Page 80 - YORAM RUDY BOOK FINAL

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The presence of a restricted extracellular (interstitial) space between fibers in cardiac tissue

affects the velocity of action potential propagation. The significant resistance of this space varies in
pathology (e.g. cell swelling, capillary volume changes). Its effect on conduction is incorporated in
so called bidomain models of cardiac tissue. 195

3.3 The Ionic Mechanisms of Conduction

This section explores the ionic mechanisms that underlie action potential propagation
in cardiac tissue. In particular, we focus on slow conduction due to reduced membrane

excitability and due to reduced intercellular coupling at gap junctions. We also investigate
conduction through various structural inhomogeneities (tissue expansion, fiber branching,
segments with reduced gap junction coupling) that are present in the heart. Action potential

propagation and its velocity are governed by the interaction between membrane processes
(source) and tissue structural properties (sink). We examine the effects of changes in either factor
(membrane or structure) on the source-sink relationship and how it affects conduction in cardiac
tissue.

Role of Membrane Excitability in Action Potential Propagation

In the myocardium, membrane excitability is determined by availability of fast sodium

channels. Various conditions can reduce this availability and lead to a smaller excitatory I current.
Na
These include genetic mutations (Brugada syndrome), remodeling processes, 197,198 administration
196
of class I antiarrhythmic drugs, 199,200 and acute ischemia. 201-204 In the simulation of Figure 3.5,
membrane excitability is progressively reduced by lowering the density of available membrane
sodium channels. Both conduction velocity (solid line) and the safety factor of conduction

(SF, dashed line) decrease monotonically with decreasing membrane excitability. Note however,
that SF decreases slowly, indicating a relative lack of sensitivity to moderate changes in membrane
excitability. Analysis of the SF computation (equation 3.2) reveals that both the charge gained by

the fiber from excitation (the numerator in equation 3.2) and the change needed to depolarize the
fiber (the denominator in equation 3.2) are only marginally affected by moderate reduction of
excitability. Therefore, in the absence of other changes, sufficient charge is generated to reach
excitation and conduction is relatively safe at moderate reduction of I . As sodium channel
Na
availability decreases below about 11% of normal, there is a dramatic increase in charge needed

from upstream fiber to reach excitation threshold (denominator in equation 3.2). Consequently,
SF drops rapidly towards 1 and when the generated depolarizing charge is not sufficient to meet
the requirement (SF<1), conduction failure occurs. The biphasic behavior of SF (slow decline

followed by an almost instantaneous drop towards 1 and conduction failure) reflects the nonlinear
properties of the cell membrane that underlie its “all or none” response.