3.1 Potassium-dependent development of a border zone
In this study, we investigated experimentally the effect of variation in
[K+] from hypokalemic (2.33 mM) to hyperkalemic (6.42 mM)
concentration on electrophysiological parameters of myocardial zones
developed at local ischemia. Of particular interest was the border zone
as a possible source of triggered activity and a substrate for reentrant
arrhythmias.
Extracellular [K+] greatly affects cardiac susceptibility to
arrhythmias. Regional heterogeneities in [K+], I(KATP), and pH
arising at coronary occlusion result in the increased dispersion of
conduction velocity, action potential duration and effective refractory
periods 14. Moreover, since extracellular potassium
flows from the ischemic zone into the normal zone 8,
9, the greatest inhomogeneity of [K+] is observed in the border
zone 10. The spatial heterogeneity of the action
potential properties, gradient in I(KATP) activation and the presence of
ischemic border zone per se provide the substrate for re-entrant
arrhythmias 15, 16.
The major question addressed in the present study was how the background
[K+] (i.e., [K+] before local ischemia) influences the formation
of electrophysiological zones of myocardium and arrhythmogenicity in
general. We found that the myocardium of the low-normal potassium
animals was electrophysiologically more heterogeneous. Besides the
normal and typical ischemic zones, there was a border zone demonstrating
ST-segment elevation, normal activation, and ARIs of intermediate
duration. At the same time, the normal-high potassium animals
(>4.7 mM) had only the typical ischemic and normal zones
with abrupt but still monotonic transition between each other.
The development of the border zone at low-normal potassium conditions
warrants explanation. We assume that the area between the typical
ischemic and normal zones experienced relatively mild ischemia.
Therefore, the formation of the electrophysiological border zone was due
to the combined effect on the electrophysiological parameters resulting
from [K+] decrease and the mild ischemia.
First, we should provide an explanation for the ST-segment elevation in
the border zone. After coronary occlusion onset, the RMP becomes
depolarized in the ischemic zone. It produces the electromotive force
responsible for the elevation of the ST-segment 17.
The decrease in extracellular [K+] leads to the opposite changes. It
means that the mildly ischemic area in the hypokalemic conditions should
experience counterbalanced effects on the RMP. However, the RMP in the
normal zone in hypokalemia gets also hyperpolarized and therefore the
potential difference between the zones persisted and the ST-segment
elevation in the border zone develops. At a higher level of
extracellular [K+], the RMP gets depolarized in the normal zone18, as well as in the ischemic zone, though to a
lesser extent, therefore the mildly ischemic transitional zone
demonstrated the less, if any, ST-segment elevation.
The other distinction of the border zone observed in the present study
is preserved activation. We suggest that the low-normal potassium
animals had not only lower blood [K+], but also lower local
extracellular [K+] in the affected area. According to this
assumption, the absence of the activation delay in the border zone of
low-normal potassium animals was due to preserved sodium channel
availability. The basis for such considerations is given below.
It is generally acknowledged that ischemia leads to impulse conduction
slowing manifesting as an AT delay or electrocardiographic QRS complex
prolongation. One of the causes of this effect is a decrease in sodium
channel availability caused by RMP depolarization due to local
accumulation of extracellular potassium in the affected region19. As expected, we observed the significant AT delay
in the ischemic zone (Fig.1) and a gradual decrease in CV from the
normal to ischemic zone (Fig. 2) with occasional development of a
conduction block.
It might be also expected that the conduction disturbances in the
affected myocardium, (whose perfusion is compromised or completely
ceased) would be determined by the severity of the ischemic injury and
local rise of extracellular [K+], which should not strongly depend
on the background level of blood [K+]. However, the low-normal
potassium animals had a less pronounced AT delay in the ischemic zone
and higher CV in all zones of myocardium as compared to the normal-high
potassium rats. It also means that although the low-normal potassium
rats demonstrated the progressive decrease in CV from the normal to
ischemic areas, the CV observed in the border zone in these animals was
still higher than CV in a spatially corresponding area, which might have
been the border zone in the normal-high potassium animals.
The explanation for these observations can be provided by the data of
IK(ATP) current measurements in the patch-clamp experiments. IK(ATP)
activation is considered as one of the major mechanisms of the
extracellular [K+] rise in the ischemic conditions20. Here, we demonstrated that the decrease in the
extracellular [K+] dramatically reduced the density of IK(ATP). The
lower IK(ATP) might underlie a less accumulation of extracellular
potassium in the affected regions, which should be associated with
lesser depolarization of the RMP and higher availability of the sodium
channels.
The above considerations suggest that the transitional area in the
low-normal potassium animals experienced several influences, which could
modify the conduction. (i) Since this area could preserve some
interaction with the normal tissue via diffusion of interstitial fluid
or partial perfusion with blood flow, the decreased blood [K+] would
decrease the local extracellular [K+], which led to
hyperpolarization of the RMP. (ii) Mild ischemia in this area would
contribute to the accumulation of extracellular potassium resulting in
the depolarization of the RMP and sodium channel inactivation. (iii) The
background low extracellular [K+] would attenuate these ischemic
consequences due to the inhibition of IK(ATP). Collectively, all these
factors would likely result in the preservation of activation in the
border zone observed in the present study.