Molecular magnetic resonance imaging of myeloperoxidase activity identifies culprit lesions and predicts future atherothrombosis

James Nadel; Xiaoying Wang; Prakash Saha; André Bongers; Sergey Tumanov; Nicola Giannotti; Weiyu Chen; Niv Vigder; Mohammed M Chowdhury; Gastao Lima da Cruz; Carlos Velasco; Claudia Prieto; Andrew Jabbour; René M Botnar; Roland Stocker; Alkystis Phinikaridou

doi:10.1093/ehjimp/qyae004

Molecular magnetic resonance imaging of myeloperoxidase activity identifies culprit lesions and predicts future atherothrombosis

Eur Heart J Imaging Methods Pract. 2024 Jan 24;2(1):qyae004. doi: 10.1093/ehjimp/qyae004. eCollection 2024 Jan.

Authors

James Nadel^{1

2

3}, Xiaoying Wang⁴, Prakash Saha⁵, André Bongers⁶, Sergey Tumanov^{1

7}, Nicola Giannotti⁸, Weiyu Chen¹, Niv Vigder¹, Mohammed M Chowdhury⁹, Gastao Lima da Cruz¹⁰, Carlos Velasco⁴, Claudia Prieto^{4

11}, Andrew Jabbour^{2

3}, René M Botnar^{4

11

12}, Roland Stocker¹, Alkystis Phinikaridou^{4

12}

Affiliations

¹ Heart Research Institute, Arterial Inflammation and Redox Biology Group, 7 Eliza St, Newtown, Sydney, NSW 2042, Australia.
² Department of Cardiology, St Vincent's Hospital, Sydney, NSW, Australia.
³ Department of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
⁴ School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK.
⁵ Academic Department of Surgery, Cardiovascular Division, King's College London, London, UK.
⁶ Biological Resources Imaging Laboratory, University of New South Wales, Sydney, NSW, Australia.
⁷ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁸ Medical Imaging Science, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁹ Department of Vascular Surgery, University of Cambridge, Cambridge, UK.
¹⁰ Department of Radiology, University of Michigan, Ann Arbor, USA.
¹¹ Pontificia Universidad Católica de Chile, Institute for Biological and Medical Engineering, Santiago, Chile.
¹² King's BHF Centre of Research Excellence, London, UK.

Abstract

Aims: Unstable atherosclerotic plaques have increased activity of myeloperoxidase (MPO). We examined whether molecular magnetic resonance imaging (MRI) of intraplaque MPO activity predicts future atherothrombosis in rabbits and correlates with ruptured human atheroma.

Methods and results: Plaque MPO activity was assessed in vivo in rabbits (n = 12) using the MPO-gadolinium (Gd) probe at 8 and 12 weeks after induction of atherosclerosis and before pharmacological triggering of atherothrombosis. Excised plaques were used to confirm MPO activity by liquid chromatography-tandem mass spectrometry (LC-MSMS) and to determine MPO distribution by histology. MPO activity was higher in plaques that caused post-trigger atherothrombosis than plaques that did not. Among the in vivo MRI metrics, the plaques' R1 relaxation rate after administration of MPO-Gd was the best predictor of atherothrombosis. MPO activity measured in human carotid endarterectomy specimens (n = 30) by MPO-Gd-enhanced MRI was correlated with in vivo patient MRI and histological plaque phenotyping, as well as LC-MSMS. MPO-Gd retention measured as the change in R1 relaxation from baseline was significantly greater in histologic and MRI-graded American Heart Association (AHA) type VI than type III-V plaques. This association was confirmed by comparing AHA grade to MPO activity determined by LC-MSMS.

Conclusion: We show that elevated intraplaque MPO activity detected by molecular MRI employing MPO-Gd predicts future atherothrombosis in a rabbit model and detects ruptured human atheroma, strengthening the translational potential of this approach to prospectively detect high-risk atherosclerosis.

Keywords: atherosclerosis; atherothrombosis; carotid endarterectomy; molecular magnetic resonance imaging; myeloperoxidase; plaque disruption.