Résumé
Abstract
Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): ESC
FRM
Lefoulon Delalande
Aims
To investigate whether extracellular hypercalcemia alters the conduction through L-type Ca2+ channels (LTCCs), impairing the pacemaker activity of the heart.
Introduction
In the sino-atrial node (SAN), membrane currents and the dynamics of intracellular Ca2+ ([Ca2+]i) generate the pacemaker activity of the heart. SAN dysfunctions (SNDs) harm heart automaticity and have been associated with abnormal dynamics of [Ca2+]i. The LTCCs, Cav1.2 and Cav1.3 carry the main Ca2+ influx of SAN cells, which is necessary to sustain [Ca2+]i dynamics. Modified extracellular Ca2+ ([Ca2+]o) could alter Ca2+ influx through these channels. For example, cancer and hyperparathyroidism can raise [Ca2+]o, causing an extracellular hypercalcemia that could alter [Ca2+]i dynamics and impair SAN activity and heart automaticity.
Methods and results
To test this hypothesis, we measured contractions, [Ca2+]i release and L-type Ca2+ current (ICa,L) in spontaneous cells of the murine SAN. Then, we recorded rate and propagation of the spontaneous action potentials (APs) generated by the SAN tissue ex-vivo.
In spontaneously beating SAN cells, we observed that the modification of [Ca2+]o affected [Ca2+]i and cell contractility through changes of ICa,L. In particular, the increase of [Ca2+]o dysregulated pacemaker activity, likely through excessive Ca2+ influx mediated by Cav1.2.
[Ca2+]o increase to hypercalcemia induced arrhythmia also in the intact SAN tissues, activating ectopic leading regions of pacemaking and impairing conduction towards the atria.
Conclusions
Hypercalcemia causes excessive Cav1.2-mediated Ca2+ influx, which alters [Ca2+]I leading to pacemaker impairment. Modulation of LTCC may reduce pacemaker dysfunctions, preventing SND progression.