Interview: Dr. Peter Libby
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Dr. Libby is Chief of Cardiovascular Medicine at the Brigham and Women's Hospital in Boston, and Professor of Medicine at the Harvard Medical School. Dr. Libby's research has helped open up a new understanding of the role of inflammation in cardiovascular disease and heart attacks.
This interview was conducted in August, 2006.
- The Heart and the Human Imagination
- How Medical Practices for Heart Attacks Have Changed Over Time
- Research Advances
- The Framingham Heart Study and Resistance to its Findings
- The Biochemistry of Heart Disease
- Changing Demographics and the Impact of Obesity
- Other Ways to Identify Who is At Risk
- The Future of Cardiovascular Medicine
The Heart and the Human Imagination
INTERVIEWER: Talk about the central role the heart plays in the human imagination and how that affects your role as a cardiologist.
LIBBY: In the profession of cardiology, we're used to thinking of the heart as a very concrete, physiologic organ that has a discrete function—pumping blood that supplies nutrients and oxygen to the tissues. But actually, the heart has had a much broader significance. Even the ancients ascribed to the heart a role in emotions. And of course we have Valentine's Day and Cupid; imagery is very current in many forms of art through the millennia, for instance. And so, we cardiologists actually have the privilege of having as our primary organ a particular body part that has emotional connotations that go far beyond its mere physiologic function.
INTERVIEWER: Can you elaborate on the relationship between the human heart and the arts?
LIBBY: I'm an opera fan, particularly the Mozart-DaPonte operas, and the heart figures very prominently in many important songs. In Mozart's opera Cosi fan Tutte, for example, there are a number of arias that actually encapsulate the heartbeat in the music as a symbol of love.
INTERVIEWER: Do these emotional and spiritual connotations affect the way that people think about heart transplants as opposed to other organ transplants?
LIBBY: While we cardiologists and cardiovascular scientists think of the heart in very concrete and abstract terms as an organ, the public ascribes magical properties to the heart. Indeed, when people receive heart transplants, there's often an emotional learning curve to understand that it really is just a pump that's been transplanted, not a part of someone's soul.
INTERVIEWER: Can you talk a little more about the connection between the heart and our emotions?
LIBBY: Because the nervous system sends signals to the heart that control its rate and also the strength of contraction, when we become excited or emotional, it can be reflected as a change that we perceive in our chest as an alteration in the rate of the heartbeat or the force of the heart's contraction. I think that's why the heart, even from the time of the ancients, took on magical properties as being a reflector of the soul, because, indeed, it's like a barometer of our emotions. When we're excited, when we're in love, when we're frightened, our heart speeds up and thumps like it's going to jump out of our chest, and when we're relaxed and calm, when we're meditating, the heartbeat slows down, and the heart's contraction is imperceptible.
INTERVIEWER: What does an actual human heart look like?
LIBBY: When I was a medical student and attended an open heart surgery for the first time, I was astonished that the human heart in one of our typical patients looks a lot different from the beef heart which you see in the supermarket, or the pictures of the pristine hearts that we commonly encounter in the anatomy textbooks. The difference was that there was an encrustation of fatty tissue surrounding the heart, so that the coronary arteries, instead of glistening on the surface, were actually hidden in a mountain of yellow fat tissue. I think that speaks to the adiposity epidemic that we have, and the link between fat and risk factors that can promote cardiovascular disease.
INTERVIEWER: Why do you think it is that nobody worries about being heart healthy until they have symptoms of heart problems?
LIBBY: When the heart works, we take it for granted. It beats regularly, it beats autonomously—we don't have to will it to act, and it's a reliable friend for most of us. It beats by itself, and serves its function without much care or maintenance. But, of course, we can sow the seeds for heart disease if we take it for granted, and the day that we develop an irregular heartbeat, or the day that we develop chest discomfort because the heart's not getting enough blood, the day that we have a sudden blood clot that causes a heart attack, or even sudden cardiac death, brings the heart to our attention in a very dramatic way. And that may be one of the reasons why the heart has taken on an aura of magic or symbolism far beyond its physiologic function, because it is a silent soldier that functions to contract 60, 80 times a minute; multiply that times the number of minutes in a day, the number of days in a year, the number of years in a lifetime, you begin to appreciate why people could think that the heart is a magical organ, because it soldiers on autonomously for decades without our giving it a thought. But then it can be the root of our demise in just a fraction of a moment.
How Medical Practices for Heart Attacks Have Changed Over Time
INTERVIEWER: How have developments in our understanding of heart disease affected medical practice and treatment of cardiovascular events?
LIBBY: Back in the middle part of the 20th century, the frequency of heart attack was increasing. Infectious diseases like pneumonia or influenza had waned as a cause of death. People were living longer. We had a diet and lifestyle that sowed the seeds for heart disease. So we were confronted with an epidemic of heart attack, particularly in middle-aged white males in the 1950s and '60s. In those days, our treatment for heart attack was minimalist. We would give morphine or other pain relievers to allay the discomfort of a heart attack, which can be quite severe. We would give oxygen. We would sometimes give other drugs that are no longer in contemporary cardiology use, in hopes that we could improve the outcome. And really, the cornerstone of treatment for heart attacks in the 1950s was bed rest. We would often put patients to bed for weeks at a time. In fact, we now recognize that that is not the right way to approach a patient with a heart attack, and our entire concept of how to manage someone with an acute heart attack has changed really diametrically since the days of watchful waiting and pain relief.
Our treatments for heart attack in the 1950s didn't address the root causes of the heart attack at all. The treatments offered symptomatic relief—analgesia to relieve the pain, and bed rest. And the reason that we did that was because we had very little else to offer patients, just half a century ago. There was no specific therapy that addressed the root cause of the dying muscle, the lack of blood flow.
INTERVIEWER: What was the theory behind prescribing bed rest for these types of patients?
LIBBY: Bed rest was thought to be important for people who had a heart attack because the concept was to avoid strain on the heart that might worsen the outcome. We know that several days after a fresh heart attack, a person is more susceptible to heart rupture, and it was thought that it was important to give the patient quiet time to heal, to lessen the chance that there might be a bursting of the heart—which, of course, is almost always fatal. But now we also know that bed rest is not the right prescription for these types of patients. We probably set people up for having blood clots in the legs that would travel to the lungs and other complications. We now have a completely different take on how to manage people with acute heart attacks. Early mobilization and avoiding loss of muscle tone and aerobic capacity is a key of our current post-heart attack rehabilitation.
INTERVIEWER: So how has treatment changed since the '50s?
LIBBY: In the 1960s, the introduction of coronary care units really revolutionized the care of individuals with acute heart attacks. Previously, patients with heart attacks had been put in rooms that might have been remote from the center of activity, the nurses' station in the hospital, to try and keep them quiet and remove them from any noxious stimuli that might excite them and cause a complication. The concept of the coronary care unit was the opposite—that you centralize the care of individuals with an acute heart attack in a special unit with specially trained nurses who are empowered not only to give drugs very rapidly on their own without calling the doctor and waiting for an order, but also to administer electrical treatments that could reverse some of the arrhythmias, some of the irregular heartbeats that were a frequent cause of complication and death in patients who were in the throes of an acute heart attack.
INTERVIEWER: Can you say more about what these "electrical treatments" were?
LIBBY: In the 1950s and '60s, there were a number of innovations in cardiac care, which involved a mastery of the electrical system of the heart. We learned how to pace the heart when its own internal machinery for setting the heartbeat failed. That was a very important advance. In patients with acute heart attacks, in some cases, there's damage to the pacemaker in your own heart that sets the mark for the heartbeat, and it was life-saving in many instances to put in a temporary pacemaker, an electronic pacemaker, which could keep the heart beating regularly in the absence of its own endogenous trigger.
Another very important electrical advance was cardioversion, or defibrillation. One of the most dreaded arrhythmias that can come about after an acute heart attack is a rapid heartbeat, known as ventricular tachycardia, which causes the heart to beat so fast that it can't pump blood and maintain blood pressure.
Another dreaded arrhythmia, or abnormality of the heart rhythm, is a totally disorganized failure of the heart to beat normally, known as ventricular fibrillation.
The introduction of direct current cardioversion and defibrillation, familiar to all of our viewers through the ER-type shows on the television, allowed us to use electrical currents, electrical discharges, to halt the rapid heartbeats, or to allow the heart to stop and reorganize and reassume a more normal heartbeat. So both of these kinds of potentially lethal arrhythmias—ventricular tachycardia, the rapid heartbeat, and ventricular fibrillation, the disorganized wiggling of the heart without an effective contraction—could be treated by electrical therapy.
Another important advance in cardiovascular electronics, in the 1950s and '60s was continuous electrocardiographic monitoring. When electrocardiography was invented, it required a roomful of equipment. Actually, the patient had to put their foot in a pail of salty water, and the instrument was called a string galvanometer, and [it] would expose a photographic plate one at a time with the inscription of the electrical activity of the heart. As we learned to miniaturize the electronics, we were able to accommodate an electrocardiograph into a box the size more of a dishwasher than a room, and ultimately [much similar].
Also, the introduction of continuous monitoring allowed us to learn the natural history of the heartbeat in patients who were undergoing an acute heart attack. That taught us that the reason that patients often died suddenly when they were hospitalized with an acute heart attack was because of disarray in the heart's rhythm. The heartbeat would become disorganized, irregular, or ineffective. And the continuous electrocardiographic monitoring that was made possible by the miniaturization of electronics in the transistor era really opened our eyes to a much more aggressive posture towards managing the heart's rhythm.
We've also improved our ability to look at the heart noninvasively by leaps and bounds over the last 30 or 40 years. Now we can use the echocardiogram, which bounces sound waves off the heart, using a source that is usually affixed to the chest wall, to take increasingly beautiful and informative pictures of the heart. It's quite dramatic, as the echocardiographers, the cardiologists, actually see the heart beating and see the valves opening and shutting, see the walls of the heart thickening and coming in to squeeze the blood out on a beat-to-beat basis. The echocardiogram has become an increasingly important noninvasive tool that allows us to not only gauge the size of the heart chambers and their structure, but also their function. And improvements over the last several decades have allowed us to actually look at whether valves are leaking or getting stuck up, what we call stenosis or regurgitation. So with the history and physical examination, and the advent of relatively low-cost and atraumatic echocardiography, we can, in a noninvasive way, really get a very good assessment of someone's cardiovascular health, just with some very simple tools.
INTERVIEWER: What advances have been made in diagnosing and treating arterial blockages?
LIBBY: The cause of much heart disease is blockage in the coronary arteries that run over the surface of the heart and then spread into the heart, supplying blood and oxygen to the heart muscle, which, as a hard-working muscle, requires a lot of oxygen and nutrients. So when we have blockages in the arteries that supply blood to regions of the heart, that can cause a lot of trouble, and ultimately a heart attack, or even sudden death.
One of the major advances in diagnosis of cardiovascular disease in the last 50 or 60 years was the introduction of the angiogram, which allows us to take pictures of the coronary artery by injecting contrast material, which opacifies the flow channel of the arteries and allows us to see the blockages that give rise to heart pains, angina, and can also cause heart attacks, when the heart muscle actually dies from starvation for oxygen. It's most often done these days by a simple needle puncture in the groin, but previously it was done by making a cut in the skin in the elbow region. One can then advance that catheter or hollow tube, to the orifices of the coronary arteries, which lie right on the route of that major artery, the aorta. One can engage the valves of these arteries and inject a contrast material, which makes them opaque to X-rays. We can take a movie film, X-ray, and then actually look at a motion picture of blood flow through the heart. That was an enormous advance in cardiology, because it allowed us to understand the anatomy of blockages in the coronary arteries.
That advance in cardiovascular imaging was not only important diagnostically, but also laid the foundation for our strategies, for supplying blood to the parts of the heart that weren't getting enough. Of course, that started with bypass surgery, but increasingly we're doing revascularization through the skin using balloons or metal stents that are propped open in the coronary arteries at places where there's a blockage that you can see on the angiogram. [By doing that we] can restore blood flow to the muscle. The problem with these therapies is that they're very high-tech and resource-intensive. We require catheterization laboratories, operating room suites, and very costly medications. I believe that while this high-tech approach, is very effective, we may look back on this era as an actual time of failure of prevention. While we are justly proud of the advances that we've made in cardiovascular care over the last several decades, this high-tech approach is really falling short of the mark of preventing the disease, sort of like putting our finger in the dike once the leak is sprung. I think we have an enormous opportunity to learn more about the preventive aspects of this disease, and put some resources into stopping heart attacks so that we won't have to deploy all of these very costly, and very resource-intensive high tech tools.
INTERVIEWER: Despite the fact that these high tech inventions can't reverse the progression of heart disease, have these high tech imaging tools furthered our understanding of the disease?
LIBBY: The advent of one advanced imaging tool, intravascular ultrasound, allows us to actually take pictures of the wall of the artery, as well as the lumen. That's really taught us a great deal about the biology of atherosclerosis in human beings. We've learned, for example, that although we traditionally conceived of atherosclerosis as segmental disease, one that only affected certain locations, because we saw on the angiogram blockages that were at specific locations, when we take a look at the artery wall by ultrasound, we see that this disease actually goes from stem to stern in the coronary artery, and even those areas which look perfectly normal on the angiogram and have no hint of a blockage can conceal a tremendous burden of disease.
Now, that concept seems counterintuitive. How can you have a large atherosclerotic plaque and not have a narrowing of the vessel? Well, it's because the body compensates for the growth of the atherosclerotic plaque by enlarging the artery. So the fatty plaque tends to protrude outward, preserving the flow channel for much of the life history of an atherosclerotic plaque. And that's why we can have an angiogram which looks innocent. We can have an angiogram which may show one or two blockages at specific points, but that then when we take a look at the cross-section with the advanced imaging technique of intravascular ultrasound, we see wall-to-wall disease that is hidden from the angiogram.
INTERVIEWER: Has the intravascular ultrasound tool affected your own research?
LIBBY: In addition to my clinical role, I have spent a lot of time in the research laboratory and looked at many atherosclerotic arteries through the microscope. It's not at all uncommon to see large atherosclerotic plaques in a cross-section of a coronary artery obtained at postmortem without there being much of a decrease in the actual flow channel. So when I first saw the advent of intravascular ultrasound, which showed us in actually living human beings, that you could have a perfectly wide open flow channel but have a great burden of atherosclerosis right in the wall where this blood's rushing past, it was a revelation that what we were seeing in the postmortem specimens under the microscope actually pertained to the living human being. And it was exciting because it gave me a tool that allowed me to make this pathophysiologic concept from the laboratory something that was understandable by my colleagues who practice mostly clinical medicine. And that has allowed us to transform our understanding of this disease, [as well as] the perception of the medical community about the way that atherosclerosis works.
So this imaging tool—which is really a research tool, not something which should be used in routine clinical practice today—this research tool has been a real eye opener for our profession, and has taught us a great deal about the biology of the atherosclerotic plaque in humans. It has [also] provided us with a tool for looking at how therapies may actually change the character of the atherosclerotic plaque, or our burden of atherosclerosis, without having any change in the flow channel or the angiogram, and [in ways that are] imperceptible to the patient. So if you look under the hood of the atherosclerotic plaque with the ultrasound, you can glean a great deal of information, which has allowed us insight into therapies that may or may not benefit patients' outcomes in the long run.
INTERVIEWER: Can you explain what new insight has been gained into what actually happens in most heart attacks?
LIBBY: We all have instances in our personal experience, certainly as cardiologists, but the general public as well, of people who are the picture of good health, who are in vigorous health, who perhaps are very active athletically, young, fit-appearing, just the flower of excellent health, yet they can drop dead of a heart attack without premonitory symptoms, with no warning.
It seems like being struck by lightning. How do we explain these individuals who have never had a symptom that could relate to a blockage in one of their heart's arteries, but are nonetheless struck dead from one moment to the other?
We now have a much more sophisticated understanding of how the disease of atherosclerosis works. Many heart attacks are caused by sudden blood clots, which do not necessarily form at places where the artery has a fatty plaque [that] has obstructed the flow channel. Many atherosclerotic plaques are hotbeds of an inflammatory process that can be prone to break open like a boil ruptures, or a pimple pops, and spew very potent blood clotting substances into the artery, [which] causes a sudden blood clot to form without there having ever been a narrowing of the artery before that moment. That is one of the ways in which our understanding of how atherosclerosis works has shifted radically in the last few years.
The Framingham Heart Study and Resistance to its Findings
INTERVIEWER: Talk about the importance of the Framingham Heart Study from your perspective.
LIBBY: In the late 1940s the federal government made an investment in an observational study in the town of Framingham, not far from Boston where I work, and followed thousands of residents in Framingham, freely living in the community, for a number of years, carefully monitoring a number of medical variables. We now accept very readily the idea that there are risk factors for cardiovascular disease, but in fact, in 1950, there was no scientific basis for the concept of risk factors. The careful correlations that were made in the Framingham study of various factors, such as blood pressure, cholesterol levels, and age and gender, actually established the entire field of cardiovascular risk prediction.
The term "risk factor," which trips lightly off our tongue these days, and is part of common parlance, actually emerged from publications of the Framingham heart study in the 1960s. Now, additional similar types of community-based studies have been done worldwide, but really, Framingham represents an enormous return on investment of federal research dollars in having provided us with the foundation not only for our ability to predict who is going to get heart disease, but also singling out those factors which we could try to modify to reduce the risk of an individual having a heart attack or stroke.
INTERVIEWER: As the new findings of the Framingham Study were reported, was there much resistance to them in the medical community?
LIBBY: The public perception is often that science worships at one temple, and that there is a received truth that we all agree upon. In fact, science and medicine are as social as any other human activity and enterprise, and there's a great deal of controversy and discussion about thing that maybe in retrospect seem obvious or well-accepted, but which were quite controversial at the time. Think of Galileo, who was, of course, condemned by the Church for having the temerity to suggest that the earth revolves around the sun, rather than the contrary. And in medicine and science, this kind of resistance to new ideas is certainly as old as Galileo.
In the particular context of cardiovascular risk factors, there are many who resisted the idea that even if cholesterol was a risk factor for heart disease, that you could do anything about it in a productive way. The argument eventually wasn't so much that cholesterol is humbug, but that, so what? If a high cholesterol level correlates with cardiovascular risk, at least in a population, it may not do so for a given individual. And even if it did, so what? What can you do about it? There were very robust arguments and discussions in the cardiovascular scientific community as recently as 20 years ago about whether efforts to lower cholesterol might do more harm than good. And indeed, some of the early medications to lower cholesterol were very difficult to tolerate, and when studied quite carefully, their ability to lower cholesterol was so modest that even with a large number of individuals studied over a long period of time—many years—the reduction in cardiovascular disease was rather small. And there was no decrease in overall mortality in these early studies with these rather weak first-generation agents. So the skeptics said, well, even if cholesterol is a risk factor, and even if you intervene, you aren't going to be able to improve someone's overall longevity, so why bother?
INTERVIEWER: Where did the idea that cholesterol matters come from?
LIBBY: The cholesterol hypothesis actually grew out of basic science work performed in the early part of the 20th century, and it had its clinical or human validation in studies like the Framingham study and Ansel Keyes' Seven Countries Study. That study went around the world and looked at diet and heart disease, and drew inferences about the role of cholesterol as a promoter of heart attack risk. What really turned the tide in the willingness of individuals to accept that treatment of cholesterol might benefit outcomes were the statin trials.
The statins are a class of drug that work by a mechanism that we understand to lower bad cholesterol levels in the blood. When these drugs were introduced, we had, for the first time, potent tools for reducing LDL, or bad cholesterol. The studies that were performed in the 1990s using the statin drugs consistently showed a benefit—and importantly, not just a benefit in terms of reducing heart attack and stroke, but also, when the studies had sufficient power, there was an actual pusdecrease in total mortality.
I actually had the privilege of being present at the unveiling of the first of these major statin trials, and at that meeting, when the results were unveiled, it was a very special moment in the history of cardiovascular medicine. And one of the individuals who had been a very vigorous opponent of the cholesterol hypothesis was in the audience, and as I recall, he stood up and said, "Gentlemen, I have to hand it to you." So it was the incontrovertible clinical evidence of benefit that really turned the tide.
The Biochemistry of Heart Disease
INTERVIEWER: What have we learned that's new about the biochemistry of heart disease?
LIBBY: Just a few years ago, most regarded the atherosclerotic plaque as an accumulation of waxy debris on the wall of the artery. What we have appreciated more and more over the last few years is that the atherosclerotic plaque itself is not just an inanimate collection of waxy debris, but is filled with cells that are busily at work exchanging messages. And the interesting insight that has emerged from the science over the last several years is that the kinds of messages that are being exchanged by the cells in the artery plaque are the same messages that our body uses in its normal defense system, the inflammatory response.
Now, when we get a splinter in our finger, the body will marshal its white blood cells, and we may get a small collection of pus around it, and that will wall off this irritative stimulus and will, if we have a normal immune and inflammatory response, lead to healing, particularly once the irritating stimulus is removed. Likewise, if we have a virus or bacteria that takes up residence in one of our organs, our body will marshal its own internal armies to deal with the invading microbial organisms.
What we now understand is that some of these same host defense mechanisms, which are so important in maintenance of health, are turned against us when they operate in the atherosclerotic plaque. [The fear is,] we now are exposed to a burden of risk factors for atherosclerosis which, from an evolutionary perspective, are very recent occurrences, and we also now have a much longer lifespan than in days gone by, so that many in our population are living to a more advanced age, [at which point] they can develop chronic diseases that involve these inflammatory pathways. [These responses and pathways] are lifesaving for the survival of the species, essential to ward off invaders and repair injuries when we're younger. But as we age, and as we have more and more aging members of our population, we're confronted by these diseases, including atherosclerosis, where the same warriors that we use to fight off invaders are turned against us and become, indeed, the disease itself.
INTERVIEWER: What role does cholesterol play in all this?
LIBBY: There's now a great deal of agreement that one of the most important risk factors for hardening of the arteries, or atherosclerosis, is high levels of bad cholesterol, what we call low-density lipoprotein. The bad cholesterol is actually the core of a form of cholesterol that's sort of coated with some water-soluble proteins that facilitate the travel of this waxy substance through blood. When we have an excess of bad cholesterol over a prolonged period of time, we can get a buildup of the cholesterol in the artery wall itself. And when the artery wall retains this cholesterol, it can undergo oxidation, because it is protected from some of the antioxidants that circulate in our blood.
The products of oxidized bad cholesterol can themselves be a stimulus for inflammation. They can unleash the body's inflammatory response. We now actually have some very specific chemical structures from among the many thousands of constituents of an oxidized bad cholesterol particle, which we can actually finger as culprits in setting off the inflammatory response. When we have an inflammatory stimulus in the artery wall, it gets the lining cells that are in contact with the blood, which we call the endothelial cells, angry and excited. Ordinarily, they're one of the few surfaces, either natural or human-made, which can maintain blood in a liquid state during prolonged contact. The normal endothelial layer that lines our blood vessels, when in contact with the blood, resists the attachment of the white blood cells, which are the foot soldiers in our inflammatory response. They ordinarily will zip past endothelial cells under healthy circumstances.
But when we have an inflammatory stimulus, such as oxidized bad cholesterol, in the artery wall, the endothelial cells get a message to shift to an inflammatory state. They will stick up a molecular "Velcro" that will allow them to recruit white blood cells, slow them down, and actually grab them, so that they can then enter the wall of the artery.
So it's like there's a traffic cop that's directing the migration of these white blood cells and telling them to take up residence in the artery wall.
Once those white blood cells are resident in the artery, they become themselves a source of much more inflammation.
They will make a number of messengers of the inflammatory response—small molecules, larger protein molecules—and create an oxidative stress environment in the artery wall. And all of this noxious mixture will conspire to make the inflammation worse.
Now, because we [also] have natural inflammation inhibitors at play, there's actually a tug of war going on in our artery walls on a daily basis between pro-inflammatory mediators and signals and those that act to quell or modulate the inflammation. And that may be why atherosclerosis is such a chronic disease that can lurk unsuspected in our arteries over decades, because there's a balance between these pro-inflammatory and anti-inflammatory factors. But ultimately, when the pro-inflammatory factors gain the upper hand over a sustained period of time, that sets the stage for the kind of atherosclerotic plaque that is likely to burst open, cause a blood clot, and a heart attack, stroke, or sudden death.
Now, we've also learned that there are different kinds of fatty plaques in arteries. They aren't all the same. There are some that are quite fibrous, leathery, and tough, characterized by a large accumulation of protein molecules, such as collagen and elastin. On the other hand, there are atherosclerotic plaques, and those are the ones that are particularly characterized by heightened inflammation, where this dense proteinaceous matrix that surrounds the cells has become weakened. In fact, we understand in exquisite molecular detail that the white blood cells that are activated in the inflammatory response can release enzymes that actually chew up these leathery protein molecules, weaken the plaque, and make it susceptible to rupture. And of course, when a plaque ruptures and pops open, it can expose its internal contents to the blood. Often when cells have been activated in an inflammatory response, they boost their production of mediators that cause blood coagulation. So when we have a popped plaque, we set the stage for a sudden blood clot, and that is all too often the root of a heart attack, a stroke, or sudden cardiac death.
Changing Demographics and the Impact of Obesity
INTERVIEWER: Since you began working in this profession, have you seen any changes in the demographics of heart attack victims?
LIBBY: When I was a young doctor getting my start in cardiovascular medicine, our typical heart attack patient was a middle-aged white male who had high blood pressure, a high bad cholesterol, and very often was a smoker. The demographics of the heart attack victim are changing before our eyes, especially with effective treatments for cholesterol and blood pressure and a trend towards a decrease in smoking. At least in the US, there's a big shift in the risk factor palette that is causing most heart attacks. The disease is, I'm sorry to say, becoming much more democratic. Women as well as men are increasingly affected by heart attack and cardiovascular risk factors. Certain minority populations, such as Hispanics and Blacks and Asian Indians are at particular risk now for cardiovascular disease. The traditional risk factors such as high cholesterol and high blood pressure have receded somewhat in terms of our typical burden of risk factors. What has replaced them is increased fat accumulation.
INTERVIEWER: What role does obesity play?
LIBBY: We now understand that fat tissue is not just an inactive storage depot for energy, but that the fat cell and the inflammatory cells that accumulate in fat, particularly the fat that accumulates at our belly, are a source for a myriad of chemical messengers, which can themselves promote inflammation. So when we have excess fat tissue, we are actually amplifying cardiovascular risk, and the kinds of mediators that are elaborated by the fat tissue are very potent promoters of the atherosclerotic process.
Also, of course, we're witnessing an explosion of diabetes and pre-diabetes which some people call metabolic syndrome. The most prevalent risk factor for diabetes in adults, and for the metabolic syndrome, is carrying around too much fat tissue in your middle. The main culprit that we're having to do battle with today, and for the foreseeable future, is excess fat tissue.
INTERVIEWER: Why is it that fat around the midsection is more risky?
LIBBY: We've learned that not all fat tissues are the same metabolically. The kind of fat that accumulates under the skin seems to be metabolically less dangerous than the kind of fat that accumulates around your organs in the belly. Men in particular tend to carry their fat tissue inside their belly—some people refer to that as the apple pattern of obesity—and women tend to carry it more in the hips and in the subcutaneous tissue that is under the skin, and that gives them more pear-shaped distribution of fat. The pear-shaped fat distribution seems to be less lethal than fat in the belly.
One of the reasons that this visceral adipose tissue, or the fat tissue that is inside the belly, seems to be so mischievous is that it can drain its contents directly to the liver and cause the liver to boost its production of certain proteins that are involved in the regulation of blood clotting. For example, when inflammatory signals are released from fat cells in your belly, then goes directly, straight chute, to the liver, which can then increase its synthesis of fibrinogen, which is the important precursor for blood clots, and also of a protein called plasminogen activator inhibitor 1 (or PAI-1), which is a blocker of our endogenous clotbusters. So we have a double whammy when a fat cell showers the liver with inflammatory signals, we increase the coagulability of blood, and we decrease the ability of the body's own clotbusting system to chew up any clots that may form—and that sets the stage for too many blood clots forming and sticking around.
I like to think of atherosclerotic risk as not limited to the particular locus, locale in the artery wall. If we have blood flowing around the plaque which is prone to coagulation, then we'll get much more mischief from a rupture of a plaque than if we have a healthy blood. So think of the solid state of the plaque as one place where there's a balance between procoagulant and anticoagulant factors. And there's also the fluid phase of the blood, which is bathing the plaque, which also has a balance between pro-clotting and anti-clotting factors. What can tip the balance in that fluid phase of blood are the products of the inflammatory response, which is incited by the excess burden of fat tissue that too many of us carry in our belies these days.
Other Ways to Identify Who is At Risk
INTERVIEWER: Besides looking at the traditional "risk factors", are there any ways of predicting who atherosclerosis and cardiovascular illness are likely to affect?
LIBBY: During the inflammatory response, the liver shifts its pattern of protein synthesis from ordinary housekeeping proteins, such as albumin, which is a major protein that flows through our bloodstream, to production of a special set of proteins called the acute phase reactants that are used in host defenses. These certainly serve as a very useful marker of the inflammatory state. Some of these acute phase reactants that are poured out of the liver when it senses danger or inflammation are easily measured in the blood, and shift from very, very low levels in the normal healthy person to extremely high levels in someone who is ill—for example, a person with pneumonia or an acute inflammation or the like.
What we've learned over the last decade or so is that people with a subtle chronic low-grade inflammatory burden of the type that we associate with atherosclerosis and atherosclerotic risk factors, show subtle elevations in some of these acute phase reactants. [These reactants] can be very conveniently and inexpensively measured in a blood sample, which actually provide us a crystal ball for looking into the future at that individual's cardiovascular risk. By measuring an inflammatory mediator, one of which is known as C-reactive protein or CRP, we can add prognostic information to [the information] we can get from the usual spectrum of cardiac risk factors such as blood pressure, gender, good cholesterol, bad cholesterol, age. And this provides us with a way to actually link the basic science of inflammation to [clinical practice], and may provide us with a new and powerful tool for picking people out of the population who do not appear, according to traditional risk factors, to be at particular risk of a heart attack or stroke, but who have a subtle inflammation that may single them out for more intensive preventive therapy.
I think it's very important to understand that the use of markers of inflammation, like C-reactive protein, are not just going to show us some people who need more intensive treatment, but they may also identify a segment of the population for whom that treatment would be superfluous. So I think we're going to be able to target our cardiovascular therapies much more intelligently by adding to our usual panel of cardiovascular risk factors some of the emerging markers such as C-reactive protein.
The Future of Cardiovascular Medicine
INTERVIEWER: What do you see as the future of cardiovascular medicine; where will cardiovascular research and treatment go from here?
LIBBY: You know, in cardiovascular medicine, we're becoming victims of our own success. We finally have therapies that are really very effective for preventing heart attack and stroke. If we want to make further inroads against the considerable residual burden of disease, we must show a statistically significant difference between baseline treatment and a new treatment added on top of the effective baseline treatment. [To do that] we need to have a large number of individuals studied over a prolonged period of time. That, of course, entails a great deal of patience, a great deal of expense, and is a great challenge in cardiovascular therapeutic development. So we desperately need ways in which we can decide which agents are going to be worthy of that kind of very intensive and expensive and prolonged investigation.
How are we to choose which emerging therapies are the most promising for continued clinical investigation? I believe that by harnessing inflammation biology, we may have tools that will help us out of this quandary. For example, we may get an early hint that an agent is affecting the biology of atherosclerosis in a beneficial way by following serially some of the inflammatory markers, like C-reactive protein. That's a hypothesis, it isn't proven, and ultimately our regulatory agencies are going to demand that we actually show a clinical benefit using hard endpoints. But I think that the harnessing of some of these biomarkers will allow us to have a weigh station for figuring out which new therapies [might merit] this arduous clinical investigation that's required.
[Also,] using imaging technologies to actually visualize inflammation in the living patient [could] be another very promising way to find out early on, with a relatively small number of patients, whether or not a given therapeutic [approach] is likely to yield a clinical benefit. If we're able to quell inflammation with a particular therapy, and show that with biomarkers or with imaging technologies that look at the molecular biology of what's happening in the plaque, then I think we're going to have a very powerful set of tools to move forward, and develop new therapies.
INTERVIEWER: How do new technologies specifically assist these processes?
LIBBY: Traditional cardiovascular imaging technologies have looked at the anatomy or structure of the blood vessels of the heart. We're now entering a new and very exciting area of molecular imaging where we're going to go beyond anatomy into actual function and biology. In partnership with Dr. Ralph Weissleder, we're learning how to image inflammation, for example, where we can actually look at the molecules that are expressed by endothelial cells to capture white blood cells. We're able to look at the white cells that are captured and take up residence in the artery wall. We're actually able to distinguish those white cells in the artery wall that are excited and angry in an inflammatory sense, versus those that are just quiet and resident, not up to any mischief. We are also learning how to measure [the permanence of] the molecular machines that we [believe] chew up the leathery matrix which ordinarily protects the plaque from rupture. These proteinases can also be visualized with molecular imaging techniques that are being developed in conjunction with Dr. Weissleder. And these techniques are really a very promising way of getting close to imaging the very processes that provoke the clots that cause a heart attack and sudden death.
So by harnessing inflammation biology, learning how to image inflammation, I think that we're going to have wonderful tools that will help us validate in living human beings our experimental laboratory work, help provide us with very important clinical tools for the evaluation of new therapies, and maybe even eventually produce routine [methods of] diagnosis.
We're [also] entering a very exciting era of individualized medicine when we'll be able to harness the mastery of the molecular biology of disease and take the fruits of the [work on mapping the] human genome, and really apply [these] into clinical medicine in terms that will allow us to provide individual, tailored treatments.
In my professional lifetime, we've undergone a revolution in our thinking about cardiovascular medicine and physiology. We actually thought very much like plumbers and hydraulic engineers when I entered cardiology. We thought of the heart as a muscle, as a mechanical device. We thought of the blood vessels as a hydraulic system of tubes. We now have entered an era of biology, of cardiovascular physiology and medicine, where we think of the heart muscle much more subtly in terms of the function of the individual heart cells, and the teeming messages that are controlling the contraction of each heartbeat. And likewise, the blood vessels are no longer viewed as mere conduits or passive tubes, but as living structures that are actually the root cause of the two major problems of heart disease, that is, high blood pressure and atherosclerosis or hardening of the arteries. So we have transitioned from being plumbers, if you will, to becoming much better biologists, and I think that these new understandings open up a wonderful window to the future in terms of what we're going to be able to offer in the way of prevention and care.