Identifying the Vulnerable Plaque (IAGS Proceedings - Part II of II)

(IAGS Proceedings - Part II of II) Nick Hopkins: The preliminary reports on intracranial angioplasty and stenting showed very high morbidity and mortality rates associated with the procedure — particularly in symptomatic patients. As Dr. Myler suggested, it is risky to treat an unstable plaque. Others have reported that if suboptimal angioplasty is performed in these really sick intracranial plaque patients who are symptomatic, the vessel can be opened slightly to improve flow with very low risk if the proper antiplatelet regimen is maintained. We performed suboptimal angioplasty in eight symptomatic patients who had some really ugly, long, eccentric lesions. We opened their vessels just slightly, pushing the plaque out against the wall. We waited a couple of months after the angioplasty procedure before placing a stent in these patients, thinking that perhaps we had injured that plaque and then created a moderate healing response that would render it more stable. Does that make any sense? Kirk Garratt: Yes, it does. Many of us have had similar feelings about acute infarct intervention. The most dreaded complication of an otherwise successful intervention would be the no-reflow phenomenon that develops when we shower debris distally, which does not usually happen with the initial balloon dilatation. Rather, it tends to happen when the stent is placed after the vessel is opened. My view, which is probably a widely held one, is that in these cases, we are shredding that friable, vulnerable plaque and its overlying thrombosis with the stent and are allowing that debris to take off. Perhaps we should do exactly what you described, Nick; that is, open the vessel, let the area heal and firm up, and then stent it. Nick Hopkins: We observed no major complications in that tiny patient subset; no major neurologic morbidity. Jim Zidar: It also may be that the intracranial vessels are more fragile. We used to try to go easy and just get the vessel open. Perhaps the coronary arteries are a tougher anatomy and the heart can handle it better. Many practitioners push forward with aggressive antiplatelet therapy and try to achieve a good outcome. Nick Hopkins: Yes, that is part of the rationale. We know that if you take acute intracranial pathology and treat it the way you would normally treat the coronary arteries, that is, achieve a pristine angiographic result, there will be a high incidence of rupture. The intracranial vessels are much more fragile. Jim Zidar: There must be a difference in the vessel wall morphology. Nick Hopkins: Yes, the intracranial vessels are much thinner. Kirk Garratt: Do they dissect, Nick? Or are there just embolic events? Nick Hopkins: Dissection and rupture occur. Raoul Bonan: I think there is smooth muscle cell proliferation. The vessel is opened slightly, just to pass through, but the injury caused by the passage stimulates smooth muscle cell proliferation. The crust needs to be thicker and that kind of fibrosis is needed to seal and pacify the vulnerable plaque. That is probably what is occurring. Nick Hopkins: We hope that’s what we are doing. Jeff Werner: The slide you showed a moment ago on the 33-year-old woman is very interesting for several reasons. An autopsy study published in the last couple of years in Circulation involved women under 55 years of age who died a sudden death on the streets of New York city. All of them had autopsies. The vast majority of these women showed exactly what you did on that slide: they had relatively non-occlusive atherosclerosis and had ruptured plaque with acute thrombosis or had intramural hemorrhage that caused closure. I have read many explanations for why women don’t have symptoms. Some women do, but we cardiologists apparently don’t listen to them or their symptoms are atypical. I believe that it is probably more likely that these women don’t have symptoms because there is something that causes this to be more common in women than in men. These patients with no symptoms represent another reason why we must identify unstable plaque early on. Kirk Garratt: Yes. Understanding the spectrum of the underlying pathology becomes key if we are talking about a medical cure, because I don’t think statins would have helped that 33-year-old patient. Perhaps anti-inflammatory and antiplatelet agents would have helped her, but they would not have helped the male patient who had sudden cholesterol emboli that killed him quickly. Thus, it is a very difficult mix. Douglas Cavaye: In Los Angeles, we tried to make plaques in dogs in the early 1990s when IVUS was new. One of the most effective methods was to use a balloon that was slightly larger than the artery. Interestingly, we had much greater success making a plaque at the bifurcation of the canine aorta than in the common iliac artery, which raises the question of whether the bifurcation itself is susceptible to mechanical stress compared to the straight vessel. We also tried to make lesions in canine external iliac arteries just proximal to the groin. When imaged with IVUS, if we went to flat, approximately 90% of them healed — no stenosis. Thus, using an angioscope, we had to subintimally inject some of the dogs’ own blood. More than 75% of the time, a good stenosis was achieved at six weeks. Admittedly, this was not plaque, but it adds weight to the argument that Michael Lawrence Brown made regarding the initiating event as perhaps being related to the site: high-sheer stress, low-sheer stress movement, as well as the subintimal hematoma, rather than just external elastic stretch leading to rupture. Richard Myler: Many of us have patients on whom we have successfully performed angioplasty and have followed them up for decades. Obviously, we have seen these patients develop atherosclerosis over that period of time. However, I cannot recall a single patient in that follow-up period who developed a new lesion on an old plaque that had been successfully treated. New lesions may form near an old one, or in other vessels, but it raises the question about taking what might have been an unstable or somewhat vulnerable plaque and healing it somehow so that a thicker fibrous cap forms and protects the plaque from future mischief. Kirk Garratt: That is a good point, Richard. It is quite a mystery in my mind, because I don’t understand why sealing over one plaque zone changes the history of atherosclerosis in that zone so dramatically. It presumably neo-endothelializes. Isn’t that a new endothelial layer that should be prone to the same systemic disease and recruit the same white cell infiltration? The vessel itself does not remain scarred on the surface. We can stop antiplatelet drugs after a period of time because the scar neo-endothelializes. I don’t understand why atheroma does not develop on top of the scar. Paul Overlie: I would like to hear from the panel members about risk stratification. We spend so much time risk stratifying patients who have acute infarcts. Are we approaching an era — and how close are we to it clinically — where we will be able to risk-stratify the lesions we observe in terms of those that need attention soon and those that can be watched? Many of us see lesions that are 50% stenosed and are embarrassed two weeks later when those patients return with an acute infarct in that exact location. Jim Zidar: At Duke, our new chief, Pascal Goldsman, is very interested in genomics, genomic markers, and platelets. A large variety of platelet receptors exists in the population. For the past year and a half, patients who come to our cath lab sign a consent form to give 35 ccs of blood. Dr. Goldsman’s goal is to acquire between 5,000–10,000 samples. He is studying these blood samples and correlating them with prior angiograms to determine which patients have subsequent events in the ensuing five years relative to various markers — whether inflammatory or platelet receptor markers — and then looking back at their pathology as a way to expand the database which has historically been comprised of normal risk factors. The ordinal scale ranges from 25%, 50%, 75%, 95% and 100% stenoses. This long-term study will thus examine genetic marker data in comparison to patient anatomy and clinical outcomes. I can’t think of any other way to get to the bottom of this question. Gary Roubin: Although I admit that Dr. Goldsman is doing excellent work, the problem I see is that there are so many steps and so many genes involved with respect to the plaque: first it’s vulnerable, then unstable, then a clinical event occurs. I think it will be a very long time before we get to the bottom of the question. But, I agree, we need to start somewhere. Mike Cowley: It may be possible to identify the patient at risk, but it is impossible at this point to determine which of the little 30%–40% stenosed plaques located in other arteries present a risk to that patient. Gary Roubin: This is another example of molecular research that has been consuming vast amounts of financial resources over the past decade without providing truly useful information to those of us in the field. A lot of money has been wasted on basic research that really has led us nowhere. In my view, the rooster and rabbit models of lipid-laden plaques merit closer study. I recently observed some truly remarkable technology tested in a rooster model that can remove lipid from plaques. In my twenty years of involvement in atherosclerosis research, I have never seen anything like this. It also removed all the fat from the abdominal cavity of the rooster as well, which has other social implications, I’m sure! (laughter) I do want to take Nick to task a moment here. Having worked in both the brain and the heart for over a decade now, I have clearly observed that the vessels in the brain are fundamentally different from those of the heart. The brain, as an organ, is far less vulnerable than the neuroradiologists, the neurosurgeons, and the vascular surgeons would have interventional cardiologists believe. The brain has an incredible ability to withstand large quantities of embolic debris and insults. Otherwise, how could you or the vascular surgeons ever have been successful? Every interventional cardiologist in this room has taken a patient for an elective procedure and had to walk out and tell the patient’s wife that her husband died on the table. There is nothing worse than having to deliver that news. It is much easier to warn every patient who goes in for elective cerebrovascular procedures that they have a 2% risk of stroke. We can at least lean on those words of warning when we have to tell the family that the patient had a stroke. That, in my opinion, is infinitely easier than what we face in interventional cardiology when a death occurs on the table. The heart is a much more difficult organ to treat than the brain, in my experience. However, we have been scared off from performing cerebrovascular interventions by people who have a vested interest in keeping this domain to themselves. I have worked in both disciplines now for over a decade, and I am much happier to work on the brain than on the heart. Kirk Garratt: Nick, you look like you have a ready response to Gary’s comments. The gun is loaded and drawn! (laughter) Nick Hopkins: The heart is nothing but a damn pump! (laughter) I agree somewhat with what Gary said: telling a family that their loved one has died hurts enormously — but only for a limited time. If a patient has a major stroke, it can hurt for months and years afterward. And every time you see that patient’s family, their look says: "You did this to him." That is very painful indeed. Gary Roubin: “A very, very complicated pump!” But if a patient dies due to an elective intervention, there is no time to adjust to the fact as there is in the case of a stroke. Paul Overlie: I want to return briefly to the subject of patients in whom angiography shows a 50% lesion stenosis. I have some of these patients undergo a stress thallium test to see if that area hypoperfuses with stress. Are these new tools — the MRA, the multi-slice CT scan — going to be able to give us any more information about patients in whom we should intervene, despite the fact that their anatomy does not show very tight lesions? Kirk Garratt: That is a very important, but perhaps different topic, because you are asking about the clinical relevance of an angiographically indeterminate lesion. I have access to tools in my cath lab that can help me sort that out. I will perform an FFR or a Doppler flow assessment which will provide the same information as a nuclear perfusion study. I am personally satisfied with that technology. What I am curious about now is the patient whose lesion passes the FFR test and then, one or two months later, suffers a big anterior MI.