Cardiac defibrillation is usually achieved using a single high-energy electric shock of up to 4,000 volts, which can be damaging to the heart tissue. Eberhard Bodenschatz and colleagues show how the disordered electrical dynamics that underlie cardiac fibrillation can be controlled using low-energy electrical pulses. They show, in tests on dogs, that intrinsic homogeneities in the cardiac tissue (such as the vasculature) serve as nucleation sites for the generation of waves of electrical activity that can target the instabilities and bring the tissue dynamics back into synchrony. The new technique, called low-energy antifibrillation pacing or LEAP, delivers five sequential low-energy electrical field pulses to the fibrillating heart — an average energy reduction of 84% compared to standard defibrillation. Controlling the complex spatio-temporal dynamics underlying life-threatening cardiac arrhythmias such as fibrillation is extremely difficult, because of the nonlinear interaction of excitation waves in a heterogeneous anatomical substrate1,2,3,4. In the absence of a better strategy, strong, globally resetting electrical shocks remain the only reliable treatment for cardiac fibrillation5,6,7. Here we establish the relationship between the response of the tissue to an electric field and the spatial distribution of heterogeneities in the scale-free coronary vascular structure. We show that in response to a pulsed electric field, E, these heterogeneities serve as nucleation sites for the generation of intramural electrical waves with a source density ρ(E) and a characteristic time, τ, for tissue depolarization that obeys the power law τ ∝ Eα. These intramural wave sources permit targeting of electrical turbulence near the cores of the vortices of electrical activity that drive complex fibrillatory dynamics. We show in vitro that simultaneous and direct access to multiple vortex cores results in rapid synchronization of cardiac tissue and therefore, efficient termination of fibrillation. Using this control strategy, we demonstrate low-energy termination of fibrillation in vivo. Our results give new insights into the mechanisms and dynamics underlying the control of spatio-temporal chaos in heterogeneous excitable media and provide new research perspectives towards alternative, life-saving low-energy defibrillation techniques.

Background— Electrically based therapies for terminating atrial fibrillation (AF) currently fall into 2 categories: antitachycardia pacing and cardioversion. Antitachycardia pacing uses low-intensity pacing stimuli delivered via a single electrode and is effective for terminating slower tachycardias but is less effective for treating AF. In contrast, cardioversion uses a single high-voltage shock to terminate AF reliably, but the voltages required produce undesirable side effects, including tissue damage and pain. We propose a new method to terminate AF called far-field antifibrillation pacing , which delivers a short train of low-intensity electric pulses at the frequency of antitachycardia pacing but from field electrodes. Prior theoretical work has suggested that this approach can create a large number of activation sites (“virtual” electrodes) that emit propagating waves within the tissue without implanting physical electrodes and thereby may be more effective than point-source stimulation. Methods and Results— Using optical mapping in isolated perfused canine atrial preparations, we show that a series of pulses at low field strength (0.9 to 1.4 V/cm) is sufficient to entrain and subsequently extinguish AF with a success rate of 93% (69 of 74 trials in 8 preparations). We further demonstrate that the mechanism behind far-field antifibrillation pacing success is the generation of wave emission sites within the tissue by the applied electric field, which entrains the tissue as the field is pulsed. Conclusions— AF in our model can be terminated by far-field antifibrillation pacing with only 13% of the energy required for cardioversion. Further studies are needed to determine whether this marked reduction in energy can increase the effectiveness and safety of terminating atrial tachyarrhythmias clinically.

Alternans of action potential duration has been associated with T-wave alternans and the development of arrhythmias because it produces large gradients of repolarization. However, little is known about alternans dynamics in large mammalian hearts. Using optical mapping to record electrical activations simultaneously from the epicardium and endocardium of 9 canine right ventricles, we demonstrate novel arrhythmogenic complex spatiotemporal dynamics. (i) Alternans predominantly develops first on the endocardium. (ii) The postulated simple progression from normal rhythm to concordant to discordant alternans is not always observed; concordant alternans can develop from discordant alternans as the pacing period is decreased. (iii) In contrast to smaller tissue preparations, multiple stationary nodal lines may exist and need not be perpendicular to the pacing site or to each other. (iv) Alternans has fully three-dimensional dynamics and the epicardium and endocardium can show significantly different dynamics: multiple nodal surfaces can be transmural or intramural and can form concave/convex surfaces resulting in islands of discordant alternans. (v) The complex spatiotemporal patterns observed during alternans are very sensitive to both the site of stimulation and the stimulation history. Alternans in canine ventricles not only exhibit larger amplitudes and persist for longer cycle length regimes compared those found in smaller mammalian hearts, but also show novel dynamics not previously described that enhance dispersion and show high sensitivity to initial conditions. This indicate some underlying predisposition to chaos and can help the design of new drugs and devices controlling and preventing arrhythmic events.

The development of new approaches to control cardiac arrhythmias requires a deep understanding of spiral wave dynamics. Optogenetics offers new possibilities for this. Preliminary experiments show that sub-threshold illumination affects electrical wave propagation in the mouse heart. However, a systematic exploration of these effects is technically challenging. Here, we use state-of-the-art computer models to study the dynamic control of spiral waves in a two-dimensional model of the adult mouse ventricle, using stationary and non-stationary patterns of sub-threshold illumination. Our results indicate a light-intensity-dependent increase in cellular resting membrane potentials, which together with diffusive cell-cell coupling leads to the development of spatial voltage gradients over differently illuminated areas. A spiral wave drifts along the positive gradient. These gradients can be strategically applied to ensure drift-induced termination of a spiral wave, both in optogenetics and in conventional methods of electrical defibrillation.

Optical mapping is a widely used imaging technique for investigating cardiac electrophysiology in intact, Langendorff-perfused hearts. Mechanical contraction of cardiac tissue, however, may result in severe motion artifacts and significant distortion of the fluorescence signals. Therefore, pharmacological uncoupling is widely used to reduce tissue motion. Recently, various image processing algorithms have been proposed to reduce motion artifacts. We will review these technological developments. Furthermore, we will present a novel approach for the three-dimensional, marker-free reconstruction of contracting Langendorff-perfused intact hearts under physiological conditions. The algorithm allows disentangling the fluorescence signals (e.g. membrane voltage or intracellular calcium) from the mechanical motion (e.g. tissue strain). We will discuss the algorithms reconstruction accuracy, resolution, and robustness using experimental data from Langendorff-perfused rabbit hearts.

We propose a solution to a long-standing problem: how to terminate multiple vortices in the heart, when the locations of their cores and their critical time windows are unknown. We scan the phases of all pinned vortices in parallel with electric field pulses (E-pulses). We specify a condition on pacing parameters that guarantees termination of one vortex. For more than one vortex with significantly different frequencies, the success of scanning depends on chance, and all vortices are terminated with a success rate of less than one. We found that a similar mechanism terminates also a free (not pinned) vortex. A series of about 500 experiments with termination of ventricular fibrillation by E-pulses in pig isolated hearts is evidence that pinned vortices, hidden from direct observation, are significant in fibrillation. These results form a physical basis needed for the creation of new effective low energy defibrillation methods based on the termination of vortices underlying fibrillation.