Evidence map›Paper›PMID 31983222›Full record

ArticleCirculation2020

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

Christopher N Toepfer, Amanda C Garfinkel, Gabriela Venturini, Hiroko Wakimoto, Giuliana Repetti, Lorenzo Alamo, Arun Sharma, Radhika Agarwal, Jourdan K Ewoldt, Paige Cloonan and 18 more

Erratum issuedOpen access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 198 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
198citing papers in PubMed, 1 pooled it
29.8field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

198 citing papers in PubMed, 1 synthesis or guideline pooled it, 315 citations in OpenAlex.

  1. Pooled it
  2. Trial
  3. Evidence for a role of adverse sarcomere signaling in atrial fibrillation induction.Journal of molecular and cellular cardiology plus · 2026
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  4. Article
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  8. Immature and mature myocardium in the pathophysiology of hypertrophic cardiomyopathy.Journal of molecular and cellular cardiology plus · 2026
    Review
  9. Article
  10. Article
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  12. Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  13. Review
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138 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

28 authors at 17 institutions in 8 countries.

Christopher N ToepferDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Amanda C GarfinkelDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Gabriela VenturiniDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Hiroko WakimotoDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Giuliana RepettiDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Lorenzo AlamoCentro de Biología Estructural, Instituto Venezolano de Investigaciones Cientifìcas (IVIC), Caracas (L.A., R.P.).
Arun SharmaDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Radhika AgarwalDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Jourdan K EwoldtDepartment of Biomedical Engineering, Boston University, MA (J.F.E., P.C., J.L., A.C., C.S.C.).
Paige CloonanDepartment of Biomedical Engineering, Boston University, MA (J.F.E., P.C., J.L., A.C., C.S.C.).
Justin LetendreDepartment of Biomedical Engineering, Boston University, MA (J.F.E., P.C., J.L., A.C., C.S.C.).
Mingyue LunDepartment of Medicine, Division of Genetics (M.L.), Brigham and Women's Hospital, Boston, MA.
Iacopo OlivottoCardiomyopathy Unit and Genetic Unit, Careggi University Hospital, Florence, Italy (I.O.).
Steve ColanDepartment of Cardiology, Boston Children's Hospital, MA (S.C.).
Euan AshleyCenter for Inherited Cardiovascular Disease, Stanford University, CA (E.A.).
Daniel JacobyDepartment of Internal Medicine, Section of Cardiovascular Diseases, Yale School of Medicine, New Haven, CT (D.J.).
Michelle MichelsDepartment of Cardiology, Thorax Center, Erasmus MC, Rotterdam, The Netherlands (M.M.).
Charles S RedwoodCardiovascular Medicine, Radcliffe Department of Medicine (C.N.T., C.S.R., H.C.W.), University of Oxford, UK.
Hugh C WatkinsCardiovascular Medicine, Radcliffe Department of Medicine (C.N.T., C.S.R., H.C.W.), University of Oxford, UK.
Sharlene M DayDepartment of Internal Medicine, University of Michigan, Ann Arbor (S.M.D.).
James F StaplesDepartment of Biology, University of Western Ontario, London, Canada (J.F.S.).
Raúl PadrónCentro de Biología Estructural, Instituto Venezolano de Investigaciones Cientifìcas (IVIC), Caracas (L.A., R.P.).
Anant ChopraDepartment of Biomedical Engineering, Boston University, MA (J.F.E., P.C., J.L., A.C., C.S.C.).
Carolyn Y HoCardiovascular Division (C.Y.H., C.E.S.), Brigham and Women's Hospital, Boston, MA.
Christopher S ChenDepartment of Biomedical Engineering, Boston University, MA (J.F.E., P.C., J.L., A.C., C.S.C.).
Alexandre C PereiraDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Jonathan G SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Christine E SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA (C.N.T., A.C.G., G.V., H.W., G.R., A.S., R.A., A.C.P., J.G.S., C.E.S.).
Boston University · USAnna Needs Neuroblastoma Answers · USBrigham and Women's Hospital · USCentre for Human Genetics · GBUniversidade de São Paulo · BRAzienda Ospedaliero-Universitaria Careggi · ITBoston Children's Hospital · USCenter for Inherited Blood Disorders · USErasmus University Rotterdam · NLHarvard University · USInstituto Venezolano de Investigaciones Científicas · VEJohn Radcliffe Hospital · GBUnited States Nuclear Regulatory Commission · USUniversity of Massachusetts Chan Medical School · USUniversity of Michigan · USWestern University · CAYale University · US

Funding

Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9M
HCMR Novel Markers of Prognosis in Hypertrophic CardiomyopathyU01HL117006 · NHLBI · UNIVERSITY OF VIRGINIA · PI KRAMER, CHRISTOPHER M., NEUBAUER, STEFAN · 2013 to 2017
$14.5M
Using Genetics For Early Phenotyping & Prevention of Hypertrophic CardiomyopathyP50HL112349 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI HO, CAROLYN Y, SEIDMAN, CHRISTINE E · 2012 to 2017
$11.2M
Mapping Transcriptional Networks in Cardiac DevelopmentU01HL098166 · NHLBI · HARVARD MEDICAL SCHOOL · PI SEIDMAN, JONATHAN G · 2009 to 2014
$9.5M
Defining Pathways from Gene Mutation to Heart FailureR01HL080494 · NHLBI · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI CHEN, CHRISTOPHER S, SEIDMAN, CHRISTINE E · 2005 to 2024
$9.4M
Molecular Signaling in Hypertrophic CardiomyopathyR01HL084553 · NHLBI · HARVARD MEDICAL SCHOOL · PI SEIDMAN, JONATHAN G · 2007 to 2022
$5.9M
Advanced Recombinase Technology for Tissue Engineering ApplicationsF31HL149334 · NHLBI · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · PI LETENDRE, JUSTIN HENRY · 2019 to 2021
$88k
British Heart Foundation CH/1992001/6764British Heart Foundation RG/12/16/29939British Heart Foundation RG/18/9/33887Howard Hughes Medical InstituteNCATS NIH HHS UL1 TR001863NHLBI NIH HHS F31 HL149334NHLBI NIH HHS P50 HL112349NHLBI NIH HHS R01 HL080494NHLBI NIH HHS R01 HL084553NHLBI NIH HHS U01 HL098166NHLBI NIH HHS U01 HL117006Wellcome Trust 206466/Z/17/Z
6 · The paper itself

Abstract

backgroundHypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.

methodsWe assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias.

resultsMyosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM.

conclusionsMyosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.

Indexed as

Adenosine TriphosphatasesAnimalsCardiac MyosinsCardiomyopathy, HypertrophicCells, CulturedEnergy MetabolismHumansInduced Pluripotent Stem CellsMiceMolecular Dynamics SimulationMuscle RelaxationMutation, MissenseMyocardial ContractionMyocytes, CardiacMyosin Heavy ChainsProtein ConformationAdenosine TriphosphatasesCardiac MyosinsMyh6 protein, mouseMYH7 protein, humanMyosin Heavy Chainscardiomyopathy, hypertrophiccardiovascular physiological phenomenamyosinssarcomeres

Identifiers

PMID31983222
PMCPMC7077965
OpenAlexW3001201582

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.