Cardiovascular disease remains the leading cause of death worldwide and in Australia. Some 30 per cent of heart attacks are thought to be caused by rupture of unstable coronary plaque that cannot be detected reliably by currently available imaging and/or diagnostic procedures. The major cause of cardiovascular disease is atherosclerosis, a progressive lipid- and inflammation-driven process characterized by the accumulation of plaque in the arterial wall. The progression of early to late stage atherosclerosis involves a myriad of biochemical changes. Identifying these changes in general, and particularly those that lead to unstable plaque vulnerable to rupture and causing a heart attack, is of great importance. This is because it may provide the basis of a novel diagnostic test to help identify and potentially treat those with unstable plaque and at high risk of a heart attack. Achieving this aim would overcome a major clinical need that is presently unmet.
Using a lab model of plaque instability and non-invasive magnetic resonance imaging (MRI) ‘top-down’ approach (Rashid et al. EHJ 2018;39:3301), we demonstrated that myeloperoxidase (MPO) activity drives formation of unstable plaque. We also showed that arterial MPO activity can be detected non-invasively using molecular imaging in combination with an MPO-specific molecular probe (MPO-Gd). Using state-of-the-art mass spectrometry-based multi-omics approach (‘bottom-up’ approach), we recently observed that unstable plaque contains a unique combination of molecules (also called a ‘signature’) different to present in stable plaque. Moreover, there is a molecular signature detectable in plasma that is unique for lab models with unstable plaque.
We hypothesise that by combining our ‘top-down’ approach of using non-invasive molecular imaging of MPO activity in vivo with a plasma metabolic signature, we can develop a novel non-invasive assay to detect the presence of unstable plaque. The present project attempts to establish such an assay in lab models, and to then expand our study to detect unstable plaque in humans by correlating lesion characteristics of unstable plaque by in vivo MR imaging of carotid arteries with both MPO activity determined ex vivo in the same carotid plaque after endarterectomy procedure and metabolic ‘signatures’ in arterial tissues and blood plasma.
If successful, this project has the potential to discover a novel and simple blood test of clinical utility to identify high-risk patients with unstable atherosclerotic plaque that have a preponderance to rupture and thereby potentially cause thrombosis and an adverse clinical event.