Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure
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.
Authors
- Andrew Perry (ORCID: https://orcid.org/0000-0003-3342-6158)
- Ryan Pfeiffer (ORCID: https://orcid.org/0000-0002-4139-4881)
- Deepak K. Gupta (ORCID: https://orcid.org/0000-0003-2191-3485)
- Kaushik V Amancherla (ORCID: https://orcid.org/0000-0003-3379-5834)
- Ravi V. Shah (ORCID: https://orcid.org/0000-0002-4471-7156)
- Dharam J. Kumbhani (ORCID: https://orcid.org/0000-0003-4321-4538)
- Saumya Das (ORCID: https://orcid.org/0000-0002-4521-4606)
- Tarek Absi (ORCID: https://orcid.org/0000-0002-6777-6132)
- Francis J. Miller (ORCID: https://orcid.org/0000-0001-5822-0549)
- Eric Farber‐Eger (ORCID: https://orcid.org/0000-0003-0281-3796)
- Matthew Nayor (ORCID: https://orcid.org/0000-0002-6993-9396)
- Quanhu Sheng (ORCID: https://orcid.org/0000-0001-8951-9295)
- Sammy Elmariah (ORCID: https://orcid.org/0000-0002-8013-8733)
- Robert E. Gerszten (ORCID: https://orcid.org/0000-0002-6767-7687)
- Linda D. Gillam (ORCID: https://orcid.org/0000-0002-1716-7574)
- Quinn S. Wells (ORCID: https://orcid.org/0000-0003-3899-0313)
- Nathan R. Tucker (ORCID: https://orcid.org/0000-0002-5071-4218)
- Jane E. Freedman (ORCID: https://orcid.org/0000-0002-0011-6164)
- Brian R. Lindman (ORCID: https://orcid.org/0000-0002-6879-5343)
- Marc R. Dweck (ORCID: https://orcid.org/0000-0001-9847-5917)
- Y. Su (ORCID: https://orcid.org/0000-0002-5096-1198)
- William F. Fearon (ORCID: https://orcid.org/0000-0003-1799-1368)
- Anna Vatterott (ORCID: https://orcid.org/0000-0002-5551-1639)
- Samir Kapadia (ORCID: https://orcid.org/0000-0002-0026-3391)
- Kelsey Tomasek (ORCID: https://orcid.org/0009-0007-6576-8933)
- Eric R. Gamazon (ORCID: https://orcid.org/0000-0003-4204-8734)
- Namju Kim (ORCID: https://orcid.org/0000-0002-4815-0804)
- Natalie Jackson (ORCID: https://orcid.org/0009-0005-0497-064X)
- Ravinder Mallugari (ORCID: https://orcid.org/0009-0002-0892-7102)
- Michelle L Lance (ORCID: https://orcid.org/0000-0001-7607-9315)
Institutions
- Broad Institute (US)
- Boston University (US)
- Beth Israel Deaconess Medical Center (US)
- Cleveland Clinic (US)
- Harvard University (US)
- University of California, San Francisco (US)
- Vanderbilt University (US)
- Cleveland Foundation (US)
- Morristown Medical Center (US)
- Massachusetts General Hospital (US)
- Masonic Medical Research Laboratory (US)
- VA Tennessee Valley Healthcare System (US)
- Stanford Medicine (US)
- The University of Texas Southwestern Medical Center (US)
- Vanderbilt University Medical Center (US)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-26
- DOI
- https://doi.org/10.1038/s41467-025-62201-2
- Citations
- 4
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 5.55
Funders
- National Institutes of Health