I-Ting Tsai1, Chia-Chang Hsu2, Wei-Chin Hung3, Chao-Ping Wang3,4, Teng-Hung Yu3, Jer-Yiing Houng5, Kun-Tai Lee6, Wei-Hua Tang7. 1. Department of Emergency. 2. Division of Gastroenterology and Hepatology. 3. Division of Cardiology, Department of Internal Medicine, E-Da Hospital, I-Shou University. 4. School of Medicine for International Students. 5. Department of Nutrition, Institute of Biotechnology and Chemical Engineering, I-Shou University. 6. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung. 7. Division of Cardiology, Department of Internal Medicine, National Yang-Ming University Hospital, Yilan, Taiwan.
Abstract
BACKGROUND: p-Cresylsulfate (PCS) is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease. Previous studies have indicated that serum total PCS levels are significantly increased in the presence of abnormal corrected QT (QTc) intervals, and that they are associated with QTc prolongation. However, the QTc prolongation effect of PCS remains unclear. The current study aimed to investigate the arrhythmogenic effect of PCS using in vitro experiments and computer simulation. METHODS: The arrhythmogenic effect of PCS was evaluated by incubating H9c2 rat ventricular cardiomyocytes in vitro with increasing concentrations of PCS. Electrophysiological studies and mathematical computer simulations were performed. RESULTS: in vitro, the delayed rectifier potassium current (IK ) was significantly decreased in a dose-dependent manner after treatment with PCS. The modulation of PCS on IK was through regulation of the phosphorylation of the major potassium ion channel protein Kv2.1. In computer simulations, the decrease in IK induced by PCS prolonged the action potential duration (APD) and sped up the re-entrant wave, which is known to be a trigger mechanism for lethal ventricular arrhythmias. CONCLUSIONS: PCS significantly downregulated the phosphorylation of the IK channel protein Kv2.1 and IK current activity, which increased the cardiomyocyte APD. This was observed both in vitro and in the computer O'Hara-Rudy dynamic human ventricular model. These findings suggest that PCS may play a key role in the development of cardiac arrhythmias.
BACKGROUND: p-Cresylsulfate (PCS) is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease. Previous studies have indicated that serum total PCS levels are significantly increased in the presence of abnormal corrected QT (QTc) intervals, and that they are associated with QTc prolongation. However, the QTc prolongation effect of PCS remains unclear. The current study aimed to investigate the arrhythmogenic effect of PCS using in vitro experiments and computer simulation. METHODS: The arrhythmogenic effect of PCS was evaluated by incubating H9c2 rat ventricular cardiomyocytes in vitro with increasing concentrations of PCS. Electrophysiological studies and mathematical computer simulations were performed. RESULTS: in vitro, the delayed rectifier potassium current (IK ) was significantly decreased in a dose-dependent manner after treatment with PCS. The modulation of PCS on IK was through regulation of the phosphorylation of the major potassium ion channel protein Kv2.1. In computer simulations, the decrease in IK induced by PCS prolonged the action potential duration (APD) and sped up the re-entrant wave, which is known to be a trigger mechanism for lethal ventricular arrhythmias. CONCLUSIONS: PCS significantly downregulated the phosphorylation of the IK channel protein Kv2.1 and IK current activity, which increased the cardiomyocyte APD. This was observed both in vitro and in the computer O'Hara-Rudy dynamic human ventricular model. These findings suggest that PCS may play a key role in the development of cardiac arrhythmias.
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