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

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 J. Kumbhani, Linda Gillam, Ravinder R. Mallugari, Deepak K. Gupta, Francis J. Miller, Anna Vatterott, Natalie Jackson, Yan Ru Su, Kelsey Tomasek, Tarek Absi, Jane E. Freedman, Matthew Nayor, Saumya Das, Quinn S. Wells, Marc R. Dweck, Robert E. Gerszten, Eric R. Gamazon, Nathan R. Tucker (), Ravi Shah () and Sammy Elmariah ()
Additional contact information
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
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62201-2

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