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Inflammation in liver fibrosis and atrial fibrillation: A prospective population-based proteomic study
Joost Boeckmans1,2,3, Maurice Michel1,2,4, Alexander Gieswinkel5
1Metabolic Liver Research Center, Department of Medicine, University Medical Center Mainz, Mainz, Germany.
Insights
Liver fibrosis, indicated by the FIB-4 index, is linked to prevalent atrial fibrillation (AFib). The protein CXCL10 is associated with both liver fibrosis and AFib, suggesting a potential therapeutic target.
Area of Science:
- Cardiology
- Hepatology
- Proteomics
Background:
- Elevated liver stiffness is associated with atrial fibrillation (AFib) in the general population, but the underlying mechanism is unclear.
- Metabolic dysfunction-associated steatotic liver disease (MASLD)-related liver fibrosis may contribute to AFib pathophysiology through systemic inflammation.
Purpose of the Study:
- To investigate the relationship between liver fibrosis markers and atrial fibrillation in a general population.
- To identify potential protein biomarkers linking liver fibrosis and AFib using targeted proteomics.
Main Methods:
- Prospective enrollment of 11,509 participants with 5-year follow-up.
- Utilized the fibrosis-4 (FIB-4) index as a liver fibrosis surrogate and performed proteomics analysis with the Olink inflammation panel.
- Validated findings using NAFLD fibrosis score (NFS), APRI, and repeat proteomics.
Main Results:
- The FIB-4 index predicted prevalent AFib (aOR 1.100 per SD, p=0.026) but not incident AFib.
- Proteomics identified CXCL10 as a key protein associated with both the FIB-4 index and prevalent AFib.
- The association between FIB-4 index, CXCL10, and AFib was confirmed at 5-year follow-up and validated with NFS and APRI.
Conclusions:
- CXCL10 is significantly linked to liver fibrosis, as measured by the FIB-4 index, and to prevalent atrial fibrillation.
- These findings suggest CXCL10 as a potential mediator in the association between liver fibrosis and AFib, offering avenues for drug development.
Background & Aims:
Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear.
Methods:
Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics.
Results:
A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p <0.0001; CXCL10 [per SD] - AFib aOR 1.455 with 95% CI 1.217-1.741, p <0.0001), reproduced using the NFS and APRI, and corresponding to increased serum levels.
Conclusions:
CXCL10 is linked to liver fibrosis, as determined by the FIB-4 index, and to prevalent AFib.
Impact And Implications:
How elevated liver stiffness relates to atrial fibrillation in the general population remains to be clarified. We hypothesized that systemic inflammation against a background of liver fibrosis produced from metabolic dysfunction-associated steatotic liver disease (MASLD), is involved in the pathophysiology of atrial fibrillation. Using large-scale targeted proteomics, we found that CXCL10 is related to both liver fibrosis, as defined by the fibrosis-4 index, and to atrial fibrillation. These results can aid evidence-based drug development for patients with atrial fibrillation and MASLD-related liver fibrosis.
