias, such as atrial fibrillation or ventricular tachycardia, is summarized. Furthermore, the role of TREK-1 and its interaction partners in the regulation of the cardiac heart rate is reviewed. Finally, we focus on the significance of TREK-1 in the development of cardiac hypertrophy, cardiac fibrosis and heart failure.

OBJECTIVE:To develop a treatment algorithm for patients with long QT syndrome (LQTS) in case they need antiallergic medications for allergic reactions, including asthma and anaphylaxis.DATA SOURCES:A literature review was performed to assess safety and to develop antiallergic treatment strategies for patients with LQTS.STUDY SELECTIONS:LQTS is a heterogeneous group of myocardial repolarization disorders characterized by prolongation of the QT interval that potentially results in life-threatening torsades de pointes tachycardia. Data on pharmacologic treatment in case of anaphylaxis in LQTS are sparse. For this narrative review, all currently available articles on the use of antiallergic drugs for allergic reactions, anaphylaxis, and asthma in patients with LQTS were used.RESULTS:Local allergic symptoms can be safely treated primarily with fexofenadine, levocetirizine, desloratadine, or cetirizine and, if needed, a short course of corticosteroids. In case of systemic symptoms, epinephrine should be administered. It may be less effective in patients with LQTS treated with β-blockers, necessitating the use of glucagon as add-on treatment. In case of lower airway obstruction, ipratropium bromide should be used, but if not effective, inhaled β2-adrenergic agents may be used. Continuous cardiac monitoring is indicated with the use of epinephrine and inhaled β2-adrenergic agents. The use of the latter also warrants intense monitoring of serum potassium levels. Clemastine and dimetindene should be avoided in patients with LQTS.CONCLUSION:Patients with LQTS have a higher risk of life-threatening complications during the treatment of their allergic reactions because of the underlying disease and concomitant treatment with β-blockers. Treatment algorithms will certainly decrease these complications.

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.

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 1year after the initial surgery. The stenosis of the LPA responded well to percutaneous balloon dilatation 12months 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.

OBJECTIVE The study aims to describe the management of a case of life-threatening yew (Taxus baccata) intoxication. BACKGROUND The needles of the yew tree contain highly cardiotoxic taxines. Intoxication with taxines, typically as part of suicide attempts, may lead to potentially lethal arrhythmias which often require prolonged cardiopulmonary resuscitation and other supportive measures. No specific therapy has been described. In some cases, extracorporeal life support has been used. CASE After an attempted suicide with yew needles and out-of-hospital cardiac arrest, a female adolescent was resuscitated for 6 hours according to Advanced Cardiovascular Life Support guidelines. Complex ventricular tachycardias were treated by repeated direct current shocks and broad complex bradycardia managed with transvenous cardiac pacing. Antiarrhythmic drugs (amiodarone, lidocaine), magnesium sulfate, and supportive measures (intravenous lipids, sodium bicarbonate) were provided. The arrhythmias finally resolved, and the patient did not show any significant neurological or cardiac short-term sequelae after 24 hours. RESULTS The authors describe the successful management of a case of severe taxine intoxication by prolonged conventional advanced cardiac life support lasting for more than 6 hours. CONCLUSIONS In life-threatening yew intoxication, prolonged cardiopulmonary resuscitation is absolutely essential owing to the long duration of the cardiotoxic action of taxines and can lead to an outcome without cardiac or neurological sequelae.

HomeCirculationVol. 133, No. 11Response to Letter Regarding Article, “Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter Regarding Article, “Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation” Constanze Schmidt, MD and Felix Wiedmann, MD Niels Voigt, MD Xiao-Bo Zhou, MD Jordi Heijman, PhD Siegfried Lang, PhD Virginia Albert, BSc Stefan Kallenberger, MD, PhD Arjang Ruhparwar, MD, Gábor Szabó, MD, PhD, Klaus Kallenbach, MD and Matthias Karck, MD Martin Borggrefe, MD Peter Biliczki, MD, PhD Joachim R. Ehrlich, MD István Baczkó, MD, PhD Patrick Lugenbiel, MD and Patrick A. Schweizer, MD Birgit C. Donner, MD, PhD Hugo A. Katus, MD, PhD Dobromir Dobrev, MD Dierk Thomas, MD Constanze SchmidtConstanze Schmidt Department of Cardiology, University of Heidelberg, Heidelberg, Germany Search for more papers by this author and Felix WiedmannFelix Wiedmann Department of Cardiology, University of Heidelberg, Heidelberg, Germany Search for more papers by this author Niels VoigtNiels Voigt Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany Search for more papers by this author Xiao-Bo ZhouXiao-Bo Zhou First Department of Medicine, University Medical Center Mannheim, Mannheim, Germany Search for more papers by this author Jordi HeijmanJordi Heijman Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands Search for more papers by this author Siegfried LangSiegfried Lang First Department of Medicine, University Medical Center Mannheim, Mannheim, Germany Search for more papers by this author Virginia AlbertVirginia Albert Department of Cardiology, University of Heidelberg, Heidelberg, Germany Search for more papers by this author Stefan KallenbergerStefan Kallenberger Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany Search for more papers by this author Arjang RuhparwarArjang Ruhparwar Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany Search for more papers by this author , Gábor SzabóGábor Szabó Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany Search for more papers by this author , Klaus KallenbachKlaus Kallenbach Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany Search for more papers by this author and Matthias KarckMatthias Karck Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany Search for more papers by this author Martin BorggrefeMartin Borggrefe First Department of Medicine, University Medical Center Mannheim, Mannheim, Germany Search for more papers by this author Peter BiliczkiPeter Biliczki Department of Cardiology, Internal Medicine III, Goethe University, Frankfurt, Germany Search for more papers by this author Joachim R. EhrlichJoachim R. Ehrlich Department of Cardiology, St. Josefs-Hospital, Wiesbaden, Germany Search for more papers by this author István BaczkóIstván Baczkó Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary Search for more papers by this author Patrick LugenbielPatrick Lugenbiel Department of Cardiology, University of Heidelberg, Heidelberg, Germany Search for more papers by this author and Patrick A. SchweizerPatrick A. Schweizer Department of Cardiology, University of Heidelberg, Heidelberg, Germany Search for more papers by this author Birgit C. DonnerBirgit C. Donner Department of Cardiology, University of Basel Children’s Hospital, Basel, Switzerland Search for more papers by this author Hugo A. KatusHugo A. Katus Department of Cardiology, University of Heidelberg, Heidelberg, Germany Search for more papers by this author Dobromir DobrevDobromir Dobrev Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany Search for more papers by this author Dierk ThomasDierk Thomas Department of Cardiology, University of Heidelberg, Heidelberg, Germany Search for more papers by this author Originally published15 Mar 2016https://doi.org/10.1161/CIRCULATIONAHA.115.020662Circulation. 2016;133:e440–e441We 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, IK2P3.1 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 significance in human pulmonary artery smooth muscle cells,2 corresponding to previous observations by our group.3 K2P3.1 current in human pulmonary artery smooth muscle cells regulates vascular tone and pulmonary arterial pressure, and IK2P3.1 reduction by endothelin-1 or genetic mutations has been implicated in the pathophysiology of pulmonary arterial hypertension. To date, clinical data on in vivo application of specific K2P3.1 inhibitors in humans or large animals have not been reported. Thus, conclusions regarding the true extent and causal relations between systemic K2P3.1 blockade and potential effects on pulmonary vasculature are limited. Nonetheless, pulmonary vascular tone should be carefully considered in future studies addressing K2P3.1 as antiarrhythmic target. Similarly, caution is required regarding potential cardiac effects when direct or indirect pharmacological K2P3.1 activation is explored as therapeutic principle in the treatment of pulmonary arterial hypertension. Increased K2P3.1 current amplitudes may result in atrial arrhythmia including AF, associated with further worsening of symptoms and prognosis.Gene therapy with greater selectivity than small molecule-based approaches may be used to exclude potential extracardiac side effects. The gene of interest is packaged into viral or nonviral carriers and delivered to the target area by means of direct injection or by use of catheter-based interventional techniques, providing the advantage of site-restricted action in contrast to systemic application of drugs. Previous studies confirmed effective use of gene therapeutic approaches targeting electric or structural substrates for rhythm control in large-animal models of AF.4,5 Similarly, a better understanding of tissue-specific K2P3.1 channel regulation and of the molecular mechanisms underlying K2P3.1 upregulation might help to identify pathways to target increased atrial IK2P3.1 without affecting channels in human pulmonary artery smooth muscle cells.In summary, K2P3.1 K+ channels are important for determining the action potential duration in human atrial myocytes,1 and they set the resting membrane potential and vascular tone in human pulmonary artery smooth muscle cells.2,3 Further therapeutic exploitation of these significant mechanistic findings in cardiovascular medicine requires consideration of the potential side effects that may be minimized by the choice of application mode, appropriate dose titration, thorough preclinical evaluation, and patient monitoring.Constanze Schmidt, MDFelix Wiedmann, MDDepartment of CardiologyUniversity of HeidelbergHeidelbergGermanyNiels Voigt, MDInstitute of PharmacologyWest German Heart and Vascular CenterUniversity Duisburg-EssenEssen, GermanyXiao-Bo Zhou, MDFirst Department of MedicineUniversity Medical Center MannheimMannheim, GermanyJordi Heijman, PhDDepartment of CardiologyCardiovascular Research Institute MaastrichtMaastricht University Medical CentreMaastricht, The NetherlandsSiegfried Lang, PhDFirst Department of MedicineUniversity Medical Center MannheimMannheim, GermanyVirginia Albert, BScDepartment of CardiologyUniversity of HeidelbergHeidelberg, GermanyStefan Kallenberger, MD, PhDDepartment for Bioinformatics and Functional GenomicsDivision of Theoretical BioinformaticsGerman Cancer Research Center (DKFZ) Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuantHeidelberg UniversityHeidelberg, GermanyArjang Ruhparwar, MDGábor Szabó, MD, PhDKlaus Kallenbach, MDMatthias Karck, MDDepartment of Cardiac SurgeryUniversity Hospital HeidelbergHeidelberg, GermanyMartin Borggrefe, MDFirst Department of MedicineUniversity Medical Center MannheimMannheim, GermanyPeter Biliczki, MD, PhDDepartment of CardiologyInternal Medicine IIIGoethe UniversityFrankfurt, GermanyJoachim R. Ehrlich, MDDepartment of CardiologySt. Josefs-HospitalWiesbaden, GermanyIstván Baczkó, MD, PhDDepartment of Pharmacology and PharmacotherapyFaculty of MedicineUniversity of SzegedSzeged, HungaryPatrick Lugenbiel, MDPatrick A. Schweizer, MDDepartment of CardiologyUniversity of HeidelbergHeidelberg, GermanyBirgit C. Donner, MD, PhDDepartment of CardiologyUniversity of Basel Children’s HospitalBasel, SwitzerlandHugo A. Katus, MD, PhDDepartment of CardiologyUniversity of HeidelbergHeidelberg, GermanyDobromir Dobrev, MDInstitute of PharmacologyWest German Heart and Vascular CenterUniversity Duisburg-EssenEssen, GermanyDierk Thomas, MDDepartment of CardiologyUniversity of HeidelbergHeidelberg, GermanyAcknowledgmentsThis study was supported in part by research grants from the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung – German Centre for Cardiovascular Research) and from the BMBF (German Ministry of Education and Research) (to C.S., F.W., X.B.Z., S.L., M.B., P.A.S., H.A.K., and D.T.)DisclosuresThe experimental compound A293 was kindly provided by Sanofi-Aventis (Frankfurt am Main, Germany). Dr Thomas served on advisory boards for and received honoraria for lectures from Sanofi-Aventis. The other authors report no conflicts.References1. Schmidt C, Wiedmann F, Voigt N, Zhou XB, Heijman J, Lang S, Albert V, Kallenberger S, Ruhparwar A, Szabó G, Kallenbach K, Karck M, Borggrefe M, Biliczki P, Ehrlich JR, Baczkó I, Lugenbiel P, Schweizer PA, Donner BC, Katus HA, Dobrev D, Thomas D. Upregulation of K(2P)3.1 K+ current causes action potential shortening in patients with chronic atrial fibrillation.Circulation. 2015; 132:82–92. doi: 10.1161/CIRCULATIONAHA.114.012657.LinkGoogle Scholar2. Olschewski A, Li Y, Tang B, Hanze J, Eul B, Bohle RM, Wilhelm J, Morty RE, Brau ME, Weir EK, Kwapiszewska G, Klepetko W, Seeger W, Olschewski H. Impact of TASK-1 in human pulmonary artery smooth muscle cells.Circ Res. 2006; 98:1072–1080. doi: 10.1161/01.RES.0000219677.12988.e9.LinkGoogle Scholar3. Seyler C, Duthil-Straub E, Zitron E, Gierten J, Scholz EP, Fink RH, Karle CA, Becker R, Katus HA, Thomas D. TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation.Br J Pharmacol. 2012; 165:1467–1475. doi: 10.1111/j.1476-5381.2011.01626.x.CrossrefMedlineGoogle Scholar4. Bikou O, Thomas D, Trappe K, Lugenbiel P, Kelemen K, Koch M, Soucek R, Voss F, Becker R, Katus HA, Bauer A. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model.Cardiovasc Res. 2011; 92:218–225. doi: 10.1093/cvr/cvr209.CrossrefMedlineGoogle Scholar5. Trappe K, Thomas D, Bikou O, Kelemen K, Lugenbiel P, Voss F, Becker R, Katus HA, Bauer A. Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study.Eur Heart J. 2013; 34:147–157. doi: 10.1093/eurheartj/ehr269.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bedoya M, Rinné S, Kiper A, Decher N, González W and Ramírez D (2019) TASK Channels Pharmacology: New Challenges in Drug Design, Journal of Medicinal Chemistry, 10.1021/acs.jmedchem.9b00248, 62:22, (10044-10058), Online publication date: 27-Nov-2019. Motta S, Lintas V, Fioretta E, Hoerstrup S and Emmert M (2017) Off-the-shelf tissue engineered heart valves for in situ regeneration: current state, challenges and future directions , Expert Review of Medical Devices, 10.1080/17434440.2018.1419865, 15:1, (35-45), Online publication date: 2-Jan-2018. Kraft M, Büscher A, Wiedmann F, L’hoste Y, Haefeli W, Frey N, Katus H and Schmidt C (2021) Current Drug Treatment Strategies for Atrial Fibrillation and TASK-1 Inhibition as an Emerging Novel Therapy Option, Frontiers in Pharmacology, 10.3389/fphar.2021.638445, 12 March 15, 2016Vol 133, Issue 11 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.115.020662PMID: 26976923 Originally publishedMarch 15, 2016 PDF download Advertisement SubjectsArrhythmiasAtrial FibrillationBasic Science ResearchElectrophysiologyIon Channels/Membrane Transport

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.

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. K 2P 3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K + channel–related acid-sensitive K + channel-1]) 2-pore-domain K + (K 2P ) 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. K 2P 3.1 subunits exhibited predominantly atrial expression, and atrial K 2P 3.1 transcript levels were highest among functional K 2P channels. K 2P 3.1 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 (APD 90 ) compared with patients in sinus rhythm. In contrast, K 2P 3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K 2P 3.1 inhibition prolonged APD 90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Conclusions— Enhancement of atrium-selective K 2P 3.1 currents contributes to APD shortening in patients with chronic AF, and K 2P 3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K 2P 3.1 as a novel drug target for mechanism-based AF therapy.