Table 2 USPIO in cardiovascular disease

Atherosclerotic plaques

Ferumoxtran-10 imaging of rabbit aorta [12].

UPSIOs identified within aortic atherosclerotic plaques. They are taken up by macrophages.

Ferumoxtran-10 & ferumoxytol in rabbit aorta [64].

Both USPIO preparations could lidentified within atherosclerotic inflammation. The peak signal for imaging was 2–3 days after ferumoxytol injection, compared to 4–5 days with ferumoxtran-10.

ApoE^−/− mice infused with angiotensin II, or angiotensin II and a p38 MAPK inhibitor with ferumoxtran-10 imaging [21].

The angiotensin II treated animals had the greatest USPIO uptake corresponding with macrophage infiltration. The angiotensin II/p38 MAPK inhibitor group had lower USPIO uptake, which was no different to untreated controls. Modulation of inflammatory cell activity within atherosclerotic plaque could be monitored with USPIO contrast.

ApoE^−/− mice treated with irbesartan were compared to non-treated mice using P904 USPIO [25]. in vivo USPIO labelled macrophages compared to in vitro USPIO labelling macrophages.

Irbesartan treatment resulted in decreased USPIO uptake compared to controls, which was associated with a significant reduction in macrophage-covered area. The use of in vitro labelled macrophages did not produce a significant difference in T2* values despite a difference in macrophage accumulation at histology.

Carotid atherosclerosis

Human carotid plaques using ferumoxtran-10 [65].

USPIOs taken up by macrophages could be identified in human atherosclerotic plaques. High risk plaques took up USPIO more avidly.

Ferumoxtran-10 uptake within carotid plaques of patients with symptomatic and asymptomatic disease [66].

There was more USPIO signal in “contralateral asymptomatic plaques” compared to “truly asymptomatic” patients. Patients with stroke disease have a higher inflammatory burden within non-culprit carotid artery plaques compared with the plaques from asymptomatic patients.

Comparison of carotid plaques of patients awaiting CABG to asymptomatic patients using ferumoxtran-10 [67].

Higher USPIO uptake within the CABG group. The plaques of the CABG patients exhibited a USPIO related signal of i 16.4 % compared to 8.4 % in asymptomatic patients. Patients awaiting CABG had higher inflammatory plaque burden.

The ATHEROMA study (Atorvastatin THerapy: Effects on Reduction Of Macrophage Activity) to investigate the effects of high-dose versus low-dose statin with ferumoxtran-10 imaging [31, 32].

Significant reduction in USPIO uptake in the high-dose atorvastatin group at 6 and 12 weeks. This correlated with favourable reductions in LDL cholesterol and micro-emboli count. Quantitative T2* values showed a highly significant reduction in USPIO-related signal over the course of follow-up. Modulation of plaque inflammation by statins can be monitored by USPIO imaging.

Stroke

Murine model of middle cerebral artery occlusion using ferumoxtran-10 [38].

48 h after stroke, USPIO signal identified within peri-infarct zone. Histology confirmed a large population of iron containing macrophages in the infarcted tissue.

Murine model with ferumoxtran-10 and T2-weighted imaging with multiple scanning points in the first 72 h after stroke [39].

Disruption of the blood brain barrier leads to leakage of USPIO into the CSF, limiting the specificity of inflammatory cell imaging.

Spatio-temporal distribution of ferumoxtran-10 was monitored in a rat model of transient cerebral infarction using T1- and T2-weighted CMR sequences [68].

Maximum USPIO related signal occurred on day 2. The technique was successful in achieving non-invasive imaging of inflammation associated with transient ischaemia, but was not sensitive enough to identify increased macrophage infiltration at later time points.

Murine model to investigate the effects of anti-inflammatory minocycline after middle cerebral artery occlusion using P904 [45].

Treatment reduced infarct size, blood–brain barrier permeability and microglia/macrophage counts. This correlated with decreased R2* value (and USPIO uptake) on imaging as well as tissue iron content.

Ferumoxtran-10 administered to patients 4–5 days after suffering a stroke with imaging performed 24–36 h and 48–72 h later [43].

T1 weighted imaging revealed parenchymal enhancement that increased between the 2 scans, corresponding to the expected macrophage distribution. T2/T2* weighted imaging revealed increased USPIO enhancement between scans, which the authors interpreted as blood pool effect. These USPIO induced changes did not correspond to conventional gadolinium enhanced changes, suggesting they occurred independent of blood–brain-barrier breakdown.

Myocardial infarction

USPIO agent NC100150 as a blood pool agent in a rodent model of reperfusion after MI [69].

Hyperenhancement of the myocardium by UPSIO was compared to infarct size. USPIO T1-weighted hyper-enhancement was larger than infarction area after reperfusion, but smaller than area at risk. UPSIO corresponded with micro vascular injury and was associated with leakage into the extravascular space.

Montet-Abou et al. studied fluorescent iron oxide nanoparticles (5–20 nm) in a rodent MI model [70].

Rats with a sham operation and those with MI but not given USPIO did not have significant change in USPIO uptake. The MI group given USPIO had a significant increase in USPIO uptake over the 3 days, with excellent correlation of monocytes/macrophages on histology. CD-68 immuno-staining confirmed co-localisation of fluorescent USPIO particles within macrophages. Rats treated with anti-inflammatory medication showed reduced USPIO signal. This corresponded with less monocyte/macrophage infiltration confirming that USPIO can track inflammation and response to therapeutic intervention within infarcted myocardium.

Ferumoxytol in human myocardial infarction [46].

USPIO uptake increased significantly in the infarct zone and also in the peri-infarct and remote myocardium to lesser extents.

Cardiac transplant

Synthesised dextran coated USPIO to investigate macrophage accumulation in a rodent cardiac allograft rejection model [71].

Control rodents did not have significant USPIO uptake at baseline. Allograft rodents exhibited large USPIO uptake which was reduced by immunosuppression. Corresponding macrophage counts were greatest in the allograft group and reduced by immunosuppressive treatment indicating that USPIOs can be used to monitor transplant rejection.