Key result
Plateau calcium current changes most strongly drive alternans onset and action potential duration.
Why the study?
Prior studies using specialized ion channel models only identified physiological phenomena from random conductances changes, leaving the sensitivity of APD alternans to ion channel conductances unclear.
Computational modeling demonstrates that APD alternans occurring under clinically-observed slow heart rate conditions is primarily driven by calcium channel currents, particularly the plateau Ca2+ current.
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May guide Ca2+ current research on alternans; leaves open translation to clinical arrhythmia risk.
Action potential duration (APD) alternans, an alternating phenomenon between action potentials in cardiomyocytes, causes heart arrhythmia when the heart rate is high. However, some of the APD alternans observed in clinical trials occurs under slow heart rate conditions of 100 to 120 bpm, increasing the likelihood of heart arrhythmias such as atrial fibrillation. Advanced studies have identified the occurrence of this type of APD alternans in terms of electrophysiological ion channel currents in cells. However, they only identified physiological phenomena, such as action potential due to random changes in a particular ion channel’s conductivity through ion models specializing in specific ion channel currents. In this study, we performed parameter sensitivity analysis via population modeling using a validated human ventricular physiology model to check the sensitivity of APD alternans to ion channel conductances. Through population modeling, we expressed the changes in alternans onset cycle length (AOCL) and mean APD in AOCL (AO meanAPD) according to the variations in ion channel conductance. Finally, we identified the ion channel that maximally affected the occurrence of APD alternans. AOCL and AO meanAPD were sensitive to changes in the plateau Ca2+ current. Accordingly, it was expected that APD alternans would be vulnerable to changes in intracellular calcium concentration.
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Jeong et al. (2022) studied Action potential duration (APD) alternans (n=59,049). Ion channel conductance variations vs. Normal conductance conditions was evaluated on Alternans onset cycle length (AOCL) and mean APD in AOCL (AO meanAPD). Parameter sensitivity analysis via population modeling revealed that alternans onset cycle length and mean action potential duration were maximally sensitive to changes in the plateau Ca2+ current.
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