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
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 ResearchMeSH KeywordsAction PotentialsAnimalsArrhythmias, CardiacCalcium SignalingConnexin 43Genetic TherapyHeart FailureHumansIon Channels