The Molecular Basis, Preventive Efficacy of Angiotension II Receptor Blockade and Quality of Life in Marfan Syndrome

Background
Marfan syndrome (MFS), an autosomal dominant hereditary disorder of connective tissue, is
caused by fibrillin-1 gene mutation. Current evidences support that except fibrillin-1,
transforming growth factor β (TGF-β) plays an additional important role in MFS, which
contributes to matrix metalloproteinase (MMP) activation and extracellular matrix (ECM)
degeneration. The expression of TGF-β will be increased while FBN1 gene mutation or by
signaling through the angiotensin II type I receptor (AGTR1). Recently, Losartan, an AGTR1
receptor blocker (ARB), had been shown to prevent aortic root dilation in a mouse model of MFS.
However, the data regarding the effects in human are still limited.
Currently, several studies with relatively small samples showed safety and efficacy of
losartan in operated or unoperated MFS. Our preliminary data suggest strongly that losartan
added to β-blockade could more effectively slow down the progression of aortic dilatation as
compared to sole β-blockade therapy. However, the drug effects seemed diverse in different
subjects. Till now, there is no report to show the relationship between drug efficacy and genotype.
From the Taiwan National Health Insurance database records, we found that aortic dissection
occurred in 226 MFS patients (10%; 61% men) at a mean age of 36.6 ± 10.7 years. The
probability of freedom from dissection was 99%, 80%, and 66% at the age of 20, 40, and 50 years,
respectively. Of the 69 deaths and 226 dissections during the follow-up period, more than half of
the cases occurred before the age of 40 years. Hence, early diagnosis and timely medical
interventions to MFS are warranted.
Besides, patients with MFS suffer from heavy physiological and psychological stresses,
which lead to anxiety, limited exercise capacity, and poor quality of life. Mental and medical
supports are important and necessary.
Hypothesis
Therefore, our hypothesis is three folds: (1) The early and timing medical intervention to
MFS even with normal aortic diameter may be effective to slow the rate of aortic dilatation and
prevent cardiovascular events. (2) The drug effects are associated with genotype of fibrillin-1
mutation. (3) Patients with MFS are associated with poor quality of life.