Early afterdepolarizations promote transmural reentry in ischemic human ventricles with reduced repolarization reserve

Abstract

Aims: Acute ischemia is a major cause of sudden arrhythmic death, further promoted by potassium current blockers. Macro-reentry around the ischemic region and early afterdepolarizations (EADs) caused by electrotonic current have been suggested as potential mechanisms in animal and isolated cell studies. However, ventricular and human-specific arrhythmia mechanisms and their modulation by repolarization reserve remain unclear. The goal of this paper is to unravel multiscale mechanisms underlying the modulation of arrhythmic risk by potassium current (IKr) block in human ventricles with acute regional ischemia.

Methods and results: A human ventricular biophysically-detailed model, with acute regional ischemia is constructed by integrating experimental knowledge on the electrophysiological ionic alterations caused by coronary occlusion. Arrhythmic risk is evaluated by determining the vulnerable window (VW) for reentry following ectopy at the ischemic border zone. Macro-reentry around the ischemic region is the main reentrant mechanism in the ischemic human ventricle with increased repolarization reserve due to the ATP-sensitive potassium current (IK(ATP)) activation. Prolongation of refractoriness by 4% caused by 30% IKr reduction counteracts the establishment of macro-reentry and reduces the VW for reentry (by 23.5%). However, a further decrease in repolarization reserve (50% IKr reduction) is less anti-arrhythmic despite further prolongation of refractoriness. This is due to the establishment of transmural reentry enabled by electrotonically-triggered EADs in the ischemic border zone. EADs are produced by L-type calcium current (ICaL) reactivation due to prolonged low amplitude electrotonic current injected during the repolarization phase.

Conclusions: Electrotonically-triggered EADs are identified as a potential mechanism facilitating intramural reentry in a regionally-ischemic human ventricles model with reduced repolarization reserve.

Keywords: Computer-based model; Ischemic heart disease; Potassium channels; Repolarization; Ventricular arrhythmia.

Fig. 1

Electrophysiological heterogeneity in the anatomically-based model of the human ventricles in acute regional ischemia. A. Resting potential distribution with elevated potentials in ischemic tissue (green solid line), location of the pseudo-ECG probe (black asterisk) and ectopic stimulation site (magenta solid line). B. Action potential duration (APD) distribution highlighting APD shortening in the ischemic central zone (ICZ) (top) and examples of action potentials in normal zone (NZ), border zone (BZ) and ICZ from the locations marked with green dots in the APD map. C. Activation times distribution (top) and pseudo-ECG (bottom) exhibiting first the QRS complex, followed by a positive T wave (due to the inverse relationship between APD and activation times) and ischemia-induced ST elevation.

Fig. 2

Electrophysiological properties in a one-dimensional homogeneous fiber of human ventricular tissue under control and acute ischemic conditions for varying degrees of the rapidly activating delayed rectifying potassium current (I_Kr) reduction. Results show steady-state values for APD, effective refractory period (ERP) and conduction velocity (CV) for cycle lengths (CL) ranging from 350 to 1500 ms. Normal and ischemic cells were assigned extracellular potassium concentration ([K⁺]_o) of 5.4 and 8.5 mmol/L, ATP-sensitive potassium current (I_K(ATP)) activation of 0 and 5%, and peak conductance of fast sodium current (I_Na) and L-type calcium current (I_CaL) of 100 and 75%, respectively, of their original values in the TP06 model.

Fig. 3

Macro-reentrant pattern of propagation in the human ventricles around the acute ischemic zone in control (top) and for 30% (middle) and 50% (bottom) I_Kr reduction following premature excitation applied with coupling intervals (CIs) of 355 ms, 360 and 361 ms, respectively. The limits of the BZ are marked with green lines and the direction of propagation with white arrows.

Fig. 4

Distribution of transmembrane voltage (V_m) throughout the ventricles at different times following ectopic excitation resulting initially in macro-reentry, but failure to support retrograde propagation (1381 ms), followed by propagation through the endocardial BZ (1775 ms) and transmurally (1831 ms), leads to intramural reentry (1831–1950 ms). For each time instant, three different views are shown, from left to right: the epicardium, the endocardium and the depolarized tissue with V_m above −20 mV (cells with V_m < −20 mV are transparent). Isopotential lines are shown in grey linking same potential levels. More details can be found in the supplemental movies.

Fig. 5

Electrotonically-triggered EADs are recorded near the BZ in the acutely-ischemic human ventricles with 50% I_Kr reduction facilitating transmural patterns of reentry. A. Snapshots of a transmural cross-section illustrating propagation of electrical excitation from endocardium to epicardium at the times indicated. B. Time course of V_m at the points indicated in panel A from endocardium to epicardium. Legend indicates the transmural location corresponding to each AP trace with % indicating transmural distance from the endocardium. Ectopic excitation is applied at t = 1181 ms (CI = 361 ms as in Fig. 3).

Fig. 6

Intramural reentry is facilitated by prolonged APD due to EAD formation in the acutely-ischemic human ventricles with reduced repolarization reserve for long CI = 430 ms. A. Ectopic excitation at t = 1253 ms (corresponding to CI = 430 ms) fails to induce reentry for 0 and 30% I_Kr reduction (first and second row, respectively), but leads to establishment of transmural reentry for 50% I_Kr reduction (third and fourth row). B. Time course of the action potential in the area of transmural reentry for 50% I_Kr reduction marked with a blue circle in panel A. Legends indicate the transmural location for each trace (percentage of transmural distance from the endocardium). More details can be found in the supplemental figure.

Fig. 7

Characterization of EADs induced by low amplitude current injected during the repolarization phase for varying current amplitudes (A) and repolarization levels (B) for human ventricular cardiomyocytes representative of NZ (top), BZ (middle) and ICZ (bottom) for 0, 30 and 50% I_Kr reduction (short dash, long dash and continuous lines, respectively) (BZ: [K⁺]_o = 7 mmol/L, I_K(ATP) activation = 3%, I_Na and I_CaL peak conductance = 85% and ICZ: [K⁺]_o = 8.5 mmol/L, I_K(ATP) activation = 5%, I_Na and I_CaL peak conductance = 75%). In panel A, current is applied at −20 mV with amplitude 0.7, 0.9, 1.1 and 1.2 pA/pF (from left to right) and 170 ms duration. In panel B, current of 1.1 pA/pF amplitude and 170 ms duration is applied at different levels of repolarization from 0 to −40 mV transmembrane potential. The stimulation protocol consisted of a train of 100 stimuli with amplitude −30 pA/pF during 1 ms (1.3*threshold for AP trigger), at a CL of 500 ms.

Fig. 8

Ionic mechanisms underlying electrotonically-triggered EAD formation. From top to bottom: time course of the action potential, I_CaL, I_CaL activation gate, calcium release current from the sarcoplasmic reticulum, I_Na and I_Kr for human ventricle cardiomyocytes representative of NZ, BZ and ICZ under varying degrees of repolarization reserve (0, 30 and 50% I_Kr reduction corresponding to short dash, long dash and continuous lines). Stimulation protocol and ischemic conditions as in Fig. 7.