Interview: Dr. Steven E. Nissen
< Interviews with Experts
Chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic in Cleveland, Ohio, Dr. Nissen pioneered the development of intravascular ultrasound (IVUS), an imaging technique that has led to new insights into the systemic character of cardiovascular disease.
This interview was conducted in August, 2006.
- The Heart's Central Role in the Human Imagination
- Heart Disease Is a Chronic Disease
- Women and Heart Disease
- The First Symptom of Heart Disease: Massive Heart Attack
- Prevention Must Become as Effective as Treatment
- Risk of Heart Disease Increases with Subsequent Treatments
- Postwar Lifestyle Changes and the Increase in Heart Disease
- The Framingham Heart Study
- Revolutionary Times in Cardiology
- The Biochemistry of Heart Attacks
- The Development of Intravascular Ultrasound
The Heart's Central Role in the Human Imagination
INTERVIEWER: For centuries, the heart has captured the popular imagination. Why do you think that is?
NISSEN: Well, the heart is really quite an amazing thing. It's hard for me to think about it in a lighthearted, lyrical way, because I spend so much of my time dealing with the heart when it's sick. But here's an amazing thing: people live now 80 years of life, and for those entire 80 years, 60 to 100 times a minute, that heart is beating. And it never stops.
Can you imagine if you [asked that] of any other muscle? Imagine if somebody told you, well, you're going to have to squeeze a ball in your hand, and you're going to have to do it 100 times a minute for the next 80 years. How long do you think you'd last? So the heart was constructed in the most extraordinary fashion. To have this attribute of being able, in the vast majority of us, to literally beat at least once a second for 80 years, isn't that an amazing thing?
It's very central, of course. It's in the center of the body, right in the middle of the chest. It's the one organ that we're always aware of. You can't feel your brain working; it doesn't pulsate. But the heart's there, and it's pulsating. It has this physical presence. It's part of everything we do. If you think about another organ, [for instance if you put your hand over your liver], you don't feel anything. You put your hand over your heart, and you feel something. I think that's why it became the center—everybody is aware of their heart beating.
Heart Disease Is a Chronic Disease
INTERVIEWER: How serious is the problem of heart disease in this country?
NISSEN: There's no question, heart disease is the number one problem in America. Disease of the heart and the blood vessels—cardiovascular disease—is responsible for up to half the deaths in America. So think about it. You take all other causes of death combined, and they just equal heart disease as a cause of death. This hasn't always been true. It's actually a phenomenon of the 20th and 21st century. But as we are today, with all of our technology, with all of our drugs, it's still 50 percent. And it's almost 50 percent even in women, who tend to think that they're going to die of something else.
We see heart attacks in a hospital like the Cleveland Clinic every day, and we're just one hospital in one city. In fact, there are several million every year in the United States. And what troubles many of us the most is what happens to many of the people that have a heart attack. We have become incredibly proficient at saving the lives of people who make it to the hospital with a heart attack, but something that has not changed during my lifetime as a practicing physician is that one-third of the patients that have a heart attack never make it to the hospital. We don't get a chance to use our drugs and our devices and our therapies to save the lives of those patients.
INTERVIEWER: Why does it seem that people aren't aware of or concerned with the threat of heart disease until it becomes a problem?
NISSEN: I think it is different for men and women. Let me tell you first for men. Heart disease does have its saving grace, and that is that many people who die of the disease die suddenly. There is a fear of chronic wasting diseases, like cancer and Alzheimer's disease, where you see your mind gradually going away, and you really can't do anything about it. [People don't include heart disease in this "chronic" category.]
But that's a misnomer, because many of the patients we see with heart disease don't have one big, sudden, catastrophic heart attack. They have several smaller ones. Maybe they have a stent or two; maybe they have bypass surgery. And they develop congestive heart failure.
Now when they try to walk across the room, they feel like they're suffocating. We give them medicines, and they can't breathe. They wake up in the middle of the night short of breath. There's a failure of many people to appreciate that heart disease, while it is a sudden killer, is also a source of this chronic disabling condition of heart rhythm problems and heart failure. That is one of the reasons why it's not feared. People don't really appreciate that it can do that.
Women and Heart Disease
INTERVIEWER: You say it's different for men and women. How?
NISSEN: Well, for women, the appearance of their bodies is a very significant factor. The disfiguring aspects of breast cancer are very traumatic in a society where appearance is such a huge focus, so I can understand why women are so fearful of breast cancer. It's about their persona, their sexuality, and all of those things.
It's also quite interesting that women are very fearful about heart disease, but not in themselves—in their husbands. I can't tell you how often the person that brings the patient in for preventive care is the spouse. You know it almost right away. You go in the exam room, and there's a wife [and] a man, middle-aged, [in his] 50s, maybe 60s, and sometimes even younger. And his wife will be the one that will speak first. She'll say: "My husband has a family history of heart disease, and I think he's got a high cholesterol—at least he was told that. But he's not getting any treatment. What should be done for him?"
Women are socialized in our society to be caregivers, to be nurturers. In many cases, they are the ones that primarily raise the children. So that nurturing behavior extends to the other members of their family—their husbands, but not to themselves.
This is something we've been really trying to attack with a public education program around heart truth, helping women understand that heart disease is the number one cause of death not just in men, but in men and women. We have to overcome that psychology of women that they want to take care of everybody else in the family, and they take care of themselves last.
INTERVIEWER: Are there other reasons that women might not perceive the same risk for heart disease in themselves as in men?
NISSEN: There is some reality there. Women get heart disease five or ten years later than men do. The reasons are not absolutely clear, but we think it's hormonal, that estrogen is probably protective, at least among younger women. So there is [greater] public understanding that men get the disease.
The other problem is that when women get heart disease, they tend not to get it at a young age. We've seen some examples of younger women with heart disease, but by and large it's a disease of older women, whereas in men this is a disease that can really strike a man in his 30s and 40s, particularly in the 40s. We see men at age 44, they come in with chest pain, and they just don't believe that they could be having a heart attack at 44 years of age, so they stay at home and they sip bicarbonate, take antacids, do anything except come to the hospital to get their heart disease treated.
This notion of the relationship of the disease to age is even more prevalent among women. They know that it's relatively uncommon for a woman in her 40s to have the disease; they don't know very many women that have the disease, so they don't believe that it can affect them.
The First Symptom of Heart Disease: Massive Heart Attack
INTERVIEWER: So what does a heart attack look like? What causes it?]
NISSEN: The first symptom of heart disease, in around 60 percent of men and around 50 percent of women, is either a large heart attack or sudden cardiac death. So in more than half of people overall, that first symptom is a catastrophic problem, and we actually understand much better now why that is. By the time a heart attack occurs, there has been buildup of plaque in the arteries for many, many years, decades even. Then triggers occur that we don't fully understand scientifically, for a variety of reasons, and that plaque [then] gets a fracture; it can even be just a little micro-tear. When the plaque tears or fractures, then the tissue is exposed to flowing blood, and it causes a blood clot to form, and that blood clot can very rapidly obstruct flow and completely stop the flow in the artery.
When that happens, within about a minute, that patient is having a pretty significant heart attack—lots of chest pain usually, but not always. What seems to happen is that, in certain individuals who are susceptible, when that blood flow is cut off, it triggers a rhythm problem, an electrical problem in the heart that causes the heart to fibrillate. It simply beats wildly and can't pump blood. Those people will collapse. Unless they are resuscitated within about four to eight minutes, you never get another chance.
INTERVIEWER: And this can just sneak up on you, with no prior warning?
NISSEN: It can happen to anybody. I had a very good friend, a cardiologist, renowned in Boston, who was a marathon runner. You never would expect this man to develop heart disease—the picture of health: thin, vibrant, wonderful person. He was starting a run one day five or six years ago in his front yard, and he collapsed. He could not be resuscitated and died on the spot. Here was somebody that knew all the symptoms and signs, that was an expert, but he didn't know that he had plaque in his coronaries. He couldn't anticipate that one of his plaques was going to rupture and was going to cause sudden death. Tragic. But it's a story that's repeated all over the country every single day.
Prevention Must Become as Effective as Treatment
INTERVIEWER: Can anything be done to treat these "catastrophic" events?
NISSEN: We've made some progress, and [there's something] that's really quite extraordinary. Look around you, and you see defibrillators in places where people congregate—in airports, stadiums. Every time I turn around, [I see] a defibrillator. They've become very inexpensive, and if people know how to use them, they literally are lifesaving. We have so many people that we've now seen who were at a public event and collapsed and a bystander put one of these things on. It has an automated approach. It can determine whether a shock will restore the heart rhythm and then administer it. A lot of lives have been saved with these devices.
But there's another way. There's a better way. If you never get the plaques in your coronaries, then you never have a plaque that's going to rupture, and you won't need a defibrillator. A lot of my attention is focused on the prevention of this disease. It's great that our treatment is so effective now, but prevention is what we've got to focus on as a society.
INTERVIEWER: Once heart disease is treated, can it be cured?
NISSEN: There is very limited reversibility [of heart disease]. Heart muscle cannot regenerate. When you have a heart attack and a blood clot forms in the coronary, cuts off blood flow, part of the heart muscle dies and is replaced by a scar. That scar can never contract again.. If you develop enough scar [tissue], then the heart can't contract, and you develop heart failure. The heart is unable to pump blood effectively, and your quality of life goes way down. So if you want to prevent heart failure, you've got to prevent the heart attack in the first place.
Now, one of the questions that I've addressed a lot of attention to in my own scientific work is, what about the plaque buildup? Can we reverse the plaque buildup? For many years, if not decades, we thought that there was no way to reverse the buildup of plaque, and to a large extent, that's probably still true. But in recent years, as we develop more and more powerful drugs to lower the bad cholesterol, the LDL, to very low levels and sometimes to raise the HDL, the good cholesterol, we have begun to publish studies that show that at least a small fraction of the plaque can actually be melted away, if you will, with drug therapy. You can't count on it, and you can't do it in everybody, and the amount of plaque you can get rid of is probably only in the range now of around 5 to 7 percent, but I think it's a door opening to the future.
The reason I'm optimistic about the future is, we've got more powerful drugs coming. Right now, the best we can hope for is to reduce the plaque growth and maybe get rid of some of the plaque in the coronaries. We cannot restore heart muscle, although there is work ongoing to use stem cells to actually regenerate heart muscle. Unfortunately, this is not being federally funded because of the current policy of our government not to fund embryonic stem cell research. Every cardiologist I know who works in this field considers it a tragedy that we are unable to pursue that strategy aggressively, because imagine what we could do if we could take that damaged area of the heart and regenerate it and restore it. I think we're going to get there, but it's not there today.
Risk of Heart Disease Increases with Subsequent Treatments
INTERVIEWER: So, in short, the heart can't be "fixed" entirely once it's damaged by disease.
NISSEN: Fixing heart disease is something we try to do, but as far as we've come, there's a lot we can't do. Bypass surgery has certainly been a wonderful development, but bypass grafts—that is, the routes that we create with bypass surgery for blood to flow—they tend to plug up over time. We get some cases [where the graft lasts] only a few years, and some cases where we're really fortunate, and we get seven, eight, 10 years or more. But many people who have had bypass surgery will require further interventions. Forty percent of the bypass surgery being done now at the Cleveland Clinic is a second operation.
And each time you go back, it's harder. The risk of not surviving the surgery goes up a bit. We have stents now to open up blocked coronaries, but they're not perfect, and they sometimes narrow again. I'm delighted that we can offer our patients so much, but it's not the same as having a healthy, functioning heart. I get a chance every now and then to see somebody in their 80s or 90s who's been really heart-healthy—low cholesterol, vigorous exercise, really good diet. They come in the office, and I say, "How old are you, Mr. Jones?," and they say, " I'm 91." And you look at them and you say, wow, this is not a 91-year-old man. Their ability to function and the vigor that they have is exceptional.
I know a cardiologist, a famous one, that's in his mid- to late 70s, and he's doing some of the best scientific work of his life. He's very fit, and he keeps his cholesterol down. When we talk about heart disease, we're not just talking about how long you live; we're talking about the quality of your life.
We must not miss that point. Many young physicians misunderstand this. They think that the purpose of modern medicine is to extend life. I don't think the purpose of modern medicine is to extend life; it's to improve the quality of life. When you can see a vigorous 85- or 90-year-old really having fun and enjoying things they want to do, that's a victory for medicine. Those are victories that are hard to achieve when you're patching up a disease that's had its ravages over a long period of time. That's the kind of outcome we can get if we can prevent the disease in the first place.
INTERVIEWER: So how can an individual prevent heart disease?
NISSEN: When you have the diagnosis of coronary heart disease, it's a diagnosis you carry for life, and it's important for people who have the disease to understand that.
I have a patient I just saw today in the coronary care unit who came in with a heart attack. The story that we heard from the patient and his family illustrates one of the big problems that we have. This patient had high cholesterol and high blood pressure many years ago and was told he had high levels. He lost a little weight, did a few things to change it, and believed that he had fixed the problem. But he didn't continue to follow up.
What we then saw was, not too many years later, the first heart attack. Once you have that diagnosis, it's a diagnosis you carry for life, which means you've got to pay attention to it. You have to get your cholesterol level rechecked. You have to get your blood pressure regularly checked. If you try to wish it away, it's going to come back to haunt you. And here's the problem: high cholesterol and high blood pressure don't hurt. You don't have any symptoms. You don't feel bad. Unless your blood pressure is really sky-high, you're not even going to feel ill until something terrible happens.
Postwar Lifestyle Changes and the Increase in Heart Disease
INTERVIEWER: When did heart disease really become an epidemic in this country?
NISSEN: The seeds of the modern coronary heart disease epidemic were sown in the post-World War II environment. All of us who have looked at this come to that conclusion. Here's what happened: every family started to have a car, and the next thing we know, two cars. And we became a wealthier nation; incomes rose. When people wanted to go visit their neighbors who lived three blocks away, they would drive. Now previous generations, they'd walk those three blocks. May not seem like much, but multiply that across millions of people across the country. So exercise levels went down.
And as we became a more wealthy and prosperous nation, the fat content in our diet went up. Meat became a much greater staple in the diet. If you go back and you look at the consumption of meat during the late '40s and '50s, it was actually rationed during World War II. But after World War II, the cuts of meat that had a premium price were prime cuts—not choice, but prime. What makes a meat prime is it has more fat. And the steak-and-potatoes diet became the mainstay of America. We began to get fatter and eat more fat and fast food.
Now all of a sudden we had couples where both [people] were working. You know, modern life, all the luxuries—you want to have that kind of income. Husband and wife both work, [which] means there's nobody to cook dinner, so up come fast-food restaurants. A whole slew of chains of fast-food restaurants grew by extraordinary rates of growth. The hamburger and french-fry dinner for the kids and for the adults became the norm.
And there's actually one more trend. During the war, the government issued cigarettes to every soldier. They were one of the few perquisites that a soldier could have. They were given a pretty good ration of cigarettes. Virtually everybody in the military smoked. They came back, and they actually introduced [smoking to women], and women began to smoke. Before the war, women rarely, if ever, smoked cigarettes.
We got to the point where we were fatter, eating more fat, exercising less, smoking more, and all of a sudden there was an extraordinary epidemic of heart disease. One of the pivotal events that brought this to national attention was in the mid-1950s when the president of the United States, Dwight Eisenhower, had a heart attack while out in Colorado. Actually, it's interesting how his heart attack was treated, because there wasn't much you could do in those days. You put the patient to bed—complete bed rest for six weeks. That's what actually was done for President Eisenhower.
All of a sudden people began to realize that the rates of heart disease were going up wildly in the country, and it was really the effects of the change in lifestyle. One of the interesting things about the changes in lifestyle is there's a lag phase. If you start to eat rich food and exercise less, and even smoke, you're probably not going to have a heart attack tomorrow. But after five years of that, or 10 years of that, those risk factors have built up the plaques in your arteries and now you're at the place where you're really at risk for having a sudden heart attack. And we had a lot of heart attacks. In fact, heart disease peaked in the 1960s and '70s.
The Framingham Heart Study
INTERVIEWER: Enter the Framingham Heart Study. Tell us about it.
NISSEN: Framingham was just an extraordinary study, and now it is such a core of our knowledge base about heart disease. It forms the basis by which we actually calculate the risk of patients in order to determine who should have their cholesterol levels treated. It was a phenomenally important project. To find out the relationship between health habits and incidence of heart disease in a single town of that size in Massachusetts was a brilliant strategy that has yielded so much insight into the disease. Ultimately it's led to many of the modern advances, because once you could show that having a higher cholesterol level was associated with a higher risk of a heart disease, people started to say, well, maybe we should try to lower cholesterol levels.
INTERVIEWER: What was the procedure for determining the range of "normal" cholesterol levels? Was "normal" just based on the average?
NISSEN: For most laboratory tests, the way you determine what's normal is you get 100 people who you think are normal and you measure the laboratory tests. You see what the average value is [with, say, cholesterol]. And then you take some statistical measure of the boundaries around that value, and you call that normal. But if those people are eating a high-fat diet, then the average cholesterol levels [are] going to be very high; that's not normal. And actually, this insight has just taken the cardiovascular community by storm, because we started to look at populations in other countries where the diet was different, like China. [We'd] find that the average cholesterol level was not 220 or 230, it was 150, and they had almost no coronary heart disease. So that understanding—that an average level may not in fact be a normal level—was a very important insight.
INTERVIEWER: Were these insights met with resistance from the medical community?
NISSEN: There was an incredible reluctance. And there were people that said, no, high blood pressure is a good thing. So we'd have to do study after study and trial after trial. There was this almost professional group of skeptics that didn't believe it, and it took a lot of societal efforts. Now, I'm going to tell you one of them that was just pivotal, as pivotal as anything that happened. It was in 1963, [when] the Surgeon General's report on smoking and health [came out.] At the time, I was 15 years old. My father, he's a gynecologist, now retired, and every physician in America was sent this big, fat book—the Surgeon General's report on smoking and health.
By the time [my father]came home [from work], his 15-year-old son, me, had been thumbing through this book. My father, like many physicians at the time, smoked cigarettes. I confronted him with the science; I said "look at this, from the Surgeon General of the United States, it says that if you smoke you have twice the risk of heart disease and five times the risk of lung cancer. Why do you smoke, Dad?" And he gave it up that day and never smoked another cigarette the rest of his life. And so this [story] is a microcosm of what was happening around the country as people were waking up to the facts.
INTERVIEWER: Of course, not everyone reacted that way immediately—surely there were a lot of people who still refused to accept the evidence?
NISSEN: Yes; it is really important to understand the extent to which denial, the unwillingness to accept one's own vulnerability to a disease, costs lives in America. If you don't believe that the fact that you smoke is putting you at risk, you convince yourself it's not going to happen to you. [Maybe] you've [even] heard from your physician your cholesterol's too high; but it's not going to happen to you. Even worse, you start to have some chest pain, and you say "it's just indigestion." In so many patients, this denial of the disease is so costly in terms of lives and misery that we really have to overcome it.
Revolutionary Times in Cardiology
INTERVIEWER: Talk about the biggest, most revolutionary innovations that have occurred in cardiology.
NISSEN: I ran the annual scientific sessions of the American College of Cardiology in 1989. It was the fortieth anniversary of the ACC, so we put on a program titled Milestones in the 40-Year History of the American College of Cardiology. Some of those [milestones] were events like the development of coronary angiography, [which] was pivotal. Now imagine a disease that was killing up to half the population, and you couldn't know if an individual actually had it or not until they actually dropped dead or had a heart attack or something else. There was no way to image the arteries in the heart, until a man working within a couple hundred feet of where we're sitting, Mason Sones, was making a picture of the aorta.
The catheter he was using accidentally dropped into the right coronary artery. And using a pressure injector, he accidentally injected the right coronary artery with dye. It was believed at the time that that would be instantly fatal, but the patient didn't die. Now most people who did that would have tucked their head between their legs and never showed their face again in a cath lab. But Mason Sones said, gee, maybe we can inject dye in the coronaries and make X-ray pictures and people will do well. And so he brought the same gentleman back a couple of days later and he put the catheter in the artery, injected dye, and made pictures. [He realized we could possibly use this technique to look for evidence of the disease,] and within months, he was doing this on a daily basis. Within a few years, people were coming from all over the world to learn this new technique, coronary angiography—because you can inject this dye, which contains iodine, make an X-ray picture, and if the artery is pinched, is narrowed, you can see it.
Now you might say, "why would you want to make that diagnosis?" Because there was absolutely nothing you could do to treat it. There was no bypass surgery. There was no angioplasty. There was no stenting. But people would have chest pain and their doctors wouldn't know if it was coming from their heart or not, so it was a pivotal breakthrough.
And then, about 10 years later, at a place that's also a few hundred feet from where we're sitting, a surgeon by the name of Rene Favalaro was inspired to try to do something about the blockages. In the mid 1950s, the heart-lung machine had been developed. And this of course was a very pivotal development. The way the heart-lung machine works is it allows you to take blood and circulate it through a pump when the heart is actually stopped. It also contains a device that bubbles oxygen through the blood so it takes over the role of the lungs. That's why it's called a heart-lung machine. [The development of this machine meant that] you could sustain the body even when the heart and lungs were not working. It [also] allowed open-heart surgery [to be] performed. Well Favalaro got a brilliant idea; He said, what if we took one of the veins from the leg, stopped the heart, put the patient on the heart-lung machine, and actually sewed a little bypass, a little detour for blood around these blockages that Dr. Sones had now shown in so many patients? He did this for a patient who had such severe chest pain he couldn't function. He couldn't walk, couldn't do anything. And that patient, who was the first bypass patient, lived another thirty years. That's an incredible story. It was one of the most successful bypasses ever. The next thing we saw, [in 1967,] was the steady stream of people coming to learn how to do this procedure. And it just took off. Here we had a disease where people had disabling symptoms from blockages [that] [we] could [now] fix by bypassing the arteries. Extraordinary.
Well then, just about 10 years after that, a Swiss man by the name of Andreas Gruentzig got an idea that at the time probably most people thought was pretty crazy. [The idea was that] if you put a balloon on the end of a little skinny tube that you could blow up, and if you took the balloon and snaked it down inside the coronary and blew it up inside of one of those blockages, that you could open it up and get blood flow. And he did it in about nine or ten patients. Nobody had ever heard of this guy; but when he came to the United States at one of our meetings of the American College of Cardiology, you couldn't get in [to the auditorium], because people had heard that this was coming, and it spread like wildfire. People jammed in this room and he showed pictures of these 10 patients before and after. They didn't have their chests opened. They didn't get put on a heart-lung machine. They got their blockages fixed by just inflating a balloon in the coronary.
And once again, the world of cardiology went crazy, and everybody sought to learn it. It led to a whole series of other developments that would make an enormous difference. But there was a problem, one that I think was fundamental: Studies seemed to show that if you blew these balloons up and opened up the arteries, the risk of dying, or having a heart attack, was not reduced. People were very disappointed that you could relieve the angina, the chest pain, but you didn't seem to prolong life. And the question was, why were these techniques for opening up the coronaries not resulting in a major change in the outcome?
Another group of people, including myself, became concerned that we weren't seeing the whole picture on the angiogram. We were just seeing the flow channel, but we weren't really seeing the wall of the blood vessel. Beginning in about 1985, we started to develop tiny devices that with sound waves could make pictures of the inside of these coronary arteries. Now remember, just a couple decades earlier, we couldn't even make a picture of the coronary artery, [and now we were] actually putting a tiny little camera inside the artery and looking at it up close and personal. We began to realize that once people began to have the first blockages in the coronaries, that these plaques were everywhere. Frighteningly diffuse. And in fact, they weren't just in the coronaries. They were in the carotid arteries to the brain, and in the arteries to the legs.
And there was again another revolution—we began to see that the disease was what we call a systemic disease, [meaning that it was everywhere, and not a focal disease. But how do you treat a systemic disease? You can't blow a balloon up in every artery. And just when we needed it, along came another revolution.
INTERVIEWER: What was that revolution?
NISSEN: [This next revolution, in 1987, came when] the first of the powerful cholesterol lowering drugs were introduced. It was a statin called Lovastatin [that] could lower cholesterol levels by about a third, and people began to treat a few patients with the statin drugs. But we really didn't know whether we doing them very much good or not. Framingham told us that high levels of cholesterol were worse than low levels, but that doesn't prove that if you bring down high levels, you can actually reduce the incidence of heart disease. The breakthrough came in 1994 when Dr. Terje Pedersen in Norway completed a very famous trial called the 4S study. This was a pivotal study where people were either given a sugar pill or a different statin for five years.
All of the subjects who participated in the study already had known heart disease, and had already had a heart attack. What they looked for was whether or not lowering their cholesterol level prevented a second heart attack. When the study was over and they looked at the data, there was an enormous benefit, about a one-third reduction in the risk of having a second heart attack. This was another enormous revolution; [we had developed a tool that could] not just treat the one narrowed spot in the artery, but could actually attack the disease throughout the body by lowering cholesterol levels and preventing plaques from accumulating and causing second heart attacks in patients.
So it's been an extraordinary period of time, but we're losing the battle once again. Each time we make an advance, we think it will be the answer. There was an editorial written by two Nobel Prize winners in 1996 titled Heart Attacks: Gone with the Century. It didn't happen, because it turned out that not only were the drugs not as effective as we had hoped, but we were changing, too. We were getting fatter and the obesity epidemic was leading to an extraordinary increase in the risk of diabetes, pushing up cholesterol levels and pushing up risk [of cardiovascular illness]. We were smoking less, but we weren't exercising more. We were eating more; we were eating the wrong kinds of things. We learned that not all fats are created equal, that some of the fats we were using in food, like trans-fats, which are made by processing certain kinds of oils, were actually fighting us, and at a time when we were trying to get cholesterol levels down, we were making the wrong kind of cholesterol.
One of the [really interesting] things is that we saw a sharp decline in the risk of heart disease throughout much of the '70s and '80s and into the '90s. [Then] it stabilized and now it's just not going down anymore. Most of us think it's because we've never really addressed those underlying lifestyle issues that are the drivers of the disease.
INTERVIEWER: It's certainly difficult to make lifestyle changes overnight; was that the case even for some of these innovators in cardiovascular medicine?
NISSEN: [Interestingly, many of these innovators met tragic ends;] Mason Sones was a chain smoker. The guy who'd invented coronary angiography died of lung cancer.
INTERVIEWER: So where have all these advances brought us? Where will the future breakthroughs come from?
NISSEN: Well I think that one of the problems with our techniques is that it's sort of a patchwork solution. You know? You can bypass the arteries, but if you don't stop the disease that's causing the plaque to build up, those bypasses plug up, too. You can put a stent in the artery at one location, but then a narrowing occurs at another location. Then you go back and you put another stent in—so you're kind of fighting a rear guard action by trying to delay the inevitable development of a disease. Many of us believe that the future is to get to the fundamental source of the disease, and that means the biochemical and genetic aspects. What's driving that disease? What is it about cholesterol levels, inflammation, and all the other targets we've developed? How does high blood pressure develop and can it be prevented?
I think that we are patching people up and sending them back into an environment where the disease is going to recur. Now, what are the breakthroughs that are likely to occur? Well, I think there are several. One of them certainly is to be able to modify HDL, the good cholesterol. Most authorities I talk to believe that this is really the next big thing. If you ask, what's the next development in this enormous change that's occurred over the last 40 or 50 years, it's the ability not only to lower bad cholesterol but [also to] raise good cholesterol. We're very close. We're perhaps within only a year or two of having very powerful drugs to do that. [EDITOR'S NOTE: In December 2006, Pfizer, the maker of the experimental drug, Torcetrapib, suspended stage 3 trials to evaluate its effectiveness due to an elevated level of adverse outcomes.]
But that alone won't be enough. We have to find new steps in the process by which the disease develops and try to attack it at its root causes, and there's a lot of great scientific work going on. But until we do that, just patching up the blockages and fixing the problems on a temporary basis is not going to dramatically alter an epidemic disease.
The Biochemistry of Heart Attacks
INTERVIEWER: How important is the recent research that Dr. Peter Libby and others have been doing on the biochemistry of the artery walls and the role of inflammation in heart disease?
NISSEN: Well it's interesting, because Peter and I agree about many things and we often will speak together at symposia and so on. The artery is not just a passive conduit for blood. It's an active, living tissue. And the one thing I've learned, if there's anything I've learned in the last decade or two, is that coronary disease is very dynamic. It can accelerate and the plaques can grow at an enormous rate. It can decelerate and slow down. And it can even reverse. And so to think of this as a static, lead pipe kind of disease, [i.e. where corrosion continues to build up over time as if in a galvanized lead pipe,] is the wrong approach. It's not how the disease works. Those cholesterol deposits are forming and going away constantly.
If you can alter the balance between the formation of new plaque and the removal of old plaque, you can potentially make an enormous difference in the outcome for patients. And as we develop more sophisticated methods, I think we're going to be able to do that.
INTERVIEWER: How much do we really understand about the immune response to the plaques and their buildup in the arteries?
NISSEN: Well there's no question [about] the inflammation that occurs. We understand that the bad cholesterol, LDL, actually gets oxidized. It gets modified, it gets into the wall, and it's a source for inflammation. Now everybody understands what inflammation is. If you've got a little infection of your skin, it gets red and hot and so on. Well we think that happens inside the arteries as well. And we believe - and there's lots of evidence to support this - that those inflamed arteries are more likely to rupture. [They are more likely to] get those fractures which cause blood clots. And recently we've had a chance to actually make some observations that have helped us better understand inflammation.
In lots of work done by Dr. Paul Ridker we learned that there's a very good blood test that can measure the level of inflammation in the body [by measuring the levels of a substance] known as C-reactive protein, or CRP. Dr. Ridker and others have shown that the higher your CRP, the more likely you are to have a heart attack or a stroke. [What] we didn't know was whether lowering CRP would make a difference; just like the cholesterol story. A little more than a year ago, there were two manuscripts published, one from the group in Boston and one from our group here, where we looked at the relationship between reductions in inflammation, as measured by CRP, and outcome.
Now there's a surprise here. The drugs that we use to lower CRP are the very same statin drugs that we use to lower cholesterol. It was a bonus that we didn't understand when the statin drugs were developing. We thought they were just lowering cholesterol. But we now know that they lowered the inflammation, or CRP. What we were able to show using these intravascular ultrasound probes that measure plaque in the coronaries is that the more you lowered CRP, the more you reduced inflammation, the more likely you were to slow down the accumulation of the plaque in the wall of the artery. The group in Boston showed that the more you lowered CRP with statin drugs, the lower the risk of death, heart attack, and stroke.
Those two papers appeared together in The New England Journal of Medicine. [They] got a great deal of attention because they closed the loop on one more piece to the puzzle. It's not the whole puzzle, but it showed that cholesterol was important. We showed that CRP or inflammation is important, and that if you can reduce both cholesterol and inflammation—if you can reduce cholesterol and CRP—you can slow progression of the disease and you can reduce the incidence of death by heart attack and stroke.
INTERVIEWER: How did your group determine that cholesterol and CRP were both important factors?
NISSEN: We used statistical techniques to determine whether the change in inflammation is actually independent. For any give[n] level of cholesterol, you can ask the question, if you got [down] to that level of cholesterol, did it matter whether your CRP was [also] lowered or not? This is a very commonly used statistical method and interestingly enough, both groups used rather similar approaches but from a very different perspective, and [both] showed exactly the same: how much you lowered CRP was an independent predictor of outcome, no matter what happened to your cholesterol levels.
INTERVIEWER: So what would be the predictable outcome if a person's CRP and cholesterol levels were not lowered?
NISSEN: You had more events, more risk of having heart attack or stroke, and you had more progression of your plaque than if your cholesterol was lowered and your CRP was also lowered. Only if you lowered both did you get the maximum benefit from the statin drugs.
The Development of Intravascular Ultrasound
INTERVIEWER: Can you talk about your group's development of the intravascular ultrasound probe?
NISSEN: As I said earlier, there was a group of people including myself who suspected we weren't getting the whole story from the angiogram. I remember one very pivotal day about 1985 when I was paid a visit by a company. They came to see me because I'd begun writing articles suggesting that there was something wrong with the angiogram, that we were seeing a lot of dissociation between the amount of disease [visible through] angiography and what actually happened to the patient. I couldn't explain that. If angiography were telling us the whole story, then it would be very clear that the more disease you had on the angiogram, the worse the outcome. We sometimes saw people that didn't have a lot of disease on the angiogram but had a heart attack anyway.
So we suspected we were missing something. And what these small companies that we worked with believed they could do was find a way to make a picture of the inside of the artery, up-close. The technique that we used was sound waves—like sonar. And when we began the work, there were ultrasound devices—techniques like obstetrical ultrasound and cardiac ultrasound were well developed—but the device that we used to make [such] pictures was the size of your fist. We called it a transducer. We increasingly began to believe that we could microminiaturize that transducer to go from something the size of you fist to something smaller than a pencil lead.
Over a five-year period of time, we actually were able to do it. I will tell you it was very frustrating. A lot of the work was done in animals because of course you can't test something like that in humans until it's been perfected. We would go into the animal lab and we would not get a picture. And we would say, all right, let's go back to the drawing board. We'd redesign and rework it. By about 1989 or 1990, we were making pictures, and I will never forget the day we made the first really good pictures. We put one of these catheters in the coronary artery and there was all that plaque that we couldn't see any other way. You could see [it] on a television screen just as if you were literally there.
One of the early articles about this that appeared in USA Today said it was like the movie Fantastic Voyage, which was a movie in the 1960s where Raquel Welch and her friends were microminiaturized and sent on a tour inside the body to fix somebody's artery. It really was like a fantastic voyage. It was a trip inside the arteries. After a few more years, by about 1992, we were making very good pictures—detailed pictures that showed us the plaque in the wall of the artery.
INTERVIEWER: How did you expect to use this new technology?
NISSEN: We thought when we first developed the technique that it would be used to guide angioplasty, because we didn't know that we were going to see something very different from [what we had been seeing]. We thought we were just going to get a better picture of these plaques. What we saw, however, which was surprising, maybe even shocking, was that in people that had just one or two blockages in their coronaries, there were plaques everywhere.