Cardiovascular Management of Adults with Marfan Syndrome

Abstract

Marfan syndrome (MFS) is a disease in which connective tissue becomes weak secondary to fibrillin-1 mutations, resulting in aortic dilatation, aneurysm formation, aortic dissection, aortic regurgitation and mitral valve prolapse (MVP; see Table 1). Epidemiology MFS is an autosomal dominant condition: 75 % of all patients inherit the condition from one affected parent and 25 % are affected as the result of a new mutation. The population incidence is 2-3 per 10,000. 1 The autosomal dominant inheritance of this disorder was described in 1934, 2 and has been ascribed to abnormalities in fibrillin-1 protein (discovered in 1990), 3 which is encoded by the FBN1 gene (reported in 1991). 4 The most common causes of death in MFS are cardiovascular, especially aortic dissection and rupture. According to a Taiwanese study, aortic dissection is the most serious complication, occurring in 9.7 % of individuals with MFS (nearly 61 % of these patients are male) and carrying an average mortality of approximately 10.6 %. 5 Cardiovascular Manifestations In MFS, the main cardiovascular manifestations are aortic dilatation and MVP. Tricuspid regurgitation (TR), pulmonary artery (PA) dilatation, ventricular arrhythmia and dilated cardiomyopathy also occur. Pro-transforming growth factor-beta (TGF-beta) binds to the latent TGF-beta binding protein-1 (LTBP-1) and forms the latency-associated peptide (LAP), followed by a complex termed the large latent TGF-beta complex (LLC). This is secreted and sequestered in the extracellular matrix (ECM). FBN1 is a matrix glycoprotein and the major constituent of ECM microfibrils comprising elastic fibres. In MFS, the ECM is not normal and when the ECM is damaged due to the force of the blood flow ejected from the heart, the mesenchymal cells promote active TGF-beta to restore the ECM. This results in excessive TGF-beta signalling, causing ECM degradation, apoptosis and an inflammatory state, leading to aneurysm formation or dissection (see Figure 1). 6,7 At present, more than 3,000 FBN1 mutations have been discovered. Almost all of them develop similar manifestations such as heart, eye and skeletal problems, and are related to excessive TGF-beta signalling via integrin, which provides a common mechanism by promoting latent TGF-beta and expressing TGF-beta. 6 Endothelial cells, smooth muscle cells and fibroblasts sense and respond to blood flow and blood pressure. Increasing or decreasing blood pressure increases or decreases wall stress. Cells sense and regulate the ECM through integrins and cytoskeletal components. Sensing high versus low stress causes different cell signalling. Misperception of high stress as low stress can cause maladaptive remodelling by activating the pathways observed in thoracic aortic aneurysms and aortic dissections (TAAD). 8 The Aorta In MFS, aortic dilatation and aneurysm formation are caused by cystic medial necrosis, in which the medial layer of the aorta demonstrates fewer cells and a lacunar appearance. Most aortic dilatation starts in the sinuses of Valsalva. A reduce...

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“…MMPs participate in the elastic fiber disintegration, which is observed in the representative microphotographs of the patients with LDS. In these patients, there is a reduction of connective tissue elasticity that results in weakness of the aneurysm aortic wall [9,16,38]. These breakings in structure could be associated with decreases in GSH and GPx.…”

Potential predictors of severe cardiovascular involvement in Marfan syndrome: the emphasized role of genotype–phenotype correlations in improving risk stratification—a literature review

“…Mitral valve prolapse is the leading cause of cardiovascular morbidity, mortality and cardiac surgery in children with severe MFS [ 2 ]. Of these cardiovascular features, aortic root dilation occurs most frequently, leading to aortic regurgitation and carrying the risk of aortic dissection and rupture [ 17 ].…”

Loeys–Dietz syndrome pathology and aspects of cardiovascular management: A systematic review

“…Optimizing treatment with prophylactic beta-adrenergic and angiotensin receptor blockade has also been proven to slow the rate of aneurysm progression as well as decrease the likelihood of post-operative aortic complications in patients with MFS, a finding which can be extrapolated to LDS. 35,36 Compared to the management of acute dissection, the decision to operate on a healthy, asymptomatic patient with a growing aneurysm is a difficult one to make. Nevertheless, elucidating the family history and offering baseline vascular investigations should be mandatory in those presenting with typical features of LDS to prevent diagnostic delay and ensure appropriate management.…”