2021
Right predominant electrical remodeling in a pure model of pulmonary hypertension promotes reentrant arrhythmias
Strauss B, Bisserier M, Obus E, Katz MG, Fargnoli A, Cacheux M, Akar JG, Hummel JP, Hadri L, Sassi Y, Akar FG. Right predominant electrical remodeling in a pure model of pulmonary hypertension promotes reentrant arrhythmias. Heart Rhythm 2021, 19: 113-124. PMID: 34563688, PMCID: PMC8742785, DOI: 10.1016/j.hrthm.2021.09.021.Peer-Reviewed Original ResearchConceptsPulmonary arterial hypertensionVT/VFExtrapulmonary toxicityPN ratsVentricular tachycardia/fibrillationCardiac magnetic resonance imagingRight ventricular hypertrophySprague-Dawley ratsMultiple reentrant circuitsConnexin 43 expressionMagnetic resonance imagingConnexin 43 phosphorylationRV activationArterial hypertensionMonocrotaline modelVentricular hypertrophyLeft pneumonectomyElectrical remodelingMyocardial fibrosisConduction slowingSevere formAP durationArrhythmic vulnerabilityReentrant circuitAP alternans
2019
Recurrence quantification analysis of complex‐fractionated electrograms differentiates active and passive sites during atrial fibrillation
Baher A, Buck B, Fanarjian M, Mounsey J, Gehi A, Chung E, Akar FG, Webber CL, Akar JG, Hummel JP. Recurrence quantification analysis of complex‐fractionated electrograms differentiates active and passive sites during atrial fibrillation. Journal Of Cardiovascular Electrophysiology 2019, 30: 2229-2238. PMID: 31507008, DOI: 10.1111/jce.14161.Peer-Reviewed Original Research
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 deliveryAcute Left Ventricular Unloading Reduces Atrial Stretch and Inhibits Atrial Arrhythmias
Ishikawa K, Watanabe S, Lee P, Akar FG, Lee A, Bikou O, Fish K, Kho C, Hajjar RJ. Acute Left Ventricular Unloading Reduces Atrial Stretch and Inhibits Atrial Arrhythmias. Journal Of The American College Of Cardiology 2018, 72: 738-750. PMID: 30092950, PMCID: PMC6160394, DOI: 10.1016/j.jacc.2018.05.059.Peer-Reviewed Original ResearchConceptsLV end-diastolic pressureEnd-diastolic pressureLV unloadingMyocardial infarctionSubacute myocardial infarctionPressure-volume loopsLA pressureAortic regurgitationRyanodine receptor phosphorylationLA tissuesLV loadingReduced LV ejection fractionAtrial arrhythmia inducibilityLV assist deviceLV ejection fractionMean LA pressureLeft ventricular performancePressure-volume catheterMaximum LA volumeLV loading conditionsReceptor phosphorylationMedian 55NOX2 levelsArrhythmia inducibilityAtrial stretchOptical Action Potential Mapping in Acute Models of Ischemia–Reperfusion Injury: Probing the Arrhythmogenic Role of the Mitochondrial Translocator Protein
Ilkan Z, Strauss B, Campana C, Akar FG. Optical Action Potential Mapping in Acute Models of Ischemia–Reperfusion Injury: Probing the Arrhythmogenic Role of the Mitochondrial Translocator Protein. Methods In Molecular Biology 2018, 1816: 133-143. PMID: 29987816, DOI: 10.1007/978-1-4939-8597-5_10.Peer-Reviewed Original ResearchConceptsOptical action potential mappingIschemia-reperfusion injuryTranslocator proteinPost-ischemic arrhythmiasIonotropic propertiesPostischemic arrhythmiasR injuryHypertensive ratsAcute modelArrhythmogenic roleElectrophysiological substrateElectrophysiological propertiesArrhythmia mechanismsPharmacological inhibitionIntact heartInjuryTSPO ligandsMitochondrial translocator proteinArrhythmiasTSPO geneHeartPatientsRatsQuantitative assessmentIncidence
2016
Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart
Nederlof R, Gürel-Gurevin E, Eerbeek O, Xie C, Deijs GS, Konkel M, Hu J, Weber NC, Schumacher CA, Baartscheer A, Mik EG, Hollmann MW, Akar FG, Zuurbier CJ. Reducing mitochondrial bound hexokinase II mediates transition from non-injurious into injurious ischemia/reperfusion of the intact heart. Journal Of Physiology And Biochemistry 2016, 73: 323-333. PMID: 28258543, PMCID: PMC5534207, DOI: 10.1007/s13105-017-0555-3.Peer-Reviewed Original ResearchConceptsIschemia/reperfusionR injuryCardiac energeticsRecovery of functionHexokinase IISignificant LDH releasePossible underlying mechanismsIschemic insultCardiac recoveryControl heartsMtHKIIReperfusionIschemiaDHE fluorescenceRat heartR intervalLDH releasePeptide treatmentIntact heartInjuryUnderlying mechanismHeartMVO2NecrosisTreatment
2015
LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation
Kim GE, Ross JL, Xie C, Su KN, Zaha VG, Wu X, Palmeri M, Ashraf M, Akar JG, Russell KS, Akar FG, Young LH. LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation. Cardiovascular Research 2015, 108: 197-208. PMID: 26378152, PMCID: PMC4571838, DOI: 10.1093/cvr/cvv212.Peer-Reviewed Original ResearchConceptsLiver kinase B1Protein kinaseLKB1 deletionMetabolic regulator AMPAtrial fibrillationChannel expressionMHC-CreElectrophysiological functionKnockout mouse modelRelated kinasesLKB1 pathwayGene expressionPerpetuation of AFKinase B1Neonatal atrial myocytesΑMHC-CreKinasePostnatal day 1Patch-clamp recordingsAtrial growthWeeks of ageDeletionSodium current densityAction potential generationSpecific roleThe Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus
Xie C, Hu J, Motloch LJ, Karam BS, Akar FG. The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus. Journal Of The American College Of Cardiology 2015, 66: 1144-1156. PMID: 26337994, PMCID: PMC4560843, DOI: 10.1016/j.jacc.2015.06.1329.Peer-Reviewed Original ResearchConceptsAction potential durationVentricular tachyarrhythmiasT2DM heartsIschemia-induced ventricular tachyarrhythmiasOptical action potential mappingType 2 diabetes mellitusAdenosine triphosphate-sensitive potassium channelsMitochondrial adenosine triphosphate-sensitive potassium channelsTriphosphate-sensitive potassium channelsLow-dose diazoxideFree fatty acid levelsIncidence of arrhythmiasNormal Sprague-Dawley ratsSprague-Dawley ratsOnset of arrhythmiasMessenger ribonucleic acid expressionFatty acid levelsRibonucleic acid expressionAPD adaptationElicit arrhythmiasUntreated T2DMIschemic eventsDiabetes mellitusDiabetic patientsIschemic challenge
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
2013
Pathophysiological Consequences of TAT-HKII Peptide Administration Are Independent of Impaired Vascular Function and Ensuing Ischemia
Nederlof R, Xie C, Eerbeek O, Koeman A, Milstein DM, Hollmann MW, Mik EG, Warley A, Southworth R, Akar FG, Zuurbier CJ. Pathophysiological Consequences of TAT-HKII Peptide Administration Are Independent of Impaired Vascular Function and Ensuing Ischemia. Circulation Research 2013, 112: e8-e13. PMID: 23329797, PMCID: PMC3596767, DOI: 10.1161/circresaha.112.274308.Peer-Reviewed Original ResearchConceptsVascular functionIschemic preconditioningMyocardial dysfunctionCardiac functionPeptide administrationHexokinase IIOptical action potential mappingAcute myocardial dysfunctionImpaired vascular functionIschemia-reperfusion injuryDeleterious effectsIschemic injuryCardioprotective effectsProtective effectIschemiaPathophysiological consequencesIntact myocardiumDehydrogenase releaseIntact heartAdministrationLactate productionDysfunctionRole of mitochondriaInjuryCritical regulator
2011
Disruption of Hexokinase II–Mitochondrial Binding Blocks Ischemic Preconditioning and Causes Rapid Cardiac Necrosis
Smeele KM, Southworth R, Wu R, Xie C, Nederlof R, Warley A, Nelson JK, van Horssen P, van den Wijngaard JP, Heikkinen S, Laakso M, Koeman A, Siebes M, Eerbeek O, Akar FG, Ardehali H, Hollmann MW, Zuurbier CJ. Disruption of Hexokinase II–Mitochondrial Binding Blocks Ischemic Preconditioning and Causes Rapid Cardiac Necrosis. Circulation Research 2011, 108: 1165-1169. PMID: 21527739, DOI: 10.1161/circresaha.111.244962.Peer-Reviewed Original ResearchConceptsIschemic preconditioningWild-type heartsCardiac functionProtective effectHKII levelsBaseline cardiac functionIschemia-reperfusion injuryNormal cardiac functionMitochondrial permeability transition openingContractile impairmentReperfusion injuryAcute reductionCardiac necrosisMyocardial functionGlycolytic enzymes hexokinaseCardiac contractionMild mitochondrial uncouplingMembrane depolarizationMitochondrial membrane depolarizationHKIIMitochondrial hexokinaseControl peptideHeartPreconditioningTissue disruption
2010
Altered Spatiotemporal Dynamics of the Mitochondrial Membrane Potential in the Hypertrophied Heart
Jin H, Nass RD, Joudrey PJ, Lyon AR, Chemaly ER, Rapti K, Akar FG. Altered Spatiotemporal Dynamics of the Mitochondrial Membrane Potential in the Hypertrophied Heart. Biophysical Journal 2010, 98: 2063-2071. PMID: 20483313, PMCID: PMC2872265, DOI: 10.1016/j.bpj.2010.01.045.Peer-Reviewed Original Research
2009
Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy
Aiba T, Hesketh GG, Barth AS, Liu T, Daya S, Chakir K, Dimaano VL, Abraham TP, O'Rourke B, Akar FG, Kass DA, Tomaselli GF. Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy. Circulation 2009, 119: 1220-1230. PMID: 19237662, PMCID: PMC2703676, DOI: 10.1161/circulationaha.108.794834.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsBundle-Branch BlockCalciumCalcium ChannelsCoronary CirculationDogsEchocardiographyElectrocardiographyHeart FailureHomeostasisKv Channel-Interacting ProteinsMaleMyocytes, CardiacPacemaker, ArtificialPatch-Clamp TechniquesPotassium Channels, Inwardly RectifyingRNA, MessengerSarcoplasmic Reticulum Calcium-Transporting ATPasesShal Potassium ChannelsConceptsCardiac resynchronization therapyAction potential durationRight atrial pacingCalcium transient amplitudeHeart failurePotential durationResynchronization therapyAtrial pacingElectrophysiological consequencesLeft bundle-branch ablationTransient amplitudeSarcoplasmic reticulumWhole-cell patch clampDyssynchronous heart failureProtein levelsIon channel remodelingSame pacing rateLeft ventricular anteriorQuantitative polymerase chain reactionSurvival benefitBiventricular pacingVentricular arrhythmiasDyssynchronous contractionPolymerase chain reactionElectrophysiological changes
2008
Effects of 4′-chlorodiazepam on cellular excitation–contraction coupling and ischaemia–reperfusion injury in rabbit heart
Brown DA, Aon MA, Akar FG, Liu T, Sorarrain N, O’Rourke B. Effects of 4′-chlorodiazepam on cellular excitation–contraction coupling and ischaemia–reperfusion injury in rabbit heart. Cardiovascular Research 2008, 79: 141-149. PMID: 18304929, PMCID: PMC2562874, DOI: 10.1093/cvr/cvn053.Peer-Reviewed Original ResearchConceptsIschaemia-reperfusion injuryExcitation-contraction couplingReperfusion arrhythmiasRabbit heartsDose-dependent negative inotropic responseCellular excitation-contraction couplingPost-ischemic cardiac dysfunctionOnset of reperfusionMin of reperfusionSingle bolus doseNegative inotropic responseIschaemia/reperfusionIntracellular calcium transientsSarcolemmal ion channelsIsolated rabbit cardiomyocytesIon channelsCardiac action potentialContractile impairmentCardiac dysfunctionBolus doseContractile dysfunctionInotropic responseGlobal ischaemiaVoltage clamp methodCalcium current
2007
Dynamic 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
2005
Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure
Akar FG, Wu RC, Juang GJ, Tian Y, Burysek M, DiSilvestre D, Xiong W, Armoundas AA, Tomaselli GF. Molecular mechanisms underlying K+ current downregulation in canine tachycardia-induced heart failure. AJP Heart And Circulatory Physiology 2005, 288: h2887-h2896. PMID: 15681701, DOI: 10.1152/ajpheart.00320.2004.Peer-Reviewed Original Research
2004
Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall
Poelzing S, Akar FG, Baron E, Rosenbaum DS. Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall. AJP Heart And Circulatory Physiology 2004, 286: h2001-h2009. PMID: 14704225, DOI: 10.1152/ajpheart.00987.2003.Peer-Reviewed Original Research
2003
Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito
Akar FG, Wu RC, Deschenes I, Armoundas AA, Piacentino V, Houser SR, Tomaselli GF. Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito. AJP Heart And Circulatory Physiology 2003, 286: h602-h609. PMID: 14527940, DOI: 10.1152/ajpheart.00673.2003.Peer-Reviewed Original ResearchConceptsTransient outwardPhenotypic differencesKv channel-interacting proteinsIndependent transient outwardChannel-interacting proteinsProtein chemical techniquesSteady-state inactivationCanine ventricular myocytesWestern blot analysisElectrical remodelingChannel subunit genesMonoexponential time coursePharmacological sensitivityVentricular repolarizationCardiac diseaseElectrophysiological roleCanine ventricularHuman cardiac diseasePosttranslational modificationsVentricular myocytesSubunit genePharmacological propertiesDiseased heartPhenotypic propertiesOxidative stressTransmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure
Akar FG, Rosenbaum DS. Transmural Electrophysiological Heterogeneities Underlying Arrhythmogenesis in Heart Failure. Circulation Research 2003, 93: 638-645. PMID: 12933704, DOI: 10.1161/01.res.0000092248.59479.ae.Peer-Reviewed Original ResearchConceptsPolymorphic ventricular tachycardiaHeart failureQT interval prolongationQT intervalM cellsConduction blockAPD prolongationTransmural wallAction potential duration prolongationRapid ventricular pacingTransmural heterogeneityFunctional conduction blockVentricular tachyarrhythmiasPremature impulsesSubepicardial zoneVentricular pacingVentricular tachycardiaHF phenotypesDuration prolongationCanine wedge preparationSelective prolongationDecremental conductionAction potentialsOptical action potentialsVentricular wall
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