Author + information
- Viviany R. Taqueti, MD, MPH†,‡,§,
- Matthias Nahrendorf, MD, PhD‖ and
- Marcelo F. Di Carli, MD†,‡,§∗ ()
- †Noninvasive Cardiovascular Imaging Program, Departments of Medicine and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- ‡Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- §Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- ‖Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Marcelo F. Di Carli, Brigham and Women’s Hospital, Radiology and Medicine, ASB-L1, Room 037 C, 75 Francis Street, Boston, Massachusetts 02115.
A wealth of basic and translational science over the last 2 decades has harnessed the cellular and molecular mechanisms underlying the initiation, progression, and complications of atherosclerosis (1–4). This progress in our fundamental understanding of the pathogenesis of atherosclerosis has provided new opportunities for targeted molecular imaging (5). Over the last 10 years, much of the molecular imaging effort in humans has focused on imaging approaches that target various aspects of inflammation within atherosclerotic plaques (5). Endothelial cell activation, cell metabolism, phagocyte function, proteinase activity, and angiogenesis are among the most studied molecular imaging targets in atherosclerosis. Although these approaches provide a useful cross-sectional snapshot of the targeted biology within atheroma, they do not allow the direct study of cell migration to atherosclerotic lesions.
In this issue of the Journal, van der Valk et al. (6) used labeled white blood cell imaging, a well-established nuclear medicine technique to assess inflammation/infection in humans, to evaluate traffic of circulating peripheral blood monocytes (PBMCs) from the blood stream into human atheroma in vivo. These mononuclear phagocytes are the most abundant leukocytes recruited to atherosclerotic lesions (3). Made in hematopoietic organs, such as the bone marrow, the number of monocytes in circulation positively correlates with outcome in cardiovascular disease (7,8). After entering the arterial wall as monocytes, these cells differentiate into macrophages and play a central role in the progression and complications of atherosclerotic plaques (3,9). In this elegant proof-of-concept study, van der Valk et al. (6) studied 10 patients with prior myocardial infarction, transient ischemic attack, or stroke with evidence of atherosclerosis by magnetic resonance imaging (MRI), all of whom were on statins. They excluded patients with active systemic inflammation, systemic anti-inflammatory drug use, and significant renal or hepatic dysfunction. Five healthy controls without evidence of cardiovascular disease, and not taking statins, were balanced to the patients for age, sex, and body mass index. In each subject, PBMCs were isolated from peripheral venous blood samples and subsequently radiolabeled with technetium 99m-hexamethylpropylene amine oxime (99mTc-HMPAO) using a clinically approved ready-for-labeling kit. Radiolabeled autologous PBMCs were then re-infused into patients, who were imaged with hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) at 3, 4.5, and 6 h post-reinfusion. Labeled PBMC trafficking was assessed in the carotid arteries and the ascending aorta; PBMC retention was evaluated by semiquantitative analysis using conventional arterial-to-blood ratios. SPECT/CT findings were correlated with 18fluorodeoxyglucose (FDG) PET/CT and MRI, which were performed at a single time point.
The authors provide in vitro evidence that the isolation and labeling procedure did not affect cell viability or PBMC adhesive or transmigratory capacity. The main finding is a time-dependent increase in PBMC accumulation within arterial segments with MRI evidence of atherosclerosis. The SPECT signal was significantly higher in patients compared to control subjects. Although the study design did not allow for immunohistochemical confirmation that the PBMC signal corresponded to areas of monocyte accumulation, the fact that peak accumulation of labeled PBMCs at 6 h correlated with FDG uptake measured by PET suggests that the imaging signal corresponded to active areas of vessel wall inflammation. Previous studies confirmed that high FDG PET signal correlates with macrophage burden in atherosclerotic lesions (10). Nonetheless, the exact function of these freshly migrated PBMC at arterial sites correlating with existing atheroma by MRI and PET cannot be discerned from this study.
Building on preclinical work documenting the use of labeled monocytes in mice with atherosclerosis (11), the study by van der Valk et al. is the first to apply this technique in humans. One important strength and appeal of the study: it employs established and approved techniques for labeling and imaging PBMCs, thereby providing a potentially useful approach for clinical monitoring of novel therapeutics that can modulate monocyte recruitment in human atherosclerotic lesions. While the work represents a very important first step, several issues need to be addressed before we can confirm that this technique provides an effective imaging approach in human atherosclerosis. First, the study includes only 10 patients with evidence of advanced atherosclerosis by MRI. Although the authors reported a significant SPECT signal increase at 6 h post-injection, there appears to be wide variation among individual patients, so further studies should be conducted to confirm the sensitivity of this approach. In a related issue, there was no additional imaging later than 6 h after cell injection and we do not know whether the 6-hour time point captured the peak monocyte recruitment into atherosclerotic plaques. Previous work in ApoE-/- mice using a similar imaging approach but with 111Indium (with a longer ∼2.8-day physical half-life) suggested that peak accumulation of labeled PBMCs occurred at 5 days post-injection (11). While it is likely that monocyte kinetics differ in humans, this presents an area for further investigation/optimization of the technique. The need for later imaging time points may be addressed by replacing 99mTc for 111In, which is also approved for clinical use. Additionally, all of the patients, but none of the controls, were on statins and exhibited a lower median serum C-reactive protein (CRP) level than the controls. Thus, the positive and significant correlation between CRP and arterial wall PBMC accumulation described by the authors may have been driven by a few patients with extreme CRP values.
Could targeted monocyte imaging be used as a surrogate marker of high-risk atherosclerotic plaques and guide the timing and intensity of new therapeutics in research trials? The answer to this question will require considerably more evidence supporting a pathophysiologic link between trapping of labeled PBMCs and high-risk features of plaques. While experimental models of atherosclerosis offer evidence of this link (11), this needs to be evaluated in humans, ideally comparing the imaging signal to gold standard histology studies. As mentioned earlier, the colocalization of PBMCs with areas of increased FDG signal is both interesting and reassuring. Yet, the exact function of these freshly migrated PBMCs at arterial sites correlating with existing atheroma by MRI and PET cannot be discerned from this study. As the authors note, PBMCs comprise a heterogeneous population of cells, some of which may exhibit anti-inflammatory, rather than proinflammatory, properties. Future studies also will have to demonstrate that this is a potentially modifiable imaging target with existing or novel medical interventions and, more importantly, that such modification leads to decreased high-risk plaque features and/or improved clinical outcomes. The fact that statin treatment of ApoE−/− mice can lead to significant reduction (∼5-fold) in monocyte recruitment to plaques compared with placebo-treated mice (11) suggests that monocyte tracking to atherosclerotic plaque may be a viable imaging alternative for clinical translation, especially in the setting of clinical trials that aim to modulate the migration of innate immune cells, including enhancing the accumulation of regulatory cells. The approach also could be expanded to other cells that may contribute to atherosclerosis pathology, such as lymphocytes.
In summary, the study by van der Valk et al. (6) provides important preliminary evidence documenting the potential of targeted cell imaging for phenotyping human atherosclerosis. If confirmed by future studies, such an approach will expand and complement our growing armamentarium of structural and functional imaging techniques and help us capture new biology and, potentially, enable early diagnosis and guide management of the disease.
↵∗ 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.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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