2024
Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction
Rudokas M, McKay M, Toksoy Z, Eisen J, Bögner M, Young L, Akar F. Mitochondrial network remodeling of the diabetic heart: implications to ischemia related cardiac dysfunction. Cardiovascular Diabetology 2024, 23: 261. PMID: 39026280, PMCID: PMC11264840, DOI: 10.1186/s12933-024-02357-1.Peer-Reviewed Original ResearchConceptsReactive oxygen speciesMitochondrial network remodelingDamaged mitochondrial DNAEfficiency of oxidative phosphorylationImpaired ATP productionMitochondrial ultrastructural alterationsCardiac functionDiabetic heartCellular energy metabolismProduction of reactive oxygen speciesMitochondrial DNAMitochondrial networkMitochondrial fissionExcessive production of reactive oxygen speciesOxidative phosphorylationATP productionResponse to ischemic insultGlobal cardiac functionCell deathOverall cardiac functionCardiac ischemic injuryResponse to injuryCardiac mitochondriaIrreversible cell deathMitochondriaTop Stories: Mitochondrial origin of inherited cardiac arrhythmias
Akar F, Maack C. Top Stories: Mitochondrial origin of inherited cardiac arrhythmias. Heart Rhythm 2024, 21: 235-236. PMID: 38296456, PMCID: PMC10857749, DOI: 10.1016/j.hrthm.2023.10.020.Peer-Reviewed Original ResearchArrhythmias, CardiacHumans
2023
A unifying mechanism for the initiation of torsade de pointes: blurring the distinction between trigger and substrate
McKay M, Akar F. A unifying mechanism for the initiation of torsade de pointes: blurring the distinction between trigger and substrate. Cardiovascular Research 2023, 119: 333-335. PMID: 36869679, DOI: 10.1093/cvr/cvad033.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
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 penetranceModern Day Wearables to Evade the Widow-Ghost in Brugada Syndrome From Mythology to Deep-Learning Methodology ∗
Karam CS, Akar FG. Modern Day Wearables to Evade the Widow-Ghost in Brugada Syndrome From Mythology to Deep-Learning Methodology ∗. JACC Clinical Electrophysiology 2022, 8: 1021-1023. PMID: 35981789, DOI: 10.1016/j.jacep.2022.06.017.Commentaries, Editorials and LettersA novel exosome-based therapy for post-MI arrhythmias
Cacheux M, Akar FG. A novel exosome-based therapy for post-MI arrhythmias. European Heart Journal 2022, 43: 2157-2159. PMID: 35325140, DOI: 10.1093/eurheartj/ehac155.Peer-Reviewed Original ResearchGene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact
Dave J, Raad N, Mittal N, Zhang L, Fargnoli A, Oh JG, Savoia ME, Hansen J, Fava M, Yin X, Theofilatos K, Ceholski D, Kohlbrenner E, Jeong D, Wills L, Nonnenmacher M, Haghighi K, Costa KD, Turnbull IC, Mayr M, Cai CL, Kranias EG, Akar FG, Hajjar RJ, Stillitano F. Gene editing reverses arrhythmia susceptibility in humanized PLN-R14del mice: modelling a European cardiomyopathy with global impact. Cardiovascular Research 2022, 118: 3140-3150. PMID: 35191471, PMCID: PMC9732517, DOI: 10.1093/cvr/cvac021.Peer-Reviewed Original ResearchConceptsAdeno-associated virus 9Ventricular tachycardiaCardiac functionStroke volumeHigh arrhythmia burdenSustained ventricular tachycardiaSudden cardiac deathCardiac magnetic resonancePre-symptomatic carriersYoung adult miceWeeks of ageDroplet digital polymerase chain reactionArrhythmia burdenVulnerable myocardiumCardiac deathEjection fractionPreclinical evidenceMalignant arrhythmiasVentricular dilationHumanized miceWT miceCardiac outputPolymerase chain reactionPLN-R14DelAdult mice
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 LettersArrhythmia 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
2020
‘Social distancing’ of the neuronal nitric oxide synthase from its adaptor protein causes arrhythmogenic trigger-substrate interactions in long QT syndrome
Tieu A, Akar FG. ‘Social distancing’ of the neuronal nitric oxide synthase from its adaptor protein causes arrhythmogenic trigger-substrate interactions in long QT syndrome. Cardiovascular Research 2020, 117: 338-340. PMID: 32589704, PMCID: PMC7820852, DOI: 10.1093/cvr/cvaa179.Commentaries, Editorials and Letters
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
2017
Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes
Karam BS, Chavez-Moreno A, Koh W, Akar JG, Akar FG. Oxidative stress and inflammation as central mediators of atrial fibrillation in obesity and diabetes. Cardiovascular Diabetology 2017, 16: 120. PMID: 28962617, PMCID: PMC5622555, DOI: 10.1186/s12933-017-0604-9.Peer-Reviewed Original ResearchConceptsAtrial fibrillationOxidative stressCommon sustained cardiac arrhythmiaMaintenance of AFSustained cardiac arrhythmiaDiabetic heartElectrical remodelingRisk factorsAtrial excitabilityTherapeutic strategiesCardiac arrhythmiasInflammationCentral mediatorObesityDiabetesFibrillationMechanistic linkMellitusArrhythmiasExcitability
2016
Starve a fever to heal a heart? Interleukin-18 gives new meaning to an old adage
Akar FG. Starve a fever to heal a heart? Interleukin-18 gives new meaning to an old adage. AJP Heart And Circulatory Physiology 2016, 311: h311-h312. PMID: 27342879, DOI: 10.1152/ajpheart.00445.2016.Commentaries, Editorials and Letters
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 systemThe Mitochondrial Translocator Protein and Arrhythmogenesis in Ischemic Heart Disease
Motloch LJ, Hu J, Akar FG. The Mitochondrial Translocator Protein and Arrhythmogenesis in Ischemic Heart Disease. Oxidative Medicine And Cellular Longevity 2015, 2015: 234104. PMID: 25918579, PMCID: PMC4397036, DOI: 10.1155/2015/234104.Peer-Reviewed Original ResearchConceptsIschemic heart diseaseHeart diseaseTranslocator proteinAcute ischemia-reperfusion injuryReactive oxygen speciesIschemia-reperfusion injuryMultiple organ systemsExcitation-contraction couplingMultiple cardiovascular disordersPermeability transition poreRole of TSPOMyocardial infarctionInflammatory processDiverse pathophysiological processesImmune responseCardiovascular disordersTherapeutic targetPathophysiological processesOrgan systemsDiagnostic markerMitochondrial dysfunctionDiseaseAbundant expressionMitochondrial translocator proteinROS release
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