Shang Luxiang, Zhang Ling, Shao Mengjiao, Feng Min, Shi Jia, Dong Zhenyu, Guo Qilong, Xiaokereti Jiasuoer, Xiang Ran, Sun Huaxin, Zhou Xianhui, Tang Baopeng
Department of Pacing and Electrophysiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Institute of Clinical Medical Research, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Front Physiol. 2020 Feb 12;11:76. doi: 10.3389/fphys.2020.00076. eCollection 2020.
Beta 1-adrenergic receptor autoantibodies (β1ARAbs) have been identified as a pathogenic factor in atrial fibrillation (AF), but the underlying pathogenetic mechanism is not well understood. We assessed the hypothesis that elevated β1ARAb levels increase AF susceptibility by promoting atrial fibrosis.
A total of 70 patients with paroxysmal AF were continuously recruited. The serum levels of β1ARAb and circulating fibrosis biomarkers were analyzed by ELISA. Linear regression was used to examine the correlations of β1ARAb levels with left atrial diameter (LAD) and circulating fibrosis biomarker levels. Furthermore, we established a rabbit β1ARAb overexpression model. We conducted electrophysiological studies and multielectrode array recordings to evaluate the atrial effective refractory period (AERP), AF inducibility and electrical conduction. AF was defined as irregular, rapid atrial beats > 500 bpm for > 1000 ms. Echocardiography, hematoxylin and eosin staining, Masson's trichrome staining, and picrosirius red staining were performed to evaluate changes in atrial structure and detect fibrosis. Western blotting and PCR were used to detect alterations in the protein and mRNA expression of TGF-β1, collagen I and collagen III.
Patients with a LAD ≥ 40 mm had higher β1ARAb levels than patients with a smaller LAD (8.87 ± 3.16 vs. 6.75 ± 1.34 ng/mL, = 0.005). β1ARAb levels were positively correlated with LAD and circulating biomarker levels (all < 0.05). Compared with the control group, the rabbits in the immune group showed the following: (1) enhanced heart rate, shortened AERP (70.00 ± 5.49 vs. 96.46 ± 3.27 ms, < 0.001), increased AF inducibility (55% vs. 0%, < 0.001), decreased conduction velocity and increased conduction heterogeneity; (2) enlarged LAD and elevated systolic dysfunction; (3) significant fibrosis in the left atrium identified by Masson's trichrome staining (15.17 ± 3.46 vs. 4.92 ± 1.72%, < 0.001) and picrosirius red staining (16.76 ± 6.40 vs. 4.85 ± 0.40%, < 0.001); and (4) increased expression levels of TGF-β1, collagen I and collagen III.
Our clinical and experiential studies showed that β1ARAbs participate in the development of AF and that the potential mechanism is related to the promotion of atrial fibrosis.
β1肾上腺素能受体自身抗体（β1ARAbs）已被确定为心房颤动（AF）的致病因素，但其潜在的发病机制尚不清楚。我们评估了β1ARAb水平升高通过促进心房纤维化增加房颤易感性的假说。
连续招募70例阵发性房颤患者。采用酶联免疫吸附测定法（ELISA）分析β1ARAb的血清水平和循环纤维化生物标志物。采用线性回归分析β1ARAb水平与左心房直径（LAD）和循环纤维化生物标志物水平的相关性。此外，我们建立了兔β1ARAb过表达模型。我们进行了电生理研究和多电极阵列记录，以评估心房有效不应期（AERP）、房颤诱发率和电传导。房颤定义为不规则、快速心房搏动>500次/分持续>1000毫秒。采用超声心动图、苏木精-伊红染色、Masson三色染色和天狼星红染色评估心房结构变化并检测纤维化。采用蛋白质印迹法和聚合酶链反应检测转化生长因子-β1（TGF-β1）、Ⅰ型胶原和Ⅲ型胶原的蛋白质和mRNA表达变化。
LAD≥40mm的患者β1ARAb水平高于LAD较小的患者（8.87±3.16 vs.6.75±1.34ng/mL，P = 0.005）。β1ARAb水平与LAD和循环生物标志物水平呈正相关（均P<0.05）。与对照组相比，免疫组兔表现为：（1）心率加快、AERP缩短（70.00±5.49 vs.96.46±3.27ms，P<0.001）、房颤诱发率增加（55% vs.0%，P<0.001）、传导速度减慢和传导不均一性增加；（2）LAD增大和收缩功能障碍加重；（3）Masson三色染色（15.17±3.46 vs.4.92±1.72%，P<0.001）和天狼星红染色（16.76±6.40 vs.4.85±0.40%，P<0.001）显示左心房明显纤维化；（4）TGF-β1、Ⅰ型胶原和Ⅲ型胶原表达水平增加。
我们的临床和实验研究表明，β1ARAbs参与房颤的发生发展，其潜在机制与促进心房纤维化有关。
