Fragmentation Of Elastic Fibers Research Articles

Comprehensive analysis of pseudoxanthoma elasticum: epidemiological, genetic, and clinical findings from the leading Italian center.

Pseudoxanthoma elasticum (PXE) is a rare genetic autosomal recessive metabolic disease characterized by progressive mineralization and fragmentation of elastic fibers from soft connective tissues. The objective of our study was to analyze the epidemiological, genetic, cutaneous, and extracutaneous clinical data from the largest Italian monocentric cohort of PXE patients. We included all patients diagnosed with PXE and referred to Neurocutaneous Rare Diseases at Umberto I Polyclinic Hospital (Rome, Italy) between January 1983 and February 2024. A retrospective analysis of their data was performed. We enrolled 86 patients (77.9% women), revealing compound heterozygosity in 19.8% of cases and homozygosity in 5.8%. Missense (34.9%), non-sense (5.8%), splice-site (5.8%), deletion (4.7%), and frameshift (2.3%) mutations were disclosed. Cutaneous alterations were noted in the neck (69.7%), axilla (33.7%), inguinal (17.5%), and cubital folds (11.7%). The most common ocular findings were angioid streaks (64.0%) and choroidal neovascularization (18.6%), with blindness reported in 5.8% of cases. Thicker intima-media was observed around the mid-fifties in the supra-aortic trunks (40.7%), lower limb arteries (32.6%), and renal arteries (4.7%). Regurgitation was more common in atrioventricular valves (48.8%) than in semilunar ones (10.5% and 9.3%). Dyslipidemia (19.8%), hypertension (18.8%), and fatty liver disease (12.8%) were prevalent, with calcifications found in the kidneys (25.6%), liver (15.1%), spleen (11.6%), and testicles (8.1% of males). Autoimmune diseases and depression were observed in 11.6% and 4.7% of cases, respectively. Enhanced understanding of PXE can improve patients' quality of life and facilitate the development of more effective therapeutic strategies.

Fibulin-5 Is Required for Small Artery Development and Function

Introduction: Fibulins are a family of eight extracellular matrix proteins with diverse functions. Fibulin-4 and -5 (FBLN-4 and -5), in particular, have been shown to be important for elastic fiber assembly. Mutations in each of the genes lead to cutis laxa, a syndrome characterized by loose skin with variable organ involvement, particularly in the vasculature, lungs and skeleton. We recently characterized a mouse model carrying a disease-causing mutation in Fbln4 (E57K) and, contrary to conduit arteries that had elastic fiber fragmentation and stiffness, Fbln4E57K resistance arteries were structurally intact. Functionally however, Fbln4E57K mesenteric arteries exhibited endothelial dysfunction secondary to increased shear stress from large artery stiffness. Loss of FBLN5 has been shown to lead to elastic fiber fragmentation in conduit arteries, but the consequences of its loss on resistance arteries are unknown. Therefore, the objectives of this study were to determine the structural and functional consequences of FBLN5 loss on resistance arteries. Methods: We utilized adult Fbln5 knock-out (KO) mice and examined the ultrastructure of renal and mesenteric arteries via transmission electron microscopy. Functionally, using pressure myography, we characterized the myogenic tone and reactivity of Fbln5 KO and littermate control third-order mesenteric arteries to various vasoactive substances including acetylcholine, papaverine, angiotensin II, phenylephrine and potassium chloride. Results: While the internal elastic lamina (IEL) of Fbln5KO mice resistance arteries was largely intact, the external elastic lamina (EEL) was nearly absent. Similar to Fbln4E57K mice, Fbln5KO mesenteric arteries exhibited impaired endothelial-dependent vasorelaxation, likely secondary to proximal large artery stiffness. Unlike Fbln4E57K mesenteric arteries however, Fbln5 KO mesenteric arteries exhibited increased myogenic tone as well as a hypercontractile response to angiotensin II and potassium chloride, but not to phenylephrine. Conclusions: In addition to highlighting differences in the requirements for elastic fiber assembly along the arterial tree, these data emphasize the differential contribution of FBLN4 and FBLN5 to IEL vs. EEL in resistance arteries and suggest pathway-specific changes in smooth muscle cell contractility secondary to FBLN5 deficiency. This work was supported by the Washington University Pediatric Nephrology Research Core Pilot Grant Program to CMH. Funds were also provided by The Department of Pediatrics at Washington University in St. Louis School of Medicine to CMH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Copaiba oil minimizes inflammation and promotes parenchyma re-epithelization in acute allergic asthma model induced by ovalbumin in BALB/c mice.

Introduction: Asthma is a condition of airflow limitation, common throughout the world, with high mortality rates, especially as it still faces some obstacles in its management. As it constitutes a public health challenge, this study aimed to investigate the effect of copaiba oil (e.g., Copaifera langsdorffii), as a treatment resource, at doses of 50 and 100mg/kg on certain mediators of acute lung inflammation (IL-33, GATA3, FOXP3, STAT3, and TBET) and early mechanisms of lung remodeling (degradation of elastic fiber tissues, collagen deposition, and goblet cell hyperplasia). Methods: Using an ovalbumin-induced acute allergic asthma model in BALB/c mice, we analyzed the inflammatory mediators through immunohistochemistry and the mechanisms of lung remodeling through histopathology, employing orcein, Masson's trichrome, and periodic acid-Schiff staining. Results: Copaiba oil treatment (CO) reduced IL-33 and increased FOXP3 by stimulating the FOXP3/GATA3 and FOXP3/STAT3 pathways. Additionally, it upregulated TBET, suggesting an additional role in controlling GATA3 activity. In the respiratory epithelium, CO decreased the fragmentation of elastic fibers while increasing the deposition of collagen fibers, favoring epithelial restructuring. Simultaneously, CO reduced goblet cell hyperplasia. Discussion: Although additional research is warranted, the demonstrated anti-inflammatory and re-epithelializing action makes CO a viable option in exploring new treatments for acute allergic asthma.

Pseudoxanthoma Elasticum a Rare Genetic Disorder : A Case Report

Pseudoxanthoma elasticum (PXE) is a rare hereditary condition marked by the accumulation of fragmented and calcified elastic fibers in the body's tissues, leading to skin, vascular, and ocular involvement. In clinical practice, the most prevalent and typically earliest indication of PXE is observed through skin manifestations, which include laxity and the presence of yellowish papules and plaques. Here we report a case of a 40-year-old woman from Nepal presenting with yellowish multiple papules and plaque around the neck and axilla for 20 years, slowly increasing in size and number. A skin biopsy revealed fragmented eosinophilic elastic fibers in the dermis, consistent with PXE. Echocardiography, slit lamp, and indirect ophthalmoscopic examination were done.

The Therapeutic Effect of Ginsenoside Rb1 against Mechanical Trauma in a Rat Model of Postpartum Stress Urinary Incontinence

Aims. The aim of this study was to confirm the repairing effect of ginsenoside Rb1 (GS-Rb1) on mechanical trauma to periurethral tissues caused by childbirth and to explore its potential preventive mechanisms for mechanical trauma-induced stress urinary incontinence. Methods. 48 healthy adult female Sprague–Dawley (SD) rats were randomly divided into four groups: normal control, SUI groups, L-GS-Rb1 groups, and H-GS-Rb1 groups, with 12 rats in each group. The histopathological examinations of the urethral were performed to detect the morphological changes after repair of periurethral traumatic tissue. The TGF-β1/Smad and NRF2/ARE signaling pathways related to periurethral tissue trauma repair were determined by RT-PCR and western blot. The bladder capacity and LPP were examined in rats. Results. GS-Rb1 significantly decreased the number of fragmented and disorganized elastic and muscle fibers in the urethra and anterior vaginal wall of SUI rats. GS-Rb1 also increased the collagen content and reduced damage to the structural integrity of the periurethral myofibers. Furthermore, GS-Rb1 promoted expressions of TGF-β1, Smad2, Smad3, Smad7, p-Smad3, p-Smad2, and collagens I and III. It also increased the protein levels of Nrf2, GPX1, and MnSOD. The bladder capacity and LPP of rats in the L-GS-Rb1 group were close to those of rats in the normal groups. Conclusions. Ginsenoside Rb1 promotes the repair of periurethral tissue trauma in the postpartum period and has a preventive effect on the occurrence of stress urinary incontinence.

Insights From the Histopathologic Analysis of Acquired and Genetic Thoracic Aortic Aneurysms and Dissections.

The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases. A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74). The various types of lesions of medial degeneration and the overall severity of medial degeneration overlapped considerably between those patients with heritable disease and those with sporadic disease; however, patients with heritable thoracic aortic disease had significantly more overall medial degeneration (P = .004) and higher levels of elastic fiber fragmentation (P = .03) and mucoid extracellular matrix accumulation (P = .04) than patients with sporadic thoracic aortic disease. Heritable thoracic aortic disease with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .04), and women had more severe medial degeneration than men (P = .04). Medial degeneration scores were significantly lower for patients with bicuspid aortic valves than for patients with tricuspid aortic valves (P = .03). The study's findings indicate considerable overlap in the pattern, extent, and severity of medial degeneration between sporadic and hereditary types of thoracic aortic disease. This finding suggests that histopathologic medial degeneration represents the final common outcome of diverse pathogenetic factors and mechanisms.

Aortic elastic fiber degeneration during acute type a aortic dissection and reverse aortic remodeling

BackgroundProgression of proximal or distal aortic dilatation is defined as reverse aortic remodeling after surgery for acute type A aortic dissection (ATAAD) that may be dependent on aortic wall degeneration.MethodsWe investigated whether aortic wall degeneration is associated with reverse aortic remodeling leading to aortic reoperation after surgery for ATAAD. Altogether, 141 consecutive patients undergoing surgery for ATAAD at Tampere were evaluated. The resected ascending aortic wall at surgery was processed for 42 degenerative, atherosclerotic and inflammatory histological variables. Patients undergoing aortic reoperations (Redos) were compared with those without aortic reoperations (Controls) during a mean 4.9-year follow-up.ResultsRedos were younger than Controls (56 and 66 years, respectively, P < 0.001), and had less frequently previous cardiac surgery prior to ATAAD. Initial surgery encompassed replacement of the ascending aorta in the majority. There were 21 Redos in which one patient died during follow-up as compared with 51 deaths in Controls (log Rank P = 0.002). Histology of the aortic wall revealed increased elastic fiber fragmentation, loss, and disorganization in Redos as compared with Controls (2.1 ± 0.5 vs. 1.9 ± 0.5, Point score unit (PSU), P = 0.043 and 1.7 ± 0.8 vs. 1.2 ± 0.8, PSU, P = 0.016, respectively). Moderate atherosclerosis occurred less often in Redos vs. Controls (9.5% vs. 33%, PSU, P = 0.037, respectively).ConclusionsAccording to this exploratory study, histopathology reveals distinctive aortic wall degeneration during ATAAD. Reverse aortic remodeling after ATAAD is associated with the presence of ascending aortic wall elastic fiber fragmentation, loss and disorganization during ATAAD.

Magnesium Orotate Influence on Thoracic Aorta in Laboratory Rabbits Receiving Levofloxacin

INTRODUCTION. Fluoroquinolones are antibacterial agents associated with adverse drug reactions (ARDs), including aortic lesions; this ARD risk limits the use of fluoroquinolones. Moreover, fluoroquinolones have been reported to induce lesions in other connective tissues (cartilage, tendons), associated with magnesium deficiency.AIM. The study aimed to analyse the effects of magnesium orotate on the thoracic aorta in laboratory rabbits treated with levofloxacin.MATERIALS AND METHODS. The study randomised laboratory rabbits into 3 groups of 10 animals each to receive oral doses of either the carrier solution (control group), or 150 mg/kg/day levofloxacin (levofloxacin group), or 150 mg/ kg/day levofloxacin and 140 mg/kg/day magnesium orotate (levofloxacin/magnesium group). After 14 days of treatment, venous blood samples were taken to determine the serum levels of magnesium, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), as well as MMP-9 to TIMP-1 ratios. The authors conducted morphological and mechanical characterisation of thoracic aorta samples; the mechanical characterisation involved uniaxial tensile testing. Data are presented as the mean and standard deviation values.RESULTS. The study did not detect any changes in the serum MMP-9, TIMP-1, and magnesium levels or in the MMP-9/TIMP-1 ratios. The authors identified foci of moderate elastic fibre fragmentation in the aortic media in 5 of 10 aortic samples from the levofloxacin group, in 1 of 10 samples from the levofloxacin/magnesium group, and in none from the control group (p=0.013). Rabbits from the levofloxacin group had significantly fewer medial elastic membranes than the others (p=0.015; vs the control group: p=0.022), and their elastic mem

The Fbn1 gene variant governs passive ascending aortic mechanics in the mgΔlpn mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency.

Ascending thoracic aortic aneurysms arise from pathological tissue remodeling that leads to abnormal wall dilation and increases the risk of fatal dissection/rupture. Large variability in disease manifestations across family members who carry a causative genetic variant for thoracic aortic aneurysms suggests that genetic modifiers may exacerbate clinical outcomes. Decreased perlecan expression in the aorta of mgΔlpn mice with severe Marfan syndrome phenotype advocates for exploring perlecan-encoding Hspg2 as a candidate modifier gene. To determine the effect of concurrent Hspg2 and Fbn1 mutations on the progression of thoracic aortopathy, we characterized the microstructure and passive mechanical response of the ascending thoracic aorta in female mice of four genetic backgrounds: wild-type, heterozygous with a mutation in the Fbn1 gene (mgΔlpn), heterozygous with a mutation in the Hspg2 gene (Hspg2+/-), and double mutants carrying both the Fbn1 and Hspg2 variants (dMut). Elastic fiber fragmentation and medial disarray progress from the internal elastic lamina outward as the ascending thoracic aorta dilates in mgΔlpn and dMut mice. Concurrent increase in total collagen content relative to elastin reduces energy storage capacity and cyclic distensibility of aortic tissues from mice that carry the Fbn1 variant. Inherent circumferential tissue stiffening strongly correlates with the severity of aortic dilatation in mgΔlpn and dMut mice. Perlecan haploinsufficiency superimposed to the mgΔlpn mutation curbs the viability of dMut mice, increases the occurrence of aortic enlargement, and reduces the axial stretch in aortic tissues. Overall, our findings show that dMut mice are more vulnerable than mgΔlpn mice without an Hspg2 mutation, yet later endpoints and additional structural and functional readouts are needed to identify causative mechanisms.

Remodeling of murine vaginal smooth muscle function with reproductive age and elastic fiber disruption

Advanced maternal age during pregnancy is associated with increased risk of vaginal tearing during delivery and maladaptive postpartum healing. Although the underlying mechanisms of age-related vaginal injuries are not fully elucidated, changes in vaginal microstructure may contribute. Smooth muscle cells promote the contractile nature of the vagina and contribute to pelvic floor stability. While menopause is associated with decreased vaginal smooth muscle content, whether contractile changes occur before the onset of menopause remains unknown. Therefore, the first objective of this study was to quantify the active mechanical behavior of the murine vagina with age. Further, aging is associated with decreased vaginal elastin content. As such, the second objective was to determine if elastic fiber disruption alters vaginal contractility. Vaginal samples from mice aged 2–14 months were used in maximum contractility experiments and biaxial extension-inflation protocols. To evaluate the role of elastic fibers with age, half of the vaginal samples were randomly allocated to enzymatic elastic fiber disruption. Contractile potential decreased and vaginal material stiffness increased with age. These age-related changes in smooth muscle function may be due, in part, to changes in microstructural composition or contractile gene expression. Furthermore, elastic fiber disruption had a diminished effect on smooth muscle contractility in older mice. This suggests a decreased functional role of elastic fibers with age. Quantifying the age-dependent mechanical contribution of smooth muscle cells and elastic fibers to vaginal properties provides a first step towards better understanding how age-related changes in vaginal structure may contribute to tissue integrity and healing. Statement of significanceAdvanced maternal age at the time of pregnancy is linked to increased risks of vaginal tearing during delivery, postpartum hemorrhaging, and the development of pelvic floor disorders. While the underlying causes of increased vaginal injuries with age and associated pathologies remain unclear, changes in vaginal microstructure, such as elastic fibers and smooth muscle cells, may contribute. Menopause is associated with fragmented elastic fibers and decreased smooth muscle content; however, how reproductive aging affects changes in the vaginal composition and the mechanical properties remains unknown. Quantifying the mechanical contribution of smooth muscle cells and elastic fibers to vaginal properties with age will advance understanding of the potential structural causes of age-related changes to tissue integrity and healing.

Abstract 18901: Critical Role of Endothelial Injury in the Initiation of Aortic Dissection

Introduction: Endothelium forms a protective barrier and maintains vascular hemostasis. However, the role of endothelial injury in aortic aneurysms and dissections (AAD) remains poorly understood. Receptor-interacting protein kinase 3 (RIP3)-mediated necroptosis and gasdermin D (GSDMD)-mediated pyroptosis trigger necrotic cell death. We hypothesize endothelial cell (EC) death induced by necroptosis and pyroptosis contributes to AAD formation. Methods: Endothelial integrity and gene expression were examined in ascending aortic tissues from ascending thoracic aortic aneurysm (ATAA) patients (n=9) and organ donor controls (n=8) by single-cell transcriptome analysis. Effects of EC death on AAD formation were determined in EC-specific Rip3 knockout (EC-Rip3 -/- , n=26), EC-specific Gsdmd knockout (EC-Gsdmd -/- , n=21), and necroptosis/pyroptosis inhibitor necrosulfonamide (NSA) treated mice (n=15) in sporadic AAD models induced by angiotensin II (Ang II) infusion. Evans blue staining and nanoparticle-mediated contrast-enhanced CT (n-CECT) detected endothelial hyperpermeability Results: Single-cell transcriptome and immunostaining analyses revealed significant upregulation of pro-death genes (e.g., RIP3 and GSDMD), but downregulation of cell junction genes (e.g., TJP1 and GJA1) in ECs of ATAA patients compared with controls. In the mouse AAD model, endothelial injury and hyperpermeability were detected 2-5 days after Ang II infusion and were associated with intramural nanoparticle accumulation, elastic fiber fragmentation, and macrophage infiltration. Importantly, EC-Rip3 -/- mice and EC-Gsdmd -/- mice showed preserved EC barrier function, reduced nanoparticle accumulation and elastic fiber fragmentation, and reduced AAD incidence (including aneurysm, dissection, and rupture) compared to their littermate controls (EC-Rip3 -/- mice: 52% vs 23.1%, P=0.033; EC-Gsdmd -/- mice: 52.6% vs 14.3%, P=0.01). Blocking necroptosis/pyroptosis by NSA treatment reduced the incidence (65% vs 27%; P=0.04) and severity of AAD. Conclusions: Endothelial injury and subsequent barrier dysfunction and infiltration are key features of AAD formation. Prevention of EC necrotic cell death can be a potential AAD therapeutic target.

Abstract 17622: CCN3 Deficiency in Myeloid Cells Exacerbates Aortic Dissection by Governing a Proinflammatory Program in Macrophages

Introduction: Aortic dissection (AD) is a fatal disease. Macrophages are known central regulators of aortic inflammation and elastic fiber disruption, two major hallmarks of AD. Cellular communication network factor 3 (CCN3/NOV) is a matricellular protein associated with various biological cellular functions in cardiovascular disease and cancers. Emerging evidence strongly implicates a protective role of CCN3 against several types of vascular pathologies, however its role in AD remains unknown. Hypothesis: CCN3 deficiency in myeloid cells promotes AD development in murine models through the modulation of macrophage phenotype. Aims: We investigated the causal role of CCN3 loss in AD pathogenesis, focusing on its role in macrophages. Methods: 3-4-week-old male myeloid-specific CCN3 knockout mice (CCN3F/F;LysMCre) and control mice (LysMCre) were given BAPN (β-aminopropionitrile monofumarate; 0.2%) in their drinking water for 4 weeks for AD modeling. Mouse survival rate and histological changes of the aorta were assessed. Single cell RNA sequencing analysis was performed to recapitulate cellular transcriptome profile changes. Finally, gain and loss of function studies in bone marrow-derived macrophages (BMDMs) were performed to decipher the underlying mechanism by which CCN3 controls macrophage plasticity. Results: Following BAPN administration, myeloid-specific CCN3 knockout mice had a higher mortality rate due to AD formation and aortic rupture. In accordance with this phenotype, vascular media thickness was markedly reduced, and elastic fiber fragmentation and macrophage infiltration were elevated in myeloid-specific CCN3 knockout mice. Using single-cell RNA-seq, we found that myeloid-deficiency of CCN3 was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages. Furthermore, CCN3 deficient BMDMs are prone to M1 macrophage polarization, an effect dependent on the activation of the JAK/STAT1 signaling pathway. Conclusions: Myeloid-deficiency of CCN3 drives vascular macrophages toward an M1-like, pathogenic phenotype and promotes dissecting aortic aneurysm.

High fat diet has a protective sex-dependent effect on aortic aneurysm severity in a Marfan syndrome mouse model.

Marfan syndrome (MFS) is a genetic disorder caused by mutations in fibrillin-1 and is characterized by thoracic aortic aneurysms and other complications. Previous studies revealed sexual dimorphisms in aortic aneurysm formation in patients with MFS. The present study aimed to investigate the combined role of a high-fat diet (HFD) and biological sex in aortic disease using the mgR/mgR MFS mouse model. Male and female mgR/mgR mice as well as wild-type (WT) littermate mice were fed a control diet (CD, 10% fat) or HFD (60% fat) from 4 to 12 weeks of age. Key aortic disease parameters analyzed included the diameter of the aortic wall; elastic fiber fragmentation; proteoglycan content; mRNA levels of Mmp12, Col1a1, Col3a1, and Fbn1; and fibrillin-1 deposition in the aortic wall. HFD-fed female mgR/mgR mice had significantly reduced aortic diameters (35%), elastic fiber fragmentation (56%), pathologically enhanced proteoglycans (45%), and expression of Mmp12 (64%), Col1a1 (41%), and Col3a1 (43%) compared to male mgR/mgR mice on HFD. Fibrillin-1 deposition and Fbn1 mRNA levels were unaffected. The data reveal a protective effect of HFD in female mice. In contrast, CD did not exert any protective effects. This study demonstrates a specific sexual dimorphism in MFS mice, with HFD exerting an explicit protective effect on aortic disease severity in female mice. These preclinical data may be useful for developing nutritional recommendations for individuals with MFS in the longer term.

Histopathology of resected tissue from repair of anomalous aortic origin of a coronary artery: Potential mechanism of coronary artery compression

ObjectiveThis study aimed to describe the histomorphologic characteristics of resected (unroofed) common wall tissue from repair of anomalous aortic origin of a coronary artery and to determine whether the histologic features correlate with clinical and imaging findings. MethodsThe histology of resected tissue was analyzed and reviewed for the presence of fibrointimal hyperplasia, smooth muscle disarray, mucoid extracellular matrix accumulation, mural fibrosis, and elastic fiber disorganization and fragmentation using hematoxylin and eosin and special stains. Clinical, computed tomography imaging, and surgical data were correlated with the histopathologic findings. ResultsTwenty specimens from 20 patients (age range, 7-18 years; 14 males) were analyzed. Anomalous aortic origin of a coronary artery involved the right coronary in 16 (80%), and a slit-like ostium was noted in 18 (90%). By computed tomography imaging, the median proximal coronary artery eccentricity index was 0.4 (range, 0.20-0.90). The median length of intramural course was 8.2 mm (range, 2.6-15.2 mm). The anomalous vessel was determined to be interarterial in 14 patients (93%, 15 had evaluable images). The median distance from a commissure was 2.5 mm above the sinotubular junction (STJ) (range: 2 mm below the STJ–14 mm above the STJ). Prominent histopathologic findings included elastic fiber alterations, mural fibrosis, and smooth muscle disarray. The shared wall of the aorta and intramural coronary artery is more similar to the aorta histologically. Mural fibrosis and elastic fiber abnormalities tended to be more severe in patients >10 years of age at the time of surgery, but this did not reach statistical significance. The extent of vascular changes did not appear to have a clear relationship with the imaging features. ConclusionsThe findings confirm the aortic wall–like quality of the intramural segment of the coronary artery and the presence of pathologic alterations in the wall microstructure.

A Single-Cell Atlas of Small Airway Disease in Chronic Obstructive Pulmonary Disease: A Cross-Sectional Study.

Rationale: Emerging data demonstrate that the smallest conducting airways, terminal bronchioles, are the early site of tissue destruction in chronic obstructive pulmonary disease (COPD) and are reduced by as much as 41% by the time someone is diagnosed with mild (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1) COPD. Objectives: To develop a single-cell atlas that describes the structural, cellular, and extracellular matrix alterations underlying terminal bronchiole loss in COPD. Methods: This cross-sectional study of 262 lung samples derived from 34 ex-smokers with normal lung function (n = 10) or GOLD stage 1 (n = 10), stage 2 (n = 8), or stage 4 (n = 6) COPD was performed to assess the morphology, extracellular matrix, single-cell atlas, and genes associated with terminal bronchiole reduction using stereology, micro-computed tomography, nonlinear optical microscopy, imaging mass spectrometry, and transcriptomics. Measurements and Main Results: The lumen area of terminal bronchioles progressively narrows with COPD severity as a result of the loss of elastin fibers within alveolar attachments, which was observed before microscopic emphysematous tissue destruction in GOLD stage 1 and 2 COPD. The single-cell atlas of terminal bronchioles in COPD demonstrated M1-like macrophages and neutrophils located within alveolar attachments and associated with the pathobiology of elastin fiber loss, whereas adaptive immune cells (naive, CD4, and CD8 T cells, and B cells) are associated with terminal bronchiole wall remodeling. Terminal bronchiole pathology was associated with the upregulation of genes involved in innate and adaptive immune responses, the interferon response, and the degranulation of neutrophils. Conclusions: This comprehensive single-cell atlas highlights terminal bronchiole alveolar attachments as the initial site of tissue destruction in centrilobular emphysema and an attractive target for disease modification.

Intrinsic histological and morphological abnormalities of the pediatric thoracic aorta in bicuspid aortic valve patients are predictive for future aortopathy

BackgroundPatients with a bicuspid aortic valve (BAV) have an increased risk to develop aortic complications. Many studies are pointing towards a possible embryonic explanation for the development of both a bicuspid aortic valve as well as a defective ascending aortic wall in these patients. The fetal and newborn ascending aortic wall has however scarcely been studied in bicuspid aortic valve patients. We hypothesize that early histopathological defects might already be visible in the fetal and pediatric ascending aortic wall of bicuspid aortic valve patients, indicating at an early embryonic defect. MethodsNon-dilated BAV ascending aortic wall samples were collected (n = 40), categorized in five age groups: premature (age range 17.5 weeks + days GA till 37.6 weeks + days GA) 2. neonate (age range 1 – 21 days) 3. infant (age range 1 month – 4 years) 4. adolescent (age range 12 years – 15 years) and 5. adult (age range 41 – 72 years). Specimen were studied for intimal and medial histopathological features. ResultsThe premature ascending aortic wall has a significantly thicker intimal and significantly thinner medial layer as compared to all other age categories (p < 0.05). After birth the intimal thickness decreases significantly. The medial layer increases in thickness before adulthood (p < 0.05) with an increasing number of elastic lamellae (p < 0.01) and interlamellar mucoid extracellular matrix accumulation (p < 0.0001). Intimal atherosclerosis was scarce and medial histopathological features such as overall medial degeneration, smooth muscle cell nuclei loss and elastic fiber fragmentation were not appreciated in the BAV ascending aortic wall of any age. ConclusionsThe main characteristics of a bicuspid ascending aortic wall are already present before adulthood, albeit not before birth. Considering the early manifestations of ascending aortic wall pathology in bicuspid aortic valve patients, the pediatric population should be considered while searching for markers predictive for future aortopathy.

Changes in transmural mass transport correlate with ascending thoracic aortic aneurysm diameter in a fibulin-4 E57K knockin mouse model.

Thoracic aortic aneurysm is characterized by dilation of the aortic diameter by greater than 50%, which can lead to dissection or rupture. Common histopathology includes extracellular matrix remodeling that may affect transmural mass transport, defined as the movement of fluids and solutes across the wall. We measured in vitro ascending thoracic aorta mass transport in a mouse model with partial aneurysm phenotype penetration due to a mutation in the extracellular matrix protein fibulin-4 [Fbln4E57K/E57K, referred to as MU-A (aneurysm) or MU-NA (no aneurysm)]. To push the aneurysm phenotype, we also included MU mice with reduced levels of lysyl oxidase [Fbln4E57K/E57K;Lox+/-, referred to as MU-XA (extreme aneurysm)] and compared all groups to wild-type (WT) littermates. The phenotype variation allows investigation of how aneurysm severity correlates with mass transport parameters and extracellular matrix organization. We found that MU-NA ascending thoracic aortae have similar hydraulic conductance (Lp) to WT, but 397% higher solute permeability (ω) for 4 kDa FITC-dextran. In contrast, MU-A and MU-XA ascending thoracic aortae have 44-68% lower Lp and similar ω to WT. The results suggest that ascending thoracic aortic aneurysm progression involves an initial increase in ω, followed by a decrease in Lp after the aneurysm has formed. All MU ascending thoracic aortae are longer and have increased elastic fiber fragmentation in the extracellular matrix. There is a negative correlation between diameter and Lp or ω in MU ascending thoracic aortae. Changes in mass transport due to elastic fiber fragmentation could contribute to aneurysm progression or be leveraged for treatment.NEW & NOTEWORTHY Transmural mass transport is quantified in the ascending thoracic aorta of mice with a mutation in fibulin-4 that is associated with thoracic aortic aneurysms. Fluid and solute transport depend on aneurysm severity, correlate with elastic fiber fragmentation, and may be affected by proteoglycan deposition. Transport properties of the ascending thoracic aorta are provided and can be used in computational models. The changes in mass transport may contribute to aneurysm progression or be leveraged for aneurysm treatment.

Hallazgos histopatológicos en la disección y rotura de la aorta torácica. Estudio de 54 casos de autopsia

IntroductionThoracic aortic dissection/rupture has a high mortality, constituting 3.9-5.4% of sudden deaths in forensic series. Medial histopathological findings associated with these entities have received multiple terms and definitions. In 2016, the European Association for Cardiovascular Pathology and the Society for Cardiovascular Pathology published a consensus document, applied to surgical specimens, to unify criteria. The aim of this work is to assess its application in forensic autopsies. A secondary objective is to study inflammatory changes useful for dating. Material and methodsAortic histological preparations of the 54 cases of sudden deaths due to aortic rupture/dissection studied between 2019 and 2022 were reviewed. ResultsMedial degeneration was observed in 49 cases (90.8%) (severe in 42.9%). By lesions, the order of frequency was: fragmentation and/or loss of elastic fibers (74.1%); accumulation of extracellular mucoid matrix (61.1%); loss of smooth muscle cell nuclei (48.1%) and collapse of the media (44.4%). Some lesions of the consensus paper could not be assessed. No significant differences were found by age; presence or not of collagenopathies; or bi/tricuspid aortic valves. Granulation tissue or neutrophilic infiltrate was observed in those deceased with pain several days or <24 h before death, respectively. ConclusionWith the application of the document, lesions in the media are found in >90% of cases and fundamental lesions can be studied. The inflammatory response to rupture/dissection appears to correlate with the timing of dissection/rupture.

Morphological Features of the Ascending Aorta Remodeling and Activation of Regeneratory Potential in Intima when Forming Aneurysm.

In patients with an ascending aorta aneurysm, restructuring of all its layers and, first of all, the intima and media was revealed. The thickness of the intima was 79.3±63.1 μm in patients with aortic diameter <55 mm (group Ao<55) and 162.7±177.4 μm (p<0.05) in patients with aortic diameter ⩾55 mm (Ao⩾55 group), the thickness of the aortic media was 1184.0±198.2 and 1144.3±288.4 μm, respectively. In patients of the Ao<55 group, aortic dilatation was accompanied by compensatory thickening of the inner and middle layers of the aorta. In the Ao⩾55 group, thinning of the aortic media, fragmentation of elastic fibers, and its cystic degeneration were revealed. c-kit+ Stem cells were detected in the subendothelium of the thickened intima of the dilated ascending aorta. The appearance of c-kit+ cells correlated with intimal remodeling and its colonization with CD34+ and CD44+ myofibroblast-like cells.

Tributyrin Intake Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm in LDLR-/- Mice.

Abdominal aortic aneurysm (AAA) is a multifactorial cardiovascular disease with a high risk of death, and it occurs in the infrarenal aorta with vascular dilatation. High blood pressure acts on the aortic wall, resulting in rupture and causing life-threatening intra-abdominal hemorrhage. Vascular smooth muscle cell (VSMC) dysregulation and extracellular matrix (ECM) degradation, especially elastin breaks, contribute to structural changes in the aortic wall. The pathogenesis of AAA includes the occurrence of oxidative stress, inflammatory cell infiltration, elastic fiber fragmentation, VSMC apoptosis, and phenotypic transformation. Tributyrin (TB) is decomposed by intestinal lipase and has a function similar to that of butyrate. Whether TB has a protective effect against AAA remains uncertain. In the present study, we established an AAA murine model by angiotensin II (AngII) induction in low-density lipoprotein receptor knockout (LDLR-/-) mice and investigated the effects of orally administered TB on the AAA size, ratio of macrophage infiltration, levels of matrix metalloproteinase (MMP) expression, and epigenetic regulation. TB attenuates AngII-induced AAA size and decreases elastin fragmentation, macrophage infiltration, and MMP expression in the medial layer of the aorta and reduces the levels of SBP (systolic blood pressure, p < 0.001) and MMP-2 (p < 0.02) in the serum. TB reduces the AngII-stimulated expression levels of MMP2 (p < 0.05), MMP9 (p < 0.05), MMP12, and MMP14 in human aortic smooth muscle cells (HASMCs). Moreover, TB and valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, suppress AngII receptor type 1 (AT1R, p < 0.05) activation and increase the expression of acetyl histone H3 by HDAC activity inhibition (p < 0.05). Our findings suggest that TB exerts its protective effect by suppressing the activation of HDAC to attenuate the AngII-induced AT1R signaling cascade.