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. 2025 Sep 23;86(12):860-873.
doi: 10.1016/j.jacc.2025.06.050. Epub 2025 Aug 27.

A Polygenic Risk Score to Predict Incident Heart Failure Across the Spectrum of Cardiovascular Risk

Paul M Haller  1 , Giorgio E M Melloni  2 , David D Berg  2 , Frederick K Kamanu  2 , Yi-Pin Lai  2 , Elliott M Antman  3 , Deepak L Bhatt  4 , Marc P Bonaca  5 , Christopher P Cannon  3 , Robert P Giugliano  2 , Michelle L O'Donoghue  2 , Benjamin M Scirica  2 , Stephen D Wiviott  2 , Daniel Chasman  3 , Brendan M Everett  3 , Eugene Braunwald  2 , David A Morrow  2 , Paul M Ridker  3 , Patrick T Ellinor  6 , Marc S Sabatine  2 , Christian T Ruff  2 , Nicholas A Marston  7
Affiliations

A Polygenic Risk Score to Predict Incident Heart Failure Across the Spectrum of Cardiovascular Risk

Paul M Haller et al. J Am Coll Cardiol. .

Abstract

Background: The clinical utility of a heart failure (HF) polygenic risk score (PRS) is uncertain.

Objectives: The purpose of this study was to investigate the ability of an HF PRS to predict new-onset HF in individuals across the spectrum of cardiovascular risk.

Methods: An HF PRS (>1 million single nucleotide variations) was used to stratify individuals from 7 clinical studies to low (quintile [Q] 1), intermediate (Q2-Q4), or high (Q5) genetic risk. In 6 trials of patients at elevated cardiovascular risk, HRs adjusted for clinical factors were derived for the risk of hospitalization for HF using Cox-PH models, and discrimination and calibration was explored. Analyses were conducted in a separate data set of individuals at low cardiovascular risk.

Results: We studied 74,897 patients without HF, of which 51,627 were at elevated cardiovascular risk (median age 65 years; 71% men; median follow-up 2.5 years). After adjusting for clinical factors, individuals with intermediate and high HF PRS carried a 2- and 5-fold increased rate of new-onset HF, respectively (intermediate risk: HRadj: 2.01 [95% CI: 1.62-2.49]; P < 0.001; high-risk: HRadj: 5.00 [95% CI: 3.99-6.27]; P < 0.001). Addition of the HF PRS to a clinical model improved the AUC (0.787 [95% CI: 0.775-0.798] to 0.822 [95% CI: 0.811-0.832]). Results were consistent in 23,270 individuals at low cardiovascular risk over 20-year follow-up.

Conclusions: An HF PRS is a strong and independent predictor for new-onset HF in individuals across the spectrum of cardiovascular risk. The polygenic contribution to HF is complementary to established clinical risk assessment.

Keywords: genetics; heart failure; polygenic risk; polygenic risk score; risk prediction.

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Conflict of interest statement

Funding Support and Author Disclosures DECLARE-TIMI 58 and PEGASUS-TIMI 54 were funded by AstraZeneca; ENGAGE AF-TIMI 48 was funded by Daiichi-Sankyo Pharma; FOURIER was funded by Amgen; SAVOR-TIMI 53 was funded by AstraZeneca and Bristol Myers Squibb; and SOLID-TIMI 52 was funded by GlaxoSmithKline. Drs Haller, Melloni, Berg, Kamanu, Lai, Giugliano, O'Donoghue, Scirica, Wiviott, Braunwald, Morrow, Sabatine, Ruff, and Marston are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, The Medicines Company, and Zora Biosciences. Dr Haller has received travel grants from the German Center of Cardiovascular Research (DZHK); has received funding by the German Foundation for Heart Research; and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)–10086/1-1. Dr Berg has received institutional research grant support through Brigham and Women’s Hospital from AstraZeneca and Pfizer; has received consulting fees from AstraZeneca, Pfizer, Mobility Bio, Inc, and Youngene Therapeutics; has received honoraria from the Medical Education Speakers Network (MESN), Metabolic Endocrine Education Foundation, and USV Private Limited; and participates on clinical endpoint committees for studies sponsored by Beckman Coulter, Kowa Pharmaceuticals, Novo Nordisk, and Tosoh Biosciences. Dr Antman has received grants from Daiichi-Sankyo during the conduct of the study; and is a member of the TIMI Study Group. Dr Bhatt has served on the Advisory Board of Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; serves on the Board of Directors of American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); is a consultant for Broadview Ventures and Hims; has served on Data Monitoring Committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), JACC (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); has served as Deputy Editor of Clinical Cardiology; is named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon (neither he nor Brigham and Women's Hospital receive any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; is a Trustee of the American College of Cardiology; and has received unfunded research from FlowCo. Dr Bonaca is the Executive Director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, which receives or has received research grant/consulting funding between August 2021 and present from Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma, Alnylam Pharmaceuticals, Amgen, Angionetics, Anthos Therapeutics, ARCA Biopharma, Array BioPharma, AstraZeneca and Affiliates, Atentiv, Audentes Therapeutics, Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, Bristol-Meyers Squibb, Cambrian Biopharma, Cardiol Therapeutics CellResearch, Cleerly, Cook Regentec, CSL Behring, Eidos Therapeutics, EP Trading, EPG Communication Holdings, Epizon Pharma, Esperion Therapeutics, Everly Well, Exicon Consulting, Faraday Pharmaceuticals, Foresee Pharmaceuticals, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, IQVIA, Janssen and Affiliates, Kowa Research Institute, Kyushu University, Lexicon Pharmaceuticals, Medimmune, Medpace, Merck and Affiliates, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Osiris Therapeutics, Pfizer, PhaseBio Pharmaceuticals, Pharmaceutical Product Development LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc, Regio Biosciences, Saint Luke’s Hospital of Kansas City, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics, Smith and Nephew, Stanford Center for Clinical Research, Stealth BioTherapeutics, State of Colorado Cancer, Cardiovascular, and Pulmonary Disease Grant, Brigham and Women’s Hospital, Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, Worldwide Clinical Trials, WraSer, and Yale Cardiovascular Research Group. Dr Cannon has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Novo Nordisk, and salary support from Colorado Prevention Center Clinical Research, which gets research grant support from Amgen, Bayer, Cleerly, Esperion, Lexicon, and Silence; has received consulting fees from Amryt/Chiesi, Amgen, Ascendia, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly, Janssen, Lexicon, Milestone, Pfizer, and Rhoshan; and has served on the Data and Safety Monitoring Boards for the Areteia, Novo Nordisk, ROMTherapy, Inc, and the Veterans Administration. Dr Giugliano has received clinical trials/research support from Amgen, Anthos Therapeutics, Daiichi-Sankyo, and Ionis; has received honoraria for lectures/CME programs from Amgen, Big Sky Cardiology, CADECI, Daiichi-Sankyo, Dr Reddy’s Laboratories, Medical Education Resources (MER), Menarini, and SUMMEET; and serves as a consultant for AstraZeneca, Beckman Coulter, Daiichi-Sankyo, Inari, Inventiva, Perosphere, PhaseBio Pharmaceuticals, Samsung, and Sanofi Aventis. Dr O'Donoghue has reported grants received by The TIMI Study Group through the institution from Amgen, AstraZeneca, Novartis, Merck, and Janssen Medicines Company; has received consulting and/or DSMB fees from Amgen, Novartis, Janssen, AstraZeneca, and CRICO; and has received honoraria from Medscape Cardiology. Dr Scirica has received institutional research support through Brigham and Women’s Hospital from Amgen, Better Therapeutics, Boehringer Ingelheim, Merck, Novo Nordisk, Pfizer, and Verve Therapeutics; has received consulting fees from Abbvie (Data and Safety Monitoring Board), Amgen, AstraZeneca (Data and Safety Monitoring Board), Bayer, Boehringer Ingelheim (Data and Safety Monitoring Board), Elsevier Practice Update Cardiology, Hanmi (Data and Safety Monitoring Board), Lexeo (Data and Safety Monitoring Board), Novo Nordisk, and Verve Therapeutics; and has received equity in Health [at] Scale. Dr Wiviott has received research grants from Amgen, AstraZeneca, Janssen, Merck, and Pfizer; has received consulting fees from Icon, Novo Nordisk, and Verian; has received speaking honoraria from Harvard Medical School; and his Spouse, Dr Caroline Fox, is a former employee of Merck, Flagship Labs, and current employee of Vertex. Dr Everett has received research grants from Novo Nordisk and the Patient Centered Outcomes Research Institute; has received consulting fees from Ipsen Pharmaceuticals, Janssen Pharmaceuticals, Eli Lilly, Kowa, Merck, Novo Nordisk, and the American Heart Association; has received speaking honoraria from Harvard Medical School; and has received royalties from UptoDate. Dr Ridker has received institutional research grant support from the National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk Kowa, Amarin, Pfizer, and Esperion; has served as a consultant to Novartis, Novo Nordisk, Agepha, CSL Behring, Nodthera, Tourmaline, Cardio Therapeutics, AstraZeneca, Merck, SOCAR, Eli Lilly, New Amsterdam, and Caristo; has minority shareholder equity positions in Uppton, Bitteroot Bio, and Angiowave; and has received compensation for service on the Peter Munk Advisory Board (University of Toronto), the Leducq Foundation, Paris FR, and the Baim Institute. Dr Braunwald has received research grants through Brigham and Women’s Hospital from AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; and has consultancies with Amgen, Bristol Myers Squibb, Boehringer Ingelheim, Cardurion, Edgewise, and Verve. Dr Morrow has received consulting fees from Abbott Laboratories, ARCA Biopharma, InCarda, Inflammatix, Merck and Co, Novartis, and Roche Diagnostics. Dr Ellinor has received grants from Bayer, IBM Research, Novo Nordisk, Pfizer, and Bristol Myers Squibb; and has served on advisory boards or consulted for Bayer, MyoKardia, and Novartis. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis, Marea, Merck, Novartis, Pfizer, Saghmos Therapeutics, and Verve Therapeutics; and has served as a consultant for Amgen, AMPEL BioSolutions, Anthos Therapeutics, Inc, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Canadian Cardiovascular Research Network, Dr Reddy’s Laboratories, Fibrogen, General Medicines, Merck, Moderna, North American Thrombosis Foundation, Novo Nordisk, Precision BioSciences, and Silence Therapeutics. Dr Ruff has received research grants through Brigham and Women’s Hospital from Anthos, AstraZeneca, Daiichi-Sankyo, Janssen, and Novartis; and has received honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi-Sankyo, Janssen, and Pfizer. Dr Marston has received research grant support from the National Institutes of Health and involvement in clinical trials with Amgen, Ionis, Pfizer, Novartis, and AstraZeneca; has received consultant fees from Beckman Coulter, Cleerly, Inc (CPC Clinical Research), and Viz.ai; and has received honoraria for lectures/CME Programs from Amgen, Illumina, and Medical Education Speakers Network (MESN). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.