Large-Scale Proteomic Profiling of Incident Heart Failure and Its Subtypes in Older Adults
Year: 2026
Type: article
Study design: Observational Study
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 (NPDC1 [neural proliferation differentiation and control protein 1], APOF [apolipoprotein F], 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.
Authors: Joyce N. Njoroge, Sandra Sanders van Wijk, Thomas R. Austin, Jennifer A. Brody, Colleen M. Sitlani, Emily Hamerton, Joshua C. Bis, Albert Henry, R. Thomas Lumbers, Talia Seshaiah, Ali Shojaie, Yimin Yang, Victoria Lamberson, Bing Yu, Amil M. Shah, Nisha Bansal, Sanjiv J. Shah, Russell P. Tracy, Robert E. Gerszten, Lori L. Jennings, Valborg Gudmundsdottir, Vilmundur Gudnason, Valur Emilsson, Bruce M. Psaty, Jorge R. Kizer, Bitten Aagaard, Erik Abner, Lance Adams, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Folkert W. Asselbergs, Geraldine Asselin, Anna Axelsson Raja, Joshua D. Backman, John Baksi, Paul J. R. Barton, Traci M. Bartz, Kiran J. Biddinger, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Isabelle Bond, Jeffrey Brandimarto, Michael R. Brown, Søren Brunak, Hans-Peter Brunner-La Rocca, Mie Topholm Bruun, Rachel Buchan, Leonard Buckbinder, Henning Bundgaard, Douglas Cannie, Thomas P. Cappola, David J. Carey, Mark D. Chaffin, Philippe Charron, Daniel I. Chasman, Olympe Chazara, Xing Chen, Xu Chen, Jonathan H. Chung, William Chutkow, John G.F. Cleland, James P. Cook, Stuart A. Cook, Tomasz Czuba, Trégouët David-Alexandre, Simon de Denus, Antonio de Marvao, Abbas Dehghan, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Joseph Dowsett, J. Gustav Smith, Marie-Pierre Dubé, Samuel C. Dudley, Michael E. Dunn, Patrick T. Ellinor, Perry Elliott, Gunnar Engström, Villard Eric, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Ghazaleh Fatemifar, Stephan B. Felix, Chris Finan, Sarah Finer, Ian Ford, Francoise Fougerousse, René Fouodjio, Catherine Francis, Sophie Garnier, Mohsen Ghanbari, Sahar Ghasemi, Jonas Ghouse, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Karl Guo, Rebecca Gutmann, Sara Hägg, Christopher M. Haggerty, Brian Halliday, Åsa K. Hedman, Anna Helgadottir, Harry Hemingway, Hans Hillege, Aroon D. Hingorani, Hilma Holm, Michael V. Holmes, Craig L. Hyde, Erik Ingelsson, Hanane Issa, Jaison Jacob, Deleuze Jean-François, J. Wouter Jukema, Frederick Kamanu, Isabella Kardys, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Bill Kraus, Karoline Kuchenbaecker, Yi-Pin Lai, David Lanfear, Chim C. Lang, Claudia Langenberg, Michael Lee, Honghuang Lin, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Brandon D. Lowery, Jian’an Luan, Steven A. Lubitz, Patrik Magnusson, Anubha Mahajan, Anders Malarstig, Charlotte Manisty, Douglass Mann, Kenneth B. Margulies, Nicholas A. Marston, Hilary Martin, Winfried März, Kathryn McGurk, John J.V. McMurray, Olle Melander, Giorgio Melloni, David Miller, James C Moon, Ify R. Mordi, Thomas Morgan, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Lori Morton, Michael W. Nagle, Christopher P. Nelson, Christopher Newton-Cheh, Alexander Niessner, Teemu Niiranen, Raymond Noordam, Michela Noseda, Mahdad Noursadeghi, Christoph Nowak, Michelle L. O’Donoghue, Declan P O’Regan, Sisse Rye Ostrowski, Anjali T. Owens, Colin N. A. Palmer, Antonis Pantazis, Guillaume Paré, Helen M. Parry, Lavinia Paternoster, Ole Birger Pedersen, Markus Perola, Louis-Philippe Lemieux Perreault, Marie Pigeyre, Eliana Portilla-Fernandez, Sanjay K. Prasad, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Carolina Roselli, Jerome I. Rotter, Christian T. Ruff, Mark S. Sabatine, Neneh Sallah, Perttu Salo, Veikko Salomaa, Nilesh J. Samani, Naveed Sattar, Jessica van Setten, Sonia Shah, Svati Shah, Alaa A. Shalaby, Akshay Shekhar, Diane T. Smelser, Nicholas L. Smith, Erik Sørensen, Doug Speed, Sundararajan Srinivasan, Kari Stefansson, Steen Stender, David J. Stott, Nicholas P. Sunderland, Garðar Sveinbjörnsson, Per Svensson, Daniel I. Swerdlow, Petros Syrris, Mari-Liis Tammesoo, Jean-Claude Tardif, Upasana Tayal, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Pantazis I Theotokis, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Vinicius Tragante, Thomas A Treibel, Stella Trompet, Danny Tuckwell, Benoit Tyl, Andre G. Uitterlinden, Henrik Ullum, Ana M Valdes, Pim van der Harst, David van Heel, Ramachandran S. Vasan, Felix Vaura, Abirami Veluchamy, Monique Verschuuren, Niek Verweij, Peter M. Visscher, Christoffer Rasmus Vissing, Uwe Völker, Adriaan A. Voors, Marion van Vugt, Lars Wallentin, Xiaosong Wang, Yunzhang Wang, James S. Ware, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Quinn Wells, Harvey White, Kerri L. Wiggins, Jemma B. Wilk, L. Keoki Williams, Heming Xing, Xiao Xu, Jian Yang, Yifan Yang, Laura M. Yerges-Armstrong, Faiez Zannad, Faye Zhao, Jing Hua Zhao, Chaoqun Zheng, Sean L. Zheng
Institutions: Stanford University, Zuyderland Medisch Centrum, University of Washington, San Francisco VA Medical Center, University of California, San Francisco, San Francisco VA Health Care System, University College London, National Institute for Health and Care Research, UCL Biomedical Research Centre, Brigham and Women's Hospital, Harvard University, The University of Texas Southwestern Medical Center, The University of Texas Health Science Center at Houston, Northwestern University, Northwestern Medicine, University of Vermont, Beth Israel Deaconess Medical Center, University of Iceland, Icelandic Heart Association, University of California System
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, THE AGES STUDY - THE REYKJAVIK STUDY OF HEALTHY AGING FOR THE NEW MILLENUM, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, Discovery and Characterization of Rare Variant Effects in Dilated Cardiomyopathy via Large-Scale Biobank Analysis, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, CHS research resources for the cardiovascular health of older adults, Plasma proteomics in CHS and population biology, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Advanced Glycation Endproducts and Cardio-Renal Disease, Mentoring patient-oriented research in deep phenotyping of cardiac function for heart failure prevention, CHARGE consortium: omics discovery for CVD and aging phenotypes, CHS Events Follow-up Study, Quantifying cardiac structure and function to define the progression to hear failure in African Americans, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), Proteomic profiling to identify mechanisms of susceptibility and resilience to cardiac dysfunction in Black Americans, Late-life trajectories of cardiac function to define pathways of cardiac resilience, Infrastructure for mentored access to CHS data and specimens, Proteomic signatures to identify pathways underlying the progression to heart failure
OpenAlex ID: W7127583902