Sensitivity Analysis of Ion Channel Conductance on Myocardial Electromechanical Delay: Computational Study.

Ali Ikhsanul Qauli,Aroli Marcellinus,Ki Moo Lim

doi:10.3389/fphys.2021.697693

Ali Ikhsanul Qauli, Aroli Marcellinus + Show 1 more

Open Access

https://doi.org/10.3389/fphys.2021.697693

Copy DOI

Abstract

It is well known that cardiac electromechanical delay (EMD) can cause dyssynchronous heart failure (DHF), a prominent cardiovascular disease (CVD). This work computationally assesses the conductance variation of every ion channel on the cardiac cell to give rise to EMD prolongation. The electrical and mechanical models of human ventricular tissue were simulated, using a population approach with four conductance reductions for each ion channel. Then, EMD was calculated by determining the difference between the onset of action potential and the start of cell shortening. Finally, EMD data were put into the optimized conductance dimensional stacking to show which ion channel has the most influence in elongating the EMD. We found that major ion channels, such as L-type calcium (CaL), slow-delayed rectifier potassium (Ks), rapid-delayed rectifier potassium (Kr), and inward rectifier potassium (K1), can significantly extend the action potential duration (APD) up to 580 ms. Additionally, the maximum intracellular calcium (Cai) concentration is greatly affected by the reduction in channel CaL, Ks, background calcium, and Kr. However, among the aforementioned major ion channels, only the CaL channel can play a superior role in prolonging the EMD up to 83 ms. Furthermore, ventricular cells with long EMD have been shown to inherit insignificant mechanical response (in terms of how strong the tension can grow and how far length shortening can go) compared with that in normal cells. In conclusion, despite all variations in every ion channel conductance, only the CaL channel can play a significant role in extending EMD. In addition, cardiac cells with long EMD tend to have inferior mechanical responses due to a lack of Cai compared with normal conditions, which are highly likely to result in a compromised pump function of the heart.

Highlights

In the modern world, cardiovascular disease (CVD) remains a significant health burden worldwide (Virani et al, 2020)
We examined two quantities that are closely related to electromechanical delay (EMD): action potential duration (APD) and calcium attributes such as max-Cai concentration, resting Cai, Cai slope, and Cai duration
We found that major ion channels, such as CaL, Ks, Kr, and K1, can significantly influence APD prolongation

Summary

Introduction

Cardiovascular disease (CVD) remains a significant health burden worldwide (Virani et al, 2020). In common DHF, the workload is typically highest in the left ventricle and lowest in the septum and is accompanied by regional differences in wall stress (Vernooy et al, 2007). This condition leads to regional differences in wall thickness. One key factor in assessing DHF is electromechanical delay (EMD), which describes the time difference between the onset of action potential and starting time of myofiber shortening during the excitationcontraction process (Cordeiro et al, 2004). Electromechanical delay has two components: (a) the intrinsic latent period between the depolarization and myofilament (MF) activation in myocytes (Cordeiro et al, 2004) and (b) local myofiber mechanical loading conditions in an intact heart (Russell et al, 2011)

Methods

Results

Discussion

Conclusion