Optimization and validation of a mouse model of atherosclerotic plaque rupture.

Rupture of atherosclerotic plaques remains the main cause of acute cardiovascular syndromes and death. The need for novel plaque stabilising therapies is high, but adequate animal models are lacking. We recently discovered that ApoE-/- mice with a disturbed fibrillin production (ApoE-/-/C1039G+/- mice) fed a Western-type diet develop more unstable plaques as compared to ApoE-/- mice. Interestingly, acute plaque rupture and death occurred very frequently: 50% of the ApoE-/-/C1039G+/- mice died suddenly within 20 to 52 weeks, most likely due to cerebral embolism, whereas all ApoE-/- mice survived. Further optimisation and characterisation of this model could provide better insights in the mechanisms of plaque rupture, and also give for the first time the opportunity to evaluate potential plaque stabilising therapies on genuine clinical end points of plaque rupture (embolism, stroke and/or death) in mice. The aims of the project are:1) Further optimisation and characterisation of the model. We will investigate whether additional destabilising stimuli can augment and speed up the incidence of plaque rupture, which is important for the evaluation of plaque stabilising therapies.2) Validation of this model with established plaque stabilising drugs such as statins.3) Study of the effects of novel potential plaque stabilising therapies (phytosterols, NO-donor).

Keywords:ATHEROSCLEROTIC PLAQUE, CARDIOVASCULAR SYSTEM

Disciplines:Cardiac and vascular medicine