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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]

Aims: Ventricular arrhythmia (VA) frequently occurs in fatty infiltrative cardiomyopathy or epicardial adipose tissue (EAT) abundant hearts. Right ventricular outflow tract (RVOT), commonly covered with EAT, is vital for VA genesis. This study explored whether EAT contributes to RVOT arrhythmogenesis.Methods and Results: Conventional microelectrodes and whole-cell patch clamp were used to record electrical activity and ionic currents in rabbit RVOT tissue preparation or isolated single cardiomyocytes with or without (control) connected EAT. Epicardial adipose tissue-connected (N = 6) RVOT had more portions of fibrosis than did control (N = 5) RVOT (160.3 ± 23.2 vs. 91.9 ± 13.4 μm2/mm2, P < 0.05). Epicardial adipose tissue-connected RVOT cardiomyocytes (n = 18) had lower negative resting membrane potential (-68 ± 1 vs. -73 ± 2 mV, P < 0.05); smaller action potential (AP) amplitude (108 ± 4 vs. 135 ± 6 mV, P < 0.005); and longer 90%, 50%, and 20% of AP duration repolarization (361 ± 18 vs. 309 ± 9 ms, P < 0.05; 310 ± 17 vs. 256 ± 13 ms, P < 0.05; and 182 ± 19 vs. 114 ± 24 ms, P < 0.05, respectively) than did control (n = 13) RVOT cardiomyocytes. Moreover, compared with control RVOT cardiomyocytes, EAT-connected RVOT cardiomyocytes had larger transient outward potassium currents, similar delayed rectifier potassium currents, smaller L-type calcium currents, and inward rectifier potassium currents. After ajmaline (10 μM, a sodium channel blocker) superfusion, high VA inducibility was observed through rapid pacing in EAT-connected RVOT but not in control RVOT.Conclusions: Epicardial adipose tissue exerts distinctive electrophysiological effects on RVOT with a propensity towards VA induction, which might play a role in lipotoxicity pathogenesis-related ventricular arrhythmogenesis. [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]