IN VIVO MEASUREMENTS OF BIOPHYSICAL PROPERTIES OF A HEART AND AORTA IN A MOUSE MODEL OF MARFAN SYNDROME

Abstract

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue caused by mutations in the fibrillin-1 (FBN1) gene. Cardiovascular complications are the most life-threatening manifestations in MFS patients, and death is often sudden due to aortic dissection and rupture in young patients. In the present study, we aim to investigate the structural and functional properties of the heart and aorta in a well-established MFS mouse model by using a high resolution (50-MHz) ultrasound system. Six- and twelve-month old WT (Fbn1 +/+) and MFS [Fbn1 (C1039G/+)] mice (n = 8) were scanned using the Vevo 2100 ultrasound system (VisualSonics®). We measured several key variables including pulse wave velocity (PWV), aortic root diameter, ejection fraction, stroke volume, left ventricular (LV) wall thickness, LV mass, mitral valve early velocity/atrial velocity (E/A) ratio and LV strain analysis. Our results indicate that PWV was significantly increased in 6-mo MFS vs. WT (366.6 ± 19.9 vs. 205.2 ± 18.1 cm/s; p < 0.001) and 12-mo MFS vs. WT (459.5 ± 42.3 vs. 205.3 ± 30.3 m/s; p = 0.001) and the increased PWV directly proportional to age in MFS mice (R-squared =0.356; p = 0.02). Regarding the LV structure, interventricular septal thickness (N) (2.52 ± 0.14 vs. 2.08 ± 0.10 μm/g; p = 0.03) and LV mass (N) (3.06 ± 0.16 vs. 2.46 ± 0.09 μm/g; p = 0.007) were significantly increased in 6-month MFS mice compared with WT, as well the LV anterior wall (N) (2.72 ± 0.26 vs. 2.07 ± 0.11 μm/g; p = 0.045) and posterior wall (N) (2.35 ± 0.16 vs. 1.91 ± 0.06 μm/g; p = 0.03) thickness were significantly increased in 12-month MFS mice. We also found a significantly enlarged aortic root, decreased E/A ratio, prolonged isovolumic relaxation time (IVRT) and increased myocardial performance index (MPI) in MFS mice compared with WT for both two age groups. (N, data normalized with mice body weight.) This study shows significant aortic dilation and central aortic stiffness in the MFS mouse, which are associated with LV hypertrophy and diastolic dysfunction. Moreover, the symptoms progressed with increasing age from six months to twelve months. It is not clear whether the increased LV muscle mass and abnormal diastolic function are due to the abnormal after-load caused either by increased aortic stiffness or by abnormal myocardial connective tissue.