The Arrhythmogenic Effect of Protein-Bound Uremic Toxin p-Cresylsulfate: An In Vitro Study

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 (I-k) was significantly decreased in a dose-dependent manner after treatment with PCS. The modulation of PCS on I-k was through regulation of the phosphorylation of the major potassium ion channel protein Kv2.1. In computer simulations, the decrease in I-k 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 I-k channel protein Kv2.1 and I-k 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.