Special Episode - Heart & Calcium (uOttawa SciComm 2023)

Amy Stewart from the University of Ottawa speaks with Dr. Marta Cerruti, a professor in the Department of Mining and Materials Engineering at McGill University, a prominent figure in the research field of bio-synthetic materials, and the team leader of the Bio-Interface lab. As of today, Dr. Cerruti is the co-director of the McGill Institute for Advanced Materials and an associate member of the Faculty of Dentistry and the Department of Bioengineering. In the Bio Interface lab, her work centers around the incorporation of implants, tissues and drugs into the human body, as well as how minerals such as calcium and magnesium are formed in living organisms that help her address the questions of curing mineral-based diseases. Today, we'll be discussing her work centering around mineral deposits that lead to aortic valve stenosis.

Learn more: https://www.mcgill.ca/materials/marta-cerruti

0:15 l Introduction to BEaTS and Dr. Cerruti
1:25 l What is aortic valve calcification and what are the causes?
2:54 l Are there other minerals that develop in the heart?
3:45 l What are the methods used to view clacium deposits?
7:06 l Differences in calcification between men and women
12:01 l Future research
14:10 l Conclusion
14:45 l Credits

Podcast by Amy Stewart (Show Host), Shikshita Singh (Producer), Minh Tran (Writer Editor), Jade Gamelin Kao (Audio Master).

Soundtrack by Lexin_music featuring the song "sicence documentary". All rights reserved. Listen more: https://pixabay.com/music/build-up-scenes-science-documentary-169621/

Transcript

This video features the song “science documentary” by Lexin_music, available for free use under the Pixabay Content License.

Amy Stewart (0:15) 

Hi everyone, and thank you for tuning into BEaTS research radio, a podcast and YouTube channel that aims to disseminate science and research to the community. My name is Amy Stewart, a fourth-year undergraduate student here at the University of Ottawa, and I will be your host for today's episode. 

Joining us today is Dr. Marta Cerruti, a professor in the Department of Mining and Materials Engineering at McGill University, a prominent figure in the research field of bio-synthetic materials, and the team leader of the Bio-Interface lab. Dr. Cerruti received her PhD in Chemistry at the University of Toronto, where she studied bioactive classes for bone regeneration. She worked as a postdoctoral fellow at North Carolina State University and UC Berkeley. 

As of today, Dr. Cerruti is the co-director of the McGill Institute for Advanced Materials and an associate member of the Faculty of Dentistry and the Department of Bioengineering. In the Bio Interface lab, her work centers around the incorporation of implants, tissues and drugs into the human body, as well as how minerals such as calcium and magnesium are formed in living organisms that help her address the questions of curing mineral-based diseases. Today, we'll be discussing her work centering around mineral deposits that lead to aortic valve stenosis. Thank you so much for joining us today, Dr. Cerruti.

Dr. Marta Cerruti (1:22) 

Thank you. Thank you for having me.

Amy Stewart (1:25) 

So, I think our first question would be, what is aortic valve calcification and what causes that?

Dr. Marta Cerruti (1:31) 

Okay, so valve classification is what happens when you (when you) have a valve that doesn't work anymore. So, imagine, what's a heart valve? The valve that we have in our heart. And our aortic valve is a valve that goes from the aorta into the heart. That's why it's called aortic valve. So, we have this valve that usually has to open and close in order to have blood flow in the heart and then be pumped throughout, right. 

So, when you have certain diseases, for example, atherosclerosis, the valve gets inflamed. And not only can it get inflamed, you can also start having calcification and deposits of minerals that normally are not deposited on soft tissues like the valve. And when this happens, the valve doesn't function properly. So, it won't either close fully or open fully. And so that means that the heart doesn't work as well. And, at some point, it's useless. And then, I mean, you would have heart failure. So, the only option for treating this condition right now is, when it gets really bad, just get a heart valve replacement. So, they do an open heart surgery, and they get the heart valve out and they put a new valve in. 

Amy Stewart (2:54) 

In this paper, you guys are mostly looking at calcium deposits in the valve, are there other minerals that develop as well?

Dr. Marta Cerruti (3:02) 

No, they are all calcium deposits, a type of calcium minerals. More precisely, it's calcium phosphate minerals. It's the same kind of minerals that we have in our bones and teeth. Our bones and teeth are also made of calcium phosphate minerals that are deposited around on a soft matrix, which is collagen. And in fact, it's the same matrix that's in the heart valve. But in bones, this is the normal process, and, I mean, that's what gives your bone strength. The fact that there are these minerals, and you don't only have collagen (in bones). But in the heart valves, when you start having these minerals, like I said before, it's bad news. 

Amy Stewart (3:45) 

So, while you were studying these mineral deposits, you used a bunch of different methods to kind of quantify, like the shape and the composition of them. Do you think you could kind of talk about scanning electron microscopy or Raman Spectroscopy, or some of the bigger methods that you use?

Dr. Marta Cerruti (4:00)  

Yeah, sure. So, we use a bunch of different methods to try to understand what the minerals are right? There are a few established techniques also that biologists use to try to quantify how much minerals people have. But we really wanted to understand what they were. And so, SEM is secondary electron microscopy. It's a technique that 's kind of like a very high-resolution microscope compared to what an optical microscope can give you. So, you use electrons (in SEM) and you can get the morphology of your samples at a nanoscopic level. So that allowed us to look at the different kinds of morphology that the mineral deposits have. 

Other techniques that we used were Raman spectroscopy. This is a technique that is based on the interaction between light and compounds, and you look at (the) vibrations, basically. And so with that, we can look at the crystal linearity of the minerals. That's why we use it to see if the minerals were more or less crystallin. 

And then the other big technique that we use is called Nexus, which is near edge x ray absorption fine structure spectroscopy. This is a technique that few people use, and in order to use it, you have to go to a synchrotron. So we went to the Canadian Light Source, which is in Saskatchewan. And there (it's a) it's a national facility, everybody that has ideas to use techniques related to synchrotron. You have to put in a proposal, and then if the proposal is accepted, you get time on the beam and the beam line. So we've been using this technique for several years now. So we're pretty decent at getting beam time. 

And so, with that technique, you can basically shine X rays through and you look at the absorption through the material, and with that, you can understand, basically, the arrangement of atoms close to a central atom. So, we do calcium absorption in that case. And with that technique, we can understand the phases, the mineral phases that are present. So, because you need to understand mineral phases, you do X ray diffraction, right, XRD, and that's a valid technique. The only problem is that these are samples that have a lot of different mineral phases. And so, it's kind of difficult using XRD, to see them all, and also, some are in small amounts. So, with Nexus, you can understand complex mixtures of phases. And even if you have something that's not fully crystal, and you can also see it with XRD, you would only see the crystal in materials. So, the combination of all of these techniques were very important for us to really understand what these minerals were. And then also, the main topic of the article is the fact that we found some differences in the minerals between men and women. So, when the heart valves were extracted from men, we found more of one kind of mineral and from another kind of mineral.

Amy Stewart (7:06) 

That's really interesting. Yeah. Can you talk a little bit more about the differences in the calcification between men and women? How does that affect, like, the prognosis of the disease? Like, is it just as severe in both cases? Or do the differences not really impact, like, the disease outcome?

Dr. Marta Cerruti (7:23) 

Yeah, so I'll tell you first what was already known. So, before our study was already known that for the same severity of disease, men have more calcification than women. So even though...so let's say, when you get to the point that the valve needs to be extracted, and replaced, because it's so bad that it doesn't work anymore, men have more calcification and women have less, and most people seem to think now that females have more fibrosis. So, it's more fibrotic tissue versus men(who) have more calcified tissues. It's like two different types of pathologies that ended up leading to the same consequence, which is heart failure. 

What we found is that not only there are different amounts of minerals, but also the types of minerals were different, which we think, means that they are different because when the minerals deposit in our body, this is known. Actually, we had already discovered a few years ago for other types of pathological calcification, and it's (different types of mineral deposits) also known for bone. In the end, our bones are made of a specific type of calcium mineral, which is called hydroxyapatite. 

But it's not that when you're born, that's the mineral you have. The mineral formation starts with some precursors that are more amorphous. And then over time, they crystallize, and they change phase and they become this more stable hydroxyapatite phase. And so, what we found is that the final phase seems to be hydroxyapatite, both for men and for women in this horrible calcification, but the pathway that leads you from the more amorphous precursors to hydroxyapatite seems to be different for men and for women. And so, what we thought that could mean is that maybe there are different mechanisms that lead to one versus the other. 

And so, what does it mean in terms of disease and in terms of cure? So, I mean, in terms of disease, it's hard to say exactly what the different minerals would imply, because as I said, there's also the problem of fibrosis. So, women also have this large amounts of fibrosis that contribute to the malfunctioning of the valve. Although we do find, for example, that differences in morphology are significant. So, women tend to have more of these calcified fibers versus the spheres that we found in men. And maybe the fibers end up having, you know, worse mechanical properties or like kind of impact the mechanical properties of the valve different than the sphere. So maybe even that has an effect. But I think at least what's important is that the prevention, and possibly the cure should be different for women and men, you know, if, if the two have different mechanisms, then we should treat them as different events. And so maybe we should develop drugs that relate to, you know, the precursors that are found more in women versus the precursors that are found more in men to have a more personalized approach. 

And in another issue, this is well known already. But so, because women, like I said, have less calcification than men for the same disease severity. Because the disease is diagnosed right now, through CT scan. So basically, it's a technique that, that's using the hospitals (that) looks at how much mineral you have. So, you just (use) X rays and you look at the contrast, right, so if you have minerals, you have more contrast. And so, because females have less then they tend to be diagnosed at a later stage than men. So then, even because of that, the prognosis is worse. In fact, it's known that men are at higher risk for cardiovascular disease than women. So being men is a risk factor for having cardiovascular disease. However, after a certain age, females have worse prognosis than men. So, for example, if you have your heart valve replaced, and you look at the death rate, after that, for females, it's much worse than for men. So, like I said, maybe one point is that they're diagnosed later. And so, by that point, things have already gone worse, or maybe there's other factors. Yeah, we kind of hope that our study gives a little bit of an extra edge, you know, maybe we need to focus on the types of minerals that are present and find new strategies to maybe detect those types of minerals earlier, right? 

Amy Stewart (12:01) 

That’s interesting how you guys helped unravel, you know, the different aspects of the disease development between men and women. I think that's so important, because like you said, it's kind of treated as just like the same disease before, but when you highlight that there really are important differences, not only the development, but the outcomes. That's really cool. Do you guys have any plans to continue with this line of research and kind of characterize it more? 

Dr. Marta Cerruti (12:22) 

I have several students working on the project, one, specifically on the effects differences. So we're making some models in the lab to try to model these specific differences so that we can then, you know, develop these different diagnostic or treatment techniques. And then we're also trying to analyze more samples, both of heart valves, and also of other pathological calcification, to see if there are other sex related differences in classification that happens, for example, in the arteries. So we can have calcification not only in the heart valves, but also in the arteries. So, my group has studied that already. And so now we're looking at, ok, are there specific differences in that when we did our previous studies? We never looked into that. And in fact, we were looking at animal models, and we were only looking at male animals. It's very typical. 

When you look at biological biomedical research, very few people look at the effect of sex, and it's kind of like a new requirement. A lot of funding agencies are more and more aware of this (being) a problem, and they start asking you researchers to, for first thing, at least declare the sex of the animals. And as the cells have a sex, very few people realize, but yes, when you take cells, when you take primary cells, they come from a donor that already has a sex, and so the cell has sex. And so, you know, they will react differently, depending (on) if they come from a male or female. So, that's another thing that we're trying to hope to include cells in our models and have cells from different sexes and see also that in vitro, what happens?

Amy Stewart (14:10) 

That's really interesting. I think it's really important to highlight, again, that, like you said, whether or not the animal models that were used were male or female, or the cell lines, and it's great that you're exposing like a new generation of scientists to making sure they include that in their research. And then hopefully, these things like sex specific differences will be seen a lot earlier on. That's really cool!

Wonderful. Well, thank you so much, Dr. Cerruti, (for) this great insight into aortic valve calcification, the sex-specific formation, and as well as all the different techniques that you use to analyze it. We appreciate you coming on the show to share your amazing work with the BEaTS audience.

Dr. Marta Cerruti (14:42) 

Thank you. Thank you for having me.

Jade Gamelin-Kao (14:45) 

Thank you listeners for your time and support. And thank you to students Amy Stewart, Shikshita Singh, Minh Tran and Jade Gamelin Kao from Translational and Molecular Medicine program at UOttawa, and the rest of the BEaTS team for the research and editing of today's episode.