Inflammation plays an important role in the pathophysiology of atherosclerotic disease. We have previously shown that the targeted photosensitizer chlorin (e6) conjugated with maleylated albumin (MA-ce6) is taken up by macrophages via the scavenger receptor with high selectivity. In a rabbit model of inflamed plaque in New Zealand white rabbits via balloon injury of the aorto-iliac arteries and high cholesterol diet we showed that the targeted conjugate showed specificity towards plaques compared to free ce6. We now show that an intravascular fiber-based spectrofluorimeter advanced along the -iliac vessel through blood detects 24-fold higher fluorescence in atherosclerotic vessels compared to control rabbits (p < 0.001 ANOVA). Within the same animals, signal derived from the injured iliac artery was 16-fold higher than the contralateral uninjured iliac (p < 0.001). Arteries were removed and selective accumulation of MA-ce6 in plaques was confirmed using: (1) surface spectrofluorimetry, (2) fluorescence extraction of ce6 from aortic segments, and (3) confocal microscopy. Immunohistochemical analysis of the specimens showed a significant correlation between MA-ce6 uptake and RAM-11 macrophage staining (R = 0.83, p < 0.001) and an inverse correlation between MA-ce6 uptake and smooth muscle cell staining (R = −0.74, p < 0.001). MA-ce6 may function as a molecular imaging agent to detect and/or photodynamically treat inflamed plaques.

Introduction : It is controversial whether NMIDs can induce cardiac arrhythmias in humans. Studies in swine models have shown varying results. Two reported no induced VF, while a third showed 1 case of induced VF during epinephrine infusion. Two studies showed site sensitivity of cardiac capture depending on location of NMID electrodes. Human studies have not shown any induced arrhythmias. However, it is unclear whether electrodes were placed at the most vulnerable regions of the chest. This study sought to assess the thoracic location and range of minimum skin-to-heart distances (mSHD) and its relationship to BMI. Methods : Forty-five patients who had undergone cardiac CT scans were randomly selected for evaluation. These scans were analyzed to determine the mSHD and the location of this point on the chest surface relative to anatomic landmarks (horizontal distance from midsternum and vertical distance from sternal insertion of the lowest left rib). Linear regression analysis was performed using BMI and mSHD. Results : mSHD ranged from 1.8 cm to 6.4 cm. FIGURE 1 shows the linear regression of mSHD vs. BMI. mSHD was to the left of mid sternum (2.5 ± 2.5 cm) and slightly inferior (0.5 ± 2.0 cm) to the lowest left rib sternal insertion. The area of myocardial contact with the anterior chest wall averaged 51 ± 25 cm 2 , and was unrelated to BMI. Conclusions : In this study of adults, the average location of the site of mSHD was slightly to the left of mid sternum and just below the lowest rib insertion. There is a linear relationship between BMI and mSHD. The size of a person and the anatomic relationship of the heart to the anterior chest wall can influence the potential cardiac capture by NMIDs at the site of mSHD. Figure 1: mSHD vs. BMI

2006;48;1818-1824; originally published online Oct 16, 2006; J. Am. Coll. Cardiol. Fischman Stuart Houser, Henry Gewirtz, James E. Muller, Thomas J. Brady, and Alan J. Vermylen, Ricardo C. Cury, Denise Yates, Glenn M. LaMuraglia, Karen Furie, Ahmed Tawakol, Raymond Q. Migrino, Gregory G. Bashian, Shahinaz Bedri, David Provides a Noninvasive Measure of Carotid Plaque Inflammation in Patients F-Fluorodeoxyglucose Positron Emission Tomography Imaging 18 In Vivo This information is current as of February 9, 2008 http://content.onlinejacc.org/cgi/content/full/48/9/1818 located on the World Wide Web at: The online version of this article, along with updated information and services, is

We have previously shown that a conjugate (MA-ce6) between maleylated serum albumin and the photosensitizer chlorin(e6) (ce6) is targeted in vitro to macrophages via class A scavenger receptors. We now report on the ability of this conjugate to localize in macrophage-rich atherosclerotic plaques in vivo. Both the conjugate and the free photosensitizer ce6 are studied after injection into New Zealand White rabbits that are rendered atherosclerotic by a combination of aortic endothelial injury and cholesterol feeding into normal rabbits. Rabbits are sacrificed at 6 and 24 h after injection and intravascular fluorescence spectroscopy is carried out by fiber-based fluorimetry in intact blood-filled arteries. Surface spectrofluorimetry of numbered excised aortic segments together with injured and normal iliac arteries is carried out, and quantified ce6 content by subsequent extraction and quantitative fluorescence determination of the arterial segments and also of nontarget organs. There is good agreement between the various techniques for quantifying ce6 localization, and high contrast between arteries from atherosclerotic and normal rabbits is obtained. Fluorescence correlates with the highest burden of plaque in the aorta and the injured iliac artery. The highest accumulation in plaques is obtained using MA-ce6 at 24 h. Free ce6 gives better accumulation at 6 h compared to 24 h. The liver, spleen, lung, and gall bladder have the highest uptake in nontarget organs. Macrophage-targeted photosensitizer conjugates may have applications in both detecting and treating inflamed vulnerable plaque.

OBJECTIVES:Given the importance of inflammation in atherosclerosis, we sought to determine if atherosclerotic plaque inflammation could be measured noninvasively in humans using positron emission tomography (PET).BACKGROUND:Earlier PET studies using fluorodeoxyglucose (FDG) demonstrated increased FDG uptake in atherosclerotic plaques. Here we tested the ability of FDG-PET to measure carotid plaque inflammation in patients who subsequently underwent carotid endarterectomy (CEA).METHODS:Seventeen patients with severe carotid stenoses underwent FDG-PET imaging 3 h after FDG administration (13 to 25 mCi), after which carotid plaque FDG uptake was determined as the ratio of plaque to blood activity (target to background ratio, TBR). Less than 1 month after imaging, subjects underwent CEA, after which carotid specimens were processed to identify macrophages (staining with anti-CD68 antibodies).RESULTS:There was a significant correlation between the PET signal from the carotid plaques and the macrophage staining from the corresponding histologic sections (r = 0.70; p < 0.0001). When mean FDG uptake (mean TBR) was compared with mean inflammation (mean percentage CD68 staining) for each of the 17 patients, the correlation was even stronger (r = 0.85; p < 0.0001). Fluorodeoxyglucose uptake did not correlate with plaque area, plaque thickness, or area of smooth muscle cell staining.CONCLUSIONS:We established that FDG-PET imaging can be used to assess the severity of inflammation in carotid plaques in patients. If subsequent natural history studies link increased FDG-PET activity in carotid arteries with clinical events, this noninvasive measure could be used to identify a subset of patients with carotid atherosclerosis in need of intensified medical therapy or carotid artery intervention to prevent stroke.