Cardiovascular Research 2024

Conflicting signals

When we think about heart rhythm disorders in the heart, we tend to think about the heart as being an organ in a binary state. Either the heart is healthy, or it is diseased and shows arrhythmia. You could compare it with a light switch, where the heart can be in an "on" or "off" state. However, why wouldn't it be possible for the heart to be in a superposition of these two states? That way the heart would be "on" and "off" at the same time.

In clinical data, there are hints towards such conflicting signals that show "on" and "off" behavior at the same time. These signals come in the form of electrogram measurements. While the majority of them show normal rhythm, there sometimes is one that shows complex behavior (Fig.1 right). These conflicting signal are observed in patients with atrial fibrillation, and were previously often attributed to a malfunctioning electrode. But what if these electrodes are not malfunctioning, but rather the underlying mechanisms are not yet fully understood?

Hypothesis

To answer this question, we formulated the hypothesis that an arrhythmia can exist locally with the majority of cardiac tissue in sinus rhythm (Fig.2). This could then be made possible through dense regions of non-conducting cells (called fibrosis) that form small circuits where an excitation wave can enter, but not escape, creating a local arrhythmia. This wave would then later on be able to escape this circuit under the right conditions and start a global arrhythmia.

Since this local enclosure of an excitation wave is called "reentry" and the wave cannot escape and is "trapped", we decided to call this phenomenon "trapped reentry".

How do you test this hypothesis?

We set out to test this hypothesis by combining computational modeling with wet lab experiments using cardiac cells from rats and an optical mapping set-up (Fig.3). Using this optical mapping set-up was a new technique I learned for this study and carried out successfully. To create conduction block in the cells, we made use of optogenetics. This is a technique where we let cells express additional ion channels (a building block of ion transport in a cell). These ion channels have the special property that they react to blue light. When you shine this blue light on them, the ion channels open and create an influx of ions into the cell, pushing its membrane potential upwards. This results in a cell that is not excitable any more. This process is completely reversible by switching off the light. By shining the light in a smart way onto the cells, we devised a method to prove our hypothesis.

So where to start?

We started out by looking at a computational model of rat cardiomyocytes in a two-dimensional layer, i.e. a monolayer. In this model, we also have the equations for the aforementioned ion channels that react to blue light. With blue light we created an outer boundary and an inner obstacle for excitation waves to rotate around. In this outer boundary wee made a tiny passage called an isthmus or funnel. With this configuration it was observed that we could create "trapped reentry" in the virtual world, showing a high-frequency inner region, and normal rhythm outside (Fig.4 top panels + traces C1 and C2). Under dynamic changes at the funnel, it was possible for the high-frequent reentry to escape and influence the whole tissue (Fig.4 top panels + trace C3).

These simulations were validated by observing them in actual cardiac cells. We performed 8 successful instances of optical mapping of the trapped reentry phenomenon. Once again we could see high-frequency inner regions and normal rhythm outside, which could be transformed into the whole tissue undergoing excitation at fast rates (Fig.4 bottom panels and traces).

This is just one experimental case, how wide-spread is this phenomenon?

To see the relevance of our "trapped reentry" concept, we looked at the ranges in which this phenomenon could be observed. By trying out different funnel geometries and varying parameters that could influence entry and escape of excitation waves into the electrically isolated region (Fig.5), we found that the conditions for this phenomenon are physiologically and medically relevant. In particular people with heart excitation malfunctions (problems with I_Na) and elderly people (problems with gap junctional coupling, otherwise known in physics as diffusion).

These were all flat layers of cells. What about real 3D atria?

In a digital twin of the human atria, we revealed that the conditions for "trapped reentry" and its release can be realized as well. Unipolar pseudo-electrograms derived from these complementary computational 3D studies showed complex signals at the site of "trapped reentry" in coexistence with normal electrograms in the rest of the atria. Upon release of the reentry, acute arrhythmia onset occurred, affecting the complete atria as evidenced by wave front and electrogram visualization (Fig.6). If you would like to see the actual motion of the trapped waves and its escape in real-time (12s), you can scan the QR-code on the left.