Precise Therapy for Thoracic Aortic Aneurysm in Marfan Syndrome: A Puzzle Nearing Its Solution

Abstract

Marfan Syndrome (MFS) is a rare connective tissue disorder, resulting from mutations in the fibrillin-1 gene, characterized by pathologic phenotypes in multiple organs, the most detrimental of which affects the thoracic aorta. Indeed, thoracic aortic aneurysms (TAA), leading to acute dissection and rupture, are today the major cause of morbidity and mortality in adult MFS patients. Therefore, there is a compelling need for novel therapeutic strategies to delay TAA progression and counteract aortic dissection occurrence. Unfortunately, the wide phenotypic variability of MFS patients, together with the lack of a complete genotype-phenotype correlation, have represented until now a barrier hampering the conduction of translational studies aimed to predict disease prognosis and drug discovery. In this review, we will illustrate available therapeutic strategies to improve the health of MFS patients. Starting from gold standard surgical overtures and the description of the main pharmacological approaches, we will comprehensively review the state-of-the-art of in vivo MFS models and discuss recent clinical pharmacogenetic results. Finally, we will focus on induced pluripotent stem cells (iPSC) as a technology that, if integrated with preclinical research and pharmacogenetics, could contribute in determining the best therapeutic approach for each MFS patient on the base of individual differences. Finally, we will suggest the integration of preclinical studies, pharmacogenetics and iPSC technology as the most likely strategy to help solve the composite puzzle of precise medicine in this condition.

Myocardial Function, Heart Failure and Arrhythmia in Marfan Syndrome: A Systematic Literature Review

“…Several studies have already shown that the type of underlying FBN1 gene variant has an influence on aortic outcome [ 62 , 63 , 64 , 65 , 66 ]. Patients harbouring variants predicted to result in haploinsufficiency (HI) of fibrillin-1 show a worse outcome than carriers of variants predicted to result in a dominant negative (DN) effect [ 67 ]. In the same vein, a genotype-phenotype relationship in the myocardium can be suspected.…”

“…Similarly, in a smaller study by Rahman et al using three-dimensional speckle tracking echocardiography, LV EF, global LV circumferential strain and global LV area strain were all significantly lower in patients with variants predicted to result in HI than in those variants predicted to result in DN effect ( p < 0.05) [ 33 ]. Different types of FBN1 gene variants may also have a different effect on aortic elasticity [ 67 ], thereby potentially further contributing to impairment of myocardial function, but this has not been studied yet. In the aforementioned studies by de Witte et al and Loeper et al, the relation between aortic elasticity and predicted HI or DN effect of FBN1 gene variants was not evaluated [ 29 , 39 ].…”

“…In the aforementioned studies by de Witte et al and Loeper et al, the relation between aortic elasticity and predicted HI or DN effect of FBN1 gene variants was not evaluated [ 29 , 39 ]. Future studies should assess this relationship as the field of genotype-phenotype correlations may hold valuable information with implications for personalized therapeutic approaches [ 67 ].…”

Management of a giant aortic root aneurysm in a young patient with Marfan syndrome: a case report

“…However, more clinical trials are required to verify the ability of ARBs to interfere with the MFS pathology. Even though several novel therapeutic strategies are under investigation, the goal of precision medicine is laborious to achieve [19]. Surgical intervention remains as the gold standard treatment strategy for aneurysm in MFS.…”

Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients

“…Unfortunately, an effective pharmacological treatment for this life-threatening disease in MFS patients still remains unknown. Thus, the complete identification of the mechanisms contributing to MFS aneurysm formation and the subsequent identification of novel therapeutic targets are clinical imperatives for this patients' category [6].…”