Fibrillin-1 Gene Research Articles

Higher blood pressure in elderly hypertensive females, with increased arterial stiffness and blood pressure in females with the Fibrillin-1 2/3 genotype

BackgroundElderly patients have a relatively high cardiovascular risk due to increased arterial stiffness, elevated blood pressure and decreased amounts of elastin in the arteries. The composition of the media layer in the arterial wall, comprising elastin, collagen, smooth muscle cells, proteoglycans, fibronectin and fibrillin-1, influences its mechanical properties. Mutations in the fibrillin-1 gene leads to increased aortic stiffness, elevated pulse pressure and aortic root dilatation. This study investigates whether there is a sex difference among hypertensive elderly patients regarding blood pressure, arterial stiffness and fibrillin-1 genotypes.MethodsA total of 315 hypertensive subjects (systolic blood pressure > 140 mmHg) were included in this study (155 men and 160 women aged 71–88 years). Aortic pulse wave velocity and augmentation index were determined using SphygmoCor, and brachial blood pressure was measured using an oscillometric technique. Fibrillin-1 was genotyped by polymerase chain reaction and with a capillary electrophoresis system.ResultsFemales showed a significantly higher peripheral mean arterial pressure (females; 107.20 mmHg, males 101.6 mmHg, p = 0.008), central mean arterial pressure (females; 107.2 mmHg, males 101.6 mmHg p = 0.008), central systolic blood pressure (females; 148.1 mmHg, males 139.2 mmHg, p < 0.001) and central pulse pressure (females; 68.9 mmHg, males 61.6 mmHg, p = 0.035) than males. Females with the Fibrillin-1 2/3 genotype showed a significantly higher augmentation index (FBN1 2/3; 39.9%, FBN1 2/2 35.0%, FBN1 2/4 35.8, p = 0.029) and systolic blood pressure (FBN1 2/3; 174.6 mmHg, FBN1 2/2168.9 mmHg, FBN1 2/4169.9 mmHg, p = 0.025) than females with the 2/2 and 2/4 genotypes.ConclusionThe findings of this study may indicate that hypertensive elderly females, especially elderly females with Fibrillin-1 2/3, have increased systolic blood pressure and arterial stiffness.

Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders.

The extracellular matrix microenvironment of adipose tissue is of critical importance for the differentiation, remodeling and function of adipocytes. Fibrillin-1 is one of the main components of microfibrils and a key player in this process. Furin processing of profibrillin-1 results in mature fibrillin-1 and releases the C-terminal propeptide as a circulating hunger hormone, asprosin. Mutations in the fibrillin-1 gene lead to adipose tissue dysfunction and causes Marfan syndrome, marfanoid progeroid lipodystrophy syndrome, and neonatal progeroid syndrome. Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils. Circulating asprosin on the other hand is secreted primarily by white adipose tissue under fasting conditions and in obesity. It increases hepatic glucose production and drives insulin secretion and appetite stimulation through inter-organ cross talk. This review discusses the metabolic consequences of fibrillin-1 and fibrillin-1-derived asprosin in pathological conditions. Understanding the dynamic role of fibrillin-1 in the adipose tissue milieu and of circulating asprosin in the body can provide novel mechanistic insights into how fibrillin-1 may contribute to metabolic syndrome. This could lead to new management regimens of patients with metabolic disease.

Marfan syndrome revisited: From genetics to clinical practice

Abstract Marfan syndrome is an autosomal dominant connective tissue disease with an estimated incidence of 1 in 5000 individuals. In 90% of cases it is caused by mutations in the gene for fibrillin-1, the main constituent of extracellular microfibrils. Studies on animal models of Marfan syndrome have revealed that fibrillin-1 mutations interfere with local TGF-β signaling, in addition to impairing tissue integrity. The cardinal features involve the cardiovascular, ocular and skeletal systems. The diagnosis of Marfan syndrome is made according to the revised Ghent nosology. Early identification and appropriate management are critical for patients with Marfan syndrome, who are prone to the life-threatening cardiovascular complications of aortic aneurysms and aortic dissection. The standard treatment includes prophylactic beta-blockers in order to slow down dilation of the ascending aorta, and prophylactic aortic surgery. The success of current medical and surgical treatment of aortic disease in Marfan syndrome has substantially improved mean life expectancy, extending it above 72 years. This review aims to provide an overview of this hereditary disorder.

A case of G1013R FBN1 mutation: A potential genotype-phenotype correlation in severe Marfan syndrome.

Marfan Syndrome (MFS) is an autosomal dominant connective tissue disorder with a wide range of severities. Ninety-five percent of MFS probands have a mutation in the fibrillin-1 gene (FBN1); however, there are a high number of unique mutations complicating attempts at establishing any phenotype-genotype correlations for this disease (Tiecke et al., European Journal of Human Genetics, 2001, 9, 13-21). One of the few extant genotype-phenotype correlations is in exon 24-32 which have been associated with a severe pediatric presentation of neonatal MFS with predominately cardiovascular symptoms. We present a 24-year-old male patient with a heterozygous de novo variant NM_000138.4: c.3037G>A (p.G1013R) located in exon 25 of the FBN1 gene. The patient was found to have dysplastic mitral and tricuspid valves with dilated aortic root at 9 months of age. This is a notable case in that the location of this patient's mutation and his age of symptom onset would indicate a guarded prognosis. Further, this mutation, FBN1 G1013R, has been reported in the literature in four other unrelated patients all of whom presented at a young age with cardiac involvement and all of whom had relative longevity when compared to other patients with mutations in this exon 24-32 hot spot. These findings may represent a more specific genotype-phenotype correlation within this mutational hot spot.

A 45-year-old Italian male with p.(Gly1815Ser) FBN1 mutation causing a mild variant of Marfan syndrome: A case study

A 45-year-old Italian male was referred as suspected of having a heritable connective tissue disorders by clinical findings, including joint hyperlaxity and soft, smooth, velvety, and slightly elastic skin. Using a specific custom panel including genes involved in these disorders, next-generation sequencing (NGS) analysis led to the identification of the c. 5443G>A, p.(Gly1815Ser), (rs745680336) variant in fibrillin-1 (FBN1) gene, encoding the FBN1. Mutations in this protein are responsible for different connective tissue disorders, collectively known as type 1 fibrillinopathies, including Marfan syndrome (MFS). Multiple sequencing alignment of human FBN1 protein with various species revealed that the mutation occurred within a highly conserved region of the calcium-binding epidermal growth factor-like domain and affected the protein structure/function, suggesting its pathogenic role. NGS techniques successfully identified the molecular defect in this patient, clinically resembling as MFS, even if a clear genotype–phenotype correlation remains still challenging.

Increased frequency of FBN1 frameshift and nonsense mutations in Marfan syndrome patients with aortic dissection

BackgroundMarfan syndrome (MFS) is an inherited connective tissue disease that mainly involves Fibrillin‐1 (FBN1) mutations and aortic manifestations. In this study, we investigated the correlations between the FBN1 genotype–phenotype and aortic events (aortic dissection and aortic aneurysm) in patients with Marfan syndrome.MethodsGenotype and phenotype information was evaluated in 180 patients with MFS. DNA sequencing was performed on each patient. According to the clinical manifestation, these patients were split into two groups: the aortic dissection group and the aortic aneurysm group. Aortic wall tissue was obtained from Marfan patients who underwent surgery and was used for staining.ResultsA total of 180 patients with FBN1 mutations were grouped into four categories: 90 with missense mutations, 32 with splicing mutations, 29 with frameshift mutations, and 29 with nonsense mutations. There was a significantly higher frequency of frameshift and nonsense mutations observed in aortic dissection than in aortic aneurysm (25.58% vs. 4.35%, p = .005; 25.58% vs. 8.70%, p = .033, respectively;), while missense mutations showed a higher frequency in aortic aneurysm than in aortic dissection (69.57% vs. 32.56%, respectively; p < .001) and a higher rate of lens dislocation (34.78% vs. 13.95%, respectively; p = .008). Pathological staining showed that elastic fibers were sparser in patients with a frameshift and nonsense mutations, and the smooth muscle cells were sparser and more disorganized than those observed in patients with missense mutations.ConclusionThis study showed that FBN1 gene frameshift and nonsense mutations are more common in patients with aortic dissection and may have meaningful guidance for the treatment of Marfan syndrome patients.

Mutation analysis of FBN1 gene in two Chinese families with congenital ectopia lentis in northern China.

To summarize the phenotypes and identify the underlying genetic cause of the fibrillin-1 (FBN1) gene responsible for congenital ectopia lentis (EL) in two Chinese families in northern China. A detailed family history and clinical data from all participants were collected by clinical examination. The candidate genes were captured and sequenced by targeted next-generation sequencing, and the results were confirmed by Sanger sequencing. Haplotyping was used to confirm the mutation sequence. Real-time PCR was used to determine the FBN1 messenger ribonucleic acid (mRNA) levels in patients with EL and in unaffected family members. The probands and other patients in the two families were affected with congenital isolated EL. A heterozygous FBN1 mutation in exon 21 (c.2420_IVS20-8 delTCTGAAACAinsCGAAAG) was identified in FAMILY-1. A heterozygous FBN1 mutation in exon 14 (c.1633C>T, p.R545C) was identified in FAMILY-2. Each mutation co-segregated with the affected individuals in the family and did not exist in unaffected family members and 200 unrelated normal controls. The insertion-deletion mutation (c.2420 IVS20-8delTCTGAAACA insCGAAAG) in the FBN1 gene is first identified in isolated EL. The mutation (c.1633C>T) in the FBN1 gene was a known mutation in EL patient. The variable phenotypes among the patients expand the phenotypic spectrum of EL in a different ethnic background.

Fibrillin-2 gene mutations associated with hereditary connective tissue diseases

Fibrillin-2 (FBN2) is an important component of microfibers which are involved in the formation of elastic fibers in connective tissue throughout the human body. Hereditary connective tissue diseases may result from genetic mutations of FBN2 causing heterogeneity of fibrin. Genetic mutations of FBN2 are associated with a variety of hereditary connective tissue diseases including Congenital Contractural Arachnodactyl (CCA), Macular Degeneration (MD), and myopathy. Studies have shown that the FBN2 gene is recognized as the only pathogenic gene related to CCA and that CCA patients have different clinical presentations depending on the identified genetic mutations at different FBN2 sites. In this review, we summarize the roles of FBN2, its mutations and impact on the physiological and pathological processes of many hereditary connective tissue diseases. We include brief descriptions of clinical manifestations of these diseases providing a basis for further exploration of the specific molecular mechanism of FBN2 gene mutation pathogenesis which provides a theoretical basis for the therapy and medications for refractory diseases caused by FBN2 gene mutation.

P2577Losartan diminishes the expression of TGF-beta and improves cardiomyopathy in mice with Marfan syndrome

Abstract Introduction Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene, leading to abnormal signaling of the transforming growth factor beta (TGF-β). This results in aortic root dilation, dissection and rupture, which are the main causes of morbidity and mortality of MFS patients. Current treatment with losartan, an angiotensin-II receptor-1 blocker, has shown beneficial effect on aortic disease in MFS murine models. However, the mechanisms whereby the treatment with losartan improves cardiac remodeling and function of the left ventricle (LV) in MFS are still unknown. Purpose To investigate the effects of losartan on mechanisms of the cardiomyopathy in mice with MFS. Methods mgΔloxPneo MFS murine model from C129/sv background was utilized in this study. To evaluate the effect of the treatment with losartan on the LV of MFS and wild-type mice, animals were allocated in 2 groups of treatments: Losartan group: mice were kept with water supplemented with losartan (0.6g/L); Untreated control group: mice were kept with water only. The animals received treatment from 1 month of age until completing 6 months. After five months of treatment, LV echocardiography was performed, and fragments of LV tissue were analyzed by morphometry and protein expression analysis by Western blot. Results Losartan MFS mice showed decrease in interventricular septum and posterior wall thickness and LV mass. Furthermore, losartan prevented aortic and mitral regurgitation, arrhythmia, bradycardia, septal hypokinesia and pulmonary hypertension when compared with control MFS mice. Systolic and diastolic LV function were not different between groups. Collagen volume fraction and the disorganization and disruptions of the elastic fibers in coronary arteries were lower in losartan treatment than in controls. The protein expression of pro-apoptotic factors (BAX/Bcl-2 and caspase 3 and 9), proliferating cell nuclear antigen and hypoxia-inducible factor 1 and 2α were lower in losartan treatment, whereas the expression of vascular endothelial growth factor was increased in losartan group when compared with control MFS mice. Moreover, the treatment with losartan strongly reduced the TGF-β, ERK and p38MAPK protein expression compared to controls. Conclusion In this murine model of MFS, losartan treatment has the ability to change several pathophysiological mechanisms related with the fibrillin-1 mutation, by decreasing apoptosis, cell proliferation and increasing angiogenesis. Overall, the treatment resulted in improved structural rearrangement and attenuation of the rupture of elastic fibers in the coronary arteries, of the cardiac hypertrophy and myocardial fibrosis. These effects were possibly related with the decreased TGF-β expression by ERK and p38MAPK signaling pathways by losartan. Our findings shed a new light on the mechanisms of action of losartan on MFS cardiomyopathy. Acknowledgement/Funding FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo)

444Plasma levels of microfibrillar associated protein type 4 (MFAP4) are predictive for aortic dissection in patients with Marfan Syndrome

Abstract Aim Marfan syndrome is a disorder with mutations in the fibrillin-1 gene, leading to elastic fiber degradation and increased TGF-beta signaling. The life-threatening feature of Marfan is aneurysm formation with a risk of fatal aortic dissections. In a proteomics screen, we identified MFAP4, a protein involved in fibrillin-1 and elastic fiber formation, to be increased in the Marfan aorta. We aim to study the role of MFAP4 in Marfan aortic disease. Methods and results MFAP4 co-localizes in the aorta with elastin and collagen fibers. In vitro experiments show that MFAP4 expression is upregulated by TGF-beta, which could explain the increased MFAP4 protein levels in the Marfan aorta. In a substudy of 96 Marfan patients from the COMPARE trial, MFAP4 levels correlate with aortic root diameter (r=0.30, p=0.01). Patients previously enrolled in the COMPARE trial were retrospectively analyzed. Cardiovascular events, including aortic dissection, were assessed. Plasma samples were prospectively collected at time of inclusion in the study and analyzed retrospectively on MFAP4. In the 7 years of follow up, 5 Type B dissections occurred, all of them in patients in the upper tertile of plasma MFAP4. High plasma MFAP4 associates with poor dissection-free survival (Figure 1). Moreover, the aortic distensibility as measure for aortic stiffness and damage, was calculated throughout the aorta from available MRI images of these patients. Interestingly, in the descending thoracic aorta where type B dissections occur, the aortic distensibility is significantly lower (indicating decreased aortic elasticity) in Marfan patients with high plasma MFAP4, thus associating with aortic damage. Figure 1 Conclusion MFAP4, a protein involved in extracellular matrix assembly, is elevated in the Marfan aorta. High plasma MFAP4 seems to reflect aortic damage and predicted type B aortic dissections in up to 7 years follow up.

Alterations in phenotype and gene expression of adult human aneurysmal smooth muscle cells by exogenous nitric oxide

Abdominal aortic aneurysms (AAA) are characterized by matrix remodeling, elastin degradation, absence of nitric oxide (NO) signaling, and inflammation, influencing smooth muscle cell (SMC) phenotype and gene expression. Little is known about the biomolecular release and intrinsic biomechanics of human AAA-SMCs. NO delivery could be an attractive therapeutic strategy to restore lost functionality of AAA-SMCs by inhibiting inflammation and cell stiffening. We aim to establish the differences in phenotype and gene expression of adult human AAA-SMCs from healthy SMCs. Based on our previous study which showed benefits of optimal NO dosage delivered via S-Nitrosoglutathione (GSNO) to healthy aortic SMCs, we tested whether such benefits would occur in AAA-SMCs. The mRNA expression of three genes involved in matrix degradation (ACE, ADAMTS5 and ADAMTS8) was significantly downregulated in AAA-SMCs. Total protein and glycosaminoglycans synthesis were higher in AAA-SMCs than healthy-SMCs (p < 0.05 for AAA-vs. healthy- SMC cultures) and was enhanced by GSNO and 3D cultures (p < 0.05 for 3D vs. 2D cultures; p < 0.05 for GSNO vs. non-GSNO cases). Elastin gene expression, synthesis and deposition, desmosine crosslinker levels, and lysyl oxidase (LOX) functional activity were lower, while cell proliferation, iNOS, LOX and fibrillin-1 gene expressions were higher in AAA-SMCs (p < 0.05 between respective cases), with differential benefits from GSNO exposure. GSNO and 3D cultures reduced MMPs −2, −9, and increased TIMP-1 release in AAA-SMC cultures (p < 0.05 for GSNO vs. non-GSNO cultures). AAA-SMCs were inherently stiffer and had smoother surface than healthy SMCs (p < 0.01 in both cases), but GSNO reduced stiffness (~25%; p < 0.01) and increased roughness (p < 0.05) of both cell types. In conclusion, exogenously-delivered NO offers an attractive strategy by providing therapeutic benefits to AAA-SMCs.

Fibrillin-1 in the Vasculature: In Vivo Accumulation of eGFP-Tagged Fibrillin-1 in a Knockin Mouse Model.

Immunolocalization studies have shown that fibrillin-1 is distributed ubiquitously in the connective tissue space from early embryonic times through old age. When mutated, the gene for fibrillin-1 (FBN1) causes the Marfan syndrome, a common inherited disorder of connective tissue. The multiple manifestations of the Marfan syndrome reflect the known distribution of fibrillin-1 in cardiovascular, musculoskeletal, ocular, and dermal tissues. In this study, a mouse model of Marfan syndrome in which fibrillin-1 is truncated and tagged with green fluorescence was used to estimate the relative abundance of fibrillin-1 in developing tissues. In embryonic tissues, the aorta was the only tissue in which fibrillin-1 green fluorescence was detectable. Other arteries gained detectable fibrillin-1 green fluorescence just after birth. Fibrillin-1 fluorescence was observed at later postnatal times in the lung, skin, perichondrium, tendon, and ocular tissues, while other tissues remained negative. These results indicated that tissues most affected in the Marfan syndrome are the tissues in which fibrillin-1 is most abundant. Focus was placed on the aorta, since aortic disease is life threatening in the Marfan syndrome and fibrillin-1 green fluorescence was most abundant in this tissue. Fibrillin-1 green fluorescence and immunostaining showed that fibrillin-1 is within aortic medial elastic lamellae. Endothelial-specific compared to smooth muscle-specific fibrillin-1 green fluorescence, together with light microscopic analyses of fragmentation of aortic elastic lamellae, demonstrated that smooth muscle cell mutated fibrillin-1 contributed most to progressive aortic fragmentation. However, these studies also indicated that other cells, possibly endothelial cells, also contribute to this aortic pathology. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

Transforming Growth Factor β Receptor Type I Inhibitor, Galunisertib, Has No Beneficial Effects on Aneurysmal Pathological Changes in Marfan Mice.

Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene, has vascular manifestations including aortic aneurysm, dissection, and rupture. Its vascular pathogenesis is assumed to be attributed to increased transforming growth factor β (TGFβ) signaling and blockade of excessive TGFβ signaling has been thought to prevent dissection and aneurysm formation. Here, we investigated whether galunisertib, a potent small-molecule inhibitor of TGFβ receptor I (TβRI), attenuates aneurysmal disease in a murine model of MFS (Fbn1C1039G/+) and compared the impact of galuninsertib on the MFS-related vascular pathogenesis with that of losartan, a prophylactic agent routinely used for patients with MFS. Fbn1C1039G/+ mice were administered galunisertib or losartan for 8 weeks, and their ascending aortas were assessed for histopathological changes and phosphorylation of Smad2 and extracellular signal-regulated kinase 1/2 (Erk1/2). Mice treated with galunisertib or losartan barely exhibited phosphorylated Smad2, suggesting that both drugs effectively blocked overactivated canonical TGFβ signaling in Fbn1C1039G/+ mice. However, galunisertib treatment did not attenuate disrupted medial wall architecture and only partially decreased Erk1/2 phosphorylation, whereas losartan significantly inhibited MFS-associated aortopathy and markedly decreased Erk1/2 phosphorylation in Fbn1C1039G/+ mice. These data unexpectedly revealed that galunisertib, a TβRI inhibitor, showed no benefits in aneurysmal disease in MFS mice although it completely blocked Smad2 phosphorylation. The significant losartan-induced inhibition of both aortic vascular pathogenesis and Smad2 phosphorylation implied that canonical TGFβ signaling might not prominently drive aneurysmal diseases in MFS mice.

Analysis of FBN1 gene mutations in two pedigrees affected with Marfan syndrome

To detect mutations of fibrillin-1 (FBN1) gene in two pedigrees affected with Marfan syndrome (MFS). Peripheral blood samples were collected from MFS patients and their healthy family members for extracting genomic DNA. All of the 65 exons of the FBN1 gene were analyzed by next-generation sequencing. PolyPhen-2 and SIFT was used to predict structural and functional changes in FBN1 protein. Patients from both pedigrees presented ocular and skeletal manifestations suggestive of MFS. Two novel heterozygous mutations of the FBN1 gene, including c.1879C>T (p.R627C) in exon 16 and c.2584T>C (p.C862R) in exon 22, were identified. The same mutations were not found among unaffected members. By bioinformatic analysis, the mutations may affect the structure and function of the FBN1 protein. The c.1879C>T and c.2584T>C mutations of the FBN1 gene probably account for the disease in the two pedigrees, respectively. Identification of the c.2584T>C has enriched the spectrum of FBN1 gene mutations.

Shprintzen-Goldberg Syndrome: A Rare Disorder

The Shprintzen-Goldberg syndrome (SGS) or velo-cardio-facial syndrome (VCFS) is an extremely rare disorder of connective tissue with a characteristic facial dysmorphism, marfanoid features, craniosynostosis, dolichocephaly, cardiovascular anomalies and mild to moderate mental retardation. It may be a de novo gene mutation or inherited as an autosomal dominant disorder having SKI gene and Fibrillin-1 gene (FBN1) mutations, located on chromosome 15q21.1. We report a case of a 3-month, developmentally delayed male infant admitted to the hospital with syndromic facies, craniosynostosis, joint laxity and on echocardiography, aortic root dilatation. A probable diagnosis of SGS was made on the clinical grounds. We did not have the facility for genetic chromosomal analysis. He was discharged with family counselling and follow-up for future developmental rehabilitation.

Nitric oxide donor molsidomine favors features of atherosclerotic plaque stability and reduces myocardial infarction in mice

Nitric oxide (NO) donors are commonly used for the prevention and treatment of ischemic heart disease. Besides their effects on the heart, NO donors may also prevent hypoxic brain damage and exert beneficial effects on atherosclerosis by favoring features of plaque stability. We recently described that apolipoprotein E (ApoE) deficient mice with a mutation in the fibrillin-1 (Fbn1) gene (ApoE-/-Fbn1C1039G+/-) develop accelerated atherosclerosis, plaque rupture, myocardial infarction, cerebral hypoxia and sudden death. In the present study, we evaluated the effects of chronic treatment with the NO donor molsidomine on atherosclerotic plaque stability, cardiac function, neurological symptoms and survival in the ApoE-/-Fbn1C1039G+/- mouse model. Female ApoE-/-Fbn1C1039G+/- mice were fed a Western diet (WD). After 8 weeks of WD, the mice were divided into two groups receiving either molsidomine via the drinking water (1 mg/kg/day; n = 34) or tap water (control; n = 36) until 25 weeks of WD. Survival tended to increase after molsidomine treatment (68% vs. 58% in controls). Importantly, atherosclerotic plaques of molsidomine-treated mice had a thicker fibrous cap (11.1 ± 1.2 vs. 8.1 ± 0.7 μm) and showed an increased occurrence of plaque macrocalcifications (30% vs. 0%), indicative of a more stable phenotype. Molsidomine also improved cardiac function, as fractional shortening was increased (40 ± 2% vs. 27 ± 2%) combined with a decreased end diastolic (3.1 ± 0.2 vs. 3.9 ± 0.2 mm) and end systolic diameter (1.9 ± 0.1 vs. 2.9 ± 0.2 mm). Furthermore, perivascular fibrosis (23 ± 2 vs. 30 ± 2%) and the occurrence of myocardial infarctions (12% vs. 36%) was significantly reduced. Track width, a measure of the animal's hind limb base of support and representative of hypoxic brain damage, was also normalized as a result of molsidomine treatment (2.54 ± 0.04 vs. 2.91 ± 0.09 cm in controls). These findings demonstrate that the NO donor molsidomine improves cardiac function, reduces neurological symptoms and enhances atherosclerotic plaque stability.

Cardiovascular Magnetic Resonance Provides Evidence of Abnormal Myocardial Strain and Primary Cardiomyopathy in Marfan syndrome.

Marfan syndrome is an autosomal-dominant genetic disorder caused by mutations in the fibrillin-1 gene. The condition is a connective tissue disease that frequently involves the cardiovascular system. The existence of a primary cardiomyopathy in Marfan syndrome, however, is controversial. The aims of this study were to investigate the prevalence of left ventricular dysfunction with both transthoracic echocardiography and cardiovascular magnetic resonance (CMR) in a cohort of Marfan syndrome patients and to investigate patterns of myocardial strain across the cohort. We used an institutional database to identify all patients with a firm diagnosis of Marfan syndrome based on Ghent criteria. Inclusion required left ventricular ejection fraction (LVEF) to have been measured by both CMR and transthoracic echocardiography within 12 months of each other. Normal LVEF was defined as a value of >55% when measured by CMR. Velocity vector imaging was used to measure left ventricular longitudinal strain patterns by application of feature tracking to cine magnetic resonance images. Results were compared with data from 20 age-matched control subjects. Sixty-nine Marfan syndrome patients met the inclusion criteria. The mean age was 35.4 ± 15.0 years, and 56.5% were male. The mean LVEF was 59.0% ± 7.0% by CMR and 59.1% ± 5.8% by echo. One-fifth of Marfan syndrome patients (15/69; 21.7%) had reduced function with LVEF ≤55% by CMR, but only 5 of these were identified by echo. Furthermore, echo identified 5 Marfan syndrome patients as having reduced LVEF in the presence of a normal LVEF by CMR. Some Marfan syndrome patients had abnormal longitudinal strain patterns even with LVEF within the reference range. These data provide support for a primary cardiomyopathy in some Marfan syndrome patients. Cardiovascular magnetic resonance is more sensitive than echo for identifying cases with mild systolic dysfunction. Strain analysis may be more sensitive than simple LVEF assessment for identifying at-risk individuals.

Incomplete Mass Phenotype: Description of a New Pathogenic Variant of the Fibrillin-1 Gene.

Incomplete Mass Phenotype: Description of a New Pathogenic Variant of the Fibrillin-1 Gene.

A Review of the Type-1 Fibrillinopathies: Pathophysiology, Diagnosis and Novel Therapeutic Strategies

Type-1 fibrillinopathies are a family of connective tissue disorders with major clinical manifestations in the skeletal, ocular and cardiovascular systems. The type-1 fibrillinopathies are caused by mutations in the fibrillin-1 gene (FBN1), which encodes fibrillin-1, a large glycoprotein and a major component of the extracellular matrix microfibrils, providing both structural and regulatory support to connective tissues. The type-1 fibrillinopathies have been associated with over 1800 unique mutations within the FBN1 and demonstrate a wide range of phenotypic variability. This, in conjunction with a number of other factors has impacted on the identification of genotypephenotype correlations, pathogenesis and diagnostic tests for this family of diseases, leaving many open-ended theories. Current standard of care relies heavily on surgical intervention and lifelong use of β-blockers to slow disease progression, with research focused heavily on antagonism of transforming growth factor β, which is known to be dysregulated in patients with FBN1 mutations. Antisense oligonucleotides present a novel therapeutic strategy for the type-1 fibrillinopathies, by mediating the alteration of exon arrangement of both the normal and disease-causing mRNA transcripts, to re-establish the periodicity of fibrillin-1. The induced proteins, while internally truncated, should be homologous and thus be able to form multimer units. This treatment alone or in association with isoform switching, TGF-β antagonism or enhanced/inhibited protein degradation could facilitate the assembly of fibrillin-1 monomers into multimers and consequently a decrease in phenotypic severity. This review presents a basic overview of the past and current knowledge about the spectrum of type-1 fibrillinopathies with a particular focus on Marfan syndrome, as well as presenting novel potential therapeutic strategies.

Implications of Genetic Manipulation of Caveolin‐1 Protein Expression in a Mouse Model of Marfan Syndrome‐Associated Aortic Aneurysm

Marfan Syndrome (MFS), a connective tissue disorder, resulting from mutations in the Fibrillin‐1 gene, is associated with several clinical manifestations with the most life‐threatening being aortic aneurysm, dissection, and rupture. The mechanism underlying MFS pathogenesis seems to result from crosstalk between the Angiotensin‐II (AngII) pathway and over activation of transforming growth factor‐beta (TGF‐b) signaling. Studies show that Losartan, an angiotensin II receptor type I (ATRI) blocker, can block progression of aortic aneurysm in mice, partially due to its inhibitory effects on TGF‐b signaling. It has been established that caveolin‐1 (Cav1), a coat protein of caveolae that is highly expressed in endothelial and smooth muscle, regulates AngII and TGF‐β signaling pathways, through its interactions with ATR1 and TGF‐β receptors. Interestingly, Cav1 knockout (Cav1KO) animal models illustrated increased elastin synthesis and nitric oxide (NO) production. Our previous study in the MFS mouse model reported reduced NO production in the aortic wall, proposing a potential link between Cav‐1 activation and aneurysm progression in MFS mice. Hence, in this study, we aimed to investigate the effects of genetic manipulation of Cav1 expression on the progression of aortic aneurysm in a well‐established mouse model of MFS‐associated aortic aneurysm, by generating MFS mice lacking Cav1 expression (MFS/Cav1KO).In vivo analysis of biophysical properties in 3‐ and 6‐ month old wild type, MFS, Cav1KO, and MFS/Cav1KO mice was performed using Vevo 2100 high‐resolution ultrasound imaging system (FUJIFILM VisualSonics). Aortic diameters at the aortic annulus, sinus of Valsalva, and sinotubular junction were significantly increased in MFS and MFS/CAV1KO mice as compared to control and Cav1KO groups at 3, and 6 months in systole and diastole. Pulse wave velocity (PWV), a reliable indicator of aortic wall stiffness, was significantly increased in MFS as compared to control and Cav1KO mice, with no significant changes observed between MFS and MFS/Cav1KO groups at 3 months of age. Interestingly, at 6 months of age, MFS/Cav1KO mice presented higher values for PWV as compared to MFS groups, indicating that deletion of Cav1 gene in MFS mice may have detrimental effects on aortic wall structure as MFS mice age.Cardiac parameters were also measured. Our data showed that at 3 months of age, a marked increase in heart rate, ejection fraction, and fractional shortening were detectable in MFS mice as compared to control subjects. Measurements of cardiac output and stroke volume revealed no significant differences among experimental groups. Interestingly, left ventricular mass was significantly greater in MFS/CAV1KO compared to wild type and MFS mice, suggesting that Cav1 plays a protective role in maintaining normal cardiac structure in MFS mice. At this point, our collected data suggest that Cav1 may have some protective effects on aortic and cardiac structure and function during the development of aortic aneurysm in the mouse model of MFS.Support or Funding InformationThis study was funded by The Marfan Foundation (M.E.), and a Midwestern University Graduate Fund (T.C.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.