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Published on: August 15, 2019
Marfan syndrome: current perspectives
Guglielmina Pepe1, Betti Giusti1, Elena Sticchi1
1Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, DENOTHE Center, University of Florence, Florence, Italy; Cardiothoracovascular Department, Marfan Syndrome and Related Disorders Regional Referral Center, Careggi Hospital, Florence, Italy.
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.
Insights
Marfan syndrome (MFS) is a genetic connective tissue disorder. Beta-receptor blockers are the gold standard treatment for thoracic aortic aneurysm and/or dissection (TAAD) in MFS patients, while losartan shows limited efficacy.
Area of Science:
- Genetics and Molecular Biology
- Cardiovascular Medicine
- Pharmacology
Background:
- Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by FBN1 gene mutations.
- Cardiovascular manifestations, particularly thoracic aortic aneurysm and/or dissection (TAAD), are a major cause of morbidity and mortality in MFS.
- Understanding MFS progression and identifying effective therapies for TAAD are critical.
Purpose of the Study:
- To review the clinical manifestations, cardiovascular complications, and therapeutic strategies for Marfan syndrome.
- To analyze the efficacy of losartan and beta-receptor blockers in managing TAAD in MFS patients.
- To explore potential biomarkers for predicting TAAD progression in Marfan syndrome.
Main Methods:
- Review of existing literature on Marfan syndrome, focusing on cardiovascular aspects and treatments.
- Analysis of findings from the COMPARE clinical trial investigating losartan in MFS patients.
- Examination of a 3-year French trial comparing losartan and beta-receptor blockers in MFS.
Main Results:
- Losartan demonstrated a reduction in aortic dilatation rate in MFS patients, particularly those with FBN1 quantitative mutations.
- Beta-receptor blockers remain the established gold standard therapy for TAAD in Marfan syndrome.
- Losartan decreased blood pressure but did not significantly impact aortic diameter progression when used with beta-blockers.
Conclusions:
- Beta-receptor blockers are the current gold standard for managing thoracic aortic aneurysm and/or dissection in Marfan syndrome.
- Losartan may offer benefits for specific MFS patient subgroups but does not replace standard therapy.
- Further research into biomarkers like homocysteine, TGF-beta, lysyl oxidase, and oxidative stress markers is warranted for clinical severity prediction.
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