https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Gießen und Marburg GmbH Medizinische Klinik I - Kardiologie und Angiologie Gießen, Deutschland; 2Universitätsklinikum Regensburg Klinik und Poliklinik für Innere Med. II, Kardiologie Regensburg, Deutschland; 3Institut für Physiologie Universität Regensburg Regensburg, Deutschland; 4Universitätsklinikum Würzburg Institut für Pharmakologie und Toxikologie Würzburg, Deutschland
Background: Chronic kidney disease (CKD) impacts approximately 15-20% of the global population, contributing significantly to increased rates of mortality and morbidity. Cardiovascular disease remains the leading cause of death among individuals with CKD. For patients undergoing dialysis due to kidney failure, the annual mortality rate is around 20%, largely due to sudden cardiac death. The mechanisms leading to this elevated mortality remain unclear.
Methods: Human ventricular induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) of healthy donors were used to conduct experiments. To simulate dialysis, cardiomyocytes were repeatedly exposed to levels of potassium and phosphate similar to those seen in clinical settings. Concentrations were gradually increased to mimic clinical dialysis conditions, followed by an abrupt reduction through a medium change, reflecting patients' dialysis sessions where potassium and phosphate rapidly shift from high to low levels (figure 1). Additionally, the beta-blocker carvedilol was administered in a subset of samples to evaluate if arrhythmic events could be prevented. Arrhythmic events were categorized into early and late non-stimulated events (representing systolic and diastolic arrhythmias), as well as early and delayed afterdepolarizations which occurring during or after the action potential repolarization phase.
Figure 1: Dialysis simulation protocol.
Results: Following the final medium change, a substantial increase in early and late non-stimulated events was observed in the dialysis group compared to the control group, with no significant differences noted between groups prior to this medium change. Notably, the use of carvedilol in the dialysis group led to a marked reduction in both early and late non-stimulated events after the final medium change (figure 2).
Figure 2: Representative images of early/late non-stimulated events. Data is shown as percentages of cells with early or late non-stimulated events. Fisher’s exact test was applied.
While early afterdepolarizations showed no significant differences across groups before or after the final medium change, the dialysis group exhibited a significantly higher occurrence of delayed afterdepolarizations compared to the control group, both before and after the dialysis simulation. Treatment with carvedilol significantly reduced delayed afterdepolarizations in the dialysis group (figure 3).
Figure 3: Representative recordings of early/delayed afterdepolarizations. Data is presented as mean±SEM. Ordinary one-way ANOVA (Tukey’s test) was used.
Conclusion: This study provides the first evidence that an in vitro dialysis model replicating clinically relevant electrolyte shifts can induce cellular arrhythmias. The beta-blocker carvedilol effectively reduced the occurrence of arrhythmic events, particularly following the final dialysis simulation. A next step would be to conduct a clinical study involving dialysis patients with continuous ECG monitoring to determine if beta-blocker administration during dialysis could lower the arrhythmia risk in this population.