Welcome to Texas Heart Institute Educational Programs on Innovative Technologies and Techniques. I'm Zvonmyr Kreyser, I'm Clinical Professor of Medicine and Cardiology at Baylor College of Medicine and also International Cardiologist at Texas Heart Institute and Baylor St. Luke's Medical Center. Our special guest today are Dr. William Kohn. He's a Vice President of Johnson & Johnson Medical Device Companies, Executive Director Center for Device Innovation at Texas Medical Center and also Professor of Surgery at Baylor College of Medicine as well as Adjunct Professor of Bioengineering at Rice University and also at the University of Houston in Houston, Texas. Also joining us today is Dr. Leslie Miller. He's a past president of the International Society of Heart and Long Transplant. He's a cardiologist with more than 35 years of experience in mechanical, circulatory support and treatment of congestive heart failure. He's also a co-editor, mechanical, circulatory support, a companion to Brownhall's heart disease. Welcome gentlemen to this program. Thank you. Thank you Dr. Franco. The topic of today's discussion and presentation is ventricular assist devices, current status and future directions. Here are our disclosures for all three participants. So we know that congestive heart failure is a major concern and issue and problem for treatment of patients with advanced heart failure due to a variety of conditions. More than three centuries has passed since William Withering introduced and explained the use of digitalids for treatment of heart failure and leg edema. Since then additional treatments became available as diuretics, inotropes of different kind, the use of beta blockers, AC inhibitors and ARBs. All those medications were of certain benefit as far as treatment of heart failure is concerned, but it was only a temporary effect and the problem existed as far as the chronic use is concerned and outcomes were definitely less than favorable. So Dr. Miller, if you will be so kind, tell us a little bit about what is the current spectrum of congestive heart failure related to issues with medical therapy and a need for alternative solutions. Thank you, Dr. Cretcher. I think most of the audience would be able to tell you that cardiovascular disease is the leading cause of death in the world, but may not be aware that heart failure is actually the fastest growing form of cardiovascular disease. It affects over 7 million people in the United States and probably 25 million worldwide, but there are one million new cases per year and an American Heart Association projection estimated a 46% increase in this volume by as soon as 2030. It's unfortunately a very morbid and mortal condition that the survival average is less than 40% at five years and is worse by the class of heart failure. Heart failure accounts for more than one million hospitalizations each year for the past several years. In fact, more days spent for the care of heart failure in the hospital than any other diagnosis. Heart failure care in the hospital accounts for two thirds of the total over $50 billion total costs for caring for these patients. As such, with the economic and significant patient impact of this disease, once they're hospitalized, it's become the target of a number of pharmaceutical drug trials targeting specific mechanisms for individual agents and unfortunately, none of these trials have proven to be successful, leaving us without a pharmacologic solution for acute decompensated heart failure. The evidence of the lack of effective treatment options in that setting is really evident by it being the number one cause of readmission with only 30 days of hospitalization discharge, as many as one in four patients will be back within 30 days. Here's a series of nearly 40,000 patients that reveals this 20 to 25% readmission within 30 days, saying we really haven't changed the natural history, but impressively, one in two patients will be back, readmitted to the hospital within six months of discharge. But it's also evident of what an incredibly mortal condition this is that a third of patients will die within one year of hospital discharge and again, less than 40% survival at five years after discharge. One of the important things with regards to today's discussion is to really be aware of the decline in survival with each subsequent hospitalization. When you're hospitalized for heart failure, particularly if you're on oral medical therapy, it is the biggest change in prognosis for a patient with heart failure. And unfortunately, the survival goes down with each subsequent hospitalization, even worse for patients with also co-existent chronic kidney disease. It makes it very important to evaluate the patient in their first or certainly by their second hospitalization for more advanced therapies like the use of ventricular assist devices. Very interesting. Dr. Miller, thank you very much for this update and information and concerning issues related to medical therapy of patients with congestive heart failure. Now, what is also important is to talk a little bit about history as far as mechanical devices are concerned. Where did we start and where are we now at the present time? And there is no better person to discuss this particular issue and present the information than Dr. William Kahn, who as you have seen from previous introduction, as far as his achievements are concerned, is one of the leading scientists in new devices as far as cardiac assist treatment is concerned for heart failure. And that obviously includes all sorts of facial heart. So Dr. Kahn, if you would be so kind to go through historical landmarks related to assist devices and all sorts of facial heart. Sure, thank you for those kind words, Dr. Crazier. A lot of this really started in Houston with the legendary heart surgeon Michael DeBakey who felt that we desperately needed an artificial heart. And as part of his efforts, he recruited a brilliant Argentinian, Domingo Loyota to come down to Baylor and work on it with him and also got funding from the United States government from Lyndon B. Johnson to develop an artificial heart. And Domingo Loyota had a prototype that was working fairly well in calves, but Loyota was frustrated that it was taking so long to get to humans and in a rather rogue move while Dr. DeBakey was out of town actually in Washington DC asking for additional funding, Dr. DeBakey's partner at the time, Denton Cooley, implanted the Loyota heart at the Texas Heart Institute, what was soon to be called the Texas Heart Institute in a gravely ill patient. And that didn't, Dr. DeBakey looked at that as a betrayal and it caused a great feud between the two great surgeons. And so the whole lab moved from Baylor over to the Texas Heart Institute and became very, very involved in research. And this is in 1969. So a lot of the real milestones in this field came out of that lab, initially under the leadership of Dr. Norman, but then taken over by Bud Frazier, who I've been very fortunate to have as a mentor for the last 16, 17 years. And Dr. Frazier did a lot of the firsts in this field. There was some more work in the artificial heart, but there seemed to be a big pivot in the field based on the findings in that first clinical case with Haskell Carbon 1969. And it's sort of pivoted to assist pumps, pumps that would go next to the failing heart. It looked like that was gonna be a lower technical hurdle. And in the cardiovascular research lab under Frazier's leadership, they put pump after pump after pump in animals and then working with industry, started actually putting them in patients and had some great results. The pump was tragically flawed. We'll talk more about that later. But the pump works sort of like the original artificial heart, it would fill with blood, then eject. Fill with blood, then eject. Which seems like a great way to pump blood. That's how our own hearts pump blood. The tragic thing is though, if your pump is doing that 80 times a minute, that's about 132,000 times in a day. It's 40 to 50 million times in a year. And no man-made device can do that without falling apart, without breaking. The flexible components stiffen and fracture. The valves wear out. The cams and the high torque motors start to grind themselves up. And even using the best materials that were available, those pulsatile pumps developed in the Texas Heart Cardiovascular Research Lab would only last about a year and a half, two years on the outside. That was notwithstanding, the patients with heart failure were doing so importantly our medical management. They did a very famous study called Rematch, where they took about 150 patients with end-stage heart failure in each arm. 150 of them they managed with maximum medical therapy. 150 of them got the pump. And after a year, only 25% of the patients on medical therapy were still alive, but 50% of the patients with the pumps were still alive. And at two years, only 24% of the patients with pumps were still alive because their pumps would break and they would die, but only 8% are on medical management. And so based on that, they said, well, pumps are approved because they keep people from dying of heart failure, but we need better pumps. And that's when Dr. Frazier started working with Rob Jarvik and working with Dr. Rich Wampler, both who had the idea of using a rapidly spinning pump. That ultimately became the hema pump, which is the predecessor of the impella, which is a whole story in and of itself, but also developed the whole class of continuous flow, rapidly spinning pumps. And the first successful heart mate too was implanted in November of 2003 by Dr. Frazier and Igor Gregor and myself in a grave leal 17-year-old patient. Who did beautifully? And that was the beginning of the current era of rapidly spinning pumps. So the Texas Heart Institute has played a pivotal role in the development of this technology under Frazier's leadership. Very interesting historical information that is useful to all of us trying to learn more about assist devices than the traditional part. So obviously you mentioned that there were several generations of assist devices and artificial hearts. And so what, and you already mentioned briefly, but maybe you can emphasize again. So what were the characteristics of their first generation baths? And what were benefits? We already know you mentioned some of them, but what were the deficiencies and the need to move forward with the next generation or second generation baths? Yeah, the first generation pumps, as you can see in these pictures, sat next to the heart, usually connected by tubes, either outside the body or the heart-made XVE and the pump that preceded it, a pneumatically actuated one, sat actually in the abdomen. And there was also a pump called the Novakor, but these pumps were big, they were noisy, they were energy inefficient, but all that paled in contrast to the poor durability, the poor durability was a Achilles heel that made these pumps not important. They would only last for a year and a half and then they would break. And taking a broken pump and trying to replace it with a new pump was a prohibitively challenging operation. These pumps were so large, adhesions formed all over them. And so these keep a patient alive while they're waiting for a transplant, but as a destination device, a year and a half to two years on the outside just was not adequate. Of course, here we also have mentioned some of the issues in addition to being large and noisy. Not a unusual occurrence was actually malfunction. And I remember taking care of some of the patients, hemolysis was a very common problem, as well as thromboembolism, right? Well, yeah, but that almost always meant that there was a technical problem, a twisted graft or an inlet problem. Because actually the XDE, you didn't even need to use anticoagulants because the big clearances and tissue valves and whatnot. But yeah, infections were a bad problem and still are a problem. Durability was the biggest problem, but there were clots and there was hemolysis. If a pump was implanted properly though and was functioning properly, hemolysis was less of a problem but those big pulsatile ones, then perhaps it will be with some of the newer generation. It's not known yet. There were some patients that had no hemolysis with the first generation pumps though. Right, so now we move to the second generation vads, obviously with some significant improvements. Can you comment on those as well? Yeah, the second generation vads generally have one moving part, it's a rapidly spinning impeller. And sometimes it's the first generation ones were first generation of these second generation pumps. The spinning member was suspended on bearings and that was the Jarvik, the MicroMed, the HeartMate II shown in this picture. By having only one piece, there was no flexible members, no valves, nothing to wear out. So durability was much, much better. In fact, there's a number of patients that have had a single HeartMate II for 15 years now. And remember, the first one was just put in 2003. So some of those original pumps are still going. They were much more power efficient. It was smaller, so it was easier to get, it was a smaller operation, it was easier to get it to lie well where the inflow and outflow were laying well. They consumed a lot less power and they made a lot less noise. You still have a driveline, but getting rid of some of those problems, I think was a real big step in the adoption of VAD technology. But even though there were a lot of good things with the second generation VADs, the technology continued to improve. And so we have a third generation VADs. Why were they created and what were obvious benefits with third generation VADs? Well, it was interesting when the second generation bearing axle VADs like the Jarvik, the HeartMate II and the MicroMate came out, there are a lot of people that said you can't have bearings in the blood. All bearings in industry were lubricated. They had oil on them and how are you gonna lubricate these? But it became very evident, mainly from Rob Jarvik's work, that if the blood was flowing over the bearings fast enough, not only did it wash them, but it cooled them. So there was no frictional heat which would cook the blood and the plasma proteins and make a solid type material. So the spinning VADs with bearings actually worked well. There was though a thesis and it's turned out to be correct that you could get even better results if you got rid of the mechanical bearings. So the next generation used either electromagnetic levitation. So the spinning element wasn't touching anything at all or a combination of electromagnetic or magnetic centralization and hydrodynamic bearings. Hydrodynamic bearings are like water skis and as the rotating element spins, it levitates off on a fine layer of blood. The gaps are kind of small, so there was a real challenge to see if you could do that without causing homolysis, but with engineering wizardry and computational flow dynamics and stuff, they've now made VADs that have no mechanical bearings. The Hartmaid III, for example, is completely electromagnetically levitated. The Hartware has magnetic centralization but hydrodynamic lift. There were the Ventrosys, which is no longer round, was a beautiful levitation system. One new VAD that's just coming out and it shows great promise is a CH VAD out of China, which has an elegant electromagnetic levitation and a very interesting rotor. So that seems to be the next wave and in point of fact, performance does seem to be even better than the second generation with the ball and cup bearings. So one thing that maybe we should emphasize, again, that continuous flow pumps are now almost exclusively used. What, about 98% or so? I'd say, I don't know.  Most of the pulsatile pump companies have stopped producing them. So I would say probably close to 100%. 100%. The other advantages of these pumps though that I didn't mention is how small they are, how easy to implant they are. They are super energy efficient. It's really changed the whole field. But we didn't stop there. There's obviously still need and there's still unmet needs as far as vads are concerned. And you were on forefront or you are on forefront of investigation with still experimental artificial heart that's more than assist device. It's not a bad. From that point of view, it's total artificial heart that it has some very unique features. Can you talk a little bit about it? Yeah, and just one overarching statement about the field, the vads work brilliantly and they save a lot of lives. But there is a theoretical advantage to not going with the vad.  They're not from the pumps themselves. The pumps perform flawlessly. They're from the diseased heart that you leave just upstream. For example, two of the big complications with vads, although much better in the current era is pump thrombosis or clots going through the pump causing strokes. Those pumps don't form in the pump. They form in the diseased heart just upstream, either in the left age of appendage or around the inflow cannula or somewhere else and wash into the pump. If the clot gets stuck in the pump, it's a pump thrombosis. If it makes it through, it can manifest as a stroke. So the diseased heart is a liability. Secondly, a lot of patients succumb to progressive right heart failure. The left ventricular assist device works beautifully assisting the weak left heart, but if the right heart is weak, that can be a significant problem and a cause of mortality and morbidity. Valve degeneration and progressive aortic insufficiency can be a problem. Disrhythmias can be a problem. We can get rid of all those problems if we cut out the entire heart and replace it with an artificial heart. But no one's been able to make an artificial heart that doesn't have those problems with durability we talked about that isn't large, that doesn't have mechanical complexity and consume a lot of power. A brilliant team in Australia led by a scientist, Daniel Tims, decided to leverage what we found out with the transition from pulsatile pumps to assist the heart to continuous flow pumps to assist the heart and make a continuous flow artificial heart. And this picture here is a fairly advanced version of the Vivecore device. It has a single rotating element that's a double-sided rotor. One side takes the venous blood and pumps to the lungs. The other side takes the bright red blood, we turn it from the lungs and pumps it to the body. And it's completely magnetically levitated like we talked about. So there's no mechanical wear, it should last forever. It has some really, really unique features of the way it balances the left and right 2000 times a second, the way it would deal with clot that got washed into the pump from the lower extremity, perhaps. The way it controls shunting between the two sides. Here it says it'll do 12 liters per minute. I've seen it in a cow do 26 liters per minute. And we've now done a number of calves with this experimental device 22 in all, I believe, and seen them jog on a treadmill. And although again, I'm conflicted, I think this will be the first practical, fully implantable total artificial heart for the world. So maybe at the end of this discussion on artificial heart and bats and so on, you can kind of mention to our audience, we have different criteria in using bats, bats to transplant, bats to destination and so on. Can you maybe elaborate a little bit more on when to select one versus the other one and how often does it occur? Sure. We are correct at the very beginning what we intended to do. Well, yeah, exactly. Now they're starting to say, well, short-term or long-term, because you say, well, they're not a transplant candidate. So this is a destination device and you put it in and the patient improves dramatically and now they're a transplant candidate. Similarly, on the other perspective, you say, well, this is a bridge to transplant and the patient's doing so well and doesn't mind the VAD and says, I wanna keep this. So how often are we right? You know, I'd like to hear your perspective on that, Dr. Miller, but it's a dynamic situation and it's changing frequently. You know, as far as bridge to transplantation, that's a very important technology, but it's of limited scope and scale because we do maybe 2,200, 2,500 transplants a year in the United States because of limited organ availability. And if that's all we're gonna use these pumps for, well, that's still very important, but it's of limited impact. That said, we know several hundred thousand people are destined to die of heart failure every year and could some of those patients benefit from a destination device? And we think that that opportunity is being dramatically underutilized and perhaps it's because it's still a fairly new field and perhaps it's because we're still seeing some complications due to the fact that our understanding of how to use these and how to implement them and how to reduce complications and driveline infections and things like that is evolving, but it's been a very interesting evolution and I think it's gonna continue to evolve over the next several years. Les, I'd love to hear your comments on that. I think the key that you mentioned, Dr. Cohn, is that it's a very dynamic and bi-directional that there are people that don't look like they're going to be a good heart transplant candidate because of renal dysfunction and have a period of prolonged mechanical support and normalize their kidney function or return it to a level that would make them eligible for transplantation. Their lung pressures may look prohibitive for heart transplantation and when unloaded completely, they come down into a range that makes safety. And conversely, some people who are transplant candidates develop complications that will make them not ideal. The biggest differentiation probably I would say is within age that as you suggested, there's such a limited resource for heart transplantation that they're more directed toward people for long-term support as a permanent, as it's a destination type of therapy, but that dementia has really gone away. It really is a candidate for chronic support and we try to make the best decision as they evolve with their support. And I think as results with durable pumps continue to improve and they will, and I know we're going to talk about this later, but once we get rid of the driveline, I think that's going to have a significant impact. That's going to change the balance as well. It may turn out that a lot of patients will elect to have a durable VAD instead of a transplant, even though they're a great transplant candidate because they look at the statistics or what's involved, we know transplant science is advanced dramatically, but still, and correct me if I'm wrong, there's about 50% mortality at 10 years because of progressive... That's true. I think we have good advances on both sides, but I do think that the pendulum has swung toward long-term mechanical support as a bigger and ideal option for an increasing percentage of people without a doubt. And it's a potentially unlimited resource. I mean, everything's a limited resource, but the idea that you can take one off the shelf during the day, no one needs to get on a jet and fly to someplace and harvest an organ. It doesn't rely on someone else having a horrible tragedy. It may be that that becomes increasingly what we see. I think the one summary statement is that it's really grossly underutilized. There are a number of patients who would really do very well and have great quality of life improvement with the use of these devices, and that's one of the themes of today is to really be aware of how much we've progressed in this field and how many people could benefit from this technology.  And the burden of having a durable vad and making sure you plug in is about like a diabetic being on insulin. It takes some, you know, you have to be responsible and attentive to it, but they have very full and active lives. And I think it's like any new technology, whether it's the telephone or cell phone or electricity or the car, you go through sort of a gradual increase adoption, and then there's a big, you know, the sigmoid adoption curve. And I think we're still on the flat component of L-vads, of durable vads, but I think in the next, I know some of the industrial partners are a little dismayed. It's not picking up fast enough, but every technology has its own curve and you've got to just ride it. And I think that L-vad utilization will go up dramatically in the next. You know, as you mentioned, Billy, I think that the biggest inflection point that's ahead of us is when we really are able to have wireless power. And they're not tethered to anything. That's going to be the biggest uptick in use of these devices. Yeah, and I don't think it's just a patient perception thing. I think there's going to be some very real advantages. And we'll talk about this. I agree. So Billy, one very important thing that we would like to know from you, we are now five decades since the first artificial heart was implanted. And now you're showing the Bible core or something similar to that. There will be several devices that is what you believe the future as far as artificial heart is concerned. But we are not there yet. So what is your educated guess? When can we anticipate that this will be the treatment available for those patients that do not have other options? Sure.  But on the other extreme, we realize that there are patients, 1,000 patients a day die of heart failure. So we've met with the FDA on a number of occasions and we're crafting what the hurdles will be, what the GLP animal study will be that's good lab practices, proctored animal experiments. And the FDA is being incredibly reasonable and working with us to do this as quickly as is sound and wise. But it would not surprise me if first in man implementation of this technology happens within the next couple of years. The devices that design freeze and has had designed for manufacturing and the controller and everything are going well. So it's not gonna be that long. It's not good. That's very exciting. So I don't know whether you would like to mention, again, you did mention previously, there are obviously with the current generation VADs issues that we deal with quite frequently and maybe you can discuss that briefly. So we've talked about clot coming from the heart and causing a pump thrombosis, which I suspect is what happened in B and if that pieces of that broke off, then it could be a cold leg or a dead intestine or a stroke. And so that happens, although it happens a lot less now with better anticoagulation regimes. We still do have some hypertensive bleeds in the head which are very disturbing, but that top picture, the driveline infection, although there've been dramatic advances in techniques and whole meetings and whole sessions at meetings discussing the different ways that people try to mitigate that challenge, it's still super common. In fact, in some series, as many as half of patients have some sort of driveline infection in the first year of having a VAD. And you say, well, you can display it open and put antibiotics on it and there's ways of treating it. Yeah, often, sometimes it ascends to the pump and causes a life-threatening pump infection and many of those patients die and that's really challenging, but I think it's more diabolical than that because I think when you have any kind of infection like that, it changes your rheology. It changes the amount of inflammation in the body. And I think there's a, and I've seen papers about it, but I don't know that the verdict is in, but there seems to be an increased incidence of pump thrombosis and stroke in patients that have had driveline infections. So getting rid of the driveline and making it a leadless system that's completely closed, there's no evidence except a well-heeled scar that there's a pump inside the body. I think it will help patients with perception of getting a VAD and the physicians that refer patients for VADs, but I think there's some very real advantages of not just dealing with infections, but maybe in the incidence of stroke and pump thrombosis, if we can get rid of the driveline altogether. Les, what are your thoughts on that? Do you agree with that? Without question, I think you're absolutely right. That's, as you said, I think that's the real inflection point and there is no question, the correlation between infection and thrombosis and those are really morbid complications of the device. And as you also said, they're happily declining in prevalence and incidence, but I think that's really, as we've said, I think the most important milestone in the future is to go to wireless power. Very good gentlemen, let's shift gears now and talk about futuristic medicine. Let's talk about percutaneous approach to complex issues such as congestive heart failure. As both of you know, I'm admirer of percutaneous approach and percutaneous treatment of all kinds of conditions and this topic is very dear to me. So Les Miller is a true expert on percutaneous support, mechanical support in patient with congestive heart failure. So Les, I would like for you to mention to us a little bit about those issues that we would like to address with percutaneous approach. What is the most common need and drive as far as percutaneous use of those devices that are still experimental? Thank you, Dr. Craitra. I think one of the biggest problems that we see in acute decompensated heart failure is the development of acute kidney injury, which recent studies suggest maybe between 25 and as high as 40% of patients will exhibit some evidence of kidney injury and probably 20 to 25% of them will develop a more advanced form we refer to as cardiorenal syndrome, which is defined actually by an increase in measured creatinine of 0.3 milligrams for desiliter or an inadequate urine output in response to the first line therapy that everyone receives in the first 24 hours of aggressive doses of intravenous diuretics. The cardiorenal syndrome is actually a very dynamic interaction between the heart and the kidney. Heart failure begets the activation of a number of important mechanisms from the renautia tensin to sympathetic nervous system and a number of factors that are designed to help the heart pump more effectively, but in the advanced form and their aggressive activation leads to very significant consequences for the kidney, in particular a decline in renautery pressure and perfusion, which leads to accelerated vasoconstriction and a loss of the gradient for perfusion and filtration in the kidney. That's secondarily increase in resistance and vasoconstriction leads to increase venous pressure and fluid retention, which leads to increasing cardiac filling pressures and this loop continues. It's a very dynamic, but a very important mechanism involved in acute decompensated heart failure. There's data from large registries like the Adhere Registry that suggests that the development of worsening renal function in the hospital can have as much as a 20-fold increase of in-hospital mortality over those who maintain normal renal function. So beyond length of stay, complications, cost of care, it can be a very mortal complication. We have more recent data that if you develop cardioreal syndrome in the hospital, that mortality risk is conveyed in the following year with an increase in mortality with worsening renal function. So it is a very important target, and as I suggested earlier, has been the target of over a dozen pharmacologic trials, none of which have proven to be effective in why we believe a mechanical solution applied earlier in the course of decompensated heart failure makes the most sense. Very interesting. So basically low cardiac output definitely affects renal function and that then in turn affects not only cardiac function, but the outcome of the patient as far as morbidity and mortality is concerned. And low cardiac output affects not only or worsens the renal function, but many other organs from CNS to gastrointestinal to the lower extremity and so on. So it's a multifactorial complex condition that occurs with this type of a scenario. So obviously there was a need and there is still a need for a creation of percutaneous devices that would address this issue and improve renal function, improve renal flow and improve a patient's condition as far as congestive heart failure. So can you mention to us some of the currently available devices that are used on a daily basis for a variety of conditions in cardiology practice at the present time? So acute decompensated and more advanced severe heart failure and borderline cardiogenic shock has been a target for a number of device developments. Certainly the first forerunner was the intraortic balloon pump which inflates in diastole and causes a bit of after low reduction but has really never been shown to enhance renal function. It has some salutary effects on hemodynamics and is easy to apply and is still being used for a number of indications. The other devices that are really a reduction of preload in the right side, the left side particularly, ECMO is a system that removes blood from the right side of the heart into a essentially a cardiopulmonary bypass pump that will return blood to the body in a retrograde manner through the femoral artery can generate four or five, even six liters of flow and has added advantage of being able to oxygenate the blood. The second system that was actually developed at Texas Heart is the tandem heart which is a transceptile approach to the left atrium to remove a preload and volume that simply again has this extracorporeal motor that can drive the return of significant output and blood flow. A third type of opportunity is the centromag which has the ability to be placed and support the right side of the heart, the left side or in tandem and is quite effective way to support these patients. These are, this is a surgical approach but the more recent development is the impella device which now directly has a cannula in the left ventricular chamber and pulls most all of the preload of the ventricle so that the ventricle does not contribute very much to net cardiac output and can generate anywhere from the newest models to four to four and a half liters of flow but again removes the native contribution of cardiac output. Less in keeping with my continuous plugs for the Texas Heart Institute, I'm sure you know that the precursor to the impella which is the hema pump. The hema pump. Thoracin planted in a human also at the Texas Heart Institute by Bud Frazier. Rick Wabler had seen some Egyptian workers using an Archimedes screw to pump irrigation water up a ditch and then came home and designed the first one. He showed it to Bud Frazier, had never met Bud but knew that Bud believed in continuous flow and they did a number of cows with it and then put it in a grave leal patient who was rejecting six months after a heart transplant and it was a shot around the world. It was the first human being treated with a continuous flow pump inside the body and that of course. There's one of many as you said, I think the contributions of the Texas Heart Institute and the field of mechanical support is pretty much unparalleled and a lot of the lessons and a lot of the really fundamental understanding of different mechanisms of these pumps was really developed by you and Bud and Dejan Cooley and all the doctors there at the Texas Heart Institute. But these devices clearly have served a lot of patients particularly more in the shock realm for most of these devices but we believe that there is probably an alternative that I'd like to discuss next and that is the placement of a percutaneous temporary mechanical assist device in the descending aorta. The top field is we've kind of separated the field into what we call pushers meaning that they enhance blood flow with the kidney and generate increase in flow as opposed to what is referred to as pullers which variably either reduce venous return to the heart at the level of superior vena cava or at the level of the renal veins or another newer model, the durea catheter which is another left ventricular cavity insertion device much like the impella device. So the field is really increasing with a number of options being pursued. The top devices as I mentioned are really placed in the descending aorta intentionally to have some relative proximity to the kidney but also to get away from crossing the aortic valve and so forth. The next slide is the visualization more closely of these three devices. The original impella device called the cardio bridge or right hand device is placed as you see in the upper portion of the descending aorta. The second device, the prosyrian aortic is similarly placed in the upper part of the descending aorta and a device I'll talk a little bit more about called the second heart assist device which is actually placed only 10 centimeters above the orifice of the renal arteries to really enhance the flow into the kidney to enhance mechanical function and diuresis. So let's tell us a little bit about unique features of the second heart assist device. When we design this, we believe that the kidney which receives 20% of all cardiac output is really the key to solving the persisting congestion that is the number one presentation of patients with heart failure. And you went back to simple renal physiology that the kidney responds well to improvements in flow and pressure to enhance that perfusion gradient and enhance function. And that we believe that we could create a pump that could do both improve pressure and flow that would lead to enhanced diuresis here and output and decongestion. In so doing either directly or indirectly unload both the right and left ventricle and somewhat surprisingly significant improvement in cardiac output. So our strategy was to build this device but to place it as close to the kidney as possible to optimize improved function of both the heart and the kidney. So tell us a little bit more about specifics as far as the design of the device is concerned what is unique about it and how does it function? Happy to do so. This is a visualization of the device as it's sitting in a transparent sheet of the mock loop system. But the second heart assist device is an impeller driven mechanical pump placed in the descending aorta. It is the only true aortic stent pump in that it fills the entire aorta which is a distinct advantage in that we're able to augment the entire cardiac output and pulsatility. As I mentioned, the impellers blades are mounted on a drive shaft inside a stent cage. And this is one of the essential parts of this technology and that it's the same stent used for the development of the talent stent graph for endovascular repair of aortic aneurysm now used in over 500,000 patients with essentially no reports of movement once deployed. This stent deploys a very strong radio force along the entire length of each of the struts that you can see placed circumferentially around the aortic lumen applying a uniform pressure that will essentially we believe never cause this device to be repositioned for movement. So what is this unique feature of so-called if I'm correct, pulsatile harmonic vibration of this particular device? What are the benefits of that particular feature? Well, the harmonic device is kind of a later generation of this thing, but one of the things that we have been able to describe is that despite the strong diffuse radio force applied to the aortic wall, it's able to allow the order to maintain pulsatility which we've demonstrated visually in several mock loop systems. So that's gonna be important not only in the acute setting but certainly in the chronic setting to allow this stent to be compressed and yet preserve the function of the endothelium in the aortic wall. One of the other really important aspects of this pump is how efficient it is. It's able to generate very high flows with what we believe is the lowest RPM speed in the field and that is gonna be another important feature both acute and chronic. And finally, as you can see as a very open cage design to minimize points of stasis and potential thrombosis. So can you give me a comparison between impella as far as RPMs are concerned and the second hard assist in optimal situations and what are the true benefits? You didn't mention it's basically homolysis that occurs with high speeds and so how is this important as far as those two devices are concerned? It's a very important question and it's a very big differentiator between the two devices. The impella device currently at its optimal speed in order to generate between four and four and a half liters of flow has to function at 35,000 RPMs. The Persirian device has been reported to run between 20 and 25,000 RPMs. The higher the RPM speed, the more friction and more homolysis and breakdown of red cells with secondary acute kidney injury. So this pump will operate normally at approximately 8,000 RPMs, which is one fourth to one fifth that of the impella and certainly one third to one fourth that of the Persirian device. So we know that there are a number of acute advantages, but I think the efficiency of this pump is gonna differentiate it in the field and the lowest RPM speed of 8,000 will be a big differentiator and an important, not just from the definitive discussion of its attributes, but from a clinical perspective it should have the lowest homolysis in the field. So what kind of information can you give us as far as any animal studies are concerned? Was the first in man already done and so what is the next step with this device? There've been a number of animal studies of both these devices and interestingly, both first in man tests of these devices has been done in Paraguay for support of high risk PCI. They're really proof of concept that the device can be deployed and that they not only function and at what speed they function and that's where we defined that as 8,000 but they operate very well with renal function. This is a visualization of the deployment of the device probably the easiest to deploy in the four cases in Paraguay in the high risk PCI support. There was only required two minutes to deploy both the stent and the impeller blades in less than two minutes after arterial access. So very easy to insert. You can run that again. I think you'll see that there are wheels on a control handle that remove the sheet from the stent which automatically opens to its diameter of 22 millimeters. A second wheel allows the deployment of the impeller blades which are connected to a motor controller to adjust the speed of the impeller blades. At the end of the case, the reverse of those wheels will allow the impeller blades to collapse and the sheet to again extend over the stent collapsing it and then the entire unit removed as one. This is a very simple operation with these two wheels that turn in one direction to deploy the reverse direction to collapse and the sheet goes over the stent very easily and then the entire unit is removed in total. If I'm correct, this is a 14 French device which could be easily deployed. Yeah, it's a 13.5 French device that's deployed through a 14 French sheet very easily. And as I said, the ease of deployment is really a good feature. One of the things that we learned in the Mach loop that we think really differentiates this pump from other devices is a linear relationship between variable pump speeds and the flow that is generated, referred to as the HQ curve. We were able to simulate all levels of hardfayer in our Mach loop testing and this is perhaps the most advanced of a model where there was significant hypotension, a very low cardiac output and high filling pressure. And the kidney would respond by intense phase of constriction, limited flow, decline in function and fluid retention. And yet as we increase the pump speed to our nominal operating and then all the way to a max speed, you can see this linear relationship as absolute increase in flow on the left and on the right is the percent increase from baseline. And I think you can see that at peak flow, we're able to generate a 50% increase in renal blood flow, thereby giving the kidney about two to two and a half liters of increased flow over that native cardiac output of three liters, which we think will minimize and negate the vasoconstrictive responses in very advanced hardfayer and allow the kidney to maintain good function and adequate diuresis, a very unique but very important feature of this device. So what are the plans as far as using this device? Not only in acute scenarios, acute congestive heart failure, but also in patients with chronic condition where we use it for a relatively short period of time of days or weeks or months. And what are the developments as far as second heart is concerned to make this a reality? Well, there's no question that the largest and fastest growing segment of the entire heart failure population is referred to as the ambulatory class three heart failure patients who still exhibit significant functional limitations often have underlying chronic kidney disease that makes diuretic management challenging fluid of management challenging for the patient. And so for the last 30 years, the field has been interested in moving to chronic support in that population. But as we've said several times, a drive line makes that really prohibitive for we're talking months to years of support. This holy grail, if you will, of mechanical support, the achievement of wireless power has been very difficult to achieve for a number of reasons, but we believe that these are the important attributes of any device that's gonna be used for chronic heart failure therapy to achieve wireless power. First it has to occupy the entire order so it's not vacillating within the order and needs to be able to be fixed. And importantly, in that this is a chronic application, we need to have assurance and uniquely with this device that it should probably never need to be repositioned for movement. Importantly, as I mentioned before, is that how this device is really wonderfully applied to the aortic wall and yet allows the aortic pulsatility which will maintain the integrity and function of the endothelium and the aortic wall for long-term viability. It has to have ease of detaching the drive shaft. We have the feature in this device of being able to transition from acute to chronic very easily and for example, if it was used as a bridge to transplant situation and the device was gonna come out with a new transplant, the drive shaft can simply be reinserted, capture the stent, collapse it and pull it back out. So the manager of the drive shaft is really an important feature but it must increase renal blood flow in this circumstance up to 50% but importantly and perhaps most importantly has to operate at that very lowest pump speed possible. We believe in the chronic setting that this pump will operate very effectively and provide that necessary improve renal blood flow maybe as low as three to 5,000 RPMs which will minimize any development of hemolysis, secondary kidney injury and maintain these patients. But perhaps one of the things that has impeded the development of wireless power in the large durable vads is that they can draw as much as 20 watts of power, making it a challenge and cause the initial irritation across the skin and problems with transcutaneous energy transfer in the initial application. This pump is designed to draw perhaps less than one half of one watt which we think will really facilitate the ability to capture and have wireless power. This next slide is a visualization of the second generation which is quite far along in development. As you can see it still has the same cage and impeller and drive shaft design of the first generation. It has somewhat of an enlargement elongation of the tip in order to accommodate the receiver battery for the wireless transmission of power. On the right hand side I think you can see a very unique and novel engineering feat of the docking system which will allow it to be captured and or released electively with magnets. So we think that this is very easy to accommodate whatever need for this device for a short or long term therapy and will be operated wirelessly powered and be tested soon the Texas Heart Institute in this second generation. So Billy maybe you can mention because this is common to both current devices that will have what are their vads and also percutaneous that are particularly used for a longer period of time. You have to be able somehow to transmit that power from the battery to the device. What were the obstacles and where are we now? And before I talk about that I just want to say last that that system looks really, really nice. The first generation device looks great. I think it's going to be a winner. That second generation though is super, super appealing as well. And I just want to congratulate you and that team on that amazing work. So beaming wire beaming power to something without a drive line is going to be a really important inflection point in this field. And people have been talking about it for years but the challenge hasn't been getting the power through the skin. In fact, there was a device called the Aero Lionheart and they put 40 of them in. The device itself is one of the pulsatile devices so it had limited durability. It had an air compliance chamber that was challenging. Those were its shortcomings. They had very few problems with beaming the power through the skin. Similarly, the Abium Edd Artificial Heart 14 of those were implanted in 2000 and 2001. It was a big device. It consumed a lot of power. It had very bad durability for all the reasons we've talked about but the transcutaneous power transmission worked okay. The challenge with transcutaneous power transmission systems has not been getting power through the skin. It's having an implantable battery that'll keep the device running if the connection gets unhooked for a minute or two. And it turns out that battery technology, to have a battery that could power one of these devices for 15 minutes or so while you got your TETS system, you're out of the coil, lined up with your implantable coil again has been the real limitation because a battery to have enough energy density to power a 10 watt system say for an hour until fairly recently has been too dangerous, generated too much heat and couldn't really safely be put in the body. And so the major companies in this space, now Abbott and Medtronic, historically Thorotek and Hardware had tried several different times to make pushes to come up with leadless systems. And it was always the battery that was the challenge. That said, because of advances in technology driven by non-medical devices, cars, driverless cars, cell phones and other technology, the batteries have gotten better and better. So now these are a near-term technology that both Medtronic and Abbott are gonna bring into clinical practice or leadless systems. Beaming power from one place to another was demonstrated by Nikola Tesla at the Chicago World's Fair in 1893. That's not new. Getting it so it doesn't hurt the skin and having a battery inside that can power the device for a meaningful amount of time if that became unhooked has been the challenge. And as I mentioned, battery technology advanced dramatically and is getting ready to advance another quantum leap with the new graphene sulfur electrodes. So in the next couple of years, battery technology is gonna take another big jump. So leadless systems are coming. They will be here. It's gonna be a huge inflection point for the whole mechanical circuitry assist field. But I think devices like second heart, like you just described Les, even has an additional advantage because it's non-obligatory. Any of these vads like shown in that left picture that go from the heart to the aorta with a little turbine, if that pump stops for a minute, it's a huge liability. You have open reflux from your aorta back in your left ventricle and would get very, very sick. The second heart, if it stops spinning, really doesn't cause a risk to the patient. So I think maybe those type of devices have an advantage about being powered by a test system that some of the durable implantable systems don't. I think you're really right about all those aspects of the benefit of this device. But one of the things that's also coming across the board is wireless charging, remote charging. I think at night being able to charge it, but this battery is really, we think it's gonna have quite a durability during the day, but I think that that's one of the things that's gonna go very rapidly is to really enhance the amount of battery power and longevity. Exactly. And just to cover what's on this slide, the way these systems all work, if you take a coil or wire and put it in an alternating magnetic field, current starts to flow in it. So you have a battery outside the body, some circuitry that makes an oscillating current, alternating current, you put it through a coil of wire, you have a magnetic field that flips back and forth outside the body, that beams through the skin to another coil that's bathed in that oscillating magnetic field. It causes electricity, alternating current to flow in that coil. It's then put through a rectifier and turned into a direct current, DC. And you guys, everybody has a lot more familiarity with this technology than you think. The ubiquitous wall warts that we use to charge our cell phones or power our computers, all the little black, fusiform things that plug in the wall, that's inductive coupling. It's a coil that's driven by your wall current, 60 Hertz, AC, another coil that picks it up and turns it into whatever power your device needs. These test coils, transcutaneous energy transmission systems are the same as those ubiquitous black wall warts, but instead of an air gap, they have skin and soft tissue between the two coils. So it's something that's been around forever. As you said, historically that Penn State experience was now over two decades ago and we've been working on trying to get there. So this is not a simple task to achieve but what progress has been made in the last four years has really advanced the field dramatically. Absolutely. Well gentlemen, this has been a true pleasure looking into the future. And I think the future is really bright as far as assist device is a concern and all sorts of official part and you are truly leaders in this field. And we at Texas Heart Institute greatly appreciate your participation in this program on innovative technologies in our educational programs. Thank you once again for joining me for this program. Thank you. Yeah, thanks for the opportunity. Good talking with you, Les. See you soon. See you, Billy.