Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences.

Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGFß) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1mgR/mgR mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae revealed a lower ratio of trabecular bone volume to tissue volume, reduced trabecular number and thickness, and greater trabecular separation in females vs. males. Three-point bending of femora revealed significantly lower post-yield displacement and work-to-fracture in females vs. males. Mechanistically, we found higher Smad2 and ERK1/2 phosphorylation in females vs. males, demonstrating a greater activation of TGFß signaling in females. In summary, the present findings show pronounced sex differences in the matrix and function of bones deficient in fibrillin-1 microfibrils. Consequently, sex-specific analysis of bone characteristics in patients with MFS may prove useful in improving the clinical management and life quality of these patients, through the development of sex-specific therapeutic approaches.

A clinical appraisal of different Z-score equations for aortic root assessment in the diagnostic evaluation of Marfan syndrome.

PURPOSE: Aortic sinus diameter dilatation expressed as a Z-score >2.0 is diagnostic in Marfan syndrome. In addition to the classic equation (Z1) for calculating Z-scores, two new equations were recently introduced (Z2 and Z3). METHODS: We studied the effects of obesity, age, and the absolute cut point of 40 mm on these three equations in 2,674 echocardiographic measurements of 260 patients with Marfan syndrome. RESULTS: Diameters ≥40 mm were associated with Z1 scores <2.0 in 109 measurements (11.0%; 35 patients), Z2 scores <2.0 in 37 measurements (3.8%; 13 patients), and Z3 scores <2.0 in 24 measurements (2.4%; 11 patients). Mean diameters increased after the 40th birthday: 42.0 (37.3-44.8 mm interquartile range) to 42.5 (39.0-45.0 mm interquartile range; P = not significant) and mean Z1 scores decreased from 3.60 to 2.17 (P < 0.01), whereas Z2 and Z3 scores tended to increase (Z2: 3.04-3.27; Z3: 3.39-3.55; P = not significant for both). Comparing Z-scores between patients with body mass index <25 kg/m² (group A) and those with body mass index ≥25 kg/m² (group B), median Z1 scores differed between groups (Z1 = 3.00 in group A, Z1 = 1.78 in group B; P = 0.012), whereas Z2 (Z2 = 2.82 in group A, Z2 = 2.47 in group B; P = 0.52) and Z3 scores (Z3 = 2.72 in group A, Z2 = 3.12 in group B; P = 0.32) did not. CONCLUSION: Z1 scores are inferior to Z2 and Z3 scores in Marfan syndrome. In particular, the Z3 score, correcting aortic sinus diameter for body height, seems excellent.

Age-related and regional changes of aortic stiffness in the Marfan syndrome: assessment with velocity-encoded MRI.

PURPOSE: To study age-related change in aortic stiffness in patients with Marfan syndrome (MFS) versus healthy volunteers using velocity-encoded (VE) MRI. MATERIALS AND METHODS: Twenty-five MFS patients (age range, 18-63 years; mean age 36 ± 14 years, 13 men) and 25 age-/gender-matched healthy volunteers were examined with VE-MRI. Aortic stiffness was expressed by pulse wave velocity (PWV), assessed in the proximal and distal part of the aorta and in the total aorta. PWV was compared between patients and volunteers and age-relation was determined by linear regression. RESULTS: PWV was significantly higher in all parts of the aorta in patients when compared with healthy volunteers (proximal aorta 5.7 ± 1.5 m/s versus 4.8 ± 0.9 m/s, distal aorta 6.4 ± 2.4 m/s versus 5.0 ± 1.2 m/s and total aorta 5.9 ± 1.7 m/s versus 4.9 ± 1.1 m/s, all P < 0.004). PWV correlated significantly with age (Pearson R between 0.45 and 0.94). Only in the proximal aorta, the increase in PWV with age was significantly higher in patients (7 ± 2 cm/s increase with age) than in volunteers (3 ± 1 cm/s increase, P = 0.03); in the distal or total aorta, the increase in PWV with age was not different between patients and volunteers. CONCLUSION: Velocity-encoded MRI detects more pronounced age-related aortic stiffening in the proximal aorta in MFS patients versus healthy volunteers, suggesting more severe wall disease in MFS.

Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome.

AIMS: Elastin is the primary component of elastic fibres in arteries, which contribute significantly to the structural integrity of the wall. Fibrillin-1 is a microfibrillar glycoprotein that appears to stabilize elastic fibres mechanically and thereby to delay a fatigue-induced loss of function due to long-term repetitive loading. Whereas prior studies have addressed some aspects of ageing-related changes in the overall mechanical properties of arteries in mouse models of Marfan syndrome, we sought to assess for the first time the load-carrying capability of the elastic fibres early in maturity, prior to the development of ageing-related effects, dilatation, or dissection. METHODS AND RESULTS: We used elastase to degrade elastin in common carotid arteries excised, at 7-9 weeks of age, from a mouse model (mgR/mgR) of Marfan syndrome that expresses fibrillin-1 at 15-25% of normal levels. In vitro biaxial mechanical tests performed before and after exposure to elastase suggested that the elastic fibres exhibited a nearly normal load-bearing capability. Observations from nonlinear optical microscopy suggested further that competent elastic fibres not only contribute to load-bearing, they also increase the undulation of collagen fibres, which endows the normal arterial wall with a more compliant response to pressurization. CONCLUSION: These findings support the hypothesis that it is an accelerated fatigue-induced damage to or protease-related degradation of initially competent elastic fibres that render arteries in Marfan syndrome increasingly susceptible to dilatation, dissection, and rupture.

Magnetic resonance imaging of the main pulmonary artery: reliable assessment of dimensions in Marfan patients on a simple axial spin echo image.

OBJECTIVE: To investigate if a simple axial spin echo (SE) image can be used for reliable assessment of pulmonary artery dimensions in patients with Marfan syndrome. METHODS: Fifty Marfan patients (mean age 33 +/- 10 years; 34 men, 16 women) and 15 normal subjects (mean age 28 +/- 4 years; nine men, six women) underwent cardiac magnetic resonance imaging (MRI). Pulmonary artery dimensions were obtained on axial SE images at two different levels: (1) the level of the pulmonary artery root, and (2) the level of the pulmonary artery bifurcation. To evaluate the accuracy of axial plane measurements 10 Marfan patients also underwent contrast-enhanced MR angiography (CE-MRA). RESULTS: In the 10 Marfan patients who also underwent CE-MRA, the mean diameter at the pulmonary bifurcation assessed with CE-MRA (31.5 +/- 3.6 mm) was almost equal to mean diameter assessed with axial SE (30.7 +/- 3.6 mm). Agreement of methodology according to Bland and Altman analysis showed a 95% confidence interval ranging from -2.6 to + 4.4 mm for all distances of the pulmonary artery root. In Marfan patients the mean right-left diameter measured on both axial SE images and CE-MRA was approximately 2.5 mm larger than the anterior-right and anterior-left diameters (p < 0.001). CONCLUSIONS: Axial SE MRI is a reliable and easy acquisition to measure pulmonary artery dimensions in patients with Marfan syndrome, and could be used for follow-up, especially in patients with severe involvement of the cardiovascular system. Not only the pulmonary artery trunk but also the asymmetric pulmonary root should be measured, although the clinical relevance of the asymmetric root is not yet known.