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In Silico Investigation into Cellular Mechanisms of Cardiac Alternans in Myocardial Ischemia
Jiaqi Liu1, Yinglan Gong1, Ling Xia1
1Department of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China.
Insights
Myocardial ischemia causes hyperkalemia, affecting ionic channels and leading to cardiac alternans. Computational simulations reveal hyperkalemia impairs calcium current recovery, driving alternans formation.
Area of Science:
- Cardiology
- Computational Biology
- Electrophysiology
Background:
- Myocardial ischemia induces hyperkalemia, acidosis, and hypoxia.
- These conditions alter ionic channel function, potentially causing cardiac alternans.
- Cardiac alternans are linked to altered cellular electrophysiology during ischemia.
Purpose of the Study:
- Investigate the roles of hyperkalemia and calcium handling in ischemia-induced alternans.
- Utilize computational simulations to explore cellular mechanisms of alternans.
- Elucidate the contribution of ionic currents to alternans at the cellular level.
Main Methods:
- Computational simulations of cellular electrophysiology.
- Modeling of ionic channel function under ischemic conditions.
- Analysis of calcium handling components and their impact on alternans.
Main Results:
- Hyperkalemia reduced cell excitability and delayed depolarization current recovery.
- Inactivation time constant of L-type calcium current (ICaL) increased, hindering ICaL recovery.
- Decreased Sarcoplasmic Reticulum Calcium-ATPase (SERCA2a) function and enhanced Na+-Ca2+ exchange current (INCX) amplified calcium alternans, leading to APD alternans.
Conclusions:
- Hyperkalemia and altered calcium handling are key drivers of cardiac alternans during ischemia.
- Impaired ICaL recovery and dysregulated intracellular calcium dynamics contribute to alternans.
- Computational modeling provides insights into the cellular basis of alternans in myocardial ischemia.
Abstract:
Myocardial ischemia is associated with pathophysiological conditions such as hyperkalemia, acidosis, and hypoxia. These physiological disorders may lead to changes on the functions of ionic channels, which in turn form the basis for cardiac alternans. In this paper, we investigated the roles of hyperkalemia and calcium handling components played in the genesis of alternans in ischemia at the cellular level by using computational simulations. The results show that hyperkalemic reduced cell excitability and delayed recovery from inactivation of depolarization currents. The inactivation time constant τ of L-type calcium current (ICaL) increased obviously in hyperkalemia. One cycle length was not enough for ICaL to recover completely. Alternans developed as a result of ICaL responding to stimulation every other beat. Sarcoplasmic reticulum calcium-ATPase (SERCA2a) function decreased in ischemia. This change resulted in intracellular Ca (Ca ) alternans of small magnitude. A strong Na+-Ca2+ exchange current (INCX) increased the magnitude of Ca alternans, leading to APD alternans through excitation-contraction coupling. Some alternated repolarization currents contributed to this repolarization alternans.
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