Ferumoxytol-enhanced magnetic resonance imaging assessing inflammation after myocardial infarction

Abstract

Objectives: Macrophages play a central role in the cellular inflammatory response to myocardial infarction (MI) and predict subsequent clinical outcomes. We aimed to assess temporal changes in cellular inflammation and tissue oedema in patients with acute MI using ultrasmallsuperparamagnetic particles of iron oxide (USPIO)-enhanced MRI.

Methods: Thirty-one patients were recruited following acute MI and followed up for 3 months with repeated T2 and USPIO-enhanced T2*-mapping MRI. Regions of interest were categorised into infarct, peri-infarct and remote myocardial zones, and compared with control tissues.

Results: Following a single dose, USPIO enhancement was detected in the myocardium until 24 hours (p<0.0001). Histology confirmed colocalisation of iron and macrophages within the infarcted, but not the non-infarcted, myocardium. Following repeated doses, USPIO uptake in the infarct zone peaked at days 2-3, and greater USPIO uptake was detected in the infarct zone compared with remote myocardium until days 10-16 (p<0.05). In contrast, T2-defined myocardial oedema peaked at days 3-9 and remained increased in the infarct zone throughout the 3-month follow-up period (p<0.01).

Conclusion: Myocardial macrophage activity can be detected using USPIO-enhanced MRI in the first 2 weeks following acute MI. This observed pattern of cellular inflammation is distinct, and provides complementary information to the more prolonged myocardial oedema detectable using T2 mapping. This imaging technique holds promise as a non-invasive method of assessing and monitoring myocardial cellular inflammation with potential application to diagnosis, risk stratification and assessment of novel anti-inflammatory therapeutic interventions.

Trial registration number: Trial registration number: 14663. Registered on UK Clinical Research Network (http://public.ukcrn.org.uk) and also ClinicalTrials.gov (https://ichgcp.net/clinical-trials-registry/NCT02319278?term=DECIFER&rank=2).

Keywords: Cardiac; Inflammation; MRI; Molecular Imaging; Myocardial Infarction; USPIO.

Conflict of interest statement

Competing interests: None declared.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

(A) Duration and distribution of USPIO enhancement after single-dose administration in the first week after MI. (B) Repeated myocardial uptake of USPIO following MI. MI, myocardial infarction; USPIO, ultrasmall superparamagnetic particles of iron oxide.

Figure 2

Histology section of trucut biopsy from infarcted myocardium. (A) Haematoxylin and eosin (×5 magnification) stain displaying a thin region of viable healthy myocardium (strip of dark pink) surrounded by infarcted myocardium (lighter pink). (D) Infarcted myocardium shows an abundance of inflammatory cells and early granulation formation. (B) Prussian blue (×5) staining revealing intracellular iron (E, ×20 and G, ×50), not seen in the region of healthy myocardium. (C) CD68 (×5) staining revealing macrophages within the infarcted myocardium (F, ×20 and H, ×50), again not seen in healthy myocardium. G+H show colocalisation of iron within macrophages.

Figure 3

(A) USPIO uptake in myocardium after MI with repeated USPIO administration. (B) R2* 24 hours following USPIO (without subtraction of baseline values). Time course variation in USPIO uptake was seen in the infarct zone peaking at days 2 and 3. No variation of USPIO uptake was seen in peri-infarct and remote myocardium. Compared with remote myocardium, increased USPIO uptake was seen in the infarct zone until days 10–16 post MI. (****p

Figure 4

Examples of myocardial oedema and USPIO enhancement in the infarct zone after MI. Three examples of MI (1—anteroseptal, 2—lateral and 3—inferior) illustrating LGE, USPIO enhancement (R2* map) and oedema (T2 map) at early (up to 10 days) and late (3 months) time points. Early inflammation and oedema seen on R2* (dark region) and T2 maps (light region), respectively, have improved or resolved by 3 months. LGE, late gadolinium enhancement; MI, myocardial infarction; USPIO, ultrasmall superparamagnetic particles of iron oxide.

Figure 5

T2 value in the myocardium after MI. Time course variation in infarct and peri-infarct T2 was seen in the 3-month period following MI, both peaking at days 3–9. Compared with remote myocardium, higher T2 was seen in the infarct zone throughout the duration of the study and in the peri-infarct zone until days 17–24 (****p

Figure 6

USPIO enhancement after single-dose administration in the first week following MI. Following single-dose administration, USPIO enhancement was detected in all myocardial regions at 24 hours. USPIO was detected in bone marrow until 4–9 days, and spleen and liver until 13–21 days (****p