Efficient termination of cardiac arrhythmias using optogenetic resonant feedback pacing.

Malignant cardiac tachyarrhythmias are associated with complex spatiotemporal excitation of the heart. The termination of these life-threatening arrhythmias requires high-energy electrical shocks that have significant side effects, including tissue damage, excruciating pain, and worsening prognosis. This significant medical need has motivated the search for alternative approaches that mitigate the side effects, based on a comprehensive understanding of the nonlinear dynamics of the heart. Cardiac optogenetics enables the manipulation of cellular function using light, enhancing our understanding of nonlinear cardiac function and control. Here, we investigate the efficacy of optically resonant feedback pacing (ORFP) to terminate ventricular tachyarrhythmias using numerical simulations and experiments in transgenic Langendorff-perfused mouse hearts. We show that ORFP outperforms the termination efficacy of the optical single-pulse (OSP) approach. When using ORFP, the total energy required for arrhythmia termination, i.e., the energy summed over all pulses in the sequence, is 1 mJ. With a success rate of 50%, the energy per pulse is 40 times lower than with OSP with a pulse duration of 10 ms. We demonstrate that even at light intensities below the excitation threshold, ORFP enables the termination of arrhythmias by spatiotemporal modulation of excitability inducing spiral wave drift.

Electromechanical vortex filaments during cardiac fibrillation.

The self-organized dynamics of vortex-like rotating waves, which are also known as scroll waves, are the basis of the formation of complex spatiotemporal patterns in many excitable chemical and biological systems. In the heart, filament-like phase singularities that are associated with three-dimensional scroll waves are considered to be the organizing centres of life-threatening cardiac arrhythmias. The mechanisms that underlie the onset, maintenance and control of electromechanical turbulence in the heart are inherently three-dimensional phenomena. However, it has not previously been possible to visualize the three-dimensional spatiotemporal dynamics of scroll waves inside cardiac tissues. Here we show that three-dimensional mechanical scroll waves and filament-like phase singularities can be observed deep inside the contracting heart wall using high-resolution four-dimensional ultrasound-based strain imaging. We found that mechanical phase singularities co-exist with electrical phase singularities during cardiac fibrillation. We investigated the dynamics of electrical and mechanical phase singularities by simultaneously measuring the membrane potential, intracellular calcium concentration and mechanical contractions of the heart. We show that cardiac fibrillation can be characterized using the three-dimensional spatiotemporal dynamics of mechanical phase singularities, which arise inside the fibrillating contracting ventricular wall. We demonstrate that electrical and mechanical phase singularities show complex interactions and we characterize their dynamics in terms of trajectories, topological charge and lifetime. We anticipate that our findings will provide novel perspectives for non-invasive diagnostic imaging and therapeutic applications.

Electromechanical optical mapping.

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.