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Arrhythmogenicity of fibro-fatty infiltrations
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Authors
Tim De Coster
Piet Claus
Ivan V Kazbanov
Peter Haemers
Rik Willems
Karin R Sipido
Alexander V Panfilov
Funding
Interuniversity Attraction Poles (IAP P7/10) Program (to RW, KRS and AVP)
Our heart cells can propagate electrical signals. These signals go through the heart in a regular pattern. However, when this pattern gets disturbed, we speak of a heart rhythm disorder. A disturbance of this pattern can come in two ways: 1) The electrical properties of the cells get influenced and make that the regular propagation pattern gets disorganized, and 2) There appear structural changes in the tissue and obstacles appear that block the regular propagation pattern. This last case can happen due to the presence of a large number of non-excitable cells in the heart. The most well-known example of such non-conducting cells that interfere with cardiac cells, is fibrosis (connective tissue that pops up when cells die or an injury occurs). Fat tissue also contains non-conducting cells that can serve as obstacles. Fat tissue has been shown to be able to infiltrate the heart wall from outside in people with high BMIs or who have very particular diseases. These fat infiltrations remodel towards fibrotic tissue over time. It was already shown before that fibrosis can cause rhythm disorders. Here, I wanted to look at the influence of fat tissue on the origin of rhythm disorders.
Fat tissue infiltrates
Fat tissue infiltrations have a different spatial texture than fibrosis (see Figure 1). In general, fat infiltrates are larger than fibrosis. Based on experimental data that was available from the hospital in Leuven, an estimate could be made about the size of these infiltrations. Unfortunately, the images that were available were all side cuts through the heart wall. Electrical signals that travel through the heart most of the time travel parallel to the wall. Since the fat infiltrates are a strong cell type, the assumption was made that they would form into half-spherical regions, which give circles when you slice through them (see Figure 1b). The size of these infiltrates will now have an influence on the electrical propagation in the heart.
Figure 1: A comparison between simulated geometries and clinically observed ones. For clarity, a similar color scheme was used. Fat tissue is the lightest color, heart cells the middle shade and fibrotic tissue has been given the darkest color. In the simulation data (Fig. 1a and b), there was 40% fat tissue (radius 400μm per infiltrate) and 9% fibrotic tissue . The histological cut is from sheep data and has a scale bar which denotes 500 μm. Figure 1c shows one infiltrate which consists of individual adipocytes which can be seen as small circular shapes. Each circle in Fig. 1b accounts for the whole infiltrate and is not subdivided into individual adipocytes.
Starting a rhythm disorder
To test what effect these infiltrations have, a mathematical model was used to simulate what would happen to the tissue in case we would give fast pacing pulses from one side of the tissue (Figure 2). For every radius of fat tissue infiltrates, 10 different simulations were performed to see whether at least 25% of the simulations resulted in rhythm disorders. It was observed that you need more non-conducting tissue to create rhythm disorders when the radius of the fat infiltrates become larger. This is not very surprising since the area of the infiltrates becomes larger. What is noteworthy though, is that there is a limit to the size of the infiltrates to generate rhythm disorders. When the radius becomes larger than 600μm, no rhythm disorder could be started. However, it should be noted that this could be a result of the computational limitations of this study. The smallest radius that was tested, is in correspondence with fibrotic tissue. When we zoom in into one point of the a-graph in Figure 4, a full distribution can be shown, which is shown in the b-graph for the radii 50 and 400μm. In this b-graph we can see that we not only need more non-conducting tissue to create rhythm disorders for fat tissue (400μm) in comparison with fibrotic tissue (50μm), but that these break-up probabilities are also lower.
Figure 2: Generation of rhythm disorders by high frequency pacing versus size of the fat infiltrates (adipose tissue). The percentage of total in-excitable tissue is shown at which arrhythmia occurred and sustained for 1.68 s with a probability higher than 25% after 10 external stimuli with a period of 240 ms (a). Detailed probability distribution for radius 50 μm and radius 400 μm (b). The peak of the distributions was found in a and was denoted by the same color, green and red. Simulations were carried out in a tissue of area 76.8×76.8 mm2, where the radius of adipose infiltrates equals 400 μm.
From fat tissue to fibrotic tissue
As it was mentioned in the beginning, adipose tissue can transform itself into fibrotic tissue. This means that both types of tissue can occur at the same time. Two kinds of obstacles can therefore exist at the same time in the cardiac tissue. We looked at combinations of both types of obstacles and tried to induce heart rhythm disorders again (Figure 3). You can see that sometimes this works, and sometimes not. Every combination was tested 10 times to see how frequent rhythm disorders could be induced. Based on these data, we could find a region in which rhythm disorders can occur. Based on this region, we found that when fat infiltrates transition into fibrotic tissue, that tissue that was previously not prone to heart rhythm disorders, suddenly can have a very large probability to start a rhythm disorder. This shows that there is a hidden risk present in fat infiltrates into the cardiac wall.
Figure 3: Initiation of rhythm disorders using a burst pacing protocol for various fat (ATI) and fibrosis (F) percentages. The left column shows activation maps for the first wave over a timespan of 300 ms. The white lines show the region activated during a time interval of 25 ms (from 75 ms till 100 ms). The gray scale pictures show the distribution of the transmembrane potential at given times t.
What does this all mean?
We showed that although presence of fat infiltrates can result in the onset of rhythm disorders, its impact is less than that of fibrosis. However, over time these fat infiltrates transition into fibrosis, which forms a much larger risk. Therefore, it is key to live healthy, not eat too fat and exercise such that your heart can have a longer lifespan.
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