July 2025, Nature Communications: Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure

How can we prioritize biomarkers and therapeutic targets in pressure overload induced cardiac dysfunction? In this collaborative effort, data from large cardiac imaging cohorts was integrated with circulating proteomic signatures and single nucleus RNAseq in cardiac tissue from normal and aortic stenosis patients. Ultimately, this work implicates a series of potential targets which are primed for focused follow up in human and model organism studies. Excellent collaboration with expertise from UCSF, Vanderbilt UMC, and others, Nate (Co-senior author), Michelle, and Ryan coordinated the generation, analysis and integration of all RNAseq data.

Abstract from DOI: https://doi.org/10.1038/s41467-025-62201-2

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.