Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure
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...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62201-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Brian R. Lindman |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4cf8cfbea3864915abf8b73b470ea50d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4cf8cfbea3864915abf8b73b470ea50d2025-08-20T03:43:16ZengNature PortfolioNature Communications2041-17232025-07-0116111610.1038/s41467-025-62201-2Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failureBrian R. Lindman0Andrew S. Perry1Michelle L. Lance2Kaushik Amancherla3Namju Kim4Quanhu Sheng5Phillip Lin6Ryan D. Pfeiffer7Eric Farber-Eger8William F. Fearon9Samir Kapadia10Dharam J. Kumbhani11Linda Gillam12Ravinder R. Mallugari13Deepak K. Gupta14Francis J. Miller15Anna Vatterott16Natalie Jackson17Yan Ru Su18Kelsey Tomasek19Tarek Absi20Jane E. Freedman21Matthew Nayor22Saumya Das23Quinn S. Wells24Marc R. Dweck25Robert E. Gerszten26Eric R. Gamazon27Nathan R. Tucker28Ravi Shah29Sammy Elmariah30Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineMasonic Medical Research InstituteVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineDepartment of Biostatistics, Vanderbilt University Medical CenterVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineMasonic Medical Research InstituteVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineDepartment of Medicine, Division of Cardiology, Stanford Medical CenterDepartment of Medicine, Division of Cardiology, Cleveland Clinic FoundationDepartment of Medicine, Division of Cardiology, University of Texas Southwestern Medical CenterDepartment of Cardiovascular Medicine, Morristown Medical CenterVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineVeterans Affairs Tennessee Valley Healthcare SystemVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineDepartment of Medicine, Vanderbilt University Medical CenterDepartment of Medicine, Vanderbilt University Medical CenterDepartment of Cardiac Surgery, Vanderbilt University Medical CenterVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineDepartment of Cardiovascular Medicine, Boston UniversityCardiology Division, Massachusetts General Hospital, Harvard Medical SchoolVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineBHF Centre for Cardiovascular Science, University of EdinburghCardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Vanderbilt University Medical CenterMasonic Medical Research InstituteVanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of MedicineDepartment of Medicine, Division of Cardiology, University of CaliforniaAbstract 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.https://doi.org/10.1038/s41467-025-62201-2 |
| spellingShingle | 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 Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure Nature Communications |
| title | Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure |
| title_full | Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure |
| title_fullStr | Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure |
| title_full_unstemmed | Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure |
| title_short | Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure |
| title_sort | integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure |
| url | https://doi.org/10.1038/s41467-025-62201-2 |
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