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Connective Tissue Research May 2024Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is...
PURPOSE
Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints, scoliosis, pectus deformities, and crumpled ears, but rarely with lethal cardiovascular manifestations as in Marfan syndrome. It is imperative to conduct a comprehensive analysis and review of the pathogenesis of CCA resulting from pathogenic variants in FBN2 gene.
MATERIALS AND METHODS
Using whole-exome sequencing and Sanger sequencing, we identified a novel pathogenic splice-altering variant (c.4472-3C>A) in intron 34 of FBN2 gene in a CCA pedigree. The transcriptional result of the splicing-altering variant was analyzed by RNA sequencing. We systematically analyzed the clinical manifestations of all reported cases of CCA caused by splicing-altering pathogenic variants and focused on all the pathogenic variants in FBN2 gene that are associated with severe cardiovascular manifestations.
RESULTS
The splice-altering variant (c.4472-3C>A) in FBN2 was demonstrated to result in the exon 35 skipping and cause an in-frame deletion. Furthermore, we identified exons 31 to 35 may be a hotspot region in FBN2 gene associated with severe cardiovascular phenotype.
CONCLUSIONS
This study enriched the pathogenic spectrum of CCA and identified a hotspot region in FBN2 gene associated with severe cardiovascular manifestations. We recommend that patients carrying pathogenic variants in exons 31 to 35 of FBN2 pay more attention to cardiac evaluation.
Topics: Fibrillin-2; Humans; Arachnodactyly; Contracture; Male; Female; Pedigree; Mutation
PubMed: 38602424
DOI: 10.1080/03008207.2024.2340004 -
Arteriosclerosis, Thrombosis, and... May 2024AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention... (Review)
Review
AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating -floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.
Topics: Animals; Humans; Cardiovascular Diseases; Angiotensinogen; Metabolic Diseases; Renin-Angiotensin System; Molecular Targeted Therapy
PubMed: 38572647
DOI: 10.1161/ATVBAHA.124.318374 -
Journal of Cardiothoracic Surgery Apr 2024Acute Type A aortic dissection (ATAAD) is a life-threatening cardiovascular disease associated with high mortality rates, where surgical intervention remains the primary...
BACKGROUND
Acute Type A aortic dissection (ATAAD) is a life-threatening cardiovascular disease associated with high mortality rates, where surgical intervention remains the primary life-saving treatment. However, the mortality rate for ATAAD operations continues to be alarmingly high. To address this critical issue, our study aimed to assess the correlation between preoperative laboratory examination, clinical imaging data, and postoperative mortality in ATAAD patients. Additionally, we sought to establish a reliable prediction model for evaluating the risk of postoperative death.
METHODS
In this study, a total of 384 patients with acute type A aortic dissection (ATAAD) who were admitted to the emergency department for surgical treatment were included. Based on preoperative laboratory examination and clinical imaging data of ATAAD patients, logistic analysis was used to obtain independent risk factors for postoperative in-hospital death. The survival prediction model was based on cox regression analysis and displayed as a nomogram.
RESULTS
Logistic analysis identified several independent risk factors for postoperative in-hospital death, including Marfan syndrome, previous cardiac surgery history, previous renal dialysis history, direct bilirubin, serum phosphorus, D-dimer, white blood cell, multiple aortic ruptures and age. A survival prediction model based on cox regression analysis was established and presented as a nomogram. The model exhibited good discrimination and significantly improved the prediction of death risk in ATAAD patients.
CONCLUSIONS
In this study, we developed a novel survival prediction model for acute type A aortic dissection based on preoperative clinical features. The model demonstrated good discriminatory power and improved accuracy in predicting the risk of death in ATAAD patients undergoing open surgery.
Topics: Humans; Hospital Mortality; Retrospective Studies; Aortic Dissection; Risk Factors; Marfan Syndrome
PubMed: 38566106
DOI: 10.1186/s13019-024-02687-x -
Journal of Vascular Nursing : Official... Mar 2024Patients with Marfan syndrome, who present with a variety of symptoms and complex psychosocial problems, require interprofessional collaboration in their care. However,...
BACKGROUND AND AIM
Patients with Marfan syndrome, who present with a variety of symptoms and complex psychosocial problems, require interprofessional collaboration in their care. However, it is unclear how health care providers contribute to interprofessional collaboration for these patients. The purpose of this study was to determine the characteristics of interprofessional collaboration for patients with Marfan syndrome in the cardiovascular field.
METHODS
Semi-structured interviews were conducted with health care specialists (5 physicians, 2 nurses, and 3 certified genetic counselors) were analyzed qualitatively.
RESULTS
Based on the medical collaboration for the management of cardiovascular complications in patients and their relatives, interprofessional collaboration was identified, such as collaboration and cooperation between physicians and certified genetic counselors, and nursing practice to facilitate interprofessional collaboration. In addition, issues such as difficulties in dealing with and coordinating medical care for noncardiovascular complications, lack of specialist physicians, and lack of opportunities to collaborate with nurses were identified.
CONCLUSIONS
Effective interprofessional collaboration requires the acquisition of Marfan syndrome and genetic knowledge by healthcare providers and the development of a healthcare delivery system based on departments that can provide leadership. In addition, the assignment of nurses to work across organizational boundaries and effective collaboration between genetic counselors and nurses should be considered.
Topics: Humans; Marfan Syndrome; Delivery of Health Care; Qualitative Research; Health Personnel; Physicians; Cooperative Behavior
PubMed: 38555174
DOI: 10.1016/j.jvn.2023.11.005 -
Advanced Science (Weinheim,... Jun 2024Aortic root aneurysm is a potentially life-threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome...
Aortic root aneurysm is a potentially life-threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single-nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell-type-specific transcriptomic and cis-regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans.
Topics: Humans; Phenotype; Aortic Aneurysm; Muscle, Smooth, Vascular; Marfan Syndrome; Myocytes, Smooth Muscle; Transcriptome; Aorta; Gene Expression Profiling
PubMed: 38552156
DOI: 10.1002/advs.202400444 -
Zhonghua Wai Ke Za Zhi [Chinese Journal... May 2024To evaluate the clinical outcomes of thoracic endovascular aortic repair (TEVAR) in the treatment of Stanford type B aortic dissection (TBAD) in Marfan syndrome...
To evaluate the clinical outcomes of thoracic endovascular aortic repair (TEVAR) in the treatment of Stanford type B aortic dissection (TBAD) in Marfan syndrome patients who had no history of aortic arch replacement. This is a retrospective case-series study. From January 2009 to December 2019,the clinical data of Marfan syndrome patients who underwent TEVAR for TBAD at the Department of Vascular Surgery were collected. A total of 23 patients were enrolled,including 15 males and 8 females. The age was (38.0±11.0) years (range:24 to 56 years). Among them,12 patients had history of ascending aortic surgery. Details of TEVAR,perioperative complications and reintervention were recorded and survival rate was analyzed by Kaplan-Meier curve. Technical success was 91.3% (21/23). Two patients with technical failure were as follows:one patient had type Ⅰa endoleak at the completion angiography,which healed spontaneously during the follow-up,and the other patient suffered aortic intimal intussusception after the deployment of the first stent-graft, and the second stent-graft was deployed. However, type Ⅲ endoleak was detected,which disappeared during the follow-up. One patient died during hospitalization. The median follow-up time ((IQR)) was 60 (48) months (range:12 to 132 months). Reintervention was performed on 7 patients,including 3 distal stent-graft-induced new entry,2 distal aortic dilation,1 Ⅰa endoleak and 1 retrograde type A aortic dissection,respectively. Five-year cumulative survival rate was 86.7% (95%:86.6% to 86.8%) and the 5-year freedom from reintervention rate was 81.8% (95%:61.8% to 92.8%). TEVAR is feasible in the treatment of TBAD in Marfan syndrome patients who has no history of aortic arch replacement. It has high technical success rate and low perioperative complication.
Topics: Humans; Male; Female; Adult; Aortic Dissection; Marfan Syndrome; Middle Aged; Retrospective Studies; Endovascular Procedures; Blood Vessel Prosthesis Implantation; Treatment Outcome; Stents; Aortic Aneurysm, Thoracic; Young Adult; Aorta, Thoracic; Postoperative Complications
PubMed: 38548614
DOI: 10.3760/cma.j.cn112139-20230905-00092 -
The American Journal of Pathology Jul 2024Two major constituents of exfoliation material, fibrillin-1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1), are implicated in exfoliation glaucoma, yet their...
Two major constituents of exfoliation material, fibrillin-1 and lysyl oxidase-like 1 (encoded by FBN1 and LOXL1), are implicated in exfoliation glaucoma, yet their individual contributions to ocular phenotype are minor. To test the hypothesis that a combination of FBN1 mutation and LOXL1 deficiency exacerbates ocular phenotypes, the pan-lysyl oxidase inhibitor β-aminopropionitrile (BAPN) was used to treat adult wild-type (WT) mice and mice heterozygous for a missense mutation in Fbn1 (Fbn1) for 8 weeks and their eyes were examined. Although intraocular pressure did not change and exfoliation material was not detected in the eyes, BAPN treatment worsened optic nerve and axon expansion in Fbn1 mice, an early sign of axonal damage in rodent models of glaucoma. Disruption of elastic fibers was detected only in Fbn1 mice, which increased with BAPN treatment, as shown by histologic and immunohistochemical staining of the optic nerve pia mater. Transmission electron microscopy showed that Fbn1 mice had fewer microfibrils, smaller elastin cores, and a lower density of elastic fibers compared with WT mice in control groups. BAPN treatment led to elastin core expansion in both WT and Fbn1 mice, but an increase in the density of elastic fiber was confined to Fbn1 mice. LOX inhibition had a stronger effect on optic nerve and elastic fiber parameters in the context of Fbn1 mutation, indicating the Marfan mouse model with LOX inhibition warrants further investigation for exfoliation glaucoma pathogenesis.
Topics: Animals; Mice; Adipokines; Amino Acid Oxidoreductases; Aminopropionitrile; Disease Models, Animal; Elastic Tissue; Fibrillin-1; Fibrillins; Glaucoma; Intraocular Pressure; Marfan Syndrome; Mice, Inbred C57BL; Microfilament Proteins; Optic Nerve; Protein-Lysine 6-Oxidase
PubMed: 38548269
DOI: 10.1016/j.ajpath.2024.03.002 -
Turk Gogus Kalp Damar Cerrahisi Dergisi Jan 2024A 30-year-old woman with ankylosing spondylitis was referred to our clinic with abnormal fetal echocardiography findings, including ascending aortic dilatation, giant...
A 30-year-old woman with ankylosing spondylitis was referred to our clinic with abnormal fetal echocardiography findings, including ascending aortic dilatation, giant main pulmonary artery aneurysm, and aortic and pulmonary valve stenosis at 22 weeks of gestation. The full-term male neonate was born by cesarean section and was transferred to the cardiac intensive care unit soon after delivery for respiratory distress with low percutaneous oxygen saturation. Based on cardiovascular and genetic analysis findings, the patient was diagnosed with Marfan syndrome. Surgery was performed; however, the patient died due to cardiac arrest. In conclusion, main pulmonary artery dilatation and aneurysms are uncommon in Marfan syndrome; therefore, presentation with these findings during the fetal life, as in the present case, is likely a sign of severe Marfan syndrome-related cardiac involvement.
PubMed: 38545352
DOI: 10.5606/tgkdc.dergisi.2024.24850 -
Frontiers in Cardiovascular Medicine 2024Ascending thoracic aortic aneurysms arise from pathological tissue remodeling that leads to abnormal wall dilation and increases the risk of fatal dissection/rupture....
INTRODUCTION
Ascending thoracic aortic aneurysms arise from pathological tissue remodeling that leads to abnormal wall dilation and increases the risk of fatal dissection/rupture. Large variability in disease manifestations across family members who carry a causative genetic variant for thoracic aortic aneurysms suggests that genetic modifiers may exacerbate clinical outcomes. Decreased perlecan expression in the aorta of mgΔ mice with severe Marfan syndrome phenotype advocates for exploring perlecan-encoding as a candidate modifier gene.
METHODS
To determine the effect of concurrent and mutations on the progression of thoracic aortopathy, we characterized the microstructure and passive mechanical response of the ascending thoracic aorta in female mice of four genetic backgrounds: wild-type, heterozygous with a mutation in the gene (mgΔ), heterozygous with a mutation in the gene (), and double mutants carrying both the and variants (dMut).
RESULTS
Elastic fiber fragmentation and medial disarray progress from the internal elastic lamina outward as the ascending thoracic aorta dilates in mgΔ and dMut mice. Concurrent increase in total collagen content relative to elastin reduces energy storage capacity and cyclic distensibility of aortic tissues from mice that carry the variant. Inherent circumferential tissue stiffening strongly correlates with the severity of aortic dilatation in mgΔ and dMut mice. Perlecan haploinsufficiency superimposed to the mgΔ mutation curbs the viability of dMut mice, increases the occurrence of aortic enlargement, and reduces the axial stretch in aortic tissues.
DISCUSSION
Overall, our findings show that dMut mice are more vulnerable than mgΔ mice without an mutation, yet later endpoints and additional structural and functional readouts are needed to identify causative mechanisms.
PubMed: 38545339
DOI: 10.3389/fcvm.2024.1319164 -
Journal of Clinical Medicine Mar 2024Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave...
Thoracic aortic aneurysms (TAAs) associated with Marfan syndrome (MFS) are unique in that extracellular matrix metalloproteinase inducer (EMMPRIN) levels do not behave the way they do in other cardiovascular pathologies. EMMPRIN is shed into the circulation through the secretion of extracellular vesicles. This has been demonstrated to be dependent upon the Membrane Type-1 MMP (MT1-MMP). We investigated this relationship in MFS TAA tissue and plasma to discern why unique profiles may exist. : Protein targets were measured in aortic tissue and plasma from MFS patients with TAAs and were compared to healthy controls. The abundance and location of MT1-MMP was modified in aortic fibroblasts and secreted EMMPRIN was measured in conditioned culture media. : EMMPRIN levels were elevated in MFS TAA tissue but reduced in plasma, compared to the controls. Tissue EMMPRIN elevation did not induce MMP-3, MMP-8, or TIMP-1 expression, while MT1-MMP and TIMP-2 were elevated. MMP-2 and MMP-9 were reduced in TAA tissue but increased in plasma. In aortic fibroblasts, EMMPRIN secretion required the internalization of MT1-MMP. : In MFS, impaired EMMPRIN secretion likely contributes to higher tissue levels, influenced by MT1-MMP cellular localization. Low EMMPRIN levels, in conjunction with other MMP analytes, distinguished MFS TAAs from controls, suggesting diagnostic potential.
PubMed: 38541774
DOI: 10.3390/jcm13061548