Molecular Mechanisms and Electrophysiological Phenotypes of Atrial Cardiomyopathy

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Featured is the presentation entitled “Molecular Mechanisms and Electrophysiological Phenotypes of Atrial Cardiomyopathy” from Session 1 of WAFib 2023.

Good morning, everybody. First of all, I'd like to thank the organizers for inviting me again. It's a fantastic meeting and I'm very happy to be back. It's my task to add a little basic science to this session, which I do with great pleasure. But don't worry, I will keep it easy, and I will also explain why it might matter for clinical research. So, the title is “Molecular Mechanisms and Electrophysiological Phenotypes of Atrial Cardiomyopathy.” That is a concept that was established 10-15 years ago because we recognized more and more that atrial fibrillation is just an electrical manifestation of something that is ongoing in the atria as a response to multiple comorbidities. This is my disclosure slide. This was taken from the consensus paper published by Andreas Goette. You certainly know this work from a couple of years ago, showing that atrial cardiomyopathy is the consequence of well-known risk factors listed on the right side, but also atrial fibrillation is a risk factor for an atrial cardiomyopathy, but at the same time, is also a result of it. So, it has a dual function. As soon as it occurs, it's some kind of an accelerator of the progression of an atrial cardiomyopathy, and the atrial cardiomyopathy and AF together cause the relevant cardiovascular and cerebrovascular outcomes. Now, the most important manifestation of an atrial cardiomyopathy is atrial fibrosis. So, we talked about this already in this session. Atrial fibrosis can come in very different forms. You can have reactive fibrosis, which is usually the result of long-lasting moderate stimuli, such as inflammation. It occurs very often between the muscle bundles as perimysial fibrosis or within the muscle bundles between the myocytes as endomysial fibrosis. Completely different is replacement fibrosis. That type of fibrosis is reparative. It occurs as a response to cell death usually induced by apoptosis and then very often in the context of myocardial infarction. The result of that, you see that on the right side, are often these very thick strands of connective tissue. In the context of atrial fibrillation, we believe that endomysial fibrosis is particularly important, and we have 2 reasons to believe that. The first reason is shown on this slide. This is work we did more than 10 years ago. You may have seen this slide. This is the first documentation of endomysial fibrosis in the classical model of atrial fibrillation. The message of this work is endomysial fibrosin is the kind of fibrosin that occurs as a consequence of AF. You see the result on the right side the histology in the atrium after 6 months of AF, and you see this very tiny, thin septae between the myocytes. It’s not the strands of connective tissue, the very fine, small septae. That's endomysial fibrosis measured in micrometer distance between myocytes, and this is not present yet after 2 weeks of atrial fibrillation. We have a second reason to believe that endomysial fibrosis is particularly important in the context of AF, because in this recent work by Bart Maesen, we could demonstrate this aspect of fibrosis that actually correlates very well with conduction disturbances. You see here 2 correlations on the lower panels. On the y axis, you see the AF complexity. That's the degree of conduction block. On the x axis on the left side, you see the overall connective tissue content. No correlation at all. This was very much to our surprise. This is the very site that we also mapped. So, this is a one-to-one comparison of conduction disturbances and histology at the same site in the atria. On the right side, you see the same correlation, but then we see endomysial fibrosis. This correlation is significant. It remains significant after correction for rhythm history in these patients. So, this is why we believe that endomysial fibrosis is important. We also looked at other potential contributors to the conduction disturbances such as cell size or connexin 43 lateralization. All those correlations did not remain significant after correction for rhythm history. Only endomysial fibrosis remains significant. For this reason, we are very interested in studying the main biology of the endomysial fibrosis. We are running 2 large atrial tissue bank projects for this purpose. One is the CATCH ME consortium, which is European consortium, and one is RACE V. That is a Dutch consortium. The backbone of this analysis is a combination of transcriptomics and histology. From that, we tried to identify the leading molecular mechanisms and tried to build a mechanism-based classification of AF. This is a large-scale study. We have hundreds of patients. We look at dozens of slices per patient, which means that in order to do such kind of research, you need high throughput automated histological analysis, which is very difficult to set up, but it is absolutely necessary to have that because you deal with dozens of parameters in thousands of tissue slices. We have developed such a technique and carefully validated it. On the next slide, you can see one of the first results in the CATCH ME consortium. On the left-hand side, you see the results in the left atrium, and on the right side in the right atrium. After multivariate correction for all the clinical confounders, which is also very important, because in patients undergoing open-chest surgery, you have a very heterogeneous patient population, so you need to carefully correct for all the confounders. We did that, and we found that female sex and heart failure and ultra-persistent atrial fibrillation, but particularly female sex and heart failure are associated with the total connective tissue content on the left side. Heart failure, persistent AF, and female sex are associated with endomysial fibrosis on the left side. While on the right side, only persistent AF is associated with endomysial fibrosis. Interesting is the fact that female sex had such an important and strong effect size—that was a surprise to us. There are quite a few MRI studies suggesting this, but I think this is the first histological study that really demonstrated this. This is, potentially, a lack of physiological result of this. This is taken from a study that we performed a couple of years ago. Theo Lankveld did this work. We investigated the predictive value of the dominant frequency, the fibrillatory rate of the atrium, whether it could predict or not recurrences of atrial fibrillation in patients undergoing electrical cardioversion, and that is possible to some extent. Here you see the result of an analysis in 125 male and 125 female patients matched based on age, comorbidities, and medication. The first thing you notice is that female atria fibrillate more slowly, the dominant frequency is lower, and that may have to do with fibrosis, because we do know that when atrial fibrosis occurs in the atrium, you get a longer excitable gap and longer atrial fibrillation cycle lengths. More importantly, on the right side, you see that the predictive value is very different in men and women of the dominant frequency. While the dominant frequency could predict recurrences of AF pretty well in men, this was not at all the case in women. Meaning that, obviously, the recurrences after electrical cardioversion have something to do with the fibrillatory rate, and this may actually also be related to atrial fibrosis. This is also a very important result of our tissue bank projects. Nassir, I put this slide in for you. This is the overall correlation between endomysial fibrosis and the total connective tissue content. I think it's important to study this because you may say that MRI technology most likely is not able to pick up endomysial fibrosis, but there is at least a moderate correlation between the total connective tissue content and the endomysial fibrosis. So, if MRI technologies are able to pick up total connective tissue content or something that is associated with this, then it may also, to some extent, correlate with endomysial fibrosis. So, we also did gene expression studies, genome wide, gene expression study. We found that atrial fibrillation is associated with changes in pathways involved in fibrosis, inflammation, and endothelial dysfunction. We found that heart failure is a very important determinant of gene expression and modelizes this in an important way. This is the result that I would like to share with you. We looked at the genes that are actually responsible for the left atrial endomysial fibrosis. This is the list of transcripts that are independently from the clinical trades, associated with left atrial endomysial fibrosis. Among the protein coding genes, BMP 10 is the one that is most strongly associated with endomysial fibrosis. On the right side, you see that among a list of biomarkers that we studied in the control, in a validation cohort, BMP 10 that was actually also measured in the blood was the one that was more strongly associated with endomysial fibrosis. So, BMP10, which is an interesting molecule, is emerging as a relevant, and potent, biomarker for endomysial fibrosis. That is what I wanted to show you. Thank you very much for your attention. Here are the names of the people who did this work. Thank you very much.

The transcripts have been edited for clarity and length.