2024
Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants
Halder S, Rynkiewicz M, Kim L, Barry M, Zied A, Sewanan L, Kirk J, Moore J, Lehman W, Campbell S. Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy associated TPM1 variants. Journal Of Clinical Investigation 2024 PMID: 39436707, DOI: 10.1172/jci179135.Peer-Reviewed Original ResearchTPM1 mutationActin thin filamentsDilated cardiomyopathyE54KPhenotypic diversityMyosin activityStem cell-derived cardiomyocytesGene expressionHuman engineered heart tissueIncreased calcium sensitivitySarcomeric proteinsCell-derived cardiomyocytesThin filamentsK mutationMolecular eventsTPM1MutationsClinical phenotypePhenotypeAllosteric interactionsGenesMuscle contractilityCalcium sensitivityInherited disorderAssociation rateIn silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R
Creso J, Gokhan I, Rynkiewicz M, Lehman W, Moore J, Campbell S. In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R. Frontiers In Physiology 2024, 15: 1452509. PMID: 39282088, PMCID: PMC11392859, DOI: 10.3389/fphys.2024.1452509.Peer-Reviewed Original ResearchDilated cardiomyopathyManifestation of dilated cardiomyopathyTropomyosin-actin interactionsIntact cardiac muscleIsometric twitch forceCardiac muscle disordersSevere heart failureHuman engineered heart tissueGenotype-phenotype relationshipsDose-dependent mannerDuration of contractionIn silico predictionIn vitro modelDepressed contractilityMutant tissueCardiac sarcomereLinkage studiesHeart failureTropomyosin chainTwitch contractionsCardiac thin filamentsInherited disorderMuscle disordersMutation pathogenicityCardiac muscleEngineered heart tissue: Design considerations and the state of the art
Gokhan I, Blum T, Campbell S. Engineered heart tissue: Design considerations and the state of the art. Biophysics Reviews 2024, 5: 021308. PMID: 38912258, PMCID: PMC11192576, DOI: 10.1063/5.0202724.Peer-Reviewed Original ResearchDifferent mechanistic and molecular cues modulate divergent phenotypes in HCM and DCM mutations to TPM1
Halder S, Rynkiewicz M, Moore J, Lehman W, Campbell S. Different mechanistic and molecular cues modulate divergent phenotypes in HCM and DCM mutations to TPM1. Biophysical Journal 2024, 123: 18a. DOI: 10.1016/j.bpj.2023.11.222.Peer-Reviewed Original ResearchContractile phenotypes of engineered heart tissues derived from hypertrophic cardiomyopathy patients lacking sarcomeric mutations
Rasheed Y, Young S, Halder S, Li X, Stendahl J, Campbell S. Contractile phenotypes of engineered heart tissues derived from hypertrophic cardiomyopathy patients lacking sarcomeric mutations. Biophysical Journal 2024, 123: 388a. DOI: 10.1016/j.bpj.2023.11.2357.Peer-Reviewed Original ResearchTTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance
Hinson J, Campbell S. TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance. Journal Of Clinical Investigation 2024, 134: e175206. PMID: 38226618, PMCID: PMC10786689, DOI: 10.1172/jci175206.Peer-Reviewed Original ResearchConceptsTruncating variantsSubcellular localizationTitin truncating variantsComplex proteinsSarcomere integrityGenetic lesionsTitin proteinDilated cardiomyopathyFunctional consequencesProteinVariable penetranceSarcomeric dysfunctionImpaired cardiac contractilityTitinSarcomeric structural integrityAlternative therapeutic approachCardiac contractilityVariantsPotential mechanismsTherapeutic approachesHaploinsufficiencyDCM samplesClassifying pathogenicity of TPM1 variants of unknown significance using in vitro and in silico approaches
Campbell S, Creso J, Firlar I, Halder S, Lehman W, Rynkiewicz M, Moore J. Classifying pathogenicity of TPM1 variants of unknown significance using in vitro and in silico approaches. Journal Of Cardiac Failure 2024, 30: s3. DOI: 10.1016/j.cardfail.2023.11.005.Peer-Reviewed Original ResearchHypertrophic cardiomyopathyUnknown significanceContractile forceOngoing clinical challengeFirst-degree relativesGenetic testing yieldSlowing of relaxationViral exposureContractile weaknessClinical challengeHypercontractile phenotypeHCM mutationsMyofilament activityHeart tissueMild phenotypeFurther studiesContractile behaviorSignificant increaseHEHTTesting yieldDCM mutationsMinimal effectVUSPathogenicityPhenotype
2023
Rational engineering of lung alveolar epithelium
Leiby K, Yuan Y, Ng R, Raredon M, Adams T, Baevova P, Greaney A, Hirschi K, Campbell S, Kaminski N, Herzog E, Niklason L. Rational engineering of lung alveolar epithelium. Npj Regenerative Medicine 2023, 8: 22. PMID: 37117221, PMCID: PMC10147714, DOI: 10.1038/s41536-023-00295-2.Peer-Reviewed Original ResearchMulti-scale modeling will unravel connections between sarcomeric mutations and cardiomyopathies
Campbell S, Moore J, Rynkiewicz M, Lehman W. Multi-scale modeling will unravel connections between sarcomeric mutations and cardiomyopathies. Journal Of Molecular And Cellular Cardiology Plus 2023, 3: 100025. DOI: 10.1016/j.jmccpl.2022.100025.Peer-Reviewed Original ResearchMechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L
Halder S, Rynkiewicz M, Creso J, Sewanan L, Howland L, Moore J, Lehman W, Campbell S. Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L. PNAS Nexus 2023, 2: pgad011. PMID: 36896133, PMCID: PMC9991458, DOI: 10.1093/pnasnexus/pgad011.Peer-Reviewed Original ResearchIncreased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy
Rupert C, López J, Cortez-Toledo E, De la Cruz Cabrera O, Chesler N, Simpson P, Campbell S, Baker A. Increased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy. AJP Heart And Circulatory Physiology 2023, 324: h293-h304. PMID: 36637971, PMCID: PMC9886349, DOI: 10.1152/ajpheart.00279.2022.Peer-Reviewed Original ResearchConceptsHuman heart failureHeart failureAR stimulationChronic stimulationLength-dependent activationVehicle treatmentHeart tissueAdrenergic receptorsHuman EHTsAnimal heart failure modelNovel heart failure therapiesHeart failure therapyHeart failure modelMultiple preclinical modelsFailure therapyAgonist treatmentSeparate control experimentsPreclinical modelsDrug washoutTherapeutic effectTranslational significanceHuman myocardiumBaseline testingRNA-seq analysisPig myocardium
2022
Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy
Khalilimeybodi A, Riaz M, Campbell S, Omens J, McCulloch A, Qyang Y, Saucerman J. Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy. Journal Of Molecular And Cellular Cardiology 2022, 174: 1-14. PMID: 36370475, PMCID: PMC10230857, DOI: 10.1016/j.yjmcc.2022.10.006.Peer-Reviewed Original ResearchHumanized 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 penetrancePhysiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue
Shen S, Sewanan LR, Shao S, Halder SS, Stankey P, Li X, Campbell SG. Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue. Stem Cell Reports 2022, 17: 2037-2049. PMID: 35931080, PMCID: PMC9481907, DOI: 10.1016/j.stemcr.2022.07.006.Peer-Reviewed Original ResearchConceptsHuman-induced pluripotent stem cell-derived cardiomyocytesWide potential applicationsRegenerative medicineScalable platformElectrical pacingPotential applicationsForce-frequency behaviorCardiac troponin IPluripotent stem cell-derived cardiomyocytesStem cell-derived cardiomyocytesAdrenergic responseCell-derived cardiomyocytesFunctional maturationHiPSC-CM maturationTroponin IClinical researchTwitch kineticsHeart tissuePhysiological CaPacingPhysiological calciumApplicationsBasic researchRole of CaMaturationMuscle 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 relaxationGSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation
Stachowski-Doll MJ, Papadaki M, Martin TG, Ma W, Gong HM, Shao S, Shen S, Muntu NA, Kumar M, Perez E, Martin JL, Moravec CS, Sadayappan S, Campbell SG, Irving T, Kirk JA. GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation. Circulation Research 2022, 130: 871-886. PMID: 35168370, PMCID: PMC8930626, DOI: 10.1161/circresaha.121.319491.Peer-Reviewed Original ResearchConceptsZ-discGSK-3βZ-disc proteinsCardiac Z-diskLength-dependent activationKnockout miceKinase localizationPhosphorylation sitesNegative regulatorGenetic knockdownVivo roleDependent activationNeonatal rat ventricular cardiomyocytesNovel mechanismGSK-3β levelsHeart failureMyofilament localizationTitin phosphorylationVentricular myocardiumPossible therapeutic targetTitin isoformsTitin stiffnessTherapeutic targetPassive tensionHuman heartIncreased length-dependent activation of human engineered heart tissue after chronic treatment with alpha-1A-adrenergic agonist
Rupert C, Cortez-Toledo E, Lopez J, Chesler N, Simpson P, Campbell S, Baker A. Increased length-dependent activation of human engineered heart tissue after chronic treatment with alpha-1A-adrenergic agonist. Biophysical Journal 2022, 121: 397a-398a. DOI: 10.1016/j.bpj.2021.11.785.Peer-Reviewed Original ResearchGlycogen synthase kinase 3β localizes to the Z-disc to maintain length dependent activation
Stachowski M, Papadaki M, Martin T, Ma W, Gong H, Shao S, Shen S, Muntu N, Martin J, Moravec C, Campbell S, Irving T, Kirk J. Glycogen synthase kinase 3β localizes to the Z-disc to maintain length dependent activation. Biophysical Journal 2022, 121: 395a. DOI: 10.1016/j.bpj.2021.11.774.Peer-Reviewed Original ResearchEngineered Lung Tissues Prepared from Decellularized Lung Slices
Leiby K, Ng R, Campbell S, Niklason L. Engineered Lung Tissues Prepared from Decellularized Lung Slices. Journal Of Visualized Experiments 2022 DOI: 10.3791/63151-v.Peer-Reviewed Original Research
2021
MAVACAMTEN PRESERVED LENGTH-DEPENDENT CONTRACTILITY AND IMPROVED DIASTOLIC FUNCTION IN HUMAN ENGINEERED MYOCARDIUM
Sewanan L, Shen S, Campbell S. MAVACAMTEN PRESERVED LENGTH-DEPENDENT CONTRACTILITY AND IMPROVED DIASTOLIC FUNCTION IN HUMAN ENGINEERED MYOCARDIUM. Journal Of The American College Of Cardiology 2021, 77: 536. DOI: 10.1016/s0735-1097(21)01895-7.Peer-Reviewed Original Research