2024
Quantitative Assessment of Mitochondrial Morphology and Electrophysiological Function in the Diabetic Heart
Cacheux M, Rudokas M, Tieu A, Rizk J, Hummel M, Akar F. Quantitative Assessment of Mitochondrial Morphology and Electrophysiological Function in the Diabetic Heart. Methods In Molecular Biology 2024, 2803: 75-86. PMID: 38676886, DOI: 10.1007/978-1-0716-3846-0_6.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsDiabetes Mellitus, ExperimentalElectrophysiological PhenomenaMitochondria, HeartMyocardiumMyocytes, CardiacRatsConceptsMitochondrial shapeMitochondrial networkMitochondrial architectureSubcellular localizationMitochondrial morphologyDiabetic heartOxidative phosphorylationATP synthesisAction potentialsSarcolemmal ion channelsExcitation-contraction couplingFission eventsOptical action potentialsExcitation-contractionCardiac myocytesElectrophysiological properties
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 alternansArrhythmia Mechanism and Dynamics in a Humanized Mouse Model of Inherited Cardiomyopathy Caused by Phospholamban R14del Mutation
Raad N, Bittihn P, Cacheux M, Jeong D, Ilkan Z, Ceholski D, Kohlbrenner E, Zhang L, Cai CL, Kranias EG, Hajjar RJ, Stillitano F, Akar FG. Arrhythmia Mechanism and Dynamics in a Humanized Mouse Model of Inherited Cardiomyopathy Caused by Phospholamban R14del Mutation. Circulation 2021, 144: 441-454. PMID: 34024116, PMCID: PMC8456417, DOI: 10.1161/circulationaha.119.043502.Peer-Reviewed Original ResearchConceptsHuman PLNRapid pacingInterventricular activation delayHumanized mouse modelAction potential prolongationLocal conduction blockSteep repolarization gradientsArrhythmogenic featuresMacroreentrant circuitHemodynamic changesElectric remodelingElectrophysiological remodelingRight ventricleVentricular tachycardiaPotential prolongationSudden deathConduction blockMouse modelAdult knockArrhythmia susceptibilityAdrenergic stimulationStructural remodelingArrhythmogenic phenotypeArrhythmia mechanismsRegulatory protein phospholamban
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 eventsRecurrence 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 delivery
2014
Gene therapies for arrhythmias in heart failure
Akar FG, Hajjar RJ. Gene therapies for arrhythmias in heart failure. Pflügers Archiv - European Journal Of Physiology 2014, 466: 1211-1217. PMID: 24566976, PMCID: PMC4070506, DOI: 10.1007/s00424-014-1485-3.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsArrhythmias, CardiacCalcium SignalingConnexin 43Genetic TherapyHeart FailureHumansIon Channels
2013
Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs
Xie C, Biary N, Tocchetti CG, Aon MA, Paolocci N, Kauffman J, Akar FG. Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs. AJP Heart And Circulatory Physiology 2013, 304: h916-h926. PMID: 23376824, PMCID: PMC3625895, DOI: 10.1152/ajpheart.00026.2012.Peer-Reviewed Original ResearchConceptsSham-operated heartsChronic hyperglycemiaOxidative stressAPD heterogeneityGuinea pigsOptical action potential mappingType 1 diabetes mellitusVT/VFGuinea pig modelAction potential durationDaily insulinDiabetes mellitusArrhythmia suppressionProarrhythmic propertiesGlycemic levelsVentricular tachycardiaSaline injectionVentricular fibrillationSudden deathGlucose levelsStreptozotocinArrhythmic triggersNormal heartsTreatment groupsPotential duration
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
2009
Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy
Jin H, Chemaly ER, Lee A, Kho C, Hadri L, Hajjar RJ, Akar FG. Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy. The FASEB Journal 2009, 24: 451-463. PMID: 19825979, PMCID: PMC2812033, DOI: 10.1096/fj.09-136622.Peer-Reviewed Original ResearchConceptsConduction delayLeft ventricular mechanical dysfunctionEnd-stage heart failureTissue levelsVentricular mechanical dysfunctionIncidence of arrhythmiasSudden cardiac deathZO-1Pressure overload hypertrophyAction potential prolongationProgression of hypertrophyDisease developmentLV dysfunctionCardiac deathDephosphorylation of Cx43Heart failureAortic bandingElectrical remodelingVentricular tachycardiaMechanical dysfunctionOverload hypertrophyElectrophysiological changesRat modelPotential prolongationProtein ZO-1Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes†
Aiba T, Hesketh GG, Liu T, Carlisle R, Villa-Abrille MC, O'Rourke B, Akar FG, Tomaselli GF. Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes†. Cardiovascular Research 2009, 85: 454-463. PMID: 19797425, PMCID: PMC2802203, DOI: 10.1093/cvr/cvp324.Peer-Reviewed Original ResearchConceptsAutocamtide-2-related inhibitory peptideDependent protein kinase IIProtein kinase IIKinase IIChannel gatingGlutathione S-transferase fusion peptidesCAMP-dependent proteinIQ-like motifSpecific CaMKII inhibitorC-terminusChannel regulationPresence of CaMInactivation phenotypeCaMKIICaMKII inhibitorFusion peptideInactivationSlow inactivationFraction of channelsDistinct effectsInhibitorsPeptidesInhibitory peptidesGatingCalmodulinElectrophysiological 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
Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling
Gao Z, Barth AS, DiSilvestre D, Akar FG, Tian Y, Tanskanen A, Kass DA, Winslow RL, Tomaselli GF. Key pathways associated with heart failure development revealed by gene networks correlated with cardiac remodeling. Physiological Genomics 2008, 35: 222-230. PMID: 18780759, PMCID: PMC2585017, DOI: 10.1152/physiolgenomics.00100.2007.Peer-Reviewed Original ResearchEffects 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 currentMechanisms of Disease: ion channel remodeling in the failing ventricle
Nass RD, Aiba T, Tomaselli GF, Akar FG. Mechanisms of Disease: ion channel remodeling in the failing ventricle. Nature Clinical Practice Cardiovascular Medicine 2008, 5: 196-207. PMID: 18317475, DOI: 10.1038/ncpcardio1130.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
2007
The Perfect Storm
Akar FG. The Perfect Storm. Circulation Research 2007, 101: 968-970. PMID: 17991890, DOI: 10.1161/circresaha.107.164426.Commentaries, Editorials and LettersRegulation 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 ResearchConceptsIschemic 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
2005
The mitochondrial origin of postischemic arrhythmias
Akar FG, Aon MA, Tomaselli GF, O'Rourke B. The mitochondrial origin of postischemic arrhythmias. Journal Of Clinical Investigation 2005, 115: 3527-3535. PMID: 16284648, PMCID: PMC1280968, DOI: 10.1172/jci25371.Peer-Reviewed Original ResearchMeSH KeywordsAction PotentialsAnimalsAnionsArrhythmias, CardiacDose-Response Relationship, DrugElectrophysiologyGuinea PigsHeartIntracellular MembranesIon ChannelsIschemiaMembrane PotentialsMicroscopy, ConfocalMitochondria, HeartMyocardial IschemiaMyocardial ReperfusionMyocardial Reperfusion InjuryMyocardiumMyocytes, CardiacOscillometryReactive Oxygen SpeciesReceptors, GABA-AReperfusion InjuryTemperatureTime FactorsConceptsAction potentialsVentricular fibrillationPostischemic functional recoveryIschemic heart diseaseGuinea pig heartsNew therapeutic targetsAbnormal electrical activationPostischemic arrhythmiasReperfusion arrhythmiasFunctional recoveryGlobal ischemiaHeart diseaseBolus infusionArrhythmia preventionElectrophysiological changesAP shorteningControl heartsPostischemic heartsBenzodiazepine receptorsElectrophysiological substrateTherapeutic targetArrhythmiasReperfusionPig heartsMitochondrial benzodiazepine receptorAbnormal 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