Mucoid Extracellular Matrix Research Articles

Integrated Biofilm Dispersion and Virulence Responsiveness for Targeted Treatment of Pseudomonas aeruginosa Infection in Lungs

AbstractThe self‐organization of microbes into biofilms provides multiple benefits including tolerance to mechanical stress and resistance to immune defences and antibiotics. Coupled to a compromised mucociliary function, these traits have dire consequences in cystic fibrosis patients – persistent infections are the main reason for morbidity and mortality. Thereby, disease progression is associated with universal colonization by Pseudomonas aeruginosa, which selects for a slimy phenotype to adapt to the lung microenvironment. Recognizing this, drug‐delivery vehicles that break down the mucoid extracellular matrix made of alginate are designed to enable better penetration and biofilm dispersion. In parallel, a protective layer responds to the proteolytic activity of the pathogen and thus controls drug availability. To realize this architecture, silica nanoparticles are loaded with imipenem, and then coated with elastin and alginate lyase in a layer‐by‐layer fashion using ultrasound. The nanoscale formulations eradicate up to 80% of the total biomass and reduce the bacterial viability in biofilms by 3 logs, considerably outperforming the bulk antibiotic in vitro, whereby the effects are correlated to changes in the viscoelasticity. Furthermore, the stimuli‐responsive nanocarriers are safe and effective in animal models of P. aeruginosa infection, presenting a considerable therapeutic promise in the challenging context of lung diseases.

The proximal extension of acute type A aortic dissection is associated with ascending aortic wall degeneration.

Aortic root involvement during acute type A aortic dissection (ATAAD) may depend on ascending aortic wall degeneration. Surgical decision-making for extended resection of the aortic root is clinically made without histopathology. The aim of the study was to investigate whether the degree of degeneration of the ascending aortic wall found in patients with ATAAD is associated with the aortic root involvement. Collectively, 141 consecutive patients undergoing ATAAD surgery at Tampere University Heart Hospital were investigated. The ascending aortic wall resected in surgery was processed for 11 different variables that describe medial and adventitial degeneration. In addition, atherosclerosis and inflammation were separately evaluated. Patients undergoing aortic root replacement were compared with those with supracoronary reconstruction of the ascending aorta with/without aortic valve surgery (root-sparing surgery) during a mean 4.9-year follow-up. Aortic root replacement together with the ascending aortic replacement was performed in 39% of the patients (n=55). The mean age for all patients was 65 years [standard deviation (SD 13)]. Many patients with aortic root replacement had moderate to severe aortic valve regurgitation (85.5%). Most of the patients with aortic root-sparing surgery included a supracoronary tube prosthesis (89.5%), while nine patients also had aortic valve replacement. The degree of mucoid extracellular matrix accumulation was more prominent in patients with aortic root replacement compared to patients with root-sparing surgery (2.1 SD 0.4 vs. 1.9 SD 0.4, P=0.04, respectively). During follow-up, there were 52 deaths among patients (log rank P=0.79). Histopathology of the ascending aorta during ATAAD reveals distinctive aortic wall degeneration in patients with aortic root involvement vs. not. The degree of mucoid extracellular matrix accumulation assessed postoperatively is associated with the choice of surgical procedure in many patients.

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.

Sex Differences in the Histopathology of Acute Type A Aortic Dissections.

Although sex-related differences in cardiovascular surgery outcomes have increasingly garnered attention in the past decades, knowledge about sex disparities in the pathophysiology of acute type A aortic dissections (ATAADs) remains sparse. In this study, we evaluate the histopathologic and atherosclerotic lesions in female and male ATAAD patients. A total of 68 patients were studied: 51 ATAAD patients (mean age: 62.5 ± 10.8 years; 49% women) and 17 control patients (mean age: 63 ± 5.5 years; 53% women). Cardiovascular risk factors were assessed clinically. Intimal and medial histopathological features were systematically evaluated in all. Compared to the control group, all ATAAD patients showed significantly more elastic fiber pathology, mucoid extracellular matrix accumulation, smooth muscle cell nuclei loss, and overall medial degeneration (p < 0.0001). The tunica intima was significantly thinner in the ATAAD patients than in the control group (p < 0.023), with the latter exhibiting significantly more progressive atherosclerotic lesions than the former. No difference in medial vessel wall pathology was seen between female and male patients. As compared to male ATAAD patients, atherosclerotic lesions were more severe in female ATAAD patients, independent of age and the cardiovascular risk factor hypertension. All ATAAD patients had a significantly thinner tunica intima and significantly diseased tunica media compared to the control patients. Our results suggest that the severity of medial aortic pathology is not sex specific in ATAAD patients. Intimal differences between females and males could, however, be considered a potential risk factor for the development of an aortic dissection.

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.

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.

Nondestructive Evaluation of Mechanical and Histological Properties of the Human Aorta With Near-Infrared Spectroscopy

IntroductionAscending aortic dilatation is a well-known risk factor for aortic rupture. Indications for aortic replacement in its dilatation concomitant to other open-heart surgery exist; however, cut-off values based solely on aortic diameter may fail to identify patients with weakened aortic tissue. We introduce near-infrared spectroscopy (NIRS) as a diagnostic tool to nondestructively evaluate the structural and compositional properties of the human ascending aorta during open-heart surgeries. During open-heart surgery, NIRS could provide information regarding tissue viability in situ and thus contribute to the decision of optimal surgical repair. Materials and methodsSamples were collected from patients with ascending aortic aneurysm (n = 23) undergoing elective aortic reconstruction surgery and from healthy subjects (n = 4). The samples were subjected to spectroscopic measurements, biomechanical testing, and histological analysis. The relationship between the near-infrared spectra and biomechanical and histological properties was investigated by adapting partial least squares regression. ResultsModerate prediction performance was achieved with biomechanical properties (r = 0.681, normalized root-mean-square error of cross-validation = 17.9%) and histological properties (r = 0.602, normalized root-mean-square error of cross-validation = 22.2%). Especially the performance with parameters describing the aorta's ultimate strength, for example, failure strain (r = 0.658), and elasticity (phase difference, r = 0.875) were promising and could, therefore, provide quantitative information on the rupture sensitivity of the aorta. For the estimation of histological properties, the results with α-smooth muscle actin (r = 0.581), elastin density (r = 0.973), mucoid extracellular matrix accumulation(r = 0.708), and media thickness (r = 0.866) were promising. ConclusionsNIRS could be a potential technique for in situ evaluation of biomechanical and histological properties of human aorta and therefore useful in patient-specific treatment planning.

Structural abnormalities in the non-dilated ascending aortic wall of bicuspid aortic valve patients

BackgroundA bicuspid aortic valve (BAV) is the most common congenital cardiac malformation. The development of the aortic valve is closely related to the development of the ascending aorta, associated with structural differences in the bicuspid aorta. Here we describe the non-dilated ascending aortic wall in bicuspid aortic valve patients. MethodsBAV (n=41) and tricuspid aortic valve (TAV) (n=18) non-dilated ascending aortic wall samples were studied. We investigated the following features of the aortic wall: vessel wall thickness, endothelial cell morphology, atherosclerosis, and elastic lamellae organization. Medial pathologic features encompassing elastic fiber thinning, fragmentation and degeneration, overall medial degeneration, mucoid extracellular matrix accumulation, and smooth muscle cell nuclei loss were studied. Furthermore, we included apoptosis, periaortic inflammation, and the level of expression of differentiated vascular smooth muscle cells. ResultsThe non-dilated BAV ascending aortic wall is characterized by a significantly thinner intimal layer, without features of atherosclerosis (P<.001). The medial layer is significantly thicker (P<.001) with more mucoid extracellular matrix accumulation (P<.001). All other medial pathologic features were more prominent in the TAV (P<.001). The media has significantly less differentiated vascular smooth muscle cells (P<.001) between the neatly regulated elastic lamellae which are thinner in the BAV as compared to the TAV (P<.0001). ConclusionsThe BAV ascending aorta without dilatation is characterized by a differentiation defect of vascular smooth muscle cells in the media and a significantly thinner intimal layer without overt pathologic features.

A Case of Odontogenic Myxoma of the Mandible with Expansion to the Alveolar Crest – Comparison of Imaging Findings and Pathological Findings: A Case Report

Background: An odontogenic myxoma is an intraosseous tumor characterized by stellate and spindle-shaped cells embedded in an abundant myxoid or mucoid extracellular matrix. We herein describe an odontogenic myxoma that expanded not only to the bone marrow but also to the outside of the alveolar bone. Diagnosis of an odontogenic myxoma in a tooth-deficient region by imaging findings alone was difficult because the positional relationship between the tumor and the tooth is unknown. Furthermore, some of these odontogenic myxomas reportedly show rapid growth. Case Report: Here, we present the case of a patient, a 44-year-old man, who had a hard, bone-like swelling on his right mandible molar region and mild paresthesia on his right cheek. An odontogenic myxoma and ameloblastoma were suspected based on the imaging findings; however, pathological examination of the biopsy led to a diagnosis of odontogenic myxoma. Right segmental mandibulectomy was performed, and there was no recurrence observed after surgery. Conclusion: To improve the accuracy of imaging diagnosis, it is important to compare the imaging findings with the pathological findings of the surgical specimen. This comparison in the present case revealed differences in the magnetic resonance imaging signal intensity in regions with different types of cell components.

Assessment of Computational Histopathology in Thoracic Aortic Aneurysm

Background and Hypothesis: Thoracic aortic aneurysm (TAA) histopathology includes elastic fiber (EF) abnormalities, mucoid extracellular matrix (MECM) accumulation, and smooth muscle derangement in the aortic medial layer. While semi-quantitative grading of these characteristics is a standard practice, computational characterization of medial layer components may facilitate novel quantitative analyses at higher throughput. We hypothesized that computational results would correlate with results of semi-quantitative grading of aortic histopathology.&#x0D; Experimental Design: Formalin-fixed, paraffin-embedded human aortic tissue sections were stained with Movat’s pentachrome to characterize aortic microstructure. Sections were also immunostained for nitrotyrosine residues to assess oxidative stress. Samples were initially graded semi-quantitatively by two independent blinded readers. Next, computational histopathology software was used a) to quantify the proportions of EF, MECM, and cellular area in the medial layer of pentachrome-stained sections and b) to quantify the distribution and intensity of positive nitrotyrosine staining in immunostained sections. Association between semi-quantitative grading and computed values was tested with ANOVA.&#x0D; Results: The cohort included 74 participants who underwent prophylactic aortic replacement for TAA and 23 healthy controls. The mean age was 54±17 years. On average, EFs accounted for 49% (range 6-90%) of medial tissue area, whereas MECM accounted for 25% (1-73%). The overall semi-quantitative grade of medial degeneration severity was associated with decrease in EF fraction (p=0.02). The grade of EF thinning also strongly correlated with decrease in EF fraction (p=1x10-6). Meanwhile, grade for accumulation of MECM was associated with increase in MECM (p=0.004). Increased semi-quantitative grading for nitrotyrosine levels was associated with increased nuclear signal optical density (p=9x10-10) and greater percentage of cells labeled as strongly positive (p=8x10-10).&#x0D; Conclusion and Potential Impact: We observed significant correlations between computed quantitative values and semi-quantitative grading. This suggests that computational histopathology is a valid method for investigation of human TAA tissues.

Sex Differences in Proximal Thoracic Aortic Disease Pathology: A Call to Action

Abstract Introduction/Objective Sex disparity is reported across all forms of cardiovascular diseases. Only few studies have focused on sex differences in thoracic aortic disease pathology. We aim to identify and understand sex differences in this patient group to bridge the knowledge gap and improve clinicopathologic outcomes. Methods/Case Report This is a retrospective analysis of 83 proximal thoracic aortic aneurysm and dissection (TAAD) cases treated at a single quaternary care center in 2019. Chart review was done for demographics. Consensus criteria (Stone JR et al. Cardiovasc Pathol 2015; 24:267-78; Halushka MK et al. Cardiovasc Pathol 2016; 25:247-57) and a scoring system (Waters KM et al. Cardiovasc Pathol 2017; 30:6-11) were used for pathology reporting. Clinical correlation was also made. Pearson’s chi-square test was used for statistical analysis. Results (if a Case Study enter NA) 83 patients (61 male and 22 female) were retrieved. Overall thoracic aortopathy was higher among males, accounting for 73.4% of individuals with TAAD. In a subgroup analysis, there was no sex difference in dissection, aortic root involvement, and bicuspid aortic valve (p&amp;gt;0.05). Genetic aortopathy was more prevalent in females than males (27.2% vs 9.8%, p=0.04) alongside early age at first aortic event (median age: 31y vs 52y). Histopathologically, females had frequent translamellar mucoid extracellular matrix accumulation (45.4% vs 22.9%, p=0.04), extensive (54.5% vs 27.8%, p=0.02) and severe (59% vs 34.4%, p=0.04) elastic fiber fragmentation, higher band like (9% vs 6.5%, p&amp;gt;0.05) plus extensive (13.6% vs 4.9%, p&amp;gt;0.05) smooth muscle nuclei loss, and extensive (13.6% vs 1.6%, p=0.01) plus dense (4.5% vs 1.6%, p&amp;gt;0.05) laminar medial collapse than males. Conclusion In our patient population, females have a lower prevalence of thoracic aortic disease treated with open repair. However, those who develop TAAD harbor a greater burden of wall pathology and probable worse outcomes. We recommend sex-based analysis of all research on thoracic aortic diseases.

Relationship between the aortic root Z-score and degree of translamellar mucoid extracellular matrix accumulation.

A retrospective analysis was performed to compare the pathological findings and aortic root Z-score in patients with and without connective tissue disease (CTD). Twenty-two patients {47.5 [15-85] years old, 18 males} underwent surgery for aortic root dilatation without aortic dissection: 10 {40 [16-59] years old} with CTD and 12 {57.5 [15-85] years old} without CTD (non-CTD; p = 0.049). Systemic hypertension (p = 0.043) and the degree of preoperative aortic regurgitation (p = 0.017) were higher in the non-CTD patients than in the CTD patients. The diameters of the sinotubular junction (STJ) (p = 0.048) and ascending aorta (Asc.Ao.) (p = 0.020) and the Z-scores of the STJ (p = 0.027) and Asc.Ao. (p = 0.009) were significantly higher in the non-CTD patients than in the CTD patients. The degree of translamellar mucoid extracellular matrix accumulation (T-MEMA) of the Asc.Ao. was significantly higher in the non-CTD patients than in the CTD patients (p = 0.037) and was significantly correlated with the Z-scores of the aorta (R = 0.746, p < 0.01 in the sinus of Valsalva and R = 0.382, p = 0.031 in the Asc.Ao.), although there was no significant correlation between the diameter of the STJ and that of Asc.Ao. In non-CTD patients, not only the aortic root but also Asc.Ao. tended to dilate with age, and a significant correlation between the Z-scores of the aorta root and the Asc.Ao. and the degrees of T-MEMA was observed.

Application of deep learning neural network in pathological image classification of non-inflammatory aortic membrane degeneration

Objective: To investigate the value of deep learning in classifying non-inflammatory aortic membrane degeneration. Methods: Eighty-nine cases of non-inflammatory aortic media degeneration diagnosed from January to June 2018 were collected at Beijing Anzhen Hospital, Capital Medical University, China and scanned into digital sections. 1 627 hematoxylin and eosin stained photomicrographs were extracted. Combined with the ResNet18-based deep convolution neural network model, 4-category classification of pathological images were performed to diagnose the non-inflammatory aortic lesion. Results: The prediction model of artificial intelligence assisted diagnosis had the best accuracy, sensitivity and precision in identifying lesions with smooth muscle cell nuclei loss, which were 99.39%, 98.36% and 98.36%, respectively. The classification accuracy of elastic fiber fragmentation and/or loss lesions was 98.08%, while that of intralamellar mucoid extracellular matrix accumulation lesions was 96.93%. The overall accuracy of the classification model was 96.32%, and the area under the curve was 0.982. Conclusions: The accuracy of deep learning neural network model in the 4-category classification of non-inflammatory aortic lesionsis confirmed based on digital photomicrographs. This method can effectively improve the diagnostic efficiency of pathologists.

Aortic aneurysms with tricuspid aortic valve have more degeneration than unicuspid aortic valve aneurysms.

The unicuspid aortic valve (UAV) is a rare cardiac malformation and is associated with the formation of ascending aortic aneurysms. To characterize its associated aortic wall changes, normal and aneurysmatic ascending aortic wall specimens were analysed, focusing on the potential mechanisms of aneurysm formation. Patients with tricuspid aortic valve (TAV) served as controls. In a retrospective observational study, 74 specimens (dilated and non-dilated aortas; individuals with UAV and TAV) obtained intraoperatively were studied. Standard stains and immunohistochemical labelling of cleaved caspase-3, cluster of differentiation 31 and endothelial nitric oxide synthase (eNOS) were performed to assess the degree of apoptosis, distribution of eNOS within the aortic wall, smooth muscle cell (SMC) nuclei loss and mucoid extracellular matrix accumulation (MEMA). Deeper ingrowth of vasa vasorum was found in dilated aortas. Interestingly, eNOS was expressed mostly in vasa vasorum. More apoptosis was seen in UAV aortas compared to TAV aortas (P < 0.001). Both UAV and TAV aortas were comparable regarding SMC nuclei loss (P = 0.419). In dilated compared to non-dilated aortas regardless valve morphology SMC nuclei loss was increased (P = 0.005) and more pronounced translamellar MEMA was present (P = 0.011). The highest grade of distribution (P = 0.043) and the highest severity (P = 0.005) regarding MEMA were seen in TAV dilated specimens compared to UAV dilated specimens. Aneurysms with UAV show increased apoptosis, the role of which is unclear. Strikingly, more severe MEMA was found in TAV aneurysms compared to UAV aneurysms. Thus, UAV-associated aortic wall changes and resulting aneurysm may be less aggressive than aneurysms with TAV.

Comparison of the damage to aorta wall in aortitis versus noninflammatory degenerative aortic diseases

BackgroundNot rarely aortitis is firstly identified in thoracic aorta aneurysm/dissection specimens only by histopathology in the absence of clinical evidence of systemic inflammatory disease emphasizing the importance of histology for the diagnosis of aortitis. Regardless of the improvement of the pathological assessment of aortic diseases by the recent consensus statements on surgical pathology of the aorta, histology can be confusing since medial degenerative changes (MDC) can be prominent in a background where inflammation is sometimes limited. This raises the question of the role of aging or other degenerative process versus the role of inflammation in the damage to aorta wall. Patients and MethodsIn this study, besides inflammation, we evaluated aorta samples from aortitis cases focusing on the histological scoring of MDC. In this retrospective single center study, we retrieved 719 cases of ascending aorta aneurysms or dissections operated on from January 2010 until June 2018. MDC (elastic fiber fragmentation and/or loss, smooth muscle nuclei loss, mucoid extracellular matrix accumulation intralemellar or translamellar) were estimated using a scoring system derived from that of the consensus statement. Noninfectious aortitis group versus age-matched non-inflammatory degenerative aortic disease group were compared. ResultsNoninfectious aortitis was pathologically diagnosed in 62 patients (8.6%). Among the 62 noninfectious aortitis patients, 47 patients (75.8%) had aortitis identified pathologically prior to the clinical diagnosis. Higher MDC scores were observed at all aortic sizes in aortitis group versus non-aortitis group, especially for elastic fiber damage and smooth muscle cell loss. ConclusionsAortitis is remarkably associated with severe damage to the aorta wall resulting in advanced MDC scores. Inflammatory process is responsible for higher MDC in the aorta wall than aging or other degenerative process.

A Systematic Histopathologic Evaluation of Type-A Aortic Dissections Implies a Uniform Multiple-Hit Causation.

(1) Background: The pathophysiologic basis of an acute type A aortic dissection (TAAD) is largely unknown. In an effort to evaluate vessel wall defects, we systematically studied aortic specimens in TAAD patients. (2) Methods: Ascending aortic wall specimens (n = 58, mean age 63 years) with TAAD were collected. Autopsy tissues (n = 17, mean age 63 years) served as controls. All sections were studied histopathologically. (3) Results: Pathomorphology in TAAD showed predominantly moderate elastic fiber fragmentation/loss, elastic fiber thinning, elastic fiber degeneration, mucoid extracellular matrix accumulation, smooth muscle cell nuclei loss, and overall medial degeneration. The control group showed significantly fewer signs of those histopathological features (none-mild, p = 0.00). It was concluded that the dissection plane consistently coincides with the vasa vasorum network, and that TAAD associates with a significantly thinner intimal layer p = 0.005). (4) Conclusions: On the basis of the systematic evaluation and the consistent presence of diffuse, pre-existing medial defects, we hypothesize that TAAD relates to a developmental defect of the ascending aorta and is caused by a triple-hit mechanism that involves (I) an intimal tear; and (II) a diseased media, which allows (III) propagation of the tear towards the plane of the vasa vasorum where the dissection further progresses.

Aortic Regurgitation Is Associated With Ascending Aortic Remodeling in the Nondilated Aorta.

The probability of aortic complications in patients with bicuspid aortic valve is higher in association with aortic regurgitation (AR) compared with aortic stenosis (AS) or normally functioning valves. The objective of this study was to determine whether this is related to the specific characteristics of aneurysmatic dilatation that includes AR or whether AR itself has a negative impact on the aortic wall, independent of aneurysmatic dilatation. Approach and Results: Nondilated aortic specimens were harvested intraoperatively from individuals with tricuspid aortic valves and either AS (n=10) or AR (n=16). For controls, nondilated aortas were harvested during autopsies from individuals with tricuspid aortic valves and no evidence of aortic valve disease (n=10). Histological and immunohistochemical analyses revealed that compared with control aortas, overall medial degeneration was more severe in AR-aortas (P=0.005) but not AS-aortas (P=0.23). This pathological remodeling included mucoid extracellular matrix accumulation (P=0.005), elastin loss (P=0.003), elastin fragmentation (P=0.008), and decreased expression of fibrillin (P=0.003) and collagen (P=0.008). Furthermore, eNOS (endothelial nitric oxide synthase) expression was decreased in the intima (P=0.0008) and in vasa vasorum (P=0.004) of AR-aortas but not AS-aortas (all P>0.05). Likewise, subendothelial apoptosis was increased in AR-aortas (P=0.03) but not AS-aortas (P=0.50). AR has a negative effect on the nondilated ascending aortic wall. Accordingly, our results support the need for more detailed studies of the aortic wall in relation to aortic valve disease and may ultimately lead to more aggressive clinical monitoring and/or surgical criteria for patients with relevant AR. Graphic Abstract: A graphic abstract is available for this article.

Histopathological changes in dilated ascending aorta associated with aortic valve cuspidity.

Patients with a bicuspid aortic valve (BAV) often present with a dilated ascending aorta. However, the underlying pathogenesis for the observed changes in the aortic wall and the resulting aneurysmal dilation remains a subject of debate. This study aims to compare the histological abnormalities of the ascending aorta in BAV and tricuspid aortic valve (TAV) patients and their correlation with aortic diameter and patient age. A total of 376 patients from our institution's clinical database were included in the retrospective analysis. These patients underwent either elective surgery for ascending aorta dilation or emergency surgery for aortic dissection, either isolated or with a structurally diseased aortic valve. After excision, the ascending aorta samples were analysed by a pathologist. On histological examination, a higher degree of elastic fibre fragmentation and loss and mucoid extracellular matrix accumulation was present in the samples from TAV patients when compared with that from BAV patients (P < 0.001). However, correlation was poor for all variables when considering aortic diameter and histological abnormalities or age and histological abnormalities in both BAV and TAV patients. Our study demonstrates a greater incidence of severe histological abnormalities in TAV patients when compared with BAV patients.

Age-Related Changes in the Canine Aorta.

Degenerative changes in the aorta are commonly observed in both dogs and humans, and those changes that occur with age morphologically overlap with those observed in genetic or degenerative diseases. Therefore, recognition of age-related aortic changes is important for diagnosticians, as such histologic findings should be distinguished from lesions of specific diseases. The aortas from 37 dogs without clinical cardiovascular disease ranging in age from 2 months to 15 years were divided into 3 cohorts to assess age-relatedness, and evaluated histologically using standardized nomenclature and diagnostic criteria adapted and modified from the human literature. We found that the histopathologic severity scores for intimal thickening, translamellar medial fibrosis, loss of smooth muscle cell nuclei, and medial microcalcification were higher in older dogs, whereas the scores for both intralamellar and translamellar mucoid extracellular matrix accumulation ("cystic medial necrosis") were not different among age groups. Dogs with translamellar medial fibrosis and aortic medial microcalcification were significantly older compared with dogs without these findings, while the presence of aortic medial chondro-osseous metaplasia was not related to age. Taken together, we demonstrate a range of age-related aortic histologic changes in dogs without clinical cardiovascular disease and suggest that integration of signalment and clinical data can aid in the differentiation of such findings from non-age-related disease processes.

Impact of histopathological changes in ascending aortic diseases

AimsTo better understand relationship between histological medial degenerative changes (MDC), pathological status [thoracic aorta aneurysm (TAA), thoracic aorta dissection (TAD), bicuspid aortic valve (BAV), and non-BAV] and aortic size at imaging. Methods and resultsWe collected 496 ascending aorta surgical specimens from patients with degenerative aortic diseases (mean age, 61 years) whose imaging data were available, including BAV in 191 (TAD 4%, TAA 96%) and with non-BAV in 305 (TAD 45%, TAA 55%). We analyzed them according to the pathology consensus statement and scored MDC [elastic fiber fragmentation and/or loss (EFFL); smooth muscle nuclei loss (SMNL); mucoid extracellular matrix accumulation (MEMA), intralamellar (I) or translamellar (T)] and measured medial wall thickness on correlation with imaging data and the status (TAA, TAD, BAV, or non-BAV). In TAA subset, EFFL, SMNL and MEMA-T scores were lower in BAV than in non-BAV. In relation to the aortic diameter, EFFL, SMNL and MEMA-T scores were more important in TAD subset than in TAA at the small aortic diameters. Independent predictors of aortic dissection included thicker medial wall (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.4 to 17.6; p < 0.0001) and greater SMNL score (OR, 1.2; 95% CI, 1.1 to 1.3; p = 0.003). ConclusionsThis large cohort study confirms that non-BAV aortas present higher MDC scores than BAV aortas. Higher MDC scores are correlated with increased aortic diameter. TAD can occur not infrequently in smaller aortas associated with high MDC scores. This suggests that risk stratification of aortic dissection based on aorta dimensions is imperfect.