Sensitive magnetic particle imaging of haemoglobin degradation for the detection and monitoring of intraplaque haemorrhage in atherosclerosis

Abstract

Background: Intraplaque haemorrhage (IPH) drives atherosclerosis progression and is a key imaging biomarker of unstable plaques. Non-invasive and sensitive monitoring of IPH is challenging due to the compositional complexity and dynamic nature of atherosclerotic plaques. Magnetic particle imaging (MPI) is a highly sensitive, radiation-free, and no-tissue-background tomographic technique that detects superparamagnetic nanoparticles. Thus, we aimed to investigate whether MPI can in vivo detect and monitor IPH.

Methods: Thirty human carotid endarterectomy samples were collected and scanned with MPI. The tandem stenosis (TS) model was employed to establish unstable plaques with IPH in ApoE^-/- mice. MPI and 7 T T1-weighted magnetic resonance imaging (MRI) were performed on TS ApoE^-/- mice. Plaque specimens were analyzed histologically.

Findings: Human carotid endarterectomy samples exhibited endogenous MPI signals, which histologically colocalized with IPH. In vitro experiments identified haemosiderin, a haemoglobin degradation product, as a potential source of MPI signals. Longitudinal MPI of TS ApoE^-/- mice detected IPH at unstable plaques, of which MPI signal-to-noise ratio values increased from 6.43 ± 1.74 (four weeks) to 10.55 ± 2.30 (seven weeks) and reduced to 7.23 ± 1.44 (eleven weeks). In contrast, 7 T T1-weighted MRI did not detect the small-size IPH (329.91 ± 226.82 μm²) at four weeks post-TS. The time-course changes in IPH were shown to correlate with neovessel permeability providing a possible mechanism for signal changes over time.

Interpretation: MPI is a highly sensitive imaging technology that allows the identification of atherosclerotic plaques with IPH and may help detect and monitor unstable plaques in patients.

Funding: This work was supported in part by the Beijing Natural Science Foundation under Grant JQ22023; the National Key Research and Development Program of China under Grant 2017YFA0700401; the National Natural Science Foundation of China under Grant 62027901, 81827808, 81730050, 81870178, 81800221, 81527805, and 81671851; the CAS Youth Innovation Promotion Association under Grant Y2022055 and CAS Key Technology Talent Program; and the Project of High-Level Talents Team Introduction in Zhuhai City (Zhuhai HLHPTP201703).

Keywords: Atherosclerosis; Endogenous component; Haemosiderin; Intraplaque haemorrhage; Magnetic particle imaging.