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Publications

Journal Article Ahead of print

PubMed: 41636061 DOI: 10.1161/CIRCGEN.124.005031

Large-Scale Proteomic Profiling of Incident Heart Failure and Its Subtypes in Older Adults.

Circ Genom Precis Med

Authors: Joyce N Njoroge, Sandra Sanders van Wijk, Thomas R Austin, Jennifer A Brody, Colleen M Sitlani, Emily Hamerton, Joshua Bis, Albert Henry, R Thomas Lumbers, Talia Seshaiah, Ali Shojaie, Yimin Yang, Victoria Lamberson, Bing Yu, Amil M Shah, Nisha Bansal, Sanjiv Shah, Russell P Tracy, Robert E Gerszten, Lori L Jennings, Valborg Gudmundsdottir, Vilmundur Gudnason, Valur Emilsson, Bruce M Psaty, Jorge R Kizer

Affiliations

  • Division of Cardiology, Department of Medicine, Stanford University, Palo Alto, CA (J.N.N.).
  • Division of Cardiology, Department of Medicine, Zuyderland Medical Center, Heerlen, the Netherlands (S.S.v.W.).
  • Cardiovascular Health Research Unit, Epidemiology and Health Systems & Population Health (T.R.A. J.B. B.M.P.), University of Washington, Seattle.
  • Cardiovascular Health Research Unit, Department of Medicine (J.A.B. B.M.P.), University of Washington, Seattle.
  • Department of Biostatistics (C.M.S. T.S. A.S.), University of Washington, Seattle.
  • Cardiology Section, San Francisco Veterans Affairs Health Care System & Department of Medicine (E.H. J.R.K.), University of California.
  • Institute of Cardiovascular Science (A.H.), University College London, United Kingdom.
  • Institute of Health Informatics (A.H. R.T.L.), University College London, United Kingdom.
  • The National Institute for Health Research University College London Hospitals Biomedical Research Centre (R.T.L.), University College London, United Kingdom.
  • Department of Medicine, Brigham and Women's Hospital (The HERMES Consortium, Y.Y.), Harvard Medical School, Boston, MA.
  • Division of Cardiovascular Medicine, Department of Medicine, University of Texas Southwestern Medical Center (V.L. A.M.S.).
  • School of Public Health, University of Texas Health Science Center at Houston (B.Y.).
  • Division of Nephrology, Department of Medicine & Kidney Research Institute (N.B.), University of Washington, Seattle.
  • Division of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, IL (S.S.).
  • Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington (R.P.T.).
  • Division of Cardiology, Department of Medicine, Beth Israel Deaconess Hospital (R.E.G.), Harvard Medical School, Boston, MA.
  • Novartis Institute for Biomedical Research, Cambridge, MA (L.L.J.).
  • University of Iceland, Faculty of Medicine, Reykjavik (V. Gudmundsdottir, V. Gudnason, V.E.).
  • Icelandic Heart Association, Kopavogur (V. Gudmundsdottir, V. Gudnason, V.E.).
  • Department of Epidemiology and Biostatistics (J.R.K.), University of California.

Abstract

BACKGROUND

Heart failure (HF) and its main subtypes, heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), impose an enormous health burden on elders. Assessment of the circulating proteome to illuminate pathogenesis could open new opportunities for treatment.

METHODS

We conducted a plasma proteomics screen of incident HF and its subtypes in 2 older population-based cohorts, the CHS (Cardiovascular Health Study) and the AGES-RS (Aging, Gene/Environment Susceptibility-Reykjavik Study). The 2 studies used SomaLogic platforms, with 4404 aptamers in common. Multivariable Cox models were fit to evaluate individual-protein associations with HF, HFpEF, and HFrEF separately in each cohort, and study-specific associations were combined by fixed-effects meta-analysis. Replication was performed in the ARIC (Atherosclerosis Risk in Communities) cohort. Two-sample Mendelian randomization of HF and its subtypes, along with colocalization analysis, was performed to support causal inference.

RESULTS

Among 8599 participants, 1590 experienced incident HF (536 HFpEF, 471 HFrEF). There were 119 proteins associated with HF, 15 proteins with HFpEF, and 11 proteins with HFrEF, at Bonferroni-corrected significance. Among these, 9 have never previously been identified for cardiovascular diseases, and another 61 represent new associations with incident HF or its subtypes. Of these 70 proteins, 55 of the 66 available replicated externally. Mendelian randomization analysis revealed 7 proteins genetically associated with HF at nominal significance; 2 were separately associated with HFpEF, and another 2 with HFrEF. Seven of these 9 proteins (NCDP1, APOF, LMAN2 [lectin, mannose-binding 2], ADIPOQ [adiponectin], CD14 [cluster of differentiation 14], ARHGAP1 [Rho GTPase-activating protein 1], C9 [complement 9]) showed new, possibly causal associations, although we did not detect evidence for colocalization.

CONCLUSIONS

In this large-scale proteomic study involving 3 longitudinal cohorts of older adults, we identified and replicated 55 novel protein markers of HF or its subtypes, and 7 new, possibly causal proteins. These proteins may enhance risk prediction, improve understanding of pathobiology, and help prioritize targets for therapeutic development of these foremost disorders in elders.

MeSH

Genes, Myocardial Infarction, Heart Failure, Heart, Cardiovascular Diseases, Heart Failure, Diastolic, Heart Failure, Systolic, Proteomics, Therapeutics, Random Allocation, Complement C9