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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]

BNP Modulates PV Electrophysiology Background Heart failure (HF) plays a critical role in the genesis of atrial fibrillation (AF). A high B-type natriuretic peptide (BNP) level occurs in patients with HF and in patients with AF. However, the role of BNP in the pathophysiology of AF is not clear. The purposes of this study were to evaluate the effects of BNP on pulmonary vein (PV) arrhythmogenesis. Methods and Results Whole-cell patch clamp and fluorescence were used to study the action potential, ionic currents, and calcium homeostasis in isolated single rabbit PV cardiomyocytes before and after a BNP infusion, with or without ODQ (10 μM), milrinone (50 μM), or ouabain (1 μM). BNP increased PV spontaneous activity by 28.2 ± 7.5% at 100 nM and by 23.8 ± 9.1% at 300 nM. Similar to those with BNP, milrinone 50 μM increased the PV beating rate from 3.0 ± 0.2 to 3.6 ± 0.3 Hz (P < 0.0005, n = 7). In the presence of ODQ application, BNP didn't change PV spontaneous activity. BNP (100 nM) increased calcium transients (F/F0 from 1.6 ± 0.1 to 1.9 ± 0.2, n = 20, P < 0.05) and increased the pacemaker current (0.4 ± 0.1 to 1.0 ± 0.2 pA/pF, n = 17, P < 0.0005) in PV cardiomyocytes. Moreover, BNP (100 nM) increased the transient inward current, sodium currents, sodium-calcium exchanger currents, and L-type calcium current; but reduced late sodium currents and the Na-K pump in PV cardiomyocytes. Conclusion BNP increases PV arrhythmogenesis, which may contribute to the genesis of atrial tachyarrhythmogenesis in HF. Cyclic GMP activation, phosphodiesterase 3 inhibition and Na+/K+-ATPase inhibition might participate in the BNP modulation of PV electrophysiology. [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]