4:OOpm - 4:30pm (Invited) ML10.2

Plaque Localization Enhanced by Exogenous Chromophore &Carotene

Biqing Ye and George S. Abela New England Deaconess Hospital, Harvard Medical Schaal,Baston, MA

8-carotene, an antioxidant which may alter the course of atherosclerosis by preventing the oxidation of LDL, has potential therapeutic benefit in humans. Gaziano et al. have shown that O-carotene therapy (50mg on alternate days) can reduce subsequent cardiovascular events in patients with chronic stable angina (1). Furthermore, yellow pigment O-carotene, which is widely distributed throughout nature, strongly absorbs blue-green light at 430-530 nm and preferentially binds to lipid-rich atherosclerotic plaques. These characteristics, i.e. color, absorption and lipophilia, also have attracted considerable attention.

Late in the fifties, Blankenkorn et al. demonstrated that atheromas contained varying amounts of carotenoids, as evidenced by the various intensities of yellow staining. They also demonstrated that the amount of carotenoid in atheromas significantly increases with the severity of the lesion (2). This kind of xanthomatous plaque has been frequently observed in angioscopic macro-morphology studies. Mizuno et al. reported that xanthomatous plaques were more common in patients with acute coronary disorders than in those with stable angina or old myocardial infarction. Six of the 7 plaque ruptures or ulcerations occurred on xanthomatous plaques (3). Nesto et al. identified 16 ruptured and 10 non-ruptured plaques with angioscopy and showed that the area immediately adjacent to the rupture was yellow in 15 of the 16 ruptures (4).

Blanken horn reported that the &carotene content of xanthomas increased about 30% in a single patient with oral administration of 0- carotene (17mg/dayfor 5 weeks) (5 ) . Prince et al. scheduled ten voluntary patients to take orally 180mg O-carotene each day in three divided doses for periods from 8 to 41 days before surgery (6). They found that 0- carotene-treated patients had a 50-fold increase in plaque &carotene levels, i.e., from 0.066 to 3.3 p g &carotene / g plaque, and a 58-fold increase in serum &carotene levels,

Recently %carotene uptake into plaque using an atherosclerotic rabbit model has been investigated (7-8). The cholesterol-fed rabbits with endothelial debridement and a R-carotene treatment of 30 mg/kg tw ice weekly for 3 weeks were sacrificed two weeks after the last R-carotene injection. The atherosclerotic plaques were dark orange in color indicative of O-carotene staining. O-carotene-stained plaques were readily visible by the bright orange color when compared to the adjacent normal artery (7). Furthermore, the absorption of %carotene severely decreased the optical penetration thickness of the stained plaque and greatly attenuated

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the fluorescence emission from the plaque at 488 nm laser excitation (9- IO). Our experiments showed that 8-carotene-stained plaques attenuated total fluorescence 17 times more than normal controls (0.89k0.29 vs. 15.06+3.12) and unstained plaques attenuated total fluorescence twice as much as normal controls (7.55k1.46 vs. 15.06k3.12).

Mitchell et al. showed that the B-carotene content of normal aortae is 1.5 p g / g , which can be increased to 237 p g / g in the plaques of atherosclerotic rabbits treated by B-carotene of 40 mg/kg twice weekly for 4 weeks (8). The laser ablation threshold in normal walls was three times higher than that in 13-carotene-stained plaques. These results were consistent with the early analysis of selective ablation by Prince et al. (1 1 ) -

All the studies mentioned above illustrate that yellow &carotene is only present in atherosclerotic plaque but not in the normal artery. By absorbing the 450-500 nm laser radiation, 6-carotene confers preferential absorption to the plaque, making both selective ablation therapy and selective fluorescence detection possible. Furthermore, yellow coloration of plaques can also improve plaque visualization by angioscopy. Recently pathological studies suggest that vulnerable plaques may have thin fibrous caps overlying cholesterol-rich lipid cores. Therefore, yellow color variation in plaque visualization by angioscopy may be related to the cap thickness which is potentially important for predicting plaque disruption and thrombus formation.

( 1 ) GAziano JM, Manson JE, Ridker PM, Buring JE, Hennekens CH. Beta carotene ththerapy for chronic stable angina. Circulation 1990; 82 Suppl 111:111-201 (abstract). ( 2 ) Blankenhorn DH, Freiman DC, Knowles HC Jr. Carotenoids in man: The distribution of apiphasic carotenoids in atherosclerotic Lesions. J Clin Invest 1956: 35:1243-1247. ( 3 ) Mizuno K, Miyamoto A, Satomura K. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet 1991 : 337:809-812. ( 4 ) Nesto RW, Sassower M, Koch JM, Abela GS. Angioscopic features of ruptured plaques in patients with unstable coronary syndrome. Circulation 1992; 86 Suppl 1:1650 (abstract). ( 5 ) Blankenhorn DH. The infiltration of carotenoids into human atheroma and xanthomas. Ann Intern Med 1960; 53:944-954. ( 6 ) Prince MR, LaMuraglia GM, MacNichol EF Jr. Increased preferential absorption in human atherosclerotic plaque with oral beta carotene: Implications for laser endarterectomy. Circulation 1988; 78:338-344. ( 7 ) Ye B, Abela GS. O-carotene enchances plaque detection by fluorescence attenuation in an atherosclerotic rabbit model. Lasers Surg Med 1993; 13:393-404. ( 8 ) Mitchell DC, Prince MR, Frisoli JK, Smith RE, Wood RFM. Beta carotene uptake into atherosclerotic plaque: Enhanced staining and preferential ablation with the pulsed dye laser. Lasers Surg Med 1993; 13:149-157. ( 9 ) Ye B, Abela GS. Fluorescence behaviour of human arterial tissue. Lasers in Medical Science 1992; 7:311-318. ( 1 0 ) Ye 8, Abela GS. Beta carotene decreases total fluorescence from human arteries. Optical Engineering 1993; 32:326-333. ( 1 1 ) Prince MR, Deutsch TF, Mathews-Roth MM, Margolis R, Parrish JA, Oseroff AR. Preferential light absorption in atheromas in vitro. J Clin Invest 1986; 78:295-302.

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