EFFECTS OF ANGIOTENSIN II RECEPTOR BLOCKER (LOSARTAN) VS SELECTIVE ß1 RECEPTOR BLOCKER (NEBIVOLOL) VS THE ASSOCIATION OF BOTH ON THE QUANTITATIVE GENE EXPRESSION OF THE TGFß PATHWAY AND TGFß LEVELS IN 300 FBN1-GENOTYPED PATIENTS WITH MARFAN SYNDROME

More than 12.000 patients are expected to be affected by Marfan Syndrome (MFS) in Italy (1:5000). The major clinical problem is the potentially fatal aortic aneurysm/dissection. There is no cure available, but recently drugs routinely used to treat hypertension, AT1R-blockers (ARB), were shown to prevent the aortic damage that underlies the aneurysm and dissection, opening new hopes for preventing life-threatening events. The project will evaluate the differential clinical benefits on the rate of aortic aneurysm progression in 300 patients diagnosed with MFS and causative gene mutations of the Fibrillin 1 gene treated for 48 months with ARB (Losartan, n =100) vs. BB (Nebivolol, n=100), vs. the association of both (n=100). The benefits will be comparatively evaluated measuring, with non-invasive tools, the aortic root diameter and the indexes calculated on the body surface area by age. The effects of the drugs will be further evaluated by measuring the levels of transcription of the causative gene and of the key genes playing in the complex pathway of the Transforming Growth Factor beta (TGFb), a molecule exerting its effects on the growth of many organs and tissues, cell growth, differentiation, survival and death, and expression of various growth factors/cytokines/chemokines. TGFb activity and peripheral levels are increased in patients with MFS and aortic aneurysm and is antagonised by ARB. Blocking Angiotensin II (a molecule that increases TGFb) the level of TGFb decreases, its profibrotic and related cascade of collagenolitic effects are prevented, thus explaining the benefits experimentally shown with ARB. The elucidation of the effects of the different treatments on the transcriptional activity of the genes playing in the TGFb pathway will constitute the major aim of this project. The way gene transcription is either activated or inhibited could elucidate the molecular mechanisms of the drugs and provide new-biomarkers for monitoring their effects.