Abstract 037: Proteo-Transcriptional Characterization of Aortic Stenosis Prioritizes Novel Targets Relevant to Heart Failure

Background: Aortic stenosis (AS) initiates a series of molecular alterations that predate cardiac remodeling and development of heart failure (HF). We hypothesized that integrating circulating mediators (proteome) from large-scale epidemiological cohorts with their cell-specific gene expression in the heart (transcriptome) may prioritize novel targets in human AS. Methods: Among individuals with severe AS, we measured the circulating proteome (Olink) and examined associations with myocardial structure/function (N=519), cardiac MRI-based tissue fibrosis (N=145), and clinical outcomes (N=802). We constructed proteomic signatures of cardiac remodeling and tested their association with mortality and HF in the UK Biobank (UKBB; N=36,668). We then examined a "remodeling proteome” prioritized by proteome-phenotype relations at the transcriptional level via single nuclear RNA-sequencing in 20 human hearts (11 with AS at the time of SAVR and 9 donor hearts unused for transplant). Results: We identified three principal components (PCs) of cardiac remodeling (across 12 echocardiographic measures in 503 patients with severe AS) loaded on cardiac morphology, systolic, and diastolic function traits. Proteins associated with these PCs specified both known and novel mediators of fibrosis, LVH, and oxidative stress. Proteomic signatures were strongly linked to mortality (AS cohort, UKBB) and incident HF (UKBB). At a myocardial level, we observed cell-specific differential gene expression, particularly prominent in fibroblasts, cardiomyocytes, and endothelial cells, featuring convergent fibrosis pathways ( WNT9A , ITGA6 , AGRN , CRIM1 , SEMA4C , LAYN, PTX3 , HMOX1 ) and metabolic-inflammatory signaling ( ENPP2/ATX, TNF), among others. Conclusions: Proteo-transcriptional prioritization in human AS identifies both known and novel targets that are mechanistically relevant to HF pathogenesis. Future integrative studies that link longitudinal circulating biomarkers in large-scale cohorts directly to myocardial tissue are warranted to inform pathways of HF progression.

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Publication Details

Journal
Circulation
Published
2025-03-11
DOI
https://doi.org/10.1161/cir.151.suppl_1.037
Citations
1
Primary Topic
Cardiac Valve Diseases and Treatments
Type
article
Field-Weighted Citation Impact
1.39
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article

Abstract 037: Proteo-Transcriptional Characterization of Aortic Stenosis Prioritizes Novel Targets Relevant to Heart Failure

Andrew Perry, Yanru Su, Deepak K. Gupta, Kaushik V Amancherla et al.
1 citations
Circulation
Cardiac Valve Diseases and Treatments
1.39
article

Abstract 037: Proteo-Transcriptional Characterization of Aortic Stenosis Prioritizes Novel Targets Relevant to Heart Failure

Andrew Perry, Yanru Su, Deepak K. Gupta, Kaushik V Amancherla, Ravi V. Shah, Dharam J. Kumbhani, Natalie Jackson, Tarek Absi, Francis J. Miller, Eric Farber‐Eger, Matthew Nayor, Quanhu Sheng, Ryan Pfeiffer, Sammy Elmariah, Robert E. Gerszten, Linda D. Gillam, Quinn S. Wells, Nathan R. Tucker, Jane E. Freedman, Brian R. Lindman, Marc R. Dweck, William F. Fearon, Anna Vatterott, Samir Kapadia, Kelsey Tomasek, Saumya Das, Ravinder Mallugari, Michelle L Lance
article en
1 citations

Abstract

Background: Aortic stenosis (AS) initiates a series of molecular alterations that predate cardiac remodeling and development of heart failure (HF). We hypothesized that integrating circulating mediators (proteome) from large-scale epidemiological cohorts with their cell-specific gene expression in the heart (transcriptome) may prioritize novel targets in human AS. Methods: Among individuals with severe AS, we measured the circulating proteome (Olink) and examined associations with myocardial structure/function (N=519), cardiac MRI-based tissue fibrosis (N=145), and clinical outcomes (N=802). We constructed proteomic signatures of cardiac remodeling and tested their association with mortality and HF in the UK Biobank (UKBB; N=36,668). We then examined a "remodeling proteome” prioritized by proteome-phenotype relations at the transcriptional level via single nuclear RNA-sequencing in 20 human hearts (11 with AS at the time of SAVR and 9 donor hearts unused for transplant). Results: We identified three principal components (PCs) of cardiac remodeling (across 12 echocardiographic measures in 503 patients with severe AS) loaded on cardiac morphology, systolic, and diastolic function traits. Proteins associated with these PCs specified both known and novel mediators of fibrosis, LVH, and oxidative stress. Proteomic signatures were strongly linked to mortality (AS cohort, UKBB) and incident HF (UKBB). At a myocardial level, we observed cell-specific differential gene expression, particularly prominent in fibroblasts, cardiomyocytes, and endothelial cells, featuring convergent fibrosis pathways ( WNT9A , ITGA6 , AGRN , CRIM1 , SEMA4C , LAYN, PTX3 , HMOX1 ) and metabolic-inflammatory signaling ( ENPP2/ATX, TNF), among others. Conclusions: Proteo-transcriptional prioritization in human AS identifies both known and novel targets that are mechanistically relevant to HF pathogenesis. Future integrative studies that link longitudinal circulating biomarkers in large-scale cohorts directly to myocardial tissue are warranted to inform pathways of HF progression.

CirculationVol. 151(Suppl_1)
Boston University (US), Boston Medical Center (US), Beth Israel Deaconess Medical Center (US), Cleveland Clinic (US), Vanderbilt University (US), Morristown Medical Center (US), British Heart Foundation (GB), Massachusetts General Hospital (US), Masonic Medical Research Laboratory (US), Southwestern Medical Center (US), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US), Stanford University (US)
Openalex Percentile: Top 20%
Cardiac Valve Diseases and Treatments
1.39
DOISourceOpenAlex
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