OK, I was instructed to start at two after, and I follow the rules. So welcome, everybody to Medical Grand Rounds. And the Medical Grand Rounds is the Grollman lecture. And Dr. Bill O'Neill is our Grollman lecture for this talk, and he's going to give a fascinating one. Bill gave a cardiology grand rounds last night, and was a guest at our dinner, so I've actually-- I was an interventional cardiology fellow with Bill a few years ago, and I've introduced him now twice in a day. So I won't do his introduction, but I will introduce Dr. Grollman. 

Dr. Jaye Grollman received his medical degree from the University of Maryland, and his training in obstetrics and gynecology at Baltimore City Hospital and the University of Nebraska. He then undertook basic endocrinology research in collaboration with his brother, Dr. Arthur Grollman at Johns Hopkins. 

He subsequently started a private OB/GYN practice in Washington D.C., where he was on staff at the Washington Hospital Center. 45 years later, he retired to a second career in farming in Gordonsville, Virginia. Marjorie Grollman received her bachelor's science degree from the University of Maryland in 1941. She then underwent dietetic training at the University of Maryland, after which she served as a nutritionist at the Union Memorial Hospital in Baltimore. 

To the best of anybody's knowledge, there are no Grollman family members in the area or around. But again, we're very grateful for this lasting gift for the education. 

Thank you, Dr. Annex. It's a great honor to have Dr. William O'Neill here with us today as our annual Grollman speaker. Just to give you all a little bit of background, Dr. O'Neill grew up in Michigan and began his cardiology training there, before kind of going on to become the director of their cardiac cath lab. 

He then moved on over to William Beaumont Hospital as Director of the Division of Cardiovascular Disease. And then from there, corporate chief of cardiology. After that, his career took him down to Miami, in the University of Miami where he served as the Chief Medical Officer, as well as Executive Dean for Clinical Affairs. And then in 2012, he came back to the Midwest, and has since been serving as the Medical Director of the Center for Structural Heart Disease at Henry Ford Hospital. 

Now, throughout his career, Dr. O'Neill has been an international pioneer in the field, pushing forward innovation through his research, his clinical efforts, as well as his leadership. And among his many achievements, which are far, far too long to list in the limited time I have for this introduction, he's pioneered the use of angioplasty, he completed the first TAVR and the first cardiac stem cell injection in the United States and has recently led local and national efforts to apply protocols using mechanical circulatory support for patients in cardiogenic shock. 

For his contributions to the field, he's been honored with multiple awards, including the Transcatheter Cardiovascular Therapeutics Lifetime Achievement Award, as well as the Seymour Gordon Award for Distinguished Achievement from the American Heart Association. So with that background, we're again very, very honored and very fortunate to have Dr. O'Neill here to speak with us. So without further ado, if you could join me in welcoming to the podium. 

[APPLAUSE] 

Thank you, [INAUDIBLE]. Should I put this on? 

If you want to use that one or that one, whichever is more convenient for you. 

I'll just use that one. It's fine. Thank you. OK, great. 

Well, thanks very much, [INAUDIBLE], and thank you, Brian. It is a pleasure and an honor to be down here today. It's been a thoroughly enjoyable two-day trip, and I just can't thank you enough for inviting me here. I had the pleasure of being a host yesterday to go for a tour of Monticello, which is absolutely unbelievable. And has to be one of my highlights. 

When I was in fifth grade, I had a passion for history. And I just absolutely fell in love with it. I don't know why, but in seventh grade I was thinking, well, I wonder how can I use this? And at that time I didn't know that actually you could be a historian. So I just said, well, I have to go get a job. So my dad insisted that we had a profession either doctor or lawyer. So anyways, so that fell apart. But I've always had this love of history. 

And so I want to kind pg give you this historical tour, and try to sort of weave in a little bit of stuff about politics, which I think you'll find quite fascinating. So without ado, and the only disclosures that are relevant is that I am a consultant to Abviomed. But none of this other really is relevant to this discussion. 

So let's go back to World War II, OK, if we're going to have a historical tour. 1945, if a patient came into hospital, there were no coronary care units. So if a patient came in to a hospital in the United States, the treatment for myocardial infarction was nitroglycerin, which had formerly helped the patient was generally useless. Large doses of morphine should be given subcutaneously, and then in a number of circumstances, no other medication was necessary, because there really wasn't any other medication. It was basically morphine and bed rest. 

Now, I can tell you when I was your age as a house staff at the University of Michigan in 1980, this is exactly the same therapy. So between 1945 and 1980, nothing changed. And to see these patients-- young people in their 45s and 50-- they would come into the hospital, writhing chest pain, admitted to the coronary care unit, and then you would watch them sort of wither. And many of them, there was nothing you could do. They would die. 

And so it was it was really incredibly frustrating to be practicing at that time. Our level of ignorance of atherosclerosis, and of actually the inciting events of acute myocardial infarction were absolutely abysmal. And so going there to now has been just an absolute amazing saga of discovery. 

So 1949, this is Eisenhower-- Dwight Eisenhower-- he was vacationing in Key West. And you can see-- I don't have very good eyes, but right here in his hands he's got a cigarette. He was a very heavy smoker. And he had-- and he was admitted in 1952 to a hospital in Key West with sort of the epigastric discomfort. And probably that was the first infarct. It's really hard to know, the medical records are sort of buried. But retrospectively, he probably had an event in 1952. 

Then in September of 1955, while vacationing in Denver, he started having severe pain. He went home, he thought he was having a-- he had a Bermuda onion on his hamburger, he started having some bowel problems. And so he went home went to bed. He actually, at that time was staying with his mother-in-law. They didn't have any sort of tight security or anything. His mother-in-law lived in a suburb of Denver, and he was upstairs on the second floor. 

And so the hospital, his physician-- his private physician was called to see him about midnight that night, and he was having severe unremitting pain. And the doctor, in the notes that were written said that for about 15 minutes he lost his pulse. So basically retrospectively, he was having an acute infarction with cartogenic shock. right? No one really recognized it at the time, but at that time, cartogenic shock had a 90% mortality. So he was one of the fortunate 10% that survived this. 

But I wonder if you could tell me who the Vice President was in September of 1955. Who was the Vice President of the United States? Richard Nixon. OK? So if he had died that night, Richard Nixon would have become the President of the United States in September of 1955. No doubt he would have been reelected in 1956, and the trajectory of the course of American and world history would have been entirely different. 

Who knows if the Bay of Pigs would have happened? Who knows if the Vietnam War would have happened? Who knows if the actual hot war with Russia would have happened? So the course of history would have been entirely different based on what happened to this particular individual in September of 1955. Anyway, he survived. 

It's interesting. He had chest pain the next day, sort of revive. They thought that he was having a heart attack. They called Fitzsimmons Army Hospital and had them transport this massive EKG machine which took four Army corpsman to take upstairs to the second floor of the bedroom, and they didn't EKG. And lo and behold, he was having an angi infarction. 

Eisenhower was kind of worried about appearances, because by then there's all sorts of press around outside. So during the face of this infarct, he walked downstairs and walked himself into the ambulance. Now that was really kind of considered heresy, because remember, the treatment for acute infarct at that time was bed rest and nitroglycerin. 

And so they in fact, did that. And he was in the hospital for 12 weeks. And at that time, there was no 25th Amendment. Remember, the 25th Amendment happened after Kennedy. So he was hospitalized for 12 weeks, and basically he ran the US out of a hospital bed at Fitzsmmons Army Hospital in Denver. 

He was discharged, went home. Paul Dudley White was the famous cardiologist at the time. Advised him to retire because he thought he wasn't going to survive. And the guy, against doctor's advice, continued to sort of rehabilitate. Went on to kind of be re-elected in 1956 and then sort of served his term. So this is 1956. 

And interesting, right around the same time-- it's fascinating how things happened-- in 1959, there was a doctor at the University of Miami that was actually exploring this new approach. They thought that people had coronary thrombosis. That's what it was called when Eisenhower had his coronary. They called it coronary thrombosis, because they thought clots were causing occlusion. And so this Dr. [INAUDIBLE] at the University of Miami and Jackson Memorial Hospital was doing arterial cut downs in the coronary arteries, and putting a catheter at the osteum of the coronaries, and then infusing this new drug which had just been developed in 1955 called fibrinolysin, which is the first thrombolytic. 

And they thought that they could actually demonstrate that there was value to this. This is an EKG, and you can see that he's got-- this particular patient had ST segment elevation in the inferior leads, and then an hour later, electrocardiogram had resolved. So I think this is actually the very first scientific proof of the efficacy of thrombolytic therapy in 1960. 

The fellow that was working at the time was Dr. Paduckas. I actually got to talk with him and interview him. And it was really fascinating. He's the one that showed me this article, because nobody ever paid any attention to it. And so he said-- I said, well, this looks fantastic. Why the hell didn't you guys continue it? 

And he said that when they published this paper in the American Journal of Cardiology, the critique from the scientific community was so profound-- he was like ridiculed at doing something so drastic. How could you possibly do a heart cath in someone that's having a heart attack? And you don't even know whether or not it works or not. And so he said he just got discouraged and stopped doing the research. And then all of the research on thrombolytic therapy actually went to Europe, and it continued through the '70s. 

So this is what happened to Eisenhower. This is 10 years later. Now remember, in the '50s, from the onset of an acute manifestation of coronary disease the average life expectancy was 10 years. So from the first event to death is 10 years. This is Eisenhower in 1964. He was hospitalized at Walter Reed Hospital with an illness called status angiosis. And what is that? That's severe unremitting cardiac pain for which there is no cure and there's no treatment. 

And he was defibrillated like 20 times, had multiple cardiac arrests, kept coming around. In 1962, Christian Bernard did the first heart transplant in South America. And there was a thought about doing a heart transplant for Eisenhower. Nine Americans volunteered to be donors for Eisenhower. Think about that for a second, OK? So that's kind of like the love and affection that this guy kept. Could you imagine anybody in America now wanting to donate their hearts to our politicians? 

So anyway, he died. And at autopsy, he was found to have a complete total occlusion of his LAD with three previous infarcts. And then in the circumflex artery, he had a very tight focal stenosis of a mid-circumflex artery, which today our fellows would treat with a stent in five seconds. So that kind of tells you the trajectory of what's happened to the natural history and the therapy of acute infarction, because had President Eisenhower come into this hospital yesterday with an anterior infarction, he would have been treated immediately with emergency angioplasty, and the trajectory of his entire life would have been entirely different, because he died 10 years after he had his massive infarct. 

And you can see that with presidential politics, because this is Bill Clinton. And Bill Clinton had his first coronary event around 2001. And he is alive, and vital, and running around as far as we can see. I think, actually if you see him, he's become a vegan. He was a good old boy at the time with this coronary event happened. But he's actually sort of turned his life around. 

And I now routinely see patients 25, 30, 40 years out from the first coronary event. So it's really just absolutely amazing how the trajectory of the life of the patients in the United States has really changed by this course of therapy that we've given them. There's actually been about a 10-point increase in life expectancy. In 1973, the onset of death in patients was sort of in the mid-50s. Now between 1973 and 1988, life expectancy actually increased by 10 years. 

And if you can take a look at the life expectancy, it's all related to changes in acute cardiovascular mortality. There's been absolutely no difference in cancer-related deaths and no difference in stroke-related deaths. But there's been a dramatic decline in cardiovascular mortality driven by a decrease in mortality from acute infarction, and that's really had enormous, positive societal benefits. 

So how did how did this journey start? This is a patient when I was a first-year cardiology fellow at the University of Michigan in 1980. I happened to be the doctor that was in the coronary care unit. I was a CCU fellow. And we just started a protocol for using intracoronary streptokinase. 

And they called me to the ER, it was an Arabic guy that was in his late '30s-- 39. And he had an acute infarct. He arrested in the ER, so they defibrillated him. That's why everybody came running down. His STs were elevated. We talked to his family, got them to sign consents. Took him to the cath lab, and in the cath lab we did a brachial cut down, because we're doing Sones procedures at the time, put a cath in his right coronary, and then started infusing streptokinase. It was the very first time we'd seen it. 

And he was ashen and gray, having sort of substernal pain, doaphoresis. About 30 minutes into the infusion, and he started to look better. He felt better. He said, Doc, I'm feeling better. My chest pain's better. And we shot a coronary angiogram, and we saw that now dye was going forward in his coronary artery. 

And this is the very first patient I'd ever seen with reperfusion therapy. As a first-year fellow, it's like the old Jerry Maguire saying, "You had me at hello." Well, he had me a patient 001. It was just absolutely-- and I walked out of that room and I said, holy crap. This is going to totally change medicine, and totally change-- because I've been dealing with these infarcts for a long time and watching these people dye, and we finally had hope. 

And so we did the first placebo-controlled randomized trial. Now, we cycle forward probably 30 years later. This is a patient that presented to the University of Miami Hospital with an acute anterior infarct. Fascinating. My son was the first-year cardiology fellow that saw this patient and bragged about him to the cath lab. Said it was like one of the coolest things I've ever done in my life is to do an emergency angioplasty with my son as the fellow and me as the attending, in a patient with an acute infarction that was identical to the patient that I saw a generation before. 

Anyway, so the artery was occluded. And I put a stent in, reperfused, had a little brady arrhythmia, electrocardiogram completely resolved. And so now we treat these patients. Actually, they get admitted to the stepped down unit. They don't go to the coronary care unit anymore. They basically get admitted and discharged within three days. So from point A to point B, there's been a dramatic change. And it's been amazing to sort of see how this all developed. 

First of all, understanding the disease. When Eisenhower had his event they called it coronary thrombosis. In the mid '70s there were studies, pathologic studies said that only about 50% of the patients that acute infarction actually had a clot. And so in the '70s there was actually a controversy about what actually caused it. Was it a clot that closed the coronary, or was that sort of a past phenomenon? And now we know that there's vulnerable plaque, the plaque rupture with deposition of cholesterol plaque and thrombin formation. 

And we've developed all of these therapies. Very, very powerful antiplatelets in 1980. We had no clue that aspirin had anything to do with acute infarction. It was actually given as an adjunct to streptokinase. But no one knew if you needed to do an intervention, whether or not you need any form of antiplatelet therapy. Now we have all sorts of antiplatelet therapies. We have oral-- they're dramatically effective antiplated agents. 

Thrombotic therapy. So again in 1980, we thought that we had to anticoagulate the patients, but we didn't know for how long. So we gave them heparin during the procedures, but then stopped it afterwards. Now we've got a variety of agents, primarily [INAUDIBLE] and heparin, a thrombolytic therapy-- that's also an interesting sort of side story that I'll tell you about-- and then balloon angioplasty with stenting. 

So this has been-- but each one of these have required multiple studies. And I have to tell you that acute myocardial infarction STEMI is probably one of the best studied diseases that we have in America, and the entire world. Number one, because there's a large number of these patients. Number two, because it's a very easy diagnosis to make with electrocardiogram. Number three, because it's a life-threatening illness. So there's probably been over a quarter of a million patients that have been in randomized trials on this particular disease throughout the world in the last 40 years. So it's an incredibly well-studied, well-defined entity. 

I started doing this before that first patient with streptokinase. I was a resident, and my friend, Richard Stack who was at Duke, and I did some studies with non-invasive evaluations of myocardial performance. And we found that people that survived infarcts, if they had poor ventricular function had a markedly worse prognosis over five years. 

And so the thought was that, well, if you can reperfuse the patient-- 

You can keep going. I'm just going to turn this on because some people are having trouble hearing you in the back. 

Oh, OK. Great, great. Sure. I'm sorry. I just [INAUDIBLE]. 

There you go. Try that right there. 

Sorry. 

I tend to mumble, so I'll try to be better. Anyway, if you could reperfuse the patient, you would improve ventricular function, and that was what the original streptokinase trials were about. Can we make ventricular function better? This is Dr. Bert Pitt, who was my mentor. And amazing to allow me to do some of the really kind of ridiculous stuff that we were doing in a university environment, which is always very risk adverse. So I really always want to thank and honor him for allowing me to do this. 

You can see that what's happened with the historical view is that before reperfusion therapy, patients coming in with STEMI had a 13% mortality. In the recent modern era trials, routinely were getting mortalities of under 2% with acute STEMI care. And I think that this is really dramatically demonstrated the efficacy of this procedure. 

The first study that we did was a randomized trial published in the New England Journal in 1983. Imagine having now randomized trial of 39 patients published in the New England Journal. But it was also it was also fascinating because the way we did it, we took the patients to the cath lab, and then if the artery was occluded, we had an envelope, and it would either say D5 or SK. 

And we knew what the patients were getting. And so I was the one that were consenting the patients and following. I remember a young guy that had the therapy, and he had a glucose. And so the next day I went to see him and follow-up. And I said, did you want to know what you got? And he said, I knew I got glucose. I mean, I knew I got water because I could see it in your eyes. So doing these single blind things are just really, really incredibly difficult. 

But this is a negative trial. There was no change in ejection fraction between placebo and control. And so again, this is sort of in the area where everybody was so hyped for reperfusion with streptokinase. And we sort of threw a cold blanket over it because we said that reperfusion therapy really didn't work to open up-- to improve myocardial function. 

Now, we didn't have a very good way of assessing ventricular function. I think you guys would laugh right now if you said that I was using a contrast ventriculargram to measure infarct size. I mean, now we've got all these incredibly fancy MRI techniques, and we're doing much more sophisticated ways of assessing it. So it didn't work, but it did improve survival. 

And at the same time that these trials are going on, this gentleman, Dr. Andreas Gruentzig was doing some pioneering work with angioplasty. Again, two entirely different fields of endeavor. Streptokinase opening up a coronary artery with the pharmacology. And Andreas Gruentzig opening up coronary arteries with balloon angioplasty. 

This was the first patient that he treated in 1977. A focal lesion of aproximal LAD, which he treated with a balloon, and then he opened up the vessel. This patient actually had a 30-year angiogram as part of one of the courses. So he's been alive forever. But Gruentzig felt that this was a very good therapy, but the equipment was very primitive and he didn't think that you should use it in high-risk patients. 

So initially he was completely opposed to using angioplasty for treatment of acute myocardial infarction. He thought it was too dangerous, it was too risky. And this cowboy in Kansas City by the name of Geoffrey Hartzler, in a community practice actually started doing angioplasty. And again, really considered complete heresy. And I can tell you that all the universities, the Harvard's, and Stanford's, and all those of the world were completely aghast that anybody was doing anything that radical and that stupid. 

Now, what Hartzler did is he looked at patients consecutive, and he found that he was actually having a significant improvement in ejection fraction in the patients that he was treating with primary angioplasty. And I saw this article in November of 1982. I'd already been doing the streptokinase stuff. I would really discourage we weren't seeing improvements in ejection fraction. And so I said, all right, well maybe angioplasty does work. 

And I went and spent time with Hartzler, and then I brought the protocol. And then in December of 1983, we had a patient that was transferred from a community hospital nearby. He'd had a cath in the morning, and then about an hour later he started having chest pain and ST segment elevation in the anterior leads. The cath and the visualization that we had at that time was just absolutely horrible. 

It wasn't any of these high-risk image reviews and still frames, and all of that. We had these projectors where films were developed. They're actually films. But the fluoro imaging was so terrible that often we had to stop, have the people develop the films and then look at them to see what was going on. So this patient had an occlusion. Again, it was really difficult to figure out where it was, but then we found that his LAD was occluded in this portion of the vessel. 

We put a balloon across, and then we opened up the artery, and you could reestablish antegrade flow. So this looked very effective. And we did a number of patients-- 200 patients-- with primary angioplasty in sort of a non-randomized way. And so the problem with that is that at the University of Michigan, there weren't very many infarcts that were coming in. Most of the patients were kind of being sent in from the community hospital. 

And this is in 1985. At that same time, streptokinase-- IV streptokinase-- therapy became available. So there was a real interest in people saying, well, look, if I can take a drug in a needle and give it in a small hospital, why shouldn't I just treat these patients locally? And so we thought, well, maybe that's a good idea. Let's marry the two. Let's put angioplasty and thrombolytic therapy together. 

They get thrombolytic therapy in the local hospital, they get transported. If the arteries open, great. If the arteries close, you can open them. And so Eric Topol joined me at that time, and we conducted-- so this is the first study that we did before the Tammy trials. We did this randomized trial. And this is randomized angioplasty versus thrombolytic therapy. 

was actually the first study published in the New England Journal in 1986. And it really demonstrated that angioplasty was better than streptokinase therapy. But we hadn't proven whether or not it was better than IV thrombolytic therapy, because again, streptokinase intracoronary you to take to the cath lab, and there was a long delay. 

And so we decided to look at the TAMI trial. This is a study that Eric Topol, Richard Stack and Rob Califf and I organized. And that was actually the foundation of the TAMI trial which ultimately ended up becoming the DCRI. So we took patients to the cath lab. If the artery was open, if the already was failed, and so a quarter of the patients had rescue angioplasty. But half of the patients the artery was open, and we did immediate angioplasty versus deferring. 

And when I first started doing this, again, the thing that's really important is that I think that you have to be an active participant in these trials, because if you're not actually watching what's happening with this therapy, you don't have sort of an immediate gut feel for what's going on. I had a patient that was treated with TPA. We took him to the cath lab, the artery was closed. I open it, perfect, brisk flow. And then as we're watching it, the artery starts clotting up again. And we're kind of, what the hell? I've never seen this before. 

I've been doing angioplasty for two years, I never see acute reocclusion like that. There have been dissections. But so something odd was going on and we couldn't figure it out. But anyway, this was a study that was done, TAMI trial. And it was bitterly disappointing to me because it was a negative trial. It's actually showed that angioplasty in combination with TPA was harmful. And but it was truth. 

So what we're doing in medicine is we're trying to find the truth. And what I tell the Fellows is, I don't really care what you show in your study, but just give me a clean answer. It might not be the answer that you want, but it's a clean answer. Because if it's a clean answer, then it will be replicated. And if it's not, then it's going to be ignored. So you have to be careful about trying to please your superiors, or to come up with what's called a positive trial. 

Because you don't want a positive trial, you want a clean, definitive trial. Where you've asked the scientific question and you answered it in a truthful way. And if you do that, then your data will be replicated. 

So this is what happened. There were three trials. We did the TAMI trial, the TIMI group, this trial, the European group. And they all found the same thing, that if you did immediate angioplasty there was worse outcome with the combined mortality that was higher. So this is now 1989. And if you see what our academic colleagues were talking about, we were considered knuckle-dragging gorillas that were doing these unnecessary procedures for a profit. OK, that's kind of how it was painted at the big national meetings. And honestly, this is all funded by incredibly well-funded thombolytic trials that sort of made the DCRI and Harvard like sort of start their wonderful runs. 

But I still had a feeling that we hadn't really gotten the answer right. I saw the data, and I was convinced that that combo was ineffective. But what we looked at when we actually started looking at getting blood flow to the heart, if we looked at all the thrombolytic trials, the best that thrombolytic therapy could do is about a 70% opening in the coronary arteries. And we did like three studies where we were opening up many more arteries with angioplasty than we were with thrombolytic therapy. So this really didn't make sense to me. 

I couldn't understand why, if it was so good at opening up arteries, when we've combined them that it was so harmful. And so what I saw was a very small study that was done by Bruce Waller, who was a pathologist in Indianapolis. And he autopsied a number of patients that had a combination of thrombolytic therapy and angioplasty. And what he found was that when angioplasty is done on the face of thrombolytic therapy, there's this massive intraplaque hemorrhage that happens that actually causes a reocclusion. 

And so what I'd been seeing was that the artery-- that the plaque was getting ruptured, and then hemorrhaged inside the plaque and the artery was closing. We didn't have stents at the time, and so the army would reocclude. And that's really what caused that to be a mess. 

And so with Bruce Brody and at Moses Cone Hospital, we did a another trial. By this time I realized that if I wanted to do heart attack research, I couldn't do it at a university where they weren't getting acute infarcts. And that was really the main reason that I moved from the University of Michigan to William Beaumont Hospital, which is a very large community hospital with a large population of patients that were coming into their ERs with acute infarction. 

And we did this study combining angioplasty and streptokinase versus angioplasty alone. And we found that when you combine the two, it was very harmful. The rate of a bypass-- 10% rate of bypass. Almost a 40% rate of blood transfusions. And there was no real effort, no benefit in giving these patients in terms of better preservation of ventricular function. 

So finally, the mystery was solved. It's like, OK, why is this true? And then we finally decided to do angioplasty alone versus thrombolytic therapy. And that was all-out war. I have to tell you that it was absolute war, because people-- if you think Republicans and Democrats are at war, you should have seen the thrombolytics versus the angioplasters circa 1995. 

But the way to settle it is to do trials. And so this is the first trial that we did. We organized it in Michigan and people around the country. Dr. Greg Stone, who many of you know, was a junior attending an El Camino Hospital outside of San Francisco. And he wanted to be in the trial. He got involved, and that was the first randomized trial of acute infarction that he was involved with. 

And so we randomized. And we found when we did angioplasty alone versus TPA, that the rate of combined-- this is the combined endpoint-- excuse me, the re-infarction was different. The combined endpoint of 5% for angioplasty and 12% for thrombolytic therapy. And if you take a look at the 26 trials that subsequently were done to this, they all kind of showed an identical sort of number. 

And people did not believe our trial. There were two other trials published in the same issue of The New England Journal-- one from Belgium and one from the Mayo Clinic. And we showed exactly the same results. But people still didn't believe it. And it took more than a decade-- from 1995 to 2005-- with 27 randomized trials of angioplasty versus thrombolytic therapy before people finally concluded that that was the truth. 

So I think it's very difficult to change people's firm beliefs. There's a lot of emotionalism involved with this, and honestly, I think the best way to answer this is to try to do these well-conducted randomized trials. Then Ellen Keeley, who was from this institution, published which I think is probably the most important and most read data published in The Lancet on a meta analysis of all the trials. And they found that this combined endpoint was death of re-infarction was substantially reduced. 

Don't comment about the other major advantage with angioplasty was a dramatic reduction in stroke. So I did my ACLS training last weekend. And I was doing my ACLS training, and then we were going through this stuff, and then I heard them say, well, if you come in with a STEMI, you should have primary angioplasty. I thought, oh, my God, I finally made it. We finally made it to the ACLS course. So I think it's finally been validated. 

But it was really interesting to sort of, in the middle of this war, to really figure out how much emotionalism was involved. Brian remembers it, and how finding the scientific truth. So I feel very validated because we did find the scientific truth. We found that death of re-infarction was substantially reduced. And then when we combine all these trials of death and re-infarction are substantially reduced. So it really is a demonstration that it was very, very effective therapy. 

So we now are getting routine mortalities of 1% with acute infarction with primary angioplasty. So there's going to be very little that's going to be done to further limit mortality. There are some things, structurally, that I think can be done in terms of well-established ambulance programs and getting STEMI centers where the ambulance bring patients to the STEMI centers. I think those kind of things are going to further help decline. But I think that this disease now has become a very predictable one with a very, very good outcome for the large majority of patients. 

Let me just go forward then. So we've kept the patients alive. But conversely, we may actually be increasing the numbers of congestive heart failure patients that are alive. So what will happen is that you bring the patient in, you open up his LAD, you keep him alive, but he goes home with an injection fraction of 30% 35%. And then over time, he's going to have global remodeling. 

And so there's a prediction that there's actually going to be many, many more heart failure admissions because we're creating the substrate for patients that have going home with poor ventricular function. So the next line of approach is going to be to take a look at systems to try to further decrease infarct size. I'll tell you about three specific strategies that may have promise. 

This is a novel device that's called super-saturated oxygen. What happens is the blood is taken from the artery, it gets put into this hyperbaric chamber, and then oxygenated blood with the [INAUDIBLE] 700 is put back into the coronary arteries. In patients that have anterior infarcts, there is a significant decrease in infarct size. This now has become FDA-approved about a month ago. And so people probably are going to be looking at doing this in infusing patients with anterior infarction with 60 minutes of super-saturated oxygen. 

So I sort of say that to you because it's now FDA approved. You guys will be having some discussions about whether or not to use it or not. And I think it is certainly very promising. 

The other area that hasn't yet been completely studied, but of all the stuff I think I have more hope for this than practically anything else, which is endovascular cooling. We did a study with cooling catheters and with animals. I mean, it's a dramatic reduction of infarct size. And these are patients-- and unfortunately it doesn't really show very well, but in patients that get cooled, there's a dramatic reduction of MRI infarct size if you can get them cooled appropriately. 

There were two studies that were done that were sort of moderate-sized. And what we found was in patients that had anterior infarcts where the target temperature was cooled, there was a substantial reduction in infarct size. And when all of these studies are meta analyzed, if you can get the target temperature down to less than 35, there is a substantial reduction of infarct size. 

The problem has been that the doctors haven't been wanting to wait. The catheters that were used before took about 35 minutes to cool down to target. We now have a new [INAUDIBLE]. That [INAUDIBLE] has a new catheter that will cool temperature down in nine minutes. So there is now going to be a national-- they're just sort of negotiating with the FDA right now to do a national trial. But that's going to be coming out. And I'm looking forward a lot to that, because I think of all the stuff physiologically and practically, this may be the one that has the most promise for further decreasing infarct size. 

And then finally, another area that I'm involved with Naveen Kapoor is looking at unloading, meaning putting in an impeller catheter in patients to try to unload the ventricle and decrease infarct size. Again, if you unload-- this is in an animal model-- this is what an infarct looks like after three hours. And then if the animal is unloaded and the arteries open and reperfuse, their infarct size is significantly reduced. 

So there is some fairly good animal models. There actually has been a pilot study that we finished and we can be presented at the American Heart last fall, looking at patients that again, if you think about the hysteria about waiting for half an hour, I think again-- so it sounds like incredibly radical. OK, you're going to take the patient to the cath lab, the LAD is occluded, and you're going to have an impeller in, and then you're going to wait for half an hour before you open the artery. So you trust me, it's been a little bit of a difficult, daunting challenge to kind of convince the investigators to do it. 

So we did a pilot. Before we did anything else, we did a pilot. And these are the patients that had 30 minutes of opening, and none of them crossed over to immediate therapy, meaning that the doctors felt comfortable enough that the patients were doing well, and anecdotally, there was a number of patients where the ST segments came down while they were being unloaded. And so there is a possibility that this is going to work. 

There was a significant reduction in microvascular obstruction, which is a way of telling whether or not there's flow into the myocardium. And in the patients that were treated, very interesting observation that the larger the infarct is by electrocardiogram ST segment elevation-- and this is now human data from the pilot-- that there's actually sort of a flat infarct size, whereas the larger he ST elevation infarct is on an electrocardiogram in the usual care group, the larger the MI. So this is the hope that in these large infarcts they will show a substantial decrease in infarct size. 

And there's enough pilot data to demonstrate that we can do a randomized trial. So now there's going to be a very large national randomized trial that the FDA has approved. We'll be starting that trial sometime in November. So I think that's kind of like where the chain is going with all of this. And this is the door to unload a pivotal trial. 

So I want to conclude that probably what we can do, if you're saying, how are we going to really get these patients treated? Ideally, doing things at home, process things where the patients are identified early, taken to the cath early, and getting the vessel early, of all the stuff that we can do to really dramatically impact the life, and survival and ventricular function, doing these things which are process issues, which some people find boring, but in this setting are incredibly important. Getting the artery open-- we can do that very well. 

There is a lot of interest about distal embolization. That does not turn out to be as much of a problem for us as it does for the neurologist. And then metabolic support and microcirculatory protection. So I think this is kind of where we are in the phase of investigation. 

The hope, the dream would be that when a patient comes into STEMI in any STEMI capable hospital in America, that the patients are reperfused, that they leave the cath lab 99% of the time with a patent vessel with TIMI-3 flow. And hopefully with a chance that before they go home, they're going to have relative well-preserved ventricular function. 

So that's kind of like the dream. It's been an amazing sort of journey. But I think the main thing for you young people is that I think you have to, first of all, be open minded. Don't be closed minded about a hypothesis. How crazy it is, think about it, it's possible. Make sure that it's correct and ethical to do a trial, and then look at the science, because I think the science will guide us. 

So I think that that's the wonderful thing about academic medicine is while you all are here, you're looking for the truth-- the scientific truth-- whatever field you're in. And if you're lucky enough to find the truth, it will be replicated time and again. Thanks very much. 

[APPLAUSE] 

Questions? Brian? 

Bill, thank you again. It is a very good lesson. Sometimes you've got to have enough ability to ask the questions to know which direction you're going. I actually find it very interesting, the last part of this. The whole field about people with positive stress tests and no epicardio coronary disease, who have some form of microvascular disease. And now the recognition that the prognosis for those patients is every bit as bad [INAUDIBLE]. 

In some ways, these may be even better environment if you test that, than those microcirculation questions that are being done in other labs. So to what extent do you think the field would be open to trying to merge those? Because you could get pretty good data on microvascular function and particularly in [INAUDIBLE]. 

Yeah, I think that the ways of measuring stuff often sort of tell you what the knowledge. So in 1975, if you were to ask a group of cardiologists, what causes an acute MI? Well, there would have been, again, controversy with people who said absolutes of thrombus. No, it's not. 

And we didn't have a very good way of studying it, because autopsy is not a good way of studying it, because the patients have died, so it's sort of a selection bias. And so then coronary angiography became available. The reason that [INAUDIBLE] couldn't prove that his therapy worked was because they weren't doing selective coronary angiograms. 

So I think that's part of the thing is that we have to be humble enough to know whether or not we've got an effective tool to manage, to diagnose the disease process, right? So microvascular flow is very, very difficult to sort of diagnose. The best you can probably do is stress testing, or some sort of fancy imaging. So I think that's really the real key question. The reason that STEMIs are so well studied is because we have a very simple non-invasive tool, electrocardiogram. And then we have a definitive diagnostic test, a coronary angiogram. So that really allows us to really get a very good circumference around that particular disease. 

The reason why so stroke is so hard, is because if they had an electrocardiogram on their brain, I mean there would be 25 years ahead of their time for stroke therapy. They're using sort of emergency [INAUDIBLE] or very crude instruments. So I mean I think that the field has evolved because of the diagnostic testing. I'm not sure that we have a very good diagnostic test for microvascular function yet. 

There's definitely a huge amount of microvascular dysfunction with acute infarction. And one of the hopes is some of these things like cooling are going to further improve them. Thank you. Yes, sir? 

You spoke a lot to the fact that one of the major consequences of doing such a good job with coronary disease is on the back end you kind of increased the prevalence of heart failure. So in getting at some of the approaches that you mentioned-- some of things they're trying to do to mitigate that effect, specifically the unloading study, [INAUDIBLE] data outside of the infarct. That neatly translate to EF six months down the road? Do you have echos that correlate with that? Or do you have [INAUDIBLE]? 

Yeah, echo ejection fractions correlates to the-- the ventricular function is more well-preserved with the smaller the infarct. So they do track. So I think there is some logic. But we need bigger studies with longer follow-up to see whether or not that's actually a clinical consequence. The one real problem with the TherOx, the super-saturated oxygen, they showed smaller infarcts, but the survival curves at a year look very parallel. So there's something that isn't quite right with them. 

OK, Thanks very much. 

[APPLAUSE]