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Proteomic architecture of frailty across the spectrum of cardiovascular disease |
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| Authors: | Andrew S. Perry Shilin Zhao Priya Gajjar Venkatesh L. Murthy Benoit Lehallier Patricia Miller Sangeeta Nair Colin Neill J. Jeffrey Carr William Fearon Samir Kapadia Dharam Kumbhani Linda Gillam JoAnn Lindenfeld Laurie Farrell Megan M. Marron Qu Tian Anne B. Newman Joanne Murabito Robert E. Gerszten Matthew Nayor Sammy Elmariah Brian R. Lindman Ravi Shah |
| Affiliation: | 1. Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA;2. Cardiovascular Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA;3. Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA;4. Alkahest, Inc., San Carlos, California, USA;5. Department of Medicine, and Department of Biostatistics, Boston University School of Medicine, Boston, Massachusetts, USA;6. Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin Hospital and Clinics, Madison, Wisconsin, USA;7. Department of Medicine, Division of Cardiology, Stanford Medical Center, Palo Alto, California, USA;8. Department of Medicine, Division of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA;9. Department of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA;10. Department of Cardiovascular Medicine, Morristown Medical Center, Morristown, New Jersey, USA;11. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA;12. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;13. National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA;14. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Departments of Medicine and Clinical and Translational Science, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;15. Sections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA;16. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA;17. Department of Medicine, Division of Cardiology, The University of California, San Francisco, California, USA |
| Abstract: | While frailty is a prominent risk factor in an aging population, the underlying biology of frailty is incompletely described. Here, we integrate 979 circulating proteins across a wide range of physiologies with 12 measures of frailty in a prospective discovery cohort of 809 individuals with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation. Our aim was to characterize the proteomic architecture of frailty in a highly susceptible population and study its relation to clinical outcome and systems-wide phenotypes to define potential novel, clinically relevant frailty biology. Proteomic signatures (specifically of physical function) were related to post-intervention outcome in AS, specifying pathways of innate immunity, cell growth/senescence, fibrosis/metabolism, and a host of proteins not widely described in human aging. In published cohorts, the “frailty proteome” displayed heterogeneous trajectories across age (20–100 years, age only explaining a small fraction of variance) and were associated with cardiac and non-cardiac phenotypes and outcomes across two broad validation cohorts (N > 35,000) over ≈2–3 decades. These findings suggest the importance of precision biomarkers of underlying multi-organ health status in age-related morbidity and frailty. |
| Keywords: | cardiovascular disease frailty proteomics |