Spatiotemporal Multi-Omics Mapping Generates a Molecular Atlas of the Aortic Valve and Reveals Networks Driving Disease
Open accessAbstract
Background: No pharmacological therapy exists for calcific aortic valve disease (CAVD), which confers a dismal prognosis without invasive valve replacement. The search for therapeutics and early diagnostics is challenging because CAVD presents in multiple pathological stages. Moreover, it occurs in the context of a complex, multi-layered tissue architecture; a rich and abundant extracellular matrix phenotype; and a unique, highly plastic, and multipotent resident cell population. Methods: A total of 25 human stenotic aortic valves obtained from valve replacement surgeries were analyzed by multiple modalities, including transcriptomics and global unlabeled and label-based tandem-mass-tagged proteomics. Segmentation of valves into disease stage–specific samples was guided by near-infrared molecular imaging, and anatomic layer-specificity was facilitated by laser capture microdissection. Side-specific cell cultures were subjected to multiple calcifying stimuli, and their calcification potential and basal/stimulated proteomes were evaluated. Molecular (protein–protein) interaction networks were built, and their central proteins and disease associations were identified. Results: Global transcriptional and protein expression signatures differed between the nondiseased, fibrotic, and calcific stages of CAVD. Anatomic aortic valve microlayers exhibited unique proteome profiles that were maintained throughout disease progression and identified glial fibrillary acidic protein as a specific marker of valvular interstitial cells from the spongiosa layer. CAVD disease progression was marked by an emergence of smooth muscle cell activation, inflammation, and calcification-related pathways. Proteins overrepresented in the disease-prone fibrosa are functionally annotated to fibrosis and calcification pathways, and we found that in vitro, fibrosa-derived valvular interstitial cells demonstrated greater calcification potential than those from the ventricularis. These studies confirmed that the microlayer-specific proteome was preserved in cultured valvular interstitial cells, and that valvular interstitial cells exposed to alkaline phosphatase–dependent and alkaline phosphatase–independent calcifying stimuli had distinct proteome profiles, both of which overlapped with that of the whole tissue. Analysis of protein–protein interaction networks found a significant closeness to multiple inflammatory and fibrotic diseases. Conclusions: A spatially and temporally resolved multi-omics, and network and systems biology strategy identifies the first molecular regulatory networks in CAVD, a cardiac condition without a pharmacological cure, and describes a novel means of systematic disease ontology that is broadly applicable to comprehensive omics studies of cardiovascular diseases.
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An effort to identify a gene expression signature for the aortic valve and transfer this knowledge to discover specific biomarkers and therapeutic targets has not been attempted.
“Although studies attempted to elucidate the transcriptomic profile of human aortic valves with aortic stenosis,11,12,13,14,15,16 an effort to identify a gene expression signature for the aortic valve and transfer this knowledge to discover specific biomarkers and therapeutic targets has not been attempted.”
From Aortic valve-specific genes dysregulated in calcific aortic valve stenosis as potential biomarkers and therapeutic targets (2025) · cites this paper as [14]
The Results section reports distinct aortic-valve gene-expression signatures across non-diseased, fibrotic, and calcific stages. The Discussion says the work enables identification of targets for early diagnosis and treatment. Thus, this paper describes an effort of the kind the claim says had not been attempted, although the cited paper does not establish whether other efforts existed. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCOL3A1, PRG4, COMP, and TIMP3 were overrepresented in fibrotic samples and increased in the fibrosa layer in a proteomics study of human aortic valve tissues.
“COL3A1, PRG4, COMP, and TIMP3 were overrepresented in fibrotic samples and shown to be increased in the fibrosa layer, supporting the validity of our findings and their translation to the protein level.”
From Aortic valve-specific genes dysregulated in calcific aortic valve stenosis as potential biomarkers and therapeutic targets (2025) · cites this paper as [14]
In Results (OMICs Studies of Disease Stages in CAVD; page unavailable), PRG4 appears among proteins shared by the fibrotic-stage transcriptomics and proteomics datasets. Results (The Proteomes of Distinct Aortic Valve Microlayers) identifies TIMP3 as enriched in the fibrosa, and the Discussion places COMP there. Our copy does not establish that all four proteins were overrepresented in fibrotic samples and increased in the fibrosa; it provides no corresponding finding for COL3A1. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOf the 261 prioritized genes, 127 (47%) were expressed in the AV as evidenced by a transcript or protein product observed in human AV proteomics or transcriptomics or by genetically predicted expression substantially modifying AS risk in TWAS using AV tissue transcriptomes.
“Of the 261 prioritized genes, 127 (47%) were expressed in the AV as evidenced by having either a transcript or a protein product observed in proteomics or transcriptomic data of the human AV18,19 or with genetically predicted expression substantially modifying risk of AS in TWAS using AV tissue transcriptomes.”
From Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction (2026) · cites this paper as [19]
Transition of VICs into myofibroblast-like cells is an early process in the development of CAVS.
“Data have consistently shown that transition of VICs into myofibroblast-like cells was an early process in the development of CAVS (Latif et al., 2015; Schlotter et al., 2018; Taylor et al., 2000).”
From Enhancer-associated aortic valve stenosis risk locus 1p21.2 alters NFATC2 binding site and promotes fibrogenesis (2021) · cites this paper as Schlotter et al., 2018
Many of the most differentially expressed genes in severe forms of CAVS were previously reported in smaller studies.
“As expected, many of the most differentially expressed genes in severe forms of CAVS were previously reported in smaller studies (PDK4, BTG2, SLC16A9, GPR68, FAP, CNTFR, PLEKHS1, THY1, SCG2, CXCL5, TNC, TDO2, LINC01614).9,12,13,28, 29, 30, 31, 32, 33”
From Transcriptomic signatures of calcific aortic valve stenosis severity in human tricuspid and bicuspid aortic valves (2025) · cites this paper as [12]
IBSP, MMP9 and MMP13 were previously shown to be up-regulated in both tricuspid and bicuspid valves with late-stage severe CAVS.
“Among these genes, IBSP (Integrin Binding Sialoprotein), which encodes a structural protein of the bone matrix, as well as MMP9 and MMP13, matrix metalloproteinases, were previously shown to be up-regulated in both tricuspid and bicuspid valves with late-stage severe CAVS.9, 10, 11, 12”
From Transcriptomic signatures of calcific aortic valve stenosis severity in human tricuspid and bicuspid aortic valves (2025) · cites this paper as [12]
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- Authors
- Schlotter, F., Halu, A., Goto, S., Blaser, M. C., Body, S. C., Lee, L. H., Higashi, H., DeLaughter, D. M., Hutcheson, J. D., Vyas, P., Pham, T., Rogers, M. A., Sharma, A., Seidman, C. E., Loscalzo, J., Seidman, J. G., Aikawa, M., Singh, S. A., & Aikawa, E.
- Affiliations
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine (F.S., A.H., S.G., M.C.B., L.H.L., H.H., J.D.H., P.V., T.P., M.A.R., M.A., S.A.S., E.A.)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Florida International University (US)
- Channing Division of Network Medicine (A.H., A.S., M.A.)
- Corresponding author
- Schlotter, Florian
- Halu, Arda
- ORCID
- Venue
- Circulation
- Published
- 2018-07-24
- Volume
- 138
- Issue
- 4
- Pages
- 377-393
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC6160370
- OpenAlex
- W2795030131
- Cited by
- 256
- References
- 47
- Citations by year
- 2026: 22 · 2025: 39 · 2024: 27 · 2023: 28 · 2022: 39 · 2021: 40 · 2020: 33 · 2019: 21 · 2018: 7
- FWCI
- 19.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL114805, R01HL114823, R01HL136431, R01HL061795, R01HL119798)
- National Institute of General Medical Sciences (P50GM107618)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
- Keywords
- calcific aortic valve disease, aortic valve, molecular atlas, valvular interstitial cells, valve calcification, fibrosis, protein-protein interaction network, proteome, transcriptome, glial fibrillary acidic protein, smooth muscle cell activation, inflammation, disease progression, multi-omics
- MeSH terms
- Aortic Valve, Aortic Valve Stenosis, Cells, Cultured, Fibrosis, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Severity of Illness Index, Signal Transduction, Case-Control Studies, Gene Expression Profiling, Proteomics, Gene Regulatory Networks, Tandem Mass Spectrometry, Transcriptome, Protein Interaction Maps
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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