Page 59 - YORAM RUDY BOOK FINAL

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The mechanism of action potential prolongation in this case (a late component of inward

current carried by Na through the I channel) is similar to the mechanism of action potential
+
Kr
prolongation in the SCN5A mutation ΔKPQ (see previous section), where mutant channels carry a
significant component of late I current.
Na

The simulations of HERG mutations demonstrate that the classification into “loss-of-
function” or “gain-of-function” is not sufficient. The effect of an ion-channel mutation on the
action potential depends on the details of the mutation-induced kinetic changes and at what
phase of the action potential they exert their effects.

2.10. Beyond Rate-Adaptation: Action Potential Alternans

Section 2.4 provided a discussion of action potential adaptation to rate changes. In

particular, steady-state action potential shortening at fast rate (adaptation) is an important
physiological property, essential for normal cardiac function. However, when rate is increased
above a certain threshold frequency, the cellular system cannot follow in a 1:1 response pattern
and repolarization properties alternate between beats. 139-144 This beat-to-beat variation is

reflected in T-wave alternans on the ECG, a marker known to be associated with dispersion of
repolarization, ventricular arrhythmias and sudden death. 145-149

Figure 2.39 A and B, show steady-state APD and Ca-transient adaptation curves generated
by the guinea-pig (LRd) cell model. Figure 2.39, C and D, depict similar plots for the canine (HRd).
APD shortens as rate is increased, until a critical rate is reached (CL = 250ms for the guinea pig
and 275 ms for the canine) at which APD bifurcates and oscillates between long and short values
on a beat-to-beat basis. 42,150 The range of cycle lengths over which this alternations occur is 150-

250ms for the guinea pig and 155-275 for the canine (insets in panels A and C) and the maximum
amplitudes of APD oscillation are 12ms and 35ms, respectively. The corresponding Ca-transients
(Panels B and D) increase in amplitude as rate increases until, at exactly the same rate as APD,
bifurcation occurs. The frequency range of alternans and the amplitudes of APD oscillations are

consistent with those measured experimentally.

Figure 2.40 examines the link between APD (electrical) and Ca (mechanical) alternans.
Figure 2.40A shows APD alternans (top), Ca alternans (middle) and I Ca,L (bottom) during pacing

at 4 Hz; note that long APD corresponds to a large Ca-transient. In Figure 2.40B, APD alternans is
eliminated by clamping the action potential to either its short APD = 133ms (gray) or long
APD = 165ms (black). Despite elimination of action-potential alternans, alternans of the
Ca-transient persists (Figure 2.40B, bottom). Clamp protocol of the Ca-transient (Figure 2.40C) to

either its small or large morphology, eliminates action-potential alternans. These results establish
cause and effect of alternans generation; Ca-alternans is the cause of action-potential alternans. In
other words, oscillations of the Ca-subsystem drive the action-potential oscillations. Figure 2.40D