Network Dynamics in Cardiac Electrophysiology - Systems Biology of Metabolic and Signaling Networks - page 237

subnetworks. A defect (such as a gene mutation) may or may not cause erroneous
electrical dynamics at the tissue scale to result in lethal arrhythmias, which depends
not only on the defect itself but also on the network that the defect resides. To
understand how such a complex system works and develop effective therapeutics,
systems biology and multi-scale modeling approaches are needed to elucidate the
underlying dynamics at each scale (or the dynamics of the subnetworks) and how
the dynamics at smaller scales (subnetworks) integrate to result in complex dynam-
ics at larger scales (whole networks).
In this chapter, we provide an overview of the networks in the heart and a current
understanding of the network dynamics in the context of cardiac electrophysiology.
We first review current knowledge of the genetic, signaling, and metabolic
networks and their links to arrhythmias. We then review the emergent properties
from the mitochondrial and CRU networks, the cellular dynamics, and the electrical
dynamics arising from the cellular networks. Finally, we discuss future challenges
and systems biology approaches to overcome these challenges.
10.2 Molecular and Organelle Networks and Network
Dynamics in Cardiac Myocytes
A cell is a spatial entity, which contains not only networks of genes, proteins, and
metabolites but also networks of spatially distributed organelles such as the CRU
network, the mitochondrial network, and the myofilament network. Novel dynam-
ics arise from these networks and from their interactions, which regulate cellular
Ca 2+ cycling and action potential dynamics for normal rhythms and arrhythmias of
the heart.
10.2.1 Genetic, Signaling, and Metabolic Networks
Clinical, experimental, and computational studies have begun to reveal the gene,
protein, and metabolic networks that link to cardiac arrhythmias.
Single gene mutations causing cardiac arrhythmias have been widely studied in
the last two decades (Sanguinetti et al. 1995 ; Napolitano et al. 2012 ). These
mutations, through altering ion channel conductance and kinetics to change the
action potential and Ca 2+ cycling dynamics, cause different diseases, such as long
QT syndrome (Keating and Sanguinetti 2001 ; Sanguinetti and Tristani-Firouzi
2006 ; Moss and Kass 2005 ), Brugada syndrome (Hedley et al. 2009 ), and catechol-
aminergic polymorphic ventricular tachycardia (Cerrone et al. 2009 ). However,
these monogenic diseases only account for a very small portion of the sudden
cardiac death syndrome. Gene loci that are associated with common forms of
cardiac diseases and arrhythmias have also been identified (Bezzina et al. 2010 ;