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Original research
Proteomics profiling reveals a distinct high-risk molecular subtype of hypertrophic cardiomyopathy
  1. Lusha W Liang1,
  2. Yoshihiko Raita2,
  3. Kohei Hasegawa2,
  4. Michael A Fifer3,
  5. Mathew S Maurer1,
  6. Muredach P Reilly1,4,
  7. Yuichi J Shimada1
  1. 1Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York City, New York, USA
  2. 2Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  3. 3Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  4. 4Irving Institute for Clinical and Translational Research, Columbia University Irving Medical Center, New York City, New York, USA
  1. Correspondence to Yuichi J Shimada, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York City, New York, USA; ys3053{at}cumc.columbia.edu

Abstract

Objective Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease, likely encompassing several subtypes of disease with distinct biological mechanisms (ie, molecular subtypes). Current models based solely on clinical data have yielded limited accuracy in predicting the risk of major adverse cardiovascular events (MACE). Our aim in this study was to derive molecular subtypes in our multicentre prospective cohort of patients with HCM using proteomics profiling and to examine their longitudinal associations with MACE.

Methods We applied unsupervised machine learning methods to plasma proteomics profiling data of 1681 proteins from 258 patients with HCM who were prospectively followed for a median of 2.8 years. The primary outcome was MACE, defined as a composite of arrhythmia, heart failure, stroke and sudden cardiac death.

Results We identified four molecular subtypes of HCM. Time-to-event analysis revealed significant differences in MACE-free survival among the four molecular subtypes (plogrank=0.007). Compared with the reference group with the lowest risk of MACE (molecular subtype A), patients in molecular subtype D had a higher risk of subsequently developing MACE, with an HR of 3.41 (95% CI 1.54 to 7.55, p=0.003). Pathway analysis of proteins differentially regulated in molecular subtype D demonstrated an upregulation of the Ras/mitogen-activated protein kinase and associated pathways, as well as pathways related to inflammation and fibrosis (eg, transforming growth factor-β pathway).

Conclusions Our prospective plasma proteomics study not only exhibited the presence of HCM molecular subtypes but also identified pathobiological mechanisms associated with a distinct high-risk subtype of HCM.

  • Hypertrophic cardiomyopathy
  • Biomarkers
  • Heart Failure

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • LWL and YR contributed equally.

  • Presented at An earlier version of this study has been previously presented as an oral abstract at the European Society of Cardiology Congress 2021, The Digital Experience, 27–30 August 2021.

  • Contributors LL, YR, KH and YJS contributed to conception and design, analysis and interpretation of data, as well as manuscript preparation and revision. YJS is the guarantor. MAF, MSM and MPR contributed to the design of the study as well as interpretation of the data and manuscript revision. All authors have read and approved the final manuscript. The authors certify that there have been no previous publications from the same study. Neither this manuscript nor one with substantially similar content under our authorship is being considered for publication elsewhere.

  • Funding YJS was supported by research grants from the National Institutes of Health (Bethesda, Maryland; R01 HL157216), American Heart Association (Dallas, Texas) National Clinical and Population Research Awards and Career Development Award, Feldstein Medical Foundation (Clifton, New Jersey) Medical Research Grant, Korea Institute of Oriental Medicine (Daejeon, Republic of Korea), Columbia University Irving Medical Center Irving Institute for Clinical and Translational Research (New York, New York) Precision Medicine Pilot Award, and Columbia University Irving Medical Center (New York, New York) Lewis Katz Cardiovascular Research Prize. MSM was supported by the National Institutes of Health (K24 AG036778). MPR was supported by the National Institutes of Health (UL1 TR001873 and K24 HL107643). The funding organisations did not have any role in the study design, collection, analysis or interpretation of data, in writing of the manuscript, or in the decision to submit the article for publication. The researchers were independent from the funding organisations.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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