Molecular imaging of atherosclerosis: clinical state-of-the-art

Abstract

Molecular imaging is a burgeoning field that aims to image molecular and cellular detail in living subjects. In cardiovascular research, many exciting approaches have emerged, and several are utilized in the clinic or are in the process of translation. Here, we discuss high priority clinical developments in molecular imaging of atherosclerosis, and showcase examples that may enable improved detection of high-risk plaques, clinical risk stratification, and biological assessment of pharmacotherapeutic approaches.

Figure 1

Clinical molecular imaging concepts. (A) Schematic representation of the value of molecular imaging in the detection of early disease or even pre-disease changes in patients, compared to anatomical imaging capabilities. Patient symptoms usually occur in a later phase where physiological and/or anatomical changes have occurred. (B) Comparative overview table of electromagnetic energy, spatiotemporal resolution of clinical systems, advantages/disadvantages of molecular imaging modalities. PET=positron emission tomography, SPECT=single photon emission computed tomography, MRI=magnetic resonance imaging, CT=computed tomography.

Figure 2

The use of ¹⁸F-FDG PET/CT imaging of inflammation in carotid artery atherosclerosis to assess anti-inflammatory effects of statins. (A) ¹⁸F-FDG PET and merged PET/CT images of carotid artery atherosclerosis in patients undergoing dietary intervention without (1st panel) and with simvastatin (2nd panel, 3 months later) treatment. ¹⁸F-FDG uptake was significantly decreased after statin treatment (white arrows), while dietary changes alone negligibly affected carotid and aortic uptake. (B) In a statin inflammation dose-response serial PET/CT study, 67 patients were randomized and started atorvastatin 10mg or 80mg per day. They underwent ¹⁸F-FDG imaging at baseline, and after 4 and 12 weeks of treatment. After 4 weeks of statin treatment, a significant reduction ¹⁸F-FDG uptake (MDS-TBR) was observed in both 10mg and 80mg groups (6.4%, 12.5% respectively). However, after 12 weeks this effect was diminished to 4.3% (p>0.10) in the 10mg group. In the 80mg group the effect further increased significantly to 14.4% at 12 weeks treatment. MDS-TBR=most diseased segment - target-to-background ratio. Reproduced by permission from references [9, 10].

Figure 3

Assessment of statin anti-inflammatory effects using serial USPIO-enhanced molecular MRI of patients with carotid vascular disease. Patient underwent molecular MRI at baseline, and then started either low-dose 10mg or high-dose 80mg atorvastatin, and then underwent repeat MRI at 6 and 12 weeks. T2-weighted MR imaging of carotid artery before USPIO infusion (A) and after infusion (B) in patients receiving a low dose of atorvastatin (10mg). (A) Carotid MRI images remain similar to baseline at 6 and 12 weeks suggesting no or negligible USPIO uptake in the vessel wall from prior injections. (B) Post-injection USPIO uptake was found at all time-points (dark areas indicating MRI signal loss, yellow arrows), suggesting minimal anti-inflammatory effect of atorvastatin 10mg. (C) The 80mg atorvastatin group also demonstrated elevated USPIO plaque uptake at baseline (dark area, small yellow arrow). However, at 6 and 12 weeks after treatment, enhanced MRI signal (small blue arrows) rather than signal voids were noted, consistent with a decrease in USPIO uptake and plaque macrophages induced by high-dose statin treatment. Reproduced by permission from reference [8].

Figure 4

Coronary molecular imaging using noninvasive PET/CT. (left panels) ¹⁸F-FDG PET/CT preliminary imaging of coronary artery inflammation in subjects with CAD. (A) ¹⁸F-FDG uptake in the left main coronary artery (LMCA) and stented lesion in a patient with an ACS. (B) In a patient with stable CAD, ¹⁸F-FDG uptake was found in a recently stented mixed plaque in the LMCA, although to a lesser extent (C) modest ¹⁸F-FDG uptake in a lesion that was stented months before. (D) ¹⁸F-FDG uptake at the LMCA trifurcation in an ACS patient. The box plot depicts ¹⁸F-FDG aortic uptake in ACS and stable CAD patients. The mean target-to-background ratio was higher in ACS patients as expected. (right panels) ¹⁸F-NaF PET/CT imaging of plaque osteogenic activity in CAD patients. Two examples of patients (A) without and (B) with coronary calcification. Both patients showed lack of ¹⁸F-NaF plaque osteogenic activity, consistent with absent and “burnt out” CAD, respectively. (C) Clear focal ¹⁸F-NaF uptake in the proximal left anterior descending artery (LAD). (D) Increased focal ¹⁸F-NaF uptake bordering calcified regions of mid-LAD. The graph plots the Framingham risk scores (FRS) in patients. Patients with elevated ¹⁸F-NaF uptake had a higher FRS. Error bars denote SD of the mean. Reproduced by permission from references [14, 16].

Figure 5

Emerging high-resolution approaches for coronary artery molecular imaging of inflammation using intravascular NIRF imaging. (A) Standalone intravascular NIRF molecular imaging of inflammatory cathepsin protease activity in atherosclerosis. A rabbit with atheroma was injected with a specialized NIRF cathepsin protease-activatable imaging agent, Prosense VM110, 24 hours prior to imaging. (a) Angiography of rabbit aorta, showing radiopaque tip of the imaging catheter in distal aorta, co-registered with intravascular ultrasound (IVUS) shown in a longitudinal view (b) with 2 plaque zones (P1,P2). (c) Aligned pullback image of measured NIRF signal of the catheter along the aorta (vertical axis is rotational 0-360 degrees), demonstrating increased signal in small volume plaques. (d) Fused IVUS and NIRF longitudinal map (yellow/white = strongest NIRF signal, red/black = lowest NIRF signal). High magnification (f,g) and axial IVUS images (h,i) of plaque zones P1 and P2. Scale bars, 500 μm (a,b,c). (B) Hybrid, fully integrated NIRF/OFDI imaging of atherosclerosis using a single catheter. Rabbits were similarly pre-injected with Prosense VM110 24 hours beforehand. (a) OFDI image showing a plaque from 2-10 o'clock with elevated NIRF signal (yellow/white = high NIRF signal), and corresponding (b) hematoxylin/eosin (H&E) and (c) cathepsin B staining. (d) NIRF-OFDI imaging of smaller plaques, demonstrating relatively lower NIRF signal and lower levels of (e) plaque area and (f) cathepsin B reactivity. Scale bar, 1mm. Reproduced by permission from references [17, 18]