2022
Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes
Stevens TL, Manring HR, Wallace MJ, Argall A, Dew T, Papaioannou P, Antwi-Boasiako S, Xu X, Campbell SG, Akar FG, Borzok MA, Hund TJ, Mohler PJ, Koenig SN, El Refaey M. Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes. Cells 2022, 11: 3049. PMID: 36231013, PMCID: PMC9562631, DOI: 10.3390/cells11193049.Peer-Reviewed Original ResearchConceptsArrhythmogenic cardiomyopathyMouse modelStructural phenotypesFibro-fatty infiltrationFirst mouse modelHeart failureChamber dilationVentricular arrhythmiasPressure overloadArrhythmic eventsCardiac performanceCardiac stressSudden deathCardiovascular stressInherited disorderG variantConnexin 43MiceDesmosomal genesReduced expressionExternal stressorsACM familyDisease developmentMurine equivalentIncomplete penetrance
2018
Primary 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
2017
Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure
Watanabe S, Ishikawa K, Fish K, Oh JG, Motloch LJ, Kohlbrenner E, Lee P, Xie C, Lee A, Liang L, Kho C, Leonardson L, McIntyre M, Wilson S, Samulski RJ, Kranias EG, Weber T, Akar FG, Hajjar RJ. Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure. Journal Of The American College Of Cardiology 2017, 70: 1744-1756. PMID: 28958332, PMCID: PMC5807083, DOI: 10.1016/j.jacc.2017.08.013.Peer-Reviewed Original ResearchConceptsNonischemic heart failureHeart failureEjection fractionIntracoronary deliveryTherapeutic efficacyLeft ventricular end-diastolic pressureDp/dt maximumLeft ventricular ejection fractionVentricular end-diastolic pressureVolume overload heart failureAdverse electrical remodelingIschemic heart failureVentricular ejection fractionVentricular volume indexAtrial ejection fractionEnd-diastolic pressureSevere mitral regurgitationCellular immune responsesCalcium transient amplitudeLarge animal modelGene therapyActive inhibitor-1Improved contractilityInhibitor-1 geneCardiac dysfunction
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 ResearchConceptsHeart 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
Cardiac I-1c Overexpression With Reengineered AAV Improves Cardiac Function in Swine Ischemic Heart Failure
Ishikawa K, Fish KM, Tilemann L, Rapti K, Aguero J, Santos-Gallego CG, Lee A, Karakikes I, Xie C, Akar FG, Shimada YJ, Gwathmey JK, Asokan A, McPhee S, Samulski J, Samulski RJ, Sigg DC, Weber T, Kranias EG, Hajjar RJ. Cardiac I-1c Overexpression With Reengineered AAV Improves Cardiac Function in Swine Ischemic Heart Failure. Molecular Therapy 2014, 22: 2038-2045. PMID: 25023328, PMCID: PMC4429688, DOI: 10.1038/mt.2014.127.Peer-Reviewed Original ResearchConceptsIschemic heart failureHigh-dose groupHeart failureCardiac functionLarge anterior myocardial infarctionLeft ventricular ejection fractionPreload recruitable stroke workChronic heart failureAdvanced heart failureLow-dose groupVentricular ejection fractionAnterior myocardial infarctionActive inhibitor-1Ejection fractionIntracoronary injectionSaline groupContractility indexMyocardial infarctionPressure-volume analysisStroke volumeStroke workCardiac performanceHemodynamic parametersCardiovascular systemCardiac gene therapyEffect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure
Chaanine A, Nonnenmacher M, Kohlbrenner E, Jin D, Kovacic J, Akar F, Hajjar R, Weber T. Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure. Gene Therapy 2014, 21: 379-386. PMID: 24572786, PMCID: PMC3976435, DOI: 10.1038/gt.2014.7.Peer-Reviewed Original ResearchConceptsHeart failureCardiac functionRodent heart failure modelsRat cardiomyocytesHeart failure modelPressure overload modelEffect of bortezomibProteasome inhibitor bortezomibNeonatal rat cardiomyocytesAdult rat cardiomyocytesWestern blot analysisSERCA2a proteinPressure-volume analysisSERCA2a levelsBortezomib treatmentConcurrent treatmentSERCA2a mRNAInhibitor bortezomibBortezomibHeart samplesHuman SERCA2aSerotype 1Proteasome inhibitorsAAV serotypes 1Proteasome inhibitionGene 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 Research
2013
Mitochondrial targets for arrhythmia suppression: is there a role for pharmacological intervention?
Akar FG. Mitochondrial targets for arrhythmia suppression: is there a role for pharmacological intervention? Journal Of Interventional Cardiac Electrophysiology 2013, 37: 249-258. PMID: 23824789, DOI: 10.1007/s10840-013-9809-3.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMitochondrial targetsMitochondrial dysfunctionCritical cellular functionsCell death pathwaysCellular redox statusIon channel functionMitochondrial networkCellular functionsDeath pathwaysMitochondrial originIschemia-reperfusion injuryCommon cardiovascular disordersMitochondrial bioenergeticsExcitation-contraction couplingChannel functionRedox statusMechanistic linkHeart failureArrhythmia suppressionPharmacological interventionsCardiovascular disordersCentral mechanismsDysfunctionArrhythmogenesisEnergy productionElectrophysiological Remodeling in Heart Failure
Akar F, Tomaselli G. Electrophysiological Remodeling in Heart Failure. 2013, 369-386. DOI: 10.1007/978-1-4471-4881-4_22.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsHeart failureTreatment of arrhythmiasCellular electrophysiological propertiesIon channelsSafe therapyConduction abnormalitiesElectrophysiological remodelingSudden deathNovel pharmacologicalArrhythmogenic triggersElectrophysiological propertiesAction potentialsArrhythmiasFunctional consequencesIonic mechanismsMolecular mechanismsOrgan levelFailureTherapyAbnormalitiesPharmacologicalRepolarization
2011
Deciphering Arrhythmia Mechanisms: Tools of the Trade
Salama G, Akar FG. Deciphering Arrhythmia Mechanisms: Tools of the Trade. Cardiac Electrophysiology Clinics 2011, 3: 11-21. PMID: 21572551, PMCID: PMC3093299, DOI: 10.1016/j.ccep.2010.10.013.Peer-Reviewed Original ResearchArrhythmia mechanismsIschemia-reperfusion injuryCalcium handling propertiesLong QT syndromeMultiple cardiovascular disordersHeart failureCardiac functionCardiovascular disordersQT syndromeComplex arrhythmiasAction potentialsOptical action potentialsPathophysiological remodelingTissue levelsOrgan system levelRepolarization gradientsArrhythmiasSub-cellular changesSyndromeInjuryLevels
2010
Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure.
Akar FG. Left ventricular repolarization heterogeneity as an arrhythmic substrate in heart failure. Minerva Cardioangiologica 2010, 58: 205-12. PMID: 20440250.ChaptersConceptsHeart failureElectrophysiological substrateSudden cardiac deathCalcium handling proteinsRepolarization gradientsVentricular repolarization heterogeneityHeterogeneous remodelingCardiac deathCardiac functionArrhythmic substrateLeft ventriculeHandling proteinsMuscle layerPathophysiological remodelingRepolarization heterogeneityTissue levelsOrgan system levelArrhythmiasGap junctionsIon channelsOverview of mechanismsSub-cellular changesRemodelingFailureVentricule
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-1Electrophysiological 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
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 channelsDeathHeartTachyarrhythmiasAbnormalitiesMechanisms 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 StatementsElectrophysiological remodeling in Dilated Cardiomyopathy and Heart Failure
Akar F, Tomaselli G. Electrophysiological remodeling in Dilated Cardiomyopathy and Heart Failure. 2008, 290-304. DOI: 10.1007/978-1-84628-854-8_19.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsHeart failureCardiac remodelingComplete heart blockStructural heart diseaseAtrial fibrillationHeart blockMyocardial infarctionVentricular pacingElectrophysiological remodelingHeart diseaseMechanical dysfunctionHeart ratePersistent changesRemodelingActivation sequenceEntire organKey regulatory proteinsGene expressionExtracellular matrixInfarctionTachycardiaCardiomyopathyFailureDysfunctionFibrillation
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
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 ResearchConceptsConduction 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 mechanismsDysfunctionExcitabilityIon channels as novel therapeutic targets in heart failure
Akar FG, Tomaselli GF. Ion channels as novel therapeutic targets in heart failure. Annals Of Medicine 2005, 37: 44-54. PMID: 15902846, DOI: 10.1080/07853890510007214.Peer-Reviewed Original ResearchConceptsHeart failureIon channel functionAnti-arrhythmic therapyLethal ventricular tachyarrhythmiasCalcium handling proteinsNovel therapeutic targetPublic health epidemicIon channel dysfunctionChannel functionVentricular tachyarrhythmiasTherapeutic targetChannel dysfunctionHandling proteinsSodium currentHealth epidemicNovel targetImpulse generationElectrical phenotypeIon channelsCurrent understandingTachyarrhythmiasFailureDysfunctionTherapyAbnormalities