3.2 Hypokalemia-ischemia-induced changes of repolarization and
arrhythmogenesis
In addition to having the specific border zone, the low-normal potassium
rats demonstrated prolonged repolarization in all zones and attenuated
shortening of repolarization in ischemia. Moreover, the inverse
association between the blood [K+] and ARI duration was observed. It
can be explained by the suppression of K+ channels conductance at
lowering the extracellular [K+], specifically IK1 inhibition21 and reduced Na+/K+-ATPase currents22 resulting in the prolongation of the repolarization
phase. As it has been already mentioned above, the ARI shortening in the
ischemic zone might be expected to be determined not by the blood
[K+] level but by the local rise of extracellular [K+]. However,
the ARIs in the ischemic zone at lower blood [K+] were longer than
at higher blood [K+]. This observation is in line with the
previously discussed one that the low-normal potassium animals had less
affected conduction characteristics in the ischemic zone and preserved
activation in the border zone. The in vivo observations were supported
by the in vitro patch-clamp experiments, where APD shortened at
high-normal extracellular [K+] and did not change at low [K+]
under hypoxic conditions. As expected, IK1 current decreased at low
extracellular [K+] due to the hypokalemic reduction of the
conductance for K+ channels 21. The less pronounced
APD shortening in hypoxia could be explained by the found decreased
IK(ATP) at low extracellular [K+].
In the present study, we observed the increased ESB in the low-normal
potassium rats as compared to the normal-high rats. The prolongation of
APD caused by the reduction of outward potassium currents, Na,K-ATPase
inhibition, Na+ and Ca2+ intracellular overload at hypokalemic
conditions promotes the occurrence of early afterdepolarization12, 23. This fact could explain the greater
extrasystolic burden in low-normal potassium animals, with the possible
origin of triggers from the border zone, where the ischemic changes
overlapped the relatively prolonged APD. It is of note that IK(ATP)
activation has been reported to abolish triggered activity24. We found that IK(ATP) was significantly suppressed
in the low-potassium animals, which could further facilitate ectopic
activity. Interestingly, the incidence of life-threatening arrhythmias
(VT/VF) did not differ between the low-normal and normal-high potassium
animals despite the difference in ESB, which usually serves as triggers
for reentrant arrhythmias. The high ESB did not realize in an
appropriately high incidence of lethal arrhythmias in this group
possibly due to the preserved activation characteristics in the border
zone of myocardium.
Hypokalemia has long been recognized as a proarrhythmic condition as it
prolongs APD, promotes abnormal automaticity and afterdepolarizations,
affects excitation thresholds and refractoriness 25.
These effects are well documented in individual cardiomyocytes, and the
present study extends this consideration into “spatial dimension”. Our
findings demonstrated that the decrease in extracellular [K+]
resulted in the formation of the border zone adjacent to the typical
ischemic zone. It is noteworthy that the cut-off [K+] level (4.7 mM)
is far above true hypokalemia, which implies that such a phenomenon may
be quite common. Furthermore, this relatively high cut-off [K+]
level implies that the observed increased ESB was due to the presence of
the border zone itself rather than the hypokalemia-induced changes in
individual cells.
Broadly speaking, the border zone can be considered as a mildly ischemic
myocardial region with preserved activation characteristics and abnormal
repolarization. Most likely, the role of the border zone in
arrhythmogenesis could not be ascribed to the changes in dispersion of
repolarization, but its critical arrhythmogenic property appears to be
the prolonged APD 26-28, which may be caused not only
by [K+] changes studied here, but also by early ischemic APD
prolongation 29. The findings obtained in the present
and previous studies cited above suggest that the border zone can
present a source of ectopic activity, which might trigger VT/VF.
Prolonged APD prone to early afterdepolarizations in combination with
preserved excitability may underlie this activity. The chances of
inducing the reentrant arrhythmias by these extrasystoles would probably
depend on other myocardial properties, for example, characteristics of
the ischemic region.
Limitations
There are some limitations of the present study, which warrant cautious
interpretation of the findings obtained. The experimental model is far
from clinical conditions concerning mostly the species (rats), which
demonstrate specific electrophysiological myocardial properties, and the
short duration of the ischemic episode. In vitro experiments could not
technically reproduce the situation in the in vivo experiments. The
mapping technique did not allow us to characterize the entire
ventricular surface, and therefore the exact configuration of the
ischemic/border/normal zones remained unknown.
CONCLUSIONS
The present study demonstrated that the formation of the border zone
depends on the extracellular potassium concentration likely due to the
attenuation of IK(ATP) response to hypoxia in low-normal [K+]. The
border zone was characterized by the preserved excitation and altered
repolarization processes and was associated with the increased
extrasystolic burden.
METHODS
Effects of extracellular [K+] on electrophysiological parameters
were investigated in vivo in a rat model of heart
ischemia/reperfusion as well as in vitro in isolated
cardiomyocytes. Experiments were performed in a total of 26 Wistar male
rats (4-month-old, 323±8 g) obtained from the Scientific Collection of
Experimental Animals of the Institute of Biology, Federal Research
Center, Komi Scientific Center, Ural Branch of the Russian Academy of
Sciences. The study conformed to the Guide for the Care and Use of
Laboratory Animals, 8th Edition published by the National Academies
Press (US), 2011, the guidelines from Directive 2010/63/EU of the
European Parliament on the protection of animals used for scientific
purposes, and was approved by the ethical committee of the Institute of
Physiology of the Komi Science Centre, Ural Branch of Russian Academy of
Sciences (approval 08 December 2022).