Cardiovascular characteristics in Marfan syndrome and their relation to the genotype
De Backer, J.
Verhandelingen - Koninklijke Academie Voor Geneeskunde van Belgie 71(6): 335-371
2009
ISSN/ISBN: 0302-6469 PMID: 20232788 Document Number: 11319
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 demonstr ate 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
Document emailed within 1 workday
