Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling Adults: From ARIC and CHS
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.
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Received: 27 April 2024
Accepted: 15 October 2024
Published online: 21 November 2024
Published in print: 11 February 2025
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Disclosures
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.
Sources of Funding
The ARIC study (Atherosclerosis Risk in Communities) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), and Department of Health and Human Services ([HHS] contract Nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005). The ARIC Neurocognitive Study is supported by NIH (grant Nos. U01HL096812, U01HL096814, U01HL096899, U01HL096902, and U01HL096917) and NHLBI, National Institute of Neurological Disorders and Stroke, National Institute on Aging, and National Institute of Deafness and Other Communication Disorders. CHS (Cardiovascular Health Study) is supported by NHLBI (contract Nos. HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006; and grant Nos. U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114), with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through the National Institute on Aging (grant No. R01AG023629). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. FXI (factor XI) measurement was supported by NHLBI (grant No. HL0597367). This study is funded by contract No. R01HL141288. M.J.Z. is supported by grant No. F32HL152523 and American Heart Association grant No. 899027. W.W. is supported by grant No. T32HL007779. A.A. is supported by grant Nos. R01HL137338, K24HL148521, and P30AG066511. A.M.S. is supported by grant Nos. R01HL135008, R01HL143224, R01HL150342, R01HL148218, and K24HL152008. L.Y.C. is supported by grant Nos. R01HL141288, R01HL126637, RF1NS127266, R01HL158022, R01AG075883, and K24HL155813. The sponsor had no role in the design and conduct of the study; data collection, management, analysis, or interpretation; manuscript preparation, review, or approval; nor the decision to submit the manuscript for publication.
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