Abstract
BackgroundInsulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes develops. The pathophysiology and underlying mechanism are largely unclear.MethodsWe 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.ResultsBoth 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.ConclusionsIR 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.
Highlights
Insulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes devel‐ ops
As shown in Additional file 1: Figure S1, after insulin was intravenously administered, the expression of p-Akt and the p-Akt-to-t-Akt ratio in response to insulin were significantly reduced in the atria from the HFr and HFa rats compared with control rats, indicating that both the HFa and HFr hearts were compatible with the condition of IR
These results suggest that the increased triggered activities observed in the IR atrial myocytes and atria were likely contributed by increased expression of NCX1 and Ca2+/calmodulindependent protein kinase IIδ (CaMKIIδ)-mediated activation of RyR2
Summary
Insulin resistance (IR) is considered as a risk factor for atrial fibrillation (AF) even before diabetes devel‐ ops. Previous studies have demonstrated the pathological mechanisms of overt hyperglycemia-related atrial remodeling and arrhythmogenesis in animal models of diabetes [10, 11]. We established two IR rat models by feeding them high-fat (HFa) and highfructose/high-cholesterol (HFr) diets [14]. We demonstrated significant remodeling in HFa and Hfr rat atria, including changes in the expression of calcium handling–related proteins, increased interstitial fibrosis, and increased oxidative stress and expression of transforming growth factor (TGF)-β1. We showed that oxidized calcium/calmodulin-dependent protein kinase II (CaMKII) may mediate the AF arrhythmogenesis in rats fed HFa and HFr diets
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