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bioRxiv · 10.1101/2022.03.01.482518

Remodelling of potassium currents underlies arrhythmic action potential prolongation under beta-adrenergic stimulation in hypertrophic cardiomyopathy

Doste, R.·Coppini, R.·Bueno-Orovio, A.
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Abstract

Hypertrophic cardiomyopathy (HCM) patients often present an enhanced arrhythmogenicity that can lead to lethal arrhythmias, especially during exercise. Recent studies have indicated an abnormal response of HCM cardiomyocytes to {beta}-adrenergic receptor stimulation ({beta}-ARS), with prolongation of their action potential rather than shortening. The mechanisms underlying this aberrant response to sympathetic stimulation and its possible proarrhythmic role remain unknown. The aims of this study are to investigate the key ionic mechanisms underlying the HCM abnormal response to {beta}-ARS and the resultant repolarisation abnormalities using human-based experimental and computational methodologies. We integrated and calibrated the latest models of human ventricular electrophysiology and {beta}-ARS using experimental measurements of human adult cardiomyocytes from control and HCM patients. Our major findings include: (1) the developed in silico models of {beta}-ARS capture the behaviour observed in the experimental data, including the aberrant response of HCM cardiomyocytes to {beta}-ARS; (2) the reduced increase of potassium currents under {beta}-ARS was identified as the main mechanism of action potential prolongation in HCM, rather than a more sustained inward calcium current; (3) dispersion of repolarisation between healthy and HCM tissue was increased upon {beta}-ARS, while transmural dispersion in HCM tissue was reduced; (4) models presenting repolarisation abnormalities were characterised by downregulation of the rapid delayed rectifier potassium current and the sodium-potassium pump, while inward currents were upregulated. In conclusion, our results identify causal relationships between the HCM phenotype and its arrhythmogenic response to {beta}-ARS through the downregulation of potassium currents.

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Doste, R., Coppini, R., Bueno-Orovio, A.. 2022-03-04. Remodelling of potassium currents underlies arrhythmic action potential prolongation under beta-adrenergic stimulation in hypertrophic cardiomyopathy. https://doi.org/10.1101/2022.03.01.482518

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