A New Strategy for Treating Inflammation in Atherosclerotic Plaque: Photodynamic Therapy

Photodynamic therapy involves the following basic process: 1. A medication is administered intravenously; 2. It is taken up by inflammatory cells in the vessel wall; 3. The medicine is activated using a specific wavelength of light; 4. The inflammatory cells die. It’s a very attractive concept, even in the era of drug-eluting stents, because of the importance of vulnerable plaque. We are quickly moving into an era where cardiologists will not only find vulnerable plaque, but treat it. Unlike our current patient population, future patients may not have severe stenoses, but they may have minimal stenoses with intense macrophage infiltration a very active plaque that could rupture. None of the current treatments (balloon or stent) address the biology of the vessel wall, meaning the inflammatory process. We now know that the inflammatory process drives acute events, restenosis, and possibly late events, such as sudden death years after having an angioplasty. In addition, these events may in part be due to an inflammatory response to the stent procedure itself. Furthermore, what we’re treating with percutaneous revascularization a high grade stenosis is merely the tip of the iceberg, because for every patient with a severe blockage we’re going to revascularize, there’s a hundred more who have active inflammation in their arteries. Photodynamic therapy (PDT) will have its major role in treating these patients. PDT treats the biology of the vessel wall, whereas mechanical disruption doesn’t (if anything, it elicits an inflammatory response as a result of injury to the vessel wall). What percentage of patients who have undergone balloon angioplasty or stenting could be treated at an earlier stage with this therapy? A large percentage. How much is completely speculative. But to be honest, probably the majority, because inflammation plays a role in plaque progression. Can you explain more about how photodynamic therapy works? The whole concept of photodynamic therapy involves the exposure of a photosensitive drug (a photochemical sensitizer) to a specific wavelength of light which activates the drug and produces singlet oxygen. These oxygen radicals are toxic to the cell that has taken up the photosensitive drug (Figure 1). Drug activation results in apoptosis (cell death). After the cells die, they are reabsorbed by the normal cleansing process of the body. The specific lightwave that activates the photosensitizer drug is delivered by a laser catheter (Figure 2). At present, more than 350 photo sensitizers have been defined. They include: texaphrins porphyrins benzochlorins chloryphll benzoporphyrins synthetic porphyrins like Antrin® (motexafin lutetium, Pharmacyclics, Sunnyvale, CA) and chlorins. These drugs are disproportionately taken up by plaque compared with normal arterial wall. For example, Antrin is concentrated in plaque ninefold compared to the normal adjacent aortic wall. Many of these drugs ride on the LDL receptor, a lipid transport mechanism, to enter the macrophage or smooth muscle cell. Miravant (Santa Barbara, CA) has a photosensitive agent (PhotoPoint) that can be administered intravenously and attains high concentrations in the arterial wall between one and four hours after bolus. Pharmacyclics’ agent, Antrin, is administered on the day prior to the procedure. Photosensitive drugs are taken into the wall of the artery primarily by smooth muscle cells (SMC) and macrophages. Macrophages are the underlying cause of sudden cardiac death and myocardial infarction. When you expose the photosensitive drug to a specific wavelength of light, there is a resulting reduction in smooth muscle cell and macrophage content. The effects of using light exposure alone can be seen in Figure 3. Light does very little, but light plus a photosensitizing drug kills the inflammatory cells. Figure 4 shows the iliac artery of a rabbit following balloon angioplasty performed with Antrin photoangioplasty. Special macrophage staining shows a virtual absence of macrophages and marked reduction in inflammatory infiltrate. In regard to subsequent scar tissue formation, the neointima is markedly reduced and lumen size is improved following PDT. This therapy can be used in conjunction with angioplasty or as a stand-alone treatment? Yes. The only advantage of doing balloon angioplasty at the time of photodynamic therapy is that if the patient has a severe blockage, the patient might otherwise have myocardial infarction or sudden death if the blockage is not ameliorated. If you look at a cross-section of a human coronary artery following balloon angioplasty, you can see that the plaque has been disrupted or torn (Figure 5). Remarkably, two-thirds of the time, this result heals open over time. The stent tacks the disrupted artery up very nicely, and provides a much more predictable and reliable result. If I were to use photodynamic therapy, I would prefer to use it as a stand-alone treatment, performed at a time when the artery does not have 90% blockage. With severe blockage, time is not on our side. I’d want to utilize this therapy earlier, before arterial blockage is present. With photodynamic therapy, I could kill the underlying inflammatory cells and make that lesion regress. How many patients were treated in the Phase I trial of Antrin? Approximately 85 patients in the multicenter coronary Phase I trial with about 20 enrolled at The Lindner Center/Christ Hospital. That’s not a huge volume, but we were the first center in the world to do this procedure, which was quite a complex project to enroll in. Patients received Antrin on the day prior to percutaneous intervention and at the time of the procedure had intravascular ultrasound performed prior to laser light exposure and after stent deployment. What were some of the results of the Phase I trials? In the Phase I coronary trial of Antrin photodynamic therapy, incremental doses of Antrin and light energy were administered to sequential cohorts of patients. This study was performed to determine optimal dose ranges for both drug and light administration. This therapy will likely be best suited for those patients with an active coronary disease process. As you can see in Figure 6, macrophage infiltration of plaque parallels coronary disease activity. Patients with unstable angina or non Q-wave MI have an increase in macrophage infiltration of plaque. Macrophage infiltration of plaque also predicts restenosis following angioplasty and stenting (Figure 7). Patients with a greater degree of plaque inflammation are more likely to have restenosis than patients who have plaque with little or no inflammation. Figure 8 shows the results of pathology studies published by Michael Davies, MD, almost ten years ago. It shows that plaques prone to rupture, which cause myocardial infarction or sudden cardiac death and which have ulcerative thrombotic characteristics, have a marked increase in monocyte/macrophage content, and a reduction in smooth muscle cell content. Most interestingly, we now have a technique for measuring heat emission from plaque, which reflects macrophage density and macrophage metabolic activity. Chris Stefanadis at the University of Athens in Greece has developed a thermistor catheter which detects heat emission from plaque in vivo. In addition, Jim Willerson, Ward Casscells and Morteza Naghavi have developed another thermistor catheter called the Volcano catheter, which detects heat emission from plaque as well. This technique could be used to reflect the efficacy of photodynamic therapy to reduce macrophage infiltration or conversely, the efficacy of non-invasive medical therapies such as statins and/or ACE inhibitors to reduce macrophage infiltration of plaque. These catheters can detect very subtle increments in temperature across areas of plaque where macrophage density is greatest. These catheters are a diagnostic tool, and have no therapeutic role at this time. The Phase I trial of Antrin photodynamic therapy in the coronary vasculature demonstrated this treatment to be well tolerated, without edge stenosis and without significant angiographic or clinical side effects. This trial suggests a potential role for Antrin photodynamic therapy in the treatment of coronary atherosclerosis and has defined the range of optimal drug and light doses to be tested in future studies. In the Phase I study of Antrin photodynamic therapy for the treatment of peripheral vascular disease, quantitative angiography was performed at baseline and 28 days after stand-alone Antrin photodynamic therapy in large arteries. The majority of patients had some reduction in the severity of obstruction over 28 days (Figure 9, below). Does photodynamic therapy affect restenosis in stented patients? We are analyzing the answer to that question at present. In the phase I coronary trial, all patients received Antrin photodynamic therapy prior to undergoing stent deployment. Laser light was administered immediately prior to stenting. On quantitative coronary angiography performed at six months, some reduction in late restenosis was observed during the phase of incremental light energy adjustments. In general, adjunctive photodynamic therapy provided a result similar to that of stenting alone. Antrin photodynamic therapy was well tolerated and did not seem to have any adverse effects. At the present time, it does not appear to reduce restenosis. The late vessel loss of 0.9-1.0 mm is basically what one sees following standard stenting with a typical stainless steel stent. It is important to point out that Antrin photodynamic therapy was performed as an adjunct to stenting in this phase I trial and we did not specifically treat vulnerable plaque. Regardless of the results observed in the phase I trial, the major application of photodynamic therapy will likely be for the treatment of vulnerable plaque. You mentioned that Antrin is administered the day before. Antrin, the Pharmacyclics product, is administered the day prior to percutaneous coronary intervention. Antrin is approximately 95% cleared from the circulation in 24 hours. It is water soluble and mostly concentrated in plaque. The Miravant PhotoPoint product can be administered 1-4 hours prior to percutaneous intervention. How difficult is this therapy to utilize? This therapy is not very difficult, and in fact is similar to other laser systems. Physicians and ancillary personnel wear photo protective lenses or green eyeglasses. The photo illumination or laser treatment phase was 12 minutes in duration. What about treatment costs? These agents, when used to treat vulnerable plaque, could provide a cost savings downstream. Potentially, patients who receive this treatment would have a reduction in late clinical events (heart attack or stroke). It is possible that such patients could be spared coronary revascularization. I don’t think the cost will be exceptional compared to the cost of doing an angioplasty procedure. Do you have any plans to do a live case study in the near future? We’ve been asked to do a live case study on September 25th of this year, at TCT. How long do you think before this ends up in cath labs everywhere? It is incredibly hard to say. There’s been some financial setbacks for some of these companies, what with the stock market debacle that’s gone on in the last year. Some of them are now capitalized at half of what they were, as their stock price has fallen. Many are looking forward to increased financing, and if they’re able to get that, I think they will continue to go forward with evaluation of the technology. I think it’s an exciting technology because it’s one of the first strategies for treating the biology of the vessel wall. If offers us a way to treat inflammation, the mediator of bad outcomes in coronary disease. The inflammation is actually not limited only to coronaries it’s in the carotids, the aorta¦ This kind of a treatment could be administered in multiple circulations. There has been some talk about cardiologists starting to treat stroke. Yes, it’s a stone’s throw away. I personally have not been doing it, but we have several cardiologists in our group that are very capable. The long and short of it is, this is solely a turf battle between radiology and cardiology. It’s a political football. In most hospitals, the radiologists are fighting tooth and nail to keep the cardiologists out of the carotid/cerebral circulation. The reason for that is obvious. Cardiologists control the flow of patients, much more so than radiologists. Few practices have successfully integrated radiologists and cardiologists in a collaberative vascular center, which would be the optimal approach. Each group has complementary attributes.

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