Marfan Syndrome Patients Research Articles

Abstract 16846: Three-Dimensional Assessment of Ascending Aortic Motion by Dynamic CT in Sporadic and Marfan Thoracic Aortic Aneurysm

Background: The ascending aorta exhibits a complex, 3D motion related to cyclic pressure changes and downward traction forces related to left ventricular contraction. However, most metrics of disease severity are static (i.e., diameter) and among prior studies that have investigated ascending aortic motion, 2D imaging is typically employed. Vascular deformation mapping (VDM) is an image analysis technique that accurately quantifies 3D displacement of the aortic wall. Aims We aimed to quantify 3D metrics of cyclic ascending aortic motion and distensibility in patients with aTAA, and evaluate associations between motion metrics and patient characteristics in sporadic TAA (SaTAA) and Marfan syndrome (MFS). Methods: We included adult patients with aTAA, either SaTAA or MFS, and multi-phasic CTA of the thoracic aorta. VDM analysis of CTA data was performed with metrics including: 1) Axial, in-plane and rotational displacements at the root, 2) distensibility assessed by cyclic 2D cross-sectional area change (Dist-2D) at the root [(ΔA/A diastole х PP)], and 3) distensibility assessed by VDM-derived cyclic surface area stretch [(Area ratio-1)*1/PP] at the root and tubular ascending (Dist-3D). Aortic growth rate (GR) was measured from follow-up CTA. Results: We analyzed 51 with SaTAA (33% female, 62 ± 11 years old), and 14 with MFS (50% female, 42 ± 13 years old). In SaTAA, Dist-2D was associated (β=0.59, p=0.047) with axial displacement and AI was strongly associated (β=1.03 p=0.001) with rotation. In MFS, BAV and diameter were associated with in-plane displacement (β=5.50, p=0.004; β=-0.026, p=0.001). Among MFS patients with follow-up CTAs (n=10), ascending distensibility (Dist-3D) was marginally negatively associated with ascending GR (β= -0.27, p=0.058) Conclusion: 3D analysis of aortic motion in aTAA showed differences in root motion, namely related to valve disease and age, as well as differences in aortic distensibility that may predict ascending aortic GR in MFS.

Abstract 16995: Distensibility and Aortic Growth Rate Predict Type B Aortic Dissection in Marfan Syndrome

Introduction: Marfan syndrome (MFS) is associated with high aortic growth rate (GR) and incidence of aortic dissection (AD), including delayed type B AD (TBAD) after prophylactic root repair. Elevated aortic stiffness has been investigated as a biomarker in MFS, but it remains uncertain how stiffness relates to GR and risk of AD. Vascular deformation mapping (VDM) is a technique that uses clinical CT angiography (CTA) to yield accurate, 3D maps of aortic growth over surveillance (VDM-G). This technique can also be used to assess aortic stiffness via quantification of cyclic wall stretch between systole and diastole (VDM-D) using multi-phasic dynamic CTA. Research Question: Is distensibility of the descending thoracic aorta associated with aortic GR or development of TBAD in MFS patients? Goal: The aim of this study was to analyze stiffness of the descending thoracic aorta in MFS and its association with aortic GR and occurrence of TBAD. Methods: We identified 36 adult MFS patients with dynamic CTA studies (>1 year interval) between 2004-2020. Growth was quantified by VDM-G, and linearized descending aortic stiffness by VDM-D - via calculation of distensibility - as the ratio of cyclic aortic surface area change (AR) over pulse pressure [(AR-1)/PP]. Results: Patients were 38.9 ± 12.1 years old, 58% were male and 25 (69%) had prior ascending repair. Mean CT follow-up interval was 5.7 ± 3.4 years and 8 developed TBAD during follow-up with pre-dissection diameter of 31.12 ± 6.01 mm at tear location. Age (β -0.4, 95%CI: -0.07, -0.01, p=0.015) and baseline diameter (β 0.10, 95%CI: 0.02, 0.18, p=0.017 ) independently predicted GR on multivariable analysis, but distensibility did not (p=0.38). Both distensibility (OR 0.02, 95% CI: 0.00, 0.68, p=0.03) and GR (OR 8687.05, 95% CI: 1.43, 5x10^7, p=0.04) were independent predictors of TBAD during follow-up, but diameter was not (p=0.49). Conclusion: Aortic stiffness and growth rate are likely predictors of type B aortic dissection in MFS.

Abstract 13204: Single-Nucleus Multiomic Analyses Identifies Gene Regulatory Dynamics of Phenotypic Modulation in Human Aneurysmal Aortic Root

Introduction: Aortic root aneurysm is a potentially life-threatening condition because it may lead to aortic rupture. However, a single-nucleus transcriptomic and epigenomic landscape in the aortic root tissue of humans is lacking, and the regulatory mechanism of pathogenesis in aneurysmal aortic root remains elusive. We sought to identify molecular triggers for aortic root aneurysm in Marfan syndrome patients. Methods: Aneurysmal aortic root tissues from MFS patients (n=6) and normal aortic root tissues from age-matched, heart transplantation recipients (n=6) were collected. Samples from four subjects of each group were individually subjected to single-nucleus multiomic sequencing (gene expression and chromatin accessibility). Spatial transcriptomic assays were applied to aortic root tissue sections from two subjects of each group. Results: The single-nucleus dataset revealed three subclusters for the vascular smooth muscle cells (VSMCs) lineage including contractile VSMC1 (expressed a high level of RYR2 ), modulated VSMC2 and VSMC3(expressed a high level of CFH ). Statistically significant expansion of the modulated VSMCs was observed in MFS patients. In addition, the modulated VSMCs are not only associated with the diseased states but also associated with the spatial location. The modulated VSMCs are preferentially located in the inner layer of the tunica media close to the intima in both healthy and diseased conditions. Based on the evidence from comparative analyses, we obtained 11 candidate key regulators (such as FOXN3, TEAD1, and BACH1) that potentially drive the phenotypic modulation of VSMCs and the pathogenesis of aortic root aneurysms. The experimental evidence supporting that the forkhead transcription factor FOXN3 may function as a key regulator for maintaining the contractile phenotype of human aortic VSMCs, whose expression decreased during phenotypic modulation and was downregulated in MFS VSMCs. Conclusions: We present the first atlas of gene expression and chromatin accessibility in human aortic root tissue at single-nucleus and spatial resolution. FOXN3 was identified as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs, which may serve as a potential therapeutic target.

Is Marfan Syndrome Associated with Primary Structural Changes in the Left Atrium?

Marfan syndrome (MFS) is an autosomal-dominant multisystem connective tissue disorder that is based on mutations in the FBN1 gene and variably affects different organs, including the heart. In this study, we investigated cardiac function with a focus on the left atrium (LA) in a relatively large cohort of patients with MFS. After screening of 1165 patients that had been examined in our center between 2016 and 2020, 231 adult MFS patients with and without aortic operation were included in our study and compared to a healthy control group (n = 106). Cardiac function was assessed by transthoracic echocardiography and NT-proBNP was used as a secretory marker. Most (94.8%) of the patients received genetic testing. Left ventricular function was within normal ranges and not impaired. Interestingly, we found that LA size and secretory activity were increased in MFS patients, despite normal left ventricular filling pressures. This finding was even more pronounced in MFS patients with prior aortic surgery. A correlation between LA size or NT-proBNP levels and the type of pathogenic FBN1 variant could not be identified. Right ventricular function and right atrial size were increased only in MFS patients that had undergone aortic surgery. In conclusion, these findings suggest that MFS leads to structural changes in the LA that are not solely resulting from left ventricular dysfunction, but probably can be considered a primary pathology of MFS.

Abstract P3151: A Unique Profile Of Extracellular Vesicles In Marfan Patients With Thoracic Aortic Aneurysm

Objectives: Extracellular vesicles (EVs) [exosomes and microvesicles] have significant diagnostic and therapeutic potential, but clinical application is limited by disparate methods of data collection. Exosomes are 30-100nm, and microvesicles are 100-300nm lipid bilayer vesicles that originate from all cell types. Marfan Syndrome (MFS) is a connective tissue disorder. Thoracic aortic aneurysm (TAA) formation and dissection are the leading causes of death in MFS patients. Early identification of TAAs in MFS patients is imperative and will mitigate morbidity and mortality. This study’s goal was to develop a reproducible workflow for isolation and quantification of EVs 30-300nm and test the hypothesis that number and size distribution are altered in MFS patients with TAA. Methods: A method of standardized reproducible measurement of EVs isolated from plasma was developed. This includes isolation by automated size exclusion chromatography and quantification of size distribution by tunable resistive pulse sensing. Characteristic markers specific to both EV subtypes were confirmed by immunoblot. Results: EVs isolated from control plasma (n=12) and Marfan TAA plasma (n=6) were measured for concentration (control 0.60 x 10 11 particles/mL, MFS TAA 1.47 x 10 11 particles/mL), mean diameter (control 77.75nm, MFS TAA 69.92nm), mode diameter (control 65.50nm, MFS TAA 60.50nm), and d90/d10 ratio (control 1.68, MFS TAA 271 1.57). Conclusion: MFS patients with TAA have more EVs with a smaller diameter, suggesting increased export and a shift in ratio of microvesicles:exosomes. This may be used as a diagnostic tool or potential therapeutic target. This scalable protocol ensures recovery of intact EVs suitable for downstream biochemical and functional analyses. Simultaneous measurement quantifies EV concentration and size distribution absolutely, correcting for variations, providing a novel method of standardization.

Abstract P1047: The Extracellular Matrix Metalloproteinase Inducer And The Membrane Type 1 Matrix Metalloproteinase In Marfan Syndrome Related Thoracic Aortic Aneurysm

Objectives: Marfan Syndrome (MFS) is a connective tissue disorder commonly associated with Thoracic Aortic Aneurysms (TAAs). TAAs occur because of abnormal remodeling of the aortic extracellular matrix (ECM). The balance between matrix metalloproteinases (MMPs) and the Tissue Inhibitors of MMPs (TIMPs), regulates these processes. The extracellular MMP inducer (EMMPRIN), is a widely expressed glycoprotein capable of stimulating the production of various MMPs, suggesting a direct role in driving pathology. The Membrane Type-1 MMP (MT1-MMP) can cause proteolytic shedding of EMMPRIN. Therefore, we investigated this relationship in MFS TAA tissue and plasma and tested the hypothesis that a unique proteolytic profile may exist. Methods: Levels of EMMPRIN, MT1-MMP, MMP-2, MMP-9, MMP-3, MMP-8, TIMP-1, and TIMP-2 were measured in aortic tissue and plasma from MFS patients with TAA and compared to healthy controls. Following modification of the abundance and location of MT1-MMP in isolated primary aortic fibroblasts, secreted EMMPRIN was measured in conditioned culture media. Results: Compared to controls, EMMPRIN is elevated in MFS TAA tissue and reduced in the plasma. Elevation of EMMPRIN abundance in tissue does not induce MMP-3, MMP-8, or TIMP-1 expression. MT1-MMP and TIMP-2 are elevated in MFS TAA tissue. MMP-2 and MMP-9 are reduced in MFS TAA tissue while increased in the plasma. In aortic fibroblasts we found that MT1-MMP must be internalized from the plasma membrane for EMMPRIN secretion. Conclusions: Our findings indicate that the pathological consequences of MFS cause the shedding of EMMPRIN and its secretion from cells to be blocked, which leads to higher EMPRINN abundance in MFS TAA tissue. This process depends upon the cellular location of MT1-MMP. Taken together, these observations suggest that internalization of MT1-MMP from the plasma membrane is required for the cellular secretion of EMMPRIN from aortic fibroblasts.

Health-related quality of life and psychosocial effects of the diagnosis of aortovascular manifestations in Marfan syndrome patients: a qualitative study

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Barts Charity Background Marfan Syndrome (MFS) is a rare autosomal-dominant connective tissue disorder with serious and life-threatening cardiovascular manifestations. Despite the severity of this life-long condition, there is very little evidence on the health-related quality of life (HRQoL) and psychosocial effects of living with MFS and no available evidence on the effect of the aortovascular manifestations. Purpose This study is part of a programme of work aiming to identify the HRQoL and the psychosocial factors affecting MFS patients following the diagnosis of an aortovascular manifestation. Methods This single site qualitative exploratory study was designed to identify quality of life issues affected by the aortovascular diagnosis in MFS from patients’ lived experience. Convenience sampling was employed for this study, with an expected sample size of 20 adult participants who had validated diagnosis of MFS using the revised Ghent criteria[1] and diagnosed with aortovascular manifestations. Interviews, lasting up to 1 hour, were conducted using a semi-structured interview schedule. Each interview was audio-taped and transcribed verbatim. Data saturation assessment was done using the Guest et al.[2] method. Data analysis was undertaken using the Framework method[3], which follows a seven-stage process Results Twenty interviews were undertaken, transcribed and analysed. Participants ranged from 24 to 71 years old (M = 39.6); were 55% male, were primarily Caucasian (n=17, 85%), and 80% completed secondary and post-secondary education. Majority were employed (n=12, 70%) and 40% had greater than average household income. The results identified that patient reported HRQoL and psychosocial factors affecting MFS patients following aortovascular diagnosis include: social and self-stigma, depression, social and health anxiety, loss of personal efficacy, financial burden, loss of self-esteem, worry in building a relationship or family and vital exhaustion. However, patients also expressed that the diagnosis led to disease acceptance, constructive engagement in coping with the condition and self-acceptance. Conclusion These results assist in better understanding the HRQoL and psychosocial factors that affect patients with MFS. This information can support the development of a patient care pathway that includes HRQoL and psychosocial aspects of care to provide a holistic and comprehensive service for this patient group.

Abnormal Left Ventricular Strain Correlates with Left Ventricular Dysfunction but not Aortic Pathology in Marfan Syndrome in Children.

Cardiomyopathy is a complication in adults with Marfan syndrome (MFS). Early recognition of MFS patients at high risk of cardiomyopathy could impact monitoring and treatment. Abnormal ventricular strain has been associated with impaired ventricular function among adults with MFS but remains understudied in children. We retrospectively analyzed a cohort of patients with MFS undergoing cardiac magnetic resonance imaging (CMR) performed in 2003-2018 at age < 19years. Correlations were evaluated between initial global circumferential strain (GCS) and global longitudinal strain (GLS) and the outcomes of left ventricular ejection fraction (LVEF), aortic root z-score, and vertebral artery tortuosity index corrected for height (VTI-h), all measured from CMR, using Spearman correlation. In those with serial CMR, the ability of ventricular strain to predict development of abnormal LVEF within a 5-year period was assessed. A total of 31 subjects were included (median age at initial CMR 13.5 years, Q1Q3 10.7-16.2 years), with 48% (n = 15) having LVEF < 55%. Worse GCS and worse GLS were associated with lower LVEF (ρ = - 0.629, p < 0.001 and ρ = - 0.411, p = 0.030, respectively). A clinical cutoff of GCS = - 34% predicted LVEF < 55% with sensitivity = 80% and specificity = 50%. Neither GCS nor GLS was associated with aortic root z-score (GCS: p = 0.524; GLS: p = 0.624) nor VTI-h (GCS: p = 0.949; GLS: p = 0.593). Of those with LVEF ≥ 55%, initial GCS and GLS did not differ between those with later normal versus abnormal LVEF (GCS: p = 0.505; GLS: p = 0.232). In this cohort, abnormal LV strain was associated with abnormal LVEF, but not with aortic dilation or low LVEF within the 5years post-CMR.

Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome

ObjectivesPatients with Loeys-Dietz syndrome demonstrate a heightened risk of distal thoracic aortic events after valve-sparing aortic root replacement. This study assesses the clinical risks and hemodynamic consequences of a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome and characterizes smooth muscle cell phenotype in Loeys-Dietz syndrome aneurysmal and normal-sized downstream aorta. MethodsPatients with genetically confirmed Loeys-Dietz syndrome (n = 8) underwent prophylactic aortic arch replacement during valve-sparing aortic root replacement. Four-dimensional flow magnetic resonance imaging studies were performed in 4 patients with Loeys-Dietz syndrome (valve-sparing aortic root replacement + arch) and compared with patients with contemporary Marfan syndrome (valve-sparing aortic root replacement only, n = 5) and control patients (without aortopathy, n = 5). Aortic tissues from 4 patients with Loeys-Dietz syndrome and 2 organ donors were processed for anatomically segmented single-cell RNA sequencing and histologic assessment. ResultsPatients with Loeys-Dietz syndrome valve-sparing aortic root replacement + arch had no deaths, major morbidity, or aortic events in a median of 2 years follow-up. Four-dimensional magnetic resonance imaging demonstrated altered flow parameters in patients with postoperative aortopathy relative to controls, but no clear deleterious changes due to arch replacement. Integrated analysis of aortic single-cell RNA sequencing data (>49,000 cells) identified a continuum of abnormal smooth muscle cell phenotypic modulation in Loeys-Dietz syndrome defined by reduced contractility and enriched extracellular matrix synthesis, adhesion receptors, and transforming growth factor-beta signaling. These modulated smooth muscle cells populated the Loeys-Dietz syndrome tunica media with gradually reduced density from the overtly aneurysmal root to the nondilated arch. ConclusionsPatients with Loeys-Dietz syndrome demonstrated excellent surgical outcomes without overt downstream flow or shear stress disturbances after concomitant valve-sparing aortic root replacement + arch operations. Abnormal smooth muscle cell–mediated aortic remodeling occurs within the normal diameter, clinically at-risk Loeys-Dietz syndrome arch segment. These initial clinical and pathophysiologic findings support concomitant arch replacement in Loeys-Dietz syndrome.

Thoracic aorta diameters in Marfan patients: Intraindividual comparison of 3D modified relaxation-enhanced angiography without contrast and triggering (REACT) with transthoracic echocardiography

ObjectiveTo compare the measurement of aortic diameters using a novel flow-independent MR-Angiography (3D modified Relaxation-Enhanced Angiography without Contrast and Triggering (modified REACT)) and transthoracic echocardiography (TTE) in Marfan syndrome (MFS) patients. Material and methodsThis retrospective, single-center analysis included 46 examinations of 32 MFS patients (mean age 37.5 ± 11.3 years, 17 women, no prior aortic surgery) who received TTE and 3D modified REACT (ECG- and respiratory-triggering, Compressed SENSE factor 9 for acceleration of image acquisition) of the thoracic aorta. Aortic diameters (sinus of Valsalva (SV), sinotubular junction (STJ), and ascending aorta (AoA)) were independently measured by two cardiologists in TTE (leading-edge) and two radiologists in modified REACT (inner-edge, using multiplanar reconstruction). Intraclass correlation coefficient, Bland-Altman analyses, and Pearson's correlation (r) were used to assess agreement between observers and methods. ResultsInterobserver correlation at the SV, STJ, and AoA were excellent for both, TTE (ICC = 0.95–0.98) and modified REACT (ICC = 0.99–1.00). There was no significant difference between TTE and modified REACT for diameters measured at the SV (39.24 ± 3.24 mm vs. 39.63 ± 3.76 mm; p = 0.26; r = 0.78) and the STJ (35.16 ± 4.47 mm vs. 35.37 ± 4.74 mm; p = 0.552; r = 0.87). AoA diameters determined by TTE were larger than in modified REACT (34.29 ± 5.31 mm vs. 30.65 ± 5.64 mm; p < 0.01; r = 0.74). The mean scan time of modified REACT was 05:06 min ± 02:47 min, depending on the patient's breathing frequency and heart rate. ConclusionsBoth TTE and modified REACT showed a strong correlation for all aortic levels; however, at the AoA, diameters were larger using TTE, mostly due to the limited field of view of the latter with measurements being closer to the aortic valve. Given the excellent interobserver correlation and the strong agreement with TTE, modified REACT represents an attractive method to depict the thoracic aorta in MFS patients.

Systematical analysis of underlying markers associated with Marfan syndrome via integrated bioinformatics and machine learning strategies

Marfan syndrome (MFS) is a hereditary disease with high mortality. This study aimed to explore peripheral blood potential markers and underlying mechanisms in MFS via a series bioinformatics and machine learning analysis. First, we downloaded two MFS datasets from the GEO database. A total of 215 differentially expressed genes (DEGs) and 78 differentially expressed miRNAs (DEMs) were identified via “Limma” package. 60 DEGs, mainly enriched in abnormal transportation of structure and energy substances, were selected after protein-protein interaction (PPI) network construction, of which 20 were chosen for machine learning after three algorithms (betweenness, closeness, and degree) filtration using Cytoscape. Four overlapping DEGs (ACTN1, CFTR, GCKR, LAMA3) were finally selected as the candidate markers based on three machine-learning approaches (Lasso, random forest, and support vector machine-recursive feature elimination). Furthermore, we collected peripheral blood from MFS patients and healthy control to validate the findings and the results showed that compared with the control, the expression of the four DEGs was all statistically different in MFS patients validated by qRT-PCR. Besides, the area under the receiver operating characteristics curve was greater than 0.8 for each DEG. Single-sample gene-set enrichment analysis showed that the four DEGs were strongly associated with inflammation and myogenesis pathway. Finally, we constructed the mRNA-miRNA network based on the intersection of DEMs and predicted miRNAs targeting DEGs. In conclusion, our study partially provided four potential markers for MFS pathogenesis. Communicated by Ramaswamy H. Sarma

Marfan Syndrome: Enhanced Diagnostic Tools and Follow-up Management Strategies

Marfan syndrome (MFS) is a rare inherited autosomic disorder, which encompasses a variety of systemic manifestations caused by mutations in the Fibrillin-1 encoding gene (FBN1). Cardinal clinical phenotypes of MFS are highly variable in terms of severity, and commonly involve cardiovascular, ocular, and musculoskeletal systems with a wide range of manifestations, such as ascending aorta aneurysms and dissection, mitral valve prolapse, ectopia lentis and long bone overgrowth, respectively. Of note, an accurate and prompt diagnosis is pivotal in order to provide the best treatment to the patients as early as possible. To date, the diagnosis of the syndrome has relied upon a systemic score calculation as well as DNA mutation identification. The aim of this review is to summarize the latest MFS evidence regarding the definition, differences and similarities with other connective tissue pathologies with severe systemic phenotypes (e.g., Autosomal dominant Weill–Marchesani syndrome, Loeys–Dietz syndrome, Ehlers–Danlos syndrome) and clinical assessment. In this regard, the management of MFS requires a multidisciplinary team in order to accurately control the evolution of the most severe and potentially life-threatening complications. Based on recent findings in the literature and our clinical experience, we propose a multidisciplinary approach involving specialists in different clinical fields (i.e., cardiologists, surgeons, ophthalmologists, orthopedics, pneumologists, neurologists, endocrinologists, geneticists, and psychologists) to comprehensively characterize, treat, and manage MFS patients with a personalized medicine approach.

Path analysis of illness uncertainty and psychosocial adaptation of patients with Marfan syndrome.

Marfan syndrome (MFS) is a genetic disorder that causes sudden or chronic cardiovascular problems, which can be fatal. Since MFS patients require regular close medical observation, it is important to understand the factors and pathways associated with psychosocial adaptation to the disease. This study aimed to identify the relationships among illness uncertainty, uncertainty appraisal, and psychosocial adaptation in MFS patients using path analysis. This descriptive cross-sectional survey study was conducted from October 2020 to March 2021, in compliance with STROBE guidelines. Using data from 179 participants aged older than 18 years, we constructed a hypothetical path model to identify determinants of illness uncertainty, uncertainty appraisal, and psychosocial adaptation. In the path analysis, disease severity, illness uncertainty, anxiety, and social support were significant factors influencing MFS patients' psychosocial adaptation. Disease severity and illness uncertainty exerted direct effects, while anxiety and social support exerted both direct and indirect (through illness uncertainty) effects. Finally, anxiety showed the greatest total effect. These findings are useful for enhancing MFS patients' psychosocial adaptation. Medical professionals should focus on managing disease severity, decreasing anxiety, and increasing social support.

Outcomes of aortic root replacement in patients with Marfan syndrome: the role of valve-sparing and valve-replacing approaches.

Marfan syndrome (MFS) is a heritable thoracic aortic disease with pervasive cardiovascular effects, including commonly, a dilated aortic root. Traditionally, the root is replaced using a mechanical composite valve graft (CVG); however, this valve-replacing (VR) approach necessitates a lifelong regimen of anticoagulation with a potential for late bleeding complications. In time, valve-sparing (VS) approaches were developed. Today, several options for aortic root replacement (ARR) exist; each has advantages and disadvantages that helps inform choice. The Aortic Valve Operative Outcomes in Marfan Patients (AVOMP) is a multi-center international registry to analyze clinical outcomes of ARR in MFS patients using either VR or VS techniques to better elucidate choice. We summarize outcomes of AVOMP and present our own experience. We performed 223 consecutive elective ARR [1991-2023] in patients with MFS; 15 such repairs were included in AVOMP. Repairs included 113 (51%) using a mechanical CVG, 62 (28%) using a VS approach, and 48 (22%) using a bioprosthetic root. Many patients underwent aortic arch repair (30% to 54% by type). The median patient age was 38 [29-52] years. In comparing VS and VR groups, patients were similar in age and rates of major comorbidities and symptoms. Patients with VR repair had a more complex aortic history. The rate of redo sternotomy was 24% (n=54). Operative death was uncommon [4% overall (10/223); ranging from 2% to 8% by type], and stroke was rare [1/223 (<1%)]. Late survival and reoperation differed by operative approach; survival was improved in patients who underwent VS repair. We found that repair in patients with MFS undergoing ARR resulted in low operative risk. Our late results were similar to those of AVOMP in that patients undergoing VS repair tended to experience greater rates of valvular-structural deterioration, although this did not appear to impact survival.

Cervical kyphosis correction in Marfan syndrome: our experience and literature review.

Spinal deformities are common in Marfan syndrome (MFS). They usually involve the thoraco-lumbar spine but rarely involves the cervical spine. Kyphosis is the common spine deformity of the cervical spine and mandates surgical correction as they are at risk of neurological deterioration since they are refractory to conservative management. Few studies of surgical correction of spine deformity included cervical deformity. To analyze the challenges faced during surgery, clinical and radiological outcome, and complications following surgical correction for cervical kyphosis in Marfan syndrome. We identified that 5 patients with a diagnosis of MFS with cervical kyphosis who underwent fusion surgery between the years 2010 and 2022 were reviewed, retrospectively. We analyzed the demographic details, radiological parameters, operative variables (blood loss and nuances), perioperative complications, length of stay, clinical and radiological outcome, and complications following fusion surgery for cervical kyphosis in MFS. The mean age of patients was 16.6 ± 4.72years (range, 12-23years). The average kyphotic vertebra involved is 3 ± 0.7 bodies (range 2-4) with 2 patients with thoracic deformity. All patients underwent surgical deformity correction. All patients improved clinically with Nurick grade (pre vs. post: 3.4 vs. 2.2) and mJOA (pre vs. post: 8.2 vs. 12.6). There was significant deformity correction from 37.48° to 9.1°. Mean blood loss encountered was 900 ± 173.2ml. Perioperative complications: wound complication with CSF leak (1). Late complications: ventilator dependence (1) and junctional kyphosis (1). Mean length of hospital stay was 103 ± 178.9days. All patients were doing symptomatically better after mean follow-up of 58 ± 28.32months. One patient is bedridden and hospitalized. Cervical kyphosis is a rare spine deformity in patients with MFS, and they usually present with neurological deterioration mandating surgical correction. Multidisciplinary approach (pediatrics, genetics and cardiology) is required for systematic evaluation of these patients. They should be evaluated with necessary imaging to rule out associated spinal deformity (atlanto-axial subluxation, scoliosis, and intraspinal pathology like ductal ectasia). Our results suggest better surgical outcome in terms of low operative complications with neurologic improvement in MFS patients. These patients require regular follow-up to identify late complications (instrument failure, non-union, and pseudarthrosis).

Reduced Levels of Selenium and Thioredoxin Reductase in the Thoracic Aorta Could Contribute to Aneurysm Formation in Patients with Marfan Syndrome

Marfan syndrome (MFS) is an autosomal dominant disorder caused by a heterozygous mutation of the FBN1 gene. MFS patients present oxidative stress that disturbs redox homeostasis. Redox homeostasis depends in part on the enzymatic antioxidant system, which includes thioredoxin reductase (TrxR) and glutathione peroxidases (GPx), both of which require an adequate concentration of selenium (Se). Therefore, the aim of this study was to determine if Se levels are decreased in the TAA of patients with MFS since this could contribute to the formation of an aneurysm in these patients. The results show that interleukins IL-1β, IL-6 TGF-β1, and TNF-α (p ≤ 0.03), and carbonylation (p ≤ 0.03) were increased in the TAA of patients with MFS in comparison with control subjects, while Se, thiols (p = 0.02), TrxR, and GPx (p ≤ 0.001) were decreased. TLR4 and NOX1 (p ≤ 0.03), MMP9 and MMP2 (p = 0.04) and NOS2 (p &lt; 0.001) were also increased. Therefore, Se concentrations are decreased in the TAA of MFS, which can contribute to a decrease in the activities of TrxR and GPx, and thiol groups. A decrease in the activities of these enzymes can lead to the loss of redox homeostasis, which can, in turn, lead to an increase in the pro-inflammatory interleukins associated with the overexpression of MMP9 and MMP2.

Modified Ravitch procedure for pectus excavatum in Marfan syndrome with annuloaortic ectasia.

This case series aimed to determine the feasibility of simultaneous modified Ravitch and David procedure for Marfan syndrome patients with pectus excavatum and annuloaortic ectasia. Between March 2014 and December 2019, seven consecutive patients underwent simultaneous surgery of modified Ravitch and David procedure for pectus excavatum and annuloaortic ectasia. The completion of cardiac surgery and sternal closure were followed by the modified Ravitch procedure. The bilateral fourth to seventh costal cartilages were resected, the sternal body partially wedge resected, and the sternum raised anteriorly with re-suture. An oblique incision was performed on bilateral third costal cartilages, and they were fixed on top of each other, with the medial end superior and the lateral end inferior. The sternum was raised anteriorly, bypassing the fourth to seventh rib ends through the back of the sternum with threads. The feasibility and safety of the procedure were assessed through a retrospective review of the patients' clinical charts. The total sample had a median age of 28 years, and comprised five males and two females. There was a significant difference in the preoperative and postoperative median Haller index, which were 6.8 and 3.9, respectively. All patients were discharged without serious complications, and there was no significant recurrence of pectus excavatum at 35-92 months postoperatively. The results of our case series suggest the feasibility of one-stage surgery for pectus excavatum combined with cardiac surgery using the modified Ravitch procedure. Future efforts should be tailored for more uneventful postoperative clinical courses.

Opioid Utilization After Scoliosis Surgery is Greater in Marfan Syndrome Than Adolescent Idiopathic Scoliosis.

Retrospective matched case cohort. Compare postoperative opioid utilization and prescribing behaviors between patients with Marfan syndrome (MFS) and adolescent idiopathic scoliosis (AIS) after posterior spinal fusion (PSF). Opioids are an essential component of pain management after PSF. However, due to the potential for opioid use disorder and dependence, current analgesic strategies aim to minimize their use, especially in younger patients. Limited information exists on opioid utilization after PSF for syndromic scoliosis. Twenty adolescents undergoing PSF with MFS were matched with patients with AIS (ratio, 1:2) by age, sex, degree of spinal deformity, and the number of vertebral levels fused. Inpatient and outpatient pharmaceutical data were reviewed for the quantity and duration of opioid and adjunct medications. Prescriptions were converted to morphine milligram equivalents (MMEs) using CDC's standard conversion factor. Compared with patients with AIS, patients with MFS had significantly greater total inpatient MME use (4.9 vs . 2.1 mg/kg, P ≤ 0.001) and longer duration of intravenous patient-controlled anesthesia (3.4 vs . 2.5 d, P = 0.001). Within the first 2 postop days, MFS patients had more patient-controlled anesthesia boluses (91 vs . 52 boluses, P = 0.01) despite similar pain scores and greater use of adjunct medications. After accounting for prior opioid use, MFS was the only significant predictor of requesting an opioid prescription after discharge (odds ratio: 4.1, 95% CI: 1.1-14.9, P = 0.03). Patients with MFS were also more likely to be discharged with a more potent prescription (1.0 vs . 0.72 MME per day/kg, P ≤ 0.001) and to receive a longer-duration prescription (13 vs . 8 d, P = 0.005) with a greater MME/kg (11.6 vs . 5.6 mg/kg, P ≤ 0.001) as outpatients. Despite a similar intervention, patients with MFS and AIS seem to differ in their postoperative opioid usage after PSF, presenting an opportunity for further research to assist clinicians in better anticipating the analgesic needs of individual patients, particularly in light of the ongoing opioid epidemic.

Analysis of GPR126 polymorphisms and their relationship with scoliosis in Marfan syndrome and Marfan-like syndrome in Mexican patients.

Marfan syndrome (MFS) is an inherited connective tissue disorder. As the spinal growth depends on delicate balance of forces, conditions that affect musculoskeletal matrix often lead to spinal deformities. A large cross-sectional study revealed a 63% prevalence of scoliosis among patients with MFS. Multi-ethnic genome-wide association studies and analyses of human genetic mutations showed that variations and mutations of G protein-coupled receptor 126 (GPR126)locus are associated with multiple skeletal defects, including shorter stature and adolescent idiopathic scoliosis. The study included 54 patients with MFS and 196 control patients. The DNA was extracted from peripheral blood using the saline expulsion method and single nucleotide polymorphism (SNP) determination was carried out using TaqMan probes. Allelic discrimination was performed by RT-qPCR. Significant differences in genotype frequencies were found for SNP rs6570507 in relation to MFS and sex (recessive model, OR 2.46, 95% CI 1.03 -5.87; P = 0.03) and rs7755109 (overdominant model, OR 0.39, 95% CI 0.16-0.91; P = 0.03). The most significant association was found in SNP rs7755109, where the frequency of genotype AG was significantly different between MFS patients with scoliosis and those without (OR 5.68, 95% CI 1.09-29.48; P=0.04). This study, for the first time, examined the genetic association of SNP GPR126 with the risk of scoliosis in patients with connective tissue diseases. The study revealed that SNP rs7755109 is associated with the presence of scoliosis in Mexican patients with MFS.

Predicting axial length in patients with Marfan syndrome and ectopia lentis after modified capsular tension ring and intraocular lens implantation.

To predict the growth of axial length (AL) in patients with Marfan syndrome (MFS) and ectopia lentis (EL). Eye and ENT Hospital of Fudan University, Shanghai, China. Consecutive retrospective case series. Eyes were evaluated that had modified capsular tension ring and intraocular lens implantation. The rate of axial length growth (RALG) was calculated using AL divided by log10-transformed age. A multivariable linear regression model of RALG was developed after validation. A total of 128 patients with Marfan syndrome (MFS) and EL were enrolled with a median follow-up duration of about three years. RALG was independent of age between 3 to 15 years old (P = 0.799) and decreased to zero thereafter (P = 0.878). Preoperative AL was associated with RALG in patients under 15 years old (P = 0.003). Beta values for the final model of RALG were as below: intercept (-9.794) and pre-operative AL (0.664). The postoperative AL was predicted as: postAL = preAL + RALG × log10((postAge + 0.6) / (preAge + 0.6)). The mean prediction error was -0.003 (95%CI, -0.386, 0.3791) mm and the mean absolute percentage error was 1.93% (95%CI, 0.73%, 3.14%). A Python-based calculator was developed to use the predicted AL in selecting IOL power and setting undercorrection. The AL growth of patients with MFS followed a logarithmic pattern and ceased at about age 15. A prediction model of postoperative AL was established for individual MFS patients between 3-15 years old, which could potentially optimize the IOL power selection.