Abstract:
Regular activation of the heart originates from cyclic spontaneous depolarisations of sinoatrial node cells (SANC). Variations in electrolyte levels, commonly observed in haemodialysis (HD) patients, and the autonomic nervous system (ANS) profoundly affect the SANC function. Thus, we investigated the effects of hypocalcaemia and sympathetic stimulation on SANC beating rate (BR).The -adrenergic (-AR) signalling cascade, as described by Behar et al., was incorporated into the SANC models of Severi et al. (rabbit) and Fabbri et al. (human). Simulations were conducted across various extracellular calcium ([Ca2+]o) (0.6 to 1.8 mM) and isoprenaline concentrations [ISO] (0 to 1000 nM) for a sufficient time to allow transient oscillations to equilibrate and reach a limit cycle. The -AR cell response of the extended models was validated against new Langendorff-perfused rabbit heart experiments and literature data.The extended models revealed that decreased [Ca2+]o necessitated an exponential-like increase in [ISO] to restore the basal BR. Specifically, at 1.2 mM [Ca2+]o, the Severi and Fabbri model required 15.5 and 7.3 nM [ISO], respectively, to restore the initial BR. Further reduction of [Ca2+]o to 0.6 mM required 60.0 and 41.7 nM [ISO] to compensate for hypocalcaemia. A sudden loss of sympathetic tone at low [Ca2+]o resulted in extreme bradycardia or even loss of automaticity within seconds.These findings suggest that hypocalcaemic bradycardia can be compensated for by an elevated sympathetic tone. The integration of the -AR pathways led to a logarithmic BR increase and offers insights into potential pathomechanisms underlying sudden cardiac death (SCD) in HD patients.
