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

Abstract

Acknowledgements: We acknowledge the support of the Heart Research Institute mass spectrometry facility and the University of New South Wales Biological Resource Imaging Laboratory.Funder: National Health & Medical Research Council of Australia; DOI: https://doi.org/10.13039/501100000925Funder: National Heart Foundation; DOI: https://doi.org/10.13039/501100001516Funder: University of New South Wales; DOI: https://doi.org/10.13039/501100001773Funder: NSW Department of HealthFunder: AstraZeneca; DOI: https://doi.org/10.13039/100004325Lay Summary: Cardiovascular diseases, including heart attacks and strokes, are the leading cause of death worldwide. Most heart attacks and strokes occur because of atherosclerosis, a chronic disease of the arteries caused by reduced blood flow to the heart and brain. Atherosclerotic plaques are characterized by the accumulation of lipids and inflammatory cells. A type of atherosclerotic plaques called ‘unstable plaque’ can suddenly rupture causing blood clots that abruptly block the arteries, and this can lead to loss of blood supply to the heart and brain. In recent years, inflammation of the arteries has emerged as a key driver and therapeutic target for stroke and heart attack. However, existing diagnostic methods and medical therapies do not specifically target inflammation so that residual inflammatory risk remains untreated and undetected. Therefore, there is a clinical need to specifically identify patients with active inflammation of the arteries who may benefit from targeted treatment. Recent findings have demonstrated that the inflammatory enzyme myeloperoxidase causes the formation of unstable plaque in animal models of the disease and is abundant in life-threatening human atherosclerotic plaques that are at risk of rupturing. This identifies myeloperoxidase as a ground-breaking diagnostic tool and therapeutic target. Similarly, the development of novel targeted therapies that inhibit myeloperoxidase has shown promising results in human studies and a capacity to treat unstable plaques in animal models. This paper demonstrates the utility and application of imaging of myeloperoxidase activity by magnetic resonance imaging (MRI) to identify/detect unstable atherosclerotic plaques non-invasively. It confirms the link between myeloperoxidase activity and rupture of ‘unstable’ plaque and reports myeloperoxidase’s role as a novel non-invasive imaging biomarker for detecting life-threatening plaques prior to a potentially fatal event