Abstract
The generation of abnormal excitations in pathological regions of the heart is a main trigger for lethal cardiac arrhythmias. Such abnormal excitations, also called ectopic activity, often arise from areas with local tissue heterogeneity or damage accompanied by localized depolarization. Finding the conditions that lead to ectopy is important to understand the basic biophysical principles underlying arrhythmia initiation and might further refine clinical procedures. In this study, we are the first to address the question of how geometry of the abnormal region affects the onset of ectopy using a combination of experimental, in silico, and theoretical approaches. We paradoxically find that, for any studied geometry of the depolarized region in optogenetically modified monolayers of cardiac cells, primary ectopic excitation originates at areas of maximal curvature of the boundary, where the stimulating electrotonic currents are minimal. It contradicts the standard critical nucleation theory applied to nonlinear waves in reaction-diffusion systems, where a higher stimulus is expected to produce excitation more easily. Our in silico studies reveal that the nonconventional ectopic activity is caused by an oscillatory instability at the boundary of the damaged region, the occurrence of which depends on the curvature of that boundary. The onset of this instability is confirmed using the Schrödinger equation methodology proposed by Rinzel and Keener [SIAM J. Appl. Math. 43, 907 (1983)]. Overall, we show distinctively novel insight into how the geometry of a heterogeneous cardiac region determines ectopic activity, which can be used in the future to predict the conditions that can trigger cardiac arrhythmias.
- Received 27 October 2017
- Revised 18 April 2018
DOI:https://doi.org/10.1103/PhysRevX.8.021077
Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.
Published by the American Physical Society
Physics Subject Headings (PhySH)
Popular Summary
Arrhythmias are the most common cause of sudden cardiac death worldwide. During an arrhythmia, the heart’s electrical impulses change their pace. However, researchers still do not completely understand the underlying triggers. By combining theory with experiments, we take a first look at how the geometry of abnormal heart tissue influences the onset of unusual electrical activity.
In the heart, waves of electrical activity propagate through the tissue and trigger mechanical contraction. When additional waves (known as ectopic waves) occur, they can initiate events leading to arrhythmia. In many cases, ectopic waves are seen to emerge from areas of local tissue damage.
We study the genesis of ectopic waves by inducing damage in isolated cardiac tissue. We find that ectopic waves preferentially emanate from convex, high-curvature areas (e.g., corners) of the damaged tissue region, and we reproduce this finding in numerical simulations. This origin defies a widely accepted paradigm for wave propagation, which states that waves should arise not from corners but from the middle of a tissue region. Using a semianalytical analysis, and by drawing a mathematical analogy from quantum mechanics, we find that sharp corners lend themselves to oscillatory instability in the transition zone between normal and depolarized tissue. These oscillations overcome the passive electrical load from the surrounding normal tissue and generate propagating ectopic waves.
Our findings suggest that arrhythmias might be prevented by making the sharp corners of the damaged cardiac tissue region electrically inactive through, for example, targeted ablation.