Dr. Uriel, MD, discusses updates, regimens, and treatment for End Stage Systolic Heart Failure.
Hello. My name is Nir Ariel. I'm the director of the Heart Failure, Heart Transplant and Mechanical Circulatory Support Program at the University of Chicago Medicine. What I want to share with you today is a little bit about end state systolic heart failure-- when the end, actually, may not be the end. So how common is heart failure? What are we talking about? Worldwide, there are 23 million people now diagnosed with heart failure. In the United States alone, six million people were diagnosed with heart failure, equally distributed between men and women. There are 670,000 new cases of advanced heart failure patients diagnosed every year, and the expense on this disease alone is $40 billion a year. So what do we do for that? What we have to do for that is first and for all, give the medical treatment that is well proven by all the other studies. And let me go back and a little bit speak about history. 30 years ago, if advanced heart failure patient will come to my office, his chance of surviving one year will be 54%. However, thanks to medical progress and the studies about ACE inhibitors, spironolatone, and beta blockers, we improved these outcomes to 11% mortality rate-- meaning we reduced the mortality out from 50% to 10%-- absolute risk reduction of nearly 50%, which means that we need to treat two patients for one year in order to save one life. This is the number needed to treat with medical therapy. As you know, this is not enough, and we decided we want more, and we want to improve the long life of those patients as well. So today what we do to those patients, we put them on a cardiac resynchronization therapy. This slide is taken from the KRHS study, shows that patients that receive CRT therapy actually reduce their mortality by an addition of 10% after 2 and 1/2 years, meaning now that we need to treat 10 patients for two and a half years in order to save one life. This is common practice. That's what we do all around the world and that's what every heart failure patient should get. However, sometimes this is not enough. And sometimes, medical therapy, despite being advanced, reaches a limit. As you can see here, Elizabeth Taylor, on her glory time as Queen Cleopatra, suffered from heart failure. However, she did not receive any advanced therapy options and unfortunately passed away a few years ago from advanced heart failure. On the other hand, as you can see, we have Dick Cheney that suffered ischemic cardiomyopathy and had advanced heart failure. And as you can see him here, he's been offered advanced modality, and you see the battery that he's holding in his hand. And thanks to that, today, a few years later, he was bridged to transplant, and was transplanted and is very alive. So let's start going back in time and understand what is really advanced heart failure. Advanced heart failure is the understanding that there is a turning point, that's from that time medicine will not be enough and we need to replace the heart. We need to give heart replacement therapy. This philosophy started very early in the '60s, and was developed by several surgeons that pushed the envelope and tried to reach to a time that we can replace the heart-- mostly by other human hearts-- Norman Shumway from Stanford, Rich Lower, his partner, and eventually moved to Virginia, Adrian Kantrowitz from New York-- and who beat them all, eventually, was Christiaan Barnard from South Africa. He came to be a fellow in Minnesota University, he learned about the cardiac bypass, went back to his town in South Africa, and done the first heart transplantation in 1967. This was a turning point. That was an understanding that we can take a heart that has failed and replace it by another heart from another human being that die from other reasons. As you can see here, this is the first patient that was transplanted in 1967. Patient felt well in the beginning, but unfortunately 18 days later passed away from infection. When people asked him how he agreed to be the first one that received heart transplantation, the patient said-- and you have to remember, this is happening in Africa-- that if you have a lion chasing you and you are coming to the bank of the river, you're just going to cross this river, even if it's full with crocodiles. And that's what he thought. But today, maybe we can see the lion from far away, and maybe the river is not so full with crocodiles anymore. So from the beginning that the transplant was only an experiment to today, we've done a big progress. And if a patient now is getting a transplant in the 21st century, his chance of surviving 14 years is 50%, meaning 50% of our patients that will get heart transplantation will live more than 14 years. And they live a wonderful life and very quality life. And today we can transplant patients that have only a heart condition. However, we can do combined heart and kidney, heart and liver transplantation, we can retransplant patients, we can transplant patients that have HIV, and we can transplant patients that survived cancer. So the indication is much more. So why we don't do more transplants? Why we think we should do more? So as I just alluded before, there are 6 million people in the United States with heart failure. Of course, not all of them are advanced heart failure, but some of them are heart failure. However, in the last decade, or two decades, we are doing only 2,000 heart transplantations in the United States every year. As you can see, it's the green bar. 2,000 transplantations, and it's not changing. Heart transparent is amazing and beautiful. However, it was, and it will stay-- for the meanwhile-- a boutique medicine. So into this vacuum of a growing need for advanced heart failure options, and on the other hand, excellent outcomes with heart replacement therapy, people start thinking-- and this was thanks to the NIH in 1964-- that we should have a mechanical heart. We should replace the heart mechanically. Eventually, when we want to replace something, we want to work exactly as the normal one will, meaning a pulsatile pump. As you can see here, this is an example. of the HeartMate I that has a 70cc chamber, and blood can go into it and it's pumped out of it. When we have this activity of the blood that's going in and out, we need to pull the blood from somewhere. So there is going to be an inflow cannula-- this is going to be located in the left ventricle apex, as you can see here; the pump itself, regardless which type it is; and it's going to the ascending aorta. What it creates, it created the heart himself doesn't need to function. It only works as a conduit for blood on the left side. We have to remember, this is replacing only the left side. So we can do it in the inside and we can do it in the outside of the body. The blood can go out. However, this is mimicking the heart itself. And that's, apparently-- and I will share with you a little bit more-- changed the field, but didn't revolutionize it. So what happened later is that we start thinking, instead of mimicking the heart, let's just create something else. Instead of having pulse, let's have a pump that will rotate in a speed of 10,000 revolutions per minute instead of 80 beats per minute, and it will just suction the blood from the heart. This is the HeartMate II and this is the heart [INAUDIBLE], as you can see here. Each one of them represents what we call today a continuous flow pump. Again, there is an inflow cannula in the left ventricle apex. The blood is being pumped into the pump that's rotating a speed of 10,000 revolutions per minute, and pushing to the ascending aorta. This needs a lot of power and a lot of computerized, so there is a drive line. This is going to be from the inside of the body going out in the area of the belly into a small computer that the patients can have on a small bag, on a small pouch, and this will be connected to external batteries that can last for 12 hours. As you can see here from a closer look, the inflow cannula is inserted into the left ventricle heart apex. It has a bend, and the motor that is rotating at a speed of 10,000 revolutions per minute have bearings that hold them the right place. The outflow cannula is going as a GORE-TEX into the ascending aorta and the drive line, as I said before. So how common has this technology became? Due to the extreme need for heart transplantation and the prolonged wait, in the beginning, only 10 or 20% of the patients that needed heart transplant we're bridged to transplant with mechanical circulatory support. However, as time passed, and more people need heart transplants, more people will deteriorate, and instead of waiting for the heart transplant, they will get a pump before that. Today, we are speaking that 60% of the people that get to heart transplantation received mechanical circulatory support prior to transplant. So let's see if it works, and the combination of heart transplantation and mechanical circulatory support is the right combination. As you can see here, this is a competing analysis graph that shows that by utilizing both techniques transplant and mechanical circulatory support, patients with advanced heart failure-- to remind you, have a very high risk of mortality-- have a chance to survive two years, 87% survival. In the beginning there will be mechanical circulatory support. As time passes, they don't have mechanical circulatory support and they get a transplant. However, we are speaking about two years of 87%. This is unbelievable for patients that were actually dying. But today we know we don't want only to give, actually, survival. We want to give a good quality of life. So the question that we need to ask ourself is whether those patients have a good life. As you can see here, most of advanced heart failure patients cannot walk before the surgery, after they walk something like 10 to 20 meters. After that, they are breathless and they cannot walk. Six months post the surgery, those patients walk almost 300 meters in six minutes, meaning that they can function around the house and do well. If we'll use that in a NYHA class classification-- New York Heart Association classification-- all the patients, before the implantation of device, had a NYHA class of zero. However, six months post, 82% of the patients have NYHA 1 or 2, meaning can walk around freely is NYHA class 1, or can walk around and be exhausted only by a significant exercise limitation. So if we give them both a long life and a good life, why is it supposed to be instead of transplant-- why is it supposed to be a bridge to transplant, why it can't be instead of transplant? And what I actually want to introduce to you today is destination therapy, meaning those patients are going to get mechanical circulatory support, and this is going to be their treatment for heart failure. Originally, people felt uncomfortable of doing this to patients that are eligible to transplant. And the first study to challenge that pattern was the REMET study done in the end of the 20th century. The study took patient that are not a transplant candidate, meaning they are too sick, too old, or other comorbidity that precludes them of became transplant. However, those patients are dying from heart failure. And they put those patients into two groups in a randomized fashion. One group-- the red one-- received optimal medical therapy. The other group received mechanical circulatory support-- in this specific study, still a pump that mimicking the natural activity of the heart, the HeartMate I. Those patients were extremely sick, with ejection fraction below 25%. Their peak zero two was 12 milliliters per kilogram per minute. Or they were continuous infusion of inotrope. Let's see what happened. The patient that gets optimal medical therapy-- the best thing medicine can give them-- after one year, only 25% of the patients survive. 75% of the patient died within one year. After two years, only 8% of the patients survive, meaning 92% percent of the patients died. With the patients who received mechanical circulatory support-- still the old generation-- 52% survive one year-- dramatic improvement-- and 23% survive two years-- again, dramatic improvement. That study led to the approval of HeartMate I as a destination therapy among those patients. But let's be honest. Are we going to implant a device that's still, 75% of the patients will die within two years? Are we OK with two years, or we want more? So let's go back to what I just tell you before. We need to change the thinking. Instead of mimicking the heart, we have now continuous flow pump. And those pumps, actually, don't look like the heart, but they do the same thing. They take the blood from one place and move it to the other. So people start doing the same study again. However, now use the continuous flow LVAD in competition with the HeartMate I, because we knew that it did already better than the optimal medical therapy. So let's see the result of the HeartMate II continuous flow pump as a destination therapy. Again, the control [INAUDIBLE], 25% percent one year survival and only 8% two year survival. It's a death sentence to be advanced heart failure on optimal medical therapy. The pulsatile slope on the HeartMate I have 52 to 55%-- it depends on which study-- and 23 to 24% in two years. However, the continuous flow pump was 68% in one year and 58% in two years, meaning if we compare optimal medical therapy to continuous flow pump, there is a 50% absolute risk reduction in the mortality. We need to treat two patients for two years, and we save one life. We all agree that we put CRT, as I mentioned in the beginning of my talk, and we need to treat ten patients for 2 and 1/2 years, and we do it for everybody. Here we just need to treat two patients for two years and we are going to save one life. This of course gave to the approval, and this was a change. When this is happening, and we have such a good outcome, we can start thinking about destination therapy. If I have a patient that I can save him 70% one year and 60% two years, this is a patient that will benefit from destination therapy. However, a lot of people will say, this is in the study. What's happening in the real life? So actually, in the real life it's even better. Today, after the approval of the device for destination therapy, we know that the one year survival is in the 75% range, and the two year survival is in the 65% range, meaning absolute risk reduction of almost 60%. So I have a question for you. Is this the rise of the machine, like James Cameron and Arnold Schwarzenegger done or not? It seems to be that it is. So let me show you a little bit of the good side and a little bit of the bad side, because not everything is good in medicine, and there is thing that we have to remember. So I will share with you a patient of mine that called me. And he said to me, Nir, I'm dizzy. And because he is dizzy for four hours, and he is advanced heart failure patient, of course we are concerned. We send him to the emergency department. The patient came to the emergency department. And because of his history, immediately an EKG was done. And the EKG that you can see here was reported. We all can identify immediately that the patient is in ventricular fibrillation-- a condition that is actually-- we cannot live with this condition for more than a few seconds. And each one of us, if we have this condition, will just die immediately. So the physician in the emergency department jumped on the patient, and he said, I'm OK. I'm OK. I'm just dizzy. And he gave him a shock and defibrillated the patient out of this condition, because that's what we learn in medicine that we do in ventricular fibrillation. However, this patient was already in ventricular fibrillation for four hours. How did he survive? He had mechanical circulatory support. So this is unique. Now he's not so much dependent on the heart in order to survive, so his rhythm may be wrong. And this is the reason that he survived. So we thought of studying it a little bit more in detail in our research group, and that's what we found. We found that a lot of people that have advanced heart failure have ventricular tachyarrhythmia that are deadly. And that's the reason we put them on the ICD. However, after the device, those arrhythmia do not disappear. And as you can see in the red line, patients after device therapy that had arrhythmia before are going to be with arrhythmia also after. However if those patients, before the implantation of mechanical circulatory support, did not have a device, probably they will not have ventricular tachyarrhythmia. We all know that AICD is a must therapy to patients with ejection fraction below 35%. It's a Class 1A recommendation by the American Heart Association. However, this patient have ejection fraction below 35% but the survival were the same, because they have another safety net, which is the mechanical circulatory support. And thanks to that, we said that in LVAD patients we need to ask ourselves again-- this is the rise of the machine-- should we implement all the thing that we know from cardiology on those patients or if they need a different guideline? And we came out with those recommendations, to ask yourself whether the patient has VT before-- yes or no. If the patient did not have VT before, we will send him home without an AICD. If the patient had a VT before, we will put an AICD in. So this is just an example that this is the rise of the machine. This is a little bit different than what we want. Let me share you another example of how, actually, a machine can change other parts of the body that we do not have to think about. We all know that a lot of the patients that have advanced heart failure are actually diabetic patients. We all know, also, that it's very hard to control the diabetics. So we took a group of patients-- 15 in the number-- that have diabetes, and they were going to get mechanical circulatory support. The fasting glucose for those patients was 158. Their [INAUDIBLE] A1C was 7.7, and on average received 55 units in insulin a day. The reason that their diabetes was so poorly controlled is not because we were bad doctor, but we couldn't control the diabetes in the presence of advanced heart failure. As you can see, they received a lot of insulin. We look at those patients six months after the surgery, and what we learn is first of all, the plasma fasting glucose was 104. The [INAUDIBLE] A1C came down to 6. So now we've perfectly controlled their diabetes. However, we give them only 25 units of insulin, not 55. So what happened? Why suddenly a patient that was diabetic, so hard to control, is so much easier to control, and we can really control him with less insulin? So most of the people immediately will say, well, probably they lose weight, because we all know that diabetes relates to insulin resistance, and insulin resistance relates to obesity. On the contrary, those patients was before the surgery in a weight of 88 kilograms due to cardiac cachectia-- not so much cachectic, but not as obese. After the implantation, they just gain weight. So the device is definitely changing something. He changing, actually, the stress that's involving the body, and this phenomenon is actually uniform in every patient that's going through device therapy. Any or each one of them will improve his diabetic control, and any and each one of them almost will gain weight unless we'll do something. So hopefully up to now I convince you that this is a little bit rise of the machine, that definitely the machine can change a lot of ways that we think about medicine. But it always changes also what we know, because now instead having only a patient that have a disease, we have a patient and a machine that need to interface together. But we can-- with these together, we have an excellent quality of life. As you can see, those patients can play golf, hockey, ride a bicycle, or even do a zipline in the age of 92 or something like that. So definitely a changed life. Not everything is good, because there is nothing is medicine that there doesn't have a price. And let me share with you a little bit about the price of mechanical circulatory support. One of the things that we immediately recognize is that those patients bleed much more than others and require blood transfusion. As you can see here, we even show that 65% of the patients that's receiving mechanical circulatory support above the age of 66 will have a major bleeding event. And also the young people will have a major bleeding that will require blood transfusion. So why is that? Let's go to history. History never lie. And as you can know, in 1954, Hid reported HID syndrome. He said a patient with aortic stenosis have a very high shear stress and develop acquired Von Willebrand disease and AV malformation, and bleed from the GI tract. So if we think that the aortic stenosis creates high shear stress, what do we think about 10,000 revolutions per minute? Much more than that. And likewise, Von Willebrand disease, can it be related to bleeding? Yes, it can. To remind you all, the Von Willebrand that are coiled in our plasma and just floating around next to the platelet wait for a damage to the vascular bed that will occur. And when this occurs it uncoils himself, activates the platelets and create a platelet plaque. In mechanical circulatory support patients, due to the high shear stress that exist, those patients actually have a structural change in the Von Willebrand factor and they develop acquired Von Willebrand disease, and due to that they bleed. So when we found that out, we done a study and we took 30 patients with mechanical circulatory support, and we found that 100% of them have acquired Von Willebrand disease-- exactly like reported in 1954 by Hid about aortic stenosis. But what we've done also here, when those patients went to chart transplantation and received a heart, we measure the Von Willebrand brown factor a couple of days after the heart transplantation, and we found that none of the patient have acquired Von Willebrand disease, meaning that all the patient that developed acquired Von Willebrand disease could develop it because of the pump. This is again-- we have a machine and a body, not everything working perfect together, and the blood products may be destroyed. But if everybody developed acquired Von Willebrand disease and not everybody bleeding, probably this is not the only thing. So here, what we can see is there is another part of the equation, and this is the pulsatility. We're all born with a pulse, systolic and diastolic, and those pulsatilities create a situation that protect us from several things. One of the things, apparently, is probably GI bleeding. As you can see here, patients that were supported by mechanical circulatory device and maintained pulsatility-- the dark line-- did not have a lot of GI bleeding. However, patients that would help them with the mechanical circulatory support and they lost their pulsatility, their GI bleeding rate was tremendously higher. So what is really happen? We have decreased pulsatility. We have narrow pulse pressure that creates situation of decreasing triluminal pressure, dilatation of the mucosal vein, and eventually, a formation for LV malformation. So together, we have acquired Von Willebrand disease and the pulsatility and the medication that we give to those pumps, those patients may bleed. So again, not everything is pink and perfect with mechanical circulatory support. Let me share with you another thing-- aortic insufficiency. Now we have a pump that is suctioning the blood from a different orifice of the left ventricle, not through the left ventricle or [INAUDIBLE] track for the inflow cannula. They other door, the aortic valve is going to remain closed. Because of that, it's going to be rusty and may actually not also open very well and not close very well. So when we have aortic stenosis we don't care, because those pumps will-- the blood will go out from the inflow cannula. However, if we are going to have aortic regurgitation, the blood is going to go back to the ventricle. So let's see. What we found out here, that 25% of the patients will develop some degree of aortic insufficiency after mechanical circulatory support. 8% of them will have a significant. And as I mentioned before, this may be also clinically relevant, because now the pump is suction the blood from the left ventricle to the pump and it's going to the ascending aorta. But the blood is going to go back to the ventricle instead of going to the rest of the body. And why is that? Again, maybe a little bit because of pulsatility. When we notice that those phenomenons is happened mostly in patients that the aortic valve is closed, meaning that they don't have a pulse, as you can see the blue line. However, if we succeeding maintaining some activity of the aortic valve despite the mechanical circulatory support, those patients developed much less aortic insufficiency. And this is probably the reason the aortic commisures are fused. And they fuse because we don't use this pump. So if we summarize this, there is a continuous slow LVAD speed, increase pressure in the aorta, decrease pressure in the LV, and close the aortic valve. Because the aortic valve is closed, those cusps are going to fuse, deteriorate, and develop aortic insufficiency. And this may clinically progress. So again, another problem that we may encounter with mechanical circulatory support. But let's face it-- the main fear that we are fearing when we put mechanical circulatory support is the presence of device thrombosis. Those pumps can clot. We have now metal and we have blood. Sometimes they don't go well together. As you can see here, the development of the clot can be partial or completely clotting those parts. We have a motor that is rotating a speed of 10,000 revolutions per minute, create some heat that can denaturate some of the protein that exists in the blood, and we can find this this fibrin plaque, that eventually blood clot is going to sit on it and can clot it. This phenomenon can happen in eight to 10% of the patients, and we need to react to it, diagnose it, and replace it. However, I show you the good. I show you the bad. But I want, again, to go back to the present. In the present, then, despite all the bad-- and of course, thanks to the good-- the survival rate of patients that's supported in mechanical circulatory support is 65% in destination nation therapy patients. And actually, in center effects events, we can reach 70 or 75% of those patients. Is this the future, or do we have better things that we can encounter? So there are other pumps that are coming on the pump line that are smaller and sit inside the heart, as you can see here by the [INAUDIBLE]. That's one of his mega advantage, that instead of the driver and the [INAUDIBLE] that's coming out of the belly, the driver will come out behind the ear, in a posterior auricular place. So those patients, actually, it even doesn't have anything on the belly that will disturbs them, and it's much less driver and an infection that's related to the data drive line. So there is going to be the HeartMate III that's supposed to come line now, and it has a little bit bigger gap, and maybe prevent the acquired Von Willebrand disease that we just spoke. And there is going to be the NVAD that is so small that the surgical procedure, actually, is going to be minimized-- not as small as the CircuLite, but definitely everything is going smaller and smaller and smaller, and maybe the patient can go home. But we didn't answer one thing that I had started with. Do we really need pulsatility? We were born with a pulse, and probably there is a reason for that. And now we challenge a little bit, and we stop the pulse. So let's look at every physiology book, and what we can definitely see that there is a big pulsatility in the left ventricle and in the aorta and a the big artery. However, in the capillary level, we don't have some pulsatility. So what I want to finish with you, and tell you a story about one of our patients. She was a very young lady-- 27 years old, I think, when she came to us-- and she had advanced heart failure due to postpartum cardiomyopathy. However, she did not have the set of skills in order to be ready for heart transplantation, and she also was too sick to be transplanted at that time point. We decided, together with the patient, to put mechanical circulatory support into this patient. And she was slowly, slowly, get to understand that she need to grow up on her care and learn how to do it. However, a little bit more than a ear after mechanical circulatory support was implanted in her body, the patient came to the clinic and say, I'm pregnant. All of us were extremely, extremely, extremely surprised. First of all, we didn't know that patient with those devices are sex. Second, we didn't know that you can get pregnant on those devices. And then we start thinking. What can happen to this baby? We don't have pulsatility. There is acquired Von Willebrand disease, and she's taking all those kind of medications. This baby cannot be healthy. We don't know if, actually, organogenesis is going to be normal without a pulse. And we explain everything to the lady. However, she said, I want to have this baby. And mothers are mothers and are going to have this baby. And nine months later, as you can see here, should delivered a baby, a healthy baby, in a vaginal delivery. We need to adjust our pump, because it's not like the human body that can adjust to the changing, and we increase every visit that she came the speed in order to address the extra cardiac output that pregnancy require. | definitely this lady show us that you can get pregnant and have a full, healthy, pregnancy on mechanical circulatory support without a pulse. So I want to mention two other things. When do we do it? Who are the patients that we are looking in order to say, they need mechanical circulatory support? We want to see the patients that have heart failure and already have a problem of [INAUDIBLE] one block or even less, and develop dyspnea. We want to see the patients that, due to the heart failure medication, have hyponatremia, with a sodium level below 136. We want to see the patients that, of course, have some renal insufficiency, with increased BUN, about 40. And we want to see the patients that because of their heart failure and because of the low blood pressure, we need to start cutting back their medication. So even though we know that we need to give them ACE inhibitors and beta blockers, we start to cut the level of medication because the blood pressure cannot tolerate it. We want to see the patients that we give them a lot of diuretic, more than 1.5 milligram per kilogram per day. And definitely the patients that were admitted to the hospital in the last six months due to congestive heart failure. Those patients we will evaluate, and we will consider, is there a patient that needs advanced heart failure therapy? If mentioned, transplant or LVAD. But is this really the future? Is this where medical is going to be-- half robot, half human being? I'm not so sure. I know that we need time to let the stem cell therapy materialize and became something real. We need time that gene therapy will be a real option, and we are moving forward very fast with that as well. And we need time for metabolic alteration. However, until then, mechanical circulatory support and heart transplantation is a very good option to end stage heart failure, where the end, actually, may not be the end. Thank you very much.