Association between serum cholinesterase and the prevalence of atrial fibrillation in Chinese hypertensive population: a cross-sectional study

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting approximately 300–1000 million individuals worldwide [1]. Its incidence is positively correlated with age [2]. Epidemiological studies have demonstrated that AF prevalence ranges from 2% in the general population to 10–12% in individuals aged 80 and above [3]. With the global increase in life expectancy and the prolonged survival of individuals with chronic diseases, AF has emerged as one of the most common cardiovascular disorders in the twenty-first century, resulting in a significant rise in healthcare burden [4]. Despite significant progress in understanding AF and its corresponding treatment strategies in the past decade, early screening and diagnosis of AF remain challenging due to its asymptomatic nature and unpredictable onset time. Camm et al. proposed that one-third of all AF patients have asymptomatic AF, a finding that has been subsequently confirmed in other studies [5, 6].

The pathophysiological mechanisms of AF primarily involve electrical remodeling and structural remodeling [7]. Its occurrence and progression are influenced by various factors. These factors can increase the risk of AF to different extents, thereby promoting the initial development and onset of AF alone or in combination [8, 9]. Hypertension (HT) is the most common modifiable risk factor for AF. Studies have demonstrated that hypertensive patients have a 1.7 times higher risk of developing AF compared to individuals with normal blood pressure [10, 11]. Hypertension accounts for more than one-fifth of new cases of AF [12], and the risk of AF increases by 21% for every 20 mmHg increase in systolic blood pressure (SBP) [13, 14]. Therefore, early identification of risk factors for AF is crucial for hypertensive patients. Furthermore, emerging evidence suggests a link between non-alcoholic fatty liver disease (NAFLD) and the risk of AF [15‐17]. However, there have been conflicting reports regarding the association between fatty liver disease and AF [18, 19]. Cholinesterase, primarily synthesized by the liver, is an important laboratory indicator for the clinical diagnosis and prediction of NAFLD. Currently, it remains unclear whether serum cholinesterase (SChE) is an independent risk factor for AF. Therefore, the objective of this study is to investigate the association between the SChE index and the risk of AF in a hypertensive population.

Hypertension is widely recognized as the predominant risk factor for AF. Studies have demonstrated that individuals with hypertension are 1.7 times more likely to develop AF compared to those with normal blood pressure [10, 11]. Moreover, patients who have experienced prolonged high blood pressure or inadequate blood pressure management are at a heightened risk of experiencing complications associated with AF, notably stroke, heart failure, and bleeding [25, 26]. Consequently, the early detection of high-risk patients with AF holds significant importance, particularly for individuals with hypertension. As we know, there is a NAFLD association with AF [27]. Liver biopsy is the gold standard for the diagnosis of NAFLD, but its disadvantages such as invasiveness, sampling error, and possible complications limit its clinical application [28]. ALT is a common way to detect NAFLD and assess the severity of liver injury, but its capability to identify NAFLD is doubted [29, 30]. Therefore, the establishment of a more sensitive biomarker to detect NAFLD is necessary. In a large cross-sectional study, SChE was shown to be better markers of fatty liver than ALT [31]. However, the correlation between the SChE index and AF risk in HT patients is still unclear. In this study, we found that SChE levels were significantly associated with AF prevalence in hypertensive patients. In the adjusted model, this relationship still existed. We further stratified the sample data according to whether the participants had fatty liver disease. In the stratified data, the correlation between SChE and AF prevalence was still significant. It showed that SChE may be an independent risk factor for AF.

Serum cholinesterase, also known as pseudo- or butyryl-cholinesterase (BChE), is synthesized by hepatocytes, and its half-life in serum is 11 days [32]. The concentration of SChE is affected by a variety of factors, such as malnutrition, systemic inflammation and liver cell damage [33, 34]. In addition, studies have shown that SChE has a predictive effect on a variety of cardiovascular diseases. There is a positive correlation between high BChE activity and identified cardiovascular risk factors. For example, Goliasch and Alcantara et al. demonstrated that BChE activity values were significantly associated with arterial hypertension [35, 36]. Furthermore, several studies demonstrated an association between BChE activity and metabolic risk factors (such as obesity, hyperlipidemia and diabetes) [37‐39]. Interestingly, BChE activity is negatively correlated with cardiovascular mortality and seems to be a predictor of cardiovascular disease prognosis. Low levels of SChE increased the risk of death in patients with acute myocardial infarction [40], acute heart failure, stable coronary heart disease [41], ischemic stroke and other diseases [42]. All of the above conditions may lead to a higher risk of AF. And a study accidentally found a case of cholinesterase deficiency demonstrating sick sinus syndrome (SSS) and short paroxysms of AF associated with a relatively slow ventricular response [43]. Cholinesterase deficiency observed in this patient manifests as the loss of BChE activity. But most patients with silent cholinesterase activity showed no serious arrhythmia, suggesting that some mechanisms compensate for the cholinesterase deficiency [44]. In fact, BChE knockdown has been shown to increase the activity of AChE and other kinases [45]. Currently, most evidence supports that NAFLD may be linked to a slightly higher risk of developing AF [46]. As we all known, SChE is increased in patients with fatty liver [31]. Our research revealed a negative correlation between the SChE index and the risk of AF in hypertensive patients, which differed from our conventional comprehension. This phenomenon can potentially be explained by a new study, which suggested that higher liver stiffness, in particular among those without steatosis, was associated with prevalent atrial fibrillation [47]. This association could be driven by venous congestion instead of fibrogenesis. Therefore, further longitudinal studies with accurate standardized definitions of steatosis and AF are needed to determine strong evidence of the independent association between the two diseases. Based on the currently limited available references, we aim to provide an alternative explanation for this disparity. We hypothesize that the potential mechanism underlying the correlation between the SChE index and AF could be attributed to systemic inflammation. Firstly, our target audience is patients with high blood pressure. Chronic inflammation is involved in the pathogenesis of hypertension [48]. Secondly, it has been shown that the production of BChE and albumin in the liver is coupled, and these biochemical variables may be considered as negative inflammatory reactants whose serum levels are inversely correlated with the increase in the degree of clinical inflammation [49, 50]. In our study, we found that patients with combined AF had lower SChE levels and higher hs-CRP levels compared to patients with only hypertension, which confirmed this point.

For individuals diagnosed with hypertension, it is crucial to promptly identify high-risk patients who may develop atrial fibrillation. This early identification enables early screening, diagnosis, and intervention. Timely and accurate diagnosis of AF can effectively prevent complications, reduce hospitalization related to AF, and lower the mortality rate associated with AF. Although many studies have confirmed that serum biomarkers, echocardiographic markers and specific patterns on brain imaging can predict AF [51‐54]. However, to our knowledge, this study is the first to try to determine that SChE is a possible predictive marker of AF in hypertension patients. We found that the SChE index was significantly associated with AF prevalence in hypertensive patients. And the measurement of SChE is easy to obtain in routine blood sampling analysis. Therefore, it represents a cheap and easy-to-obtain AF risk prediction method for hypertensive patients.

Our study has some limitations. First, this was a cross-sectional study and no statements about causality are made. Second, our study had small samples and was single center, which may cause bias. Although we adjusted for confounders in the multivariate analysis, the potential confounders were not completely eliminated. Third, hospitalized patients were typically older and had more underlying diseases. Last, diagnosis of NAFLD was made by ultrasonography rather than liver biopsy, the gold standard technique for detecting fatty liver. And the subjects' drinking history also lacked detailed records, so it was still unclear whether fatty liver was caused by alcohol. In addition, we only included HT patients in this study. Therefore, the suitable population of our findings is limited. Moreover, studies of a large and diverse population should be conducted to further verify. To our knowledge, this is the first study to investigate the association between the SChE index and AF patients with HT.

In conclusion, our study showed that SChE was significantly negatively correlated with the prevalence of AF in patients with hypertension. And this correlation was not affected by whether patients with fatty liver.