Abstract 4279: Pravastatin prevents aortic root dilation in Marfan Syndrome
Aneurysm and dissection are potentially lethal sequelae of aortic root dilation in Marfan Syndrome. We used a murine model to test the hypothesis that pravastatin attenuates this aortic root dilation in Marfan Syndrome. Mice heterozygous for a mutant allele encoding a cysteine substitution in fibrillin-1 (C1039G Marfan mice) were crossbred with C57Bl6 females. Genetic analysis identified C1039G offspring Marfan mice. The effects of treatment with pravastatin 50mg/kg/day on the end-points of aortic root diameter, cardiac function, and aortic pathology was assessed using normal littermates as controls. At 6 months of age, the aortic root diameter of Marfan mice was significantly increased compared to controls (1.77±0.08mm, n=20 vs. 1.53±0.03mm, n=22; p=0.002). On histological sections of the aortic root, Marfan mice had significant thickening of the aortic media (117±4 μm, n=18 vs. controls 82±2μm, n=20; p<0.001) and abnormal aortic wall architecture characterised by elastic fibre fragmentation (histological architecture score 6.1±0.6, n=18 vs. controls 0.4±0.2, n=17; p <0.001). Marfan mice treated with pravastatin had no aortic dilation (1.2±0.02mm, n =25; p<0.001), attenuated thickening of the aortic media (106±3μm, n=22; p=0.029), and a trend to improved aortic wall architecture (histology score 4.6±0.4, n=22; p=0.064), compared to untreated Marfan mice. There was no widening of aortic pulse pressure in treated mice compared to Marfan controls (35±1mmHg, n=20 vs. Marfan untreated 45±1mmHg; p=0.001), perhaps indicating less or no secondary aortic regurgitation. The C1039G Marfan mouse develops significant aortic dilatation and pathology in the aortic wall. Treatment with pravastatin prevents this aortic root dilatation and improves aortic pathology in Marfan Syndrome. This represents a novel treatment for patients with Marfan Syndrome to attenuate the development of this life threatening complication.