Marfan syndrome: Getting to the root of the problem

In 1896 Antoine-Bernard Marfan was the first to describe a 5-year-old patient with typical Marfan features. Currently, the Marfan syndrome is known to be a heritable connective tissue disorder with a prevalence of 1 per 5000 individuals, affecting multiple organ-systems, including the lungs, eyes, the skeleton and the aorta. FBN1 mutations are the cause of the syndrome, and found in approximately 90% of the Marfan patients. In order to get to the root of the problem of the Marfan syndrome, the main objectives of this thesis were to obtain more insight in the diagnosis, prognosis and markers of aortic disease, to obtain more knowledge about the importance of genetics in Marfan syndrome, which is interlaced with all aspects of the syndrome, and to obtain more insight in novel pharmacological strategies to prevent aortic complications. We have added three novel predictors for aortic complications: the aortic tortuosity index, the biomarker TGF-β, and the haploinsufficient-FBN1 mutation. The importance of genetics was shown because losartan significantly reduce the aortic root dilation rate in the Marfan patients with a haploinsufficient-FBN1 mutation, whereas only a modest insignificant reduction is found in those with a dominant-negative-FBN1 mutation. This benefit is important, since patients with a haploinsufficient-FBN1 mutation are at increased risk for aortic growth, aortic dissection and mortality. Finally, we obtained more insight in novel pharmacological strategies to prevent aortic complications. We demonstrated that losartan on top of β-blockers is more effective than a low dose of β-blockers, especially in patients with a haploinsufficient-FBN1 mutation.