Featured Publications
Impaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2
Wleklinski M, Kryshtal D, Kim K, Parikh S, Blackwell D, Marty I, Iyer V, Knollmann B. Impaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2. Circulation Research 2022, 131: 673-686. PMID: 36102198, PMCID: PMC9529867, DOI: 10.1161/circresaha.121.320661.Peer-Reviewed Original ResearchPatient-independent human induced pluripotent stem cell model: A new tool for rapid determination of genetic variant pathogenicity in long QT syndrome
Chavali NV, Kryshtal DO, Parikh SS, Wang L, Glazer AM, Blackwell DJ, Kroncke BM, Shoemaker MB, Knollmann BC. Patient-independent human induced pluripotent stem cell model: A new tool for rapid determination of genetic variant pathogenicity in long QT syndrome. Heart Rhythm 2019, 16: 1686-1695. PMID: 31004778, PMCID: PMC6935564, DOI: 10.1016/j.hrthm.2019.04.031.Peer-Reviewed Original ResearchConceptsLong QT syndromeExtracellular field potentialsQT syndromeHiPSC-CMGenetic testingPluripotent stem cell modelsHiPSC modelsSudden cardiac deathStem cell modelUnrelated healthy volunteersVentricular action potentialPatch-clamp studiesNovel missense variantVoltage-dependent inactivationCardiac deathClinical benefitCommercial genetic testingGenetic variant pathogenicityHealthy volunteersCell modelElectrophysiological propertiesAction potentialsBeating rateUnknown significancePatch clampThyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Parikh SS, Blackwell DJ, Gomez-Hurtado N, Frisk M, Wang L, Kim K, Dahl CP, Fiane A, Tønnessen T, Kryshtal DO, Louch WE, Knollmann BC. Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes. Circulation Research 2017, 121: 1323-1330. PMID: 28974554, PMCID: PMC5722667, DOI: 10.1161/circresaha.117.311920.Peer-Reviewed Original ResearchConceptsHuman-induced pluripotent stem cell-derived cardiomyocytesExcitation-contraction couplingPluripotent stem cell-derived cardiomyocytesCa releaseGlucocorticoid hormonesStem cell-derived cardiomyocytesCell-derived cardiomyocytesCa-induced Ca releaseT-tubule developmentAdult human ventricular cardiomyocytesExtensive T-tubule networkHuman ventricular cardiomyocytesL-type Ca channelsL-type CaT-tubulesIntracellular Ca releaseCell-based therapiesConfocal line scanHeart diseaseT-tubule networkFunctional maturationVentricular cardiomyocytesPermissive roleDay 16Ca channels
2023
Regulation of Postnatal Cardiomyocyte Maturation by an RNA Splicing Regulator RBFox1
Huang J, Lee J, Rau C, Pezhouman A, Yokota T, Miwa H, Feldman M, Kong T, Yang Z, Tay W, Pushkarsky I, Kim K, Parikh S, Udani S, Soh B, Gao C, Stiles L, Shirihai O, Knollmann B, Ardehali R, Di Carlo D, Wang Y. Regulation of Postnatal Cardiomyocyte Maturation by an RNA Splicing Regulator RBFox1. Circulation 2023, 148: 1263-1266. PMID: 37844148, PMCID: PMC10593507, DOI: 10.1161/circulationaha.122.061602.Peer-Reviewed Original Research
2022
Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization
Bersell K, Yang T, Mosley J, Glazer A, Hale A, Kryshtal D, Kim K, Steimle J, Brown J, Salem J, Campbell C, Hong C, Wells Q, Johnson A, Short L, Blair M, Behr E, Petropoulou E, Jamshidi Y, Benson M, Keyes M, Ngo D, Vasan R, Yang Q, Gerszten R, Shaffer C, Parikh S, Sheng Q, Kannankeril P, Moskowitz I, York J, Wang T, Knollmann B, Roden D. Transcriptional Dysregulation Underlies Both Monogenic Arrhythmia Syndrome and Common Modifiers of Cardiac Repolarization. Circulation 2022, 147: 824-840. PMID: 36524479, PMCID: PMC9992308, DOI: 10.1161/circulationaha.122.062193.Peer-Reviewed Original ResearchConceptsPlatelet-derived growth factorInduced pluripotent stem cellsBrugada syndromeArrhythmia syndromesSerum platelet-derived growth factorSodium currentGeneral transcriptional mechanismFramingham Heart Study cohortPI3KPDGF receptor expressionLate sodium currentCardiac sodium currentCardiac transcription factorsSmall molecule perturbationsCurrent-clamp experimentsCardiac sodium channel geneSodium channel geneFramingham Heart StudyMurine model systemPluripotent stem cellsMonogenic arrhythmia syndromesReceptor blockadeElectrophysiologic abnormalitiesQTc intervalStudy cohortAutosomal dominant CPVT2 is caused by impaired dynamic calcium buffering in the sarcoplasmic reticulum
Wleklinski M, Parikh S, Kryshtal D, Knollmann B. Autosomal dominant CPVT2 is caused by impaired dynamic calcium buffering in the sarcoplasmic reticulum. Biophysical Journal 2022, 121: 12a-13a. DOI: 10.1016/j.bpj.2021.11.2644.Peer-Reviewed Original Research
2021
Autosomal-Dominant CASQ2-K180R Causes CPVT by Altering Intra-SR Calcium Buffering without Reducing Casq2 Protein Levels
Wleklinski M, Parikh S, Blackwell D, Knollmann B. Autosomal-Dominant CASQ2-K180R Causes CPVT by Altering Intra-SR Calcium Buffering without Reducing Casq2 Protein Levels. Biophysical Journal 2021, 120: 238a-239a. DOI: 10.1016/j.bpj.2020.11.1572.Peer-Reviewed Original Research
2020
Autosomal-dominant CASQ2-K180R Causes CPVT by a Different Mechanism than Autosomal-recessive Casq2 Mutations
Wleklinski M, Parikh S, Knollmann B. Autosomal-dominant CASQ2-K180R Causes CPVT by a Different Mechanism than Autosomal-recessive Casq2 Mutations. Biophysical Journal 2020, 118: 101a. DOI: 10.1016/j.bpj.2019.11.709.Peer-Reviewed Original Research
2019
An Autosomal Dominant Mutation in Calsequestrin 2 Causes CPVT Without Changing Protein Levels
Wleklinski M, Parikh S, Knollmann B. An Autosomal Dominant Mutation in Calsequestrin 2 Causes CPVT Without Changing Protein Levels. Biophysical Journal 2019, 116: 95a-96a. DOI: 10.1016/j.bpj.2018.11.556.Peer-Reviewed Original ResearchEstablishing Pathogenicity of Novel LQTS8 Variant via Genomic Editing of Human iPSC
Kryshtal D, Chavali N, Parikh S, Wang L, Glazer A, Shoemaker M, Knollmann B. Establishing Pathogenicity of Novel LQTS8 Variant via Genomic Editing of Human iPSC. Biophysical Journal 2019, 116: 99a. DOI: 10.1016/j.bpj.2018.11.573.Peer-Reviewed Original Research
2018
Cardiomyocyte-specific deletion of GSK-3β leads to cardiac dysfunction in a diet induced obesity model
Gupte M, Tumuluru S, Sui JY, Singh AP, Umbarkar P, Parikh SS, Ahmad F, Zhang Q, Force T, Lal H. Cardiomyocyte-specific deletion of GSK-3β leads to cardiac dysfunction in a diet induced obesity model. International Journal Of Cardiology 2018, 259: 145-152. PMID: 29398139, PMCID: PMC5869114, DOI: 10.1016/j.ijcard.2018.01.013.Peer-Reviewed Original ResearchConceptsHigh-fat dietAdverse ventricular remodelingCardiac dysfunctionCardiac functionVentricular remodelingBody weightGSK-3βControl dietHeart weight/tibia lengthDiet-induced cardiac dysfunctionIndependent risk factorImpaired cardiac functionSevere cardiac dysfunctionFat mass compositionLittermate control miceProtective compensatory mechanismCardiomyocyte-specific deletionComparable body weightTibia lengthTransthoracic echocardiographyControl miceObesity modelRisk factorsMyocardial diseaseDysfunctionHigh-Throughput Investigation of Contractile and Electrophysiological Properties of Optically Stimulated hiPSC-CM Monolayers
Parikh S, Chavali N, Glazer A, Shaffer C, Blair M, Roden D, Knollmann B. High-Throughput Investigation of Contractile and Electrophysiological Properties of Optically Stimulated hiPSC-CM Monolayers. Biophysical Journal 2018, 114: 384a. DOI: 10.1016/j.bpj.2017.11.2122.Peer-Reviewed Original ResearchImproved Calcium Handling in Human Induced Pluripotent Stem Cell Cardiomyocytes
Blackwell D, Parikh S, Gomez-hurtado N, Knollmann B. Improved Calcium Handling in Human Induced Pluripotent Stem Cell Cardiomyocytes. Biophysical Journal 2018, 114: 288a. DOI: 10.1016/j.bpj.2017.11.1651.Peer-Reviewed Original Research
2017
Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes
Wang L, Kim K, Parikh S, Cadar AG, Bersell KR, He H, Pinto JR, Kryshtal DO, Knollmann BC. Hypertrophic cardiomyopathy-linked mutation in troponin T causes myofibrillar disarray and pro-arrhythmic action potential changes in human iPSC cardiomyocytes. Journal Of Molecular And Cellular Cardiology 2017, 114: 320-327. PMID: 29217433, PMCID: PMC5800960, DOI: 10.1016/j.yjmcc.2017.12.002.Peer-Reviewed Original ResearchConceptsMyofilament Ca sensitivityHiPSC-CMsControl hiPSC-CMsCa handlingTroponin TAction potentialsAction potential triangulationPro-arrhythmic changesCa sensitivityHuman ventricular action potentialCardiac troponin TAction potential changesIntracellular Ca transientsVentricular action potentialHuman iPSC-cardiomyocytesRod-shaped cardiomyocytesCardiac action potentialDiastolic dysfunctionImpaired relaxationSystolic functionVentricular arrhythmiasHypertrophic cardiomyopathySudden deathArrhythmia riskCardiac hypertrophyMyofilament Calcium-Buffering Dependent Action Potential Triangulation in Human-Induced Pluripotent Stem Cell Model of Hypertrophic Cardiomyopathy
Wang L, Kryshtal DO, Kim K, Parikh S, Cadar AG, Bersell KR, He H, Pinto JR, Knollmann BC. Myofilament Calcium-Buffering Dependent Action Potential Triangulation in Human-Induced Pluripotent Stem Cell Model of Hypertrophic Cardiomyopathy. Journal Of The American College Of Cardiology 2017, 70: 2600-2602. PMID: 29145956, PMCID: PMC5805484, DOI: 10.1016/j.jacc.2017.09.033.Peer-Reviewed Original ResearchFrequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration
Patterson M, Barske L, Van Handel B, Rau CD, Gan P, Sharma A, Parikh S, Denholtz M, Huang Y, Yamaguchi Y, Shen H, Allayee H, Crump JG, Force TI, Lien CL, Makita T, Lusis AJ, Kumar SR, Sucov HM. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nature Genetics 2017, 49: 1346-1353. PMID: 28783163, PMCID: PMC5736145, DOI: 10.1038/ng.3929.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, Genetically ModifiedCells, CulturedDiploidyGene Expression ProfilingHeartImmunoblottingIn Situ Hybridization, FluorescenceMice, Inbred C57BLMice, KnockoutMice, TransgenicMicroscopy, ConfocalMyocardiumMyocytes, CardiacProtein KinasesProtein Serine-Threonine KinasesRegenerationZebrafishGeneration and Characterization of a Human iPSC Cardiomyocyte Model of Troponin T I79N Linked Hypertrophic Cardiomyopathy
Wang L, Kryshtal D, Kim K, Parikh S, Bersell K, Pinto J, He H, Knollmann B. Generation and Characterization of a Human iPSC Cardiomyocyte Model of Troponin T I79N Linked Hypertrophic Cardiomyopathy. Biophysical Journal 2017, 112: 100a. DOI: 10.1016/j.bpj.2016.11.577.Peer-Reviewed Original Research
2016
Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy
Zhou J, Ahmad F, Parikh S, Hoffman NE, Rajan S, Verma VK, Song J, Yuan A, Shanmughapriya S, Guo Y, Gao E, Koch W, Woodgett JR, Madesh M, Kishore R, Lal H, Force T. Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy. Circulation Research 2016, 118: 1208-1222. PMID: 26976650, PMCID: PMC4843504, DOI: 10.1161/circresaha.116.308544.Peer-Reviewed Original ResearchConceptsAdult cardiac myocytesCardiac myocytesCardiac homeostasisGSK-3βSerial echocardiographic analysisCardiac myocyte-specific deletionGSK-3Normal cardiac homeostasisMitotic catastropheCell cycle dysregulationDouble knockout heartsVentricular dysfunctionOverall survivalTamoxifen treatmentCardiac protectionMyocardial infarctionEchocardiographic analysisHeart functionGlycogen synthase kinaseIsolated adult cardiac myocytesSynergistic protectionGSK-3 isoformsCell cycle activityMarked activationCell cycle progression
2014
Troponin I-Interacting Protein Kinase
Lal H, Ahmad F, Parikh S, Force T. Troponin I-Interacting Protein Kinase. Circulation Journal 2014, 78: 1514. PMID: 24899531, PMCID: PMC4151348, DOI: 10.1253/circj.cj-14-0543.Peer-Reviewed Original ResearchConceptsIR injuryMyocardial infarctionCardiomyocyte deathNew drug targetsNovel genetic animal modelsEffective myocardial reperfusionAcute coronary syndromeIschemia-reperfusion injuryPercutaneous coronary interventionCoronary artery diseaseCause of deathProfound oxidative stressPromising new drug targetGenetic animal modelsCardiac troponin ITNNI3KDrug targetsCoronary syndromeCoronary interventionArtery diseaseMyocardial reperfusionReperfusion injuryCardiac dysfunctionIschemic injuryInfarct size