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- James E. Muller, MD, FACC⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. James E. Muller, 29 Studio Road, Auburndale, Massachusetts 02466
The study by Waksman et al. (1) in this issue of the Journal adds to the data indicating that photodynamic therapy (PDT) might provide a novel means to stabilize atherosclerotic plaques. The results clearly demonstrate that PDT can markedly diminish the macrophage content of lesions induced by injury and cholesterol-feeding in a 5-week rabbit model. The area of the plaque occupied by macrophages, an important component of the inflammation that occurs in plaques suspected to be vulnerable to rupture, was reduced by 98% at 7 days after PDT.
Although PDT is widely used for treatment of dermatologic and cancer patients, it is not in general use in the field of cardiology and hence is unfamiliar to many cardiovascular specialists. The technique is based on the localization and subsequent activation of a potentially destructive photosensitizing agent in a target of interest (2). The agent is activated by exposure to a small amount of light (nonionizing and nonthermal electromagnetic energy) that, in the presence of oxygen, creates reactive oxygen species that destroy cells in the area. Specificity of destruction can be achieved by: 1) selective application of the PDT agent; 2) selective uptake of the agent; and 3) selective exposure of tissue to the activating light.
These desirable attributes have led to the clinical application of PDT for the treatment of acne, nonmelanoma skin cancer, Barrett's esophagus, and wet macular degeneration (2).
An impressive feature of the current study of cardiovascular use is that the Miravant photosensitizer compound (MV0611) destroyed macrophages (and smooth muscle cells) without damaging the structural integrity of the vessel—by 28 days the tissue was intact, and repopulation with smooth muscle cells was well under way.
The findings of the current study are in accord with prior studies in animals with experimental atherosclerosis (2). Katoh et al. (3) tested a different photosensitizer in rabbits and also found that most intimal cells were destroyed at 7 days. A study in atherosclerotic miniswine provided a warning that higher doses of light could produce damage to the media (4). Tawakol et al. (5) demonstrated that a photosensitizer designed to be taken up selectively by the macrophage scavenger receptor could accumulate in macrophages without accumulating in smooth muscle cells. Hayase et al. (6), with a rabbit model similar to that employed in the current study, demonstrated that motexafin lutetium (Antrin, Pharmacyclics, Inc., Sunnyvale, California) localized in plaque and its activation produced selective depletion of macrophages.
Studies of PDT for treatment of atherosclerosis in patients are quite limited. In 1999, Jenkins et al. (7) used 5-aminolevulinic acid with percutaneous transluminal coronary angioplasty for restenosis in femoral arteries; no adverse events were noted in the uncontrolled experience. Antrin was tested by Kereiakes et al. (8) in a phase 1 study of 75 patients undergoing coronary stenting. The uncontrolled results showed no coronary complications and identified safe doses of drug and light; 1 patient developed an erythematous cutaneous reaction and several others experienced rashes and paresthesias, which were self-limited.
Although the current study supports continued research with PDT for atherosclerosis, it has limitations as noted by the authors. Given the extensive pre-existing studies in animals, this study is primarily a confirmation of prior findings. It does provide a novel emphasis on plaque stabilization, as opposed to plaque ablation or prevention of restenosis. Observations were completed at 28 days, and the long-term outcome of such extensive destruction of cells has not yet been studied. The agent, MV0611, requires activation by green light (542 nm), which in turn requires removal of blood; other agents, such as Antrin, which is activated by red light (732 nm), are more easily activated through blood. Finally, MVO611 has not been cleared for administration to humans and is therefore considerably behind Antrin and other PDT agents in development for clinical use.
There are also limitations of the cholesterol-fed, balloon-injured, 5-week rabbit model. The lesions produced in this manner are macrophage-rich and are similar to the human lesions described as “pathological intimal thickening.” They are not equivalent to the lipid-core plaques associated with coronary syndromes in patients. The diabetic, cholesterol-fed pig does develop lipid-core lesions and would be an excellent model for future studies of the effect of a PDT agent on plaques suspected to be vulnerable to rupture (9).
Finally, there are clinical limitations to the application to humans of any of the current PDT approaches. All require intravascular illumination and hence are limited to use during invasive procedures. The requirement that the PDT agent be administered 8 to 24 h before activation will hinder usage in acute coronary syndromes, and the need of some agents for 10 min or more of illumination will slow catheterization laboratory procedures. Finally, there are the issues of cutaneous and neural side effects, which seem to be relatively minor, and the need for avoidance of bright light after the procedure.
With these inherent limitations and the unresolved research issues discussed in the preceding text, it is appropriate to question the wisdom of expending additional efforts to develop PDT for the treatment of atherosclerosis. Because stenting resolved the problem of obstruction and drug-eluting stents diminished interest in the role of PDT to prevent restenosis, there are at present no commercial efforts under way to develop either MV0611 or Antrin for clinical use.
It is in this negative setting that the emphasis of Waksman et al. (1) on PDT for plaque stabilization provides a new perspective and suggests a potentially valuable role for PDT. The potential role is based on the continued occurrence of cardiac events after stenting and the pathophysiology responsible for such events. In the year after stenting, approximately 10% of patients experience an event from a lesion not considered stenotic enough for stenting at the time of the initial procedure (10).
Pathologic studies indicate that the substrates for the majority of these events are likely to be lipid-core plaques at locations other than that of the original culprit lesion. Most patients undergoing stenting have only 1 or 2 such lipid-core lesions (counting the culprit), but as many as 8 have been documented, and they might occupy over 30 mm of coronary length (11). Natural history studies are in progress to determine whether these lesions are indeed the sites responsible for future events.
If nonstenotic, inflamed lipid-core lesions are proven to cause subsequent events—to be vulnerable plaques, as suspected—or if the presence of such plaques identifies patients at higher risk of subsequent events—vulnerable patients—then what is optimal preventive therapy? Unfortunately, the optimal medical therapy currently available with statins and other agents prevents only 20% to 30% of subsequent events. If individual vulnerable plaques can be identified, then perhaps prophylactic stenting of such lesions (with improved stents) would be effective. If vulnerable plaques cannot be found but vulnerable patients can be identified, then the length of artery requiring treatment would be extensive, and the complications of prophylactic stenting would be increased.
It is in this quest for prevention of events after stenting of a culprit lesion that intracoronary PDT might have a useful role. The patient is already undergoing an invasive procedure, so the invasive nature of intravascular PDT is not an impediment. If inflamed nonstenotic plaques are found to be the cause of future events (i.e., to be vulnerable plaques), then their selective treatment with PDT might be optimal therapy. If vulnerable plaques cannot be identified but vulnerability of longer regions of artery can be detected, PDT might provide a convenient method to passivate a lengthier span of coronary atherosclerosis. In either case, continued studies, such as those conducted by Waksman et al. (1), are of value in developing this potentially important novel approach to stabilization of atherosclerotic plaques.
Dr. Muller is founder, President, and CEO of InfraReDx, Inc., a company that has developed a near-infrared spectroscopy catheter to identify lipid-core plaque. Dr. Muller owns equity in InfraReDx and is a paid employee of the company.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
- Waksman R.,
- McEwan P.E.,
- Moore T.I.,
- et al.
- Castano A.P.,
- Hamblin M.R.
- Hayase M.,
- Woodbum K.W.,
- Perlroth J.,
- et al.
- Kereiakes D.J.,
- Szyniszewski A.M.,
- Wahr D.,
- et al.
- Gerrity R.G.,
- Natarajan R.,
- Nadler J.L.,
- Kimsey T.
- Cutlip D.E.,
- Chhabra A.G.,
- Baim D.S.,
- et al.
- Cheruvu P.K.,
- Finn A.V.,
- Gardner C.,
- et al.