There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G^+/−) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE^−/−) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE^−/−Fbn1^C1039G+/− mice and was associated with myocardial infarction, stroke, and sudden death.

Female ApoE^−/−Fbn1^C1039G+/− and ApoE^−/− mice were fed a WD for up to 35 weeks. Compared to ApoE^−/− mice, plaques of ApoE^−/−Fbn1^C1039G+/− mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE^−/−Fbn1^C1039G+/− mice. In ApoE^−/− mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE^−/−Fbn1^C1039G+/− mice died suddenly, whereas all ApoE^−/− mice survived. ApoE^−/−Fbn1^C1039G+/− mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke.

Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE^−/−Fbn1^C1039G+/− mice represent a unique model of acute plaque rupture with human-like complications.