2022
Sarcomere protein modulation: The new frontier in cardiovascular medicine and beyond
Morelli C, Ingrasciotta G, Jacoby D, Masri A, Olivotto I. Sarcomere protein modulation: The new frontier in cardiovascular medicine and beyond. European Journal Of Internal Medicine 2022, 102: 1-7. PMID: 35534374, DOI: 10.1016/j.ejim.2022.04.020.Peer-Reviewed Original ResearchConceptsHeart failureCardiovascular medicineVentricular outflow obstructionHeart muscle diseaseDegenerative neuromuscular diseaseSpecific disease mechanismsCardiovascular deathOutflow obstructionSystolic functionRandomized trialsUnderlying pathophysiologyCardiac patientsOmecamtiv mecarbilHypertrophic cardiomyopathyFunctional capacityNeuromuscular diseaseMuscle diseaseAvailable evidenceContractile proteinsSkeletal muscleTranslational researchPromising targetDiseaseDisease mechanismsFailure
2021
Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy
Hegde SM, Lester SJ, Solomon SD, Michels M, Elliott PM, Nagueh SF, Choudhury L, Zemanek D, Zwas DR, Jacoby D, Wang A, Ho CY, Li W, Sehnert AJ, Olivotto I, Abraham TP. Effect of Mavacamten on Echocardiographic Features in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy. Journal Of The American College Of Cardiology 2021, 78: 2518-2532. PMID: 34915982, DOI: 10.1016/j.jacc.2021.09.1381.Peer-Reviewed Original ResearchConceptsObstructive hypertrophic cardiomyopathySystolic anterior motionAnterior motionDiastolic functionHypertrophic cardiomyopathyN-terminal pro-B-type natriuretic peptideMitral valve systolic anterior motionPro-B-type natriuretic peptidePeak exercise oxygen consumptionLeft ventricular diastolic functionVentricular outflow tract obstructionKey echocardiographic parametersAtrial volume indexOutflow tract obstructionVentricular diastolic functionExercise oxygen consumptionEffect of mavacamtenMyocardial wall stressEXPLORER-HCMLVOT gradientEchocardiographic featuresEchocardiographic parametersLVOT obstructionTract obstructionExercise capacityLoss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation
Sewanan LR, Park J, Rynkiewicz MJ, Racca AW, Papoutsidakis N, Schwan J, Jacoby DL, Moore JR, Lehman W, Qyang Y, Campbell SG. Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation. The Journal Of General Physiology 2021, 153: e202012640. PMID: 34319370, PMCID: PMC8321830, DOI: 10.1085/jgp.202012640.Peer-Reviewed Original ResearchConceptsHypertrophic cardiomyopathyHeart tissueCellular hypertrophyEngineered Heart TissuePathological cardiac hypertrophyThin filament mutationsMavacamten treatmentDiastolic dysfunctionDisease featuresHypertrophic effectCardiac hypertrophyContractile differencesHypertrophyFundamental disease mechanismsCrossbridge activityInherited disorderOverall Ca2Uncertain significancePatient phenotypesDisease mechanismsLow Ca2PatientsK mutationMavacamtenTissue
2020
Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy
Lakdawala NK, Olivotto I, Day SM, Han L, Ashley EA, Michels M, Ingles J, Semsarian C, Jacoby D, Jefferies JL, Colan SD, Pereira AC, Rossano JW, Wittekind S, Ware JS, Saberi S, Helms AS, Cirino AL, Leinwand LA, Seidman CE, Ho CY. Associations Between Female Sex, Sarcomere Variants, and Clinical Outcomes in Hypertrophic Cardiomyopathy. Circulation Genomic And Precision Medicine 2020, 14: e003062. PMID: 33284039, DOI: 10.1161/circgen.120.003062.Peer-Reviewed Original ResearchConceptsHypertrophic cardiomyopathyClinical outcomesNew York Heart Association IIIImplantable cardioverter-defibrillator utilizationSevere heart failure symptomsHeart failure symptomsReduced ejection fractionRetrospective cohort studyImpact of sexSex-based differencesHCM centersCause mortalityTract obstructionBaseline characteristicsCohort studyEjection fractionHeart failureVentricular arrhythmiasFemale sexHCM patientsMyocardial performanceFailure symptomsInternational registrySarcomere variantsHigh burdenMavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial
Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, Kubanek M, Wojakowski W, Jensen MK, Gimeno-Blanes J, Afshar K, Myers J, Hegde SM, Solomon SD, Sehnert AJ, Zhang D, Li W, Bhattacharya M, Edelberg JM, Waldman CB, Lester SJ, Wang A, Ho CY, Jacoby D, investigators E, Bartunek J, Bondue A, Van Craenenbroeck E, Kubanek M, Zemanek D, Jensen M, Mogensen J, Thune J, Charron P, Hagege A, Lairez O, Trochu J, Axthelm C, Duengen H, Frey N, Mitrovic V, Preusch M, Schulz-Menger J, Seidler T, Arad M, Halabi M, Katz A, Monakier D, Paz O, Viskin S, Zwas D, Olivotto I, Rocca H, Michels M, Dudek D, Oko-Sarnowska Z, Oreziak A, Wojakowski W, Cardim N, Pereira H, Barriales-Villa R, Pavia P, Blanes J, Urbano R, Diaz L, Elliott P, Yousef Z, Abraham T, Afshar K, Alvarez P, Bach R, Becker R, Choudhury L, Fermin D, Jacoby D, Jefferies J, Kramer C, Lakdawala N, Lester S, Marian A, Masri A, Maurer M, Nagueh S, Owens A, Owens D, Rader F, Saberi S, Sherrid M, Shirani J, Symanski J, Turer A, Wang A, Wever-Pinzon O, Wheeler M, Wong T, Yamani M. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 2020, 396: 759-769. PMID: 32871100, DOI: 10.1016/s0140-6736(20)31792-x.Peer-Reviewed Original ResearchConceptsObstructive hypertrophic cardiomyopathyKansas City Cardiomyopathy Questionnaire clinical summary scoreSymptomatic obstructive hypertrophic cardiomyopathyHypertrophic cardiomyopathyLVOT gradientNYHA classPrimary endpointDynamic left ventricular outflow tract obstructionNew York Heart Association class IILeft ventricular outflow tract obstructionTreatment-emergent adverse eventsVentricular outflow tract obstructionAvailable pharmacological optionsKey pathophysiological abnormalityNYHA class reductionNYHA functional classOutflow tract obstructionPlacebo-controlled trialPhase 3 trialML/Disease-specific treatmentPeak oxygen consumptionGreater increaseLVOT obstructionPlacebo groupMyosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy
Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, Repetti G, Alamo L, Sharma A, Agarwal R, Ewoldt JF, Cloonan P, Letendre J, Lun M, Olivotto I, Colan S, Ashley E, Jacoby D, Michels M, Redwood CS, Watkins HC, Day SM, Staples JF, Padrón R, Chopra A, Ho CY, Chen CS, Pereira AC, Seidman JG, Seidman CE. Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy. Circulation 2020, 141: 828-842. PMID: 31983222, PMCID: PMC7077965, DOI: 10.1161/circulationaha.119.042339.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAnimalsCardiac MyosinsCardiomyopathy, HypertrophicCells, CulturedEnergy MetabolismHumansInduced Pluripotent Stem CellsMiceMolecular Dynamics SimulationMuscle RelaxationMutation, MissenseMyocardial ContractionMyocytes, CardiacMyosin Heavy ChainsProtein ConformationSarcomeresConceptsProportion of myosinAdverse clinical outcomesHypertrophic cardiomyopathyHeart failureUnknown clinical significanceClinical outcomesClinical significancePathogenic variantsSarcomere functionSarcomere protein genesPathogenic missense variantsMyosin missense mutationsHemodynamic requirementsImpaired relaxationContractile abnormalitiesHealthy rodentsHypertrophic remodelingHemodynamic demandsPatient riskPoor relaxationCardiomyocyte contractilityHeart functionMyosin ATPase activityPatientsAllosteric modulators