Nonalcoholic fatty liver disease and atrial fibrillation: the main markers of this association

The prevalence of nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has increased globally in recent years. Ac - cording to recent studies, NAFLD and AF affect approximately 32 % and 0.51 % of the general population, respectively. Aim. To examine the association between NAFLD and AF by using the FibroTest-4 (FIB-4) and the NAFLD Fibrosis score (NFS) and measuring periostin

This can lead to decreased blood flow to the body and cause the heart to beat less effectively. AF increases the risk for stroke and heart failure [3]. Other dangers associated with AF include a higher risk of myocardial infarction, cognitive decline, and an increased risk of death from any cause.
The prevalence of NAFLD and AF has increased globally in recent years. According to latest studies, NAFLD affects approximately 32 % of the general population worldwide and is becoming one of the most common causes of chronic liver disease [4]. The prevalence of AF is also rising and affecting 0.51 % of the worldwide population, an increase of 33 % compared to the 1997 figures, with a higher incidence in older individuals and those with underlying medical conditions [5].
The increasing prevalence of both NAFLD and AF is likely due to the higher incidence of obesity, metabolic syndrome, and other lifestyle-related risk factors. The exact mechanism behind the association between NAFLD and AF is not fully understood, but it is thought to be related to factors such as oxidative stress, inflammation, and metabolic abnormalities that are common in both conditions [6]. Additionally, NAFLD may also increase the risk of other cardiovascular diseases, which can contribute to the development of AF [7].
In recent years, periostin has become as a promising biomarker for the evaluation of liver fibrosis in patients with NAFLD. Periostin is a protein involved in the extracellular matrix (ECM) regulation and implicated in the development of NAFLD [8]. However, more research is needed to fully understand the exact role of periostin in the development and progression of NAFLD.

Aim
To examine the association between NAFLD and AF by using the FibroTest-4 (FIB-4) and the NAFLD Fibrosis score (NFS) and measuring periostin levels.

Materials and methods
In this study, we enrolled 96 patients diagnosed with NAFLD who visited the State Institution "Territorial Medical Association of the Ministry of Internal Affairs of Ukraine in the Ivano-Frankivsk region" to examine the association between NAFLD and AF. The study population was divided into two groups: the main group -35 patients with both NAFLD and AF, and the control group -61 patients with NAFLD alone. The data were collected from medical records including demographic information, clinical and anthropometric characteristics, laboratory and imaging findings. All the patients signed their informed consent to participate in the study in accordance with the principles of the Helsinki Declaration.
The diagnosis of NAFLD and AF were made based on the EASL-EASD-EASO Clinical Practice Guidelines for the Management of NAFLD [9] and the 2020 ESC Guidelines for the diagnosis and management of AF developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS) [10], respectively.
Laboratory tests were performed in the clinical and diagnostic laboratory of State Institution "Territorial Medical Association of the Ministry of Internal Affairs of Ukraine in the Ivano-Frankivsk region". Full blood count was performed on an analyzer HTI MICROCC-20PLUS (High Technology, Inc. (HTI), Massachusetts, USA). Biochemical tests were performed on an analyzer HTI BioChem SA Semi-Auto Chemistry Analyzer BC-3002-C-UA (High Technology, Inc. (HTI), Massachusetts, USA).
All the patients underwent abdominal ultrasound examination to confirm NAFLD using a SonoScape S20 (SonoScape Medical Corporation, China) device.
To assess liver fibrosis, the following non-invasive indices were used: the FibroTest-4 (FIB-4) index and the NFS. The FIB-4 was calculated by the formula [11]: FIB-4 = Age × AST/Platelet count (109/L) ÷ √(Alanine Aminotransferase (ALT) (U/L)), where: age is the patient's age in years, AST is the patient's aspartate aminotransferase level in U/L, ALT is the patient's alanine aminotransferase level in U/L, platelet count is the patient's platelet count in 109/L. The FIB-4 score then was interpreted based on the following ranges: a score less than 1.45 was considered to indicate a low risk of liver fibrosis; a score between 1.45 and 3.25 was considered to indicate a moderate risk of liver fibrosis; a score greater than 3.25 was considered to indicate a high risk of liver fibrosis.
The formula for the NFS was [12]: NFS = -1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m 2 ) + 1.13 × AST/ALT ratio + 0.99 × Platelet count (109/L) + (0.99 if diabetic, otherwise 0) + 0.66 × Serum protein (g/dL), where: age (years) is the patient's age, BMI (kg/m 2 ) is the patient's Body Mass Index calculated as weight in kilograms divided by height in meters squared, AST/ALT ratio is the ratio of the patient's AST to ALT levels, platelet count (109/L) is the patient's platelet count in billions per liter, serum albumin (g/dL) is the patient's serum albumin level in grams per deciliter. The NFS is considered to be from 0 to 4 with higher scores indicating a greater likelihood of liver fibrosis. The NFS of less than 1.455 predicts the absence of advanced fibrosis, whereas a score greater than 0.675 predicts the presence of advanced fibrosis.
The statistical analysis for this study was conducted using IBM SPSS Statistics, version 26.0 (License Code QA2WSWS3QTR5TG6Y7TG6RF59JUY7H). Categorical variables were expressed as frequencies and percentages and compared through the use of the χ 2 and the Fisher exact test where applicable. Continuous variables were represented by their mean ± standard deviation or median with 25 % to 75 % interquartile range (IQR 25-75 %). The Kolmogorov-Smirnov and Shapiro-Wilk tests were applied to determine normal distribution. Normally distributed continuous variables were compared between groups through the independent t-test, while non-normally distributed continuous variables were compared through the Mann-Whitney test. Receiver operating characteristic (ROC) curves were plotted, and the area under the curve (AUC) was calculated. Logistic regression analysis was used to evaluate the independent impact of the study variables on the study outcomes. Results were reported as two-tailed significance tests, with a p-value of less than 0.05 considered statistically significant.
The results of the univariable binomial logistic regression have shown that NAFLD + AF was associated with a higher risk compared to NAFLD alone ( Table 2).
Age, male sex, diabetes mellitus, BMI, and obesity were all found to significantly increase the risk of NAFLD + AF with a p-value less than 0.05. The odds ratio (OR) of NAFLD + AF increased by 1 The results suggest that older individuals, males, those with diabetes, higher BMI, and obesity are at a higher risk for NAFLD + AF. Additionally, elevated periostin levels and NAFLD are also significant risk factors for NAFLD + AF.
These results suggest that NFS is the most effective variable in differentiating between the two patient groups followed by periostin and then FIB-4. However, it should be noted that there was at least one tie between the positive

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1С 1В and negative actual state groups in the data, which could potentially bias the results.
Overall, the results suggest that the NFS risk and periostin level have good discriminative ability, while the FIB-4 score has moderate discriminative ability, in predicting a positive state variable (presence of AF in patients with NAFLD) among patients enrolled in the study.

Discussion
The current healthcare is marked by the rapid increase in NAFLD and AF, two conditions which are not only affect increasing numbers of individuals globally, but also pose significant challenges to the healthcare system.
The findings about statistically significant differences in NFS, FIB-4 and periostin levels in patients with both NAFLD and AF compared to those with NAFLD alone are consistent with the growing body of evidence linking the two conditions. The presence of AF in patients with NAFLD has been shown to have a significant impact on the degree of liver fibrosis.
While the exact mechanisms linking NAFLD and AF remain unclear, several common risk factors, such as obesity, diabetes mellitus, and male sex, have been implicated in the development of both conditions.
Other studies have investigated the underlying mechanisms linking NAFLD and AF, and suggested that the presence of inflammation, oxidative stress, and metabolic dysfunction in patients with NAFLD may increase the risk of AF. A meta-analysis of 6 cohort studies including over 600.000 individuals conducted by X. Cai et al. has shown that NAFLD was associated with an increased risk of AF compared to non-NAFLD, even after adjusting for multiple cardiometabolic risk factors. The RR was 1.19 (95 % CI 1.04-1.31) with a significant increase in the absolute risk of 1.3 per 1000 person-years [13].
The use of NFS, FIB-4 in the evaluation of patients with NAFLD and AF may provide valuable information for the identification of patients at higher risk for liver fibrosis and adverse outcomes. A study by Kang et al. has found that AF patients were older, had higher BMI, and larger waist circumference than those without AF. AF was independently linked to advanced liver fibrosis in NAFLD patients, as assessed by both NFS and Fib-4 cut-off values (COVs). The final adjusted odds ratios were 2.85 (p = 0.004) for NFS low-COV group and 12.29 (p < 0.001) for NFS high-COV group, and 2.49 (p < 0.001) for FIB-4 low-COV group and 3.84 (p = 0.016) for Fib-4 high-COV group [14].
A meta-analysis by Mozes et al. has found that NFS was a reliable and non-invasive tool for the assessment of liver fibrosis in these patients. The accuracy of FIB-4, NFS and LSM-VCTE for detecting advanced fibrosis was 0.76, 0.73 and 0.85, respectively. Using a combination of FIB-4 and LSM-VCTE, 66 % of patients with advanced fibrosis were correctly identified with a specificity of 86 %, but 33 % still needed a biopsy for confirmation [15].
NFS and FIB-4 indicators have also been shown to have prognostic value in patients with NAFLD and AF after ablation. A study by Wang [16].
Several previous studies have investigated the relationship between NAFLD and AF and found that patients with NAFLD and AF tended to have higher levels of periostin.
High periostin levels are also strongly associated with severity of NAFLD and AF. A study by Zhu et al. has demonstrated that elevated NFS and periostin levels were independently associated with an increased risk of liver-related and cardiovascular events in patients with NAFLD. The frequency of NAFLD was increased with higher periostin levels (29.8 % to 67.2 %, p < 0.001) and periostin was found  were identified as independent predictors of AF recurrence [18].
The observed differences in NFS, FIB-4 and periostin levels in patients with NAFLD and AF compared to those with NAFLD alone highlight the importance of considering the presence of AF in patients with NAFLD, as it may impact the assessment of liver fibrosis and the selection of appropriate therapeutic strategies. Further studies are needed to fully examine the clinical implications of these findings and gain a better understanding of the underlying mechanisms linking NAFLD and AF.

Conclusions
1. These findings have suggested a strong association between NAFLD and AF and highlighted the importance of considering AF as a potential complication in patients with NAFLD.
2. Both the use of the FIB-4 and NFS indices and measurement of periostin levels have been proved to be effective in detecting this association.
3. Furthermore, these may work for clinical practice, including the need for greater vigilance and monitoring for AF in NAFLD patients.
Prospects for further research. Future plans include closer examination of left atrial and left ventricular changes in patients with NAFLD and AF and the development of new treatment strategies to alleviate the inflammatory damage.