Brian Firth: Thank you, Amir; that was a terrific presentation. I was talking to my colleagues at Cordis who work in this field; they said that there are really only three issues of import on the subject of vulnerable plaque: 1) definition; 2) detection; and 3) treatment. You touched on all three of these very nicely, and I really like your red wine solution! We do have much to learn in regard to vulnerable plaque. You did an excellent job of discussing the issue of the local problem; the main focus has always been on the problem presented by thin-walled plaque. Amir Lerman: We are currently missing concrete proof. Some studies are coming out suggesting that improvement of endothelial function is associated with a reduction in event rates. But we’re missing the other arm — the prospective study that is not focused on the treatment of risk factor patients, but rather on the treatment of endothelial dysfunction. Thus, we must go beyond the city health clinic-type treatment strategy. There are patients who, for example, have a cholesterol level of 250, and yet have normal endothelial function and may do just fine. On the other hand, patients who have a cholesterol level of 180, but endothelial dysfunction, should be treated with statins. We look at the cholesterol reduction with statins as a side effect. The improvement observed has nothing to do with cholesterol reduction. Kirk Garratt: Brian, you clearly outlined the 3 main issues with regard to vulnerable plaque, but you didn’t really tell us what direction Cordis is taking in the area of vulnerable plaque detection. Is this something you will continue to pursue, or are you feeling somewhat discouraged? Brian Firth: I was not being facetious when I indicated those as the three main issues. The question of definition is problematic because early on, there was intense focus on the termperature of plaques. We are faced with the question of whether it really matters to detect vulnerable plaque in the already vulnerable patient. We are still looking at the issue of vulnerable plaque detection and are actually involved with companies in the field. Second, we must ask: Is the vulnerable plaque just a site, or is it a region? The Kuntz hypothesis holds that most big myocardial infarctions (MIs) occur in the proximal third of the coronary arteries, so if they are treated, should it be done systemically or regionally? Systemic therapy presents its own pitfalls in the sense that many of these patients are on so many different drugs, that the problem of polypharmacy arises. These patients cannot tolerate another drug. Our focus at Cordis/J&J is on a device-based approach — be it local or regional. This may not, however, be the solution in the vulnerable patient. Richard Myler: Most infarctions occur proximally in the coronary arteries because most of the branches are located proximally. Thus, most of the vulnerable or unstable plaques are found at bifurcations. If you picture a riverbed, where the river divides, the silt falls out. Brian Firth: If asked where an MI is most likely to occur, the odds are that you would guess the proximal third. If local therapy were to work, then how much of the vessel should be treated? That’s just one approach. Richard Myler: Of course, there are lesions located distally as well, but most will be found where the “riverbed” divides. Kirk Garratt: Amir, you made a distinction early on regarding the different paths an atherosclerotic lesion can take and how not all lesions lead to events. Is it important to recognize that not all lesions will cause death or infarction? We can’t even accurately predict which regions are more likely to lead to death or infarction, though the proximal third portion is probably important for many reasons. Amir Lerman: First, I want to challenge this notion of most events occurring in the proximal third portion, because a number of autopsy studies suggest otherwise. Our primary aim is to prevent acute, large MIs and sudden death. More than 50% of the patients who had a large, acute myocardial infarction (AMI) resulting in sudden death had no prior symptoms; sudden death was the first manifestation of their cardiac disease. Various studies show that AMI, plaque rupture, or acute coronary syndrome (ACS) are the cause of sudden death in no more than 50% of patients. Thus, it may be that plaques undergo their own natural history; some calcify and some undergo a small rupture. In order for MI to occur, a plaque must be in the wrong place at the wrong time. There are environmental factors as well, such as the time of day. A greater percentage of MIs occur in the morning. We tell our patients to get up later, but that doesn’t seem to work! There is a sort of cross-talk between the plaque and the circulation. We must also identify the patients who are at risk and determine why their circulation is at risk. The approach must be a combined one in terms of prediction and detection. Tim Fischell: I have been thinking a lot about the problematic area of vulnerable plaque. I see a couple of salient issues. First, we don’t really know what vulnerable plaque is, and we don’t have a good means of identifying it invasively or non-invasively. There are no natural history studies to tell us what type of risk can be predicted by a given plaque’s appearance. Such a study would take 3–5 years of following thousands of patients. For the highest-risk plaques, somewhere in the range of 1–2% per year are at risk of rupturing and causing MI. And, the risk of a particular plaque that looks vulnerable today being vulnerable next year is also an unknown. The plaque may heal, while another plaque downstream ends up being the culprit. That’s the other part of the natural history that we have not yet figured out. Obviously, it is not feasible to invasively observe vulnerable plaques by putting catheters down all three coronary arteries (LAD, the circumflex, and the RCA) every six months throughout the lifetime of all 280 million American adults. Thus, the concept of invasive monitoring of vulnerable plaques is fraught with problems. It would be great to be able to use non-invasive means, such as MRI, throughout the lifetime of every patient to determine, for example, that when a plaque looks a certain way, it presents a 2%, instead of a 0.4%, risk of MI in the next two years. We are probably talking about really low risks, per plaque. Steve Ellis published a terrific paper in Circulation about 15 years ago. He found that 70–80% lesions have a much higher risk of causing MI than 50% lesions. One of the biggest misconceptions about vulnerable plaque is that minor lesions are much more likely to cause MIs, but actually, it’s just that there are a lot more of them. The risk of MI in the LAD, as a function of angiographic severity, rises until about 95% diameter stenosis, and then drops in even more severe lesions, presumably due to collateralization. Thus, the concept that 40% lesions are more dangerous than 80% lesions is probably incorrect, because there are ten times more 40%-type lesions. Second, there is the problem involving treatment. We probably already have therapies to treat vulnerable plaque. We know, for example, that LDL is a big driver of vulnerable plaque. How good are we, as a medical community worldwide, at identifying patients with high cholesterol, treating them effectively, and getting them to a target level? First of all, only 20% of Americans know what their cholesterol level is, and only 50% of those people have consulted with their physician and been put on medication to treat their high cholesterol. Only 50% of these patients have stayed on their medication because of undesirable side effects, or cost. Thus, only about 1 of every 20 Americans with high cholesterol is being treated effectively with a statin. Steve Nissen has shown that 75% of American men over the age of 40 have coronary artery disease (CAD). When patients come to see me and ask if they have CAD, I don’t need ultrafast CT to answer their question, I simply ask them their age and put that together with their gender. If the patient is male and over the age of 40, then my answer is “yes.” The answer is that everyone has CAD, and we need to decrease risk factors for the entire population. I believe that systemic treatment offers the greatest promise. The new Pfizer drug we are currently studying, for example, raises HDL to 90. When combined with a statin, you can lower LDL to 80. I think that arresting the disease by creating an HDL to LDL ratio of 1.0 will reduce event rates. But we must do better than treating only 1 out of 20 Americans with high cholesterol in order to make an impact. Another important question is: Can we afford to treat 200 million Americans with a pill that costs, say, $10 a day? Kirk Garratt: The cholesterol basis for most coronary events is well understood, but what about the 51-year-old woman whose case you discussed? She probably didn’t have a large atheromatous burden. It sounds to me like you were saying that we are focusing excessively on the subendothelial space, and that we should begin to focus more on endothelial health. Amir Lerman: The reason I presented this case example was to highlight the fact that there are several precipitating factors we fail to recognize in patients with ACS or AMI. We base our concept on the need to treat the endothelium because it is an organ, and it fails. Like renal failure or kidney failure, there is endothelial failure. Endothelial failure has many manifestations; it can have an impact on Alzheimers’s disease, dementia, and so forth. Endothelium is everywhere that blood vessels are found in the body. Research has found that if a patient has coronary arterial dysfunction, the risk of stroke is 4.1%. Thus, we must find a treatment that protects the endothelium. I don’t know what exactly the ideal treatment will be. Perhaps it will be a combination of ACE inhibitors and statins, or the new Pfizer drug, or fish oil and red wine, or less stress in one’s daily life. Environment, of course, is different for all of us. Some people are exposed to more mental stress than others, for example. One of the reasons many drug companies are entering this field is because until now, to bring a new drug to market that reduces atherosclerosis, these companies have had to conduct another 4-S trial with thousands of patients who would be followed for 10 years, and by the time the study was completed, most of the investigators would be dead! Thus, we must find a more sensitive surrogate for detecting disease, and we now have endothelial function. The FDA is now approving endothelial function testing as an end point for new drugs. Tim Fischell: The new Pfizer trial, headed by Steve Nissen, has an FDA-approved end point of IVUS plaque burden 18–20 months after starting drug therapy. This is a randomized trial with Lipitor versus Lipitor plus HDL increase. The FDA has apparently suggested that they are going to approve this drug based on a reduction of plaque volume with the assumption that it will reduce clinical events. I believe the trial will prove that this drug is effective in reducing clincial events. Amir Lerman: I still don’t completely agree with the trial, though I know that the FDA approved it with IVUS. I think there is a sub-arm of the study to look at peripheral endothelial function. It depends, I think, on what the indication will be. If the indication for the drug is a reduction in plaque volume by ultrasound, then perhaps the drug will be approved. There is no relationship between the degree of disease and ultrasound and events. There is no correlation either between ultrasound findings and coronary endothelial function. Pierre Leimgruber: I will try to be provocative here. A new drug has been introduced that may reduce plaque volume, but Amir just presented very clearly what the endothelial problem really is. Thus, unless we get to the root of the problem, we are simply continuing the Band-Aid approach. But, what causes endothelial dysfunction in some people? And why does endothelial dysfunction lead to MI in some of those people, but not in others? We currently only have one treatment, just like the balloon used to be the only treatment for stenosis; now we just treat patients prophylactically with statins, ACE inhibitors, beta-blockers — all of which amounts to a “shotgun” approach. It would be great to have some genetic information to indicate which patients will have a problem when they reach age 45. Research should target the cause of endothelial dysfunction, instead of trying new drugs that address some particular aspect of the problem. Amir Lerman: You are absolutely right. The good part is that endothelial dysfunction is reversible. Reversal can be induced. When we look at the corps postulate of CAD, we can fit endothelial dysfunction to the corps postulate and see that it fits. A patient with normal endothelial function can be infused with oxidized LDL, or given a high level of homocysteine, thereby inducing endothelial dysfunction. This can then be reversed by removing the factor. Likewise, a patient with endothelial dysfunction can be treated with ACE inhibitors for 6 months and will show improved endothelial function. Tim Fischell: Don’t you agree that most EDRF problems are actually acquired? There is obviously some genetic susceptibility, but factors such as hypertension, smoking, high LDL, and diabetes have all been independently proven, using intracoronary acetylcholine infusions, to impair EDRF production. And almost all of these are acquired, preventable, and treatable risk factors. It can be clearly shown that when a person smokes a cigarette, his EDRF goes down, or within an hour of eating a Big Mac, EDRF impairment occurs. Thus, most endothelial cell problems are largely preventable, or reversible, with lifestyle changes such as exercise, diet, and treatment of hypertension and hypercholesterolemia — it’s just a challenge to actually get patients to do what’s necessary to make these changes. John Anderson: I was glad to hear you mention Bob Vogel’s study, because he presents both good and bad news. One thing he points out is the very dynamic action in the endothelium: Give a person a Big Mac, and his endothelial function changes very rapidly. There’s a spectrum of reactivity in all of us – we’re all going to die of vascular disease if cancer or a car accident don’t kill us first. Don Honeyhuck said 15 years ago that we should put statins in the water, because endothelial dysfunction is a general problem. Whether we understand how statins work does not matter; the fact is, they do work and they do many things that we have yet to discover. I also want to emphasize the significance of the impact of stress on the endothelium. Stress can very quickly change the endothelium, and it can kill you. I think that the case of the female minister was a good one. Bob Vogel has quoted some studies recently suggesting that a woman’s daily intake of wine should be one glass per day, and a man’s should be 1.5 glasses per day. Beyond those amounts, the mortality rate begins to climb. Jeff Bradley at Duke University, who heads their Mindfulness study, has worked with Marty Sullivan at Duke, who ran their Heart Failure Center. These two believe very strongly in the mindfulness concept. Jeff just published a book on the subject. It discusses how to reduce stress. Kirk Garratt: I’d like to open the discussion now to the general audience. Jim Adams: You discussed why rupture occurs in the proximal vessels. An MIT study conducted a few years ago by a group of engineers looked at shear stress that occurs in the arteries. They found that shear stress was very high around the edges, whereas it was very low where the solid, fibrous plaque was located. I was thinking about this one recent summer as I watched my kids jump on the trampoline. We tend to think of this cross-sectionally, when we really should think about it three-dimensionally. The artery wall is like a trampoline, with a fibrous top that goes up and down. In times of stress, the stress increases in the proximal vessels where pressures are higher and where the “trampoline” gets worked much more, especially on the edges where the “springs” are located. The springs are placed around trampoline edges because they bear the most stress. During times of stress, the vessel trampoline works on the plaque, just like you work on a paper clip, so it’s no small wonder that this is where rupture occurs. Second, I would like to pay tribute to Dr. Myler’s excellent talk earlier. Dr. Myler was my attending physician in 1972–1973 at the University of California. When he returned from Switzerland in 1979, his first patient was from our practice. The patient was treated at St. Mary’s. We watched Dr. Myler develop the program in the 1980s in San Francisco. I recall a quote by Dr. “dunking doughnut” theory — that the problem is not in the hole. I’ll let you tell everyone, Dr. Myler. Richard Myler: That article titled “Bigger is Better” was one of the worst I’d ever read! The problem lies in the doughnut, not in the hole! The problem is in the endothelium in the artery wall. Barry George: I very much enjoyed your talk, Dr. Myler. I have one request: May I have a copy of your slides on plaque? They are fantastic! I think you are preaching to the wrong choir. The reason I say that is because nearly everyone in this room has dedicated his/her life to finding a mechanical solution to a biochemical problem, because we don’t know how else to approach the matter. There is much we still don’t understand. First, we don’t even know how to identify the vulnerable plaque, and then we don’t know how to treat it. But what we do know, as of 2004, is this: There are things out there that work, and they are systemic. I am intrigued by the poly-pill and I really t hink that this is the direction we should take. Let’s face it folks: endothelial dysfunction will be best treated systemically, not interventionally. There may be occasional cases where we interventionists “sneak” into a patient’s artery and place a stent that will provide some regional biochemical therapy, but endothelial dysfunction, in general, will not be treated by catheterizing everyone. That’s just reality. We interventionists are not pill-pushers; we are, by-and-large, mechanics, or “lumenologists.” We need to take a step back and determine where we are headed in the next three to five years. By the way, you still didn’t answer the question about whether Cordis is doing anything. Is Cordis looking at regional therapy using mechanical means? Brian Firth: The answer is “Yes.” Barry, your point is well-taken. I happen to agree with you that the best solution is likely a systemic one. On the other hand, our charge is to determine whether there is a local and mechanical piece to this puzzle. Amir Lerman: At an academic center-type cath lab where 6,000 cases are performed yearly, the number of interventional procedures does not exceed 30% of total volume. That means that in every cath lab, approximately 20–25% of the patients who are referred for an angiogram due to suspected ischemia do not have obstructive disease. It is true that these patients will not receive a stent, but they will be on your table. And since they are already on your table, you may want to use some device from Cordis, for example, that will help you determine if the patient is vulnerable. Bernhard Meier and Patrick Serruys published a paper in the European Heart Journal regarding sealing with stent implantation. They showed an increase in mortality in the patients they tried to seal, which led them to conclude that the current treatment is riskier than the potential event. We will see more and more of these patients in the cath lab because we treat them with statins and ACE inhibitors and find that they do not have obstructive disease. We must find a way to identify these patients in the cath lab when they arrive. Barry George: I enjoy restoring old cars. When an automobile is burning oil, I put new spark plugs in. It seems that we do a similar thing in interventional cardiology, with stenting and all the lumenology stuff we do. But, in essence, we are treating a biochemical problem with mechanical means.