Higher Monocyte/Lymphocyte Ratio Is Associated with Impaired Glomerular Function and Cardiac Remodeling in Elderly Patients with Atrial Fibrillation: A Retrospective Study

1. Introduction

Atrial fibrillation (AF) is a common supraventricular arrhythmia in clinical practice, especially in elderly population. Increased stroke risk has been confirmed in patients with AF [1]. The death rate resulted from thromboembolism-related events in elderly with AF has been shown to decrease after treatment with anticoagulant medication. However, the risk of death from cardiovascular events remains elevated in the AF patients even treated with appropriate anticoagulant medication [2]. Serious arrhythmias are usually firstly considered to be responsible for the increased cardiovascular death in the patients with AF [1]. Furthermore, cardiac adverse remodeling might be an important pathologic substrate for higher cardiovascular mortality in the patients with AF [3,4]. Studies have suggested that chronic inflammation was associated with increased incidence of AF in patients with cardiac adverse structural abnormalities [5,6]. The elevated inflammatory markers such as C-reactive protein and interleukin-6 have been reported to be associated with cardiac adverse remodeling and increased cardiovascular death in patients with AF [7,8]. Meanwhile, additional easily available inflammatory marker is monocyte/lymphocyte ratio (MLR) that has been reported to be associated with increased cardiovascular death [9]. However, it remains unclear whether the MLR is associated with cardiac adverse remodeling. Therefore, this study investigated the association of MLR with cardiac remodeling and related clinical biochemical indexes in elderly with AF.

2. Materials and Methods

2.1. Study Design and Participants

A cross-sectional study was conducted, in which 1154 of hospitalized Chinese elderly (aged ≥ 65 years) with non-valvular AF [persistent AF (n=596); long-term persistent AF (n=442); permanent AF (n=116)] were collected retrospectively by review of medical records from 2014 to 2021 in our geriatric inpatient department. All of the patients completed electrocardiographic examination, color Doppler echocardiography and biochemical tests [10]. This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of the First Affiliated Hospital of Chongqing Medical University (No. 2022-K390). The ethics committee waived the need for patients’ written informed consent because of anonymous nature of the clinical data acquired retrospectively.

White blood cell (WBC) count in peripheral blood was assessed using a Sysmex XN-1000 Analyzer (Sysmex Corporation, Kobe, Japan). The MLR was then calculated manually. The WBC and MLR were measured averagely of three times within the first week of hospitalization for each patient, respectively. The patients with AF were divided into low MLR ratio group (the ratio ≤ 0.293, n=382), moderate MLR ratio group (the ratio > 0.293 to ≤ 0.460, n=392) and high MLR ratio group (the ratio > 0.460, n=380) according to the tertiles of MLR ratio.

We excluded patients with acute stroke or myocardial infarction (MI), gout attack, hypertrophic, restrictive or dilated cardiomyopathy, valvular or congenital heart diseases, chronic obstructive pulmonary disease, infection, autoimmune diseases, glomerulonephritis and malignant tumor. The patients without electrocardiographic and echocardiographic examination and the necessary blood biochemical data have been excluded.

2.2. Diagnostic Criteria for Comorbidities:

Type 2 diabetes mellitus (DM) was defined as fasting plasma glucose (FPG) ≥7.0 mmol/L, and/or the plasma glucose ≥ 11.1mmol/L at 2 hours after oral 75 g glucose-loaded tolerance test, meanwhile the plasma insulin level was normal or elevated, or previously diagnosed type 2 DM in which the insulin or oral glucose-lowering medication has been used in the patients, meanwhile the patients with diabetic ketoacidosis or hyperosmolar state, or other types of DM were excluded [11].

Primary hypertension was defined as followings: after 10 minutes rest and two measurements of blood pressure (BP), the averaged arterial systolic BP ≥ 140mmHg and/or diastolic BP ≥ 90mmHg on different days without taking antihypertensive drugs; or the hypertension was diagnosed previously, and the antihypertensive medications have been used regularly, meanwhile secondary hypertension was excluded [12].

Gout was defined as urate crystals in the joints with gouty stones, arthralgia and arthritis [13].

The coronary heart disease (CHD) was considered if the patients had at least one main branch with atherosclerotic lumen stenosis (≥ 50%) in coronary artery confirmed by angiography; or the patient had diagnosed MI; or they had a history of coronary stent placement [14]. The severity of coronary artery lesions was assessed using the Gensini score [15].

Stroke was defined as positive brain imaging evidences from electronic computed tomography (CT) or magnetic resonance imaging (MRI), or previously confirmed stroke with or without a previous history of hemiparesis [16].

2.3. Measurement of Plasma Lipids, Glucose, Glycated Hemoglobin and High Sensitivity C-Reactive Protein

Plasma glucose was measured by hexokinase colorimetric method, and glycosylated hemoglobin (HbA1c) was measured by high performance liquid chromatography. Triglycerides and total cholesterol were measured by enzyme colorimetric method, and high-density lipoprotein cholesterol (HDL-C) was determined by homogeneous enzyme colorimetric method. Low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula [17]. Albumin was measured by bromocresol green method. D-dimer was determined by immunoturbidimetric method [18]. High sensitivity C-reactive protein (hs-CRP) was determined by immunoturbidimetric assay.

2.4. Calculation of Glomerular Filtration Rate and Body Mass Index

For men, serum creatinine (Scr) > 80 µmol/L, estimated glomerular filtration rate (eGFR) = 141 × (Scr µmol / L / 88.4 / 0.9)^-1.209 × 0.993^{Age (years)}; Scr ≤ 80 µmol/L, eGFR = 141 × (Scr µmol / L / 88.4 / 0.9)^-0.411 × 0.993^{Age (years)}. For women, Scr > 62 µmol / L, eGFR = 144 × (Scr µmol / L / 88.4 / 0.7)^-1.209 × 0.993^{Age (years)}; Scr ≤ 62 µmol / L, eGFR = 144 × (Scr µmol / L / 88.4 / 0.7)^-0.329 × 0.993^{Age (years)} [19,20]. Body mass index (BMI) was calculated as body weight (kg) / [height (m)]² [21].

2.5. Measurement of Cardiac Structure and Function

With the GE Vivid7 full digital color Doppler ultrasound diagnostic instrument, transthoracic two-dimensional M-mode echocardiography was used to determine [22]: right atrial internal diameter (RAD), right ventricular internal diameter (RVD), left atrial internal diameter (LAD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular end-systolic internal diameter (LVESD), left ventricular end-diastolic internal diameter (LVEDD), pulmonary artery pressure (PAP) and left ventricular ejection fraction (LVEF) [23,24,25].

2.6. Statistical Analysis

The statistical package for social science (SPSS) 26.0 software (IBM Company, Chicago, IL, USA) was used for the statistical analysis. The cutoff values of tertile MLR values used in the current study were calculated by the SPSS software, according to the MLR values of the elderly subjects in the present study. The continuous data were expressed as mean ± standard deviation. The normally distributed continuous data were analyzed by t-test between the two groups. If the continuous data did not follow normal distribution, the Mann Whitney U test was conducted between the two groups. The counting data is expressed as a percentage (%), meanwhile the chi square test was used. The Pearson or Spearman correlation analysis was performed for univariate analysis. Dichotomized logistic regression analysis was performed for multifactorial analysis. Because hs-CRP, neutrophil and WBC were collinear with MLR, these parameters were not included in the regression analysis. A 2-tailed value of P < 0.05 was considered significant statistically.

3. Results

3.1. Clinical Characteristics According to Tertile MLR

The clinical characteristics of subjects according to tertile of MLR are shown in Table 1. Compared with the low MLR (≤ 0.293) group, the moderate MLR (> 0.293 to ≤ 0.460) group had older age, higher prevalence rate of smoking, alcohol consumption and gout, D-dimer, hs-CRP and neutrophil (All P < 0.05, Table 1), and lower BMI, diastolic BP, TG, LDL-C, albumin and eGFR (All P < 0.05, Table 1); the high MLR (> 0.460) group had older age, higher prevalence rate of male gender, smoking, alcohol consumption and gout, D-dimer, hs-CRP, neutrophil and WBC (All P < 0.05, Table 1), and lower BMI, diastolic BP, TG, LDL-C, HDL-C, albumin and eGFR (All P < 0.05, Table 1). Compared with the moderate MLR (> 0.293 to ≤ 0.460) group, the high MLR (> 0.460) group had older age, higher prevalence rate of smoking and alcohol consumption, hs-CRP, neutrophils and WBC (All P < 0.05, Table 1), and lower HDL-C, albumin and eGFR (All P < 0.05, Table 1).

The univariate correlation analysis showed that MLR was positively correlated with age, and the prevalent ratio of male gender, smoking, alcohol consumption and gout, D-dimer, hs-CRP, neutrophils and WBC (All P < 0.05, Table 1); and negatively correlated with BMI, diastolic BP, TG, LDL-C, HDL-C, albumin and eGFR (All P < 0.05, Table 1).

3.2. Cardiac Remodeling According to Tertile MLR

Compared with the low MLR group, RAD, RVD and LAD were larger in the moderate MLR group (All P < 0.05, Table 2); RAD, RVD, LAD, LVESD and LVEDD were larger, while PAP was higher, LVEF was lower in the high MLR group (All P < 0.05, Table 2). Compared with the moderate MLR group, RAD, RVD, LVESD, LVEDD were larger, while PAP was higher, LVEF was lower in the high MLR group (All P < 0.05, Table 2).

The univariate correlation analysis revealed that MLR was positively correlated with RAD, RVD, LAD, LVESD, LVEDD and PAP (All P < 0.05, Table 2), and negatively correlated with LVEF (All P < 0.05, Table 2).

3.3. Multivariate Logistic Regression Analysis of MLR with Clinical Characteristics and Echocardiographic Parameters

Multivariate logistic binary regression analysis of high MLR group (MLR > 0.460) with clinical characteristics and echocardiographic parameters showed that high MLR was independently associated with male gender, decreased level of plasma albumin, lower eGFR, larger RVD, LVESD and LVEDD, and lower LVEF (All P < 0.05, Table 3; Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6 and Figure 7).

4. Discussion

This study showed that high MLR was independently associated with male gender, decreased level of plasma albumin, lower eGFR, cardiac adverse remodeling and dysfunction in elderly patients with AF.

Studies have suggested that dyslipidemia and obesity were associated with high-fat diet, and contributed to lipid deposition and lipotoxicity in kidney [26,27,28]. It can lead to insulin resistance and impede glucose utilization by kidney cells. Energy supply by fat oxidation was forced to increase subsequently. However, this way of energy supply can lead to release lots of pro-inflammatory factors, which increased apoptosis and necrosis of endothelial and epithelial cells in glomeruli [27,29,30], elevated urinary albumin, decreased level of plasma albumin and eGFR [31,32,33] and complicated renal dysfunction [34]. With declined eGFR and increased retention of plasma toxin, the suppressed appetite, decreased protein intake and increased leakage of plasma albumin ultimately lead to hypoalbuminemia in the metabolic nephropathy [35]. High MLR has been associated with low eGFR in chronic kidney disease [36]. However, to our knowledge, this study firstly demonstrated that high MLR was associated with low eGFR and decreased level of plasma albumin in elderly with AF. Studies have found that unhealthy lifestyles such as cigarette smoking and alcohol consumption were associated with increased systemic inflammation especially in older men [37,38]. However, our present study firstly confirmed that high inflammatory marker MLR was more tightly associated with elderly men in AF patients.

Studies have confirmed that dyslipidemia, overweight, obesity, insulin resistance, hyperglycemia, type 2 DM and hypertension were associated with the development of AF [39,40,41,42,43,44,45]. A growing body of data from both epidemiological and clinical studies have demonstrated that epicardial fat is associated with the severity of AF. Some studies have found a relationship between epicardial fat accumulation and atrial myocardial adipocyte infiltration due to increased body fatness. The Framingham heart study with CT analysis suggested that total amount of epicardial fat is associated with AF risk. These are potential mechanisms linking overweight, obesity, epicardial fat amount and AF that potentially leads to anisotropic conduction in the atrium wall, profibrotic adipokines leading to fibrosis formation, remodeling, inflammation and automatic nervous system (ANS) dysfunction. Since the imbalance of ANS represents one of the most important pathophysiological mechanisms in the genesis of AF. Positive modulation such as decreased obesity, physical activity and enhanced cardiorespiratory fitness are crucial for improving ANS function [45,46].

The metabolic disorders were tightly associated with adverse cardiac structural and dysfunctional remodeling. Epicardial fat may lead to structural and dysfunctional remodeling of the heart by both direct (e.g., by the infiltration of adipose tissue) and indirect mechanisms (e.g., by myocardial inflammation and oxidative stress) [47,48,49,50,51]. High-fat diets have been confirmed to be associated with dyslipidemia, overweight and obesity [26]. The retained lipids in tissues were considered to be responsible for the development of insulin resistance, impaired glucose tolerance and type 2 DM [52]. Insulin resistance leads to prevent cells from utilizing glucose for their energy supply, and forces them to utilize fat oxidation to provide their energy supply. As a result, more pro-inflammatory molecules were produced, while apoptosis and necrosis were increased in cardiomyocytes [53,54]. Then myocardial adverse remodeling and cardiac dysfunction occurred consequently [55,56,57,58]. Furthermore, high MLR has been proved to be associated with an increased risk of cardiac death [9,59]. However, to our knowledge, this is the first study to confirm that high MLR is associated with adverse cardiac remodeling and dysfunction in elderly with AF.

Higher MLR has been reported to be associated with the severity of coronary artery atherosclerotic stenosis in a study [60]. However, in our present study, the association of MLR with prevalent CHD has not been found. The association of MLR with the severity of CHD is needed to reconfirm furthermore in the future.

However, the present study is not without its limitations. Firstly, although this study noticed that the monocyte-to-lymphocyte ratio was associated with renal dysfunction and cardiac adverse remodeling, as this study was conducted in a single center, there is a possibility of selection bias, and therefore, caution should be exercised when generalizing the findings. Secondly, the retrospective nature of the study may have resulted in the presence of residual confounding factors, despite our attempts to adjust for possible confounders. The design was retrospective, and important data may be missing. The reasons for the missing data (especially those of estimated glomerular filtration rate and plasma albumin) were challenging to determine based on the available information. Inflammatory markers such as interleukins, cytokines were not measured in this study. Thirdly, this study included a moderate sample size and selection bias could not be avoided.

5. Conclusions

Our study suggested that high MLR is associated with male gender, decreased level of plasma albumin, low eGFR, cardiac adverse remodeling and dysfunction in elderly patients with AF. High MLR can be used as a marker of subclinical chronic kidney disease and adverse cardiac remodeling among AF patients.