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Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure

Author

Listed:
  • Brian R. Lindman

    (Vanderbilt University School of Medicine)

  • Andrew S. Perry

    (Vanderbilt University School of Medicine)

  • Michelle L. Lance

    (Masonic Medical Research Institute)

  • Kaushik Amancherla

    (Vanderbilt University School of Medicine)

  • Namju Kim

    (Vanderbilt University School of Medicine)

  • Quanhu Sheng

    (Vanderbilt University Medical Center)

  • Phillip Lin

    (Vanderbilt University School of Medicine)

  • Ryan D. Pfeiffer

    (Masonic Medical Research Institute)

  • Eric Farber-Eger

    (Vanderbilt University School of Medicine)

  • William F. Fearon

    (Stanford Medical Center)

  • Samir Kapadia

    (Cleveland Clinic Foundation)

  • Dharam J. Kumbhani

    (University of Texas Southwestern Medical Center)

  • Linda Gillam

    (Morristown Medical Center)

  • Ravinder R. Mallugari

    (Vanderbilt University School of Medicine)

  • Deepak K. Gupta

    (Vanderbilt University School of Medicine)

  • Francis J. Miller

    (Veterans Affairs Tennessee Valley Healthcare System
    Vanderbilt University Medical Center)

  • Anna Vatterott

    (Vanderbilt University School of Medicine)

  • Natalie Jackson

    (Vanderbilt University School of Medicine)

  • Yan Ru Su

    (Vanderbilt University Medical Center)

  • Kelsey Tomasek

    (Vanderbilt University Medical Center)

  • Tarek Absi

    (Vanderbilt University Medical Center)

  • Jane E. Freedman

    (Vanderbilt University School of Medicine)

  • Matthew Nayor

    (Boston University)

  • Saumya Das

    (Harvard Medical School)

  • Quinn S. Wells

    (Vanderbilt University School of Medicine)

  • Marc R. Dweck

    (University of Edinburgh)

  • Robert E. Gerszten

    (Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Eric R. Gamazon

    (Vanderbilt University Medical Center)

  • Nathan R. Tucker

    (Masonic Medical Research Institute)

  • Ravi Shah

    (Vanderbilt University School of Medicine)

  • Sammy Elmariah

    (University of California)

Abstract

Pressure overload initiates a series of alterations in the human heart that predate macroscopic organ-level remodeling and downstream heart failure. We study aortic stenosis through integrated proteomic, tissue transcriptomic, and genetic methods to prioritize targets causal in human heart failure. First, we identify the circulating proteome of cardiac remodeling in aortic stenosis, specifying known and previously-unknown mediators of fibrosis, hypertrophy, and oxidative stress, several associated with interstitial fibrosis in a separate cohort (N = 145). These signatures are strongly related to clinical outcomes in aortic stenosis (N = 802) and in broader at-risk populations in the UK Biobank (N = 36,668). We next map this remodeling proteome to myocardial transcription in patients with and without aortic stenosis through single-nuclear transcriptomics, observing broad differential expression of genes encoding this remodeling proteome, featuring fibrosis pathways and metabolic-inflammatory signaling. Finally, integrating our circulating and tissue-specific results with modern genetic approaches, we implicate several targets as causal in heart failure.

Suggested Citation

  • Brian R. Lindman & Andrew S. Perry & Michelle L. Lance & Kaushik Amancherla & Namju Kim & Quanhu Sheng & Phillip Lin & Ryan D. Pfeiffer & Eric Farber-Eger & William F. Fearon & Samir Kapadia & Dharam , 2025. "Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62201-2
    DOI: 10.1038/s41467-025-62201-2
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