for propagation is proportional to the excess of source current over the

sink needs. By this definition, conduction fails when the safety factor
drops to less than 1 and becomes increasingly stable as it rises to
more than 1.
Membrane excitability, intercellular coupling, and tissue structure
have a huge influence on the safety of propagation. The safety factor
decreases monotonically as membrane excitability is reduced. In addition,
the safety factor tends to be low for propagation that occurs from
a smaller cell to a larger cell or from a relatively small number of cells
to a larger number of cells.
On the other hand, although reduction of intercellular coupling
between the source cell and the sink leads to slowing of conduction, it
is associated with improved safety of conduction. Uncoupling the source
cells from neighboring cells prevents the source from becoming overwhelmed
by sink demand. As cells become less coupled, there is greater
confinement of depolarizing current to the depolarizing source cell,
with less electrotonic load and axial flow of charge to the downstream
“sink” cells. As a result, individual cells depolarize with a high margin
of safety, but conduction proceeds with long intercellular delays. At
such low levels of coupling, conduction is very slow but, paradoxically,
very robust. Due to the high safety factor, extremely slow conduction
velocities can be sustained in tissue with greatly reduced intercellular
coupling.25,27,31,34
EXCITATION-CONTRACTION COUPLING
Excitation-contraction coupling describes the physiological process by
which electrical stimulation of the cardiomyocytes (the action potential)
results in a mechanical response (muscle contraction). The contraction
of a cardiac myocyte is governed primarily by intracellular Ca2+ concentration
(Fig. 1.7). Ca2+ enters the cell during the plateau phase of
the action potential through the L-type Ca2+ channels that line areas
of specialized invaginations known as transverse (T) tubules. Although
the rise in intracellular Ca2+ is small and not sufficient to induce contraction,
the small amount of Ca2+ entering the cell via ICaL triggers a
massive release of Ca2+ from the sarcoplasmic reticulum (the major
store for Ca2+) into the cytosol by opening the ryanodine receptor 2
(RyR2) channels (present in the membrane of the sarcoplasmic reticulum)
in a process known as calcium-induced calcium release (CICR).
Approximately 75% of Ca2+ present in the cytoplasm during contraction
is released from the sarcoplasmic reticulum.
Each junction between the sarcolemma (T tubule) and sarcoplasmic
 reticulum, where 10 to 25 L-type Ca2+ channels and 100 to 200 RyRs
are clustered, constitutes a local Ca2+ signaling complex (called a
“couplon”). When a Ca2+ channel opens, local cytosolic Ca2+ concentration
rises in less than 1 millisecond to 10 to 20 μM in the junctional
cleft, and this activates RyR2 to release Ca2+ from the sarcoplasmic
reticulum. The close proximity of the RyR2 to the T tubule enables
each L-type Ca2+ channel to activate four to six RyR2s and generate a
“Ca2+ spark.” Ca2+ influx via ICaL simultaneously activates approximately
10,000 to 20,000 couplons in each ventricular cardiomyocyte with every
action potential.35
CICR raises cytosolic Ca2+ levels from approximately 10−7 M to
approximately 10−5 M. The free Ca2+ binds to troponin C, a component
of the thin filament regulatory complex, and thus causes a conformational
change in the troponin-tropomyosin complex, such that troponin
I exposes a site on the actin molecule that is able to bind to the myosin
ATPase located on the myosin head. This binding results in ATP hydrolysis
that supplies energy for a conformational change to occur in the
actin-myosin complex. The result of these changes is a movement
(ratcheting) between the myosin heads and the actin, such that the
actin and myosin filaments slide past each other and thereby shorten