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.

Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β–treated human AEECs, cardiac-specific TGF-β–transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β–treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β–transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.

Betatrophin, also known as TD26/RIFL/lipasin/ANGPTL8/C19orf80, is a novel protein predominantly expressed in human liver. To date, several betatrophin orthologs have been identified in mammals. Increasing evidence has revealed an association between betatrophin expression and serum lipid profiles, particularly in patients with obesity or diabetes. Stimulators of betatrophin, such as insulin, thyroid hormone, irisin and caloric intake, are usually relevant to energy expenditure or thermogenesis. In murine models, serum triglyceride levels as well as pancreatic cell proliferation are potently enhanced by betatrophin. Intriguingly, conflicting phenomena have also been reported that betatrophin suppresses hepatic triglyceride levels, suggesting that betatrophin function is mediated by complex regulatory processes. However, its precise physiological role remains unclear at present. In this review, we have summarized the current findings on betatrophin and their implications.

Whether dipeptidyl peptidase-4 inhibitor (DPP4i) is associated with a lower risk of new-onset atrial fibrillation (AF) in patients with diabetes remains unclear. This study aimed to evaluate the risk of AF associated with use of DPP4i among a longitudinal cohort of patients with diabetes. Over a 3-year period, 480,000 patients with diabetes were analyzed utilizing Taiwan’s National Health Insurance Research Database and 90,880 patients taking metformin as first-line therapy were enrolled. Patients were further divided into two groups: (1) DPP4i users: those taking DPP4i and (2) non-DPP4i users: those prescribed other hypoglycemic agents (HAs) as second-line drug. Study end point was defined by diagnosis of AF, addition of any third-line HA, or the end of the study period (December 31, 2013), whichever came first. A total of 16,017 DPP4i users and 74,863 non-DPP4i users were eligible for the study. For the DPP4i group, most patients were prescribed sitagliptin (n = 12,180; 76%). Among the non-DPP4i group, most patients took sulfonylurea (n = 60,606; 81%) as their second-line medication. DPP4i users were associated with a lower risk of new-onset AF compared with non-DPP4i users after propensity-score weighting (hazard ratio 0.65; P < 0.0001). Subgroup analysis showed that DPP4i user were associated with a lower risk of new-onset AF compared with non-DPP4i users in most subgroups. Multivariate analysis indicated that use of DPP4i was associated with lower risk of new-onset AF and age > 65 years, presence of hypertension, and ischemic heart disease were independent risk factors for new-onset AF. Among patients with diabetes prescribed with metformin, the patients with DPP4i as second HA were associated with a lower risk of AF compared with the patients with other drugs as second HAs in real-world practice.