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 tissue
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 InterventionMuscle 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
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
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
Diabetes 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 ResearchCardiomyocyte d-dopachrome tautomerase protects against heart failure
Ma Y, Su KN, Pfau D, Rao VS, Wu X, Hu X, Leng L, Du X, Piecychna M, Bedi K, Campbell SG, Eichmann A, Testani JM, Margulies KB, Bucala R, Young LH. Cardiomyocyte d-dopachrome tautomerase protects against heart failure. JCI Insight 2019, 4: e128900. PMID: 31484822, PMCID: PMC6777911, DOI: 10.1172/jci.insight.128900.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalciumCardiomegalyCytokinesDisease Models, AnimalEchocardiographyGene DeletionGene ExpressionGenetic Predisposition to DiseaseHeart FailureHumansIntramolecular OxidoreductasesMaleMAP Kinase Kinase KinasesMiceMice, Inbred C57BLMice, KnockoutMyocytes, CardiacRecombinant ProteinsSignal TransductionTranscriptomeVascular Endothelial Growth Factor AConceptsTransverse aortic constrictionHeart failureRecombinant DDTConnective tissue growth factor expressionTissue growth factor expressionMore interstitial fibrosisAdvanced heart failureCardiac pressure overloadExperimental heart failureCardiac contractile dysfunctionLittermate control miceSmad-2 activationGrowth factor expressionSarcoplasmic reticulum calcium ATPaseMacrophage migration inhibitory factor (MIF) familyReticulum calcium ATPasePulmonary edemaCardiac dilatationContractile dysfunctionControl miceInterstitial fibrosisPressure overloadAntifibrotic actionAortic constrictionLow VEGFGDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance
Luan HH, Wang A, Hilliard B, Carvalho F, Rosen CE, Ahasic A, Herzog E, Kang I, Pisani MA, Yu S, Zhang C, Ring A, Young L, Medzhitov R. GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance. Cell 2019, 178: 1231-1244.e11. PMID: 31402172, PMCID: PMC6863354, DOI: 10.1016/j.cell.2019.07.033.Peer-Reviewed Original ResearchConceptsViral infectionTriglyceride metabolismImpaired cardiac functionRole of GDF15Differentiation factor 15Plasma triglyceride levelsSympathetic outflowInflammatory damageTriglyceride levelsCardiac functionInflammatory responseExogenous administrationProtective effectFactor 15GDF15Central mediatorTissue toleranceBody temperatureInfectionMetabolismSepsisInflammationAdministrationHormonePresentation of Liver Failure From a Pericardial Mass
Nguyen VQ, Workman V, Stendahl K, Young L, Sklar J, Baldassarre LA. Presentation of Liver Failure From a Pericardial Mass. Circulation Cardiovascular Imaging 2019, 12: e008672. PMID: 31167559, DOI: 10.1161/circimaging.118.008672.Peer-Reviewed Case Reports and Technical NotesPioglitazone Therapy in Patients With Stroke and Prediabetes
Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, Furie KL, Lovejoy AM, Young LH, Kernan WN. Pioglitazone Therapy in Patients With Stroke and Prediabetes. JAMA Neurology 2019, 76: 526-535. PMID: 30734043, PMCID: PMC6515584, DOI: 10.1001/jamaneurol.2019.0079.Peer-Reviewed Original ResearchMeSH KeywordsAcute Coronary SyndromeAgedDiabetes Mellitus, Type 2Disease ProgressionFemaleGlycated HemoglobinHeart FailureHospitalizationHumansHypoglycemic AgentsInsulin ResistanceMaleMedication AdherenceMiddle AgedMyocardial InfarctionPioglitazonePrediabetic StateProportional Hazards ModelsRecurrenceSecondary PreventionStrokeConceptsAcute coronary syndromeStroke/myocardial infarctionTransient ischemic attackMyocardial infarctionCoronary syndromeHeart failureIRIS trialInsulin resistanceGood adherenceIschemic attackRecurrent strokeHazard ratioClinical trialsStroke/transient ischemic attackRandomized multicenter clinical trialAmerican Diabetes Association criteriaInsulin Resistance InterventionHemoglobin A1c levelsEffect of pioglitazoneInsulin-sensitizing agentsMulticenter clinical trialPlasma glucose levelsSerious bone fracturesPlacebo cohortPrior strokeAchievement of Guideline-Recommended Weight Loss Among Patients With Ischemic Stroke and Obesity
Dearborn JL, Viscoli CM, Young LH, Gorman MJ, Furie KL, Kernan WN. Achievement of Guideline-Recommended Weight Loss Among Patients With Ischemic Stroke and Obesity. Stroke 2019, 50: 713-717. PMID: 30786849, PMCID: PMC6391736, DOI: 10.1161/strokeaha.118.024008.Peer-Reviewed Original ResearchConceptsTransient ischemic attackBody mass indexProportion of patientsIschemic strokeMass indexVascular eventsBaseline weightWeight lossAchievement of guidelineDays of randomizationRecent ischemic strokeAcute ischemic strokeFuture vascular eventsIschemic attackPlacebo groupObese patientsDiabetes mellitusMedian ageTrial entryIRIS trialMedian timeFunctional outcomeInsulin resistanceClinical trialsPatients
2018
Metabolic syndrome identifies normal weight insulin-resistant stroke patients at risk for recurrent vascular disease
Dearborn JL, Viscoli CM, Inzucchi SE, Young LH, Kernan WN. Metabolic syndrome identifies normal weight insulin-resistant stroke patients at risk for recurrent vascular disease. International Journal Of Stroke 2018, 14: 639-645. PMID: 30507360, DOI: 10.1177/1747493018816425.Peer-Reviewed Original ResearchConceptsNormal weight patientsMetabolic syndromeMyocardial infarctionWeight patientsCause mortalityInsulin resistanceHigh riskInsulin Resistance InterventionRecent ischemic strokeRecurrent vascular diseaseNon-diabetic patientsTransient ischemic attackAdverse cardiovascular outcomesMajor comorbid conditionsIschemic attackCardiovascular outcomesObesity paradoxIschemic strokeNormal BMIObese patientsStroke populationBetter prognosisComorbid conditionsNormal weightStroke patientsMacrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy
Cui D, Peng Y, Zhang C, Li Z, Su Y, Qi Y, Xing M, Li J, Kim GE, Su KN, Xu J, Wang M, Ding W, Piecychna M, Leng L, Hirasawa M, Jiang K, Young L, Xu Y, Qi D, Bucala R. Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy. Journal Of Clinical Investigation 2018, 128: 4997-5007. PMID: 30295645, PMCID: PMC6205380, DOI: 10.1172/jci93090.Peer-Reviewed Original ResearchConceptsMacrophage migration inhibitory factorAtypical antipsychotic therapyMIF expressionMigration inhibitory factorInsulin resistanceAntipsychotic therapyAtypical antipsychoticsMetabolic dysfunctionOlanzapine-induced insulin resistanceInhibitory factorDrug-naive schizophrenic patientsMetabolic side effectsPlasma lipid concentrationsAbnormal fat depositionAdverse metabolic sequelaeMIF concentrationsOlanzapine monotherapyMetabolic sequelaeOlanzapine administrationIntracerebroventricular injectionMIF antibodyFood intakeClinical utilitySchizophrenic patientsSide effectsHeart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With Pioglitazone
Young LH, Viscoli CM, Schwartz GG, Inzucchi SE, Curtis JP, Gorman MJ, Furie KL, Conwit R, Spatz E, Lovejoy A, Abbott JD, Jacoby DL, Kolansky DM, Ling FS, Pfau SE, Kernan WN. Heart Failure After Ischemic Stroke or Transient Ischemic Attack in Insulin-Resistant Patients Without Diabetes Mellitus Treated With Pioglitazone. Circulation 2018, 138: 1210-1220. PMID: 29934374, PMCID: PMC6202153, DOI: 10.1161/circulationaha.118.034763.Peer-Reviewed Original ResearchConceptsRisk of HFTransient ischemic attackEffect of pioglitazoneHF riskHeart failureInsulin-resistant patientsMyocardial infarctionIschemic attackCardiovascular benefitsIschemic strokeDiabetes mellitusInsulin resistanceHigher C-reactive proteinComposite of strokeHF risk scoreHigher HF riskDrug dose reductionHospitalized heart failureIncident myocardial infarctionLower mean doseC-reactive proteinBaseline patient featuresHF hospitalizationCardiovascular eventsPlacebo groupEvolution of Intrahepatic Shunts in a Patient With Hereditary Hemorrhagic Telangiectasia.
Haghighat L, Brandt EJ, Proctor DD, Garcia-Tsao G, Pollak J, Young L. Evolution of Intrahepatic Shunts in a Patient With Hereditary Hemorrhagic Telangiectasia. Annals Of Internal Medicine 2018, 169: 508-509. PMID: 29868721, DOI: 10.7326/l18-0036.Peer-Reviewed Case Reports and Technical Notes
2017
Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction
Kernan WN, Viscoli CM, Dearborn JL, Kent DM, Conwit R, Fayad P, Furie KL, Gorman M, Guarino PD, Inzucchi SE, Stuart A, Young LH. Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction. JAMA Neurology 2017, 74: 1319-1327. PMID: 28975241, PMCID: PMC5710663, DOI: 10.1001/jamaneurol.2017.2136.Peer-Reviewed Original ResearchConceptsTransient ischemic attackIschemic attackMyocardial infarctionIschemic strokeHigh riskPioglitazone groupInsulin resistanceLower riskCox proportional hazards regression modelProportional hazards regression modelsMedian riskEfficacy of pioglitazoneInsulin Resistance InterventionQualifying ischemic strokePlacebo-controlled trialHazards regression modelsLow baseline riskType 2 diabetesGreater absolute benefitDay of entryFuture strokeHydrochloride therapyPlacebo groupHazard ratioSecondary preventionPioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke
Yaghi S, Furie KL, Viscoli CM, Kamel H, Gorman M, Dearborn J, Young LH, Inzucchi SE, Lovejoy AM, Kasner SE, Conwit R, Kernan WN. Pioglitazone Prevents Stroke in Patients With a Recent Transient Ischemic Attack or Ischemic Stroke. Circulation 2017, 137: 455-463. PMID: 29084736, DOI: 10.1161/circulationaha.117.030458.Peer-Reviewed Original ResearchConceptsTransient ischemic attackIschemic strokeIschemic attackNondiabetic patientsStroke outcomeStroke eventsInsulin resistanceRecent transient ischemic attackCox proportional hazards modelQualifying ischemic strokeEffect of pioglitazoneFirst stroke eventProportional hazards modelPrevents strokeHemorrhagic eventsComposite outcomeSecondary preventionRecent strokeIRIS trialMyocardial infarctionTreatment groupsHazards modelPioglitazoneConsensus criteriaSurvival analysis