Figure from my paper showing electrical activity in scar cells. Panel A: my experimental setup for recording electrical activity. Basically I loaded the hearts with voltage sensitive dye so I could record movies and SEE electrical activity. The black circles correspond to the pixel plot traces that are shown in B, and the drawn circle represents the scarred region. Panel B: Pixel plot tracings show communication between scar cells and the surrounding cells. These "hills" we see in the pixel plots indicate that the cells are depolarizing. Translation: there is electrical activity across that scar, which is occurring because the cells can communicate with one another. In C and D, we removed a protein we hypothesized was responsible for providing this interaction, and you can see many of the lines are flat, indicating no current is flowing through these cells.
For my post today, I want to direct you to the blog of my brilliant former colleague, Gary Mirams, a computer science research fellow at Oxford (click here to read his post on this subject.) Gary helped support my PhD research by convincing non-believers that the findings I gathered in mouse hearts were real, and in fact supported by math. (Or maths, as they say across the pond. )
My research investigated electrical interactions between cardiomyocytes (the primary working cell in the heart) and fibroblasts (the cells that come in to repair the heart after injuries such as heart attack). More specifically, I recorded electrical activity across the injured regions of mouse hearts, as you can see in the figure above. What did I find when I looked at the scars? Electrical signal! Using several different methods - again and again - we saw that there was electrical activity in those scars. This was pretty exciting, but also controversial: the canonical view is that cardiomyocytes are the only cells that are capable of relaying electrical current. But if we see electrical activity in the scar, and we know there are not cardiomyocytes in the scar, then it follows that fibroblasts can conduct electrical signal, too.
This is an important finding, because it would change the way we treat patients. Fibroblasts populate scars after heart attack, crowd the spaces between myocytes as we age, and proliferate like crazy in stiff, overworked hearts (think heart failure). If these cells are conducting signal, instead of being impediments to signal, this could drastically alter the way we treat the arrhythmias seen in each of these cases. If fibroblasts are actively contributing to arrhythmia development - being part of the wayward circuit - then it is possible that if we shut down that activity, we could shut down those errant arrhythmias.
But before it comes to treatment, it is necessary to verify the results of investigative science. We had a reason to look for signal in mouse hearts: there a multitude of scientific studies and clinical observations that indicate it is possible for fibroblasts to conduct electrical activity. However, none of the studies or observations were waterproof: one could always point to an explanation that weakened the "fibroblasts can communicate, too" contention. My study attempted to show, incontrovertibly, that in the intact heart, fibroblasts can conduct.
We showed evidence of electrical activity and the absence of myocytes in the heart several different ways, through several different experiments and repeats of experiments. However, we only seemed to arouse more questions in the disbelievers. And you can't blame them; it is common medical practice to go create a scar in the heart to interrupt arrhythmias. (But patients need to come back up to 50% of the time.... which argues our point.)
Anyway, enter dazzling pundit, Dr. Gary Mirams. People didn't believe that the signal we saw in intact hearts was real, so we said let's go see what happens if we model this electrical behavior with computational simulation using what we knew about the electrical properties of the cast of cardiac cells.
What we knew:
- the dimensions of the mouse heart
- the dimensions of the scar
- the electrical properties of myocytes
- most of the electrical properties of fibroblasts and other cells in the scar
What we didn't know:
- how densely packed the cells in the scar were
- how well those cells communicate with one another
Those two things we didn't know have a large effect on the coupling (electrical activity that is possible) in the scar. So, being scientists, we gathered data, made assumptions, tested a range of feasible assumptions, and ran models for each of them. The result: Gary could replicate the findings I found in mouse hearts without having to make any crazy assumptions.
This is where I will direct you to Gary's post. He shows in detail the specific equations that were used to model a wave of electrical activity moving across a scarred region. If you scroll down you'll see the videos that mimic what we saw in my mouse hearts, with Gary's comprehensive explanation of what you are seeing, why you are seeing it, and what changes if we adjust those unknown properties. I admit I'm a nerd, but it is so cool to see how you can break down a complex biological process, learn from the equation before you even get started, and make a video simulation of a cardiac electrical wave. (Note, find the actual videos of electrical activity across mouse hearts in the supplemental information section of my paper.)
I also stole Gary's blog title for this post. So perfect. Thanks, Gary. :)
Sources:
1. Gary's blog: Mathematical Matters of the Heart
2. My PhD paper
3. Al Green: How to Mend a Broken Heart
.
My research investigated electrical interactions between cardiomyocytes (the primary working cell in the heart) and fibroblasts (the cells that come in to repair the heart after injuries such as heart attack). More specifically, I recorded electrical activity across the injured regions of mouse hearts, as you can see in the figure above. What did I find when I looked at the scars? Electrical signal! Using several different methods - again and again - we saw that there was electrical activity in those scars. This was pretty exciting, but also controversial: the canonical view is that cardiomyocytes are the only cells that are capable of relaying electrical current. But if we see electrical activity in the scar, and we know there are not cardiomyocytes in the scar, then it follows that fibroblasts can conduct electrical signal, too.
This is an important finding, because it would change the way we treat patients. Fibroblasts populate scars after heart attack, crowd the spaces between myocytes as we age, and proliferate like crazy in stiff, overworked hearts (think heart failure). If these cells are conducting signal, instead of being impediments to signal, this could drastically alter the way we treat the arrhythmias seen in each of these cases. If fibroblasts are actively contributing to arrhythmia development - being part of the wayward circuit - then it is possible that if we shut down that activity, we could shut down those errant arrhythmias.
But before it comes to treatment, it is necessary to verify the results of investigative science. We had a reason to look for signal in mouse hearts: there a multitude of scientific studies and clinical observations that indicate it is possible for fibroblasts to conduct electrical activity. However, none of the studies or observations were waterproof: one could always point to an explanation that weakened the "fibroblasts can communicate, too" contention. My study attempted to show, incontrovertibly, that in the intact heart, fibroblasts can conduct.
We showed evidence of electrical activity and the absence of myocytes in the heart several different ways, through several different experiments and repeats of experiments. However, we only seemed to arouse more questions in the disbelievers. And you can't blame them; it is common medical practice to go create a scar in the heart to interrupt arrhythmias. (But patients need to come back up to 50% of the time.... which argues our point.)
Anyway, enter dazzling pundit, Dr. Gary Mirams. People didn't believe that the signal we saw in intact hearts was real, so we said let's go see what happens if we model this electrical behavior with computational simulation using what we knew about the electrical properties of the cast of cardiac cells.
What we knew:
- the dimensions of the mouse heart
- the dimensions of the scar
- the electrical properties of myocytes
- most of the electrical properties of fibroblasts and other cells in the scar
What we didn't know:
- how densely packed the cells in the scar were
- how well those cells communicate with one another
Those two things we didn't know have a large effect on the coupling (electrical activity that is possible) in the scar. So, being scientists, we gathered data, made assumptions, tested a range of feasible assumptions, and ran models for each of them. The result: Gary could replicate the findings I found in mouse hearts without having to make any crazy assumptions.
This is where I will direct you to Gary's post. He shows in detail the specific equations that were used to model a wave of electrical activity moving across a scarred region. If you scroll down you'll see the videos that mimic what we saw in my mouse hearts, with Gary's comprehensive explanation of what you are seeing, why you are seeing it, and what changes if we adjust those unknown properties. I admit I'm a nerd, but it is so cool to see how you can break down a complex biological process, learn from the equation before you even get started, and make a video simulation of a cardiac electrical wave. (Note, find the actual videos of electrical activity across mouse hearts in the supplemental information section of my paper.)
I also stole Gary's blog title for this post. So perfect. Thanks, Gary. :)
Sources:
1. Gary's blog: Mathematical Matters of the Heart
2. My PhD paper
3. Al Green: How to Mend a Broken Heart
.
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