Preventing ventricular fibrillation by flattening cardiac restitution

Abstract

Ventricular fibrillation is the leading cause of sudden cardiac death. In fibrillation, fragmented electrical waves meander erratically through the heart muscle, creating disordered and ineffective contraction. Theoretical and computer studies, as well as recent experimental evidence, have suggested that fibrillation is created and sustained by the property of restitution of the cardiac action potential duration (that is, its dependence on the previous diastolic interval). The restitution hypothesis states that steeply sloped restitution curves create unstable wave propagation that results in wave break, the event that is necessary for fibrillation. Here we present experimental evidence supporting this idea. In particular, we identify the action of the drug bretylium as a prototype for the future development of effective restitution-based antifibrillatory agents. We show that bretylium acts in accord with the restitution hypothesis: by flattening restitution curves, it prevents wave break and thus prevents fibrillation. It even converts existing fibrillation, either to a periodic state (ventricular tachycardia, which is much more easily controlled) or to quiescent healthy tissue.

Figure 1

(A) Effects of bretylium on APDR (a) and its slope (b), measured by the standard S₁-S₂ method. The effects on APDR slope in all six hearts is shown in c (thin lines are control, thick lines are bretylium). (B) The effects of increasing bretylium dose on APDR during VF. (C) Transmembrane potential recording during the bretylium-induced transition from VF to VT.

Figure 2

Effect of bretylium on spiral wave activity. Optical snapshots of voltage before and after the administration of 10 μM bretylium. Voltage is shown here color-coded, from red (highest voltage) to blue (lowest). (A) Under control (drug-free) conditions, VF was characterized by multiple irregular wave fronts. These give rise to the irregular segment of the transmembrane potential recording in Fig. 1C. (B) After bretylium administration, a pair of counter-rotating spiral waves remains in the tissue and gives rise to the periodic transmembrane potential activity in Fig. 1C. The mapped region shown contains the lower of the two counter-rotating spirals. Shown here are 10 snapshots, taken at evenly spaced 20-ms intervals. Note that two complete successive rotations of a stable spiral wave can be seen. [These were two successive rotations of a nearly identical sequence of about 15 rotations that could be observed (data not shown).] (C) Twenty successive 10-ms isochrones from the two rotations of the spiral wave shown in B. (Left) First rotation. (Right) Second rotation. Movies of the VF and VT episodes are published as supplemental data on the PNAS web site, www.pnas.org.

Figure 3

Bretylium + cromakalim. In these experiments, cromakalim was added to prevent APD prolongation by bretylium. (A) Compared with control (○ and thin lines), bretylium + cromakalim (● and thick lines) flattened APDR measured by the dynamic pacing method (a and b) and APDR during VF (c). (d) Superimposed APDR slopes before (thin lines) and after bretylium + cromakalim (thick lines) in all five preparations. (B) Transmembrane potential recording during the transition from VF to VT. (C) Gray-scale maps of voltage during VF (Left) and after bretylium + cromakalim (Right). Arrow shows fiber direction.

Figure 4

Computer simulation of effects of APD restitution on scroll wave stability. (Aa) APDR curves (APD vs. DI) for the Luo-Rudy I ventricular action potential model for two different values of Ḡ_si (the maximal value of the slow inward Ca²⁺ current). Prolonging APD by increasing Ḡ_si increased the slope of the APDR curve. The dashed lines in Aa and Ba have slope = 1. (A b and c) Snapshots of voltage [coded from red, denoting depolarized tissue (highest voltage) to blue for resting tissue (lowest voltage)], 1 sec after initiation of a single scroll wave in a three-dimensional slab of cardiac tissue. The initial scroll wave has spontaneously broken up into a fibrillation-like state for both conditions. (Ad) Transmembrane potential from one cell in simulation Ab. (Ba) Flattened APDR curves after modification of the Luo-Rudy action potential model (see Methods), for two different mean values of APD. (B b and c) Snapshots of voltage 2 sec after initiation of a single scroll wave, corresponding to the two restitution curves above. In each case, the scroll wave remained intact and did not break up into a fibrillation-like state. (Bd) Corresponding transmembrane potential from simulation Bb.