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Association of Coagulation Factor XI Level With Cardiovascular Events and Cardiac Function in Community-Dwelling
Yuekai Ji1,2, Michael J Zhang1,2, Wendy Wang3
1Cardiovascular Division, Department of Medicine (Y.J., M.J.Z., J.V-H., L.Y.C.), University of Minnesota Medical School, Minneapolis.
Insights
Lower levels of coagulation factor XI (FXI) are linked to increased heart failure (HF) risk, particularly in older adults. This finding is crucial for understanding FXI inhibitors
Area of Science:
- Cardiovascular Medicine
- Hematology
- Biochemistry
Background:
- Coagulation factor XI (FXI) inhibitors are a novel anticoagulant class.
- Animal studies suggest FXI inhibition may worsen heart failure (HF) and diastolic dysfunction.
- The ARIC study investigated the association between plasma FXI levels and cardiovascular outcomes.
Purpose of the Study:
- To examine the relationship between plasma FXI levels and cardiovascular events in humans.
- To assess the association of FXI levels with cardiac function, including HF and atrial fibrillation (AF).
- To validate findings in an independent cohort (CHS).
Main Methods:
- Analysis of 4471 participants from the ARIC study (Atherosclerosis Risk in Communities) with plasma FXI levels and echocardiographic data.
- Prospective assessment of incident HF and AF events through 2021.
- Validation of associations using an orthogonal FXI assay in the CHS cohort.
Main Results:
- Lower FXI levels were prospectively associated with a higher incidence of HF (HR, 1.36), especially in individuals aged ≥75 years.
- Lower FXI levels were cross-sectionally associated with increased odds of prevalent AF (OR, 1.96).
- Decreased FXI was linked to prevalent diastolic dysfunction, worse E/A ratio, larger left atrial volume, and increased left ventricular mass index.
Conclusions:
- Reduced plasma FXI levels are associated with increased HF incidence, particularly in older adults.
- Lower FXI is also linked to prevalent AF, diastolic dysfunction, and adverse cardiac structural/functional parameters.
- Further research is needed to evaluate potential risks of FXI inhibitors on cardiovascular events and cardiac function.
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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