Marfan syndrome (MFS) is a systemic disorder of connective tissue with autosomal 
dominant inheritance. The diagnosis of MFS is based on the identification of a 
combination of clinical manifestations in the ocular, musculoskeletal, and 
cardiovascular organ systems defined in the Ghent Nosology (De Paepe et al, 
1996). Confirmation of the diagnosis in an individual requires the presence of 
major clinical manifestations in at least two organ systems associated with 
involvement of a third organ system. In relatives of an affected proband, major 
involvement of one organ system and involvement of a second organ system 
confirms the diagnosis. Major clinical criteria are very specific for MFS and 
include a combination of (4 out of 8) skeletal manifestations, ectopia lentis, 
dural ectasia and dilatation or dissection of the ascending aorta. The 
prevalence of- and the guidelines for the assessment of each of these major 
criteria are well established. Minor clinical criteria are less typical, but 
their importance in the diagnostic process should not be underestimated. 
Unfortunately, figures on the prevalence as well as practical guidelines for the 
assessment of most minor criteria are lacking, especially for those involving 
the cardiovascular system. The major cardiovascular manifestation in MFS is a 
progressive dilatation of the ascending aorta, leading to aortic aneurysm 
formation and eventually to fatal aortic rupture or dissection. Aortic 
dissection in early adult life is the leading cause of death in MFS. Early 
diagnosis of individuals at risk of the disease is extremely important as timely 
treatment of cardiovascular complications has greatly improved life expectancy 
in MFS. Despite progress in medical and surgical treatment of aortic aneurysms, 
MFS continues to be associated with significant morbidity and mortality. This 
may be related to inadequate diagnosis or treatment, but also to the occurrence 
of cardiovascular problems in ageing MFS patients that were unrecognised until 
now, such as left ventricular (LV) dysfunction.This thesis is focused on the 
study of cardiovascular manifestations of MFS which localize beyond the aortic 
root and on the presently unknown relationship between the severity of the 
cardiovascular phenotype and the genotype. In the first part, we have studied 
the prevalence and diagnostic value of the following cardiovascular 
manifestations of MFS: mitral valve prolapse (MVP) and calcification of the 
mitral valve annulus, dilatation of the main pulmonary artery (MPA) and 
dilatation or dissection of the descending aorta. We found a significantly 
higher prevalence of MVP in MFS patients compared to normal controls, indicating 
that this feature is useful in the diagnostic evaluation of the condition. In 
contrast, calcification of the mitral valve annulus appears to be very uncommon, 
difficult to quantify and therefore not useful in the diagnosis of MFS. We also 
studied the dimension of the MPA in a series of MFS patients and defined a 
cut-of value that can be used in the diagnostic evaluation of adult MFS 
patients. In addition, we showed that diameters of the aorta measured at 
different levels beyond the aortic root are increased in MFS patients compared 
to controls. Unfortunately, there was too much overlap with the values obtained 
in the normal control population to provide cut-off values for the descending 
aorta. Based on these findings, we developed practical guidelines for the 
cardiovascular evaluation of patients referred for MFS. In the second part, we 
studied LV function in MFS patients free of valvular heart disease using a 
combination of echocardiography (both conventional echocardiography and tissue 
Doppler imaging) and Magnetic Resonance Imaging. We could demonstrate that MFS 
patients present a combination of systolic and diastolic dysfunction that is not 
related to valvular heart disease. This may be attributed to a primary 
contractile dysfunction of the myocardium and is likely related to the 
underlying alterations in the elastic features of the myocardium, resulting from 
the microfibrillar defect. This observation is important in the development of 
new therapeutic strategies for MFS. Affected individuals may benefit from a 
treatment with agents that support myocardial function such as angiotensin 
converting enzyme--inhibitors or angiotensin II type-1 receptor blockers. 
Furthermore, since MFS patients survive longer thanks to improved medical and 
surgical treatments, LV dysfunction may become an important issue in the 
follow-up of these patients. In the third part, we have studied aspects of local 
and global wave reflection in the aorta of MFS patients. Early return of 
reflected waves boosts systolic pressure and presents an extra load for the 
heart and the central vessels. As such, these wave reflections are regarded as 
one of the important determinants of central blood pressure and can contribute 
to the development of aortic dilatation in MFS. However, we were unable to 
demonstrate clear differences in both local and global parameters of wave 
reflection between MFS patients and normal controls. This could be explained by 
the fact that increased length of the aorta on the one hand and increased aortic 
stiffness on the other hand counterbalance each other in MFS patients without 
yielding any net effect on wave reflection. In the last part of this thesis, we 
investigated the correlation between the severity of the cardiovascular 
phenotype in MFS and the type of FBN1 mutation. First, we investigated the 
correlation between parameters of aortic stiffness (distensibility and pulse 
wave velocity measured by Magnetic Resonance Imaging) and the type of FBN1 
mutation (missense or in-frame deletions/insertions versus nonsense or 
out-of-frame deletions/insertions). We could not demonstrate any significant 
differences between these different mutation types, indicating that the FBN1 
genotype is not the sole determinant of aortic stiffness. Second, we provided a 
detailed description of clinical findings in three unrelated MFS families in 
which an FBN1 mutation was identified and which demonstrate striking 
intrafamilial phenotypic variability as another illustration of the absence of 
genotype/phenotype correlations in MFS. This study also illustrated several 
important issues in MFS. First, repeated clinical examination of suspected 
patients can be necessary in order to establish a correct and final diagnosis. 
Second, extensive family history taking and clinical examination of first degree 
relatives can be highly contributory to the diagnosis. Third, patients with an 
'atypical' MFS phenotype may show substantial clinical overlap with other 
connective tissue disorders such as Weill-Marchesani syndrome or Ehlers-Danlos 
syndrome and represent a diagnostic challenge. We demonstrated that additional 
mutational analysis of the FBN1 gene can be a valuable aid to the diagnosis and 
help to outline medical management options in these challenging cases. In 
conclusion, we have refined diagnostic guidelines for the assessment of minor 
cardiovascular manifestations in MFS, shown that LV dysfunction is part of the 
cardiovascular spectrum and should be followed in the management of MFS 
patients, and demonstrated that aortic wave reflection is not elevated in MFS. 
In this work, we also investigated genotype/phenotype correlations, illustrated 
the marked (intrafamilial) variability in phenotypic expression of the 
condition, and the value of molecular testing in the diagnosis of MFS. Overall, 
this thesis nicely illustrates that close interaction and collaboration between 
cardiology and genetics is an added value to the study of disease pathogenesis 
of MFS and aortic aneurysms in general.