Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential
Willem B van Ham1, Carlijn M Cornelissen1, Elizaveta Polyakova1
1Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
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.
Insights
Uremic toxins (UTs) in chronic kidney disease (CKD) prolong cardiac action potential duration by reducing the IKr current and K V 11.1 protein levels. These findings suggest a pro-arrhythmogenic mechanism in dialysis patients.
Area of Science:
- Cardiology
- Nephrology
- Electrophysiology
Background:
- Chronic kidney disease (CKD) impairs kidney filtration, leading to uremic toxin (UT) accumulation.
- UTs are implicated in cardiac remodeling and cardiovascular deaths in dialysis patients.
- Mechanisms linking UTs to cardiac dysfunction, particularly sudden cardiac death, are poorly understood.
Purpose of the Study:
- To investigate the impact of clinically relevant UT concentrations on cardiac action potential repolarization.
- To assess the effects of chronic UT exposure on cardiomyocyte electrophysiology and ion channel function.
Main Methods:
- Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 cells were chronically exposed (48h) to indoxyl sulfate, kynurenine, or kynurenic acid.
- Electrophysiological techniques (optical mapping, manual patch-clamp) were used to measure action potential duration (APD) and IKr currents.
- Molecular analysis of K V 11.1 (the channel responsible for IKr) protein levels was performed.
Main Results:
- Chronic UT exposure significantly prolonged APD in hiPSC-CMs.
- Reduced IKr current densities and decreased K V 11.1 protein levels were observed after UT exposure.
- Treatment with an IKr activator (LUF7244) reversed UT-induced APD prolongation.
Conclusions:
- Uremic toxins possess pro-arrhythmogenic potential by impairing cardiac repolarization.
- A key mechanism involves the reduction of IKr current and K V 11.1 protein levels.
- Targeting IKr current may offer a therapeutic strategy to mitigate UT-induced cardiac electrophysiological changes.
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