Multiscale analysis of a HCN4 channel double mutation in a human sinoatrial computational model

The Double Mutation (DM) I479V/A485E has been reported (Servatius et al., 2018) to determine a loss of function of the funny current (If), which is a key player of the onset of the action potential in the Sinoatrial Node (SAN). Thus, the DM can result in bradycardia. This work presents a multiscale study that links the DM (i.e. genotype) to the bradycardia (i.e. phenotype). To do this, first a tool to display and analyse electrophysiological data was developed. Thanks to it, the decrease in If conductance was quantified and used as an input for a computational model of a human SAN cell. The simulation of the action potential of this model gave a Cycle Length (CL) of 1019 ms (compared to 814 ms of the Wild Type condition, +20.1 %). After this, a 1D and 2D model of the SAN were implemented, in order to test the behaviour of more complex systems (fibre and tissue), since these can show phenomena not present at the channel or single cell level. Several values of cellular heterogeneity (σ) and coupling (ρ) were considered, in order to investigate the most physiologic degree of these properties. This was assessed relying on the most realistic results obtained for CL, Action Potential Amplitude (APA) and Conduction Velocity (CV). The results show that: I) increasing σ leads to shorter mean CLs and wider CL and APA distributions; II) increasing ρ provides wider CL and APA distributions, whereas their mean values are the highest for ρ = 1000 MΩ·m. A complete synchronization is therefore a trade-off between σ and ρ; III) for physiologic values of σ (0.1873) and ρ (~ 100 MΩ·m) cells manage to synchronize their pacing frequency and show a conduction velocity similar to that reported in literature (~ 11 cm/s) in both 1D and 2D models. This is true for both WT and DM but, in the last case, the mean CL is significantly shorter. This fact proves the detrimental effect of these mutations: in 2D, the heart rate drops from 75.6 bpm (WT) to 60.2 bpm (DM, -18.3 %).