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 deathMitochondriaDownregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia
Huang Y, Chen L, Li L, Qi Y, Tong H, Wu H, Xu J, Leng L, Cheema S, Sun G, Xia Z, McGuire J, Rodrigues B, Young L, Bucala R, Qi D. Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia. JCI Insight 2024, 9: e173240. PMID: 38973609, PMCID: PMC11383372, DOI: 10.1172/jci.insight.173240.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorDevelopment of hypertriglyceridemiaWhite adipose tissueAdipose LPLPAR2 expressionLevels of macrophage migration inhibitory factorElevated plasma TG levelsLPL expressionLipoprotein lipaseIncrease PAR2 expressionPlasma MIF levelsPlasma TG levelsMigration inhibitory factorPalmitic acid dietInhibited Akt phosphorylationMIF levelsLipoprotein lipase geneTG levelsObese humansPlasma TGHypertriglyceridemiaAkt phosphorylationLipid storageInhibitory factorAdipose tissueLDL Receptor-Related Protein 5 Selectively Transports Unesterified Polyunsaturated Fatty Acids to Intracellular Compartments
Tang W, Luan Y, Yuan Q, Li A, Chen S, Menacherry S, Young LH, and Wu D; Nature CommunicationsPeer-Reviewed Original Research In Press
2023
An explainable machine learning-based phenomapping strategy for adaptive predictive enrichment in randomized clinical trials
Oikonomou E, Thangaraj P, Bhatt D, Ross J, Young L, Krumholz H, Suchard M, Khera R. An explainable machine learning-based phenomapping strategy for adaptive predictive enrichment in randomized clinical trials. Npj Digital Medicine 2023, 6: 217. PMID: 38001154, PMCID: PMC10673945, DOI: 10.1038/s41746-023-00963-z.Peer-Reviewed Original ResearchExtracellular macrophage migration inhibitory factor (MIF) downregulates adipose hormone-sensitive lipase (HSL) and contributes to obesity
Chen L, Li L, Cui D, Huang Y, Tong H, Zabihi H, Wang S, Qi Y, Lakowski T, Leng L, Liu S, Wu H, Young L, Bucala R, Qi D. Extracellular macrophage migration inhibitory factor (MIF) downregulates adipose hormone-sensitive lipase (HSL) and contributes to obesity. Molecular Metabolism 2023, 79: 101834. PMID: 37935315, PMCID: PMC10700858, DOI: 10.1016/j.molmet.2023.101834.Peer-Reviewed Original ResearchMacrophage migration inhibitory factorExtracellular MIFHigh-fat dietHormone-sensitive lipaseDevelopment of obesityMigration inhibitory factorInhibitory factorRole of cytokinesExtracellular actionJNK phosphorylationMIF levelsSevere obesityHFD miceHFD feedingMIF antibodyWT miceAdipocyte hypertrophyCOP9 signalosome subunit 5Fat dietHSL expressionObesityAutocrine fashionHSL activationSensitive lipaseInhibitory actionA pref-1-controlled non-inflammatory mechanism of insulin resistance
Huang Y, Cui D, Chen L, Tong H, Wu H, Muller G, Qi Y, Wang S, Xu J, Gao X, Fifield K, Wang L, Xia Z, Vanderluit J, Liu S, Leng L, Sun G, McGuire J, Young L, Bucala R, Qi D. A pref-1-controlled non-inflammatory mechanism of insulin resistance. IScience 2023, 26: 106923. PMID: 37283810, PMCID: PMC10239698, DOI: 10.1016/j.isci.2023.106923.Peer-Reviewed Original ResearchInsulin resistanceMIF secretionPref-1 expressionPref-1Fat-induced insulin resistancePlasma MIF levelsNon-inflammatory mechanismsActivation of PAR2Palmitic acid dietHigh fat-induced insulin resistanceWhite adipose tissueSubsequent insulin resistanceMIF levelsPAR2 expressionM2 macrophagesAcid dietAdipose tissueAMPK-dependent mannerEndothelial cellsSecretionIntegrin β1CellsExpressionHigh levelsInflammationA Case of Fulminant Right Heart Failure Owing to Tumoral Pulmonary Hypertension
Wang K, Verma A, Fish K, Hu J, Miller P, Morrow J, Singh I, Young L. A Case of Fulminant Right Heart Failure Owing to Tumoral Pulmonary Hypertension. JACC Case Reports 2023, 10: 101715. PMID: 36974052, PMCID: PMC10039392, DOI: 10.1016/j.jaccas.2022.101715.Peer-Reviewed Case Reports and Technical NotesRole of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling
Rudokas M, Cacheux M, Wu X, Hummel M, Young L, Akar F. Role of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling. Biophysical Journal 2023, 122: 380a-381a. DOI: 10.1016/j.bpj.2022.11.2089.Peer-Reviewed Original Research
2022
MIF is a common genetic determinant of COVID-19 symptomatic infection and severity
Shin JJ, Fan W, Par-Young J, Piecychna M, Leng L, Israni-Winger K, Qing H, Gu J, Zhao H, Schulz WL, Unlu S, Kuster J, Young G, Liu J, Ko AI, Garcia A, Sauler M, Wisnewski AV, Young L, Orduña A, Wang A, Klementina O, Garcia AB, Hegyi P, Armstrong ME, Mitchell P, Ordiz DB, Garami A, Kang I, Bucala R. MIF is a common genetic determinant of COVID-19 symptomatic infection and severity. QJM 2022, 116: 205-212. PMID: 36222594, PMCID: PMC9620729, DOI: 10.1093/qjmed/hcac234.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorLow-expression MIF alleleCOVID-19 infectionMIF allelesCATT7 alleleHealthy controlsCOVID-19Serum macrophage migration inhibitory factorSymptomatic SARS-CoV-2 infectionHigher serum MIF levelsHigh-expression MIF allelesRetrospective case-control studySARS-CoV-2 infectionFunctional polymorphismsAvailable clinical characteristicsMultinational retrospective studySerum MIF levelsUninfected healthy controlsSymptomatic COVID-19Tertiary medical centerHealthy control subjectsCase-control studyMigration inhibitory factorCoronavirus disease 2019Common functional polymorphismsCentral vs site outcome adjudication in the IRIS trial
Forman R, Viscoli CM, Bath PM, Furie KL, Guarino P, Inzucchi SE, Young L, Kernan WN. Central vs site outcome adjudication in the IRIS trial. Journal Of Stroke And Cerebrovascular Diseases 2022, 31: 106667. PMID: 35901589, DOI: 10.1016/j.jstrokecerebrovasdis.2022.106667.Peer-Reviewed Original ResearchConceptsCentral adjudicationHazard ratioStroke definitionsRecent transient ischemic attackInsulin Resistance InterventionMain secondary outcomesShorter symptom durationTransient ischemic attackPrevention of strokeNormal brain imagingClinical trial researchIschemic attackIschemic strokeSecondary outcomesSymptom durationPrimary outcomeStroke trialsIRIS trialMyocardial infarctionOutcome definitionsStroke typeOutcome eventsAdjudicated eventsOutcome adjudicationResistance Intervention122-LB: Effect of Dapagliflozin on Mitochondrial Metabolism and Cardiac Function in the Failing Heart
GOEDEKE L, MA Y, ZHANG J, GUERRERA N, WU X, ZHANG D, KAHN M, ZHANG X, YOUNG L, SHULMAN G. 122-LB: Effect of Dapagliflozin on Mitochondrial Metabolism and Cardiac Function in the Failing Heart. Diabetes 2022, 71 DOI: 10.2337/db22-122-lb.Peer-Reviewed Original ResearchDAPA treatmentLV ejection fractionEjection fractionHeart failureMI ratsCardiac outputMyocardial infarctionCardiac functionLeft ventricularEffect of dapagliflozinMale Sprague-DawleyPlasma glucose concentrationMalonyl-CoA contentMitochondrial oxidationKetone availabilityΒOHB levelsVehicle treatmentPermanent ligationSGLT2 inhibitionSGLT2 inhibitorsCardioprotective effectsCoronary arteryAcetyl-CoA contentFailing HeartMitochondrial metabolismAtrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation
Su KN, Ma Y, Cacheux M, Ilkan Z, Raad N, Muller GK, Wu X, Guerrera N, Thorn SL, Sinusas AJ, Foretz M, Viollet B, Akar JG, Akar FG, Young LH. Atrial AMP-activated protein kinase is critical for prevention of dysregulation of electrical excitability and atrial fibrillation. JCI Insight 2022, 7: e141213. PMID: 35451373, PMCID: PMC9089788, DOI: 10.1172/jci.insight.141213.Peer-Reviewed Original ResearchConceptsTranscription factorsKey transcription factorMaster metabolic regulatorIon channel subunitsGap junction proteinTranscriptional reprogrammingAMPK deletionProtein kinaseBiological functionsTranscriptional downregulationMetabolic regulatorChannel subunitsIon channelsAMPK expressionMetabolic stressAtrial fibrillationAMPKJunction proteinsElectrical excitabilityHomeostatic roleStructural remodelingConnexinsAtrial ion channelsRemodelingDownregulationMuscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy
Riaz M, Park J, Sewanan LR, Ren Y, Schwan J, Das SK, Pomianowski PT, Huang Y, Ellis MW, Luo J, Liu J, Song L, Chen IP, Qiu C, Yazawa M, Tellides G, Hwa J, Young LH, Yang L, Marboe CC, Jacoby DL, Campbell SG, Qyang Y. Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy. Circulation 2022, 145: 1238-1253. PMID: 35384713, PMCID: PMC9109819, DOI: 10.1161/circulationaha.121.056265.Peer-Reviewed Original ResearchConceptsHypertrophic cardiomyopathySarcomeric mutationsFamilial hypertrophic cardiomyopathySudden cardiac deathCardiac myosin heavy chainMechanism-based treatmentsDevelopment of hypertrophyActivated T cellsCalcineurin-nuclear factorForce productionPhenotypic expressionPluripotent stem cell-derived cardiomyocytesStem cell-derived cardiomyocytesHeart failureCardiac deathVentricular hypertrophyCell-derived cardiomyocytesCardiac contractilityPharmacological interventionsT cellsCardiac diseaseCardiac hypertrophyPatient-specific induced pluripotent stem cellsPharmacological meansTwitch relaxationEfficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance
Spence JD, Viscoli C, Kernan WN, Young LH, Furie K, DeFronzo R, Abdul‐Ghani M, Dandona P, Inzucchi SE. Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance. Diabetes Obesity And Metabolism 2022, 24: 1150-1158. PMID: 35253334, DOI: 10.1111/dom.14687.Peer-Reviewed Original ResearchConceptsNew-onset diabetesAdjusted hazard ratioHazard ratioLow dosesAdverse effectsInsulin Resistance InterventionTransient ischemic attackSecondary prevention strategiesAnti-atherosclerotic propertiesInsulin-sensitizing drugsLess adverse effectsIschemic attackStudy drugHeart failureStroke trialsAdverse outcomesInsulin resistancePioglitazonePrevention strategiesHigh dosesResistance InterventionFull doseWeight gainDiabetesPatients
2021
Distinct Roles of Type I and Type III Interferons during a Native Murine β Coronavirus Lung Infection
Sharma L, Peng X, Qing H, Hilliard BK, Kim J, Swaminathan A, Tian J, Israni-Winger K, Zhang C, Habet V, Wang L, Gupta G, Tian X, Ma Y, Shin HJ, Kim SH, Kang MJ, Ishibe S, Young LH, Kotenko S, Compton S, Wilen CB, Wang A, Dela Cruz CS. Distinct Roles of Type I and Type III Interferons during a Native Murine β Coronavirus Lung Infection. Journal Of Virology 2021, 96: e01241-21. PMID: 34705554, PMCID: PMC8791255, DOI: 10.1128/jvi.01241-21.Peer-Reviewed Original ResearchConceptsType I interferonType III interferonsI interferonIII interferonsCoronavirus infectionInterferon deficiencyViral clearanceViral loadLung infectionType IHealthy young patientsImproved host survivalHost survivalRole of interferonMurine coronavirus infectionMajor health care threatViral burdenYounger patientsEarly diseaseIntranasal routeInterferon treatmentSublethal infectionEarly treatmentLethal infectionTissue injuryNAD 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 LettersRight Ventricular Fatty Infiltration With an Abnormal ECG
Odanovic N, Mojibian HR, Young LH. Right Ventricular Fatty Infiltration With an Abnormal ECG. JACC Case Reports 2021, 3: 314-318. PMID: 34317526, PMCID: PMC8310990, DOI: 10.1016/j.jaccas.2020.11.017.Peer-Reviewed Case Reports and Technical NotesFatty infiltrationCardiac magnetic resonance imagingArrhythmogenic right ventricular cardiomyopathyRight ventricular hypertrophyBenign clinical courseRight ventricular cardiomyopathyMiddle-aged womenMagnetic resonance imagingClinical courseVentricular hypertrophyVentricular thickeningRoutine electrocardiogramVentricular cardiomyopathyAbnormal ECGResonance imagingInfiltrationEchocardiogramPatientsCardiomyopathyHypertrophyElectrocardiogramWomen
2020
Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations
Kim AS, Henderson KJ, Pawar S, Kim MJ, Punjani S, Pollak JS, Fahey JT, Garcia‐Tsao G, Sugeng L, Young LH. Subaortic Membranes in Patients With Hereditary Hemorrhagic Telangiectasia and Liver Vascular Malformations. Journal Of The American Heart Association 2020, 9: e016197. PMID: 33054561, PMCID: PMC7763373, DOI: 10.1161/jaha.120.016197.Peer-Reviewed Original ResearchMeSH KeywordsActivin Receptors, Type IICardiac Output, HighDiscrete Subaortic StenosisEchocardiographyFemaleHeart Defects, CongenitalHeart FailureHumansLiverMaleMiddle AgedMutationPrognosisRetrospective StudiesSurvival AnalysisTelangiectasia, Hereditary HemorrhagicUnited StatesVascular MalformationsConceptsHigh-output cardiac failureHereditary hemorrhagic telangiectasiaLeft ventricular outflow tractVentricular outflow tractHemorrhagic telangiectasiaMild obstructionSubaortic membraneVascular malformationsOutflow tractActivin receptor-like kinase 1 mutationsHereditary hemorrhagic telangiectasia patientsLiver vascular malformationsMild aortic insufficiencyPulmonary artery pressureRight heart catheterizationCohort of patientsRetrospective observational analysisHigh cardiac outputKinase 1 mutationsArtery pressureHeart catheterizationPulmonary hypertensionAortic insufficiencyBackground PatientsTricuspid regurgitation
2019
Mitochondrial thioredoxin-2 maintains HCN4 expression and prevents oxidative stress-mediated sick sinus syndrome
Yang B, Huang Y, Zhang H, Huang Y, Zhou HJ, Young L, Xiao H, Min W. Mitochondrial thioredoxin-2 maintains HCN4 expression and prevents oxidative stress-mediated sick sinus syndrome. Journal Of Molecular And Cellular Cardiology 2019, 138: 291-303. PMID: 31751569, DOI: 10.1016/j.yjmcc.2019.10.009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBradycardiaCardiomyopathy, DilatedEnhancer Elements, GeneticHistone DeacetylasesHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsMEF2 Transcription FactorsMice, KnockoutMitochondria, HeartModels, BiologicalOxidative StressPhenotypeProtein BindingReactive Oxygen SpeciesRNA, MessengerSick Sinus SyndromeSinoatrial NodeThioredoxinsConceptsSick sinus syndromeSinus syndromeHistone deacetylase 4Lower heart rateHeart rateHCN4 expressionConduction systemSinoatrial nodeNormal heart rateCardiac conduction systemHistone 3 acetylationMitochondrial oxidative stressSinus bradycardiaCardiac functionLox/SyndromeHeart rhythmMyosin heavy chainHistological analysisMiceDeletion miceOxidative stressWhole heartProtein levelsUnderlying mechanismDiabetes prevention and cardiovascular complications
Inzucchi SE, Viscoli CM, Young LH, Kernan WN. Diabetes prevention and cardiovascular complications. Diabetologia 2019, 62: 2161-2162. PMID: 31522231, DOI: 10.1007/s00125-019-04999-3.Peer-Reviewed Original Research