Multicenter Study

. 2025 Feb 11;151(6):356-367.

doi: 10.1161/CIRCULATIONAHA.124.070278. Epub 2024 Nov 21.

Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS

Yuekai Ji^#^{1

2}, Michael J Zhang^#^{1

2}, Wendy Wang³, Faye L Norby³, Anne A Eaton⁴, Riccardo M Inciardi⁵, Alvaro Alonso⁶, Sanaz Sedaghat³, Peter Ganz⁷, Jeremy Van't Hof^{1

2}, Scott D Solomon⁸, Paulo H M Chaves⁹, Susan R Heckbert¹⁰, Amil M Shah^#¹¹, Lin Yee Chen^#^{1

2}

Affiliations

¹ Cardiovascular Division, Department of Medicine (Y.J., M.J.Z., J.V-H., L.Y.C.), University of Minnesota Medical School, Minneapolis.
² Lillehei Heart Institute (Y.J., M.J.Z., J.V-H., L.Y.C.), University of Minnesota Medical School, Minneapolis.
³ Divisions of Epidemiology and Community Health (W.W., F.L.N., S.S.), School of Public Health, University of Minnesota, Minneapolis.
⁴ Biostatistics (A.A.E.), School of Public Health, University of Minnesota, Minneapolis.
⁵ Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Italy (R.M.I.).
⁶ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia (A.A.).
⁷ Department of Medicine, University of California, San Francisco (P.G.).
⁸ Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.).
⁹ Benjamin Leon Center for Geriatric Research and Education, Department of Cellular and Molecular Medicine, Florida International University, Miami (P.H.M.C.).
¹⁰ Department of Epidemiology, University of Washington School of Public Health, Seattle (S.R.H.).
¹¹ Division of Cardiology, Department of Medicine, UT Southwestern Medical Center, Dallas, TX (A.M.S.).

^# Contributed equally.

PMID: 39569504
PMCID: PMC11810597 (available on 2026-02-11)
DOI: 10.1161/CIRCULATIONAHA.124.070278

Multicenter Study

Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS

Yuekai Ji et al. Circulation. 2025.

. 2025 Feb 11;151(6):356-367.

doi: 10.1161/CIRCULATIONAHA.124.070278. Epub 2024 Nov 21.

Authors

Affiliations

¹ Cardiovascular Division, Department of Medicine (Y.J., M.J.Z., J.V-H., L.Y.C.), University of Minnesota Medical School, Minneapolis.
² Lillehei Heart Institute (Y.J., M.J.Z., J.V-H., L.Y.C.), University of Minnesota Medical School, Minneapolis.
³ Divisions of Epidemiology and Community Health (W.W., F.L.N., S.S.), School of Public Health, University of Minnesota, Minneapolis.
⁴ Biostatistics (A.A.E.), School of Public Health, University of Minnesota, Minneapolis.
⁵ Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Italy (R.M.I.).
⁶ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia (A.A.).
⁷ Department of Medicine, University of California, San Francisco (P.G.).
⁸ Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.).
⁹ Benjamin Leon Center for Geriatric Research and Education, Department of Cellular and Molecular Medicine, Florida International University, Miami (P.H.M.C.).
¹⁰ Department of Epidemiology, University of Washington School of Public Health, Seattle (S.R.H.).
¹¹ Division of Cardiology, Department of Medicine, UT Southwestern Medical Center, Dallas, TX (A.M.S.).

^# Contributed equally.

PMID: 39569504
PMCID: PMC11810597 (available on 2026-02-11)
DOI: 10.1161/CIRCULATIONAHA.124.070278

Abstract

Background: Coagulation factor XI (FXI) inhibitors are a promising and novel class of anticoagulants, but a recent animal study found that FXI inhibition exacerbated diastolic dysfunction and heart failure (HF). In the ARIC study (Atherosclerosis Risk in Communities), we investigated whether plasma FXI level was associated with cardiovascular events and cardiac function.

Methods: ARIC was our primary analytic cohort. We included 4471 participants (median age, 75 years; 57% female; 17% Black) who attended visit 5 (2011-2013) with Somalogic-quantified plasma FXI levels and echocardiographic cardiac function. Prevalent HF and atrial fibrillation (AF) cases were defined as having HF or AF diagnosed at or before each participant's visit 5 exam date. Incident HF and AF events were ascertained through 2021. Associations were assessed using Cox, logistic, and linear regression models. Primary prospective associations were also validated in the CHS (Cardiovascular Health Study) using an orthogonal FXI assay (enzyme-linked immunosorbent assay).

Results: At ARIC visit 5, there were 665 and 419 participants with prevalent HF and AF, respectively. During a median follow-up of 9 years, there were 580 and 788 incident HF and AF events, respectively. Lower FXI level was associated prospectively with higher incidence of HF (hazard ratio [HR], 1.36 [for each 1-unit decrement of log₂-transformed FXI level] [95% CI, 1.01-1.83]) but not incident AF, and cross-sectionally with increased odds of AF (odds ratio [OR], 1.96 [95% CI, 1.23-3.07]) but not HF. In age-stratified analyses, decreased FXI was associated with higher incidence of HF in participants ≥75 years of age (HR, 1.57 [95% CI, 1.08-2.28]) but not <75 years of age (HR, 1.11 [95% CI, 0.68-1.79]). The inverse FXI-HF association was validated in CHS (HR, 1.18 [95% CI, 1.02-1.36]). At ARIC visit 5, lower FXI level was also associated with higher prevalence of diastolic dysfunction and worse E/A ratio, left atrial (LA) volume index, LA function, and left ventricular mass index, but not left ventricular ejection fraction or global longitudinal strain.

Conclusions: Decreased FXI level is associated with greater incidence of HF, especially in older adults. It is also associated with prevalent AF, worse diastolic function, worse LA function, and greater LA size. More research is needed to assess potential unwanted effects of FXI inhibition on the risk of cardiovascular events and cardiac function.

Keywords: atrial fibrillation; echocardiography; factor XI; fibrosis; follow-up studies; heart failure.

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Conflict of interest statement

Dr Shah reported funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Philips Ultrasound (grant to Brigham and Womens Hospital [BWH]), personal fees from Philips Ultrasound advisory board, grants from Novartis (to BWH), personal fees from Edwards life sciences consultant, and personal fees from Janssen advisory board outside the submitted work. Dr Solomon reported funding from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI (grant to institution, outside scope of manuscript); and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi- Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, PureHealth consulting, outside scope of work. Dr Chen reported funding from NIH. The other authors reported no conflicts.

References

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Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS

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Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS

Authors

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Abstract

Conflict of interest statement

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