444Plasma levels of microfibrillar associated protein type 4 (MFAP4) are predictive for aortic dissection in patients with Marfan Syndrome

Abstract

Abstract Aim Marfan syndrome is a disorder with mutations in the fibrillin-1 gene, leading to elastic fiber degradation and increased TGF-beta signaling. The life-threatening feature of Marfan is aneurysm formation with a risk of fatal aortic dissections. In a proteomics screen, we identified MFAP4, a protein involved in fibrillin-1 and elastic fiber formation, to be increased in the Marfan aorta. We aim to study the role of MFAP4 in Marfan aortic disease. Methods and results MFAP4 co-localizes in the aorta with elastin and collagen fibers. In vitro experiments show that MFAP4 expression is upregulated by TGF-beta, which could explain the increased MFAP4 protein levels in the Marfan aorta. In a substudy of 96 Marfan patients from the COMPARE trial, MFAP4 levels correlate with aortic root diameter (r=0.30, p=0.01). Patients previously enrolled in the COMPARE trial were retrospectively analyzed. Cardiovascular events, including aortic dissection, were assessed. Plasma samples were prospectively collected at time of inclusion in the study and analyzed retrospectively on MFAP4. In the 7 years of follow up, 5 Type B dissections occurred, all of them in patients in the upper tertile of plasma MFAP4. High plasma MFAP4 associates with poor dissection-free survival (Figure 1). Moreover, the aortic distensibility as measure for aortic stiffness and damage, was calculated throughout the aorta from available MRI images of these patients. Interestingly, in the descending thoracic aorta where type B dissections occur, the aortic distensibility is significantly lower (indicating decreased aortic elasticity) in Marfan patients with high plasma MFAP4, thus associating with aortic damage. Figure 1 Conclusion MFAP4, a protein involved in extracellular matrix assembly, is elevated in the Marfan aorta. High plasma MFAP4 seems to reflect aortic damage and predicted type B aortic dissections in up to 7 years follow up.