2021
Arrhythmia 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
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
2015
The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus
Xie C, Hu J, Motloch LJ, Karam BS, Akar FG. The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus. Journal Of The American College Of Cardiology 2015, 66: 1144-1156. PMID: 26337994, PMCID: PMC4560843, DOI: 10.1016/j.jacc.2015.06.1329.Peer-Reviewed Original ResearchConceptsAction potential durationVentricular tachyarrhythmiasT2DM heartsIschemia-induced ventricular tachyarrhythmiasOptical action potential mappingType 2 diabetes mellitusAdenosine triphosphate-sensitive potassium channelsMitochondrial adenosine triphosphate-sensitive potassium channelsTriphosphate-sensitive potassium channelsLow-dose diazoxideFree fatty acid levelsIncidence of arrhythmiasNormal Sprague-Dawley ratsSprague-Dawley ratsOnset of arrhythmiasMessenger ribonucleic acid expressionFatty acid levelsRibonucleic acid expressionAPD adaptationElicit arrhythmiasUntreated T2DMIschemic eventsDiabetes mellitusDiabetic patientsIschemic challengeGene 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
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
2005
Abnormal 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
2002
Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome
Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome. Circulation 2002, 105: 1247-1253. PMID: 11889021, DOI: 10.1161/hc1002.105231.Peer-Reviewed Original ResearchConceptsLong QT syndromeSpecific ion channel mutationsCongenital long QT syndromeM cellsQT interval prolongationIon channel mutationsInterval prolongationReentrant mechanismTdP arrhythmiasConduction blockCanine wedge preparationReentrant circuitTransmural dispersionLeft ventricleAction potentialsTransmural wallIntact myocardiumTopographical distributionChannel mutationsWedge preparationsMidmyocardial cellsRepolarizationLQT2Cellular basisElectrical instability
1999
Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation
Pastore J, Girouard S, Laurita K, Akar F, Rosenbaum D. Mechanism Linking T-Wave Alternans to the Genesis of Cardiac Fibrillation. Circulation 1999, 99: 1385-1394. PMID: 10077525, DOI: 10.1161/01.cir.99.10.1385.Peer-Reviewed Original Research