Page 119 - YORAM RUDY BOOK FINAL

P. 119
Effects of Extracellular Potassium Concentration

Hypo- and hyperkalemia are important clinical conditions. Because transmembrane
currents carried by potassium ions depend on [K ] , it is conceivable that changes in potassium
+
o
concentration are reflected in ECG waveforms. This possibility is examined in the simulations of
Figure 4.5. Extracellular potassium influences action potential repolarization mostly by
modulating I conductance, which is proportional to the square root of [K ] . Normal [K ] under
+
+
o
Kr
o
physiological conditions is 4mmol/L. Reduction of [K ] to 2mmol/L reduces I and prolongs the
+
Kr
o
action potentials in all cell types. But because I is smaller in M cells, the effect is quantitatively
Ks
greater in these cells. On the ECG waveform, it prolongs the QT interval (from 196 ms to 236 ms)
and flattens the T-wave (maximum amplitude is reduced from 0.33 mV to 0.26 mV), consistent
with experimental 250 and clinical observations. Elevated [K ] (e.g., due to acute ischemia) has an
+
o
opposite effect; it shortens the QT interval (177ms at [K ] =6mmol/L) reflecting a shorter action
+
o
potential duration, and accentuates the T-wave amplitude (to 0.4 mV) reflecting a steeper V
m
gradient during repolarization. Both effects have been observed experimentally as well. There
are also more subtle changes to the ECG waveform. At elevated [K ] the QRS is slightly narrower,
+
o
reflecting shorter activation time of the ventricles because of increased velocity (“supernormal
conduction”). Finally, I conductance is also proportional to ([K ] ]) . However, because of the
+
½
K1
o
minor role of I in determining the time course of action potential repolarization, its modulation
K1
by [K ] changes has a small effect on action potential duration.
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o
Effects of Ion Channel Mutations – Long QT and Brugada Syndromes
The Long QT (LQT) syndrome, defined clinically as a prolonged QT interval on the ECG,
could be the result of abnormal ion-channel function that leads to action potential prolongation.

A decrease in repolarizing currents or an increase in depolarizing currents can cause this
prolongation. The alteration in channel function could be a result of a mutation that alters the
ion channel protein structure (“hereditary LQT”) or as a result of drug binding to the channel
(“acquired LQT”). In Figure 4.6 , we simulate the ECG changes caused by altered function of
247
three distinct ion channels- I , I and I . We simulate hereditary LQT1 and LQT2 by reducing I
Ks
Kr
Na
Ks
or I , respectively. LQT3 is simulated by slowing I inactivation to enhance late I current.
Na
Kr
Na
Several levels of severity (degree of ionic current alteration) are modeled for each type of LQT.
All simulated mutation effects prolong the QT interval and the amount of prolongation increases
with severity. I reduction (LQT1) prolongs action potential duration less in M cells than other cell
Ks
types (the same percent decrease causes smaller absolute decrease of I in M cells because of
Ks
its smaller level of expression in these cells). As a result, the action potentials are prolonged in all
cell types, but the dispersion of action potential durations is reduced. On the ECG, the QT interval
is prolonged, but the interval between the peak and end of the T-wave (TDR), which reflects the
dispersion, is shortened. 254