The effect of clinically relevant changes in extracellular electrolyte concentrations on human atrial arrhythmias

Abstract

Background: Patients with recent-onset atrial fibrillation (AF) frequently present with plasma electrolyte imbalances. Low plasma concentrations of potassium (hypokalaemia), and more recently low plasma concentrations of sodium (hyponatremia), have both been shown to contribute to a pro-arrhythmic substrate and may affect the success of restoring the normal rhythm (cardioversion). However, the mechanistic effects of these electrolyte alterations on atrial electrophysiology remain incompletely understood. This study aims to investigate how clinically relevant variations in extracellular electrolyte concentrations influence human atrial electrical activity and arrhythmia initiation. Methods: We applied our cardiac digital twin methodology to a cohort of 100 atrial fibrillation patients (43 paroxysmal, 41 persistent, 16 long-standing persistent). For each patient-specific model, we simulated sinus rhythm and AF induction under baseline and 30 distinct combinations of extracellular potassium, sodium and calcium concentrations. Global sensitivity analysis and machine learning were used to quantify how these electrolyte alterations affect key electrophysiological markers, including action potential duration, resting membrane potential (RMP), and conduction velocity (CV), and the induction and maintenance of AF. Results: Here we show that our computational framework accurately replicates the experimentally observed sensitivity of human atrial electrophysiology to electrolyte variations. Hyponatremia significantly modifies the action potential waveform, thereby promoting AF sustainability, while hypokalaemia predominantly alters the RMP and thus CV, and only moderately increases AF inducibility. Conclusions: The combination of clinical data sets and multiscale computational analyses yields insights into cellular and tissue-level mechanisms for AF as well as suggesting personalised approaches for management and treatment.