Current Perspective

Photoangioplasty
An Emerging Clinical Cardiovascular Role for Photodynamic Therapy
Stanley G. Rockson, MD; David P. Lorenz, MD; Wai-Fung Cheong, PhD; Kathryn W. Woodburn, PhD

AbstractPhotodynamic therapy (PDT) has been studied and applied to various disease processes. The potential of PDT
for selective destruction of target tissues is especially appealing in cardiovascular disease, in which other existing
interventional tools are somewhat nonselective and carry substantial risk of damage to the normal arterial wall.
Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic and, potentially, restenotic lesions) is fueled
by more effective second-generation photosensitizers and technological advances in endovascular light delivery. This
excitement revolves around at least 4 significant attributes of light-activated therapy: the putative selectivity and safety
of photoangioplasty, the potential for atraumatic and effective debulking of atheromatous plaque through a biological
mechanism, the postulated capability to reduce or inhibit restenosis, and the potential to treat long segments of abnormal
vessel by simply using fibers with longer light-emitting regions. The available nonclinical data, coupled with the
observations of a new phase I trial in human peripheral atherosclerosis, suggest a promising future for photoangioplasty
in the treatment of primary atherosclerosis and prevention of restenosis. (Circulation. 2000;102:591-596.)
Downloaded from http://circ.ahajournals.org/ by guest on March 21, 2017

Key Words: photodynamic therapy photoangioplasty atherosclerosis restenosis

P hotodynamic therapy (PDT) is an emergent therapeutic

modality for several disease processes. The salutary
response is mediated by a photosensitizing drug, typically
administered parenterally and selectively absorbed or re-
tained within the tissues targeted for therapy.1 Differential
selectivity or retention promotes selective damage when the
target tissue is exposed to light of an appropriate wavelength;
the surrounding normal tissue, containing little or no drug,
absorbs little light and is thus spared injury.1,2 Selectivity
renders PDT particularly appealing in coronary artery dis-
ease, in which other catheter-based approaches are relatively
nonselective and carry a substantial risk of damage to the
normal arterial wall. Historically, PDT clinical research has
focused primarily and successfully on treatment of cancer.2
Recent advances in synthetic macrocyclic chemistry, laser
technology, and endovascular light delivery systems have
broadened the scope of PDT to include, among others,
ophthalmic, urologic, immunological, and more recently
atherosclerotic applications.3,4 PDT may have a viable role as
a clinical inhibitor of restenosis and de novo disease.
Mechanism of PDT Action
The PDT response begins with a differential accumulation of
a photosensitizer in the target tissue, the consequence of
either selective uptake of the drug or of preferential retention
caused by slower clearance from the abnormal tissue. Subse-
quently, the tissue is photo-illuminated at the wavelength that
favors maximal absorption by the photosensitizer. The result-
ant photobiological response (direct, rapid cell apoptosis and
delayed necrosis from neovascular damage) becomes maxi-
mal within several days.1,57 Throughout this process, the
drug serves simply as a catalyst for energy transfer. Light
absorption leads to the release of cytotoxic singlet oxygen, a
highly reactive, oxidizing agent with very short diffusion
distances (0.1 m). Cell death is thus confined to those
illuminated areas in which there is an adequate presence of
the sensitizing drug.8
The physicochemical properties of the photosensitizing
molecule will predicate preferential uptake by a target cellu-
lar population.5 In atherosclerosis, drug lipophilicity and the
high lipid content of vascular plaque both appear to predicate
selective uptake. Although these mechanisms have not been
established with certainty,4 both passive and active processes
have been identified for the uptake of hydrophobic photosen-
sitizers into atheromatous plaque.9 Interestingly enough, the
selective accumulation by atheromatous tissues of some
lipophilic and hydrophilic agents is comparable.10,11 It is
likely therefore that passive diffusion into the arterial wall
from the vasa vasorum and from the lumen, as well as
impaired endothelial permeability,12,13 can augment active
transport mechanisms.
Whether in neoplasm or in atheroma, light of the appro-
priate wavelength is necessary to activate the drug. The light
can originate from collimated sources (eg, lasers) or from
diffuse illuminators (eg, high-power lamps and light-emitting
diode panels).14,15 The emission wavelength is usually

From the Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif (S.G.R., D.P.L.), and Pharmacyclics, Inc,
Sunnyvale, Calif (W.-F.C., K.W.W.).
Correspondence to Stanley G. Rockson, MD, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, CVRC
287, Stanford, CA 94305. E-mail rockson@leland.stanford.edu
2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

591
 592 Circulation August 1, 2000
matched to the far-red absorption bandwidth of the photosen-
sitizer. The light is then delivered to the treatment site either
directly or via hollow wave guides or fibers terminating in
optical configurations to achieve either a circumferential,
segmental, or conical beam profile.16 Radially emitting fibers,
with a variety of designs, have been used for endovascular
PDT in animals,1719 and in one case, a 2-patient clinical
study.17 Another important advance in photoangioplasty is
the development of compact, portable, and relatively inex-
pensive diode-based lasers to replace the older, large systems
requiring special electrical and plumbing infrastructures; the
latter are mostly dye lasers pumped by another laser (ar-
gon,19 21 KTP YAG) or pulse lasers (copper vapor).19
Severe cellular damage is noted in atheromatous areas after
light exposure.7 However, there is demonstrable preservation
of the intact elastic lamina and of normal collagen in the
adventitia, suggesting that the functional integrity of the
vessel is conserved.22 The absence of mural inflammation,
despite extensive cell death, is consistent with the regression
of atherosclerotic plaque through a hypothesized mechanism
Downloaded from http://circ.ahajournals.org/ by guest on March 21, 2017
of apoptosis, although this has not yet been conclusively
demonstrated. Paradoxically, a so-called dark effect, ie, a
therapeutic response to the drug in the absence of light, has
also been described for the inhibitory effect on restenosis of
at least one photosensitizer, a benzoporphyrin derivative. The
therapeutic implication of this observation has not been
delineated.
Photosensitizing Drugs for PDT
Hematoporphyrin derivative (HpD) was the first of a number
of photosensitizers with demonstrable, selective accumula-
tion within atherosclerotic plaque.23 Subsequent studies have
underscored the affinity of porphyrin derivatives for diseased
arterial wall in rabbits24 26 and miniswine.12,13 There is
maximal drug concentration in the intimal surface layers,
diminishing radially into the media.27,28 Both hematoporphy-
rin29 and Photofrin,30 a more purified derivative of HpD, also
display in vitro preferential uptake by human plaque. Al-
though Photofrin is available for clinical use in antineoplastic
applications, its clinical performance in the PDT of athero-
sclerosis has been somewhat disappointing.17 Despite obvi-
ous, selective damage of the plaque and sparing of the
underlying media, the lack of efficacy might be attributable to
inadequate penetration of the 630-nm light through endolu-
minal blood. Clinical application is further hampered by the
propensity of treated subjects to display prolonged cutaneous
phototoxicity.4
Administration of 5-aminolevulinic acid (ALA), a bio-
chemical precursor for protoporphyrin IX, has been accom-
plished by topical, systemic, and local internal routes in a
variety of malignant and dysplastic conditions.8,31 However,
its administration can elicit hemodynamic changes (depres-
sion of systemic and pulmonary pressures and pulmonary
resistance) that might limit its ultimate utility in cardiovas-
cular applications.32
Newer agents with selective localization, greater PDT
efficiency, and minor, self-limited potential for cutaneous
phototoxicity are now available.4 Phototherapeutic capacity
in atherosclerosis has been described for a number of these
molecules, including the phthalocyanines (photoactivated at
675 nm),11,33 chlorins (at 660 nm),34 purpurins (at 663 nm),35
and benzoporphyrin derivatives (at 690 nm).13 However,
most of these agents require liposomal or intralipid formula-
tion before administration.
Early PDT agents for cardiovascular disease were activated
at wavelengths 700 nm, at which point blood and tissues
substantially attenuate the delivery of light to target cells.36
However, tissue optics dictate that for optimal photochemical
response, the ideal photosensitizer should display maximal
absorption in the range of 700 to 800 or 950 to 1100 nm.15
The recent renewal of interest in the therapeutic potential of
cardiovascular PDT has been prompted largely by the avail-
ability of expanded macrocycles known as the texaphyrins.
These drugs circumvent many of the physicochemical limi-
tations of previously studied sensitizers. Texaphyrins are
synthetic, water-soluble macrocycles with long wavelength-
absorbing properties. They localize both in cancerous lesions
and in atheromatous plaque.20,37,38 Incorporation of a diamag-
netic lanthanide, lutetium, into the texaphyrin molecule yields
a potent PDT agent that is activated by tissue-penetrating
far-red light (732 nm).20,21 In addition, motexafin lutetium
fluoresces at 750 nm (Figure 1); endogenous chromophores
do not emit light at 750 nm. Hence, in vivo real-time imaging
of target structures is feasible, thus facilitating clinical diag-
nosis and treatment planning. Similarly, the related, paramag-
netic gadolinium texaphyrin might facilitate MRI of athero-
matous vascular disease.37
Texaphyrins localize in and eradicate diseased tissues,20
including atherosclerotic plaque (Figure 2).21,37 PDT with
motexafin lutetium causes selective photodamage and
thereby helps to reverse both diet-induced20 and balloon-
induced39 atheromatous plaque in rabbits. The enhanced
efficacy of texaphyrins may be attributable both to a more
selective uptake and retention of the photosensitizing mole-
cules and to the depth of light penetration achievable in blood
and tissue at the longer 732-nm wavelength illumination.20
Uptake of motexafin lutetium by the atheromatous plaque
occurs in a ratio of 16:1 to 34:1 when diseased and normal
segments of the arterial wall are contrasted.40 One possible
mechanism for this selective plaque uptake of texaphyrins is
through plasma lipoprotein binding or modification.37 Unlike
HpD-based PDT,21 there is no evidence of microscopic
damage to the arterial wall after PDT with motexafin
lutetium.
Cardiovascular Applications of PDT
In Vitro Experience
The extent of the short-term angiographic improvement plays
a determining role in the durability of the clinical response to
standard, percutaneous vascular interventions; however, re-
stenosis still significantly impairs the potential for long-term
clinical benefits for many patients.41 The identified biological
determinants of the restenosis response appear to be, in
principle, amenable to the mechanisms of phototherapy.
These determinants include vascular remodeling, stimulation
of the proliferative and migratory response of vascular
smooth muscle cells (SMCs), and enhanced production of
 Rockson et al
extracellular matrix.39,42 Furthermore, neutrophil and platelet
Downloaded from http://circ.ahajournals.org/ by guest on March 21, 2017
activation has been demonstrated with angioplasty in balloon-
injured arterial plaque.43 Moreover, macrophages play an
important role in the complex activation of SMCs after
vascular injury.44
Several studies have shown that PDT inhibits SMC growth
and decreases the development of experimentally induced
intimal hyperplasia response. The effects of PDT on the
injury response seem to be rather complex. Photosensitization
can accomplish a complete cellular eradication within the
vascular wall without associated inflammation and prolifera-
tion, suggesting that PDT may induce changes in the extra-
cellular matrix of the vascular wall.45 In vitro, exposure to
PDT eliminates detectable levels of basic fibroblast growth
factor (FGF and FGF-2) in solution and significantly re-
duces the smooth muscle mitogenesis inducible by matrix-
associated FGF-2.45 In vivo, PDT of rat carotid arteries
produces a loss of FGF staining compared with control,
nontreated arteries. Furthermore, the effect of PDT on the
release and activation of transforming growth factor-1 has
also been examined in vitro.46 The data suggest that PDT may
inhibit intimal hyperplasia through local inhibition of local
cytokine release or activation.
In vitro investigations support the concept that PDT can
favorably influence endothelial vascular biology. PDT with
Photofrin II substantially impairs the growth of cultured
SMCs derived from both atherosclerotic lesions and nonath-
Photodynamic Therapy in Cardiovascular Medicine 593
Figure 1. Motexafin lutetium: chemical struc-
ture, absorbance, and fluorescence profiles.
erosclerotic arteries.30,47 The effect on SMCs obtained from
atherosclerotic lesions (activated SMCs) is much greater than
that seen in the cells obtained from the normal vascular wall.
Similarly, studies of SMCs derived from saphenous vein
grafts have shown significant inhibition of their growth after
photosensitization.48 In addition, PDT on bovine aortic endo-
thelial cell preparations in vitro induces changes in extracel-
lular matrix: SMC proliferation and migration are inhibited
and endothelial cell proliferation is enhanced.48 These PDT-
induced vascular responses may benefit the process of vas-
cular remodeling and reduce the likelihood of a restenosis
response. The preferential uptake of the drug in atheroscle-
rotic segments is further accentuated in the highly cellular
regions of restenosis, suggesting that the selective cytotoxic
effect could be applied to both the therapy and the prophy-
laxis of restenosis.45
In Vivo Experience
A benefit after photosensitization with Photofrin in athero-
sclerotic rabbits has been reported,24,49 although others have
shown only a slight to modest reduction in plaque burden.27
The lack of marked therapeutic benefit with Photofrin-
mediated PDT in atherosclerosis has been ascribed to the
ability of blood to impair light transmission at 630 nm.12
Thus, suboptimal light transmission would produce subthera-
peutic activation of the sensitizer. Furthermore, safety con-
siderations limit the maximum light dose that can be deliv-
Figure 2. Spectral bioimaging of
motexafin lutetium within atheromatous
plaque compared with surrounding nor-
mal tissue. Hypercholesterolemic rabbit
received intravenous dose of motexafin
lutetium (10 mol/kg). a, Aortic lumen
was exposed at 24 hours after injection
to fluorescence imaging. b, Spectral
classification confirms selective accumu-
lation and retention of photosensitizer
within atheroma. c, Fluorescence emis-
sion profiles of atheroma and normal
regions denoted in Figure 2a.
 594 Circulation August 1, 2000
Figure 3. Three microscopic hematoxylin and eosinstained cross sections of cholesterol-fed rabbit artery obtained 2 weeks after PDT
with motexafin lutetium. Intima is extensively thickened and heavily laden with foam cells. Photoirradiated site (b) demonstrates sub-
stantial reduction of disease burden, while vascular regions above (a) and below (c) treatment zone remain heavily burdened with
plaque.
ered. In experimental treatments of canine coronary arteries
in vivo, light doses 200 J/cm2 elicited angiographic spasm,
histological necrosis, and even transmural injury.18 In this
study, the cases of premature death were ascribed to the
effects of coronary artery spasm, because only minor medial
damage was seen in some of these specimens. In fact, even at
high light doses, no embolization, vessel perforation, or
aneurysmal dilatation was seen.
Downloaded from http://circ.ahajournals.org/ by guest on March 21, 2017
Efficient reduction of atherosclerotic plaque burden has
also been demonstrated after PDT with motexafin lutetium.
Histological analysis of the posttreatment specimens reveals
selective reduction in plaque area in a hypercholesterolemic
rabbit model (Figure 3),21 whereas in a balloon-injury model,
a significant reduction in macrophage density within the
treated lesions was observed.39
The in vivo studies on intimal hyperplasia have yielded
more universally promising results. For example, a substan-
tial reduction in intimal hyperplasia has been shown in the rat
carotid artery injury model with chloroaluminum-sulfonated
phthalocyanine and 675-nm light at a fluence (the power
density of light over time) of 100 J/cm2.50 No thermal injury
was identified in the treated vascular segments. In most cases,
inhibition of intimal hyperplasia correlates with histological
absence of inflammatory and SMCs in the media. Similar
benefits have been observed in other experimental model
systems with Photofrin51 and ALA.8 PDT at the time of
angioplasty leads to an acellular media despite regeneration
of the endothelial lining.8 On the basis of the latter study, it
would appear that it is not necessary to delay PDT after
balloon injury to prevent the injury response of restenosis,
because photoactivation at the time of angioplasty completely
abolished the expected intimal hyperplasia after this injury. In
addition, both short- and long-term benefits of PDT have
been demonstrated.45,52
In another study of PDT in a balloon-injured rodent arterial
model, the media remained acellular for several weeks to
months, and intimal hyperplasia did not occur.6 Although
endothelial regeneration occurred by 2 weeks, SMCs failed to
repopulate the media. During PDT, retraction of endothelial
cells does allow adherence of neutrophils by their 2-integrin
adhesion receptors to the subendothelial matrix, leading to the
hypothesis that successful prevention of intimal hyperplasia
by PDT relies in part on the presence of the neutrophil at the
site of the lesion. Recently, Photofrin PDT was performed
with continuous external laser irradiation in the rabbits either
1 (prevention) or 6 (treatment) weeks after balloon injury.53
PDT was quite effective in the treatment of established
intimal hyperplasia but did not prevent it. The authors
concluded that refinements in dosimetry will be necessary to
achieve long-term benefits.53
The importance of the selection of the correct arterial
region in the prevention of restenosis has been examined in
the balloon-injured rat carotid artery.54 The results of that
study indicate that a hypercellular injury response in a treated
lesion can originate from a remote source; consequently,
successful elimination of restenosis by PDT may require
inclusion of the entire injured artery in the treatment field,
perhaps including a section of uninjured margin.
Human Clinical Applications
Photoangioplasty for arterial diseases, including de novo
atherosclerosis and potentially restenosis, has reemerged
because of promising new drugs and safer, less expensive
optical devices. This approach has the intriguing potential for
invoking separate but interrelated mechanisms of benefit
from one therapeutic intervention: safe debulking of the
atheroma through selective injury and destruction of the
atherosclerotic material; inhibition of the restenosis process
through an effect on macrophages, intimal hyperplasia, and
the inhibition of SMC proliferation; and further inhibition of
restenosis through a hypothesized dark effect of some
photosensitizers.4
The clinical trials of motexafin lutetium (Antrin) were
propelled by early preclinical indications of selective and
efficacious resolution of plaque in rabbits. Clinical evaluation
of motexafin lutetium is also ongoing in patients with
recurrent breast cancer (Lutrin) and age-related macular
degeneration (Optrin). In these latter studies, the drug has
been well tolerated. The maximum tolerated dose proved to
be 5.5 mg/kg on the basis of elicitation of pain in the
treatment field and dysesthesias in light-exposed areas.55
Plasma pharmacokinetic data taken from these patients
showed the drug to be cleared relatively quickly, exhibiting a
T1/2 and T1/2 of 0.32 and 12.9 hours, respectively. Early
observations from a phase I trial in claudicants with periph-
eral arterial atherosclerosis suggest that the therapy is well
tolerated and has the capacity to invoke a therapeutic re-
sponse in these patients. In 90% of vessels treated to date,
intravascular ultrasonography has confirmed measurable im-
provement in lumen cross-sectional area after Antrin pho-
toangioplasty. The therapeutic changes are achieved without
documented adverse vascular responses or any treatment-
limiting phototoxicity. In these ongoing trials, doses of 1 to 5
mg/kg of Antrin have been administered intravenously before
 Rockson et al
PDT, although preclinical data also support the feasibility of
local endovascular drug delivery. This may ultimately be
more clinically advantageous.39,56 Endovascular light is de-
livered through a cylindrical diffuser fiber, typically 24 hours
after systemic, intravenous administration of Antrin. The
fiber is positioned adjacent to the lesion of interest by
percutaneous delivery through a standard 5F to 8F guiding
catheter. Light treatment is sustained for 941 seconds to
achieve 400-J/cm diffuser fiber over a 3-cm diffuser length
fiber. A portable, relatively inexpensive 730-nm diode system
facilitates these illumination requirements.
Of paramount interest may be the capacity of photoangio-
plasty to prevent the cellular responses of restenosis after
conventional endovascular procedures. Future investigation
will also determine the synergistic role of photoangioplasty
when performed at the time of standard endovascular proce-
dures. The available preclinical investigations, coupled with
recent and continuing improvements in laser and fiberoptic
technology, suggest a promising role for photoangioplasty in
the future prevention and treatment of restenosis. Further
Downloaded from http://circ.ahajournals.org/ by guest on March 21, 2017
clinical investigation must evaluate therapeutic outcomes and
exclude a significant potential for coronary artery spasm in
human applications. Although the time needed for full cyto-
toxic effect may limit applicability to short-term, primary
therapeutic interventions, one can envision a potential role of
photoangioplasty as an adjunct to the standard percutaneous
techniques for revascularization. Additional, ripe clinical
scenarios might include interventions for vulnerable plaque,
long coronary lesions, diffuse and distal vascular disease, and
stabilization of vulnerable plaque.
References
1. Henderson B, Dougherty T. How does photodynamic therapy work?
Photochem Photobiol. 1992;55:145157.
2. Dougherty T. Photosensitizers: therapy and detection of malignant
tumors. Photochem Photobiol. 1987;45:879 889.
3. Levy J. Photodynamic therapy. Trends Biotechnol. 1995;13:14 18.
4. Vincent G. Photodynamic therapy of atherosclerosis and restenosis: a
potentially exciting new treatment method. SPIE. 1994;2130:210.
5. Kessel D, Luo Y, Deng Y, et al. The role of subcellular localization in
initiation of apoptosis by photodynamic therapy. Photochem Photobiol.
1997;65:422 426.
6. Sluiter W, de Vree W, Pietersma A, et al. Prevention of late lumen loss
after coronary angioplasty by photodynamic therapy: role of activated
neutrophils. Mol Cell Biochem. 1996;157:233238.
7. Reed M, Miller F, Wieman T, et al. The effect of photodynamic therapy
on the microcirculation. J Surg Res. 1988;45:452 459.
8. Nyamekye I, Anglin S, McEwan J, et al. Photodynamic therapy of normal
and balloon-injured rat carotid arteries using 5-amino-levulinic acid.
Circulation. 1995;91:417 425.
9. Delettre E, Brault D, Bruneval P, et al. In vitro uptake of dicarboxylic
porphyrins by human atheroma: kinetic and analytical studies. Photochem
Photobiol. 1991;54:239 246.
10. Straight R, Vincent G, Hammond E, et al. Porphyrin retention and
photodynamic treatment of diet induced atherosclerotic lesions in pigs. In:
Jori G, Perria C, eds. Photodynamic Therapy of Tumors and Other
Diseases. Padova, Italy: Libreria Progetto; 1986:350 352.
11. Eldar M, Yerushalmi Y, Kessler E, et al. Preferential uptake of a water
soluble phthalocyanin by atherosclerotic plaques in rabbits. Atheroscle-
rosis. 1990;84:135139.
12. Vincent G, Mackie R, Orme E, et al. In vivo photosensitizer enhanced
laser angioplasty in atherosclerotic Yucatan miniswine. J Clin Laser Med
Surg. 1990;8:59 61.
13. Hsiang Y, Crespo M, Richter A, et al. In vitro and in vivo uptake of
benzoporphyrin derivative into human and miniswine atherosclerotic
plaque. Photochem Photobiol. 1993;57:670 674.
Photodynamic Therapy in Cardiovascular Medicine 595
14. Wilson B. Light sources for photodynamic therapy. Photodynamic News.
1998;1:6 8.
15. Doiron D. Photophysics and instrumentation for porphyrin detection and
activation. In: Doiron C, Gomer C, eds. Porphyrin Localization and
Treatment of Tumors. New York, NY: Liss; 1984:4173.
16. Van den Berg H. On the evolution of some endoscopic light delivery
systems for photodynamic therapy. Endoscopy. 1998;30:393 407.
17. Spears J. Photosensitization. In: Isner J, Clarke R, eds. Cardiovascular
Laser Therapy. New York NY: Raven Press Ltd; 1989:107120.
18. Mackie RW, Vincent GM, Fox J, et al. In-vivo canine coronary artery
laser irradiation: photodynamic therapy using dihematoporphyrin ether
and 632 nm laser. Lasers Surg Med. 1991;11:535544.
19. Sobeh M, Greenwald S, Ham R, et al. Induction or prevention of intimal
hyperplasia by photodynamic therapy in the porcine model. SPIE. 1995;
2395:390 395.
20. Young SW, Woodburn KW, Wright M, et al. Lutetium texaphyrin (PCI-
0123): a near-infrared, water-soluble photosensitizer. Photochem Pho-
tobiol. 1996;63:892 897.
21. Woodburn K, Fan Q, Kessel D, et al. Phototherapy of cancer and ather-
omatous plaque with texaphyrins. J Clin Laser Med Surg. 1996;14:
343348.
22. Grant W, Speight P, MacRobert A, et al. Photodynamic therapy of normal
rat arteries after photosensitisation using disulphonated aluminum phtha-
locyanine and 5-aminolaevulinic acid. Br J Cancer. 1994;70:7278.
23. Spears J, Serur J, Shropshire D, et al. Fluorescence of experimental
atheromatous plaques with hematoporphyrin derivative. J Clin Invest.
1983;71:395399.
24. Neave V, Gianotta S, Hyman S, et al. Hematoporphyrin uptake in ath-
erosclerotic plaques: therapeutic potentials. Neurosurgery. 1988;23:
307312.
25. Pollock M, Eugene J, Hammer-Wilson M, et al. Photosensitization of
experimental atheromas by porphyrins. J Am Coll Cardiol. 1987;9:
639 646.
26. Pernes JM, Brault D, Angel CY, et al. Comparative study of the selective
uptake of hematoporphyrin derivative components into experimental ath-
eromatous plaques: potential for laser angioplasty. J Intervent Radiol.
1988;3:3 8.
27. Litvack F, Grundfest WS, Forrester JS, et al. Effects of hematoporphyrin
derivative and photodynamic therapy on atherosclerotic rabbits. Am J
Cardiol. 1985;56:667 671.
28. Pagnan A, Scannapieco G, Pauletto P, et al. Haematoporphyrin and
atherosclerosis in the broad-breasted white turkey: distribution and quan-
titation in thoracic and abdominal aorta. Int J Tissue React. 1989;11:
9399.
29. Kessel D, Sykes E. Porphyrin accumulation by atheromatous plaques of
the aorta. Photochem Photobiol. 1984;40:59 61.
30. Dartsch P, Ischinger T, Betz E. Responses of cultured smooth muscle
cells from human nonatherosclerotic arteries and primary stenosing
lesions after photoradiation: implication for photodynamic therapy of
vascular stenosis. J Am Coll Cardiol. 1990;15:15451550.
31. Kennedy J, Marcus S, Pottier R. Photodynamic therapy (PDT) and pho-
todiagnosis (PD) using endogenous photosensitization induced by
5-aminolevulinic acid (ALA): mechanisms and clinical results. J Clin
Laser Med Surg. 1996;14:289 304.
32. Herman M, Webber J, Fromm D, et al. Hemodynamic effects of
5-aminolevulinic acid in humans. J Photochem Photobiol B. 1998;43:
61 65.
33. LaMuraglia G, Ortu P, Flotte T, et al. Chloroaluminum sulfonated phtha-
locyanine partitioning in normal and intimal hyperplastic artery in the rat:
implications for photodynamic therapy. Am J Pathol. 1993;142:
1898 1905.
34. Hayashi J, Kuroiwa Y, Sato H, et al. Transadventitial localization of
atheromatous plaques by fluorescence emission spectrum analysis of
mono-L-aspartyl chlorin e6. Card Res. 1993;27:19431947.
35. Narciso, H, Anderson S, DeHoratius S, et al. SnET2 for the treatment of
vascular disease: dose/response study in NZW rabbits. SPIE. 1995:2395:
409 417.
36. Vincent G, Fox J, Charlton G, et al. Presence of blood significantly
decreases transmission of 630 nm laser light. Lasers Surg Med. 1991;11:
399 403.
37. Woodburn K, Young S, Fan Q, et al. Selective uptake of texaphyrins by
atheromatous plaque. SPIE. 1996;2671:6271.
 596 Circulation August 1, 2000
38. Sessler J, Hemmi G, Mody T, et al. Texaphyrins: synthesis and appli-
cations. Acc Chem Res. 1994;27:4350.
39. Miller M, Kuntz R, Friedrich S, et al. Frequency and consequences of
intimal hyperplasia in specimens retrieved by directional atherectomy of
native primary coronary artery stenoses and subsequent restenosis. Am J
Cardiol. 1993;71:652 658.
40. Woodburn K, Qing F, Kessel D, et al. Photoeradication and imaging of
atheromatous plaque with texaphyrins. SPIE. 1997;2970:44 50.
41. Serruys PW, Luijten HE, Beatt KJ, et al. Incidence of restenosis after
successful coronary angioplasty: time-related phenomenon: a quantitative
angiographic study in 342 consecutive patients at 1, 2,3, and 4 months.
Circulation. 1988;77:361371.
42. Simons M, Leclerc G, Safian R, et al. Relation between activated smooth-
muscle cells in coronary-artery lesions and restenosis after atherectomy.
N Engl J Med. 1993;328:608 613.
43. Neumann F, Ott I, Gawaz M, et al. Neutrophil and platelet activation at
balloon-injured coronary artery plaque in patients undergoing angio-
plasty. J Am Coll Cardiol. 1996;27:819 824.
44. Hanke H, Hassenstein S, Ulmer A, et al. Accumulation of macrophages
in the arterial vessel wall following experimental balloon angioplasty. Eur
Heart J. 1994;15:691 698.
45. LaMuraglia G, Adili F, Karp S, et al. Photodynamic therapy inactivates
extracellular matrix-basic fibroblast growth factor: insights to its effect on
the vascular wall. J Vasc Surg. 1997;26:294 301.
46. Statius van Eps R, LaMuraglia G. Photodynamic therapy inhibits trans-
Downloaded from http://circ.ahajournals.org/ by guest on March 21, 2017
forming growth factor beta. J Vasc Surg. 1997;25:1044 1052.
47. Dartsch P, Ischinger T, Betz E. Differential effect of Photofrin II on
growth of human smooth muscle cells from non atherosclerotic arteries
and atheromatous plaques in vitro. Atherosclerosis. 1990;10:616 624.
48. Adili F, Statius van Eps R, Karp S, et al. Differential modulation of
vascular endothelial and smooth muscle cell function by photodynamic
therapy of extracellular matrix: novel insights into radical-mediated pre-
vention of intimal hyperplasia. J Vasc Surg. 1996;23:698 705.
49. Tang G, Hyman S, Schneider J, et al. Application of photodynamic
therapy to the treatment of atherosclerotic plaques. Neurosurgery. 1993;
32:438 443.
50. Ortu P, LaMuraglia G, Roberts G, et al. Photodynamic therapy of arteries:
a novel approach for treatment of experimental intimal hyperplasia. Cir-
culation. 1992;85:1189 1196.
51. Eton D, Colburn M, Shim V, et al. Inhibition of intimal hyperplasia by
photodynamic therapy using Photofrin. J Surg Res. 1992;53:558 562.
52. Gonschior P, Gerheuser F, Fleuchaus M, et al. Local photodynamic
therapy reduces tissue hyperplasia in an experimental restenosis model.
Photochem Photobiol. 1996;64:758 763.
53. Eton D, Shim V, Maibenco TA, et al. Cytotoxic effect of photodynamic
therapy with Photofrin II on intimal hyperplasia. Ann Vasc Surg. 1996;
10:273282.
54. Statius van Eps R, ChandraSekar N, Hasan T, et al. Importance of the
treatment field for the application of vascular photodynamic therapy to
inhibit intimal hyperplasia. Photochem Photobiol. 1998;67:337342.
55. Renschler MF, Yuen AR, Panella TJ, et al. Photodynamic therapy trials
with motexafin lutetium (Lu-Tex) in patients with locally recurrent breast
cancer. SPIE. 1998;3247:3539.
56. Gonschior P, Erdemci F, Gerheuser F, et al. Selective hematoporphyrin
(HMD) application in arterial vessels using a porous balloon catheter
results in equivalent levels as compared to high-dose systemic adminis-
tration [in German]. Z Kardiol. 1991;80:738 745.
 Photoangioplasty: An Emerging Clinical Cardiovascular Role for Photodynamic Therapy
Stanley G. Rockson, David P. Lorenz, Wai-Fung Cheong and Kathryn W. Woodburn

Circulation. 2000;102:591-596
doi: 10.1161/01.CIR.102.5.591
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Downloaded from http://circ.ahajournals.org/ by guest on March 21, 2017

Copyright 2000 American Heart Association, Inc. All rights reserved.

Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/102/5/591

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Circulation is online at:

http://circ.ahajournals.org//subscriptions/