| Title: | Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure |
| Journal: | Nature Communications |
| Published: | 26 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40715126/ |
| DOI: | https://doi.org/10.1038/s41467-025-62201-2 |
| URL: | https://www.nature.com/articles/s41467-025-62201-2.pdf |
Publication 16097
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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.</p>
16 Keywords
- Aged
- Aortic Valve Stenosis
- Female
- Fibrosis
- Gene Expression Profiling
- Heart Failure
- Humans
- Male
- Middle Aged
- Multiomics
- Myocardium
- Oxidative Stress
- Proteome
- Proteomics
- Transcriptome
- Ventricular Remodeling
31 Authors
- 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
- Sammy Elmariah
1 Application
| Application ID | Title |
|---|---|
| 57492 | Resolving the genetic architecture of complex cardiovascular disease through phenotype refinement. |
Enabling scientific discoveries that improve human health