Marfan syndrome: current perspectives

Abstract

Marfan syndrome (MFS) is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, due to mutations in the FBN1 gene encoding fibrillin 1. It is an important protein of the extracellular matrix that contributes to the final structure of a microfibril. Few cases displaying an autosomal recessive transmission are reported in the world. The FBN1 gene, which is made of 66 exons, is located on chromosome 15q21.1. This review, after an introduction on the clinical manifestations that leads to the diagnosis of MFS, focuses on cardiovascular manifestations, pharmacological and surgical therapies of thoracic aortic aneurysm and/or dissection (TAAD), mechanisms underlying the progression of aneurysm or of acute dissection, and biomarkers associated with progression of TAADs. A Dutch group compared treatment with losartan, an angiotensin II receptor-1 blocker, vs no other additional treatment (COMPARE clinical trial). They observed that losartan reduces the aortic dilatation rate in patients with Marfan syndrome. Later on, they also reported that losartan exerts a beneficial effect on patients with Marfan syndrome carrying an FBN1 mutation that causes haploinsufficiency (quantitative mutation), while it has no significant effect on patients displaying dominant negative (qualitative) mutations. Moreover, a French group in a 3-year trial compared the administration of losartan vs placebo in patients with Marfan syndrome under treatment with beta-receptor blockers. They observed that losartan decreases blood pressure but has no effect on aortic diameter progression. Thus, beta-receptor blockers remain the gold standard therapy in patients with Marfan syndrome. Three potential biochemical markers are mentioned in this review: total homocysteine, serum transforming growth factor beta, and lysyl oxidase. Moreover, markers of oxidative stress measured in plasma, previously correlated with clinical features of Marfan syndrome, may be explored as potential biomarkers of clinical severity.

Keywords: Marfan syndrome; cardiovascular manifestations; diagnosis; fibrillin 1; therapy; thoracic aortic aneurysm.

Figure 1

Marfan syndrome and related disorders: flow chart of clinical and genetic management. Note: *Clinical follow-up is required for disease progression evaluation and/or earlier diagnosis of clinical adverse manifestations and therapy management. Abbreviations: ECG, electrocardiography; echo, echocardiography; MRI, magnetic resonance imaging; NGS, next-generation sequencing.

Figure 2

Effects of drug therapies on thoracic aortic wall of MF patients. Notes: (A) Biological targets and therapies upstream of TGF-β in Marfan syndrome. Renin converts angiotensinogen to angiotensin I, which is further converted to angiotensin II by ACE, as well as tissue enzymes including chymase, thus bypassing the inhibition of ACE inhibitors. Angiotensin II then binds to either type 1 or type 2 angiotensin receptors. (B) Schematic representation of thoracic aortic wall in patients with Marfan syndrome with FBN1 dominant negative mutations or haploinsufficiency, as well as the possible explanation of the better effect of losartan in patients with haploinsufficiency. Hypertension and wall stretching represent trigger factors for upregulation of type 1 angiotensin receptor, which in turn increases TGF-β production. *Administration of Losartan decreases TGF-β production and increases proinflammatory response, myofibroblast differentiation, and reactive oxygen species. Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; ECM, extracellular matrix; FBN1, the gene encoding fibrillin 1; MF, Marfan (patients); TGF-β, transforming growth factor-β; TGF-β nAb GC-1008, human pan-TGF-β neutralizing antibody.