title: The uremic toxin indoxyl sulfate increases pulmonary vein and atrial arrhythmogenesis.
abstract: 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.
  
  
  CONCLUSIONS
  IS increases PV and atrial arrhythmogenesis through oxidative stress. They may contribute to the occurrence of AF in CKD patients.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Ta
authors.initials: WT
authors.lastname: Chen
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Ming-Hsiung
authors.initials: MH
authors.lastname: Hsieh
authors.forename: Shih-Yu
authors.initials: SY
authors.lastname: Huang
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.forename: Yi-Ann
authors.initials: YA
authors.lastname: Chen
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000322:Adrenergic Agonists / Q000633:toxicity; D000818:Animals; D001281:Atrial Fibrillation / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac / Q000295:instrumentation; D007200:Indican / Q000633:toxicity*; D008839:Microelectrodes; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011667:Pulmonary Veins / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D000322:Adrenergic Agonists; D007200:Indican; D002118:Calcium
keywords: atrial fibrillation; chronic kidney disease; indoxyl sulfate; oxidative stress; uremic toxin