Impact of genotype on the progression of aortic disease in patients with Marfan syndrome and Loeys-Dietz syndrome

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

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Concurrent End-Stage Cardiomyopathy and Aortic Disease in Patients with Marfan Syndrome: A Case Report and Literature Review

10.22541/au.162266144.45379601/v1 ◽

2021 ◽

Author(s):

Timothy Smith ◽

Jose Sleiman ◽

Nikita Zadneulitca ◽

Cedric Sheffield ◽

Viviana Navas ◽

...

Keyword(s):

Heart Failure ◽

Case Report ◽

Literature Review ◽

Marfan Syndrome ◽

Aortic Disease ◽

Connective Tissue Disorder ◽

Orthotopic Heart Transplantation ◽

Bentall Procedure ◽

Life Saving ◽

End Stage

Abstract Background: Marfan syndrome (MFS) is a connective tissue disorder that can lead to aortic disease, arrhythmias and heart failure. Many centers are reluctant to offer orthotopic heart transplantation (OHT) for patients with MFS with concurrent aortic disease due to complexity of the surgery and perceived inferior results when compared to patients without MFS. Methods: We present a case of a patient with MFS with previous Bentall procedure who underwent successful OHT, accompanied by a literature review on OHT performed for patients with MFS. Results and Conclusions: Patients with MFS who underwent OHT had no difference in mortality compared to patients without MFS. Even though OHT is technically more challenging when combined with concurrent intervention for aortic disease, it should be considered as a life-saving operation for patients with MFS.

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Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

IBJ Plus ◽

10.24217/2531-0151.21v1s4.00036 ◽

2021 ◽

Author(s):

◽

Andrea de la Fuente-Alonso ◽

...

Keyword(s):

Marfan Syndrome ◽

Aortic Disease

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Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽

10.1093/med/9780198784906.003.0160 ◽

2018 ◽

pp. 713-715

Author(s):

Dorien Schepers ◽

Bart Loeys

Keyword(s):

Extracellular Matrix ◽

Marfan Syndrome ◽

Transforming Growth Factor Beta ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Aortic Disease ◽

Extracellular Matrix Protein ◽

Genetic Defects ◽

Fibrillin 1 ◽

Growth Factor Beta

Marfan syndrome is an autosomal dominant, multisystemic disorder, presenting with skeletal, ocular, and cardiovascular symptoms. This connective tissue disease is caused by mutations in FBN1, encoding fibrillin-1, which is an important extracellular matrix protein. Marfan syndrome shows significant clinical overlap with Loeys–Dietz syndrome, which is caused by genetic defects in components of the transforming growth factor-beta pathway: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, and SMAD3. Overlapping clinical features between Marfan syndrome and Loeys–Dietz syndrome include aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity.

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Augmentation Index Relates to Progression of Aortic Disease in Adults With Marfan Syndrome

American Journal of Hypertension ◽

10.1038/ajh.2009.115 ◽

2009 ◽

Vol 22 (9) ◽

pp. 971-979 ◽

Cited By ~ 31

Author(s):

K. Mortensen ◽

M. A. Aydin ◽

M. Rybczynski ◽

J. Baulmann ◽

N. Abdul Schahidi ◽

...

Keyword(s):

Marfan Syndrome ◽

Augmentation Index ◽

Aortic Disease

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Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome

Nature Medicine ◽

10.1038/nm.4266 ◽

2017 ◽

Vol 23 (2) ◽

pp. 200-212 ◽

Cited By ~ 68

Author(s):

Jorge Oller ◽

Nerea Méndez-Barbero ◽

E Josue Ruiz ◽

Silvia Villahoz ◽

Marjolijn Renard ◽

...

Keyword(s):

Nitric Oxide ◽

Mouse Model ◽

Marfan Syndrome ◽

Aortic Disease

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Medical management of aortic disease in Marfan syndrome

Annals of Cardiothoracic Surgery ◽

10.21037/acs.2017.11.09 ◽

2017 ◽

Vol 6 (6) ◽

pp. 654-661 ◽

Cited By ~ 5

Author(s):

Syed Usman Bin Mahmood ◽

Camilo A. Velasquez ◽

Mohammad A. Zafar ◽

Ayman A. Saeyeldin ◽

Adam J. Brownstein ◽

...

Keyword(s):

Marfan Syndrome ◽

Medical Management ◽

Aortic Disease

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Treatment of Aortic Disease in Patients With Marfan Syndrome

Circulation ◽

10.1161/01.cir.0000155243.70456.f4 ◽

2005 ◽

Vol 111 (11) ◽

Cited By ~ 231

Author(s):

Dianna M. Milewicz ◽

Harry C. Dietz ◽

D. Craig Miller

Keyword(s):

Marfan Syndrome ◽

Aortic Disease

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Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316464 ◽

2021 ◽

Author(s):

Cristina I. Caescu ◽

Jens Hansen ◽

Brittany Crockett ◽

Wenzhen Xiao ◽

Pauline Arnaud ◽

...

Keyword(s):

Protein Kinase ◽

Aortic Aneurysm ◽

Aortic Dissection ◽

Marfan Syndrome ◽

Thoracic Aortic Aneurysm ◽

Acute Aortic Dissection ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Aortic Disease ◽

Computational Analyses

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic protein kinase that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted protein kinases in computational analyses of genes differentially expressed in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.

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