The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele

Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 ( Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2. We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan ( Fbn1C1039G/+) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4−/−). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm2; Marfan Nox4−/−: 8,795 ± 824 μm2; 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS.

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Losartan Increases Survival of the Fbn1mgR/mgR Mouse Model of Marfan Syndrome in an Age-Dependent Manner

10.1101/2021.02.19.429438 ◽

2021 ◽

Author(s):

Jeffrey D. Smith ◽

Jeff Z. Chen ◽

Rebecca Phillips ◽

Alan Daugherty ◽

Mary B. Sheppard

Keyword(s):

Marfan Syndrome ◽

Angiotensin Receptor Blockers ◽

Primary Objective ◽

Dependent Manner ◽

Wild Type ◽

Age Dependent ◽

Fibrillin 1 ◽

Receptor Blockers ◽

To Receive ◽

Overall Mortality

AbstractClinical trials investigating angiotensin receptor blockers (ARB) for attenuation of thoracic aortic aneurysm in people with Marfan syndrome have demonstrated variable efficacy. The primary objective of this study was to determine whether the age of mice at the time of losartan initiation affected mortality in fibrillin-1 hypomorphic (Fbn1mgR/mgR) mice. Male (n=40) and female (n=28) Fbn1mgR/mgR mice were randomized to receive losartan in drinking water (0.6 g/L) starting at either 24 or 50 days of age. Controls included Fbn1mgR/mgR mice (20M, 14F) and wild type (15M, 15F) littermates who were not administered the drug. Mortality of Fbn1mgR/mgR males receiving losartan at postnatal day 24 (P24) was not different from wild type controls (p=0.138). Survival of Fbn1mgR/mgR males administered losartan at P50 was not different compared to Fbn1mgR/mgR males receiving no drug (p=0.194) and decreased compared to wild type mice (p=0.002). Survival analysis after P50 demonstrated increased survival of Fbn1mgR/mgR males administered losartan at P50 compared to Fbn1mgR/mgR mice receiving no drug (p=0.017). Age is a critical variable that affects the therapeutic efficacy of losartan in male Fbn1mgR/mgR mice. Since overall mortality in female Fbn1mgR/mgR mice was lower than in male Fbn1mgR/mgR mice, a survival benefit with losartan was not detected in females.

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Pompe Disease Could Mimic Exam Findings of Amyloidosis: Two Rare Diagnoses Bona Fide

Case Reports in Hematology ◽

10.1155/2018/9615834 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4

Author(s):

Jithma P. Abeykoon ◽

Narjust Duma ◽

Jennifer A. Tracy ◽

Margherita Milone ◽

Ronald Go

Keyword(s):

Pompe Disease ◽

Clinical Presentation ◽

Signs And Symptoms ◽

Proximal Muscle ◽

Wild Type ◽

Physical Finding ◽

Transthyretin Amyloidosis ◽

Extensive Evaluation ◽

History Of ◽

Bona Fide

A 70-year-old female presented with a three-year history of evolving macroglossia causing dysphagia and dysarthria, with proximal muscle weakness. Given the classic physical finding of macroglossia, the patient underwent extensive evaluation for amyloidosis which proved to be negative apart from a bone marrow biopsy which stained positive for transthyretin without amino acid sequence abnormality, thus giving wild-type transthyretin amyloidosis. Since the wild-type transthyretin amyloidosis could not entirely explain her clinical presentation and evaluation, further studies were conducted in a sequential manner, thus leading to a diagnosis of Pompe disease explaining her presenting signs and symptoms including her macroglossia. Through this fascinating case, we attempt to highlight the approach for the diagnoses of two rare diseases in a patient by emphasizing the importance of having a broad differential diagnosis when presented with findings which may have been thought as pathognomonic for certain diseases.

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Early Onset Marfan Syndrome: Atypical Clinical Presentation of Two Cases

Balkan Journal of Medical Genetics ◽

10.1515/bjmg-2015-0008 ◽

2015 ◽

Vol 18 (1) ◽

pp. 71-76 ◽

Cited By ~ 2

Author(s):

Abdullah Ozyurt ◽

A. Baykan ◽

M. Argun ◽

O. Pamukcu ◽

H. Halis ◽

...

Keyword(s):

Marfan Syndrome ◽

Early Onset ◽

Poor Prognosis ◽

Clinical Presentation ◽

Severe Form ◽

Early Age ◽

Newborn Period ◽

Heart Failure Treatment ◽

Failure Treatment ◽

Atypical Clinical Presentation

Abstract Early onset Marfan Syndrome (eoMFS) is a rare, severe form of Marfan Syndrome (MFS). The disease has a poor prognosis and most patients present with resistance to heart failure treatment during the newborn period. This report presents two cases of eoMFS with similar clinical features diagnosed in the newborn period and who died at an early age due to the complications related to the involvement of the cardiovascular system.

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Anterior sacral meningocele masquerading as an ovarian cyst: a rare clinical presentation associated with Marfan syndrome

Clinics and Practice ◽

10.4081/cp.2015.752 ◽

2015 ◽

Vol 5 (2) ◽

Cited By ~ 13

Author(s):

Neslin Sahin ◽

Mine Genc ◽

Esin Kasap ◽

Aynur Solak ◽

Berrin Korkut ◽

...

Keyword(s):

Marfan Syndrome ◽

Ovarian Cyst ◽

Clinical Presentation ◽

Anterior Sacral Meningocele

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Postsystolic thickening is a potential new clinical sign of injured myocardium in marfan syndrome

Scientific Reports ◽

10.1038/s41598-021-95263-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aleksandra Mas-Stachurska ◽

Gustavo Egea ◽

Rianne de Bruin-Bon ◽

Paula Rudenick ◽

Laura Sanchis ◽

...

Keyword(s):

Marfan Syndrome ◽

Myocardial Function ◽

Myocardial Damage ◽

Preventive Therapy ◽

Systemic Arterial Pressure ◽

Lv Function ◽

Wild Type ◽

Healthy Humans ◽

Injured Myocardium ◽

Potential Association

AbstractThe mechanisms leading to cardiac remodeling in Marfan syndrome (MFS) are a matter of debate since it could be either due to structural dysfunction of the myocardial extracellular matrix or to increased afterload caused by the dilated aorta. We aim to characterize the presence of abnormal myocardial function in MFS and to investigate its potential association with increased afterload. Aorta, left ventricle (LV) and the postsystolic thickening (PST) were analyzed in echocardiography in Fbn1C1039G/+ mice and in patients with MFS in comparison with wild type (WT) mice and healthy humans. PST was more frequent in MFS than in WT mice (p < 0.05). MFS mice with PST showed larger aorta than those without PST. Patients with MFS showed larger aorta, poorer LV function and a higher prevalence of PST (56%) than did the healthy controls (23%); p = 0.003. Blood pressure was similar. The higher prevalence of PST in an experimental murine model and in MFS patients, regardless of systemic arterial pressure, suggests an increased afterload on the LV myocardium. This finding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therapy.

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A new therapy for transthyretin amyloidosis, no longer an orphan condition

European Heart Journal Supplements ◽

10.1093/eurheartj/suaa077 ◽

2020 ◽

Vol 22 (Supplement_E) ◽

pp. E125-E131

Author(s):

Candida Cristina Quarta ◽

Anna Laura Tinuper ◽

Agnese Milandri ◽

Christian Gagliardi ◽

Giuseppe Caponeti ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Clinical Presentation ◽

Accurate Estimate ◽

Clinical Suspicion ◽

Light Chains ◽

Wild Type ◽

First Line ◽

Transthyretin Amyloidosis ◽

Cardiac Amyloid ◽

Amyloid Cardiomyopathy

Abstract Amyloid cardiomyopathy is a condition characterized by intra-myocardial deposit of protein-like material, in fibrillar shape (amyloid), which presence determine a progressive thickening and stiffening of the cardiac walls leading to a cardiac dysfunction. The proteins most often involved with cardiac amyloid are the light chains of the immunoglobulin, typical of amyloidosis AL, and transthyretin, responsible for transthyretin amyloidosis, in both its forms, hereditary and wild type. An accurate estimate of the incidence of cardiac amyloidosis is still difficult due to the variety and complexity of the clinical presentation of the condition. Nonetheless, the condition has stimulated the interest of the scientific community, so that a specific diagnostic path has been developed, beginning from the clinical suspicion and first-line testing, such as electrocardiogram, echocardiogram, and blood work, to progress to the diagnostic confirmation using more sophisticated testing such as magnetic resonance, scintiscan, and eventually cardiac biopsy. To understand and recognize this condition is very important, stemming from the availability of ‘aetiology oriented therapies’ (designed to prevent, control and possibly regress amyloid deposition), which should be added to the ‘supportive therapies’, used for the treatment of the complication of the condition, namely heart failure.

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Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), previously known as senile cardiac amyloidosis: clinical presentation, diagnosis, management and emerging therapies

Journal of Thoracic Disease ◽

10.21037/jtd.2018.03.134 ◽

2018 ◽

Vol 10 (3) ◽

pp. 2034-2045 ◽

Cited By ~ 9

Author(s):

Ilia G. Halatchev ◽

Jingsheng Zheng ◽

Jiafu Ou

Keyword(s):

Cardiac Amyloidosis ◽

Clinical Presentation ◽

Wild Type ◽

Emerging Therapies

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3204 Renin-Angiotensin System Inhibitors Do Not Improve Survival in Fibrillin-1 Hypomorphic Mice with Established Aortic Aneurysm

Journal of Clinical and Translational Science ◽

10.1017/cts.2019.258 ◽

2019 ◽

Vol 3 (s1) ◽

pp. 112-113

Author(s):

Mary Burchett Sheppard ◽

Jeff Zheying Chen ◽

Debra L. Rateri ◽

Jessica J. Moorleghen ◽

Mackenzie Weiland ◽

...

Keyword(s):

Sexual Dimorphism ◽

Marfan Syndrome ◽

Renin Angiotensin System ◽

Aortic Diameter ◽

Wild Type ◽

Aortic Dilation ◽

Angiotensin System ◽

Male And Female ◽

Significant Difference ◽

Fibrillin 1

OBJECTIVES/SPECIFIC AIMS: Drugs to attenuate aortic growth are usually not initiated in patients with Marfan syndrome until aortic dilation is already present. Therefore, we measured the impact of drugs (the renin-angiotensin system inhibitors losartan and enalapril) on survival and thoracic aortic growth in a mouse model of Marfan syndrome when extensive aortic dilation was already present. METHODS/STUDY POPULATION: Male and female fibrillin-1 hypomorphic (FBN1 mgR/mgR) mice (n=10-12/group) were stratified into treatment groups by aortic diameter at 6 weeks of age to ensure an equivalent average aortic diameter in each group at the start of the study. Osmotic mini pumps filled with PBS (vehicle), enalapril (2 mg/kg/d), or losartan (20 mg/kg/d) were implanted subcutaneously into mice after stratification. Mini pumps infusing drug or vehicle were replaced every 4 weeks for a total duration of 12 weeks. Wild type littermates (n=10) were infused with PBS as a negative control to the Marfan mouse model. Ascending aortic diameters from male and female FBN1 mgR/mgR mice and their wild type littermates were assessed by ultrasound every 4 weeks from 6 to 18 weeks of age. Aortic diameters were measured luminal edge to luminal edge during diastole. RESULTS/ANTICIPATED RESULTS: 6 week old FBN1 mgR/mgR mice exhibited significantly dilated ascending thoracic aortas at study initiation compared to their wild type sex-matched littermates (in males: FBN1 mgR/mgR = 1.87 +/− 0.07mm, wild type = 1.23 +/− 0.07mm; p <0.001) (in females: FBN1 mgR/mgR = 1.56 +/− 0.07mm, wild type = 1.18 +/− 0.07mm; p <0.001). Baseline mortality of FBN1 mgR/mgR mice infused with PBS was 36% in male and 22% in female mice at the time of study termination. Within sex-matched mgR littermates, there was no significant difference in survival between groups treated with PBS, enalapril, or losartan after 12 weeks (p=0.224 for males, p=0.094 in females). In the same groups, no significant difference in maximum ascending aortic diameter was detected after treatment for 12 weeks (in males: PBS=2.69 +/− 0.19 mm, enalapril=2.04 +/− 0.27 mm, losartan=2.42 +/− 0.28 mm; p=0.24) (in females: PBS = 1.92 +/− 0.13, enalapril=1.89 +/− 0.31, losartan=1.98 +/− 0.17; p=0.86). Furthermore, aortic diameters in the FBN1 mgR/mgR mice were found to demonstrate sexual dimorphism. DISCUSSION/SIGNIFICANCE OF IMPACT: This research shows that losartan is not effective when administered after significant thoracic aortic dilation has already occurred in FBN1 mgR/mgR mice. This has important translational implications because losartan is usually not started in patients with Marfan syndrome until significant aortic dilation is already present. Therefore, more research needs to be done to determine the critical time period within which this medicine will be effective if given to patients. In addition, this research demonstrates that male FBN1mgR/mgR mice have a significantly larger aortic diameter than female FBN1mgR/mgR mice. This sexual dimorphism has recently been observed in patients with Marfan syndrome as well. Additional studies for understanding the mechanism underlying this sexual dimorphism have the potential to elucidate new therapeutic approaches for aortic disease.

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