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.