COMMENTARIES

Rationale and Use of Vascular Cell Adhesion Molecule - 1 (VCAM-1) as a Target for the Molecular Imaging of Vulnerable Plaque

Laurent M. Riou, Ph.D., Julien Dimastromatteo, M.S., Daniel Fagret, M.D., Ph.D., and Catherine Ghezzi, Ph.D.,
INSERM, U877 Radiopharmaceutiques Biocliniques
Université Joseph Fourier,
Grenoble, Faculté de Médecine de Grenoble,
38700 La Tronche,
France
Please address correspondence to:
Laurent M. Riou
Tel: (+33) 0 476-637-509
E-mail: Laurent.Riou@ujf-grenoble.fr

Atherosclerotic cardiovascular diseases (CVD) are the leading cause of mortality worldwide, accounting for > 19.10⁶ deaths annually [1,2]. Despite major advances in the treatment of CVD patients, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. Indeed, an acute heart attack is the first symptom of atherosclerosis in as much as 50% of individuals with severe disease. This is due to the fact that risk stratification is currently based on the evaluation of the Framingham risk score in the United States or the Systemic Coronary Risk Evaluation (SCORE) in Europe and that most heart attacks occur in an intermediate-risk group to which the majority of the population pertains and in which risk factors are of low predictive power [3]. The early detection of vulnerable atherosclerosis prior to the occurrence of any symptom would therefore be of great public health benefit. A potential strategy for individual risk assessment in primary prevention has been recently proposed by the Screening for Heart Attack Prevention and Education (SHAPE) task force [4]. This algorithm is based on non-invasive screening for subclinical atherosclerosis in apparently healthy men and women aged 45-75 and 55-75, respectively, using two currently available non-invasive imaging modalities, i.e. X-ray computed tomography for coronary artery calcium scoring and ultrasound imaging for carotid intima-media thickness determination. Importantly, the SHAPE task force emphasized that emerging tools such as noninvasive molecular imaging tests have great potential to significantly advance these guidelines and that those tests will also significantly determine the way in which the guidelines will be updated.

          Atherosclerosis is an inflammatory disease that is initiated by and progresses in the context of hypercholesterolemia. It is now accepted that the oxidative modification of LDLs is the key and early event that links hypercholesterolemia with inflammation in the pathogenesis of atherosclerosis [5]. Among other actions, oxLDL induce the expression of vascular cell adhesion molecule-1 at the surface of endothelial cells [6]. VCAM-1 is an immunoglobulin superfamily glycoprotein (~110 kDa) that binds to the α₄β₁ integrin which is constitutively expressed on monocytes and lymphocytes [7]. While not expressed under normal conditions, VCAM-1 expression is stimulated by pro-atherogenic conditions [8,9]. The functional role of VCAM-1 in the pathogenesis of atherosclerosis has been clearly evidenced by the landmark study of Cybulsky et al. [6]. The authors generated homozygous VCAM-1 domain 4-deficient mice (VCAM-1^D4D/D4D) and observed that atherosclerotic plaque area was reduced by ~40% in VCAM-1^D4D/D4D LDLR^-/- but not in ICAM1^-/- LDLR^-/-mice aorta , indicating that VCAM-1, but not ICAM-1, is critical in atherogenesis. More recently, the influence of shear stress on the pattern of VCAM-1 expression in the context of hypercholesterolemia has also been investigated [10,11], providing additional insights into the mechanisms of VCAM-1 expression and plaque development at predisposed sites on the arterial tree.

          In addition to being fundamental for lesion initiation, VCAM-1 also plays a major role in the development of atherosclerotic plaques with vulnerable characteristics through the angiogenic phenomenon. The role of angiogenesis in plaque vulnerability is increasingly being recognized [12]. Plaque angiogenesis is promoted (1) by the abovementioned inflammatory process which is initiated by oxLDL and (2) by the intimal thickening associated with lesion development which leads to tissue hypoxia and therefore angiogenesis [13]. Plaque neovessels have been shown to express VCAM-1 to a level that is 2- to 3-fold higher than that observed on the luminal arterial endothelium. Through VCAM-1 expression, neoangiogenesis therefore strongly contributes to the intraplaque recruitment of monocytes and lymphocytes that are ultimately responsible for plaque destabilization. Importantly, the increased VCAM-1 expression in the neovasculature of vulnerable plaques was initially observed in humans in the pivotal studies of O’Brien and colleagues [14,15].

          Considering that VCAM-1 expression is strongly correlated to macrophage and lymphocyte accumulation within the plaque, a feature that represents a major criterion for defining a vulnerable plaque [2], VCAM-1 is therefore an excellent potential target for the molecular imaging of vulnerable plaques. To date, a few studies have addressed the use of VCAM-1 as a target for the molecular imaging of vulnerable plaques. Using intravascular ultrasound and echogenic immunoliposomes (ELIPSs) targeted at VCAM-1, Hamilton and colleagues demonstrated a significant increase in mean gray scale values on endothelial images of injured carotid arteries from Yucatan miniswines when compared to images obtained with nonspecific ELIPs [16]. More recently, in vitro phage display was used by Kelly, Allport ,and co-workers to select a VCAM-1 specific peptide sequence that was used for the production of magnetofluorescent nanoparticles [17]. Although ex vivo images of VCAM-1 expression were performed, this agent revealed suboptimal for in vivo imaging. Using in vivo phage display in apoE^-/- mice, the authors then described a peptide sequence highly homologous to the known VCAM-1 ligand VLA-4 which displayed an improved affinity for VCAM-1. This peptide was used for the production of a second-generation agent detectable through MRI and optical imaging which provided very promising results with respect to the in vivo imaging of variable levels of VCAM-1 expression [18]. Using nuclear molecular imaging, we recently described the ex vivo imaging of VCAM-1 expression in hypercholesterolemic rabbits using a ^99mTc-labeled version of the HLA class I-derived peptide B2702 [19] that was previously shown to bind specifically to VCAM-1 [20].

          In conclusion, the rationale for the use of VCAM-1 as a target for the molecular imaging of vulnerable plaques is supported by large experimental and clinical evidence. Providing that the targeted agents that have been recently evaluated for the invasive and noninvasive imaging of VCAM-1 using IVUS, MRI, fluorescence, and nuclear imaging eventually allow the imaging of VCAM-1 in routine clinical practice, these agents should significantly improve the early detection of vulnerable and so far undetected patients.

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