Dr. Arash Kheradvar discusses modular TMVR, crimping, and TAVR durability

Arash Kheradvar, M.D., Ph.D., FAHA is a Professor of Biomedical Engineering, Mechanical and Aerospace Engineering, and Medicine (Cardiology) at the University of California, Irvine. Dr. Kheradvar received M.D. from Tehran University of Medical Sciences in 2000 and Ph.D. in Bioengineering in 2006 from Caltech. Dr. Arash Kheradvar founded KLAB in 2007 aiming to devise solutions in cardiovascular fundamental and translational research areas. KLAB is currently part of the Edwards Lifesciences Center for Advanced Cardiovascular Technology at UC Irvine.

Rob Fraser, ViVitro Labs, recently connected with Dr. Kheradvar to congratulate him on his new book, Principles of Heart Valve Engineering, and learn more about current KLAB research.  

Please tell us about your work in the KLAB.

We’re working on several aspects of cardiovascular disease. There are different diseases and heart valve engineering is our bread and butter. We’re also focused on cardiac imaging technologies and an area of research in interrelating the valve and imaging. More recently, we have also started working on artificial intelligence and deep learning, mainly in cardiac imaging, including cardiac MRI, and echocardiography.

On the biological side, we have been working on mitochondrial transplantation in cardiomyocytes and other cells. That’s pretty new in my lab’s project portfolio.

That’s an extremely broad focus. Can you go into a little more detail on some of your heart valve engineering projects?

Absolutely. For heart valve engineering, we have a few products in the pipeline.

We have FoldaValve, which is a transcatheter aortic valve. It is a true 14 French catheter that spares the leaflets from stent crimping. It is totally repositionable and retrievable. It is unique in that sense.

We’re also working on a transcatheter mitral valve, which is called AValve. The major advantage of this valve to the other TMVR systems that are currently under investigation is that it is a modular system with an intraventricular (intra-annular) valve equipped with an anchoring cage to the left. One of the major issues that patients have with TAVR is that there is no single valve that works for every patient. The reason is that in contrast to a transcatheter aortic valve, which is dealing with just the calcified valve, here you’re dealing with different sizes of annulus, left atrium and left ventricle.

So, the degree of freedom to accommodate mitral valve is higher and having just one single product that can accommodate the annulus, LV and LA and works for all patients is near impossible. The way we approach that problem is to make the TMVR system modular. Meaning that we have different sizes of atrial cage that can be matched with different sizes of valves. We even have a bi leaflet and a tri leaflet prototype that can be matched with either atrial cage. Based on the CT scan of the patient, the physician at the cath lab will decide on which sizes of components she/he would need to assemble together to accommodate every patient. Basically, we may see a patient that requires a larger atrial cage because of a larger left atrium, but that same patient may have smaller mitral annulus. The physician would basically mix and match different cages with different valves to ensure that the best product is provided for the patient.

So it’s a Lego style strategy where you have different pieces in your toolbox that you mix and match based on the patient patient’s specific needs.

Exactly.

We could spend the entire article on that. But to go back to your aortic valve, you mentioned it avoids crimping. Could you please walk through your thoughts on crimping and why it should be avoided?

Yes, that is very important. I wonder if you and the readers watched the movie The Big Short, which was about how the financial crisis of 2007–2008 was triggered by the United States housing bubble. The story was around a hedge fund manager who in 2005 discovered that the U.S. housing market is extremely unstable due to high-risk subprime loans, predicted the market’s collapse in a couple of years ahead, as interest rates would rise from adjustable-rate mortgages. At that time, nobody would have anticipated this to happen and while he was pitching the idea, people did not want to believe this as they used to think that the market is perfect, everything was looking perfect, and they constructed several financial products based those vulnerable subprime mortgages. And we all saw what happened at the end.

Back in 2013, I started thinking that the same unfortunate situation may happen to the transcatheter aortic valves due to stent-crimping. Currently there is no established data for the long-term durability of these valves. However, more recent clinical data is supporting my hypothesis. The reported midterm data related to five to eight years of post-TAVR follow up indicate a major patient survival bias.

A multi-center study of patients who received CoreValve™ reported that 10 out of 353 (2.8%) had at least stage 3 structural valve deterioration (SVD), 3 (0.8%) had structural valve failure, and 2 (0.6%) required a valve-in-valve reintervention.^{1, 2} A comprehensive analysis of the patients included in the PARTNER 1 randomized trial (1^st generation of Edwards’ SAPIEN valve) and continued access registry (2795 patients) showed excellent midterm TAVR durability.³ Another more recent meta-analysis of 8914 patients included in multiple observational studies reported a pooled incidence of SVD as 28 per 10,000 patients/year.^{2, 4}

Nevertheless, the foremost limitation of all these studies is the high mortality rate at 5 years (from 55 to 61%) and at 8 years (from 71 to 90%) with various degrees of severe SVD and valve failure in the survived patients.^{2, 5-13} This survivorship bias may substantially underestimate the true incidence of post-TAVR SVD at midterm follow-up studies.

Dr. Danny Dvir sent me an interesting figure below, that helps summarize the recent clinical data data. When we look into seven years follow up, for example, the study by Deutsch and colleagues in 2018, the survival rate was only 23.2 % among the 300 patients that they started to look at.¹³ Sokoloff et al.⁸ shows that among 1264 patients that they followed for seven years, the survival rate was 18.6%, meaning that 71.4% of patients died in less than eight years. So basically, whatever results about the durability they provide is from those 18.6% who survived. That means most of these patients already died before the time that we can assess the long-term durability of their transcatheter valves. These are the issues that make me a little bit worried in general, with respect to the TAVR durability.

Indeed, we love the TAVR. It just makes it much easier for the patients, much more robust for the physicians. But we need to know what the boundaries and limitations are. In fact, if your patient has a survival prognosis of less than 5 years, you might be able to safely use TAVR. But is it durable enough to have it in a 60-year-old patient who is low risk for surgery and is expected to live for at least 15 more years? I don’t know. I think we have evidence from several independent groups that stent crimping of the leaflets is one of the significant suspects for structural valve deterioration.

I am sure you have been following the recent studies that aim to quantify what the structural valve deterioration is. There are in fact quite a bit of works coming from McGill Canada. Dr. Pibarot and his colleagues have done a spectacular work to quantify the structural valve deterioration (SVD). They come with very nice criteria for that. So now when you’re looking at that, many of these patients come with structural valve deterioration in stage one, which doesn’t have any symptoms, but you will see calcification on the valve leaflet. Basically, all the evidences point to the role of the stent crimping. Because we do not see these calcifications in surgical bioprostheses as early as we observe in the transcatheter bioprostheses.

Another issue with the TAVR is subclinical leaflet thrombosis, which occurs significantly more often compared to SAVR. My hypothesis based on our preliminary results is that the stent-crimping induces micro injuries to the surface of the leaflets, and these micro defects lead to platelet aggregation and activation that result in leaflet thrombosis. Some of the other researchers suggest that subclinical leaflet thrombosis occurs because in case of TAVR, a different geometry sits in the aortic sinus compared to the surgical valve. That is another school of thought. My counter argument is that even the surgical bioprosthetic valves possess some kind of a stent, although its type of stent is a bit different; but the incidence of subclinical thrombosis post-TAVR vs. post-SAVR is almost three folds, as originally shown by Makkar et al.¹⁴

I personally don’t think the flow in the sinus around a transcatheter valve compared to a surgical valve is different enough to trigger the thrombosis. Though, these two hypotheses should be systematically compared in a large animal cohort before drawing a firm conclusion.

Yes. I think the FDA has recently approved the TAVR valves for all comers essentially. And they did make a statement to say that the valve durability is still unknown. The industry is watching very closely as survival rates get a little bit longer. It’ll be very interesting to see where that goes.

Do you have any advice for our readers who are trying to follow in your footsteps in terms of a device start-up or a successful researcher in the in the academic space?

To have a successful Startup, you need to really focus on it. There should be a clinical gap that results in an unmet clinical need. The value of your Startup is associated with the market size of that underserved population with whatever disease that they have. It is important to choose a right project that addresses a major gap in the treatment options. To duplicate something that’s kind of already existing or any incremental change doesn’t really help much, and the investors may not get too excited. The most important thing is to tap the areas that are totally underserved. That’s what makes the Startup a successful one, in my opinion.

Certainly you want to be filling that vacuum. And then from a research perspective, for someone who’s new out of grad school, what sort of advice would you give them to follow in your footsteps?

They need to pick some areas of research that are quite underserved. If you’re going with the flow that everybody’s doing, working on areas that are hot right now, it may not be the best idea as you are competing with others who may be ahead of you. When you start a new lab, you’re basically investing in some project. If you’re going over problems that are hot just now, and everybody is working on them, your chance of success would be less. But if you are investing and capitalizing on issues that are real issues but not as well-known as the current ones, and you believe that they will be more obvious in the next few years, that will make you a superstar.

Capitalize your start-up funds and resources on projects that would emerge in near future is the best strategy in my opinion. In that case, you will be ahead of the game, when the time comes. You are going to be the one with the data and you are the one who has something to say about those issues. I think that is very important for the new assistant professor who start working on their lab.

That’s great advice. Before we wrap up, I think you’ve got our SuperPump pulsatile pump in your lab. Has ViVitro Labs helped you in your work?

Yes. I’ve worked with your machines for a long time since I was a PhD student. And now I have one in my lab for a long time. Many of our research projects on imaging or heart valves use your product, your pump. It’s a great pump. And I think it’s kind of essential to any cardiovascular lab. In my opinion, during the past 20 years, your company has contributed to the advancement of cardiovascular device field more than what you think!

Below is a picture of mine and a figure from our recent paper published in Nature’s Scientific Reports that we used your pump along with our own heart chamber.

We appreciate the kind words. We encourage readers to check out Dr. Kheradvar’s interview with Dev Amatya in 2015.

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