Impact of proinflammatory epicardial adipose tissue and differentially enhanced autonomic remodeling on human atrial fibrillation

Objectives The mechanisms underlying atrial fibrillation are yet to be elucidated. We sought to investigate the interactions among autonomic remodeling, epicardial adipose tissue, inflammation, and atrial fibrillation. Methods Myocardium and adjacent epicardial adipose tissue of the left atrial appendage, right atrial appendage, and pulmonary vein muscle sleeves were obtained from 61 consecutive patients (35 with atrial fibrillation, 26 with no atrial fibrillation) during mitral valve surgeries. Patients were divided into the atrial fibrillation group and no atrial fibrillation group according to the history and Holter monitoring before surgery. Sympathetic and parasympathetic innervation were evaluated by tyrosine hydroxylase and choline acetyltransferase staining, respectively. Atrial fibrosis as well as cytokines/adipokines and related inflammatory proteins and signaling pathways in the epicardial adipose tissue were examined. Results Immunohistochemical studies revealed significantly increased tyrosine hydroxylase (+) and choline acetyltransferase (+) neural elements in the left atrial appendage and pulmonary vein muscle sleeve myocardium, as well as adjacent epicardial adipose tissue in the atrial fibrillation group, particularly the pulmonary vein muscle sleeve sites. The receiver operating curve identified a threshold ratio (tyrosine hydroxylase/choline acetyltransferase) of 0.8986 in the epicardial adipose tissue (sensitivity = 82.86%; specificity = 80.77%; area under the curve = 0.85, 95% confidence interval = 0.76-0.95, P < .0001). More patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio (≥0.8986) had atrial fibrillation. Expression levels of the genes and related proteins of the β1 adrenergic, mitogen-activated protein kinase, and nuclear factor kappa B signaling pathways were higher in patients with a higher tyrosine hydroxylase/choline acetyltransferase ratio. The tyrosine hydroxylase/choline acetyltransferase ratio also correlated with fibrosis. Conclusions Differentially enhanced autonomic remodeling and proinflammatory and profibrotic cytokines/adipokines in the epicardial adipose tissue adjacent to the pulmonary vein muscle sleeve site may work synergistically to promote atrial fibrillation.

目的 心房颤动的潜在机制尚未阐明。我们试图研究自主神经重构、心外膜脂肪组织、炎症和心房颤动之间的相互作用。 方法 在二尖瓣手术期间，从61例连续患者（35例心房颤动患者，26例无心房颤动患者）获取左心耳、右心耳和肺静脉肌袖的心肌以及相邻的心外膜脂肪组织。根据手术前的病史和动态心电图监测将患者分为心房颤动组和无心房颤动组。分别通过酪氨酸羟化酶和胆碱乙酰转移酶染色评估交感神经和副交感神经支配。检测心房纤维化以及心外膜脂肪组织中的细胞因子/脂肪因子和相关炎症蛋白及信号通路。 结果 免疫组织化学研究显示，心房颤动组左心耳和肺静脉肌袖心肌以及相邻心外膜脂肪组织中，酪氨酸羟化酶（+）和胆碱乙酰转移酶（+）神经成分显著增加，尤其是肺静脉肌袖部位。受试者工作曲线确定心外膜脂肪组织中阈值比率（酪氨酸羟化酶/胆碱乙酰转移酶）为0.8986（敏感性 = 82.86%；特异性 = 80.77%；曲线下面积 = 0.85，95%置信区间 = 0.76 - 0.95，P <.0001）。酪氨酸羟化酶/胆碱乙酰转移酶比率较高（≥0.8986）的患者更多患有心房颤动。β1肾上腺素能、丝裂原活化蛋白激酶和核因子κB信号通路的基因及相关蛋白的表达水平在酪氨酸羟化酶/胆碱乙酰转移酶比率较高的患者中更高。酪氨酸羟化酶/胆碱乙酰转移酶比率也与纤维化相关。 结论 肺静脉肌袖部位相邻心外膜脂肪组织中自主神经重构的差异增强以及促炎和促纤维化细胞因子/脂肪因子可能协同作用促进心房颤动。