Mechanisms for initiation of reentry in acute regional ischemia phase 1B

Abstract

Background: During phase 1B of acute regional ischemia, the subepicardial and subendocardial layers coupled to the inexcitable midmyocardium remain viable.

Objective: The purpose of this study was to examine how the degree of hyperkalemia in the surviving layers, the lateral width of border zone between the normal tissue and the central ischemic zone, and the degree of cellular uncoupling between the surviving layers and the midmyocardium contribute to initiation of reentry.

Methods: Simulations were conducted on the state-of-the-art model of rabbit ventricles with realistic representation of the spatial distribution of the ischemic insult.

Results: Hyperkalemia in the surviving layers led to induction of reentry by increasing refractoriness and slowing conduction in the layers. Such reentries were formed solely in the subepicardium. A minimal level of hyperkalemia was required for induction of reentry. Progress increase in hyperkalemia led to a biphasic change in vulnerability to reentry. For each level of hyperkalemia, increased cellular uncoupling between subepicardium and midmyocardium increased inducibility of reentry by restoring subepicardial tissue excitability via blocking midmyocardial electrotonic effect. In addition, increased lateral width of the border zone prevented inducibility of reentry as conduction block occurred in the central ischemic zone when the wave propagated across the border zone from the normal zone.

Conclusion: The degree of hyperkalemia in the surviving subepicardium, the lateral width of border zone, and cellular uncoupling between the subepicardium and midmyocardium determine dispersion of refractoriness, conduction velocity, excitability, and, therefore, inducibility of reentry during phase 1B.

Fig.1

A. Anterior and cross-sectional views of the rabbit ventricular model showing demarcation of the normal zone (NZ), central ischemic zone (CIZ) and border zone (BZ) following occlusion of the left anterior descending artery. Colors were used to distinguish the three zones. White dashed lines outline BZ. Asterisk indicates the stimulus site. LV-left ventricle; RV- right ventricle; Subepi-, subepicardium; Subendo-, subendocardium; Mid-, midmyocardium. B. Border zones for different ischemic parameters.

Fig.2

Changes in subepicardial electrophysiological parameters for varying degrees of hyperkalemia: resting membrane potential (RMP in black, at site 1 marked in Fig.1) and conduction velocity (CV in red, calculated from isochrones near site 1) for DOU of 0% and 100% in panels A and B, respectively, and action potential duration (APD in black, at site 1) and effective refractory period (ERP in red, at site 1) for DOU of 0% and 100% in panels C and D, respectively. Straight dotted lines correspond to normal values. Bold crosses in panels C and D indicate inexcitability. Panels E and F represent activation maps recorded on the anterior epicardial and LV endocardial surfaces for [K⁺]_o of 14mM with DOU of 0% and 100% respectively. White dashed lines outline the BZ. Area in black indicates conduction block.

Fig.3

Vulnerable window durations for different degrees of hyperkalemia, DOU values, and BZ widths.

Fig.4

Activation maps on the anterior epicardial surface and traces of transmembrane potential (V_m) and fast sodium current (I_Na, recorded from sites 2 to 5 marked in panel A) for a simulation with control BZ width in panels A and B, respectively, and those for a simulation with ¼ of control BZ width in panels C and D, respectively. The coupling is normal, and [K⁺]_o and coupling interval are 12mM and 155ms, respectively. S1, S2, and R refer to the last pacing beat, the premature beat and the reentrant beat. Black asterisk indicates the earliest site of reentrant activation. The insets show enlarged views of traces of I_Na and L-type calcium current (I_CaL) at site 4.

Fig.5

Activation maps on the anterior epicardial surface and traces of V_m and I_Na in panels A and B, respectively, for a simulation with all other conditions the same as in Fig.4A, except that DOU is 100%. All notations are the same as in Fig.4.