Network Dynamics in Cardiac Electrophysiology - Systems Biology of Metabolic and Signaling Networks - page 236

Fig. 10.1 Schematic plot of
multi-scale and multi-
network perspective of
cardiac electrophysiology

Heart

3D

Cellular
networks

2D

SR, Mito, &
MF networks

1D

Gene Gene , signaling signaling

& metabolic metabolic

networks

Ion channels

random opening and closing of the ion channels. Genes, proteins, and metabolites
form networks, which regulate intracellular calcium (Ca 2+ ) cycling, action potential
properties, and many other cellular functions. At the subcellular scale, the dynamics
of a single mitochondrion or a single Ca 2+ release unit (CRU), such as Ca 2+ sparks
or mitochondrial flickers, are collective behaviors of many ion channels. Although
aCa 2+ spark or a mitochondrial flicker exhibits certain randomness, it behaves very
differently from random opening and closing of a single ion channel, which is a
collective behavior arising from the synergistic interactions of many ion channels.
The CRUs, mitochondria, and myofilaments form interacting networks, and novel
dynamics, such as waves and oscillations, emerges from the networks to give rise to
the whole-cell dynamics. A rich spectrum of dynamics have been observed at this
scale in addition to the normal excitation-contraction-metabolism coupling, such
as action potential duration alternans, early afterdepolarizations (EADs) and
delayed afterdepolarizations (DADs), and automaticity. At the tissue scale, cardiac
myocytes and other types of cells form cellular networks to generate and conduct
electrical signals for contraction. Most of these wave dynamics are tissue-scale
emergent properties that cannot be simply derived from single cell properties. In
addition, feedback loops form between scales. For example, fast heart rate or
arrhythmic wave dynamics of the heart may cause ischemia , intracellular Ca 2+
and Na + accumulation , and molecular and cellular remodeling (e.g., as indicated by
the green arrows in Fig. 10.1 ), which then affect the wave dynamics in the heart.
Therefore, in a network perspective, the heart is a network composed of many