Search Results (140)

Marfan syndrome (MFS) is a genetic disorder caused by mutations in the fibrillin-1 (Fbn1) gene, leading to structurally abnormal elastic fibers and diverse clinical manifestations. Aortic root dilation represents the most serious threat, often requiring prophylactic surgical repair. Emerging evidence suggests that MFS patients experience increased pain sensitivity, contributing to functional impairment and reduced quality of life. Here, we used C57BL/6 wild-type and Fbn1^C1041G/+ (MFS) mice to examine brain transcriptomics, aortic histology, nociceptive behaviors, grip strength, and spinal cord gene expression in both sexes at 2, 4, 6, 8, and 16 months of age. Transcriptomic analysis revealed reduced activation of pain-related pathways in young males and aged females, with a reversal in aged males, suggesting age- and sex-dependent differences in pain modulation. Behavioral testing showed progressive mechanical and thermal hypersensitivity in MFS mice, with cold allodynia as the earliest manifestation with late-onset muscle weakness. In the spinal cord of 16-month-old MFS mice, increased expression of key excitatory and nociceptive markers was observed, consistent with the pain hypersensitivity phenotype. In addition, aged female MFS mice exhibited elevated spinal expression of pro-inflammatory cytokines, inducible nitric oxide synthase, and Nox4, whereas males showed increased transforming growth factor-β1 and Nox1, reflecting distinct inflammatory and oxidative stress profiles. These findings demonstrate that Fbn1^C1041G/+ mice reproduce pain hypersensitivity and muscle deficits observed in MFS patients, supporting their use as a preclinical model. Our results suggest that enhanced spinal excitatory/nociceptive signaling, together with neuroinflammation and oxidative stress, contributes to sex- and age-specific pain mechanisms in MFS. Full article

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect, and its complications (namely, dilatation of the thoracic ascending aorta) raise concerns regarding the proper timing of aortic surgery. The study aim is to unravel the genetic basis of BAV and its complications through a high-throughput sequencing (HTS) approach and segregation analysis if family members were available. Methods: Fifty-two Italian BAV patients were analyzed by HTS using the Illumina MiSeq platform. Targeted sequencing of 97 genes known to be or plausibly associated with connective tissue disorders or aorthopathy was performed. Thirty-five first-degree relatives of N = 10 probands underwent mutational screening for variants identified in the index cases. Results: HTS identified 194 rare (MAF < 0.01) variants in 63 genes. Regarding previously reported genes, five NOTCH1 variants in four BAV patients, four FBN1 variants in two patients and one GATA5 variant in one patient were identified. Interestingly, among further loci, the possible contribution of PDIA2, LRP1 and CAPN2 was suggested by (a) the increased prevalence of rare genetic variants, independently from their ACMG classification in the whole BAV cohort, and (b) segregation analyses of variants identified in family members. Moreover, the present data also suggest the possible contribution of rare variants to BAV complications, specifically MYLK in aortic dilatation, CAPN2 in BAV calcification and VHL and AGGF1 in valve stenosis. Conclusions: Our results underline clinical and genetic diagnosis complexity in traits considered monogenic, such as BAV, but characterized by variability in disease phenotypic expression (incomplete penetrance), as well as the contribution of different major and modifier genes to the development of complications. Full article

Background: Marfan syndrome is an autosomal dominant connective tissue disorder that affects multiple organ systems, with cardiovascular complications posing a major risk. With advancements in medical care and the increasing lifespan of patients with Marfan syndrome, the spectrum of medical issues has evolved. This case report highlights the complex anaesthetic management of a patient with Marfan syndrome during elective ventral hernia repair. Case presentation: A 37-year-old male with Marfan syndrome was admitted for elective open ventral hernia repair. Challenges included severe arterial hypertension, prior aortic valve replacement, scoliosis, and an anticipated difficult airway, as the patient presented with restricted mouth opening due to craniofacial abnormalities consistent with difficult laryngoscopy. Preoperative assessments included routine tests, echocardiography and chest X-ray. The anaesthetic management focused on specific patient positioning with head-up tilt, maintenance of haemodynamic stability with the insertion of an arterial line before the induction of anaesthesia and neuromuscular block (NMB) monitoring, followed by titrated doses of all medications. Lung ventilation strategies were specifically adjusted to address the patient’s underlying comorbidities. The patient was extubated and transferred to the recovery unit. The intraoperative and immediate postoperative periods were relatively uneventful. Dyspnea due to external pressure on the abdominal wall caused by a specific binder was treated with the release of pressure. Later postoperative recovery was complicated by hydrothorax and pneumonia, both treated successfully. Conclusions: This case emphasises the importance of multidisciplinary approaches and vigilant monitoring in the management of a patient with Marfan syndrome perioperatively, even for seemingly low-risk operations. Appropriate anaesthetic management helped to avoid major perioperative complications. Full article

Pectus excavatum (PE) is the most frequent chest wall deformity, representing 65–95% of all cases, with an estimated prevalence of up to 1 in 300 births. Despite its frequency, it remains underrecognized in sports cardiology. PE results from sternal depression and narrowing of the anterior chest, which may lead to cardiac compression, impaired diastolic filling, and reduced stroke volume during exercise. Consequently, athletes with PE often present with cardiovascular symptoms such as exercise-induced dyspnoea, chest pain, palpitations, presyncope, or reduced physical fitness. Electrocardiographic changes, including right bundle branch block, axis deviation, atrial enlargement, T-wave inversion, QS complexes or Brugada phenocopies, are frequent and may mimic serious cardiovascular conditions, complicating pre-participation screening. Furthermore, PE is associated with potentially high-risk conditions including mitral valve prolapse, ventricular arrhythmias, and connective tissue disorders such as Marfan syndrome, which carry implications for sports eligibility and safety. Assessment of athletes with PE requires multimodal imaging (echocardiography, computed tomography, magnetic resonance), cardiopulmonary exercise testing, and exclusion of concomitant cardiovascular disease. Treatment strategies range from conservative approaches (physiotherapy, vacuum bell therapy) to surgical correction, most commonly with the Nuss procedure, which can improve cardiac function, exercise capacity, and quality of life. Management should involve shared decision making between clinicians, athletes, and families, weighing potential risks against athletic aspirations. Awareness of PE in sports cardiology is crucial, as it not only influences differential diagnosis and screening outcomes but also impacts career decisions and the psychological well-being of athletes. Full article

Congenital genetic heart defects are major contributors to pediatric morbidity and mortality, underscoring the importance of early detection and individualized therapeutic strategies. This review aimed to summarize current knowledge on a spectrum of inherited cardiovascular disorders, with a focus on their genetic etiology, molecular pathogenesis, and phenotypic presentation in children. Conditions discussed include Marfan syndrome, Noonan syndrome, various cardiomyopathies, Duchenne muscular dystrophy, DiGeorge syndrome, and the tetralogy of Fallot. These six conditions were selected to represent the spectrum of pediatric cardiovascular genetic diseases, encompassing connective tissue disorders, multisystem syndromes, primary myocardial diseases, neuromuscular cardiac involvement, and structural congenital defects, thereby illustrating how distinct genotypes lead to diverse phenotypes. For each disorder, the underlying genetic mutations, associated molecular pathways, cardiovascular involvement, clinical features, and approaches to diagnosis and management are examined. Emphasis is placed on the role of timely diagnosis, genetic counseling, and personalized treatment in improving patient outcomes. The review concludes by highlighting emerging research directions and novel therapeutic interventions aimed at enhancing care for these complex pediatric conditions. Full article

Pulse wave velocity (PWV) is a key marker of aortic stiffness and cardiovascular risk, yet current methods typically offer only global or regional estimates and lack the possibility to measure local variations along the thoracic aorta. This study aimed to develop and evaluate a pipeline for assessing local aortic PWV using the flow–area (QA) method (PWV_QA) by combining high-resolution 4D MRI techniques. A 3D cine balanced steady-state free precession (bSSFP) sequence was used to capture dynamic changes in aortic geometry, while 4D flow MRI measured time-resolved blood flow. The QA method was applied during the reflection-free early systolic phase. Scan–rescan reproducibility was assessed in six healthy volunteers, and feasibility was additionally explored in Marfan syndrome patients. The mean ± SD values of the Pearson correlation coefficients for per-slice maximum area, velocity, flow, and PWV_QA were 0.99 ± 0.00, 0.82 ± 0.11, 0.96 ± 0.01, and 0.20 ± 0.35, respectively. The median (Q1–Q3) average PWV_QA was 6.6 (5.4–9.4) m/s for scan 1 and 9.1 (6.7–11.3) m/s for scan 2 (p = 0.16) in healthy volunteers and 7.1 (6.9–8.0) m/s in Marfan patients. Combining 4D bSSFP and 4D flow MRI is technically feasible, but the derived PWV_QA maps show high variability, particularly in the aortic root and descending aorta, requiring further optimization. Full article

Background/Objectives: The primary aim of this study was to describe all cases of fetal hemivertebrae diagnosed prenatally at the Hospital Clínico Universitario de Salamanca over the last 15 years. Additionally, the presence of associated malformations was assessed, pregnancy outcomes were evaluated, and child development results were analyzed in affected cases. Methods: We undertook a prospective observational analysis of all cases (N = 10) of prenatally diagnosed hemivertebrae at our hospital between 2007 and 2022. Postnatal follow-up was performed through telephone interviews and reviewing medical records. Results: Most cases were diagnosed during the second-trimester ultrasound, with the lumbar region being the most frequently affected site (60%). Multiple hemivertebrae were detected in 4 of 10 cases. One case of Marfan syndrome and two cases of VACTERL association (vertebral defects, anal atresia, tracheoesophageal fistula, renal dysplasia, and limb abnormalities) were documented. Six cases presented with additional malformations. Cases involving multiple hemivertebrae (40%) were more likely to be associated with other anomalies and poorer prognoses, while isolated single hemivertebra showed favorable outcomes, with normal development during childhood. Vaginal delivery occurred in six cases, while cesarean sections were performed for standard obstetric indications unrelated to the hemivertebra diagnosis. Conclusions: Prenatal diagnosis of hemivertebra is achievable and holds critical neonatal and postnatal relevance. Hemivertebrae are often linked to additional disorders, including genetic syndromes, and carry significant prognostic implications depending on the associated anomalies and the extent of vertebral involvement. Full article

Background/Objectives: The etiology of congenital diaphragmatic hernia (CDH) remains unknown in over 50% of cases, although multiple heterogeneous causative defects have been identified. Emerging evidence suggests that specific genes and molecular pathways involved in connective tissue biology may contribute to CDH development. Associations between CDH and connective tissue disorders have been reported, including cases in Marfan syndrome and a prevalence of CDH in 34% of patients with arterial tortuosity syndrome. Noticing joint laxity in several CDH patients, we aimed to investigate the presence of genetic variants linked to connective tissue disorders in this subgroup, focusing on patients enrolled in the follow-up program at Bambino Gesù Children’s Hospital. Methods: We selected patients diagnosed with CDH who also exhibited joint laxity based on a positive Beighton scale. These individuals underwent molecular analysis targeting genes known to be associated with heritable connective tissue disorders. Results: Genetic testing revealed variants in several genes across our patient series. These included mutations in FBN1, FBN2, ZNF469, VEGFA, NOTCH1, ELN, MCTP2, and SMAD6. In some cases, the variants were inherited paternally, while others appeared de novo. Most of these variants were classified as of unknown significance according to ACMG guidelines. Conclusions: (1) Several “variants of unknown significance” in different genes causative for connective tissue disorders have been detected in half of the present series of patients with CDH and joint laxity; (2) although the majority of the variants are classified accordingly to the ACMG as “variants of unknown significance”, a role of predisposition or susceptibility to CDH cannot be excluded; (3) a precise clinical evaluation for features of connective disorders should be recommended in the diagnostic workflow of patients with CDH. Full article

Background/Objectives: Fatigue is a highly prevalent and burdensome symptom among individuals with Marfan syndrome (MFS), yet its heterogeneity and underlying psychosocial and clinical correlates remain underexplored. This study aimed to identify and characterize distinct fatigue-related profiles in MFS patients using a data-driven cluster analysis approach. Methods: A cross-sectional study was conducted involving 127 patients with MFS from a specialized connective tissue disorder center in Italy. Participants completed self-reported measures of fatigue severity (Fatigue Severity Scale, FSS), depressive symptoms (Patient Health Questionnaire-9, PHQ-9), and insomnia (Insomnia Severity Index, ISI). The body mass index (BMI) and clinical data were also collected. A t-distributed stochastic neighbor embedding (t-SNE) analysis was performed to reduce dimensionality, followed by hierarchical clustering (Ward’s method), exploring solutions from k = 2 to k = 10. The optimal cluster solution was identified based on silhouette scores and clinical interpretability. Results: Three distinct clusters emerged: (1) a cluster characterized by low fatigue with minimal psychological and sleep-related symptoms (younger patients, lower PHQ-9 and ISI scores), (2) a cluster characterized by moderate fatigue with moderate psychological and sleep-related symptoms (intermediate age, moderate PHQ-9 and ISI scores), and (3) a cluster characterized by high fatigue with elevated psychological and sleep-related symptoms (older patients, higher PHQ-9, ISI, and FSS scores). Significant differences were observed across clusters in age, BMI, depressive symptoms, insomnia severity, and fatigue levels (all p < 0.05). Conclusions: Our findings highlight the heterogeneity of fatigue experiences in MFS and suggest the importance of profiling patients to guide personalized interventions. This approach may inform precision medicine strategies and enhance the quality of life for individuals with this rare disease. Full article

Autosomal recessive types of both syndromic and non-syndromic inherited myopia are common in Saudi Arabia (SA) because many people marry their relatives. The prevalence of syndromic myopathies in SA, like Stickler syndrome (SS), Knobloch syndrome (KS), and Marfan syndrome (MFS), further complicates the disease spectrum. The causative genes linked to the Knobloch, Marfan, and Pierson syndromes are COL18A1, FBN1, and LAMB2, respectively. Additionally, we found recessive types of non-syndromic high myopia that have a high chance of causing retinal detachment, like those linked to LRPAP1 and LEPREL1. In these cases, regular evaluation and early intervention, including prophylactic laser photocoagulation and pars plana vitrectomy, may improve the outcome. Advancements in genetic testing for diagnosis and prevention accelerate detection, facilitate early interventions, and provide genetic counseling. The utilization of artificial intelligence (AI), machine learning (ML), and the advancement of gene therapy offer promising avenues for personalized care. We place a high value on using genetic knowledge to create a national screening program and patient registry aimed at understanding the national burden of myopia, knowing that we have a high rate of consanguinity, which reflects pathogenic homozygous alleles and founder mutations. This initiative will incorporate genetic counseling and leverage innovative technologies, which are crucial for disease management, early identification, and prevention in Saudi Arabia’s healthcare system. Full article

Background: The PATHFINDER-CHD Registry is a prospective, multicenter, non-interventional registry across tertiary care centers in Germany. The aim is to analyze real-world data on adults with congenital heart defects (ACHD) or hereditary connective tissue disorders who have manifest heart failure (HF), a history of HF, or are at significant risk of developing HF. This analysis investigates the prevalence and clinical impact of overweight and obesity in this unique population. Methods: As of 1st February, 2025, a total of 1490 ACHD had been enrolled. The mean age was 39.4 ± 12.4 years, and 47.9% were female. Patients were categorized according to Perloff’s functional class and the Munich Heart Failure Classification for Congenital Heart Disease (MUC-HF-Class). Results: The most common congenital heart disease (CHD) in this cohort was Tetralogy of Fallot, transposition of the great arteries, and congenital aortic valve disease. Marfan syndrome was the most common hereditary connective tissue disease. Of the patients, 46.1% were classified as overweight (32.8%) or obese (13.3%), while 4.8% were underweight. The highest prevalence of overweight (47.1%) was observed among patients who had undergone palliative surgery, whereas untreated patients showed the highest proportion of normal weight (57.2%). Cyanotic patients were predominantly of normal weight. Patients with univentricular circulation exhibited significantly lower rates of overweight and obesity (35%; p = 0.001). Overweight and obesity were statistically significantly associated with arterial hypertension, diabetes mellitus, and sleep apnea (all p < 0.001). High BMI was linked to increased use of HF-specific medications, including SGLT2 inhibitors (p = 0.040), diuretics (p = 0.014), and angiotensin receptor blockers (p = 0.005). Conclusions: The data highlight the clinical relevance of overweight and obesity in ACHD with HF, emphasizing the need for individualized prevention and treatment strategies. The registry serves as a critical foundation for the optimization of long-term care in this population. Full article

Mitral annular calcification (MAC) is usually considered an incidental, benign, age-related finding without serious complications in patients evaluated for cardiovascular or pulmonary disease with imaging studies that may result in mitral regurgitation or stenosis when severe. Therefore, it is usually not considered a significant alteration. However, there is accumulating evidence that it is associated with a higher risk of cardiovascular events, such as atherosclerotic coronary artery disease, aortic artery disease, carotid artery disease, peripheral artery disease, stroke, atrial fibrillation, atrioventricular and/or intraventricular conduction disturbance, systemic embolization, infective endocarditis, heart failure and mortality. The presence of MAC also significantly influences the outcome of mitral valve transcatheter and surgical interventions. Several conditions may predispose to MAC. MAC is strongly related to cardiovascular risk factors, such as hypertension, diabetes, smoking and cardiovascular atherosclerosis, and inflammation may also play a role in the pathogenesis of MAC. Also, conditions that increase mitral valve stress, such as hypertension, aortic stenosis and hypertrophic cardiomyopathy, predispose to accelerated degenerative calcification of the mitral annulus area. Congenital disorders, e.g., Marfan syndrome and Hurler syndrome, are also associated with MAC, due to an intrinsic abnormality of the connective tissue composing the annulus. Full article

Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of ACTA2^R179H and TGFBR2^G357W in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD⁺ precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy. Full article

Marfan syndrome is caused by a mutation in the FBN1 gene encoding fibrillin-1. This extracellular matrix glycoprotein, which assembles into microfibrils, is best known for its scaffolding role in the production of elastic fibers responsible for connective tissue elasticity and tensile strength. Research into Marfan syndrome mainly focuses on the pathophysiology involved in the degeneration of elastin-rich elastic fibers, which are essential components of the aortic wall. However, fibrillin-1 also exists in elastin-poor (elaunin) or elastin-free (oxytalan) microfibril bundles that were first described in the periodontal ligament (PDL). This dynamic, densely cellular, and highly vascularized tissue anchors teeth in their bone sockets and acts as a protective shock absorber during chewing. Current knowledge suggests that fibrillin microfibrils mechanically support blood vessels in the PDL and ensure their proper functioning. However, many more insights on the roles of fibrillin, especially independently of elastin, can be extracted from this tissue. Here, we review the phenotypic and functional characteristics of the PDL in connection with fibrillin-1, focusing on those related to microvessels. This review aims to shed light on this often-overlooked fibrillin-rich resource as a model for future studies investigating fibrillin functions in health and Marfan disease. Full article

Thoracic aortic aneurysms (TAAs) pose a significant health burden due to their asymptomatic progression, often culminating in life-threatening aortic rupture, and due to the lack of effective pharmacological treatments. Risk factors include elevated hemodynamic stress on the ascending aorta, frequently associated with hypertension and hereditary genetic mutations. Among the hereditary causes, Marfan syndrome is the most prevalent, characterized as a connective tissue disorder driven by FBN1 mutations that lead to life-threatening thoracic aortic ruptures. Similarly, mutations affecting the TGF-β pathway underlie Loeys–Dietz syndrome, while mutations in genes encoding extracellular or contractile apparatus proteins, such as ACTA2, are linked to non-syndromic familial TAA. Despite differences in genetic origin, these hereditary conditions share central pathophysiological features, including aortic medial degeneration, smooth muscle cell dysfunction, and extracellular remodeling, which collectively weaken the aortic wall. Recent evidence highlights mitochondrial dysfunction as a crucial contributor to aneurysm formation in Marfan syndrome. Disruption of the extracellular matrix–mitochondrial homeostasis axis exacerbates aortic wall remodeling, further promoting aneurysm development. Beyond its structural role in maintaining vascular integrity, the ECM plays a pivotal role in supporting mitochondrial function. This intricate relationship between extracellular matrix integrity and mitochondrial homeostasis reveals a novel dimension of TAA pathophysiology, extending beyond established paradigms of extracellular matrix remodeling and smooth muscle cell dysfunction. This review summarizes mitochondrial dysfunction as a potential unifying mechanism in hereditary TAA and explores how understanding mitochondrial dysfunction, in conjunction with established mechanisms of TAA pathogenesis, opens new avenues for developing targeted treatments to address these life-threatening conditions. Mitochondrial boosters could represent a new clinical opportunity for patients with hereditary TAA. Full article