Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization

Abstract

Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients are cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible remain poorly understood. The current study aimed to assess the vulnerability of action potential repolarization caused by exposure to pre-identified UTs at clinically relevant concentrations. We exposed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 chronically (48 h) to the UTs indoxyl sulfate, kynurenine, or kynurenic acid. We used optical and manual electrophysiological techniques to assess action potential duration (APD) in the hiPSC-CMs and recorded IKr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of KV11.1, the ion channel responsible for IKr, was performed to further understand the potential mechanism underlying the effects of the UTs. Chronic exposure to the UTs resulted in significant APD prolongation. Subsequent assessment of the repolarization current IKr, often most sensitive and responsible for APD alterations, showed decreased current densities after chronic exposure to the UTs. This outcome was supported by lowered protein levels of KV11.1. Finally, treatment with an activator of the IKr current, LUF7244, could reverse the APD prolongation, indicating the potential modulation of electrophysiological effects caused by these UTs. This study highlights the pro-arrhythmogenic potential of UTs and reveals a mode of action by which they affect cardiac repolarization.

Impact of Impaired Kidney Function on Arrhythmia-Promoting Cardiac Ion Channel Regulation

“…On a molecular level, van Ham et al conducted in vitro experiments with the incubation (48 h) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and immortalized HEK293 cells with IS. They found decreased repolarizing potassium currents (I Kr ) and lowered protein levels of K V 11.1, which subsequently resulted in prolonged action potential duration [ 80 , 81 ]. Furthermore, indoxyl sulfate decreased gap junction intercellular communication by downregulating connexin 43 in cultured neonatal rat cardiomyocytes, leading to increased spontaneous contractions [ 82 ].…”