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Myocyte remodeling due to fibro-fatty infiltrations influences arrhythmogenicity
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Authors
Tim De Coster
Piet Claus
Gunnar Seemann
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. In this study I looked at the first kind of change. The electrical properties of cardiac cells can change due to rhythm disorders (usually elicited due to fibrosis, i.e. connective tissue that is non-conducting), where the most occurring disorder is atrial fibrillation (an irregular rhythm in the upper chambers of the heart which is a major problem in the Western world). However, the electrical properties of cardiac cells can also change due to fat tissue that is in their near presence since these secrete chemicals that influence the properties and working of the cell. This fat tissue can appear in the heart in the form of infiltrates from outside, which occurs in people with high BMIs or who have very particular diseases.
What changes are we talking about?
The electrical activity in a cardiac cell is regulated with the use of certain channels. These channels are small pores in the membrane of the cell that let through certain chemicals (Na, K, Ca). The interaction of all these pores (called ion channels) makes that the cell can produce an electrical signal that can propagate to the next cell. Remodeling occurs when these ion channels get different properties. When that happens, the resulting electrical signal will be different and the cells will communicate differently with each other. This can then cause rhythm disorders. I looked at the changes in these ion channels due to the influence of fat tissue infiltrates. I based my calculations upon experimental results that I found in another paper, which measured ion channel activity after letting cells be in the presence of fat tissue for a long time. I then constructed two extra mathematical models (Figure 1), one for a healthy cell in the presence of fat tissue, and one for a cell that is already in atrial fibrillation and additionally is in the presence of fat tissue.
Figure 1: The changes in ionic currents due to the presence of fat tissue (adipose tissue). The peak values of the currents are presented. The blue curves denote the data of an established healthy cardiac cell model (Courtemanche), while the orange curve denotes the same with additional changes due to remodeling induced by the fat tissue. Dashed curves show the data for additional atrial fibrillation remodeling (a persistent rhythm disorder in the upper chambers of the heart). The experimental measurements and error bars are extracted from Lin et al. (2012) and shown in green. In orange the simulation results are shown.
How does remodeling influence rhythm disorders?
I used the cell models that I generated to check what their influence would be on rhythm disorders. To do so, I started a rhythm disorder (a spiral wave) and looked at how the different cell models would influence this (Figure 2). The simulations show that the electrical signal (action potentials) of the regular cell model (Courtemanche) and the one under atrial fibrillation show quite regular signals, while both fat tissue remodeled signals are much more irregular. This is also visible in the spatial patterns of the rhythm disorders, where the first two patterns show regular spirals, while the second two patterns (with fat tissue remodeling) show irregular patterns and break-up of the spiral (creating more spirals).
I also looked at whether this remodeling could easily induce rhythm disorders. The result was that you need a very large region of remodeled cells to do so, and therefore this mechanism is very unlikely since fat infiltrates are usually grouped together in certain regions of the heart and not necessarily very widespread.
Figure 2: Action potential traces and voltage snapshots of an induced spiral in all four of the studied atrial cell models. The action potential traces were taken at the point denoted by a star in the first depicted time frame.
And what with realistic heart shapes?
After testing everything in a single cell and in two dimensional simulations, it was time to check what would happen in actual hearts (Figure 3). For this, realistic three dimensional simulations were performed. Since the model was made for the upper two chambers of the heart (the atria), a human atrial heart model was used. To make it realistic, the orientation of the cardiac cells (which plays a big role in the electrical signal propagation, and is called the fiber orientation) was taken into account. Fat infiltrations happen most in the region of the atria that is called the appendages. It is therefore that this region was given the cells with the remodeled properties. Once again, an arrhythmia was then induced in the heart (once on the right side, once on the left side). It could be seen that fat remodeling made the pattern more complex and created additional spirals/rotors in the electrical signal.
Figure 3: Arrhythmia patterns in three dimensional realistic atria. The top two rows of panels show the configuration in five different orientations. The top row provides a view on the geometry of the atria where the appendages are colored in yellow, and the remaining part of the atria is colored in red. The second row provides the corresponding fiber orientation colored according to its orientation along one of the axes (X). The three lower rows (split into two columns) show one frame out of an S1-S2 induced arrhythmia in three different orientations. Each row corresponds to the tissue types that were used (healthy cell or Courtemanche, fat remodeled appendages, atrial fibrillation and fat remodeled appendages). Each column corresponds to the location where the arrhythmia was initialized (in the right atrium, or in the left atrium). One can see different kinds of electrical wave propagation complexity for the different combinations present. The cores of spirals are denoted by either circles or stars. The circle denotes a rotor that remains during the whole arrhythmia simulation. The star indicates that the rotor disappears over the course of time.
What does this mean?
In combination with the Scientific Reports study, we can say that the obstacle nature of a fat infiltration creates conditions for the onset of heart rhythm disorders, while the remodeling part makes it more persistent and increases complexity. Together they form the basis of a rhythm disorder that is difficult to terminate.
This gives rise to two ways of handling fat induced arrhythmias. On the one hand by focusing on prevention of fat infiltrates themselves such that one can take and remove the trigger mechanism. On the other hand one could suppress the fat infiltrates from changing ionic cell properties which helps to make rhythm disorders less complex.
Journal info
Article type: Research article
Impact factor: 4.755
ISSN: 1664042X
Frontiers in Physiology is a leading journal in its field, publishing rigorously peer-reviewed research on the physiology of living systems, from the subcellular and molecular domains to the intact organism, and its interaction with the environment. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
The central tenet of physiology, that unites its various sub-disciplines, is the quest to understand how the various components of the organism work together to maintain a healthy state. It is only by understanding normal bodily function that the disruptions that lead to disease can be determined and ultimately corrected to restore the healthy state.
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