Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models.
Early afterdepolarization (EAD) is known as a cause of ventricular arrhythmias in long QT syndromes. We theoretically investigated how the rapid (IKr) and slow (IKs) components of delayed-rectifier K+channel currents, L-type Ca2+channel current (ICaL), Na+/Ca2+exchanger current (INCX), Na+-K+pump current (INaK), intracellular Ca2+(Cai) handling via sarcoplasmic reticulum (SR), and intracellular Na+concentration (Nai) contribute to initiation, termination, and modulation of phase-2 EADs, using two human ventricular myocyte models. Bifurcation structures of dynamical behaviors in model cells were explored by calculating equilibrium points, limit cycles (LCs), and bifurcation points as functions of parameters. EADs were reproduced by numerical simulations. The results are summarized as follows: 1) decreasing IKsand/or IKror increasing ICaLled to EAD generation, to which mid-myocardial cell models were especially susceptible; the parameter regions of EADs overlapped the regions of stable LCs. 2) Two types of EADs (termination mechanisms), IKsactivation-dependent and ICaLinactivation-dependent EADs, were detected; IKswas not necessarily required for EAD formation. 3) Inhibiting INCXsuppressed EADs via facilitating Ca2+-dependent ICaLinactivation. 4) Caidynamics (SR Ca2+handling) and Naistrongly affected bifurcations and EAD generation in model cells via modulating ICaL, INCX, and INaKParameter regions of EADs, often overlapping those of stable LCs, shifted depending on Caiand Naiin stationary and dynamic states. 5) Bradycardia-related induction of EADs was mainly due to decreases in Naiat lower pacing rates. This study demonstrates that bifurcation analysis allows us to understand the dynamical mechanisms of EAD formation more profoundly.
We investigated mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of human ventricular myocyte (HVM) models. EAD formation in paced HVMs basically depended on bifurcation phenomena in non-paced HVMs, but was strongly affected by intracellular ion concentrations in stationary and dynamic states. EAD generation did not necessarily require IKs.
Department of Physiology, Kanazawa Medical University, Ishikawa, Japan; yasu@kanazawa-med.ac.jp.
Yasutaka
Y
Kurata
Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Kunichika
K
Tsumoto
Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; and.
Kenshi
K
Hayashi
Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science, Yonago, Japan.
Ichiro
I
Hisatome
Department of Physiology, Kanazawa Medical University, Ishikawa, Japan.
Mamoru
M
Tanida
Department of Physiology, Kanazawa Medical University, Ishikawa, Japan.
Yuhichi
Y
Kuda
Department of Physiology, Kanazawa Medical University, Ishikawa, Japan.
Toshishige
T
Shibamoto
D000200:Action Potentials; D001919:Bradycardia / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism*; D006329:Heart Conduction System / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D008133:Long QT Syndrome / Q000378:metabolism; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D051668:Delayed Rectifier Potassium Channels; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium
bifurcation analysis; computer simulation; early afterdepolarization; long QT syndrome; mathematical model