Key result
Modern numerical modeling demonstrates that cardiac pacemaker function relies on a tightly coupled system of both a voltage membrane clock and an intracellular calcium clock.
Modern numerical modeling of cardiac pacemaker cells must incorporate both intracellular Ca2+ cycling and cell membrane processes as a coupled-clock system to accurately reflect physiological and experimental behaviors.
Hypothesis-generating for biological pacemakers; leaves open clinical translation pending experimental validation.
Cardiac pacemaking is a complex phenomenon that is still not completely understood. Together with experimental studies, numerical modeling has been traditionally used to acquire mechanistic insights in this research area. This review summarizes the present state of numerical modeling of the cardiac pacemaker, including approaches to resolve present paradoxes and controversies. Specifically we discuss the requirement for realistic modeling to consider symmetrical importance of both intracellular and cell membrane processes (within a recent "coupled-clock" theory). Promising future developments of the complex pacemaker system models include the introduction of local calcium control, mitochondria function, and biochemical regulation of protein phosphorylation and cAMP production. Modern numerical and theoretical methods such as multi-parameter sensitivity analyses within extended populations of models and bifurcation analyses are also important for the definition of the most realistic parameters that describe a robust, yet simultaneously flexible operation of the coupled-clock pacemaker cell system. The systems approach to exploring cardiac pacemaker function will guide development of new therapies such as biological pacemakers for treating insufficient cardiac pacemaker function that becomes especially prevalent with advancing age.
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Maltsev et al. (2014) conducted a review in Cardiac pacemaker cell function. Numerical modeling of coupled-clock system was evaluated. Modern numerical modeling demonstrates that cardiac pacemaker function relies on a tightly coupled system of both a voltage membrane clock and an intracellular calcium clock.
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