2021
NAD Repletion Therapy
Akar FG, Young LH. NAD Repletion Therapy. Circulation Research 2021, 128: 1642-1645. PMID: 34043421, PMCID: PMC8513806, DOI: 10.1161/circresaha.121.319308.Commentaries, Editorials and Letters
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
A formidable “TASK”: Tipping the balance in favor of rhythm control for the management of atrial fibrillation
Akar FG. A formidable “TASK”: Tipping the balance in favor of rhythm control for the management of atrial fibrillation. Heart Rhythm 2014, 11: 1806-1807. PMID: 25041966, DOI: 10.1016/j.hrthm.2014.07.018.Commentaries, Editorials and LettersCardiac 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
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.ChaptersMeSH KeywordsArrhythmias, CardiacCardiomyopathy, DilatedHeart FailureHumansVentricular Function, LeftConceptsHeart 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 changesRemodelingFailureVentriculeUltrastructure and Regulation of Lateralized Connexin43 in the Failing Heart
Hesketh GG, Shah MH, Halperin VL, Cooke CA, Akar FG, Yen TE, Kass DA, Machamer CE, Van Eyk JE, Tomaselli GF. Ultrastructure and Regulation of Lateralized Connexin43 in the Failing Heart. Circulation Research 2010, 106: 1153-1163. PMID: 20167932, PMCID: PMC2896878, DOI: 10.1161/circresaha.108.182147.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutophagyConnexin 43Disease Models, AnimalDogsGap JunctionsHeart FailureHeart VentriclesHeLa CellsHumansMembrane MicrodomainsMicroscopy, ConfocalMicroscopy, Electron, TransmissionMicrotubule-Associated ProteinsMyocardiumPhosphorylationRatsRats, Sprague-DawleyRecombinant Fusion ProteinsTransfectionConceptsGFP-LC3Gap junctionsLateral membranesDistinct phosphorylated formsGap junction turnoverGap junction internalizationForm of LC3Internalized gap junctionsGap junction proteinJunction turnoverSubcellular locationBiochemical regulationCellular pathwaysMultilamellar membrane structuresEndogenous Cx43Phosphorylated formNeonatal rat ventricular myocytesHeLa cellsIntracellular Cx43Membrane structureJunction proteinsCx43ProteinPotential therapeutic implicationsConnexin43
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
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 ResearchArrhythmia 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 Statements
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
Ion 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 understandingTachyarrhythmiasFailureDysfunctionTherapyAbnormalitiesMolecular 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
2003
Transmural 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 ResearchMeSH KeywordsAction PotentialsAnimalsArrhythmias, CardiacDogsElectrophysiologyHeartHeart FailureIn Vitro TechniquesMaleConceptsPolymorphic 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