Page 7 - YORAM RUDY BOOK FINAL

P. 7

2. THE CARDIAC VENTRICULAR ACTION POTENTIAL

Together with skeletal muscle and nerve, cardiac muscle is classified in the category of
excitable tissues that can generate propagating electrical impulses (action potentials). At the level
of a single cardiac cell, the electrical action potential triggers mechanical contraction by inducing
a transient increase of the intracellular calcium concentration which, in turn, carries the contraction
message to the contractile elements of the cell. This process is termed excitation-contraction

coupling. The cardiac action potential is characterized by long plateau and repolarization phases
that follow the fast depolarization upstroke. The action potential morphology, time course and
duration are precisely controlled by multiple ionic processes. During the action potential,

membrane ion channels interact with dynamically varying ionic concentrations and membrane
potential, and are modulated by various regulatory processes. These interactions are complex,
dynamic and non-linear, making it very difficult (if not impossible) to predict their outcomes and
to elucidate mechanisms without the aid of computational models and mathematical analysis.

During the last decade, a large body of knowledge has accumulated on the molecular
structure of cardiac ion channels, on their function and kinetic properties in relation to this
structure, and on modification of the structure/function by genetic mutations associated with

cardiac arrhythmias 6,7,8,9 . Most of these data were acquired in expression systems (e.g. Xenopus
oocyte, HEK cells) and isolated membrane patches, removed from the highly interactive
physiological environment of the cardiac cell where ion channels function to generate the action
potential. An important objective for the next decade is to integrate this information back into the
cellular and tissue environments in order to relate the molecular processes and their alteration by

disease to cardiac excitation and arrhythmia.

This section applies computational biology approaches to integrate structural and functional

properties of ion channels into the whole-cell environment in order to relate cellular electrophysi-
ological function to the biophysical principles that govern ion-channel behavior. As stated above,
the single cardiac cell is a complex interactive system where high degree of synthesis occurs.
Mathematical models of cardiac ion channels and cells can be used to link the whole-cell function
to biophysical processes that underlie the functioning of ion channels at the molecular scale .
10

2.1 Computing the Action Potential From Macroscopic Transmembrane Currents

Action potentials are generated by the movement of ions across the cell membrane. This
process displaces charge on the membrane capacitance (C ) and changes the membrane
m
potential (V ) according to the following equation:
m