Dr Dan Simon (Host): Hello, everyone. My name is Dr. Daniel Simon. I am your host of the Science at UH Podcast, sponsored by the University Hospitals Research and Education Institute. This podcast series features University Hospitals' cutting edge research and innovations. Thank you for listening to another episode.

Today, I am happy to be joined by our guest, Dr. Mehdi Shishehbor, UH Harrington Heart and Vascular Institute President, and the Angela and James Hambrick Chair in Innovation. Dr. Shishehbor is a world-renowned cardiologist with areas of expertise in vascular medicine and minimally invasive catheter-based procedures to reconstruct lower extremity arteries in order to treat critical limb ischemia and prevent amputation. Welcome, Mehdi.

Dr Medhi Shishehbor: Thank you. Good morning.

Host: So, Mehdi, it's great to have you here. How exciting to have a first author New England Journal publication in 2023 about critical limb ischemia. So, arterial revascularization is a standard of care for patients with chronic limb threatening ischemia. But despite advances in endovascular and surgical treatment, up to 20% of these patients end up with an amputation. What are the challenges currently in practice of patients with chronic limb-threatening ischemia and risk for amputation? What's the real challenge for you as an endovascular interventionalist?

Dr Medhi Shishehbor: Let me just share with you some staggering numbers. Over 185,000 amputations occur in the United States yearly. One in 190 Americans is living with a limb loss currently as we speak. And 50% of the patients that do get an amputation, they die within five years. This is not to include the psychological impact, the social impact, and the financial impact of a major amputation on these patients. So, it's really a big problem that we are trying to solve here for patients that require an amputation.

Now, you asked a great question regarding the challenges. The number one challenge, Dr. Simon, as you know, many of these patients have diabetes mellitus and chronic kidney disease. Indeed, in our own population, 80% of our patients that require an amputation have diabetes or chronic kidney disease or both.

The second big challenge is that many of these patients have disease involving the arteries below the knee, near the foot and the ankle. And as you know, these arteries are sometimes even are smaller than the arteries of the heart. And the disease is very progressive and very diffused and calcified, making it difficult to treat.

The third challenge is the socioeconomic status of these patients. Many of these patients come from a lower socioeconomic status. And unfortunately, in many cases, they do not understand the gravity of their disease, so they present to us in the later stages of their disease, when the options may be more limited.

And then lastly, I would say we are still struggling with some of the techniques and technologies that we use, and we need to continue to innovate in this area to be able to help these patients.

Host: So Mehdi, before we get in to the details of your New England Journal publication and the LimFlow technology, tell me a little bit about your program prior to the study. In other words, patients were coming from all over the region in the U.S. to you and your group, because of your anterograde and retrograde procedures to try to establish straight line blood flow to the foot. So, tell us a little bit about that. Although I'm an interventional cardiologist focused on the heart, I do recall from anatomy that there are three arteries to the foot. So, tell us about your approaches for amputation prevention before LimFlow.

Dr Medhi Shishehbor: So, the first step, honestly, was to create a limb salvage advisory council. As you know, one of the biggest challenges in medicine is that we unfortunately don't put the patient at the center. And there is a lot of heterogeneity of care, meaning it just depends on where you live or who is most available that's willing to see you when you need a doctor to be evaluated. What we wanted to create was a limb salvage advisory council that could see patients that are at risk of amputation regardless of their location or who was treating them first. So, we set the rule across UH about three, four years ago that any patient that needs a major amputation, we will do a pause, we will do a limb salvage advisory council activation; experts and interdisciplinary team of experts from vascular surgery, interventional cardiology, podiatry, wound care, and vascular medicine. We'll evaluate that patient virtually through Zoom, so we can join the team from anywhere you are. You could be on vacation in Europe and you could join and give your input to the case. And then, we will decide whether the patient should get an amputation or not. We published our work, Dan, as you know, and we showed that 95% of the time, we could offer a patient an alternative. And over 80% of the time, we could save the limb of the patient that was determined that they have no option, that they were undergoing a major amputation.

In addition to that is the technical aspect of this, we have made a commitment to identify different pathways to treat these patients, as you mentioned, the so called the retrograde approach. So as for your audience, typically when we treat these patients, we come from the groin down towards the foot and we treat arteries in what we call the antegrade fashion. But in many cases, we cannot cross these blockages, which are sometimes 20, 30, 40 centimeters long in an antegrade fashion. In these situations, we have been very fortunate, and we have mastered the retrograde technique. So, we can even come from the arteries of the toe. We can come from the arteries near the ankle. We can come from the arteries behind the knee. And we can cross these blockages and treat these patients that have been told they have no option. Indeed, in our program, 95% of the time, when a patient has been told that they have no option in other centers in the United States, we are able to treat them and revascularize them.

Host: Wow, it's really incredible. And I think it's interesting. It's taking a page, I guess, out of the chronic total occlusion playbook in the heart, which is that we learned also predominantly from very creative Japanese investigators that retrograde approaches could also be very effective in chronic total occlusion in the heart. So, that's really terrific. Okay. So now for the exciting part, you served as the co-principal investigator of a multicenter randomized trial called PROMISE II, which used this LimFlow technology for amputation prevention. Why don't you tell us a little bit behind this technology and how it works, because I have to say, it's really amazing and promises to transform the care of these patients.

Dr Medhi Shishehbor: It's been extremely rewarding, and It's been a pleasure to identify other opportunities to prevent amputation in our patients. The beauty of this technique is that, as I mentioned earlier, these arteries are very small and they have diffused disease, 20, 30 centimeters of occlusion. And in most cases, they're extremely calcified because of diabetes and chronic kidney disease. In these patients, we cannot bypass the arteries because they are too diseased and we cannot cross them because they are too hard, we say they are like concrete, and we cannot go through them.

So, what we decided to do is that, is there a possibility that we can divert the blood from the arteries prior to the occlusion into the veins, reverse the blood flow in the veins and get the good blood, the oxygenated blood, into the foot to perfuse the tissue and save the limbs of these patients. And that was the whole premise of the LimFlow technology and deep venous arterization.

Host: So, let me get this straight, we know from anatomy that a vein travels next to the artery. And you're leveraging the fact that, for whatever reason, veins don't have the same disease as arteries, probably because of lower pressure, and you're converting a vein into an artery. Okay. So, let me understand this, as we said, three arteries to the foot, so three veins going back, so you're basically saying that the blood flow can go down the vein to become an artery, but then it can go back up the other two veins that are there.

Dr Medhi Shishehbor: What actually turns out that there are more than two veins, three veins coming back, there are about 30 of them. So yes, each artery has about two veins that travels with it, two major veins. And then, we have the small saphenous vein, we have the greater saphenous vein. So, there are a number of tributaries and it ends up that the venous system is much more complicated than the arterial system. So, we typically do not see swelling. I think that's why you're asking the question. One of the concerns we had was that if you divert the blood into the veins, which are supposed to bring the blood back into the heart, you will get edema and swelling in the foot. And luckily, we didn't see that in the trial, because you know, there are many many other veins that can return the blood to the heart after it has delivered the oxygen and the nutrients to the tissue.

Host: Great. So, you have this covered stent then, that diverts blood flow from the artery into the vein. And I guess the question is, what about the valves in the vein? Do you get rid of those valves? How does the blood travel down to the foot?

Dr Medhi Shishehbor: You're absolutely correct. As I mentioned, each of the arteries in the calf, and you said there are three of them and that's correct. They have two veins associated with them. In most of the cases where we do a deep venous arterization, we use the posterior tibial vein, and one of them, but this vein has a lot of tributaries and collaterals and connections with the other veins. In order to prevent steel, meaning that the good blood that we just diverted into the posterior tibial vein to get a stolen and be returned back to the heart, we put covered stents inside the vein to direct the reverse blood into the foot and into the tissue that needs the nutrients and the oxygen. The valves themselves, we destroyed the valves using the cutting technology, it's called a cutting device, and that device just goes inside the posterior tibial vein and destroys those valves so we can then place the stent and divert the blood to the foot.

Host: Wow. So, that's really cool. So now, let's get to the trial results, you know. So for the big moment, what did the trial show with respect to the LimFlow device?

Dr Medhi Shishehbor: Dan, it was incredible. It was incredible. We showed a 99% technical success rate. Remember, this is a very new technology. As a matter of fact, in order to do this procedure, and you are an interventional cardiologist, we have to get access into the lateral plantar vein, which means at the bottom of the foot, which, as you know, we never do. So, it was a new thing for all of us, getting access into a vein at the bottom of the foot. But we had 99% technical success rate, which is fantastic. And we had a 76% limb salvage rate, which is unbelievable. Remember, these are patients that are destined to undergo a major amputation, either below the knee or above the knee, and we were able to save 76% of them from getting a major amputation.

Host: You know, it's really incredible when you think about that with 185,000 amputations alone in the United States. This is completely transformational, and I think probably similar to TAVR in the aortic stenosis field, something that we probably couldn't imagine that a technology could prevent so many amputations.

So, tell me, what is the next phase now? So, this technology goes to the FDA, gets approved by the FDA. How does it get incorporated into practice? How are you going to train physicians to use it more broadly? What are the next follow-on trials that you anticipate?

Dr Medhi Shishehbor: Well, we were the only site in the state of Ohio that offered this technology, as a matter of fact, we were one of few sites in the whole northeast of United States offering this technology. We had patients coming from Pennsylvania, from Kentucky, from Indiana, and from Michigan that we took care of as part of the trial and even outside of the trial as part of the off-the-shelf kind of approach. But given our experience and number of cases that we have performed and our role within the trial, the company has decided that we are a center of excellence for LimFlow. There are going to be many physicians that are going to be brought to Cleveland to university hospitals to be trained across the United States so they can take this technology back home and save many limbs in their communities.

In addition to that, there are a number of other educational webinars that we are involved, that we are conducting to try to bring everybody up to speed in regards to this technology, provide education. And as you and I have discussed before, it's not just a procedure. These patients have chronic disease wounds, unlike TAVR, where you do the procedure, you're done. The patient is feeling great, the next day they may be going for a jog or a walk. In these patients, we need wound care and that requires a lot of education, communication, alignment, and coordination for these patients who have diabetes, chronic kidney disease, end-stage renal disease to be taken care of so that the wound is healed, and that we do not need a major amputation for them.

Host: Well, you know, it's really an incredible story and journey, and we really want to congratulate you. You know, as you pointed out, this is a team sport. Amputation prevention has a very large team. Your council meets on every single case. And I think it's really that dedication to saying this is about to dramatically change somebody's life. And before we cut off the limb, we're going to see if we have another option. And the fact that you've been able to save somewhere between 70% and 80% of limbs is truly incredible. It's very inspiring to hear you talk. I guess the question that a lot of people also would want to have for you is, we slipped in that you're now the third president of the Harrington Heart and Vascular Institute. That's a very big responsibility with over 2,500 employees and 50 sites and 10 cath labs and 23,000 cath and EP procedures. How do you do all this? How do you run this massive organization and continue to do procedures?

Dr Medhi Shishehbor: Well, I've been very fortunate, Dr. Simon. As you said yourself, you founded the Harrington Heart and Vascular Institute and set the foundation for us to be successful. We are just building on that. And most importantly is about the team. And I've been fortunate to have trained a number of young new stars and you know many of them, dr. Jun Lee, Dr. Tarek Hammad, Dr. Clint Oomen, and Dr. Yulanka Castro. So, my team has expanded exponentially, and we have an elite team of interventional cardiologists, vascular surgeons, Dr. Jae Cho and others, that are performing these procedures. They are supporting me and our team and we are all fully committed to every patient that walks through the door here at UH.

Host: Wow, what a great story. Can't wait to get you back and hear about the next frontiers. Thank you for taking the time to speak with us today, Mehdi. To learn more about research at University Hospitals, please visit uhhospitals.org/uhresearch. Thank you very much.