Simulated heterogeneity in purkinje-ventricular electrophysiology following acute myocardial infarction remodelling
Authors: Trovato C , Zhou X , Rodriguez BR 
Published: May 2021

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences

Background

Coronary heart disease is a common substrate for sudden cardiac death. Several clinical and experimental studies on ischemic heart diseases have highlighted the involvement of the His-Purkinje system in the initiation and maintenance of ventricular arrhythmias.  Biophysically-detailed mathematical models and computational multiscale simulations can help in gather insights of the cellular and tissue mechanisms underlying the trigger and maintenance of arrhythmias.

Purpose

The goal of this study is to evaluate the effects of ionic remodelling on human Purkinje and ventricular cells in the acute stage post myocardial infarction.

Methods

Two recently published computational models were used to represent the electrophysiology of cardiac Purkinje and ventricular cells, including transmural heterogeneity (endo, mid, epi myocytes). Cardiac ionic remodelling was observed at the border zone of the infarcted region, mostly in canine and porcine models. For both ventricular and Purkinje models, remodelling was implemented as a variation of the number of function channels, i.e., of the current conductance for Na+, Ca2+ and K+ currents. Simulations were performed for both models at different pacing frequencies (cycle length from 400 to 1000 ms) to assess a set of action potential (AP)  biomarkers and  AP rate-dependence at fast pacing. Early afterdepolarisation (EADs) were induced at slow pacing under hERG block.

Results

Figure 1 reports the results for the ventricular (A) and Purkinje (B) electrophysiology for the healthy (blue) and post-infarction (red) tissues at 1 Hz (left), at different frequencies (middle) and under 85% hERG block at 0.25 Hz (right). At 1 Hz, ionic remodelling reduced the AP depolarisation rate, abolished the AP notch and led to AP prolongation for both models. Purkinje AP showed also elevated resting membrane potentials and increased diastolic depolarisation. The mid-cardiomyocyte and Purkinje models showed a small increase in the APD- rate dependence slope. Ionic remodelling did not affect significantly the EAD dynamics in the ventricular model, apart from further delaying the AP repolarisation. In the Purkinje model, ionic remodelling led to automaticity and changed the EAD dynamics, which disappeared from the paced AP but occurred after the spontaneous AP.

Conclusion

In this study we investigated the effects of ionic current remodelling in ventricular and Purkinje cells following acute myocardial infarction. Results showed that remodelling at the border zone increased the heterogeneity between Purkinje and ventricular cells. A further step into the investigation of pro-arrhythmic mechanisms induced by myocardial infarction will be to perform multiscale simulations at whole organ level in 3D anatomical models of human ventricles, including the His-Purkinje system. Abstract Figure 1