- Email: [email protected]
Roundtable discussion
Roundtable Discussion Dr. William C. Roberts (Dallas, Texas): The connection between thrombosis and lipids and the substances secreted by cells within the blood and those within the walls of vessels is really coming to the forefront now. This conference is an attempt to interrelate these things a little better. Dr. Daniel Steinberg (San Diego, California): What is most impressive to me about what has happened during the last decade is the convergence of approaches from different directions. We no longer have a wall between the lipidologists, who don't know what a growth factor is, the people who look at vessel walls but don't know what a lipoprotein is, and the thrombosis people, who don't care much about anything except why blood clots. Dr. Erling Falk (Odense, Denmark): There are a lot of well-known risk factors for ischemic heart disease. I would like to know how these risk factors work at the plaque level. If I look in the microscope at coronary plaque, I cannot tell whether it is from a male or a female, an old or young person, a smoker or nonsmoker, a patient with hypertension or one with hypercholesterolemia--and this bothers me because I expect there must be differences in the way a lesion progresses in a patient with hypertension or a smoker or a patient with hypercholesterolemia. But in the literature there are no characteristic features of the plaque that help us to differentiate between patients with different risk factors for ischemic heart disease. I would also like to know how lipid-lowering therapy reduces the risk of a thrombosis-related heart attack, without reducing the degree of stenosis to any significant degree.
- Dr. R. Wayne Alexander (Atlanta, Georgia): I think that the evidence that this is, in fact, an episodic disease is becoming compelling, at least in the later stages at which we deal with it clinically. It seems to me that in the past we have had the attitude that this is just a linear, progressive disease, and then something bad happens. Angiographic data, in fact, suggest that there must be episodic growth and change in lesion development. We see lesions that have been stable from one angiographic encounter to another, separated by years; sometimes the lesion will be perfectly stable; on the other hand, you may see one that goes from nonexistent, or virtually nonexistent, to being occlu-
sive in just a few months. One of the major issues we need to define is who is susceptible to this disease? We know a lot, in general, about risk factors, but we have no good methodology for identifying susceptibility: Who has the disease as opposed to who is at risk for the disease. And we have no diagnostic modalities that are based on the disease itself. Virtually all of our diagnostic modalities are based on hemodynamic consequences of the disease, and we have no therapeutic endpoint for the disease itself. We can lower blood pressure, we can lower cholesterol, we can do other kinds of interventions--and we still don't know w h e n the disease is being treated. Dr. Falk: I think that a severe stenosis is just a marker of coronary artery disease. Dr. Roberts has shown that patients with ischemic heart disease have either diffuse coronary artery disease or confluent plaquing. For every apparent angiographic stenosis there may be 10-20 plaques that don't appear on an angiogram.
Dr. Alan M. Fogeiman (Los AJ~.:~..~, C a l o r . nla): You may have a flow-limiting lesion, but it is not going to kill you; it is much more probable that you will have a number of non-flow-limiting lesions, some of which may be at very high risk for rupture and cause thrombosis with complete occlusion and myocardial infarction. Dr. Falk: No one disputes that there is an association between the level of serum cholesterol and subsequent development of acute myocardial infarction, but only a small fraction of patients with acute myocardial infarction have very high serum cholesterol; there are so many more patients at risk with "normal" or only moderately elevated serum cholesterol. It is the same with lesions in the coronary arteries. There are so many more lesions at risk that are only moderately stenosed, and they are the ones that give rise to the great majority of cases of acute myocardial infarction.
Dr. H. Bryan Brewer (Bethesda, Maryland): The study of lipoproteins is becoming much more sophisticated. There is a very clear indication that subfractions of lipoproteins within the plasma have very different physiologic roles in terms of lipid transport and, therefore, may be very difficult to measure. It may be that it is abnormalities in the lipid subfractions that are causing very clear abnormalities in lipoprotein metabolism in those paA SYMPOSIUM: ATHEROTHROMBOSIS
tients who seem "relatively normal" in terms of the stages of disease progression, we have to ask how lipid. In fact, many patients who have coronary the vessel wall integrates a variety of pathogenic artery disease may have only mild elevations of stimuli into these outcomes. Dr. Falk: The risk associated with coronary cholesterol, and a number of kinetic studies have shown that many patients who have normal or only atherosclerosis has something to do with thrombus slightly abnormal fasting lipid levels may have formation. If we can eliminate thrombus formamarkedly abnormal lipid metabolism. Thus, tion, survival is good. The patient may have angina whereas testing may reveal only mildly elevated pectoris, but will survive. We know from experimenfasting LDL, HDL, or triglyceride levels, there may tal studies in which atherosclerotic lesions are still be a very abnormal lipoprotein metabolism, induced in animals that when yott place the lewhich cannot be assessed by simply measuring the sioned animal on a lipid-lowering diet, the first cell fasting lipid level. This suggests that it is the flux of that disappears from the lesion is the macrophage/ lipoproteins, an entirely different issue, that we macrophage-foam cell. It is the first to appear need to address. when you induce the lesion, and it is the first to Dr. Peter Ganz (Boston, Massachusetts): I disappear with "regression." So the macrophage/ agree that there has been too much emphasis by macrophage-foam cell probably has something to cardiologists on measuring severity of stenoses, as do with stability of the lesion. if that measurement in some way can predict the Dr. Xl~utmi~n. There is clear evidence that, on clinical course in patients. It has become quite lesion rupture, the plaque shoulder is associated clear that, in fact, the most serious manifestations with intense deposition of white cells. This probof atherosclerosis are not related to the severity of ably indicates breakdown and compromise of the luminal narrowing. The severe stenoses are respon- plaque. Is that something that occurs episodically sible for exertional angina, but patients don't die of and acutely? What are the cellular and molecular exertional anginamthey die of myocardial infarc- mechanisms that account for the white cell accumution. It is an important distinction that certain lation? Dr. G i m b t ~ ' - For me an important working lesions cause angina while other lesions cause infarction, and the mechanisms are quite different. concept is that the cells of the wall, and the cells Dr. F a l l There is no good correlation between that migrate into the wall and take up residence plaque volume, stenosis severity, and the risk there, are not passive targets but active particiassociated with the lesion, probably because the pants. The notion of activation extends to all of the main component of atherosclerotic plaque is fi- cells we have been discussing: the endothelial cell, brous tissue, and only a minor component of the the smooth muscle cell, the macrophage, the T cell, lesion is the lipid-rich atheromatous component, and certainly, the platelet interacting at the vessel which is dangerous. It may very well be possible to interface. Which brings up the issue of what stabilize a lesion without any major reduction in dysfunction means. If all of these cells can be plaque volume, thus reducing the risk for a heart activated, is this activation really dysfunctional? attack. Well, not really. I prefer to define dysfunction as a Dr. Gatm~ With that in mind, one needs to nonadaptive phenotype; conceptually, I think that rethink the importance of regression trials for works. And for endothelium, as we tried to illusatherosclerosis. If mild lesions can cause myocar- trate, this might have to do with increase in dial irffarction, what is the use of trying to alter the adhesion molecules, secretion of cytokines that are severity of stenosis by a relatively small amount, c.hemoattractant, modification of permeability, and when, in fact, the manifestations have little to do modification of the oxidative state. But again, it is with the severity of stenoses. Cholesterol lowering not the stimuli that are critical but the context in is very importantmin terms of improving the clini- which the end result is being expressed. If we are cal course in patients--but it is likely so not going to develop new strategies for diagnosis and because of anatomic regression, b u t because of treatment, the major gains must be made by focusing (Dr. Alexander alluded to it earlier) on some functional change in the vessel wall. Dr. Michael A. Gimbrone (Boston, Massachu- the earliest events of lesion initiation, or at critical ~): Lipid accumulation and scarring, the hall- transition events. Dr. AIIoJtamdk~. One can at least rationalize the marks of atherosclerosis, are dysfunctional responses of the vessel wall, as are the inflammatory episodic nature of the disease on the basis of processes we have been discussing; and certainly, episodic activation of resident inflammation. Is so is plaque rupture or thrombosis. At different there continuing trafficking of white cells into THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75
FEBRUARY23, 1995
lesions? Is that a legitimate therapeutic target? Is the gruel and the thrombogenic core of these lesions due to white cell death? And is the source of that continued white cell accumulation--foam cell formation---death? And does a therapeutic strategy need to address this question? Dr. Falk: There has been a lot of talk about tissue factor. If there is significant tissue factor in the gruel, then it is probably derived from macrophages. By reducing the macrophage content, you may reduce the thrombogenicity of the lesion in case of plaque rupture. By lipid lowering, you may improve endothelial function and reduce thrombotic propensity of the blood, so that in case of plaque rupture it will not go on to thrombose because the balance has shifted in a lessened thrombotic direction. I don't think we need aim for plaque regression; we can just stabilize the lesion. Dr. George J. Miller (London, England): Much of what we have been talkingabout for the last day and a half has been a description of what are basically normal protective responses of the system concerned with homeostasis. Endothelial cell activation, monocyte activation, clotting factor activat i o n - t h e s e are all normally parts of a protective mechanism concerned with repair of ongoing damage to the vascular system; therefore, we have to think very carefully before we attempt to intervene at specific points in any of these systems. Dr. Steinberg: In picking targets for intervention one should ask this question: Is it a target that is going to cause trouble? If you start fooling around with interleukin-1 or cytokines, maybe there will be trouble, because they are presumably there for some good reason--but I don't think there is any particular function served by oxidation of LDL, so that seems like a very attractive target. Dr. David G. Harrison (Atlanta, Georgia): It is quite clear that certain things occur very early on in hypercholesterolemia that lead to induction of oxidative events, perhaps by turning on certain enzyme ~stems such as lipoxygenase, xanthine, and xanthine oxidase. It is actually possible to envision vicious cycles occurring in which oxidation of LDL leads to toxic metabolite formation, which can generate free radicals, which inactivate nitric oxide (NO), which then leads to production of other toxic metabolites through degradation products of NO, which can then further oxidize lipoproteins and other important cellular proteins. And this may, in fact, contribute to the episodic nature of the disease process. Dr. Ganz: The reason we've been interested in NO is because it is a property of the vessel wall
measurable in vivo. But we hope that NO in some way gives us a window on some of the other dysfunctions in the vessel wall that may be occurring at the same time. So, we hope that NO dysfunctions are a part of the generalized activated endothelium. Dr. RonaM M. Krauss (Berlteley, California): The lipoprotein transport system may be built as much around triglyceride transport as around cholesterol transport. I wonder whether the role of some of the triglyceride-rich lipoprotei~s is linked to the inflammatory response in a way that has some biologic thrust in terms of fighting infect i o n - i n terms of its actual role in the inflammatory response, delivering certain agents to sites of inflamm a t i o n - p e r h a p s even some of the oxidizable lipids that may participate in the antimicrobial defense mechanism. I wonder whether part of the episodic nature of the disease we have been talking about, as some have suggested, could actually be linked to processes that are infectious or autoimmune in nature. Lipoproteins may, at least initially, be helpful; but in the increased state of lipid flux that we are all exposed to, they can then become toxic. Dr. Miller:. What seems to be happening against a background of hypercholesterolemia is that these systems become perverted in some way, so that the normal tissue repair pattern no longer occurs. The continuous bathing of the vascular system with high levels of LDL and minimally oxidized LDL disturbs the system and provokes an abnormal response, leading to plaque formation at sites where the vasculature is particularly vulnerable. It may well be that minimally oxidized LDL in high concentrations is itself enough to provoke damage at discrete sites on the endothelium. It may also be that when there is background damage going on at branches and so on due to hemodynamic stresses or toxins, then at such times high levels of oxidized LDL step in and pervert and prolong what normally would be a simple repair process. Dr. Brewer: Clearly we are learning a great deal about the heterogeneity of the plasma lipoproteins. The clear indication that it may be useful in the future to measure subfractions of lipoproteins, because it may give us new insights, for example, in identifying which patients are at risk and--which is clearly the real challenge for those involved with lipoproteins--what to do now for the clinician who is seeing patients in the office. While we have provided very good guidelines as to what to do with elevated levels of LDL, the physician is reading all the articles about Lp(a), HDL (whether high or A SYMPOSIUM: ATHEROTHROMBOSIS 9 ~
low), what to do about oxidation of lipoproteins, and what is the dense LDL particle. In particular, with a patient who has mild hypertriglyceridemia there is, I think, a great deal of dissatisfaction with the clinician's ability to know what to do. Dr. Scott M. Grundy (Dallas, Texas): Certainly, we should continue the public health approach toward primary prevention; that is extremely important. We are making great strides in that area, as evidenced by the fact that cholesterol levels in Americans have been coming down progressively, particularly in the last 10 years. So, the public is getting the message, and we should reinforce that. From the clinical point of view, more emphasis on secondary prevention is very important right now. Dr. Steinberg: What about the interaction of lipids with the thrombosis system? I know there has been some work done, but I don't know where it stands now. Dr. Miller: This really is a quite intriguing field. We have a limited number of markers in the clotting system that we know definitely indicate the level of risk for an individual. One of these is factor VII activity, which, as I mentioned in the presentation, is one of the clotting factors that we use in our risk score. And ever since factor VII activity was looked at, it became very apparent that it was correlated quite strongly with plasma triglyceride concentrations. You just cannot get away from it. Anything that raises plasma triglyceride concentrations raises factor VII coagulant activity, except one condition--lipoprotein lipase deficiency. In lipoprotein lipase deficiency, despite massive triglyceride concentrations, factor VII activity is normal, and, of course, that is interesting to anybody in the thrombogenesis field because it is one of the conditions that is not associated with a high risk for coronary disease despite the massive triglyceridemia. One of the easiest ways to manipulate triglyceride levels is with dietary fat, and there is a very strikirlg effect, highly repeatable, on factor VII induced by a high-fat meal. Within 6 hours of taking a high fat meal, factor VII activity is raised quite considerably, and we now have assays that measure the level of activated factor VII circulating in the plasma. About 1% of factor VII normally circulates in the basal state, in its activated enzyme condition; after a high-fat meal this increases in a way that raises factor VII coagulant activity--to the level we quite frequently see in men at high risk for coronary artery disease. Now, this raises all sorts of intriguing questions. We've heard quite a bit about the importance of tissue factor in the gruel, in the soft pulp of an atherosclerotic plaque, ~B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75
and there is no more potent clotting factor, cofactor rather, than tissue factor--it is extremely potent: A few molecules of it combined with a few molecules of activated factor VII is all that is needed to get the system going. Epidemiologically, one of the striking findings coming out of long-term follow-up studies is that factor VII activity is not a particularly good marker for risk for nonfatal events but is a very striking marker for fatal events. It seems to tell more about what is going to happen if a man has'a heart attack, than whether or not he is going to have a heart attack in the first place. It obviously has some role in overall coronary events, but the association with fatal events is very striking. So, what happens to a patient when the atheromatous plaque ruptures? It depends, as we heard yesterday, on a number of factors. One is the thrombogenicity of the gruel itself, how much functioning tissue factor is in there. Another is the responsiveness of the blood at the time the lesion ruptures. Now, if it ruptures when the patient has twice the level of circulating activated factor VII as in the normal state, then it would seem fairly evident that the risk of serious thrombosis is much higher than at a time when factor VII is in a very quiescent state. So acute fluctuation in triglyceride levels may be very important for short-term risk of coronary disease. Dr. Jeffrey I. Weltz (Hamilton, Canada): We are really at a crossroads, because we have the pharmacologic tools to interrupt the mechanism at various points; but none of these agents--they are all parenteral--is of any use in large prospective studies. So, one of the things we need is to determine the key events and develop oral agents that can block these events. Dr. Miller:. When we think about the clotting system, we often think about fibrin formation and actual thrombosis. But it is worthwhile remembering that in all of us, at all times, the clotting system is in a basal level of activation. We are all generating thrombin right now, albeit at basal levels, and we can, in fact, raise this basal activity without actually promoting macroscopic thrombus formation. We are hearing more and more about thrombin and its effects on the endothelial cell in various systems. As we saw yesterday, it has a whole series of effects other than simple macroscopic fibrin deposition. And so, it may well be that the basal state in which the clotting system finds itself is something that we need to consider more. The rate at which thrombin is being formed in the basal state may have a lot to do with what is going on at the endothelial surface. FEBRUARY23, 1995
Or. Laurence A. Harker (Atlanta, Georgia): Most of what we have learned about the role of thrombosis in relation to atherosclerosis has been a result of intervention. There was a great debate about the importance of thrombosis in acute MI until we had streptokinase to document it; in fact, there was benefit--likewise, tissue plasminogen activator (tPA) was also found to be beneficial. Knowing that antithrombotic measures could be used to analyze specific mechanisms has enabled us to find out a lot about the pathogenesis of the process. Very good data suggest, in fact, that the episodic nature of the whole process may be entirely dependent upon the thrombotic complications superimposed upon a rupture. Dr. Grundy:. If thrombosis occurs with small plaques and they then grow larger, and then there is another plaque rupture and this leads to repetition of this process of growth and organization--if that is a critical part of atherogenesis--we need to understand this better, and it could be a potential point of attack very early in development of the disease. Dr. Harker: If, in fact, the hypothesis is correct, that when rupture occurs, tissue factor is critical to initiate the thrombotic response, then we should in a very short period of time have a way of testing this using a tissue factor inhibitor or equivalent to block this pathway, and to determine what the relative
benefit is going to be, both in terms of acute events that may complicate atherosclerosis and the actual progression process as it evolves. There is an important additional issue that underlies any analysis of the role of thrombosis in these events, and that is a safety issue. Obviously, the hemostatic process is there for a very good reason, and once there is clinical intervention in this process--and we must bear this burden--this indeed underlies the concerns about the direct antithrombins. Those dosages required to interrupt platelet-del3endent processes are going to be high, and one needs to minimize the risk by either decreasing the duration to an absolute minimum, so that the period of risk is minimized, or to determine ways of selecting those agents that have preferential antithrombotic versus antihemostatic effects. We have not been very successful doing this with the antithrombins, and it suggests that antithrombin therapy of the direct type illustrated by hirudin must be selected for already-established lesions--presumably by parenteral administration--and we need to define for how long and for which patients this may be appropriate. On the other hand, if we are going to consider large prevention trials, then we are really talking about figuring out what the trigger is. If that, in fact, is tissue factor, then we clearly need agents that lend themselves to oral administration.
A SYMPOSIUM: ATHEROTHROMBOSIS 9 7 B
- Dr. R. Wayne Alexander (Atlanta, Georgia): I think that the evidence that this is, in fact, an episodic disease is becoming compelling, at least in the later stages at which we deal with it clinically. It seems to me that in the past we have had the attitude that this is just a linear, progressive disease, and then something bad happens. Angiographic data, in fact, suggest that there must be episodic growth and change in lesion development. We see lesions that have been stable from one angiographic encounter to another, separated by years; sometimes the lesion will be perfectly stable; on the other hand, you may see one that goes from nonexistent, or virtually nonexistent, to being occlu-
sive in just a few months. One of the major issues we need to define is who is susceptible to this disease? We know a lot, in general, about risk factors, but we have no good methodology for identifying susceptibility: Who has the disease as opposed to who is at risk for the disease. And we have no diagnostic modalities that are based on the disease itself. Virtually all of our diagnostic modalities are based on hemodynamic consequences of the disease, and we have no therapeutic endpoint for the disease itself. We can lower blood pressure, we can lower cholesterol, we can do other kinds of interventions--and we still don't know w h e n the disease is being treated. Dr. Falk: I think that a severe stenosis is just a marker of coronary artery disease. Dr. Roberts has shown that patients with ischemic heart disease have either diffuse coronary artery disease or confluent plaquing. For every apparent angiographic stenosis there may be 10-20 plaques that don't appear on an angiogram.
Dr. Alan M. Fogeiman (Los AJ~.:~..~, C a l o r . nla): You may have a flow-limiting lesion, but it is not going to kill you; it is much more probable that you will have a number of non-flow-limiting lesions, some of which may be at very high risk for rupture and cause thrombosis with complete occlusion and myocardial infarction. Dr. Falk: No one disputes that there is an association between the level of serum cholesterol and subsequent development of acute myocardial infarction, but only a small fraction of patients with acute myocardial infarction have very high serum cholesterol; there are so many more patients at risk with "normal" or only moderately elevated serum cholesterol. It is the same with lesions in the coronary arteries. There are so many more lesions at risk that are only moderately stenosed, and they are the ones that give rise to the great majority of cases of acute myocardial infarction.
Dr. H. Bryan Brewer (Bethesda, Maryland): The study of lipoproteins is becoming much more sophisticated. There is a very clear indication that subfractions of lipoproteins within the plasma have very different physiologic roles in terms of lipid transport and, therefore, may be very difficult to measure. It may be that it is abnormalities in the lipid subfractions that are causing very clear abnormalities in lipoprotein metabolism in those paA SYMPOSIUM: ATHEROTHROMBOSIS
tients who seem "relatively normal" in terms of the stages of disease progression, we have to ask how lipid. In fact, many patients who have coronary the vessel wall integrates a variety of pathogenic artery disease may have only mild elevations of stimuli into these outcomes. Dr. Falk: The risk associated with coronary cholesterol, and a number of kinetic studies have shown that many patients who have normal or only atherosclerosis has something to do with thrombus slightly abnormal fasting lipid levels may have formation. If we can eliminate thrombus formamarkedly abnormal lipid metabolism. Thus, tion, survival is good. The patient may have angina whereas testing may reveal only mildly elevated pectoris, but will survive. We know from experimenfasting LDL, HDL, or triglyceride levels, there may tal studies in which atherosclerotic lesions are still be a very abnormal lipoprotein metabolism, induced in animals that when yott place the lewhich cannot be assessed by simply measuring the sioned animal on a lipid-lowering diet, the first cell fasting lipid level. This suggests that it is the flux of that disappears from the lesion is the macrophage/ lipoproteins, an entirely different issue, that we macrophage-foam cell. It is the first to appear need to address. when you induce the lesion, and it is the first to Dr. Peter Ganz (Boston, Massachusetts): I disappear with "regression." So the macrophage/ agree that there has been too much emphasis by macrophage-foam cell probably has something to cardiologists on measuring severity of stenoses, as do with stability of the lesion. if that measurement in some way can predict the Dr. Xl~utmi~n. There is clear evidence that, on clinical course in patients. It has become quite lesion rupture, the plaque shoulder is associated clear that, in fact, the most serious manifestations with intense deposition of white cells. This probof atherosclerosis are not related to the severity of ably indicates breakdown and compromise of the luminal narrowing. The severe stenoses are respon- plaque. Is that something that occurs episodically sible for exertional angina, but patients don't die of and acutely? What are the cellular and molecular exertional anginamthey die of myocardial infarc- mechanisms that account for the white cell accumution. It is an important distinction that certain lation? Dr. G i m b t ~ ' - For me an important working lesions cause angina while other lesions cause infarction, and the mechanisms are quite different. concept is that the cells of the wall, and the cells Dr. F a l l There is no good correlation between that migrate into the wall and take up residence plaque volume, stenosis severity, and the risk there, are not passive targets but active particiassociated with the lesion, probably because the pants. The notion of activation extends to all of the main component of atherosclerotic plaque is fi- cells we have been discussing: the endothelial cell, brous tissue, and only a minor component of the the smooth muscle cell, the macrophage, the T cell, lesion is the lipid-rich atheromatous component, and certainly, the platelet interacting at the vessel which is dangerous. It may very well be possible to interface. Which brings up the issue of what stabilize a lesion without any major reduction in dysfunction means. If all of these cells can be plaque volume, thus reducing the risk for a heart activated, is this activation really dysfunctional? attack. Well, not really. I prefer to define dysfunction as a Dr. Gatm~ With that in mind, one needs to nonadaptive phenotype; conceptually, I think that rethink the importance of regression trials for works. And for endothelium, as we tried to illusatherosclerosis. If mild lesions can cause myocar- trate, this might have to do with increase in dial irffarction, what is the use of trying to alter the adhesion molecules, secretion of cytokines that are severity of stenosis by a relatively small amount, c.hemoattractant, modification of permeability, and when, in fact, the manifestations have little to do modification of the oxidative state. But again, it is with the severity of stenoses. Cholesterol lowering not the stimuli that are critical but the context in is very importantmin terms of improving the clini- which the end result is being expressed. If we are cal course in patients--but it is likely so not going to develop new strategies for diagnosis and because of anatomic regression, b u t because of treatment, the major gains must be made by focusing (Dr. Alexander alluded to it earlier) on some functional change in the vessel wall. Dr. Michael A. Gimbrone (Boston, Massachu- the earliest events of lesion initiation, or at critical ~): Lipid accumulation and scarring, the hall- transition events. Dr. AIIoJtamdk~. One can at least rationalize the marks of atherosclerosis, are dysfunctional responses of the vessel wall, as are the inflammatory episodic nature of the disease on the basis of processes we have been discussing; and certainly, episodic activation of resident inflammation. Is so is plaque rupture or thrombosis. At different there continuing trafficking of white cells into THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75
FEBRUARY23, 1995
lesions? Is that a legitimate therapeutic target? Is the gruel and the thrombogenic core of these lesions due to white cell death? And is the source of that continued white cell accumulation--foam cell formation---death? And does a therapeutic strategy need to address this question? Dr. Falk: There has been a lot of talk about tissue factor. If there is significant tissue factor in the gruel, then it is probably derived from macrophages. By reducing the macrophage content, you may reduce the thrombogenicity of the lesion in case of plaque rupture. By lipid lowering, you may improve endothelial function and reduce thrombotic propensity of the blood, so that in case of plaque rupture it will not go on to thrombose because the balance has shifted in a lessened thrombotic direction. I don't think we need aim for plaque regression; we can just stabilize the lesion. Dr. George J. Miller (London, England): Much of what we have been talkingabout for the last day and a half has been a description of what are basically normal protective responses of the system concerned with homeostasis. Endothelial cell activation, monocyte activation, clotting factor activat i o n - t h e s e are all normally parts of a protective mechanism concerned with repair of ongoing damage to the vascular system; therefore, we have to think very carefully before we attempt to intervene at specific points in any of these systems. Dr. Steinberg: In picking targets for intervention one should ask this question: Is it a target that is going to cause trouble? If you start fooling around with interleukin-1 or cytokines, maybe there will be trouble, because they are presumably there for some good reason--but I don't think there is any particular function served by oxidation of LDL, so that seems like a very attractive target. Dr. David G. Harrison (Atlanta, Georgia): It is quite clear that certain things occur very early on in hypercholesterolemia that lead to induction of oxidative events, perhaps by turning on certain enzyme ~stems such as lipoxygenase, xanthine, and xanthine oxidase. It is actually possible to envision vicious cycles occurring in which oxidation of LDL leads to toxic metabolite formation, which can generate free radicals, which inactivate nitric oxide (NO), which then leads to production of other toxic metabolites through degradation products of NO, which can then further oxidize lipoproteins and other important cellular proteins. And this may, in fact, contribute to the episodic nature of the disease process. Dr. Ganz: The reason we've been interested in NO is because it is a property of the vessel wall
measurable in vivo. But we hope that NO in some way gives us a window on some of the other dysfunctions in the vessel wall that may be occurring at the same time. So, we hope that NO dysfunctions are a part of the generalized activated endothelium. Dr. RonaM M. Krauss (Berlteley, California): The lipoprotein transport system may be built as much around triglyceride transport as around cholesterol transport. I wonder whether the role of some of the triglyceride-rich lipoprotei~s is linked to the inflammatory response in a way that has some biologic thrust in terms of fighting infect i o n - i n terms of its actual role in the inflammatory response, delivering certain agents to sites of inflamm a t i o n - p e r h a p s even some of the oxidizable lipids that may participate in the antimicrobial defense mechanism. I wonder whether part of the episodic nature of the disease we have been talking about, as some have suggested, could actually be linked to processes that are infectious or autoimmune in nature. Lipoproteins may, at least initially, be helpful; but in the increased state of lipid flux that we are all exposed to, they can then become toxic. Dr. Miller:. What seems to be happening against a background of hypercholesterolemia is that these systems become perverted in some way, so that the normal tissue repair pattern no longer occurs. The continuous bathing of the vascular system with high levels of LDL and minimally oxidized LDL disturbs the system and provokes an abnormal response, leading to plaque formation at sites where the vasculature is particularly vulnerable. It may well be that minimally oxidized LDL in high concentrations is itself enough to provoke damage at discrete sites on the endothelium. It may also be that when there is background damage going on at branches and so on due to hemodynamic stresses or toxins, then at such times high levels of oxidized LDL step in and pervert and prolong what normally would be a simple repair process. Dr. Brewer: Clearly we are learning a great deal about the heterogeneity of the plasma lipoproteins. The clear indication that it may be useful in the future to measure subfractions of lipoproteins, because it may give us new insights, for example, in identifying which patients are at risk and--which is clearly the real challenge for those involved with lipoproteins--what to do now for the clinician who is seeing patients in the office. While we have provided very good guidelines as to what to do with elevated levels of LDL, the physician is reading all the articles about Lp(a), HDL (whether high or A SYMPOSIUM: ATHEROTHROMBOSIS 9 ~
low), what to do about oxidation of lipoproteins, and what is the dense LDL particle. In particular, with a patient who has mild hypertriglyceridemia there is, I think, a great deal of dissatisfaction with the clinician's ability to know what to do. Dr. Scott M. Grundy (Dallas, Texas): Certainly, we should continue the public health approach toward primary prevention; that is extremely important. We are making great strides in that area, as evidenced by the fact that cholesterol levels in Americans have been coming down progressively, particularly in the last 10 years. So, the public is getting the message, and we should reinforce that. From the clinical point of view, more emphasis on secondary prevention is very important right now. Dr. Steinberg: What about the interaction of lipids with the thrombosis system? I know there has been some work done, but I don't know where it stands now. Dr. Miller: This really is a quite intriguing field. We have a limited number of markers in the clotting system that we know definitely indicate the level of risk for an individual. One of these is factor VII activity, which, as I mentioned in the presentation, is one of the clotting factors that we use in our risk score. And ever since factor VII activity was looked at, it became very apparent that it was correlated quite strongly with plasma triglyceride concentrations. You just cannot get away from it. Anything that raises plasma triglyceride concentrations raises factor VII coagulant activity, except one condition--lipoprotein lipase deficiency. In lipoprotein lipase deficiency, despite massive triglyceride concentrations, factor VII activity is normal, and, of course, that is interesting to anybody in the thrombogenesis field because it is one of the conditions that is not associated with a high risk for coronary disease despite the massive triglyceridemia. One of the easiest ways to manipulate triglyceride levels is with dietary fat, and there is a very strikirlg effect, highly repeatable, on factor VII induced by a high-fat meal. Within 6 hours of taking a high fat meal, factor VII activity is raised quite considerably, and we now have assays that measure the level of activated factor VII circulating in the plasma. About 1% of factor VII normally circulates in the basal state, in its activated enzyme condition; after a high-fat meal this increases in a way that raises factor VII coagulant activity--to the level we quite frequently see in men at high risk for coronary artery disease. Now, this raises all sorts of intriguing questions. We've heard quite a bit about the importance of tissue factor in the gruel, in the soft pulp of an atherosclerotic plaque, ~B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75
and there is no more potent clotting factor, cofactor rather, than tissue factor--it is extremely potent: A few molecules of it combined with a few molecules of activated factor VII is all that is needed to get the system going. Epidemiologically, one of the striking findings coming out of long-term follow-up studies is that factor VII activity is not a particularly good marker for risk for nonfatal events but is a very striking marker for fatal events. It seems to tell more about what is going to happen if a man has'a heart attack, than whether or not he is going to have a heart attack in the first place. It obviously has some role in overall coronary events, but the association with fatal events is very striking. So, what happens to a patient when the atheromatous plaque ruptures? It depends, as we heard yesterday, on a number of factors. One is the thrombogenicity of the gruel itself, how much functioning tissue factor is in there. Another is the responsiveness of the blood at the time the lesion ruptures. Now, if it ruptures when the patient has twice the level of circulating activated factor VII as in the normal state, then it would seem fairly evident that the risk of serious thrombosis is much higher than at a time when factor VII is in a very quiescent state. So acute fluctuation in triglyceride levels may be very important for short-term risk of coronary disease. Dr. Jeffrey I. Weltz (Hamilton, Canada): We are really at a crossroads, because we have the pharmacologic tools to interrupt the mechanism at various points; but none of these agents--they are all parenteral--is of any use in large prospective studies. So, one of the things we need is to determine the key events and develop oral agents that can block these events. Dr. Miller:. When we think about the clotting system, we often think about fibrin formation and actual thrombosis. But it is worthwhile remembering that in all of us, at all times, the clotting system is in a basal level of activation. We are all generating thrombin right now, albeit at basal levels, and we can, in fact, raise this basal activity without actually promoting macroscopic thrombus formation. We are hearing more and more about thrombin and its effects on the endothelial cell in various systems. As we saw yesterday, it has a whole series of effects other than simple macroscopic fibrin deposition. And so, it may well be that the basal state in which the clotting system finds itself is something that we need to consider more. The rate at which thrombin is being formed in the basal state may have a lot to do with what is going on at the endothelial surface. FEBRUARY23, 1995
Or. Laurence A. Harker (Atlanta, Georgia): Most of what we have learned about the role of thrombosis in relation to atherosclerosis has been a result of intervention. There was a great debate about the importance of thrombosis in acute MI until we had streptokinase to document it; in fact, there was benefit--likewise, tissue plasminogen activator (tPA) was also found to be beneficial. Knowing that antithrombotic measures could be used to analyze specific mechanisms has enabled us to find out a lot about the pathogenesis of the process. Very good data suggest, in fact, that the episodic nature of the whole process may be entirely dependent upon the thrombotic complications superimposed upon a rupture. Dr. Grundy:. If thrombosis occurs with small plaques and they then grow larger, and then there is another plaque rupture and this leads to repetition of this process of growth and organization--if that is a critical part of atherogenesis--we need to understand this better, and it could be a potential point of attack very early in development of the disease. Dr. Harker: If, in fact, the hypothesis is correct, that when rupture occurs, tissue factor is critical to initiate the thrombotic response, then we should in a very short period of time have a way of testing this using a tissue factor inhibitor or equivalent to block this pathway, and to determine what the relative
benefit is going to be, both in terms of acute events that may complicate atherosclerosis and the actual progression process as it evolves. There is an important additional issue that underlies any analysis of the role of thrombosis in these events, and that is a safety issue. Obviously, the hemostatic process is there for a very good reason, and once there is clinical intervention in this process--and we must bear this burden--this indeed underlies the concerns about the direct antithrombins. Those dosages required to interrupt platelet-del3endent processes are going to be high, and one needs to minimize the risk by either decreasing the duration to an absolute minimum, so that the period of risk is minimized, or to determine ways of selecting those agents that have preferential antithrombotic versus antihemostatic effects. We have not been very successful doing this with the antithrombins, and it suggests that antithrombin therapy of the direct type illustrated by hirudin must be selected for already-established lesions--presumably by parenteral administration--and we need to define for how long and for which patients this may be appropriate. On the other hand, if we are going to consider large prevention trials, then we are really talking about figuring out what the trigger is. If that, in fact, is tissue factor, then we clearly need agents that lend themselves to oral administration.
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