Key result
Dialysis-related electrolyte shifts promote arrhythmogenesis in computational cardiomyocyte models with fibrosis and uremia.
Why the study?
The simultaneous presence of altered electrolytes and fibrosis or uremia in renal failure patients undergoing dialysis is thought to be pro-arrhythmogenic but not well understood.
Electrolyte shifts during dialysis may not eliminate arrhythmia risk in renal failure; leaves open independent pro-arrhythmic effects of fibrosis or uremia.
Dialysis is prescribed to renal failure patients as a long-term chronic treatment. Whereas dialysis therapeutically normalizes serum electrolytes and removes small toxin molecules, it fails to alleviate fibroblast induced structural fibrosis, and unresponsive uremia. The simultaneous presence of altered electrolytes and fibrosis or uremia is thought to be pro-arrhythmogenic. This study explored potential arrhythmogenesis under pre-dialysis (high electrolyte levels) and post-dialysis (low physiological electrolyte levels) in the presence of fibrosis and uremia in human atrial and ventricular model cardiomyocytes.Two validated human cardiomyocyte models were used in this study that permitted simulation of cardiac atrial and ventricular detailed electrophysiology. Pathological conditions simulating active fibrosis and uremia were implemented in both models. Pre- and post-dialysis conditions were simulated using high and low electrolyte levels respectively. Arrythmogenesis was quantified by computing restitution curves that permitted identification of action potential duration and calcium transient alternans instabilities. In comparison to control conditions, fibrosis abbreviated action potential durations while uremia prolonged the same. Under pre-dialysis conditions, an elevation of serum electrolyte levels caused action potential durations to be abbreviated under both fibrosis and uremia. Alternans instability was observed in the ventricular cardiomyocyte model. Under post-dialysis conditions, lower levels of serum electrolytes promoted an abbreviated action potential duration under fibrosis but caused a large increase of the control and uremic action potential durations. Alternans instabilities were observed in the atrial cardiomyocyte model under post-dialysis conditions at physiological heart rates. The calcium transient restitution showed similar alternans instabilities. Co-existing conditions such as fibrosis and uremia in the presence of unphysiological electrolyte levels promote arrhythmogenesis and may require additional treatment to improve dialysis outcomes.Clinical Relevance. Knowledge of model response to clinically relevant conditions permits use of in silico modeling to better understand and dissect underlying arrhythmia mechanisms.
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Sanjay Kharche (2020) studied Renal failure (simulated fibrosis and uremia). Pre- and post-dialysis electrolyte levels vs. Control conditions was evaluated on Arrhythmogenesis (action potential duration and calcium transient alternans instabilities). In virtual human cardiomyocyte models, unphysiological electrolyte levels simulating pre- and post-dialysis conditions promoted arrhythmogenesis in the presence of fibrosis and uremia.
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