BACKGROUND Insulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes develops. The pathophysiology and underlying mechanism are largely unclear. METHODS We investigated the corresponding mechanism in two IR models of rats fed 15-week high-fat (HFa) and high-fructose/cholesterol (HFr) diets. AF was evaluated and induced by burst atrial pacing. Isolated atrial myocytes were used for whole-cell patch clamp and calcium assessment. Ex vivo whole heart was used for optical mapping. Western blot and immunofluorescence were used for quantitative protein evaluation. RESULTS Both HFa and HFr rat atria were vulnerable to AF evaluated by burst atrial pacing. Isolated atrial myocytes from HFa and HFr rats revealed significantly increased sarcoplasmic reticulum calcium content and diastolic calcium sparks. Whole-heart mapping showed prolonged calcium transient duration, conduction velocity reduction, and repetitive ectopic focal discharge in HFa and HFr atria. Protein analysis revealed increased TGF-β1 and collagen expression; increased superoxide production; abnormal upregulation of calcium-homeostasis-related proteins, including oxidized CaMKIIδ, phosphorylated-phospholamban, phosphorylated-RyR-2, and sodium-calcium exchanger; and increased Rac1 activity in both HFa and HFr atria. We observed that inhibition of CaMKII suppressed AF in both HF and HFr diet-fed rats. In vitro palmitate-induced IR neonatal cardiomyocytes and atrial fibroblasts expressed significantly more TGF-β1 than did controls, suggesting paracrine and autocrine effects on both myocytes and fibroblasts. CONCLUSIONS IR engenders both atrial structural remodeling and abnormal intracellular calcium homeostasis, contributing to increased AF susceptibility. The inhibition of CaMKII may be a potential therapeutic target for AF in insulin resistance.

中文翻译：

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心房纤颤及其心律失常与胰岛素抵抗有关。

背景技术即使在糖尿病发展之前，胰岛素抵抗（IR）也被认为是房颤（AF）的危险因素。病理生理和基本机制尚不清楚。方法我们研究了两种在15周高脂（HFa）和高果糖/胆固醇（HFr）饮食中的大鼠的IR模型的相应机制。心房颤动被评估并诱发房颤。分离的心房肌细胞用于全细胞膜片钳和钙评估。离体全心脏用于光学标测。Western印迹和免疫荧光用于定量蛋白质评估。结果HFa和HFr大鼠心房均易受房颤起搏评估。从HFa和HFr大鼠中分离出的心房肌细胞显示肌浆网中钙含量和舒张期钙火花明显增加。全心图显示HFa和HFr心房中钙瞬变持续时间延长，传导速度降低和重复性异位局灶性放电。蛋白质分析显示TGF-β1和胶原蛋白表达增加；超氧化物产量增加；钙稳态相关蛋白的异常上调，包括氧化的CaMKIIδ，磷酸化的磷脂酰磷脂，磷酸化的RyR-2和钠钙交换剂；并增加了HFa和HFr心房中Rac1的活性。我们观察到，CaMKII的抑制作用可抑制HF和HFr饮食喂养的大鼠的房颤。体外棕榈酸酯诱导的IR新生儿心肌细胞和心房成纤维细胞表达的TGF-β1明显高于对照组，表明旁分泌和自分泌对肌细胞和成纤维细胞的影响。结论IR引起心房结构重塑和异常的细胞内钙稳态，导致房颤敏感性增加。CaMKII的抑制可能是胰岛素抵抗中AF的潜在治疗靶标。