血清sST2、FGF-23、GDF-15对阵发性房颤的预测价值探讨
Prognostic Value of Serum sST2, FGF-23 and GDF-15 in Paroxysmal Atrial Fibrillation
DOI: 10.12677/acm.2024.1492525, PDF, HTML, XML,   
作者: 赵立新, 朱 清*：络病理论创新转化全国重点实验室；教育部和国家卫健委心血管重构与功能研究重点实验室；山东大学齐鲁医院心内科，山东 济南
关键词: 心房颤动；可溶性生长刺激基因表达蛋白2；成纤维细胞生长因-23；生长分化因子-15；Atrial Fibrillation； Soluble Growth Stimulating Gene Expression Protein 2； Fibroblast Gowth Factor-23； Growth Differentiation Factor 15
摘要: 目的：检测阵发性心房颤动(Paroxysmal Atrial Fibrillation, PAF)患者与非心房颤动(Atrial Fibrillation, AF)患者血清可溶性生长刺激基因表达蛋白2 (Soluble Growth Stimulating Gene Expression Protein 2, sST2)、成纤维细胞生长因子-23 (Fibroblast Gowth Factor-23, FGF-23)、人生长分化因子15 (Growth differentiation factor 15, GDF-15)水平，探讨此三个因子对PAF的预测价值。方法：选取符合入排标准的PAF患者61例作为观察组，非AF患者61例作为对照组。应用酶联吸附免疫实验法(Enzyme linked immunosorbent assay, ELISA)测定两组患者血清sST2、FGF-23、GDF-15的浓度。比较两组患者的临床资料、血液学检测指标。采用Spearman相关性分析sST2、FGF-23、GDF-15与炎症指标及其与超声心动图各参数的相关性。采用单因素及多因素logistic回归分析PAF发生的相关因素。结果：与非AF组比较，PAF组血清sST2、FGF-23、GDF-15水平均明显升高(P < 0.05)。Spearman相关性分析显示，血清sST2与FGF-23呈正相关(r = 0.219, P = 0.015)，sST2与GDF-15呈正相关(r = 0.211, P = 0.020)，FGF-23与GDF-15呈正相关(r = 0.198, P = 0.028)。sST2与中性粒细胞呈正相关(r = 0.268, P = 0.003)、与NLR呈正相关(r = 0.265, P = 0.003)，与白细胞、淋巴细胞无显著相关性；FGF-23、GDF-15与炎症指标均无显著相关性。sST2、FGF-23、GDF-15均与超声心动图各参数无显著相关性。单因素logistic回归分析显示，年龄、心率、舒张压、左房前后径、右房长径、右房横径、sST2、FGF-23、GDF-15、谷丙转氨酶、总胆红素、直接胆红素、肌酐、肾小球滤过率、高密度脂蛋白胆固醇(P < 0.05)是PAF的危险因素。多因素logistic回归分析显示，年龄(OR = 1.197, 95%CI 1.066~1.343, P = 0.002)、FGF-23 (OR = 1.006, 95%CI 1.002~1.011, P = 0.009)、GDF-15 (OR = 1.003, 95%CI 1.001~1.005, P < 0.001)、高密度脂蛋白胆固醇(OR = 19.136, 95%CI 1.050~348.601, P = 0.046)是PAF的独立危险因素。结论：1) PAF组血清sST2、FGF-23、GDF-15水平较非AF组明显升高，多因素logistic回归分析显示FGF-23、GDF-15是PAF的独立危险因素。2) 血清sST2、FGF-23、GDF-15浓度两两呈正相关性，sST2与中性粒细胞、NLR呈正相关性，提示炎症反应参与了PAF的发生发展。3) 血清sST2、FGF-23、GDF-15水平均与超声心动图参数无显著相关性，其与房颤发生的相关性可能独立于心脏结构改变之外。
Abstract: Objective: To detect the levels of serum sST2, FGF-23 and GDF-15 in patients with PAF and without AF, and investigate the predictive value of these three factors on PAF. Methods: 61 patients with PAF who met the inclusion criteria were selected as the observation group, and 61 patients without AF were selected as the control group. Serum levels of sST2, FGF-23 and GDF-15 were determined by ELISA. The clinical data and hematological indicators of the two groups were compared. Spearman correlation analysis was used to analyze the correlation between sST2, FGF-23, GDF-15 and inflammatory indicators and echocardiographic parameters. The factors related to the occurrence of PAF were analyzed by univariate and multivariate logistic regression. Results: Compared with non-AF group, serum levels of sST2, FGF-23 and GDF-15 in PAF group were significantly increased (P < 0.05). Spearman correlation analysis showed that serum sST2 was positively correlated with FGF-23 (r = 0.219, P = 0.015), and sST2 was positively correlated with GDF-15 (r = 0.211, P = 0.020). FGF-23 was positively correlated with GDF-15 (r = 0.198, P = 0.028). sST2 was positively correlated with neutrophils (r = 0.268, P = 0.003) and NLR (r = 0.265, P = 0.003), but had no significant correlation with leukocytes and lymphocytes. There was no significant correlation between FGF-23, GDF-15 and inflammatory indexes. sST2, FGF-23 and GDF-15 were not significantly correlated with echocardiographic parameters. Univariate logistic regression analysis showed that age, heart rate, diastolic blood pressure, left anteroposterior atrial diameter, right atrial long diameter, right atrial transverse diameter, sST2, FGF-23, GFF-15, alanine aminotransferase, total bilirubin, direct bilirubin, creatinine, glomerular filtration rate, and high density lipoprotein cholesterol were risk factors for PAF (P < 0.05). Multivariate logistic regression analysis showed that Age (OR = 1.197, 95%CI 1.066~1.343, P = 0.002), FGF-23 (OR = 1.006, 95%CI 1.002~1.011, P = 0.009), GDF-15 (OR = 1.003, 95%CI 1.001~1.005, P < 0.001), high density lipoprotein cholesterol (OR = 19.136, 95%CI 1.050~348.601, P = 0.046) were independent risk factors for PAF. Conclusion: 1) Serum levels of sST2, FGF-23 and GDF-15 in PAF group were significantly higher than those in non-AF group, and multiple logistic regression analysis showed that FGF-23 and GDF-15 were independent risk factors for PAF. 2) Serum sST2, FGF-23 and GDF-15 concentrations were positively correlated, and sST2 was positively correlated with neutrophils and NLR, suggesting that inflammation was involved in the occurrence and development of PAF. 3) Serum sST2, FGF-23 and GDF-15 levels were not significantly correlated with echocardiographic parameters, and their correlation with atrial fibrillation may be independent of cardiac structural changes.
文章引用：赵立新, 朱清. 血清sST2、FGF-23、GDF-15对阵发性房颤的预测价值探讨[J]. 临床医学进展, 2024, 14(9): 745-757. https://doi.org/10.12677/acm.2024.1492525

1. 引言

心房颤动(Atrial Fibrillation, AF)是临床上最常见的心律失常之一，AF与脑卒中、短暂性脑缺血发作、全身血管栓塞发病密切相关，会严重影响患者的生活质量[1] [2]。然而在临床上，AF的检出率却很低，很多AF患者在血栓栓塞事件发生后才被诊断为AF。目前越来越多的证据表明AF发生可能与炎症、心脏纤维化、心脏重构、氧化应激等相关[3] [4]。寻找更具特异性的AF相关生物学标志物，早期识别AF患者已成为当前的研究热点[5]。

可溶性生长刺激基因表达蛋白2 (Soluble Growth Stimulating Gene Expression Protein 2, ST2)是IL-33的诱骗受体，可竞争性地与IL-33结合抑制IL-33/ST2L信号途径，从而减弱对心肌的保护作用[6]。人成纤维细胞生长因子-23 (Fibroblast Gowth Factor-23, FGF-23)参与血磷代谢，其水平升高与心肌纤维化、左心室肥厚、左室射血分数降低相关[7]-[9]。人生长分化因子-15 (Growth differentiation factor 15, GDF-15)浓度升高与心血管、肿瘤、糖尿病和肾功能不全等疾病的不良预后密切相关[10]。研究表明，GDF-15浓度升高与急性冠脉综合征发作后不良左室重构和心力衰竭风险增加相关[11]；GDF-15在多种肿瘤中浓度均升高，与肿瘤的进展及预后相关[12]-[14]；GDF-15浓度升高与糖尿病患者癌症发病率、心血管发病率和死亡率增加相关[15] [16]；GDF-15浓度升高与慢性肾脏病患者死亡风险、心血管疾病发病率增加相关[17]。本研究采用ELISA法分别检测血清sST2、FGF-23、GDF-15在阵发性心房颤动(Paroxysmal Atrial Fibrillation, PAF)患者及非AF患者中的浓度，并探讨此三个因子对PAF的预测价值。

2. 资料与方法

2.1. 研究对象

选取2023年10月至2024年3月于山东大学齐鲁医院心内科住院治疗的符合入组标准的PAF患者61例作为观察组，同时选取此时间段内于山东大学齐鲁医院心内科住院治疗的符合入排标准的非AF患者61例作为对照组(control)。

纳入标准：PAF组：既往曾有心电图或动态心电图示AF，且有相关心电图或动态心电图作为依据；均符合PAF的相关诊断标准。非AF组：既往无AF病史，心电图及动态心电图均无AF发作。

排除标准：PAF组：合并严重充血性心力衰竭、严重心脏瓣膜病、心肌病、急性冠脉综合征、先天性心脏病、慢性阻塞性肺疾病、严重肝肾功能障碍、重度骨质疏松、恶性肿瘤、自身免疫性疾病等疾病者；其他类型AF。非AF组：合并严重充血性心力衰竭、严重心脏瓣膜病、心肌病、急性冠脉综合征、先天性心脏病、慢性阻塞性肺疾病、严重肝肾功能障碍、重度骨质疏松、恶性肿瘤、自身免疫性疾病等疾病者。

2.2. 临床资料收集

2.2.1. 基线资料

(1) 人口统计学资料：包括年龄、性别、血压、心率、身高、体重，根据身高、体重计算其BMI。

(2) 合并症及个人史资料：包括高血压病史、糖尿病病史、CAD病史、脑卒中病史、周围动脉栓塞病史、吸烟史、饮酒史。

2.2.2. 经胸超声心动图

包括LVEF、左房前后径、左室前后径、室间隔厚度、左室后壁厚度、右室前后径、右房长径、右房横径，以上指标均由我院心脏彩超室医生测得。

2.3. 血标本采集及检测

当日上午8时前在患者空腹状态下采集右上肢肘正中静脉5 ml，采血后2 h内分离出血清，置于−80℃冰箱暂时保存。应用酶联吸附免疫实验法(Enzyme linked immunosorbent assay, ELISA)检测PAF组和非AF组患者血清sST2、FGF-23、GDF-15浓度。同时于山东大学齐鲁医院检验科检测肝肾功能、血糖、血脂、电解质、血常规等指标。

2.4. 统计学方法

本研究使用统计软件SPSS 27.0进行统计学分析。连续变量使用Shapiro-Wilk进行正态性检验。符合正态分布的变量应用均数 ± 标准差表示，不符合正态分布的变量应用中位数(四分位数)表示。分类变量应用频数和百分比表示。当P < 0.05时，差异具有统计学意义。

对PAF组与非AF组患者两组变量进行差异性比较，符合正态分布的变量采用两独立样本t检验分析组间差异。对不符合正态分布的变量采用非参数秩和检验分析组间差异。对分类变量采用卡方检验或连续性矫正的卡方检验分析组间差异。因经Shapiro-Wilk正态性检验血清sST2、FGF-23、GDF-15均不符合正态分布，本研究采用Spearman相关性分析三者之间的相关性及三者与炎症指标、超声心动图参数的相关性。对两组具有显著性差异的指标进行单因素logistic及多因素Logistic回归分析。

3. 结果

3.1. PAF组与非AF组临床资料比较

3.1.1. PAF组与非AF组基线资料比较

与非AF组比较，PAF组年龄较高、基础心率偏慢、舒张压偏低(P < 0.05)，见表1。两组在合并症和个人史方面无显著性统计学差异，见表2。

3.1.2. PAF组与非AF组超声心动图参数比较

与非AF组比较，PAF组左房前后径、右房长径、右房横径较大(P < 0.05)，见图1；其他指标无显著性统计学差异。见表3。

Table 1. Comparison of demographic data between PAF group and non-AF group

表1. PAF组和非AF组人口统计学资料比较

变量

 PAF

(n = 61)

 非AF

(n = 61)

 P值
年龄(岁)

 65.00 (56.00~72.00)

 54.00 (45.00~59.00)

 <0.001
男性

 36 (59.02%)

 35 (57.37%)

 0.854
BMI (Kg/m2)

 25.35 (23.38~28.48)

 25.76 (23.13~28.01)

 0.838
心率(bpm)

 70.48 ± 13.28

 77.39 ± 12.84

 0.004
收缩压(mmHg)

 135.61 ± 20.04

 137.03 ± 17.72

 0.678
舒张压(mmHg)

 78.34 ± 12.51

 83.23 ± 13.67

 0.042
脉压差(mmHg)

 56.00 (47.00~65.50)

 52.00 (44.50~61.50)

 0.200

Table 2. Comparison of comorbidities and personal history between PAF group and non-AF group

表2. PAF组和非AF组合并症及个人史资料比较

变量

 PAF

(n = 61)

 非AF

(n = 61)

 P值
高血压病史

 37 (60.66%)

 31 (50.82%)

 0.274
糖尿病病史

 10 (16.39%)

 11 (18.03%)

 0.810
CAD病史

 26 (42.62%)

 37 (60.66%)

 0.070
脑卒中病史

 5 (8.20%)

 5 (8.20%)

 1.000
周围动脉栓塞病史

 1 (1.64%)

 0 (0.00%)

 1.000
吸烟史

 18 (29.51%)

 18 (29.51%)

 1.000
饮酒史

 20 (32.79%)

 21 (34.43%)

 0.848

Table 3. Comparison of echocardiographic parameters between PAF group and non-AF group

表3. PAF组和非AF组超声心动图参数比较

变量

 PAF

(n = 61)

 非AF

(n = 61)

 P值
LVEF

 0.64 ± 0.05

 0.66 ± 0.04

 0.055
左房前后径(mm)

 38.13 ± 5.69

 35.00 ± 4.39

 <0.001
左室前后径(mm)

 46.67 ± 4.21

 45.21 ± 4.08

 0.055
室间隔厚度(mm)

 10.71 (9.00~12.00)

 11.00 (9.00~12.00)

 0.930
左室后壁厚度(mm)

 9.00 (9.00~10.00)

 10.00 (9.00~11.00)

 0.328
右室前后径(mm)

 23.41 (22.00~25.00)

 23.00 (21.50~25.00)

 0.680
右房长径(mm)

 46.15 ± 4.92

 43.95 ± 3.88

 0.007
右房横径(mm)

 38.00 (36.00~41.50)

 36.00 (34.00~39.00)

 0.001

Figure 1. Comparison of echocardiographic parameters with statistical difference between PAF group and non-AF group. (A) Comparison of left anterior and posterior atrium diameter between PAF group and non-AF group; (B) Comparison of right atrial length and diameter between PAF group and non-AF group; (C) Comparison of right atrial transverse diameter between PAF group and non-AF group. (Compared with non-AF group, *P < 0.05, **P < 0.01, ***P < 0.001)

图1. PAF组和非AF组有统计学差异的超声心动图参数比较。(A) PAF组和非AF组左房前后径比较；(B) PAF组和非AF组右房长径比较；(C) PAF组和非AF组右房横径比较。(与非AF组相比，*P < 0.05，**P < 0.01，***P < 0.001)

3.1.3. PAF组与非AF组sST2、FGF-23、GDF-15检测结果比较

与非AF组比较，PAF组sST2、FGF-23、GDF-15浓度均升高(P < 0.05)，见表4、图2。

Table 4. Comparison of sST2, FGF-23 and GDF-15 concentrations between PAF group and non-AF group

表4. PAF组和非AF组sST2、FGF-23、GDF-15浓度比较

变量

 PAF

(n = 61)

 非AF

(n = 61)

 P值
sST2 (pg/mL)

 137.81 (53.45~510.84)

 85.46 (44.67~350.13)

 0.045
FGF-23 (pg/mL)

 661.16 (514.01~913.14)

 500.98 (363.59~597.62)

 <0.001
GDF-15 (pg/mL)

 2099.85 (1765.92~2551.99)

 1448.15 (1186.20~1915.73)

 <0.001

Figure 2. Comparison of sST2, FGF-23 and GDF-15 concentrations between PAF group and non-AF group. (A) Comparison of serum sST2 concentration between PAF group and non-AF group; (B) Comparison of serum FGF-23 concentration between PAF group and non-AF group; (C) Comparison of serum GDF-15 concentration between PAF group and non-AF group. (Compared with non-AF group, *P < 0.05, **P < 0.01, ***P < 0.001)

图2. PAF组和非AF组sST2、FGF-23、GDF-15浓度比较。(A) PAF组和非AF组血清sST2浓度比较；(B) PAF组和非AF组血清FGF-23浓度比较；(C) PAF组和非AF组血清GDF-15浓度比较。(与非AF组相比，*P < 0.05，**P < 0.01，***P < 0.001)

3.1.4. PAF组与非AF组其他血液学检测指标比较

与非AF组比较，PAF组谷丙转氨酶较低，总胆红素、直接胆红素、间接胆红素较高，肌酐较高，肾小球滤过率较低，高密度脂蛋白胆固醇较高(P < 0.05)；其他指标无显著性统计学差异，见表5。两组血常规指标比较无显著性统计学差异，见表6。

Table 5. Comparison of serological indicators between PAF group and non-AF group

表5. PAF组和非AF组血清学指标比较

变量

 PAF

(n = 61)

 非AF

(n = 61)

 P值
谷丙转氨酶(U/L)

 14.00 (11.00~21.00)

 22.00 (13.00~30.50)

 0.008
谷草转氨酶(U/L)

 17.00 (15.00~20.00)

 18.00 (15.00~22.00)

 0.235
γ-谷氨酰转肽酶(U/L)

 20.00 (15.50~27.00)

 24.00 (18.50~34.00)

 0.050
总胆红素(μmol/L)

 11.30 (9.35~14.45)

 9.10 (7.20~12.35)

 0.003
直接胆红素(μmol/L)

 4.10 (3.40~4.70)

 3.10 (2.55~4.10)

 <0.001
间接胆红素(μmol/L)

 7.50 (5.85~10.20)

 5.70 (4.40~8.25)

 0.008
总蛋白(g/L)

 67.09 ± 5.34

 68.01 ± 4.14

 0.288
白蛋白(g/L)

 42.40 (39.75~44.65)

 43.10 (41.45~45.80)

 0.073
尿素氮(mmol/L)

 5.60 (4.57~6.62)

 5.29 (4.57~6.40)

 0.477
肌酐(μmol/L)

 77.00 (66.50~90.50)

 67.00 (60.00~78.50)

 0.005
肾小球滤过率(mL/min/1.73 m2)

 92.46 ± 20.84

 108.77 ± 24.79

 <0.001
葡萄糖(mmol/L)

 5.00 (4.58~5.82)

 5.19 (4.68~6.01)

 0.522
甘油三酯(mmol/L)

 1.27 (0.89~1.59)

 1.36 (0.91~2.02)

 0.138
总胆固醇(mmol/L)

 3.99 (3.38~4.80)

 4.16 (3.28~4.93)

 0.671
低密度脂蛋白胆固醇(mmol/L)

 2.35 ± 0.89

 2.43 ± 0.91

 0.620
高密度脂蛋白胆固醇(mmol/L)

 1.20 (0.99~1.38)

 1.10 (0.95~1.24)

 0.022
钾(mmol/L)

 4.07 ± 0.33

 4.10 ± 0.30

 0.676
钠(mmol/L)

 143.00 (142.00~144.00)

 142.00 (141.00~143.00)

 0.090
氯(mmol/L)

 107.20 ± 3.04

 106.74 ± 2.63

 0.374

Table 6. Comparison of blood routine indexes between PAF group and non-AF group

表6. PAF组和非AF组血常规指标比较

变量

 PAF

(n = 61)

 非AF

(n = 61)

 P值
白细胞(*109/L)

 5.67 ± 1.38

 5.85 ± 1.57

 0.498
中性粒细胞计数(*109/L)

 3.33 ± 1.06

 3.45 ± 1.11

 0.552
淋巴细胞计数(*109/L)

 1.79 (1.41~2.10)

 1.75 (1.46~2.11)

 0.910
中性粒细胞/淋巴细胞

 1.86 (1.39~2.44)

 1.83 (1.46~2.31)

 0.969
血红蛋白(g/L)

 136.94 ± 14.62

 139.21 ± 15.45

 0.405
血小板(*109/L)

 206.00 (170.50~240.50)

 217.00 (189.50~238.50)

 0.249

3.2. sST2、FGF-23、GDF-15与炎症指标及超声心动图参数相关性分析

3.2.1. sST2、FGF-23、GDF-15相关性分析

血清sST2、FGF-23、GDF-15水平数值经Shapiro-Wilk检验均不符合正态分布，采用Spearman相关性分析三者有无显著相关性。经Spearman相关性分析：sST2与FGF-23呈正相关(r = 0.219, P = 0.015)，sST2与GDF-15呈正相关(r = 0.211, P = 0.020)，FGF-23与GDF-15呈正相关(r = 0.198, P = 0.028)，相关性分析见表7、图3。

Figure 3. Correlation analysis of sST2, FGF-23 and GDF-15 (A) Correlation analysis of sST2 and FGF-23; (B) Correlation analysis of sST2 and GDF-15; (C) Correlation analysis of FGF-23 and GDF-15

图3. 血清sST2、FGF-23、GDF-15相关性分析(A) 血清sST2与FGF-23相关性分析；(B) 血清sST2与GDF-15相关性分析；(C) 血清FGF-23与GDF-15相关性分析

Table 7. Correlation analysis of sST2, FGF-23 and GDF-15 (r)

表7. sST2、FGF-23、GDF-15相关性分析(r)

变量

 sST2

 FGF-23

 GDF-15
sST2 (pg/mL)

 1.00

 0.219*

 0.211*
FGF-23 (pg/mL)

 0.219*

 1.00

 0.198*
GDF-15 (pg/mL)

 0.211*

 0.198*

 1.00

3.2.2. sST2、FGF-23、GDF-15与炎症指标相关性分析

经Spearman相关性分析：sST2与中性粒细胞呈正相关(r = 0.268, P = 0.003)，sST2与NLR正相关(r = 0.265, P = 0.003)，与白细胞、淋巴细胞无相关性，结果见表8、图4。FGF-23、GDF-15与炎症指标均无显著相关性，结果见表9、表10。

Table 8. Correlation analysis between sST2 and inflammatory indicators

表8. sST2与炎症指标相关性分析

变量

 r值

 P值
白细胞(*109/L)

 0.171

 0.060
中性粒细胞(*109/L)

 0.268

 0.003
淋巴细胞(*109/L)

 −0.019

 0.828
NLR

 0.265

 0.003

Figure 4. Correlation analysis between sST2 and inflammatory indicators (A) Correlation analysis between sST2 and neutrophil; (B) Correlation analysis between sST2 and NLR

图4. 血清sST2与炎症指标相关性分析(A) 血清sST2与中性粒细胞相关性分析；(B) 血清sST2与NLR相关性分析

Table 9. Correlation analysis between FGF-23 and inflammatory indicators

表9. FGF-23与炎症指标相关性分析

变量

 r值

 P值
白细胞(*109/L)

 −0.096

 0.294
中性粒细胞(*109/L)

 −0.044

 0.627
淋巴细胞(*109/L)

 −0.097

 0.288
NLR

 0.023

 0.802

Table 10. Correlation analysis between GDF-15 and inflammatory indicators

表10. GDF-15与炎症指标相关性分析

变量

 r值

 P值
白细胞(*109/L)

 0.108

 0.235
中性粒细胞(*109/L)

 0.088

 0.333
淋巴细胞(*109/L)

 0.088

 0.333
NLR

 0.019

 0.834

3.2.3. sST2、FGF-23、GDF-15与超声心动图各参数相关性分析

经Spearman相关性分析：sST2、FGF-23、GDF-15分别与超声心动图各参数均无显著相关性，见表11~13。

Table 11. Correlation analysis between sST2 and echocardiography

表11. sST2与超声心动图各参数相关性分析

变量

 r值

 P值
LVEF

 0.008

 0.929
左房前后径(mm)

 0.070

 0.446
左室前后径(mm)

 0.056

 0.539
右房长径(mm)

 0.044

 0.628
右房横径(mm)

 0.094

 0.303

Table 12. Correlation analysis between FGF-23 and echocardiography

表12. FGF-23与超声心动图各参数相关性分析

变量

 r值

 P值
LVEF

 0.034

 0.709
左房前后径(mm)

 0.105

 0.250
左室前后径(mm)

 0.017

 0.855
右房长径(mm)

 0.114

 0.212
右房横径(mm)

 0.046

 0.612

Table 13. Correlation analysis between GDF-15 and echocardiography

表13. GDF-15与超声心动图各参数相关性分析

变量

 r值

 P值
LVEF

 −0.127

 0.162
左房前后径(mm)

 0.160

 0.078
左室前后径(mm)

 0.149

 0.101
右房长径(mm)

 0.117

 0.199
右房横径(mm)

 0.084

 0.360

3.3. 单因素及多因素Logistic回归分析影响AF因素

两组具有显著性差异的指标(P < 0.05)先进行单因素logistic回归分析，发现年龄、心率、舒张压、左房前后径、右房长径、右房横径、sST2、FGF-23、GDF-15、谷丙转氨酶、总胆红素、直接胆红素、肌酐、肾小球滤过率、高密度脂蛋白胆固醇是PAF的危险因素，见表14。将上述指标纳入多因素logistic回归分析，发现年龄(OR = 1.197, 95%CI 1.066~1.343, P = 0.002)、FGF-23 (OR = 1.006, 95%CI 1.002~1.011, P = 0.009)、GDF-15 (OR = 1.003, 95%CI 1.001~1.005, P < 0.001)、高密度脂蛋白胆固醇(OR = 19.136, 95%CI 1.050~348.601, P = 0.046)是PAF的独立危险因素，sST2 (OR = 0.996, 95%CI 0.993~1.000, P = 0.060)未被纳入回归公式中，见表15。

Table 14. Logistic regression analysis of single factor influencing PAF

表14. 影响PAF的单因素logistic回归分析

变量

 OR值

 95%CI

 P值
年龄

 1.098

 1.054~1.143

 <0.001
心率

 0.960

 0.932~0.988

 0.006
舒张压

 0.971

 0.944~0.999

 0.045
左房前后径

 1.135

 1.048~1.229

 0.002
右房长径

 1.123

 1.029~1.226

 0.010
右房横径

 1.165

 1.061~1.278

 0.001
sST2

 1.002

 1.000~1.003

 0.029
FGF-23

 1.003

 1.001~1.004

 <0.001
GDF-15

 1.002

 1.001~1.003

 <0.001
谷丙转氨酶

 0.965

 0.936~0.996

 0.028
总胆红素

 1.110

 1.015~1.215

 0.022
直接胆红素

 1.699

 1.206~2.394

 0.002
肌酐

 1.025

 1.003~1.048

 0.026
肾小球滤过率

 0.969

 0.953~0.986

 <0.001
高密度脂蛋白胆固醇

 5.468

 1.350~22.148

 0.017

Table 15. Logistic regression analysis of multiple factors influencing PAF

表15. 影响PAF的多因素logistic回归分析

变量

 OR值

 95%CI

 P值
年龄

 1.197

 1.066~1.343

 0.002*
心率

 0.950

 0.895~1.009

 0.095
舒张压

 1.026

 0.957~1.099

 0.475
左房前后径

 1.095

 0.879~1.366

 0.418
右房长径

 0.900

 0.705~1.149

 0.397
右房横径

 1.210

 0.971~1.508

 0.090
sST2

 0.996

 0.993~1.000

 0.060
FGF-23

 1.006

 1.002~1.011

 0.009*
GDF-15

 1.003

 1.001~1.005

 <0.001*
谷丙转氨酶

 1.026

 0.970~1.085

 0.367
总胆红素

 1.305

 0.906~1.879

 0.152
直接胆红素

 0.915

 0.241~3.469

 0.896
肌酐

 0.976

 0.883~1.080

 0.642
肾小球滤过率

 0.933

 0.860~1.012

 0.093
高密度脂蛋白胆固醇

 19.136

 1.050~348.601

 0.046*

4. 讨论

AF是最常见的心律失常之一，据统计，2018年我国心血管病患病总人数约3.3亿，其中AF患者约487万，患病率日益升高[18]。AF的诊断除依靠心电图外，还可以借助其临床特征和血清生物学标志物等协助诊断。血清生物学标志物可有助于临床识别AF高危患者，从而实现AF患者的早期诊断，早期干预。

sST2是由心肌成纤维细胞和心肌细胞在损伤或应激时产生的，可竞争结合IL-33从而抑制ST2L/IL-33信号途径[19]，高水平sST2可阻断ST2L/IL-33的保护作用，从而引发心肌纤维化。sST2和IL-33mRNA的表达与纤维化程度存在相关性[20]，除抑制IL-33效应外，还可通过NF-κB磷酸化过程，上调促纤维化转化生长因子(TGF)-β1的调节因子，促使心肌纤维化过程加快[21]。FGF-23是骨细胞和成骨细胞分泌产生的，参与钙磷代谢中，其与慢性肾脏疾病患者预后密切相关[22]。FGF-23增高对慢性肾脏病合并有心血管并发症、尤其是CAD患者的生存率有不良影响[23]。研究显示，在透析患者中，高水平FGF-23独立于Cox回归分析包含的混杂因素，与心血管疾病发病率、死亡风险增加相关[24]。在透析患者中，有心血管疾病的男性患者，FGF23浓度 > 中位数与死亡风险增加相关(HR 2.19, P = 0.04) [25]。FGF-23可通过激活磷脂酶C (PLC)-γ-钙调神经磷酸酶–活化T细胞核因子(NFAT)依赖途径诱导左心室肥大，使心肌舒张功能障碍及左房充盈压增加，导致左心房扩大并纤维化，进而促进AF发生[26]。GDF-15是转化生长因子-β超家族中的一员，生理条件下，GDF-15在前列腺、胎盘组织中高表达，在肾脏、肝脏、消化道及呼吸道上皮等多种组织器官低表达，在心脏中不表达或微量表达[27]。GDF-15可通过磷脂酰肌醇3-激酶、细胞外信号调节激酶信号通路激活Smad1 [28]，促进成熟心肌细胞肥大，从而促进AF发生。

有研究发现[29]，慢性肾脏病患者发生AF与发生心力衰竭的风险接近6倍，肾功能不全会增加AF的发生率，这与本研究得出PAF组肌酐较高、肾小球滤过率较低的结果一致。有研究表明[30]，总胆红素升高是AF发生的独立危险因素(OR = 0.899, P = 0.009)。本研究PAF组总胆红素、直接胆红素、间接胆红素均较高，单因素logistic回归分析总胆红素、直接胆红素均为AF发生的危险因素，多因素logistic回归分析总胆红素、直接胆红素均未被纳入回归方程，与国内研究不完全一致，这可能由于入选对象的不完全相同所致[18]。研究表明，AF可促进左心房结构重构[31]，AF患者左心房压力升高进一步诱发左心房扩大，以代偿左心室僵硬度增加和顺应性降低。也有研究表明，AF也可导致右心房的结构重构、电生理重构。右心房结构和容积大小与AF发生呈相关性[32]，右心房电生理重构与AF发生和持续时间存在相关性，部分PAF由右心房异位引发，并由右心房中折返回路维持[33]。本研究PAF组左房前后径、右房长径、右房横径较大，这与目前国内外研究一致。

本研究结果表明：PAF组sST2、FGF-23、GDF-15水平高于非AF组(P < 0.05)，Spearman相关性分析示，sST2、FGF-23、GDF-15浓度两两呈正相关性。sST2与中性粒细胞计数呈正相关性(r = 0.268, P = 0.003)，与NLR呈正相关性(r = 0.265, P = 0.003)，与白细胞、淋巴细胞无显著相关性，提示炎症反应参与了PAF的发生，但FGF-23、GDF-15与炎症指标无显著相关性。研究发现，sST2与AF患者左心房内径呈正相关性(r = 0.562, P = 0.002) [34]；FGF-23与左室舒张末期内径呈正相关性(r = 0.163, P < 0.05)，与LVEF呈负相关性(r = −0.171, P < 0.05) [35]。本研究示sST2、FGF-23、GDF-15浓度均与超声心动图参数无显著相关性，提示其与AF发生的相关性可能独立于心脏结构改变之外。但目前关于三者与心脏结构相关性的研究较少，三者水平升高与心脏结构变化的关系需要进一步探索。单因素logistic回归分析显示，sST2、FGF-23、GDF-15是PAF发生的危险因素(P < 0.05)。多因素logistic回归分析显示，FGF-23、GDF-15是PAF的独立危险因素(P < 0.05)。本研究有以下不足：(1) 本研究纳入的研究对象均为心内科住院治疗的患者，心血管系统疾病患病率普遍偏高，包括CAD、高血压等疾病，对数据分析带来一定影响。(2) 本研究样本量较少，仍需要大量的临床实验证实。相信新的生物学标志物会帮助医生更清楚地了解AF的发病机制，更早地识别AF高危患者，以改善患者预后，达到降低AF并发症的目的。

NOTES

*通讯作者。

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