Search Results (153)

Background and Clinical Significance: Marfan syndrome (MFS) is an autosomal-dominant connective-tissue disorder caused by pathogenic FBN1 variants. Aortic-root dilation and dissection are the canonical complications, whereas spontaneous vertebral artery dissection (VAD) is described only sporadically. Yet, cerebrovascular events are several-fold more common in MFS, and up to 74% of patients exhibit increased vertebral artery tortuosity, a validated predictor of dissection; Case Presentation: A 32-year-old African man with hypertension, type 2 diabetes mellitus, tobacco use, and headaches labelled as migraine presented with acute agitation, visual disturbance, vertigo, dysarthria, and right-sided weakness of two hours’ duration. Examination disclosed previously unrecognised marfanoid stigmata: arachnodactyly with positive wrist and thumb signs, reduced upper-to-lower segment ratio, increased arm-span-to-height ratio, dolichocephaly, pectus excavatum, and a high-arched palate. Non-contrast CT showed left occipital and posterior inferior cerebellar hypodensities. CT angiography demonstrated discontinuous intraluminal filling defects in the left vertebral artery at C4 and C2, and MR angiography confirmed long-segment occlusion/stenosis of the intracranial left vertebral artery. Echocardiography revealed mild aortic-root dilation (4.0 cm; Z-score +2.53) and a small patent foramen ovale (PFO) with a positive bubble study. The patient received intravenous thrombolysis followed by antiplatelet therapy, a high-intensity statin, antihypertensive therapy, and intensified glycaemic control. Because the infarct territory matched the dissected vessel and the small PFO carried no high-risk features (RoPE score 6; PASCAL category “unlikely”), VAD was designated the culprit lesion and the PFO incidental; Conclusions: Spontaneous VAD may be the inaugural manifestation of unrecognised MFS, antedating aortic complications. In young adults with cryptogenic posterior-circulation stroke and marfanoid features, early cervical imaging and Ghent assessment are warranted, and a coexistent PFO should not be assumed causal. Multidisciplinary evaluation supports accurate attribution and surveillance. Full article

Background: Heritable thoracic aortic disease (HTAD) encompass a heterogeneous spectrum of conditions characterized by increased susceptibility to developing thoracic aortic aneurysm and life-threatening complications, including aortic dissection and rupture. Despite distinct underlying mechanisms involving extracellular matrix integrity, vascular smooth muscle cell function, and dysregulation of signaling pathways, these disorders converge on a shared vulnerability of the aortic wall. Although acute events typically occur in adulthood, the disease process often begins early in life, making HTAD highly relevant in pediatric practice, where early recognition and longitudinal management are essential. Aims: This narrative review provides a biology- and genetics-oriented, translational complement to current consensus recommendations, framing pediatric HTAD as a developmentally shaped disorder of the aortic wall in which genotype increasingly informs diagnosis, surveillance, and treatment. Methods: Relevant studies were identified through a comprehensive PubMed search, with particular focus on pathogenic mechanisms, current clinical guidelines, follow-up strategies and emerging genetic perspectives. Results: Genetic testing is emerging as a key tool for the management of HTAD, although its clinical utility remains limited by provisional genotype–phenotype correlations and inconclusive results. Current risk stratification is still mainly based on aortic diameter surveillance, while pharmacological strategies are predominantly extrapolated from Marfan syndrome trials, highlighting important gaps in evidence. Conclusions: Genetic advances are expanding management opportunities in HTAD, but their clinical translation remains challenging. Disease-specific risk models integrating genetic and clinical data may improve individualized risk stratification, treatment strategies and clinical outcomes. Full article

Marfan syndrome (MFS) is characterized by progressive aortic aneurysm formation resulting from mutations in the fibrillin-1 (Fbn1) gene. Although the thoracic aorta is the primary site of pathology, accumulating evidence indicates that vascular dysfunction in MFS extends beyond the aorta to involve multiple arterial beds. Statins have been shown to attenuate aneurysm progression in experimental models of MFS; however, their effects on systemic vascular remodeling and arterial stiffness outside the aorta remain poorly characterized. In this study, we investigated the impact of chronic atorvastatin therapy on vascular structure and hemodynamic function across multiple vascular beds in the Fbn1^C1041G/+^ mouse model of MFS. Male and female control and MFS mice received drinking water with or without atorvastatin (1 g/kg/day) from 4 weeks to 6 months of age, enabling the effects of atorvastatin to be assessed in both healthy and MFS arteries. High-frequency ultrasound imaging was used to assess vascular parameters in the aorta, left common carotid artery (LCCA), and posterior cerebral artery (PCA). Atorvastatin treatment significantly attenuated aortic root dilation in both male and female MFS mice and reduced aortic pulse wave velocity (PWV), indicating improved arterial compliance. In the carotid circulation, atorvastatin significantly reduced LCCA wall thickness and carotid PWV, although carotid wall strain did not improve. Atorvastatin raised both systolic and diastolic blood pressure in male and female MFS mice relative to untreated MFS animals, reaching levels not significantly different from untreated controls in both sexes, while having little effect in healthy controls apart from a rise in female diastolic pressure. In the posterior cerebral artery, peak systolic velocity, a hemodynamic index rather than a direct measure of perfusion, showed similarly sex-dependent changes, increasing in female MFS mice but decreasing further in males after atorvastatin. Collectively, these findings demonstrate that atorvastatin exerts systemic but heterogeneous vascular effects in MFS, improving arterial stiffness and structural remodeling across multiple arterial beds while producing sex-specific hemodynamic responses that warrant further investigation. Full article

Heritable thoracic aortic diseases (HTADs) comprise a genetically heterogeneous group of disorders predisposing patients to thoracic aortic aneurysm and dissection, yet current medical therapies remain limited to slowing disease progression rather than preventing aortic wall failure. Although pathogenic variants affect diverse genes encoding extracellular matrix (ECM) components, smooth muscle contractile proteins, and signaling molecules, these defects converge on disruption of the mechanobiological systems that maintain aortic wall integrity. The thoracic aorta functions as a mechanically integrated tissue in which endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells and ECM continuously sense and respond to pulsatile biomechanical forces. Genetic perturbations affecting ECM architecture, contractile force generation, or growth factor signaling alter force transmission across this multicellular network, leading to maladaptive mechanotransduction, cellular phenotypic modulation, and progressive aneurysm formation. Using Marfan syndrome as a paradigmatic ECM-driven aortic disease, this review synthesizes current understanding of how altered biomechanics, biochemical signaling and immune responses reshape intercellular communication and activate disease-associated signaling pathways, including dysregulated TGF-β, nitric oxide, angiotensin receptor, calcium-dependent, and metabolic signaling. We highlight how single-cell transcriptomic analyses have elaborated changes in different cell-level functions including, ECM degradation, iron homeostasis, circadian/stress responses. Changes in iron metabolism in different cell types in the aorta suggest possible coordinated metabolic changes in aneurysm progression. These mechanistic insights enable the identification of cell-type–specific pathogenic programs and therapeutic discovery through systems-level approaches. We highlight the translational opportunities and challenges emerging from mouse models and human studies, emphasizing that therapeutic efficacy depends not only on pathway selection but also on disease stage, cellular context, and timing of intervention. Together, these findings support a model in which HTAD progression reflects dynamic, multicellular failure of mechanobiological homeostasis and provide a framework for the development of more precise, mechanism-based therapies. Full article

Background: Marfan syndrome (MFS) is a connective tissue disorder caused by FBN1 mutations, leading to elastic fiber disarray and early thoracic aortic aneurysm (TAA) formation. Currently, pharmacological treatments lack specificity and only delay progression. We previously reported a specific TGFβ-driven miR-632 upregulation in MFS TAA tissues and blood causing smooth muscle cell dedifferentiation and aortic wall degeneration. This study evaluated the effects of three conventional antihypertensive drugs (β-blocker, ACE inhibitor, and sartan) on parietal remodeling, comparing them with a miR-632 inhibitor in an ex vivo TGFβ1-induced model of MFS TAA. Methods and Results: Using an ex vivo paired experimental framework based on independent biological pools of human TAA tissue, gene expression and Western blot analyses demonstrated that only losartan significantly reduced miR-632 and vascular degeneration markers. Notably, combined treatment with ramipril and carvedilol compromised losartan’s efficacy, highlighting the need for careful therapeutic selection. In this ex vivo setting, miR-632 inhibition demonstrated a promising capacity to counteract aortic remodeling, serving as a mechanistic proof-of-concept that warrants further preclinical in vivo validation. Conclusions: Our data emphasize that choosing the right treatment in MFS aortopathy requires understanding its specific impact on cellular pathways. Our findings identify losartan as the most effective standard drug in this model, while suggesting miR-632 as a potential future target to stabilize the aortic wall and, prospectively, delay surgery. Full article

Marfan syndrome (MS), Loeys–Dietz syndrome (LDS), Beals–Hecht syndrome (BHS), Ehlers–Danlos syndrome (EDS), and individuals with undifferentiated connective tissue disease (UCTD) exhibit phenotypic overlap, suggesting a likelihood of genotypic coexistence. Our objective was to evaluate genetic variants (GVs), encoding 174 genes related to aortopathies, cardiomyopathies, arrhythmias, structural heart disease, and hypercholesterolemia, and their relationship to clinical and cardiovascular damage in these syndromes. This was a prospective study in Mexican patients with MS, LDS, EDS, BHS, and UCTD. One hundred and seventy-four genes related to hereditary diseases were studied using next-generation sequencing targeting coding regions. Of the 136 patients, 25 were identified with the recurrent and coexisting GV of MYBPC3. In the MS group, in addition to the presence of GV in FBN1, eight patients had GV in MYBPC3, six in FBN2, and five in COL3A1 and COL5A1. In the LDS group, in addition to GV in TGFBR1, TGFBR2, and SMAD3, four patients presented with GV in MYBPC3 and two with FBN2. In the BHS group, in addition to FBN2, two patients had GV in MYBPC3 and one with TGFBR2. In the UCTD group, nine patients had GV in MYBPC3 and two in COL5A1 and COL5A2. All syndromes coexisted with GV in genes related to arrhythmias, sarcomeres, and hypercholesterolemia. In EDS, coexistence with several sarcomere proteins was found. Full article

Heritable thoracic aortic diseases (HTAD) are inherited conditions that increase the risk of thoracic aortic aneurysms, dissections, and premature aortic rupture. Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based view involving extracellular matrix (ECM) architecture, transforming growth factor-β (TGFβ) signaling, and vascular smooth muscle cell contractility. Marfan syndrome, Loeys–Dietz syndrome, and nonsyndromic HTAD demonstrate how genetic mutations can disrupt the components that stabilize the aortic wall. These pathogenic mechanisms influence matrix organization, intracellular signaling, and the contractile machinery within the mechanically stressed proximal aorta. In this review, we summarize current mechanistic insights into the major forms of HTAD and discuss how new molecular and cellular concepts could influence surveillance, genetic counseling, and genotype-guided therapeutic strategies. Full article

Bicuspid aortic valve (BAV) is one of the most common congenital heart defects, introducing significant hemodynamic disturbances to the circulatory system. This narrative review analyzed articles published between 2012 and 2025 and indexed in PubMed. The aim was to synthesize key information on the etiopathogenesis of BAV, its potential complications and associated risks, as well as available pharmacological and surgical treatment strategies, with emphasis on indications and contraindications for specific surgical techniques. Analyses demonstrate that isolated BAV with typical valvular aortopathy is associated with a more favorable prognosis compared to valvular aortopathy syndromes. Valve phenotype shows important sex-related relationships in its presentation and progression. From a hemodynamic perspective, BAV alters blood flow angles, which may contribute to weakening of the aortic wall and secondary valve changes. BAV is also frequently associated with genetic disorders such as Marfan syndrome. The heterogeneity of aortopathies linked to BAV creates significant challenges for echocardiographers, cardiologists and cardiac surgeons, particularly in determining the optimal timing and strategy for surgical intervention. Full article

Objectives: Several measurement techniques have been proposed to address the non-circular geometry of the aortic root. The Laplace diameter metric incorporates the cloverleaf anatomy of the aortic root and is derived via measurement of sinus-to-commissure lengths with subsequent doubling of the largest radius from the center. This study compares the conventional sinus-to-sinus with the novel Laplace method for sizing the aortic root and quantifying its implication on surgical decision-making. Methods: Patients undergoing surveillance at a high-volume aortic center were categorized by aortic root morphology as nondilated, non-syndromic dilated, bicuspid aortic valve and Marfan syndrome. Aortic root diameters by sinus-to-sinus and Laplace diameter methods were measured on computed tomography, compared using paired t-tests, and correlated using Spearman rank coefficients. Results: Of the 1297 patients assessed, 530 were included in the final analysis (nondilated n = 113, non-syndromic dilated n = 347, bicuspid aortic valve n = 50, Marfan syndrome n = 17). Aortic root diameters were significantly larger by Laplace than sinus-to-sinus diameter across all groups (sinus-to-sinus: 1.9 ± 5.5 mm; Laplace: 44.9 ± 7.0 mm; 95% confidence interval 2.72–3.34; p < 0.0001). Although Laplace and sinus-to-sinus diameter were correlated (Spearman r = 0.6789, 95% CI 0.6–0.7; p < 0.0001), the relationship was non-linear (R² = 0.492). Laplace diameter increased the proportion of patients meeting surgical thresholds (2022 AHA/ACC guidelines) versus sinus-to-sinus: nondilated 0% vs. 1.77%, non-syndromic dilated 4.9% vs. 25.1%, bicuspid aortic valve 10.0% vs. 26.0%, and Marfan syndrome 23.5% vs. 52.9%. Conclusions: On average, Laplace diameter exceeded sinus-to-sinus diameter by 3 mm and would extend surgical eligibility to an additional 21% of patients under current guidelines. Full article

Background/Objectives: Cardiovascular manifestations in pediatric Marfan syndrome (MFS) exhibit substantial heterogeneity. Early identification of patients at elevated risk of requiring cardiac surgery is essential to optimizing outcomes. This study aimed to determine phenotypic features associated with cardiovascular surgery in genetically confirmed pediatric MFS. Methods: Among the 1006 children evaluated, 214 with genetically verified MFS were included in the analysis. We categorized patients by the presence or absence of cardiac surgery during childhood. Systemic and cardiovascular features were assessed. We applied binary logistic regression to identify independent associated manifestations with surgical intervention. Results: 20/214 patients (9.3%, 11.5 ± 5.5 years) underwent cardiac surgery (50% aortic root replacement, 20% mitral valve surgery, 30% combined interventions). Extracardiac features—Marfan-type facial features, pectus carinatum, pes planus, hindfoot deformity, and myopia of ≥3 diopters—were significantly associated with an increased probability of surgery (OR 3.0–4.6). Tricuspid valve prolapse and pulmonary artery dilatation were more prevalent in surgical patients. Surgical patients exhibited higher systemic manifestation scores (9.2 vs. 5.2; p ≤ 0.05) per revised Ghent criteria (RGC). Conclusions: A higher systemic score (RGC) correlates with increased risk for surgery. Marfan-type facial features, pectus carinatum, pes planus, hindfoot deformity, and myopia ≥ 3 diopters were strongly associated with the need for early cardiac surgery. Comprehensive phenotypic assessment, including systemic manifestation scoring, enables risk stratification and supports timely surgical planning in pediatric MFS. Full article

Background/Objectives: Thoracic aortic aneurysms have long been associated with germline mutations such as FBN1, TGFBR2, and COL3A1, which predispose to Marfan, Loeys–Dietz, and Ehlers–Danlos syndromes, respectively. However, recent research has identified a correlation between the JAK2 V617F somatic mutation and thoracic aortic aneurysm formation. This review aims to synthesize the current evidence on the relationship between JAK2 V617F and TAA development. Methods: A literature review was conducted using PubMed reviewed articles up to June 2025. Search terms included “thoracic aortic aneurysm”, “somatic mutations” and “JAK2 V617F”. Relevant clinical datasets and population-based cohort studies were identified and evaluated. Results: The available studies demonstrated a consistent association between JAK2 V617F and thoracic aortic aneurysm formation, with JAK2 V617F variant allele frequency (VAF) being a valuable biomarker of aneurysm risk. The mutation is accompanied by the onset of increased cytokine production, pro-inflammatory leukocytes, and elevated expression levels of MMPs—all of which drive elastin degradation and are classically associated with thoracic aortic aneurysm development. Conclusions: Compelling emerging evidence supports an association between the JAK2 V617F somatic mutation and the formation of thoracic aortic aneurysms, with VAF acting as a valuable biomarker for aneurysm risk. However, no studies have evaluated whether increasing VAF influences aneurysm growth rate, highlighting the need for future clinical research. Full article

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