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Diabetes mellitus is associated with cardiovascular disease and cardiac arrhythmia. Accumulation of advanced glycation end products closely correlates with cardiovascular complications through mitochondrial dysfunction or oxidative stress and evoke proliferative, inflammatory, and fibrotic reactions, which might impair cardiac electrophysiological characteristics and increase the incidence of cardiac arrhythmia. This study examined the mechanisms how advanced glycation end products may contribute to arrhythmogenesis of right ventricular outflow tract—a unique arrhythmogenic substrate. A whole‐cell patch clamp, conventional electrophysiological study, fluorescence imaging, Western blot, and confocal microscope were used to study the electrical activity, and Ca2+ homeostasis or signaling in isolated right ventricular outflow tract myocytes with and without advanced glycation end products (100 μg/ml). The advanced glycation end products treated right ventricular outflow tract myocytes had a similar action potential duration as the controls, but exhibited a lower L‐type Ca2+ current, higher late sodium current and transient outward current. Moreover, the advanced glycation end products treated right ventricular outflow tract myocytes had more intracellular Na+, reverse mode Na+–Ca2+ exchanger currents, intracellular and mitochondrial reactive oxygen species, and less intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content with upregulated calcium homeostasis proteins and advanced glycation end products related signaling pathway proteins. In conclusions, advanced glycation end products modulate right ventricular outflow tract electrophysiological characteristics with larger late sodium current, intracellular Na+, reverse mode Na+–Ca2+ exchanger currents, and disturbed Ca2+ homeostasis through increased oxidative stress mediated by the activation of the advanced glycation end products signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Calcium overload increases the risk of atrial fibrillation (AF). Levosimendan, a calcium sensitizer, increases myofilament contractility. Clinical reports suggested that levosimendan might increase AF occurrence, but the electrophysiological effects of levosimendan on AF substrates and triggers (pulmonary veins, PVs) are not clear. Methods and results: Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial nodes (SANs), the left atrium (LA), and right atrium (RA) before and after application of different concentrations of levosimendan with or without milrinone (a phosphodiesterase [PDE] III inhibitor), and glibenclamide (an ATP‐sensitive potassium channel [KATP] inhibitor). Levosimendan (0.03, 0.1, 0.3, and 1 μM) significantly increased spontaneous rates from 2.1 ± 0.2 to 2.5 ± 0.2, 2.5 ± 0.2, 2.5 ± 0.1, and 2.7 ± 0.2 Hz, respectively, in PVs (n = 10), but had no effects on denudated PVs (n = 9). Additionally, levosimendan significantly induced burst firing and/or triggered beats in intact PVs, but not in denudated PVs. In contrast, levosimendan at 0.3 and 1 μM increased the SAN spontaneous rate. In the presence of milrinone (10 μM), levosimendan (1 μM) did not increase the PV spontaneous activity. Moreover, glibenclamide (100 μM) prevented acceleration of the levosimendan‐induced SAN and PV rates. In the LA, levosimendan at 0.3 and 1 μM shortened the AP duration, and increased contractility at 0.03, 0.1, 0.3, and 1 μM. In contrast, levosimendan did not change the RA contractility, and shortened the AP duration only at 1 μM. Conclusions: Levosimendan increased PV arrhythmogenesis through activating endothelial PDE III and the KATP, and modulating PV tension. [ABSTRACT FROM AUTHOR]

Effects of Indoxyl Sulfate on Pulmonary Vein and Atrial Arrhythmogenesis Background Chronic kidney disease (CKD) is associated with a higher incidence of atrial fibrillation (AF) with unclear mechanisms. Indoxyl sulfate (IS) accumulates in CKD patients. IS increases oxidative stress, which contributes to the genesis of AF. The arrhythmogenic effect of IS is unclear. Methods Conventional microelectrodes recorded the action potentials (AP) of isolated rabbit left atrium (LA), right atrium (RA), pulmonary vein (PV), and sinoatrial nodes (SANs) before and after treatment with IS with and without an antioxidant (ascorbic acid). Confocal microscopy with fluorescence and whole-cell patch clamp were used to evaluate intracellular calcium in isolated PV cardiomyocytes with and without IS. Results Compared to the control, IS induced more PV delayed afterdepolarizations at 0.1, 1, 10, and 100 μM, and induced more PV burst firings at 1, 10, and 100 μM. In contrast, IS (10 and 100 μM) reduced the SAN spontaneous beating rate. IS (100 μM) significantly shortened LA AP durations, but not RA. IS (100 μM)-treated PV cardiomyocytes had a similar calcium transient and sarcoplasmic reticulum calcium content, but a larger calcium leak than control PV cardiomyocytes. Burst pacing and isoproterenol induced a greater AF occurrence (50% vs. 100%; P = 0.009) and a longer AF duration (26 ± 9 vs. 5 ± 3 seconds; P < 0.05) in the LA (n = 8) with IS (100 μM) than without IS. Moreover, ascorbic acid (1 mM) attenuated the effects of IS on the LA, PV, and SANs. Conclusion IS increases PV and atrial arrhythmogenesis through oxidative stress. They may contribute to the occurrence of AF in CKD patients. [ABSTRACT FROM AUTHOR]

Background Renal failure (RF) increases the risk of atrial fibrillation (AF), but arrhythmogenic mechanism is unclear. The present study investigated the electrophysiological effects of RF on AF trigger (pulmonary veins, PVs) and substrate (atria) and evaluated potential underlying mechanisms. Methods Electrocardiographic, echocardiographic, and biochemical studies were conducted in rabbits with and without antibiotic-induced mild (creatinine = 1.5–6.0 mg/dl) and advanced (creatinine > 6.0 mg/dl) RF. Conventional microelectrode techniques, western blotting, and histological examinations were performed using the isolated rabbit PV, left atrium (LA), right atrium (RA) and sinoatrial node (SAN). Results Advanced RF rabbits (n = 18) had a higher incidence (33.3% vs. 11.1% and 0%, p < 0.05) of atrial arrhythmia than mild RF (n = 18) and control (n = 18) rabbits. Advanced RF rabbits exhibited faster PV spontaneous activities, longer action potential duration (APD) in the LA, higher fibrosis in the LA, and slower SAN beating rates than control rabbits, but had a similar APD and fibrosis in the RA. Caffeine (1 mM) increased advanced RF PV arrhythmogenesis, which is blocked by flecainide (10 μM), or KB-R7943 (10 μM). Moreover, advanced RF rabbits had a higher expression of the Na + /Ca 2 + exchanger, protein kinase A, phosphorylated ryanodine receptor (Serine 2808), and phosphorylated phospholamban (Serine 16) in PVs, and a higher expression of Ca v 1.2 in the LA, and a lower expression of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 in the SAN. Conclusions Advanced RF increases atrial arrhythmia by modulating the distinctive electrophysiological characteristics of the PV, LA, and SAN. [ABSTRACT FROM AUTHOR]