Interview: Dr. Stephanie Sellers on the Mechanisms of Bioprosthetic Valve Degeneration

Dr. Stephanie Sellers is an Assistant Professor in the Division of Cardiology and Department of Medicine at the University of British Columbia. Her research program is based at the Centre for Heart Lung Innovation at St. Paul’s Hospital in Vancouver where she co-directors the Cardiovascular Translational Laboratory – A Centre for Excellence for Vivitro Labs.

While working on the January 17, 2022, Cardiovascular Translational Research Webinar, Hemodynamics after TAVR! featuring Dee Dee Wang MD and Amr Abbas MD., she spoke with Rob Fraser, ViVitro Labs Applications Manager, mechanisms of cardiovascular disease and determining mechanisms of bioprosthetic valve degeneration.

Rob Fraser Please tell us about your current work.

Dr. Stephanie Sellers I’m a vascular biologist at St. Paul’s Hospital and the University of British Columbia. By training, I focus on the mechanisms of cardiovascular disease. My current work is centered on determining mechanisms of bioprosthetic valve degeneration.

We approach that two main ways: first, from understanding biologically how the mechanism of degeneration occurs in terms of the signaling that goes on in tissue and cells, and second, from a bench testing and mechanical perspective, understanding how we can use basic science tools to predict valve degeneration or study the mechanisms by which valves may be injured during deployment or after they are implanted in a patient, etc.

Rob Fraser How’s the work going?

Dr. Stephanie Sellers Excellent. Together with my academic research partner, Janar Sathananthan, we started a new lab based at St. Paul’s / UBC Centre for Heart Lung Innovation, the Cardiovascular Translational Laboratory, where we’ve been having great success in partnering with other academic institutions and companies like ViVitro, and advancing research looking at things like redo TAVR, valve fracture, valve degeneration, and so forth.

We’ve brought on our first graduate students and full-time lab manager, who work alongside clinical fellows and medical students doing rotations in the lab. We’re looking forward to the work we do in the future.

Rob Fraser You have been prolific in the number of papers you’ve published. What reactions are you getting to these publications?

Dr. Stephanie Sellers We’re excited to be able to contribute to the field and help answer key questions on the use of bioprosthetic valves and ways to detect, predict, and prevent degeneration. The number of academic and industry partnerships that we bring into those papers is really reflective of the field supporting this kind of research. I take that as a positive response to our papers.

Rob Fraser One of the big debates is how durable TAVI valves or transcatheter valves are going to be compared to surgical valves. What are your thoughts on that from the three different lenses that you look at these problems?

Dr. Stephanie Sellers As a vascular biologist, my first instinct is to consider this from that perspective. If we reflect on the literature, there hasn’t been a definitive head-to-head analysis on mechanisms of degeneration in surgical versus transcatheter valves. That’s a study we need to work towards collectively as a field. That’s obviously made challenging by access to explants, but could be informed by different imaging techniques to detect a degeneration.

It’s certainly something we’ll start to get a better feel of in the next five to ten years through fundamental and translational science paired with on-going clinical studies. These will allow us to dissect out the different aspects of tissue pathology contributing to degeneration as well as the mechanisms that drive that paired with analyses of mechanics and ultimately how that science plays out in

Rob Fraser So you really just don’t think there’s enough data out there?

Dr. Stephanie Sellers To comment on differences in mechanisms of degeneration from the biological / cellular perspective between SAVR and TAVR? I would say we probably don’t have enough data to make a definitive conclusion. We need to continue to do detailed studies, translational studies.

Rob Fraser Do you think the mechanisms are wildly different between the two different valves?

Dr. Stephanie Sellers We haven’t had a chance in our lab to look head-to-head at surgical versus transcatheter valves. If you look retrospectively in the data on surgical valves by many groups, such as the work done by Phillipe Pibarot and Patrick Mathieu and others out of Quebec Heart & Lung Institute, it gives indications that there are similar patterns of degeneration and long-term calcification, which is preceded by inflammatory processes and breakdown of the leaflet matrix. They appear to be similar and compare well to our studies of explanted TAVR valves.

Further, the recent paper we collaborated on with the University of Edinburgh looking at sodium fluoride PET/CT in SAVR vs. TAVR valves points towards similar degeneration processes so far. But that’s a short-term study and needs to be looked at in a larger population longer term. Our analysis of explants is limited – further detailed analyses of degeneration mechanisms are needed.

Rob Fraser You mentioned you’re doing a cellular approach, but then also bench testing and a mechanical approach.

Dr. Stephanie Sellers Bench testing helps us design better experiments to understand the cellular part of valve degeneration; for example, we can model mechanical damage to leaflets through durability testing and thereby have the opportunity to explore how biological aspects of degeneration might change under different conditions, which is really interesting to me as a vascular biologist. On the flip side, my colleagues who focus more on mechanics and valve function through hemodynamic and durability testing can glean procedural insights into design and use of these valves to improve durability.

Rob Fraser Has ViVitro helped you with this work?

Dr. Stephanie Sellers The ViVitro system is key for us to be able to design ex vivo and in vitro systems to study these kinds of processes. Without it, we would be using non rigorous pulse duplicators in a highly variable heart model set up, which would create variability in our data. Having this kind of system allows us to produce high quality, reproducible data in a system that mimics an in vivo system as closely as possible.

Rob Fraser Earlier you mentioned the tissue library at St Paul’s and your access to specimens as soon as they come out of the O.R. Could you tell us a little more about that? Particularly, trying to close the loop with clinicians on what you learn and pass it to them so they can modify their feedback.

Dr. Stephanie Sellers The Center for a Heart Lung Innovation is based within St. Paul’s Hospital in Vancouver. That gives us the advantage of being a research institute right inside the hospital with access to explants at time of surgery thanks to partnerships with Cardiovascular Surgery and Pathology, and the Cardiovascular Tissue Registry.

The Cardiovascular Translational Laboratory also runs the Explanted Valve Registry which partners with sites around the world to biobank explanted native, surgical, and transcatheter valves. This allows us to have a large breadth of material to use in studying valvular heart disease including exploring how these can be used in ex-vivo models, and integrate critical tools such as the ViVitro hydrodynamic tester. This tissue resource is central to our work and we’re thankful to everyone that supports it.

Rob Fraser What are your plans for the future?

Dr. Stephanie Sellers Ultimately, I hope to continue to develop our ex-vivo and in-vitro systems and utilize those to help inform optimizing use of bioprosthetic valves and test different mechanisms to prevent degeneration. That may be through testing different uses of different transcatheter valves or different setups, as well as looking at pharmaceuticals or methods to prevent some of the biological causes of degeneration.

Rob Fraser You’re a highly accomplished academic with a number of citations and lots of success at getting grants. Do you have any advice for our readers and people wishing to follow in your footsteps?

Dr. Stephanie Sellers My advice is to always work with as inclusive of a team as you possibly can. As a basic and translational scientist, co-directing a translational research lab with an interventional cardiologist provides a unique intersection of skills and expertise to approach research questions. Also, the larger team that we work with on projects is highly diverse – spanning from basic scientists and engineers, technicians, clinical colleagues, allied health professionals, and industry partners. Bringing together all those skill sets allows us to complete studies which can help inform the questions that the field currently has. So, I would say overall, build a diverse team, and find an equitable way to bring everybody’s opinion into the collaborative tent.

Rob Fraser Do you have any tips for handling diversity, with a lot of diverging ideas, a lot of egos at play? How to be the ringleader of that big tent circus?

Dr. Stephanie Sellers Just open channels of communication, stay focused on the primary goal of the project and the goals that are going to answer that question. And make sure that everyone has the opportunity to contribute and utilize their unique skills.

Read Dr. Sellers’ published articles citing ViVitro equipment here.

Read about other Cardiovascular Pioneers here.