Synergistic anti-arrhythmic effects in human atria with combined use of sodium blockers and acacetin

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Developing effective and safe anti-AF drugs remains an unmet challenge. Simultaneous block of both atrial-specific ultra-rapid delayed rectifier potassium (K⁺) current (I Kur ) and the Na⁺ current (I Na ) has been hypothesized to be anti-AF, without inducing significant QT prolongation and ventricular side effects. However, the antiarrhythmic advantage of simultaneously blocking these two channels vs. individual block in the setting of AF-induced electrical remodeling remains to be documented. Furthermore, many I Kur blockers such as acacetin and AVE0118, partially inhibit other K⁺ currents in the atria. Whether this multi-K⁺ -block produces greater anti-AF effects compared with selective I Kur -block has not been fully understood. The aim of this study was to use computer models to (i) assess the impact of multi-K⁺-block as exhibited by many I Kur blokers, and (ii) evaluate the antiarrhythmic effect of blocking I Kur and I Na , either alone or in combination, on atrial and ventricular electrical excitation and recovery in the setting of AF-induced electrical-remodeling. Contemporary mathematical models of human atrial and ventricular cells were modified to incorporate dose-dependent actions of acacetin (a multichannel blocker primarily inhibiting I Kur while less potently blocking Ito, I Kr , and I Ks ). Rate- and atrial-selective inhibition of I Na was also incorporated into the models. These single myocyte models were then incorporated into multicellular two-dimensional (2D) and three-dimensional (3D) anatomical models of the human atria. As expected, application of I Kur blocker produced pronounced action potential duration (APD) prolongation in atrial myocytes. Furthermore, combined multiple K⁺-channel block that mimicked the effects of acacetin exhibited synergistic APD prolongations. Synergistically anti-AF effects following inhibition of I Na and combined I Kur /K⁺-channels were also observed. The attainable maximal AF-selectivity of I Na inhibition was greatly augmented by blocking I Kur or multiple K⁺-currents in the atrial myocytes. This enhanced anti-arrhythmic effects of combined block of Na⁺- and K⁺-channels were also seen in 2D and 3D simulations; specially, there was an enhanced efficacy in terminating re-entrant excitation waves, exerting improved antiarrhythmic effects in the human atria as compared to a single-channel block. However, in the human ventricular myocytes and tissue, cellular repolarization and computed QT intervals were modestly affected in the presence of actions of acacetin and I Na blockers (either alone or in combination). In conclusion, this study demonstrates synergistic antiarrhythmic benefits of combined block of I Kur and I Na , as well as those of I Na and combined multi K⁺-current block of acacetin, without significant alterations of ventricular repolarization and QT intervals. This approach may be a valuable strategy for the treatment of AF

Applying computational approaches to the understanding of the consequences and opportunities of ion channel properties in atrial fibrillation

Cardiac arrhythmias are disorders of the electrical system of the heart and an often clinically-challenging group of disorders. Atrial fibrillation (AF) is the most common cardiac arrhythmia in the general population; it is associated with significant morbidity and mortality. Available antiarrhythmic drugs (AADs) for the treatment of AF are older molecules with sub- optimal efficacy and safety profiles. Recent advances in basic electrophysiology and the development of sophisticated mathematical modeling approaches could help in expanding our understanding of the basic mechanisms of AF and assist in the development of novel AF- selective AADs. The purpose of this thesis was to utilize computational approaches to the understanding of the consequences and opportunities of ion channel properties, with a special emphasis on AF. The cardiac action potential is the basic functional unit of the electrical system of the heart and is the manifestation of coordinated current fluxes through specialized proteins known as ion channels. Antiarrhythmic drugs act through modulation of ion channel properties. We hypothesized that mathematical modeling could be used to study and optimize the pharmacodynamic properties of AADs for the treatment of AF. We demonstrated that the pharmacodynamic properties (binding/unbinding characteristics) of a state-dependent Na+- channel blocker modulate the drug’s anti-/proarrhythmic actions with inactivated-state blockers being optimally AF-selective. The optimized drug’s selectivity for AF was the result of its rate- selectivity (stronger effects at fast vs slow cardiomyocyte activation rates) with relatively mild atrial-selective (stronger effects in atrial vs ventricular cardiomyocytes) actions. We found that the optimally AF-selective Na+-channel blocker had sub-optimal anti-AF efficacy, but that slightly less selective drugs had favorable AF-termination rates. We then sought to explore potential current-block combinations with synergistic AF- selective properties. Using mathematical modeling and laboratory experiments, we demonstrated that the combination of optimized state-dependent Na+-channel block and K+- channel block had synergistic effects, significantly augmenting AF termination rates for any level of AF-selectivity vs pure Na+-channel block. The mechanisms of these synergistic effects were found to be mediated by the functional interaction between the action potential prolonging- v effects of K+-channel block, the Na+-channel blocker’s voltage-dependent binding/unbinding properties and the Na+ channel’s inactivation characteristics, highlighting the non-linear nature of the cardiac action potential’s dynamics. Traditional K+ currents targeted by AADs have significant ventricular proarrhythmic liabilities. Using recent experimental observations, we updated the mathematic formulation for the inactivation dynamics of the ultra-rapid delayed-rectifier K+ current (IKur), an atrial-specific current. Using this model, we showed that, contrary to what had been proposed in the published literature, IKur rate-dependent properties are mediated by its activation properties with minimal contribution from inactivation, under physiological conditions. We also demonstrated that the contribution of IKur to action potential repolarization is preserved, or even increased, in the setting of electrical remodeling-induced IKur downregulation. Finally, we described the mechanisms of the forward rate-dependent of IKur block, mediated by functional non-linear interactions with the rapid delayed inward-rectifier K+ current (IKr), the only K+ current with such properties. Until recently, fibroblasts were considered to be electrically inactive. More recently, experimental work demonstrated the presence of functional ionic current on the fibroblast and possible cardiomyocyte-fibroblast coupling. Here, we described a novel kind of heart failure- induced electrical remodeling involving the fibroblasts ion channels. This was characterized by downregulation of the fibroblast voltage-dependent K+ current (IKv,fb) and upregulation of the fibroblast inward-rectifier K+ current (IKir,fb). We then implemented our experimental findings into a mathematical model of cardiomyocyte-fibroblast coupling and found fibroblast electrical remodeling to have significant effects on the cardiomyocyte’s electrophysiological properties. In a 2-dimension model of simulated AF, downregulation of IKv,fb had an antiarrhythmic effect whereas IKir,fb upregulation was found to be proarrhythmic. The studies presented here utilized mathematical modeling to study non-linear systems in cardiac electrophysiology to tackle questions that would have been difficult to approach with traditional laboratory-based experimentation. They also showcased how theoretical results can help orient and receive confirmation with subsequent experimental work or, conversely, novel experimental findings results be implemented into a mathematical model to investigate potential consequences. Mathematical modeling is a promising tool to help in studying the complex and vi non-linear effects of pharmacological modulation of ion channel properties and assist in the development of optimized antiarrhythmics for the treatment of AF, a major unmet need in clinical medicine. As models increase in sophistication to better represent the cardiomyocyte’s electrophysiology, they will almost certainly play an ever-growing role in expanding our understanding of the mechanisms of complex arrhythmias.Les arythmies cardiaques représentent une famille de pathologies du système électrique cardiaque. La fibrillation auriculaire (FA), est l’arythmie cardiaque la plus fréquente dans la population générale et est associée à un fardeau de morbidité et mortalité cardiovasculaire important. Les médicaments antiarythmiques utilisées dans le traitement de la FA sont de vieilles molécules avec une efficacité sous-optimale et des effets secondaires importants. Les avancées récentes en électrophysiologie cardiaque fondamentale et le développement d’outils de modélisation mathématique ont le potentiel d’élargir notre compréhension des mécanismes pathophysiologiques en FA et contribuer au développement de nouveaux médicaments antiarythmiques optimisés pour le traitement de la FA. L’objectif global de cette thèse est d’utiliser les méthodes de modélisation mathématique pour étudier les conséquences et opportunités thérapeutiques de la modulation des canaux ioniques cardiaques, avec une emphase sur la FA. Le potentiel d’action cardiaque est l’unité fonctionnelle de base du système électrique cardiaque ; il est le résultat du flux coordonné de courants électriques à travers de protéines spécialisées, les canaux ioniques. Les molécules antiarythmiques agissent à travers la modulation des canaux ioniques cardiaques. Nous avons posé l’hypothèse que des modèles mathématiques pourraient être utilisés pour étudier et optimiser les propriétés pharmacodynamiques d’un médicament antiarythmique pour le traitement de la FA. Nous avons démontré que les propriétés pharmacodynamiques (propriétés de liage et déliage) d’un bloqueur des canaux Na+ état-dépendant modulent les effets anti- et pro-arythmiques de la molécule ; un bloqueur Na+ sélectif pour l’état inactivé du canal serait maximalement FA-sélectif. Cette sélectivité pour la FA est la conséquence de la sélectivité pour la fréquence (effet thérapeutique plus important à des fréquences d’activation du cardiomyocyte élevées vs basses) avec une contribution relativement faible de la sélectivité auriculaire (effet thérapeutique plus important sur les cardiomyocytes auriculaires vs ventriculaires). Par la suite, nous avons exploré des combinaisons de bloqueurs ioniques ayant des propriétés anti-FA synergiques. En utilisant des modèles mathématiques et des expériences en laboratoire, nous avons démontré que la combinaison d’un bloqueur des canaux Na+ et d’un iii bloqueur des canaux K+ a des effets synergiques, augmentant de façon importante l’efficacité anti-FA pour un même degré de sélectivité vs un bloqueur des canaux Na+ seul. Le mécanisme de synergie a été élucidé et consiste d’effets fonctionnels médiés par l’interaction du prolongement de la durée du potentiel d’action causé par le bloque des canaux K+, les propriétés voltage-dépendantes du liage et déliage du bloqueur des canaux Na+ ainsi que des propriétés d’inactivation des canaux Na+, démontrant la nature hautement non-linéaire des dynamiques du potentiel d’action cardiaque. Les courants K+ ciblés par les médicaments antiarythmiques ont des effets proarythmiques ventriculaires importants. En utilisant des données expérimentales récentes, nous avons proposé une formulation mise à jour des dynamiques d’inactivation du courant K+ IKur, un courant auriculo-sélectif. En utilisant ce modèle, nous avons démontré que, contrairement à ce qui avait été précédemment proposé, les propriétés fréquence-dépendantes du courant IKur dépendent de ses caractéristiques d’activation avec une contribution négligeable de ses propriétés d’inactivation, sous conditions physiologiques normales. Nous avons également démontré que la contribution de IKur à la repolarisation du potentiel d’action est maintenue, voir augmentée, dans le contexte de la diminution de IKur en situation de remodelage électrique induit par la FA. Finalement, nous avons décrit le mécanisme qui sous-tend les propriétés fréquence-dépendantes du bloque de IKur, l’unique courant K+ avec de telles caractéristiques. Jusqu’à très récemment, les fibroblastes cardiaques étaient considérés comme électriquement inactifs. Des travaux expérimentaux ont démontré la présence de canaux ioniques sur la surface de ces fibroblastes ainsi que la possibilité de couplage électrique entre cardiomyocytes et fibroblastes. Nous avons décrit un nouveau type de remodelage électrique en situation d’insuffisance cardiaque, le remodelage des courants ioniques des fibroblastes cardiaques. Ce remodelage est caractérisé par une diminution du courant K+ voltage-dépendant IKv,fb et une augmentation du courant K+ IKir,fb. Nous avons par la suite incorporé ces trouvailles expérimentales dans un modèle mathématique simulant l’interaction électrique entre cardiomyocytes et fibroblastes et montré que le remodelage électrique des fibroblastes peut avoir un impact important sur les propriétés électrophysiologiques des cardiomyocytes. Dans iv un modèle 2-dimensionel de FA, nous avons trouvé que la diminution de IKv,fb a un effet antiarythmique alors que l’augmentation de IKir,fb a des effets proarythmiques. Les études ici présentées utilisent les méthodes de modélisation mathématique pour l’étude de systèmes non-linéaires en électrophysiologie cardiaque et aborder des avenues de recherche difficilement accessibles aux méthodes de laboratoire traditionnelles. Elles démontrent également comment des résultats théoriques peuvent orienter et trouver confirmation dans des travaux expérimentaux subséquents ou, à l’inverse, des trouvailles expérimentales peuvent être implémentées dans les modèles mathématiques pour investiguer les conséquences de celles-ci. La modélisation mathématique est un outil prometteur pour l’étude des effets complexes et non-linéaires de la modulation pharmacologique des canaux ioniques et ainsi contribuer au développement de médicaments antiarythmiques optimisés pour le traitement de la FA, un besoin clinique majeur

Mechanisms of termination and prevention of atrial fibrillation by drug therapy

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I–IV drugs, namely Na+ channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca2+ channel blockers; the “upstream therapies”, e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as “atrial-selective” multiple ion channel blockers, gap junction-enhancers, and intracellular Ca2+-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms. Keywords: Atrial fibrillation; Cardiac arrhythmia mechanisms: reentry, afterdepolarisations; In-vivo animal models; Pathological electrical remodelling; Pharmacological treatment; Anti-arrhythmic drug mechanisms Abbreviations: ACE, angiotensin-converting enzyme; AF, atrial fibrillation; AFCL, AF cycle length; APD, action potential duration; DAD, delayed afterdepolarisation; EAD, early afterdepolarisation; ERP, effective refractory period; ICaL, L-type Ca2+ current; ICaT, T-type Ca2+ current; If, funny current; IK1, inward rectifier K+ current; IKACh, acetylcholine-activated K+ current; IKr, rapid delayed rectifier K+ current; IKS, slow delayed rectifier K+ current; IKur, ultra-rapid delayed rectifier K+ current; INa, Na+ current; INa/Ca, Na+-Ca2+ exchanger current; INa/H, Na+-H+ exchanger current; INaL, late INa; ISKCa, small conductance Ca2+-activated K+ current; ITO, transient outward K+ curren

25 years of basic and translational science in EP Europace: novel insights into arrhythmia mechanisms and therapeutic strategies.

In the last 25 years, EP Europace has published more than 300 basic and translational science articles covering different arrhythmia types (ranging from atrial fibrillation to ventricular tachyarrhythmias), different diseases predisposing to arrhythmia formation (such as genetic arrhythmia disorders and heart failure), and different interventional and pharmacological anti-arrhythmic treatment strategies (ranging from pacing and defibrillation to different ablation approaches and novel drug-therapies). These studies have been conducted in cellular models, small and large animal models, and in the last couple of years increasingly in silico using computational approaches. In sum, these articles have contributed substantially to our pathophysiological understanding of arrhythmia mechanisms and treatment options; many of which have made their way into clinical applications. This review discusses a representative selection of EP Europace manuscripts covering the topics of pacing and ablation, atrial fibrillation, heart failure and pro-arrhythmic ventricular remodelling, ion channel (dys)function and pharmacology, inherited arrhythmia syndromes, and arrhythmogenic cardiomyopathies, highlighting some of the advances of the past 25 years. Given the increasingly recognized complexity and multidisciplinary nature of arrhythmogenesis and continued technological developments, basic and translational electrophysiological research is key advancing the field. EP Europace aims to further increase its contribution to the discovery of arrhythmia mechanisms and the implementation of mechanism-based precision therapy approaches in arrhythmia management

In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human atrial action potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF

Differential Modulation of I-K and I-Ca,I-L Channels in High-Fat Diet-Induced Obese Guinea Pig Atria

[EN] Obesity mechanisms that make atrial tissue vulnerable to arrhythmia are poorly understood. Voltage-dependent potassium (I-K, I-Kur, and I-K1) and L-type calcium currents (I-Ca,I- L) are electrically relevant and represent key substrates for modulation in obesity. We investigated whether electrical remodeling produced by high-fat diet (HFD) alone or in concert with acute atrial stimulation were different. Electrophysiology was used to assess atrial electrical function after short-term HFD-feeding in guinea pigs. HFD atria displayed spontaneous beats, increased I-K (I-Kr + I-Ks) and decreased I-Ca,I- L densities. Only with pacing did a reduction in I-Kur and increased I-K1 phenotype emerge, leading to a further shortening of action potential duration. Computer modeling studies further indicate that the measured changes in potassium and calcium current densities contribute prominently to shortened atrial action potential duration in human heart. Our data are the first to show that multiple mechanisms (shortened action potential duration, early after depolarizations and increased incidence of spontaneous beats) may underlie initiation of supraventricular arrhythmias in obese guinea pig hearts. These results offer different mechanistic insights with implications for obese patients harboring supraventricular arrhythmias.This study was supported by an AHA (13SDG16850065 to AA), NIH (R01 HL147044 to AA), and Programa Prometeu de la Conselleria d Educació, Formació I Ocupació de la Generalitat Valenciana, award number PROMETEU/2016/088.Martínez-Mateu, L.; Saiz Rodríguez, FJ.; Aromolaran, A. (2019). Differential Modulation of I-K and I-Ca,I-L Channels in High-Fat Diet-Induced Obese Guinea Pig Atria. Frontiers in Physiology. 10:1-18. https://doi.org/10.3389/fphys.2019.01212S11810Abed, H. S., & Wittert, G. A. (2013). Obesity and atrial fibrillation. Obesity Reviews, 14(11), 929-938. doi:10.1111/obr.12056Angelin, B., Olivecrona, H., Reihnér, E., Rudling, M., Ståhlberg, D., Eriksson, M., … Einarsson, K. (1992). Hepatic cholesterol metabolism in estrogen-treated men. Gastroenterology, 103(5), 1657-1663. doi:10.1016/0016-5085(92)91192-7Aoki, Y., Hatakeyama, N., Yamamoto, S., Kinoshita, H., Matsuda, N., Hattori, Y., & Yamazaki, M. (2012). Role of ion channels in sepsis-induced atrial tachyarrhythmias in guinea pigs. British Journal of Pharmacology, 166(1), 390-400. doi:10.1111/j.1476-5381.2011.01769.xAromolaran, A. S., & Boutjdir, M. (2017). Cardiac Ion Channel Regulation in Obesity and the Metabolic Syndrome: Relevance to Long QT Syndrome and Atrial Fibrillation. Frontiers in Physiology, 8. doi:10.3389/fphys.2017.00431Aromolaran, A. S., Colecraft, H. M., & Boutjdir, M. (2016). High-fat diet-dependent modulation of the delayed rectifier K + current in adult guinea pig atrial myocytes. Biochemical and Biophysical Research Communications, 474(3), 554-559. doi:10.1016/j.bbrc.2016.04.113Aromolaran, A. S., Subramanyam, P., Chang, D. D., Kobertz, W. R., & Colecraft, H. M. (2014). LQT1 mutations in KCNQ1 C-terminus assembly domain suppress IKs using different mechanisms. Cardiovascular Research, 104(3), 501-511. doi:10.1093/cvr/cvu231Ashrafi, R., Yon, M., Pickavance, L., Yanni Gerges, J., Davis, G., Wilding, J., … Boyett, M. (2016). Altered Left Ventricular Ion Channel Transcriptome in a High-Fat-Fed Rat Model of Obesity: Insight into Obesity-Induced Arrhythmogenesis. Journal of Obesity, 2016, 1-12. doi:10.1155/2016/7127898Bai, J., Gladding, P. A., Stiles, M. K., Fedorov, V. V., & Zhao, J. (2018). Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells. Scientific Reports, 8(1). doi:10.1038/s41598-018-33958-yBarana, A., Matamoros, M., Dolz-Gaitón, P., Pérez-Hernández, M., Amorós, I., Núñez, M., … Caballero, R. (2014). Chronic Atrial Fibrillation Increases MicroRNA-21 in Human Atrial Myocytes Decreasing L-Type Calcium Current. Circulation: Arrhythmia and Electrophysiology, 7(5), 861-868. doi:10.1161/circep.114.001709Bar�, I., & Escande, D. (1989). A Ca2+-activated K+ current in guinea-pig atrial myocytes. Pfl�gers Archiv European Journal of Physiology, 414(S1), S168-S168. doi:10.1007/bf00582286Bar�, I., & Escande, D. (1989). A long lasting Ca2+ -activated outward current in guinea-pig atrial myocytes. Pfl�gers Archiv European Journal of Physiology, 415(1), 63-71. doi:10.1007/bf00373142Bhuyan, R., & Seal, A. (2016). Dynamics and modulation studies of human voltage gated Kv1.5 channel. Journal of Biomolecular Structure and Dynamics, 35(2), 380-398. doi:10.1080/07391102.2016.1144528Boden, G., She, P., Mozzoli, M., Cheung, P., Gumireddy, K., Reddy, P., … Ruderman, N. (2005). Free Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor- B Pathway in Rat Liver. Diabetes, 54(12), 3458-3465. doi:10.2337/diabetes.54.12.3458Bosch, R. F., Schneck, A. C., Csillag, S., Eigenberger, B., Gerlach, U., Brendel, J., … Kühlkamp, V. (2003). Effects of the chromanol HMR 1556 on potassium currents in atrial myocytes. Naunyn-Schmiedeberg’s Archives of Pharmacology, 367(3), 281-288. doi:10.1007/s00210-002-0672-5BOUTJDIR, M., HEUZEY, J. Y., LAVERGNE, T., CHAUVAUD, S., GUIZE, L., CARPENTIER, A., & PERONNEAU, P. (1986). Inhomogeneity of Cellular Refractoriness in Human Atrium: Factor of Arrhythmia?. Pacing and Clinical Electrophysiology, 9(6), 1095-1100. doi:10.1111/j.1540-8159.1986.tb06676.xBrundel, B. J. J. M., Van Gelder, I. C., Henning, R. H., Tieleman, R. G., Tuinenburg, A. E., Wietses, M., … Crijns, H. J. G. M. (2001). Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation. Circulation, 103(5), 684-690. doi:10.1161/01.cir.103.5.684Bünemann, M., Liliom, K., Brandts, B. K., Pott, L., Tseng, J. L., Desiderio, D. M., … Tigyi, G. (1996). A novel membrane receptor with high affinity for lysosphingomyelin and sphingosine 1-phosphate in atrial myocytes. The EMBO Journal, 15(20), 5527-5534. doi:10.1002/j.1460-2075.1996.tb00937.xCaballero, R., de la Fuente, M. G., Gómez, R., Barana, A., Amorós, I., Dolz-Gaitón, P., … Delpón, E. (2010). In Humans, Chronic Atrial Fibrillation Decreases the Transient Outward Current and Ultrarapid Component of the Delayed Rectifier Current Differentially on Each Atria and Increases the Slow Component of the Delayed Rectifier Current in Both. Journal of the American College of Cardiology, 55(21), 2346-2354. doi:10.1016/j.jacc.2010.02.028Caillier, B., Pilote, S., Patoine, D., Levac, X., Couture, C., Daleau, P., … Drolet, B. (2012). Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: A possible ‘anti-proarrhythmic’ role for amlodipine. Pharmacological Research, 65(3), 320-327. doi:10.1016/j.phrs.2011.11.015Chiu, H.-C., Kovacs, A., Ford, D. A., Hsu, F.-F., Garcia, R., Herrero, P., … Schaffer, J. E. (2001). A novel mouse model of lipotoxic cardiomyopathy. Journal of Clinical Investigation, 107(7), 813-822. doi:10.1172/jci10947Christ, T., Boknik, P., Wöhrl, S., Wettwer, E., Graf, E. M., Bosch, R. F., … Dobrev, D. (2004). L-Type Ca2+Current Downregulation in Chronic Human Atrial Fibrillation Is Associated With Increased Activity of Protein Phosphatases. Circulation, 110(17), 2651-2657. doi:10.1161/01.cir.0000145659.80212.6aCourtemanche, M., Ramirez, R. J., & Nattel, S. (1998). Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. American Journal of Physiology-Heart and Circulatory Physiology, 275(1), H301-H321. doi:10.1152/ajpheart.1998.275.1.h301Czick, M. E., Shapter, C. L., & Silverman, D. I. (2016). Atrial Fibrillation: The Science behind Its Defiance. Aging and Disease, 7(5), 635. doi:10.14336/ad.2016.0211Dan, G.-A., & Dobrev, D. (2018). Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging. IJC Heart & Vasculature, 21, 11-15. doi:10.1016/j.ijcha.2018.08.005Daoud, E. G., Knight, B. P., Weiss, R., Bahu, M., Paladino, W., Goyal, R., … Morady, F. (1997). Effect of Verapamil and Procainamide on Atrial Fibrillation–Induced Electrical Remodeling in Humans. Circulation, 96(5), 1542-1550. doi:10.1161/01.cir.96.5.1542De Sensi, F., Costantino, S., Limbruno, U., & Paneni, F. (2019). Atrial fibrillation in the cardiometabolic patient. Minerva Medica, 110(2). doi:10.23736/s0026-4806.18.05882-2Dey, S., DeMazumder, D., Sidor, A., Foster, D. B., & O’Rourke, B. (2018). Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure. Circulation Research, 123(3), 356-371. doi:10.1161/circresaha.118.312708Diness, J. G., Sørensen, U. S., Nissen, J. D., Al-Shahib, B., Jespersen, T., Grunnet, M., & Hansen, R. S. (2010). Inhibition of Small-Conductance Ca 2+ -Activated K + Channels Terminates and Protects Against Atrial Fibrillation. Circulation: Arrhythmia and Electrophysiology, 3(4), 380-390. doi:10.1161/circep.110.957407Djoussé, L., Benkeser, D., Arnold, A., Kizer, J. R., Zieman, S. J., Lemaitre, R. N., … Ix, J. H. (2013). Plasma Free Fatty Acids and Risk of Heart Failure. Circulation: Heart Failure, 6(5), 964-969. doi:10.1161/circheartfailure.113.000521Ehrlich, J. R., Ocholla, H., Ziemek, D., Rütten, H., Hohnloser, S. H., & Gögelein, H. (2008). Characterization of Human Cardiac Kv1.5 Inhibition by the Novel Atrial-selective Antiarrhythmic Compound AVE1231. Journal of Cardiovascular Pharmacology, 51(4), 380-387. doi:10.1097/fjc.0b013e3181669030Feng, J., Yue, L., Wang, Z., & Nattel, S. (1998). Ionic Mechanisms of Regional Action Potential Heterogeneity in the Canine Right Atrium. Circulation Research, 83(5), 541-551. doi:10.1161/01.res.83.5.541Fernandez, M. L., Conde, A. K., Ruiz, L. R., Montano, C., Ebner, J., & McNamara, D. J. (1995). Carbohydrate type and amount alter intravascular processing and catabolism of plasma lipoproteins in guinea pigs. Lipids, 30(7), 619-626. doi:10.1007/bf02536998Fretts, A. M., Mozaffarian, D., Siscovick, D. S., Djousse, L., Heckbert, S. R., King, I. B., … Lemaitre, R. N. (2014). Plasma Phospholipid Saturated Fatty Acids and Incident Atrial Fibrillation: The Cardiovascular Health Study. Journal of the American Heart Association, 3(3). doi:10.1161/jaha.114.000889Gaborit, N., Steenman, M., Lamirault, G., Le Meur, N., Le Bouter, S., Lande, G., … Demolombe, S. (2005). Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation. Circulation, 112(4), 471-481. doi:10.1161/circulationaha.104.506857Garnvik, L. E., Malmo, V., Janszky, I., Wisløff, U., Loennechen, J. P., & Nes, B. M. (2018). Physical activity modifies the risk of atrial fibrillation in obese individuals: The HUNT3 study. European Journal of Preventive Cardiology, 25(15), 1646-1652. doi:10.1177/2047487318784365Gaspo, R., Bosch, R. F., Talajic, M., & Nattel, S. (1997). Functional Mechanisms Underlying Tachycardia-Induced Sustained Atrial Fibrillation in a Chronic Dog Model. Circulation, 96(11), 4027-4035. doi:10.1161/01.cir.96.11.4027Goette, A., Honeycutt, C., & Langberg, J. J. (1996). Electrical Remodeling in Atrial Fibrillation. Circulation, 94(11), 2968-2974. doi:10.1161/01.cir.94.11.2968González de la Fuente, M., Barana, A., Gómez, R., Amorós, I., Dolz-Gaitón, P., Sacristán, S., … Delpón, E. (2012). Chronic atrial fibrillation up-regulates β1-Adrenoceptors affecting repolarizing currents and action potential duration. Cardiovascular Research, 97(2), 379-388. doi:10.1093/cvr/cvs313Grandi, E., Dobrev, D., & Heijman, J. (2019). Computational modeling: What does it tell us about atrial fibrillation therapy? International Journal of Cardiology, 287, 155-161. doi:10.1016/j.ijcard.2019.01.077Grandi, E., Pandit, S. V., Voigt, N., Workman, A. J., Dobrev, D., Jalife, J., & Bers, D. M. (2011). Human Atrial Action Potential and Ca2+Model. Circulation Research, 109(9), 1055-1066. doi:10.1161/circresaha.111.253955HADIAN, D., ZIPES, D. P., OLGIN, J. E., & MILLER, J. M. (2002). Short-Term Rapid Atrial Pacing Produces Electrical Remodeling of Sinus Node Function in Humans. Journal of Cardiovascular Electrophysiology, 13(6), 584-586. doi:10.1046/j.1540-8167.2002.00584.xHeijman, J., Guichard, J.-B., Dobrev, D., & Nattel, S. (2018). Translational Challenges in Atrial Fibrillation. Circulation Research, 122(5), 752-773. doi:10.1161/circresaha.117.311081Huang, H., Amin, V., Gurin, M., Wan, E., Thorp, E., Homma, S., & Morrow, J. P. (2013). Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels. Journal of Molecular and Cellular Cardiology, 59, 151-158. doi:10.1016/j.yjmcc.2013.03.007Hume, J. R., & Uehara, A. (1985). Ionic basis of the different action potential configurations of single guinea-pig atrial and ventricular myocytes. The Journal of Physiology, 368(1), 525-544. doi:10.1113/jphysiol.1985.sp015874INOUE, M., INOUE, D., ISHIBASHI, K., SAKAI, R., OMORI, I., YAMAHARA, Y., … NAKAGAWA, M. (1993). Effects of Pilsicainide on the Atrial Fibrillation Threshold in Guinea Kg Atria. A Comparative Study with Disopyramide, Lidocaine and Flecainide. Japanese Heart Journal, 34(3), 301-312. doi:10.1536/ihj.34.301Inoue, D., Shirayama, T., Omori, I., Inoue, M., Sakai, R., Ishibashi, K., … Nakagawa, M. (1993). Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers. Cardiovascular Drugs and Therapy, 7(3), 373-378. doi:10.1007/bf00880161Iwasaki, Y., Nishida, K., Kato, T., & Nattel, S. (2011). Atrial Fibrillation Pathophysiology. Circulation, 124(20), 2264-2274. doi:10.1161/circulationaha.111.019893Jensen, M. D., Ryan, D. H., Apovian, C. M., Ard, J. D., Comuzzie, A. G., Donato, K. A., … Yanovski, S. Z. (2013). 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults. Circulation, 129(25 suppl 2), S102-S138. doi:10.1161/01.cir.0000437739.71477.eeJi, Y., Varkevisser, R., Opacic, D., Bossu, A., Kuiper, M., Beekman, J. D. M., … van der Heyden, M. A. G. (2017). The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models. British Journal of Pharmacology, 174(15), 2576-2590. doi:10.1111/bph.13869Kanner, S. A., Jain, A., & Colecraft, H. M. (2018). Development of a High-Throughput Flow Cytometry Assay to Monitor Defective Trafficking and Rescue of Long QT2 Mutant hERG Channels. Frontiers in Physiology, 9. doi:10.3389/fphys.2018.00397Killeen, M. J., Sabir, I. N., Grace, A. A., & Huang, C. L.-H. (2008). Dispersions of repolarization and ventricular arrhythmogenesis: Lessons from animal models. Progress in Biophysics and Molecular Biology, 98(2-3), 219-229. doi:10.1016/j.pbiomolbio.2008.10.008Killeen, M. J., Thomas, G., Sabir, I. N., Grace, A. A., & Huang, C. L.-H. (2008). Mouse models of human arrhythmia syndromes. Acta Physiologica, 192(4), 455-469. doi:10.1111/j.1748-1716.2007.01822.xKoivumäki, J. T., Korhonen, T., & Tavi, P. (2011). Impact of Sarcoplasmic Reticulum Calcium Release on Calcium Dynamics and Action Potential Morphology in Human Atrial Myocytes: A Computational Study. PLoS Computational Biology, 7(1), e1001067. doi:10.1371/journal.pcbi.1001067LAU, C.-P., TSE, H.-F., SIU, C.-W., & GBADEBO, D. (2012). Atrial Electrical and Structural Remodeling: Implications for Racial Differences in Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 23, s36-s40. doi:10.1111/jce.12022Leopoldo, A. S., Lima-Leopoldo, A. P., Sugizaki, M. M., Nascimento, A. F. do, de Campos, D. H. S., Luvizotto, R. de A. M., … Cicogna, A. C. (2011). Involvement of L-type calcium channel and serca2a in myocardial dysfunction induced by obesity. Journal of Cellular Physiology, 226(11), 2934-2942. doi:10.1002/jcp.22643Lima-Leopoldo, A. P., Leopoldo, A. S., Silva, D. C. T., Nascimento, A. F. do, Campos, D. H. S. de, Luvizotto, R. de A. M., … Cicogna, A. C. (2013). Influence of Long-Term Obesity on Myocardial Gene Expression. Arquivos Brasileiros de Cardiologia, 100(3). doi:10.5935/abc.20130045Lima-Leopoldo, A. P., Sugizaki, M. M., Leopoldo, A. S., Carvalho, R. F., Nogueira, C. R., Nascimento, A. F., … Cicogna, A. C. (2008). Obesity induces upregulation of genes involved in myocardial Ca2+ handling. Brazilian Journal of Medical and Biological Research, 41(7), 615-620. doi:10.1590/s0100-879x2008000700011Liu, T., Takimoto, E., Dimaano, V. L., DeMazumder, D., Kettlewell, S., Smith, G., … O’Rourke, B. (2014). Inhibiting Mitochondrial Na + /Ca 2+ Exchange Prevents Sudden Death in a Guinea Pig Model of Heart Failure. Circulation Research, 115(1), 44-54. doi:10.1161/circresaha.115.303062Mancarella, S., Yue, Y., Karnabi, E., Qu, Y., El-Sherif, N., & Boutjdir, M. (2008). Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse. American Journal of Physiology-Heart and Circulatory Physiology, 295(5), H2017-H2024. doi:10.1152/ajpheart.00537.2008Mangoni, M. E., Couette, B., Bourinet, E., Platzer, J., Reimer, D., Striessnig, J., & Nargeot, J. (2003). Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proceedings of the National Academy of Sciences, 100(9), 5543-5548. doi:10.1073/pnas.0935295100Martinez-Mateu, L., Romero, L., Ferrer-Albero, A., Sebastian, R., Rodríguez Matas, J. F., Jalife, J., … Saiz, J. (2018). Factors affecting basket catheter detection of real and phantom rotors in the atria: A computational study. PLOS Computational Biology, 14(3), e1006017. doi:10.1371/journal.pcbi.1006017Matafome, P., & Seiça, R. (2017). Function and Dysfunction of Adipose Tissue. Obesity and Brain Function, 3-31. doi:10.1007/978-3-319-63260-5_1Matsimra, H., & Ehara, T. (1997). Selective Enhancement of the Slow Component of Delayed Rectifier K+Current in Guinea-Pig Atrial Cells by External ATP. The Journal of Physiology, 503(1), 45-54. doi:10.1111/j.1469-7793.1997.045bi.xMichael, G., Xiao, L., Qi, X.-Y., Dobrev, D., & Nattel, S. (2008). Remodelling of cardiac repolarization: how homeostatic responses can lead to arrhythmogenesis. Cardiovascular Research, 81(3), 491-499. doi:10.1093/cvr/cvn266Mickelson, A. V., & Chandra, M. (2017). Hypertrophic cardiomyopathy mutation in cardiac troponin T (R95H) attenuates length-dependent activation in guinea pig cardiac muscle fibers. American Journal of Physiology-Heart and Circulatory Physiology, 313(6), H1180-H1189. doi:10.1152/ajpheart.00369.2017Nakaya, H., Furusawa, Y., Ogura, T., Tamagawa, M., & Uemura, H. (2000). Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts. British Journal of Pharmacology, 131(7), 1363-1372. doi:10.1038/sj.bjp.0703713Nattel, S. (2002). New ideas about atrial fibrillation 50 years on. Nature, 415(6868), 219-226. doi:10.1038/415219aNattel, S., & Dobrev, D. (2017). Controversies About Atrial Fibrillation Mechanisms. Circulation Research, 120(9), 1396-1398. doi:10.1161/circresaha.116.310489Nattel, S., & Harada, M. (2014). Atrial Remodeling and Atrial Fibrillation. Journal of the American College of Cardiology, 63(22), 2335-2345. doi:10.1016/j.jacc.2014.02.555Nerbonne, J. M., & Kass, R. S. (2005). Molecular Physiology of Cardiac Repolarization. Physiological Reviews, 85(4), 1205-1253. doi:10.1152/physrev.00002.2005Ni, H., Whittaker, D. G., Wang, W., Giles, W. R., Narayan, S. M., & Zhang, H. (2017). Synergistic Anti-arrhythmic Effects in Human Atria with Combined Use of Sodium Blockers and Acacetin. Frontiers in Physiology, 8. doi:10.3389/fphys.2017.00946O’Connell, R. P., Musa, H., Gomez, M. S. M., Avula, U. M., Herron, T. J., Kalifa, J., & Anumonwo, J. M. B. (2015). Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture. PLOS ONE, 10(8), e0133052. doi:10.1371/journal.pone.0133052OCHI, R., MOMOSE, Y., OYAMA, K., & GILES, W. (2006). Sphingosine-1-phosphate effects on guinea pig atrial myocytes: Alterations in action potentials and K+ currents. Cardiovascular Research, 70(1), 88-96. doi:10.1016/j.cardiores.2006.01.010O’Hara, T., & Rudy, Y. (2012). Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. American Journal of Physiology-Heart and Circulatory Physiology, 302(5), H1023-H1030. doi:10.1152/ajpheart.00785.2011Osadchii, O. E. (2012). Electrophysiological determinants of arrhythmic susceptibility upon endocardial and epicardial pacing in guinea-pig heart. Acta Physiologica, 205(4), 494-506. doi:10.1111/j.1748-1716.2012.02428.xPatoine, D., Levac, X., Pilote, S., Drolet, B., & Simard, C. (2013). Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved? Drug Metabolism and Disposition, 41(5), 952-957. doi:10.1124/dmd.112.050641Paulino, E. C., Ferreira, J. C. B., Bechara, L. R., Tsutsui, J. M., Mathias, W., Lima, F. B., … Negrão, C. E. (2010). Exercise Training and Caloric Restriction Prevent Reduction in Cardiac Ca 2+ -Handling Protein Profile in Obese Rats. Hypertension, 56(4), 629-635. doi:10.1161/hypertensionaha.110.156141Pérez-Hernández, M., Matamoros, M., Barana, A., Amorós, I., Gómez, R., Núñez, M., … Caballero, R. (2015). Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancingIKsand decreasingICa,L. Cardiovascular Research, 109(3), 431-441. doi:10.1093/cvr/cvv280A, P., H, C., MC, F., L, B., JN, W., & HS, K. (2018). Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Eff

Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology

In silico Assessment of Pharmacotherapy for Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, IKr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs–disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant IKr was incorporated into a contemporary human atrial action potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for IKr/hERG and sodium current, INa, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined IKr and INa block based pharmacological strategies in the treatment of SQT1-linked AF.</p

ATP-sensitive Potassium Channels and Cardiac Arrhythmia

PhDATP-sensitive potassium channels (KATP) open in response to metabolic challenge. They form of pore subunits (Kir6.1 or Kir6.2) and modulatory subunits (SUR1, SUR2A or SUR2B) and are ubiquitously expressed. Differential subunit composition between cardiac chambers was investigated, as were atrial anti-arrhythmic effects of KATP modulation. Selective pharmacology of KATP openers and inhibitors was confirmed in a heterologous expression system through whole-cell patch clamp. Isolated HL-1 cells (a murine atrial cardiomyocyte model) and murine atrial cardiomyocytes showed identical KATP pharmacological responses representing Kir6.2/SUR1 channels. Relative quantification of murine whole atrial RNA concurred, and was distinct from the ventricles (Kir6.2/SUR2). Human whole heart RNA from normal hearts exhibited a different pattern with no obvious chamber specificity. Kir6.1-/- and Kir6.2-/- mice demonstrated that both pore types contribute to electrophysiological parameters in isolated atrial cardiomyocytes, but Kir6.2 appears more important. In atrial tissue (Langendorff hearts), Kir6.2-/- more than Kir6.1-/- mice demonstrated increased effective refractory periods and reduced conduction velocity at baseline, and during hypoxia, compared to wildtype. A trend to reduced arrhythmogenicity was observed during programmed electrical stimulation in the Kir6.2-/- mouse. In syncytia of spontaneously beating HL-1 cells, KATP activation with diazoxide was met with rotational to uniform wavefront organisation and silencing of electrical activity in a dose-dependent manner, reversed with channel blockade. In Langendorff mouse hearts KATP inhibition reversed hypoxia induced slowing of spontaneous sinus node activation, but pharmacological activation alone did not, suggesting different mechanisms with hypoxic channel activation. Thus, both pore subunits contribute to the cardiac electrophysiology of murine atria, but Kir6.2 appears more important. HL-1 cells exhibit identical KATP pharmacology to murine atrial myocytes, which have a differential subunit composition compared to the ventricle. Any human cardiac KATP differential subunit expression needs further exploration. KATP activation and inhibition have anti-arrhythmic effects and this might be explored further clinically.Medical Research Council MR/L016230/1