Myocardial infarction is caused by rupture of the fibrous cap, with exposure of the lipid-rich core, or erosion, resulting in subsequent thrombosis and vessel occlusion. Plaques consist of a vascular smooth muscle cell (VSMC)-rich, fibrous cap, composed of collagen and extracellular matrix, which separates a lipid-rich core from the lumen. Our research studies the regulation of cell accumulation and interactions in vascular disease, using both human and mouse cells in vitro and models of atherosclerosis with genetic manipulation. We also have a major interest in vulnerable plaque imaging in patients using both invasive and non-invasive modalities.

Plaque stability is determined by its mechanical properties, in particular, the number of VSMCs and their extracellular matrix products including collagen. VSMC number is determined by the net effect of VSMC proliferation, migration, death and recruitment from circulating precursors. Low levels of VSMC proliferation and cellular senescence are found in advanced human lesions. Apoptosis (programmed cell death) of VSMCs also occurs in advanced plaques at higher levels than in normal vessels and is increased in unstable vs. stable angina patients. In addition, direct induction of apoptosis induces plaque rupture of mouse plaques. These studies all indicate that VSMC proliferation, apoptosis, and cell senescence are all major determinants of VSMC number and plaque stability.

We use both human and mouse cells in vitro and models of atherosclerosis with genetic manipulation to study the role of specific gene products or cells in atherosclerosis. In particular, we have developed unique cell-type ablation systems to analyse the role of specific cells in vivo. Recent work has focussed on the protective mechanisms that ensure survival in VSMCs, and their defects in disease as well as the triggers for VSMC apoptosis and cell senescence. We have also identified novel mechanisms of regulating cell death receptors in vascular cells and how cell: cell interactions govern cell death.

Our clinical studies have used radiofrequency (virtual histology) intravascular ultrasound and computed tomography to determine the types and composition of plaques that determine patient presentation and future events, and are refining these techniques to examine vulnerable plaque characteristics. Collaborations with physical scientists are ongoing to model the mechanical properties of vulnerable plaques.