2019
Renewal Theory as a Universal Quantitative Framework to Characterize Phase Singularity Regeneration in Mammalian Cardiac Fibrillation
Dharmaprani D, Schopp M, Kuklik P, Chapman D, Lahiri A, Dykes L, Xiong F, Aguilar M, Strauss B, Mitchell L, Pope K, Meyer C, Willems S, Akar FG, Nattel S, McGavigan AD, Ganesan AN. Renewal Theory as a Universal Quantitative Framework to Characterize Phase Singularity Regeneration in Mammalian Cardiac Fibrillation. Circulation Arrhythmia And Electrophysiology 2019, 12: e007569. PMID: 31813270, DOI: 10.1161/circep.119.007569.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAtrial FibrillationBiological EvolutionComputer SimulationDisease Models, AnimalHeart Conduction SystemHeart RateHumansModels, CardiovascularMulticenter Studies as TopicObservational Studies as TopicRatsReproducibility of ResultsSheep, DomesticStochastic ProcessesTime FactorsVentricular FibrillationConceptsPoisson renewal processRenewal theoryRenewal processPhase singularityMaximum entropy theoryExponential probability distribution functionProbability distribution functionFormation/destructionConstant rate parametersEntropy theoryInterevent timesDistribution functionExponential distributionRotational eventsCardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans
Cacheux M, Strauss B, Raad N, Ilkan Z, Hu J, Benard L, Feske S, Hulot JS, Akar FG. Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans. Circulation Arrhythmia And Electrophysiology 2019, 12: e007382-e007382. PMID: 31726860, PMCID: PMC6867678, DOI: 10.1161/circep.119.007382.Peer-Reviewed Original ResearchConceptsVT/VFAPD alternansStore-operated CaVentricular tachycardia/ventricular fibrillationOptical action potential mappingAdult heartVT/Adult murine modelDiscordant alternansConduction velocity slowingSarcoplasmic reticulum CaArrhythmogenic discordant alternansInitial beatsEarly mortalityFlox/Poor survivalVentricular fibrillationDiscordant APD alternansMurine modelCardiac hypertrophyConduction velocityLittermate controlsAdult miceRapid pacingElectrophysiological substrate
2018
Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension
Strauss B, Sassi Y, Bueno-Beti C, Ilkan Z, Raad N, Cacheux M, Bisserier M, Turnbull IC, Kohlbrenner E, Hajjar RJ, Hadri L, Akar FG. Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension. Journal Of Molecular And Cellular Cardiology 2018, 127: 20-30. PMID: 30502350, PMCID: PMC6561115, DOI: 10.1016/j.yjmcc.2018.11.017.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAerosolsAnimalsArrhythmias, CardiacConnexin 43Disease Models, AnimalGene Transfer TechniquesGenetic TherapyHeart Conduction SystemHumansMalePotassium ChannelsPulmonary Arterial HypertensionRats, Sprague-DawleyRNA, MessengerSarcoplasmic Reticulum Calcium-Transporting ATPasesTracheaConceptsPulmonary arterial hypertensionSudden cardiac deathVentricular tachyarrhythmiasCTRL heartsExpression of Cx43Conduction velocityArterial hypertensionHeart rateAP durationAdvanced pulmonary arterial hypertensionIncidence of VTOptical action potential mappingPacing-induced ventricular tachyarrhythmiasRisk of VTAEP substrateElectro-mechanical dysfunctionImpaired chronotropic responseMinimal conduction velocitiesRight ventricular failureSustained ventricular tachyarrhythmiasAPD heterogeneityPulmonary vascular remodelingRapid heart rateAge-matched ratsIntra-tracheal deliveryPrimary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction
Motloch LJ, Cacheux M, Ishikawa K, Xie C, Hu J, Aguero J, Fish KM, Hajjar RJ, Akar FG. Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction. Journal Of The American Heart Association 2018, 7: e009598. PMID: 30371209, PMCID: PMC6222964, DOI: 10.1161/jaha.118.009598.Peer-Reviewed Original ResearchConceptsMyocardial infarctionVentricular tachycardiaSERCA 2aVirus serotype 1Heart failureOptical action potential mappingPacing-induced ventricular tachycardiaIschemic heart failureNonischemic heart failureSerotype 1SERCA2a gene transferChronic myocardial infarctionExpression of Cx43Contractile reserveVelocity reserveHemodynamic functionDobutamine stressAnterior MIElectrophysiological effectsQRS durationConduction reserveConduction velocityNaive pigsAnimal modelsElectrophysiological substrate
2015
Gene therapy to restore electrophysiological function in heart failure
Motloch LJ, Akar FG. Gene therapy to restore electrophysiological function in heart failure. Expert Opinion On Biological Therapy 2015, 15: 803-817. PMID: 25865107, PMCID: PMC5547747, DOI: 10.1517/14712598.2015.1036734.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArrhythmias, CardiacBrugada SyndromeCardiac Conduction System DiseaseElectrocardiographyGenetic TherapyHeart Conduction SystemHeart FailureHumansConceptsHeart failureHF patientsMajor public health epidemicPro-arrhythmic activitySafe therapeutic optionSudden cardiac deathCause of morbidityGene therapyPublic health epidemicAbnormal excitabilityCardiac deathTherapeutic optionsTherapeutic effectMyocardial conductionHeart rateLethal arrhythmiasGene therapy approachesElectrophysiological functionUnmet needArrhythmogenic disordersGene-based approachesCalcium cyclingHealth epidemicCardiac gene therapyConduction system
2014
Emergence of Atrial Repolarization Alternans at Late Stages of Remodeling: The “Second Factor” in Atrial Fibrillation Progression?
Akar FG. Emergence of Atrial Repolarization Alternans at Late Stages of Remodeling: The “Second Factor” in Atrial Fibrillation Progression? Journal Of Cardiovascular Electrophysiology 2014, 25: 428-430. PMID: 24479610, DOI: 10.1111/jce.12377.Commentaries, Editorials and Letters
2010
Use‐Dependent Modulation of Myocardial Conduction by a New Class of HERG Agonists: Deal Breaker or Cherry on Top?
AKAR FG. Use‐Dependent Modulation of Myocardial Conduction by a New Class of HERG Agonists: Deal Breaker or Cherry on Top? Journal Of Cardiovascular Electrophysiology 2010, 21: 930-932. PMID: 20367661, DOI: 10.1111/j.1540-8167.2010.01747.x.Commentaries, Editorials and Letters
2008
Arrhythmia Mechanisms in the Failing Heart
JIN H, LYON AR, AKAR FG. Arrhythmia Mechanisms in the Failing Heart. Pacing And Clinical Electrophysiology 2008, 31: 1048-1056. PMID: 18684263, DOI: 10.1111/j.1540-8159.2008.01134.x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHeart failureArrhythmia mechanismsFundamental arrhythmia mechanismsSudden cardiac deathLethal ventricular tachyarrhythmiasCalcium handling proteinsEffective treatment strategiesCardiac deathMalignant arrhythmiasVentricular tachyarrhythmiasElectrical remodelingConduction abnormalitiesFailing HeartTreatment strategiesLethal arrhythmiasElectrophysiological substrateHandling proteinsAction potentialsPatientsArrhythmiasIon channelsDeathHeartTachyarrhythmiasAbnormalitiesTargeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f
Roepke TK, Kontogeorgis A, Ovanez C, Xu X, Young JB, Purtell K, Goldstein PA, Christini DJ, Peters NS, Akar FG, Gutstein DE, Lerner DJ, Abbott GW. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f. The FASEB Journal 2008, 22: 3648-3660. PMID: 18603586, PMCID: PMC2537427, DOI: 10.1096/fj.08-110171.Peer-Reviewed Original ResearchConceptsAlpha subunitKv4 alpha subunitsAction potential durationVentricular action potential durationFunctional promiscuityVentricular membrane fractionsLong QT syndromeVentricular repolarizationAncillary subunitsWild typeNovel roleMembrane fractionKcne2 deletionKv1.5 proteinTargeted deletionSubunitsKcne2 disruptionMiRP1Cardiac roleProteinKCNE2DeletionKv1.5Sevoflurane anesthesiaDisruption
2007
Regulation of ion channels and arrhythmias in the ischemic heart
Akar JG, Akar FG. Regulation of ion channels and arrhythmias in the ischemic heart. Journal Of Electrocardiology 2007, 40: s37-s41. PMID: 17993326, DOI: 10.1016/j.jelectrocard.2007.05.020.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsHeart Conduction SystemHumansIon Channel GatingIon ChannelsMembrane PotentialsModels, CardiovascularMyocardial IschemiaConceptsIschemic injuryElectrophysiological changesIschemic heart diseaseBest treatment strategyCoronary eventsReperfusion phaseVentricular arrhythmiasIschemic episodesHeart diseaseLeading causeElectrical dysfunctionTreatment strategiesIschemic heartMetabolic substratesPatientsArrhythmiasKey cellularTime courseInjuryIon channelsHeartDysfunctionMortalityDiseaseDynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure
Akar FG, Nass RD, Hahn S, Cingolani E, Shah M, Hesketh GG, DiSilvestre D, Tunin RS, Kass DA, Tomaselli GF. Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. AJP Heart And Circulatory Physiology 2007, 293: h1223-h1230. PMID: 17434978, DOI: 10.1152/ajpheart.00079.2007.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsCardiac Pacing, ArtificialConnexin 43Disease Models, AnimalDogsDown-RegulationGap JunctionsHeart Conduction SystemHeart FailureMalePhosphorylationProtein IsoformsTachycardia, VentricularTime FactorsVentricular Function, LeftVentricular PressureVentricular RemodelingConceptsEnd-stage heart failureHeart failureConduction velocityMechanical dysfunctionCV slowingPacing-induced heart failureDevelopment of HFOnset of HFMechanical functionCx43 isoformConduction abnormalitiesCx43 lateralizationAdvanced stageBaseline levelsMyocardial preparationsPhosphorylation of Cx43High-resolution optical mappingSustained downregulationMarked increaseDephosphorylated Cx43LVEDPGap junction propertiesConduction changesDysfunctionTime course
2006
Mapping arrhythmias in the failing heart: from Langendorff to patient
Akar JG, Akar FG. Mapping arrhythmias in the failing heart: from Langendorff to patient. Journal Of Electrocardiology 2006, 39: s19-s23. PMID: 16920143, DOI: 10.1016/j.jelectrocard.2006.03.011.Peer-Reviewed Educational MaterialsConceptsHeart failureVentricular arrhythmiasOptical action potential mappingSudden cardiac deathCardiac deathIntact tissue preparationsCardiac remodelingMost arrhythmiasArrhythmic substrateArrhythmiasElectrophysiological propertiesMapping arrhythmiasTissue levelsIndividual myocytesMajor causeReentrant excitationOrgan system levelPatientsMultiple mechanismsTissue preparationsHeartRecent findingsHost of changesCellular studiesLangendorff
2005
Conduction Abnormalities in Nonischemic Dilated Cardiomyopathy: Basic Mechanisms and Arrhythmic Consequences
Akar FG, Tomaselli GF. Conduction Abnormalities in Nonischemic Dilated Cardiomyopathy: Basic Mechanisms and Arrhythmic Consequences. Trends In Cardiovascular Medicine 2005, 15: 259-264. PMID: 16226681, DOI: 10.1016/j.tcm.2005.08.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnisotropyArrhythmias, CardiacCardiomyopathy, DilatedHeart Conduction SystemHumansConceptsConduction abnormalitiesVentricular dysfunctionHeart failureMolecular mechanismsLeft ventricular dysfunctionNonischemic heart failureIschemic heart diseaseExtracellular matrixGenesis of arrhythmiasMyocyte excitabilityMechanistic differencesOrgan levelMembrane excitabilityVentricular tachyarrhythmiasDisease etiologyMyocardial infarctionHeart diseaseArrhythmogenic substrateSudden deathArrhythmic consequencesCell couplingAbnormalitiesBasic mechanismsDysfunctionExcitabilityAbnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts
Spragg DD, Akar FG, Helm RH, Tunin RS, Tomaselli GF, Kass DA. Abnormal conduction and repolarization in late-activated myocardium of dyssynchronously contracting hearts. Cardiovascular Research 2005, 67: 77-86. PMID: 15885674, DOI: 10.1016/j.cardiores.2005.03.008.Peer-Reviewed Original ResearchConceptsAction potential durationConduction velocityRefractory periodElectrophysiological remodelingArrhythmia susceptibilityIntraventricular conduction delayLeft ventricular dyssynchronyGap junction protein expressionJunction protein expressionCalcium cycling proteinsTotal expressionDyssynchronous heartsLV dysfunctionMechanical dyssynchronyUntreated dogsVentricular dyssynchronyCardiac dyssynchronyControl dogsLateral LVRadiofrequency ablationAnterior wallConduction delayDyssynchronyMyocardial segmentsPotential duration
2004
Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes
Xue T, Cho HC, Akar FG, Tsang SY, Jones SP, Marbán E, Tomaselli GF, Li RA. Functional Integration of Electrically Active Cardiac Derivatives From Genetically Engineered Human Embryonic Stem Cells With Quiescent Recipient Ventricular Cardiomyocytes. Circulation 2004, 111: 11-20. PMID: 15611367, DOI: 10.1161/01.cir.0000151313.18547.a2.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAdrenergic beta-AgonistsAnimalsCell DifferentiationCell FusionCells, CulturedDefective VirusesElectrophysiologyFemaleGenes, ReporterGenetic VectorsGiant CellsGreen Fluorescent ProteinsGuinea PigsHeartHeart Conduction SystemHeart VentriclesHIV-1HumansIsoproterenolLidocaineMiceMyocardial ContractionMyocytes, CardiacOrgan Culture TechniquesPericardiumPluripotent Stem CellsPyrimidinesRatsTransduction, GeneticConceptsVentricular cardiomyocytesCardiac impulse generationBeta-adrenergic agonist isoproterenolGuinea pig heartsSite of injectionStem cellsHuman embryonic stem cellsCell-based therapiesContractile activityAgonist isoproterenolPharmacological agentsVentricular myocardiumLeft ventricleEx vivoDonor cardiomyocytesPig heartsHuman cardiomyocytesRecombinant lentivirusMembrane depolarizationCardiomyocytesFunctional syncytiumImpulse generationEmbryonic stem cellsMyocardiumEpicardial surfaceMechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy
Akar FG, Spragg DD, Tunin RS, Kass DA, Tomaselli GF. Mechanisms Underlying Conduction Slowing and Arrhythmogenesis in Nonischemic Dilated Cardiomyopathy. Circulation Research 2004, 95: 717-725. PMID: 15345654, DOI: 10.1161/01.res.0000144125.61927.1c.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsArrhythmias, CardiacBlotting, WesternCadherinsCardiac Pacing, ArtificialCardiomyopathy, DilatedCell SizeConnexin 43DogsFibrosisGap JunctionsHeart Conduction SystemMicroscopy, ConfocalMicroscopy, FluorescenceMyocardiumMyocytes, CardiacNeural ConductionPatch-Clamp TechniquesPhosphorylationProtein Processing, Post-TranslationalSubcellular Fractions
2002
Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome
Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome. Circulation 2002, 105: 1247-1253. PMID: 11889021, DOI: 10.1161/hc1002.105231.Peer-Reviewed Original ResearchConceptsLong QT syndromeSpecific ion channel mutationsCongenital long QT syndromeM cellsQT interval prolongationIon channel mutationsInterval prolongationReentrant mechanismTdP arrhythmiasConduction blockCanine wedge preparationReentrant circuitTransmural dispersionLeft ventricleAction potentialsTransmural wallIntact myocardiumTopographical distributionChannel mutationsWedge preparationsMidmyocardial cellsRepolarizationLQT2Cellular basisElectrical instability
2001
Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation
Akar F, Roth B, Rosenbaum D. Optical measurement of cell-to-cell coupling in intact heart using subthreshold electrical stimulation. AJP Heart And Circulatory Physiology 2001, 281: h533-h542. PMID: 11454554, DOI: 10.1152/ajpheart.2001.281.2.h533.Peer-Reviewed Original ResearchAnimalsCell CommunicationGap JunctionsGuinea PigsHeartHeart Conduction SystemMyocardiumOptics and Photonics
1999
Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation
Pastore J, Girouard S, Laurita K, Akar F, Rosenbaum D. Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation. Circulation 1999, 99: 1385-1394. PMID: 10077525, DOI: 10.1161/01.cir.99.10.1385.Peer-Reviewed Original Research