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tissue more vulnerable to arrhythmia. The concept of the vulnerable window provides a

mechanistic basis for evaluation of arrhythmia vulnerability in the clinical setting. In the cardiac
electrophysiology catheterization laboratory, premature stimuli are delivered at various degrees
of prematurity (a protocol called “programmed electrical stimulation”). Successful initiation of

an arrhythmia defines vulnerability. As explained above, the probability of arrhythmia induction
increases with the size of the vulnerable window, which reflects arrhythmogenic properties of the
electrophysiological substrate in a given heart.

3.5 Ion Channels Heterogeneities and Action Potential Propagation

In addition to structural inhomonogeneities of tissue architecture, heterogeneities exist
throughout the myocardium in the expression levels of various ion channels. In particular, there

is transmural heterogeneity in I (low in mid-myocardial (M) cells) and a progressive reduction
Ks
in I from epicardium to endocardium (I is not expressed in endocardial cells). 226,227,228 Also, I is
to to to
expressed at high levels in right ventricular epicardium. During periodic excitation, especially at
fast rate, a propagating action potential may encounter tissue that is not yet fully recovered from
excitation by the previous action potential. The presence of heterogeneities in action potential

duration and repolarization properties may, therefore, affect conduction. This possibility was
examined in the context of the clinical Brugada syndrome, 196 defined phenotypically by
characteristic ST segment elevation in the right precordial ECG leads (see section 4). The Brugada

phenotype is associated, in many cases, with mutations in the SCN5A gene encoding the ∝-sub-
unit of the cardiac sodium channel, which lead to reduced function of the channel and reduced
I current. 226 In reference to section 3.3, this constitutes a reduction of sodium channel availability
Na
and reduced membrane excitability. One particular SCN5A mutation, the heterozygous missense
mutation F2004L, encodes sodium channels with decreased peak and persistent current

magnitudes by enhancing inactivation and slowing recovery from inactivation. 227 These properties
were introduced into a Markov model of I in a simulation of action potential propagation in an
Na
inhomogeneous fiber containing endocardial, mid-myocardial (M), and epicardial cells (Figure

3.18). Propagation from endocardium to epicardium (as occurs during normal sinus rhythm) was
simulated in both wild type and mutant fibers at fast (CL=300 msec) and slow (CL=1,000 msec)
pacing rates (Figure 3.19A). In the wild-type fiber, propagation was uniform and continuous with
physiological (normal) velocity of 45.3 cm/sec and 44.4 cm/sec at CL=300 msec and 1,000 msec,
respectively. In the mutant fiber at CL=300msec, propagation was continuous but slow (velocity

of 25.2 cm/sec). In contrast, at CL=1,000 msec propagation across the transition zone from M to
epicardial segments was discontinuous. Conduction in this zone was extremely slow at 9.2 cm/sec
and the I -dependent action potential front failed to propagate (“phase - 0 block”). The
Na
amplitude of the action potential plateau (dome) was higher than the I dependent upstroke in
Na
M cells (see cell 80, Figure 3.19A) and sub-epicardial (see cell 115 in the figure) segments. Beyond
the transition region, following a long delay of 116.5 msec, the excitatory axial current was provided
by the dome of the M-cell action potentials (“phase -2 conduction”) and depended on I .
Ca,L