Abstract 12751: Impaired Elastin Function Promotes Acute Plaque Rupture, Cerebral Infarction and Sudden Death in ApoE-deficient Mice
Background: Arterial stiffness is an independent predictor of cardiovascular risk. The aim of this study was to investigate the effects of arterial stiffness on the progression of atherosclerosis.
Methods and results: Mice with a mutation (C1039G+/−) in the fibrillin-1 gene, leading to fragmentation of the elastic fibers and increased arterial stiffness, were cross-bred with ApoE−/− mice. Subsequently, ApoE−/− (n=8) and ApoE−/−C1039G+/− mice (n=10) were fed a Western-type diet for 52 weeks. Arterial stiffening in ApoE−/−C1039G+/− mice was associated with an increase in systolic blood pressure and pulse pressure. Moreover, atherosclerotic plaques in ApoE−/−C1039G+/− mice showed a more unstable plaque phenotype, characterized by a decrease in collagen content and enlargement of the necrotic core. There were no premature deaths in the ApoE−/− mice. However, fifty percent of the ApoE−/−C1039G+/− mice died suddenly. Sudden death in ApoE−/−C1039G+/− mice was associated with the presence of acute plaque rupture in the proximal ascending aorta. Furthermore, magnetic resonance imaging of the brain showed the presence of a high number of cerebral infarctions in the surviving ApoE−/−C1039G+/− mice (median number of lesions = 3 [range 3 – 5] in ApoE−/−C1039G+/− mice vs. 0 [range 0 – 3] in ApoE−/− mice). The cerebral infarctions were characterized by the presence of foam cells and cholesterol clefts, indicating that these lesions were caused by cerebral embolization of plaque debris after rupture of atherosclerotic plaques in the aortic arch or a carotid artery.
Conclusions: Our results indicate that arterial stiffness increases the risk of acute plaque rupture, cerebral infarction and sudden death. In addition, ApoE−/−C1039G+/− mice represent a promising model of acute plaque rupture, enabling the investigation of novel plaque stabilizing therapies on clinical end points such as stroke and sudden death.
- © 2010 by American Heart Association, Inc.