title: Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients.
abstract: Total mortality and sudden cardiac death is highly prevalent in patients with chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the underlying mechanisms of this association have yet to be elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation. In a cohort of 100 early CKD patients, patients with corrected QT (QTc) prolongation had higher IS levels. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In a computer simulation, the decrease of IK by IS could prolong the action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated IK channel protein phosphorylation and the IK current activity that in turn increased the cardiomyocyte APD and QTc interval in vitro and in the computer ORd model. These findings suggest that IS may play a role in the development of arrhythmogenesis in CKD patients.
authors.affiliation: Graduate Institute of Medicine, Collage of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Division of Cardiology, Department of Internal Medicine E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Chao-Ping
authors.initials: CP
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Internal Medicine E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Fu-Mei
authors.initials: FM
authors.lastname: Chung
authors.affiliation: Institute of Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Lynn L H
authors.initials: LL
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Department of Internal Medicine E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Teng-Hung
authors.initials: TH
authors.lastname: Yu
authors.affiliation: Division of Cardiology, Department of Internal Medicine E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Wei-Chin
authors.initials: WC
authors.lastname: Hung
authors.affiliation: Division of Cardiac Surgery, Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Li-Fen
authors.initials: LF
authors.lastname: Lu
authors.affiliation: Institute of Electric Engineering, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chen
authors.affiliation: Institute of Electric Engineering, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Ching-Hsing
authors.initials: CH
authors.lastname: Luo
authors.affiliation: Graduate Institute of Medicine, Collage of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Kun-Tai
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Lee's Endocrinologic Clinic, Pingtung, Taiwan.
authors.forename: Yau-Jiunn
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medicine, Collage of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Ter
authors.initials: WT
authors.lastname: Lai
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007200:Indican / Q000097:blood* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011446:Prospective Studies; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D051669:Shab Potassium Channels / Q000378:metabolism*
chemical_list: C496988:KCNB1 protein, human; D051669:Shab Potassium Channels; D007200:Indican