Reentry in survived subepicardium coupled to depolarized and inexcitable midmyocardium: insights into arrhythmogenesis in ischemia phase 1B

Abstract

Background: Delayed ventricular arrhythmias during acute myocardial ischemia (1B arrhythmias) are associated with an increase in tissue impedance and are most likely sustained in a thin subepicardial layer.

Objective: The goal of this study was to test the hypothesis that heterogeneous uncoupling between depolarized midmyocardium and surviving subepicardium results in heterogeneous refractoriness in the latter, providing the reentry substrate after a premature beat.

Methods: A 3-dimensional bidomain slab was constructed comprising a normal subepicardial layer coupled to a slightly depolarized (-80 to -60 mV) but inexcitable midmyocardium. Experimentally measured tissue impedance served as input for the model. Four stages of heterogeneous uncoupling between the 2 layers were simulated, each corresponding to an experimental ischemic impedance value. Effective refractory periods (ERP), conduction velocities, and inducibility of reentry were examined.

Results: Heterogeneous uncoupling resulted in subepicardial ERP dispersion, allowing reentry to occur. The minimum ERP dispersion needed to induce reentry was 28 ms. Reentry induction was only possible in this model at the 2 intermediate stages of uncoupling, and only when midmyocardial resting membrane potential was more negative than -60 mV. Complete uncoupling of the layers resulted in normal subepicardial conduction without arrhythmias. The minimum length of the reentrant pathway was 2.5 cm, comparable to 2.4 cm reported in previous experiments.

Conclusion: Heterogeneous uncoupling to a negative sink such as depressed inexcitable midmyocardium may be a substrate for ischemia 1B arrhythmias. Total uncoupling removes the arrhythmogenic substrate.

Figure 1

A: Ventricular slab model of uncoupling in ischemia phase 1B, including a subepicardium, a coupling layer, and an inactive midmyocardium with dimensions as indicated. A centrally located circular region in the coupling layer with an additional decrease in transmural intracellular conductivity was incorporated to represent heterogeneities in uncoupling between viable subepicardium and inactive midmyocardium within the central ischemic zone (CIZ). Fiber direction is denoted by arrow on the slab surface. Stimuli were applied on the transmural side of the subepicardial and coupling layers only, as indicated by dark gray color, because the midmyocardium was assumed inactive. The asterisk marks the subepicardial site from which action potential traces were taken. Note that the scaling in the thickness direction has been greatly expanded. B: Experimental evidence used to construct the model. Shown is a slice of a pig heart stained with 2,3,5-triphenyltetrazolium chloride 60 minutes postischemia. Viable Lactate dehydrogenase (LDH) containing tissue appears in red (surviving subepicardium). The inset shows periodic acid Shiff staining of a microsection from the slice, with dark purple staining corresponding to the presence of glycogen and indicating subepicardium viability (up to 8 cell layers). Adapted with permission from de Groot et al.

Figure 2

Time course of tissue resistance within the central ischemic zone (CIZ) (open circles) and the normal zone (NZ, closed triangles), as obtained from measurements in isolated perfused pig hearts 90 minutes after occlusion. Circled numbers denote stages of ischemia. Stage 1 represents uncoupling at the onset of ischemia phase 1B. Stages 2 and 3 are of intermediate uncoupling, whereas stage 4 corresponds to uncoupling at the end of ischemia phase 1B.

Figure 3

Changes in subepicardial electrophysiological parameters: action potential duration (APD) (A), resting membrane potential (RMP) (B), effective refractory period (ERP) (dashed line), postrepolarization refractory period (PRRP) (solid line) (C), and conduction velocity (CV) (D) for different degrees of homogeneous uncoupling (DOU, with values of 0, 50% and 100%). Midmyocardial transmembrane potential is −80 (triangles), −70 (stars), and −60 mV (circles).

Figure 4

A: Progression of the spatial distribution of transmembrane potential on the surface of the preparation for an episode of figure-of-eight reentry induction. The sequences of snapshots are labeled by the instant of time measured from the premature stimulus application. Arrows indicate activation sequence. DOU_ IN/DOU_ OUT is 100%/50% and premature stimulation is at CI = 104 ms. The radius of the central region of uncoupling is 14 mm, and the midmyocardium is depolarized at −70 mV. B: Isochronal activation maps for the first 2 reentrant cycles during ventricular fibrillation after 40 minutes of ischemia used as a comparison to the simulation results (adapted with permission from de Groot et al2). Areas with dV/dt_min less negative than −2.5 V/s are highlighted with dashed lines. Arrows indicate gross activation sequence. Numbers and lines indicate activation times and 20 ms isochrones, respectively. CI = coupling interval; DOU_ IN/DOU_OUT = degree of uncoupling within/outside the central region.

Figure 5

Progression of the spatial distribution of transmembrane potential on the surface of the preparation for an episode of no reentry induction. The sequences of snapshots are labeled by the instant of time measured from the premature stimulus application. DOU_ IN/DOU_OUT is 50%/0%, and premature stimulation is at CI = 95 ms. The radius of the central region of uncoupling is 14 mm, and the midmyocardium is depolarized at −70 mV. Abbreviations as in Figure 4.

Figure 6

Progression of the spatial distribution of subepicardial transmembrane potential in an episode of figure-of-eight reentry induction (A) and of no induction (B) for 2 values of the radius of the central region of increased uncoupling, 7.6 mm (A) and 6.6 mm (B). The sequences of snapshots are labeled by the instant of time from the premature stimulus application. Arrows indicate activation sequence. Premature stimulus CI = 94 ms for both A and B. In both cases DOU_ IN/DOU_OUT is 100%/0% and the midmyocardium is depolarized at −70 mV. Abbreviations as in Figure 4.

Figure 7

A: Vulnerable windows for different cases of heterogeneous uncoupling, DOU_IN/DOU_OUT, and different degrees of midmyocardial depolarization, V_mid (black, gray, and white). Radius of central region of uncoupling is 14.0 mm. Vulnerable window duration is zero for V_mid of −60 mV. B: Vulnerable window for different radii of the central region. DOU_IN/DOU_OUT is 100%/0%, and V_mid is −70 mV. ΔERP is an estimate of the maximum dispersion in effective refractory period in the subepicardium (see text for more detail). Abbreviations as in Figure 4.