Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure
Abstract
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.
Article Details
Authors (31)
Brian R. Lindman
From Gagnon Cardiovascular Institute, Morristown Medical Center, Morristown, NJ (P.G.); Columbia University Medical Center/New York Presbyterian Hospital (A.S., R.T.H., M.B.L.), the Cardiovascular Research Foundation (D.J.C., R.T.H., B.R., M.B.L.), and Weill Cornell Medicine (B.R.), New York, and St. Francis Hospital and Heart Center, Roslyn (D.J.C.) — all in New York; University of Colorado Health, Medical Center of the Rockies, Loveland (J.B.O.); Laval University, Quebec, QC (P.P.), St. Paul’s Hospital, University of British Columbia, Vancouver (P.B., J.L.), and McMaster University, Hamilton, ON (T.S.) — all in Canada; Vanderbilt University Medical Center, Nashville (B.R.L., K.G.); Emory University, Atlanta (V.B.); the Division of Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, Stanford (W.F.F.), VA Palo Alto Health Care System, Palo Alto (W.F.F.), California Pacific Medical Center, San Francisco (D.V.D.), Cedars–Sinai Medical Center, Los Angeles (R.R.M.), and Edwards ...
Andrew S. Perry
Michelle L. Lance
Kaushik Amancherla
Namju Kim
Department of Chemistry
Quanhu Sheng
Phillip Lin
Ryan D. Pfeiffer
Eric Farber-Eger
William F. Fearon
Division of Cardiovascular Medicine and Stanford Cardiovascular Institute, Stanford University, Stanford, CA
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