Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome.

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.

Circ_0000006 and circ_0000160 regulate hsa-let-7e-5p/UBQLN4 axis in aortic dissection progression.

Aortic aneurysms (AA) and aorta dissection (AD) are life-threatening conditions with a rising incidence and high mortality rate. Recent research has linked non-coding RNAs to the regulation of AA and AD progression. In this study, we performed circRNA sequencing, microRNA (miRNA) sequencing, and messenger RNA (mRNA) sequencing on plasma samples from AA and AD patients to identify the key circRNA-miRNA-mRNA axis involved in the transition from AA to AD. Our results showed elevated levels of circ_0000006 and circ_0000160, along with decreased levels of hsa-let-7e-5p in AD samples compared to AA samples. Predictive analysis suggested that circ_0000006 and circ_0000160 potentially target hsa-let-7e-5p, which in turn may bind to the mRNA of Ubiquilin 4 (UBQLN4). In an AD cell model using vascular smooth muscle cells (VSMCs), silencing circ_0000006 and circ_0000160 attenuated the effects of platelet-derived growth factor (PDGF)-induced phenotypic changes, proliferation, and migration. This effect was partially reversed by inhibiting hsa-let-7e-5p. Furthermore, we found that overexpression of UBQLN4 counteracted the effects of hsa-let-7e-5p, suggesting UBQLN4 as a downstream mediator of hsa-let-7e-5p. In an animal model of AD, knockdown of circ_0000006 and circ_0000160 also showed protective effects against aortic septation. Overall, our findings indicate that the upregulation of circ_0000006 and circ_0000160 contributes to the progression from AA to AD by influencing abnormal phenotypic changes, migration, and proliferation of VSMCs. The Hsa-let-7e-5p/UBQLN4 axis may play a critical role in AD development. Targeting circ_0000006 and circ_0000160 could be a potential therapeutic strategy for preventing the progression of AD.

Region-specific delamination strength of ascending thoracic aortic aneurysm of elderly hypertensive patients with bicuspid and tricuspid aortic valves.

Both ageing and hypertension are clinical factors that may lead to a higher propensity for dissection or rupture of ascending thoracic aortic aneurysms (ATAAs). This study sought to investigate effect of valve morphology on regional delamination strength of ATAAs in the elderly hypertensive patients. Whole fresh ATAA samples were harvested from 23 hypertensive patients (age, 71 ± 8 years) who underwent elective aortic surgery. Peeling tests were performed to measure region-specific delamination strengths of the ATAAs, which were compared between patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). The regional delamination strengths of the ATAAs were further correlated with patient ages and aortic diameters for BAV and TAV groups. In the anterior and right lateral regions, the longitudinal delamination strengths of the ATAAs were statistically significantly higher for BAV patients than TAV patients (33 ± 7 vs. 23 ± 8 mN/mm, p = 0.01; 30 ± 7 vs. 19 ± 9 mN/mm, p = 0.02). For both BAV and TAV patients, the left lateral region exhibited significantly higher delamination strengths in both directions than the right lateral region. Histology revealed that disruption of elastic fibers in the right lateral region of the ATAAs was more severe for the TAV patients than the BAV patients. A strong inverse correlation between longitudinal delamination strength and age was identified in the right lateral region of the ATAAs of the TAV patients. Results suggest that TAV-ATAAs are more vulnerable to aortic dissection than BAV-ATAAs for the elderly hypertensive patients. Regardless of valve morphotypes, the right lateral region may be a special quadrant which is more likely to initiate dissection when compared with other regions.

The distribution of the depth of aortic dissection and the correlation of the dissection depth index with other parameters.

BACKGROUND: In patients with aortic dissection, the aortic wall is separated into two layers along a dissection plane. In this study, a survey was performed to investigate the distribution of the depth of dissection plane and its correlation with other clinical and pathological parameters to help understand and expand the current knowledge of aortic dissection. METHODS: Pathology information system were searched for patients with aortic dissection who had undergone aortic replacement between 2019 and 2022 in Wuhan Asia General Hospital. The depth of dissection plane and dissection depth index were measured in the area around the edge of dissection plane. Correlation between parameters was calculated using Spearman's rank correlation coefficient. RESULTS: 124 patients were included in this study. The depth of dissection plane ranged from 533 to 2335 microns, and the 5th percentile was 778 microns. The dissection depth index ranged from 0.320 to 0.972, and the 5th percentile was 0.503. The correlation coefficients were -0.305 (P=.0007), -0.259 (P=0.0111), 0.188 (P=0.0367), 0.189 (P=0.0359) respectively for male gender, the length of aortic dissection, atherosclerosis, and translamellar mucoid extracellular matrix accumulation. CONCLUSIONS: In 95% of patients with aortic dissection, the depth of dissection plane is larger than 778 microns, and the dissection depth index is greater than 0.503. In other words, aortic dissection rarely occurs in the inner 50.3% of the aortic media. The dissection depth index is negatively correlated with male gender and the length of aortic dissection, and positively correlated with atherosclerosis and translamellar mucoid extracellular matrix accumulation.

Histone deacetylase 9-mediated phenotypic transformation of vascular smooth muscle cells is a potential target for treating aortic aneurysm/dissection.

Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the ß-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.

Histopathological Gap in Aortic Diseases: A Prospective Analysis.

Aortic dissection (AD) is a critical cardiovascular condition with the potential for devastating consequences. This study evaluated the histological changes in the aorta wall in patients with AD and aortic aneurysm (AA) who received surgical aortic replacement. Histopathological data showed that modifications of the media layer (p = 0.0197), myxomatous aspect (p = 0.0001), and subendothelial layer degeneration (p = 0.0107) were more frequently seen in AA versus AD samples. Patients with AA were approximately twice as likely to develop histological changes than those with AD (p = 0.0037). Patients with moderate or severe medial degeneration had a higher chance of developing AD (p = 0.0001). Because the histopathological score proved to be a predictor of both in-hospital and overall mortality, its evaluation should become the standard of care in any patients who undergo aortic replacement. Individualized postoperative management might be influenced by the histopathological aspect of the aortic layer.

Smooth Muscle Heterogeneity and Plasticity in Health and Aortic Aneurysmal Disease.

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching to contribute to the deteriorating aortic wall structure. Recently, the unprecedented heterogeneity and diversity of VSMCs and their complex relationship to aortic aneurysms (AAs) have been revealed by high-resolution research methods, such as lineage tracing and single-cell RNA sequencing. The aortic wall consists of VSMCs from different embryonic origins that respond unevenly to genetic defects that directly or indirectly regulate VSMC contractile phenotype. This difference predisposes to hereditary AAs in the aortic root and ascending aorta. Several VSMC phenotypes with different functions, for example, secreting VSMCs, proliferative VSMCs, mesenchymal stem cell-like VSMCs, immune-related VSMCs, proinflammatory VSMCs, senescent VSMCs, and stressed VSMCs are identified in non-hereditary AAs. The transformation of VSMCs into different phenotypes is an adaptive response to deleterious stimuli but can also trigger pathological remodeling that exacerbates the pathogenesis and development of AAs. This review is intended to contribute to the understanding of VSMC diversity in health and aneurysmal diseases. Papers that give an update on VSMC phenotype diversity in health and aneurysmal disease are summarized and recent insights on the role of VSMCs in AAs are discussed.

Influence of aortic aneurysm on the local distribution of NO and O2 using image-based computational fluid dynamics.

There is a pressing need to establish novel biomarkers to predict the progression of thoracic aortic aneurysm (TAA) dilatation. Aside from hemodynamics, the roles of oxygen (O2) and nitric oxide (NO) in TAA pathogenesis are potentially significant. As such, it is imperative to comprehend the relationship between aneurysm presence and species distribution in both the lumen and aortic wall. Given the limitations of existing imaging methods, we propose the use of patient-specific computational fluid dynamics (CFD) to explore this relationship. We have performed CFD simulations of O2 and NO mass transfer in the lumen and aortic wall for two cases: a healthy control (HC) and a patient with TAA, both acquired using 4D-flow magnetic resonance imaging (MRI). The mass transfer of O2 was based on active transport by hemoglobin, while the local variations of the wall shear stress (WSS) drove NO production. Comparing hemodynamic properties, the time-averaged WSS was considerably lower for TAA, while the oscillatory shear index and endothelial cell activation potential were notably elevated. O2 and NO showed a non-uniform distribution within the lumen and an inverse correlation between the two species. We identified several locations of hypoxic regions for both cases due to lumen-side mass transfer limitations. In the wall, NO varied spatially, with a clear distinction between TAA and HC. In conclusion, the hemodynamics and mass transfer of NO in the aorta exhibit the potential to serve as a diagnostic biomarker for TAA. Furthermore, hypoxia may provide additional insights into the onset of other aortic pathologies.

Pregnancy-associated aortopathy and sudden postpartum death.

A 39-year-old woman who had undergone an uncomplicated elective cesarean section for a low-lying placenta collapsed and died the following day. At autopsy, there was dissection of an aneurysmally-dilated thoracic aorta with 400 mls of fluid and clotted blood in the pericardial sac. There were no features of Marfan syndrome or other connective tissue disorders. Histology revealed thinning of the aortic wall with fragmentation of elastic fibers and no inflammation. Vessels elsewhere were normal. This case demonstrates a rare complication of pregnancy that may not present until after delivery with unexpected collapse and sudden death. Predisposing factors include an increased cardiac output, reduction in systemic vascular resistance, an increase in left ventricular muscle mass, and alterations in serum progesterone and estrogen levels which may cause structural changes to the aortic wall. The possibility of syndromic and familial connective tissue disorders should also be considered.

[Clinical characteristics and placental pathology analysis of 14 cases of pregnancy with aortic dissection/aortic aneurysm].

Objective: To investigate the pathological changes of placenta in pregnant women with aortic dissection/aneurysm and their relationship with clinical features. Methods: The placental samples of 14 pregnant women with aortic dissection/aneurysm diagnosed from January 2012 to October 2021 and 10 normal placental samples of pregnant women from January 2021 to December 2021 at Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, China were selected. Routine H&E staining and immunohistochemistry were used to analyze the histological features under light microscope. The clinical data were also analyzed. Results: The age of 14 pregnant patients with aortic dissection/aneurysm for placental examination ranged from 22 to 38 years (median, 28 years). The gestational ages ranged from 22 to 39 weeks (median, 34 weeks). The pregnancy of second trimester was noted in 2 cases, and the third trimester in 12 cases. All cases were singleton pregnancy. Seven cases were Stanford type A aortic dissection, 6 cases were Stanford type B aortic dissection, and one case was aortic root aneurysm. Four of the pregnant women underwent aortic dissection surgery after caesarean section, three underwent caesarean section after aortic dissection surgery, and seven underwent both caesarean section and aortic dissection procedures. Among the newborns, 2 cases were full-term birth, and 12 cases were premature birth. Twelve cases had alive newborns, and 2 cases stillbirths. Fetal/placental weight ratio (FPR)<10th percentile was in 5 cases and FPR>90th percentile in one case. Compared with the normal group, accelerated villus maturation and distal villus dysplasia were more frequently found in pregnancy with aortic dissection group (P<0.05). There was no significant difference in villi infarction and decidua vascular lesions between the two groups (P>0.05), nor was there correlation between the type of aortic dissection and distal villus dysplasia and accelerated villus maturation of placentas (P>0.05). The number of villous interstitial blood vessels in the placentas of pregnancy with aortic dissection group was significantly fewer than that in the normal control group (P<0.01). Conclusions: There are considerable pathological changes in the placentas of pregnant women with aortic dissection/aneurysm. The main histological features are accelerated villus maturation and distal villus dysplasia, which are manifestations of villous ischemia and hypoxia, and also a part of the placental pathological manifestations of maternal vascular dysperfusion.

[Aortic valve repair surgery : state of the art and clinical experience of the university hospital center of Liege]. / Chirurgie de réparation de la valve aortique : statut actuel de la technique et expérience clinique du CHU de Liège.

In the past 20 years, there has been a real development of aortic valve repair techniques with an increasing number of publications describing the long-term benefits of aortic valve repair in terms of survival, freedom from major adverse valve related-events and reoperations. Aortic valve repair can now be considered as a valuable alternative to prosthetic valve replacement in patients with dystrophic ascending aorta pathology associated or not to aortic insufficiency with pliable leaflets. In this paper, the authors describe the state of the art of aortic valve repair and present their clinical experience with aortic valve repair surgery in the university hospital center of Liege from April 2021 to September 2022.

Les techniques de réparation de la valve aortique se sont considérablement développées ces 20 dernières années. Plusieurs publications confirment les bénéfices à long terme de ces techniques en termes de survie, d'absence de complications majeures et de réinterventions pour récidive d'insuffisance aortique. La réparation de la valve aortique apparaît ainsi comme une véritable alternative au remplacement valvulaire aortique prothétique chez certains patients qui présentent une pathologie dystrophique de l'aorte ascendante associée ou non à une insuffisance aortique sur valve souple. Dans cet article, les auteurs parcourent la littérature actuelle sur le sujet et décrivent leur expérience clinique avec la chirurgie de réparation de la valve aortique au sein du centre hospitalier universitaire de Liège d'avril 2021 à septembre 2022.

Differences between inflammatory cells infiltrated into tunica intima, media, and adventitia of ascending aortic aneurysms within diabetic and hypertensive patients.

The risk factors that are the most significant for the development of most cardiovascular diseases are arterial hypertension (AH), type 2 diabetes (DM), and inflammation. However, for the development of aortic aneurysms, DM is not one of them. Our study aimed to evaluate the difference between inflammatory infiltration in three individual layers of the ascending aortic aneurysm within diabetic and hypertensive patients. Forty-five patients aged 36 to 80 were divided into a group with diabetic patients without AH (group DM, N=8) and hypertensive patients without DM (group AH, N=37). For the histological analysis, aortic aneurysms were stained with hematoxylin eosin and Movat. We used immunochemical methods to detect pro- (M1), anti-inflammatory (M2) macrophages, T-helper, T-killer cells, B cells, and plasma cells. Statistical analysis was done by independent-samples Kruskal-Wallis test adjusted by Bonferroni correction for multiple tests (P<0.05). We found no difference in the volume density of collagen, elastin, vascular smooth muscle cells (VSMC), and ground substance between groups. In the DM group, there were significantly fewer M2, T-helpers, and T-killers in the media than in the intima and the adventitia (P<0.05). There were no significant differences in the number of M1, B, and plasma cells between all three vascular layers (P<0.05). In the AH group, there were significantly fewer B and plasma cells, T-helper, T-killer cells, M1, and M2 in the media than in the intima and adventitia (P<0.05). Our results conclude that the tunica media in the aneurismal wall of the AH group retained immune privilege. In contrast, in the DM group, all three layers were immune-privileged.

Hemodynamic Study of Stanford Type B Aortic Dissection Based on Ex Vivo Porcine Aorta Models.

BACKGROUND: In this study, we aimed to evaluate hemodynamic influence of the dissected aortic system via various ex vivo type B aortic dissection (AD) models. METHODS: Twenty-four raw porcine aortas were harvested and randomly divided into 4 groups to create various aortic models. Model A was the control group, while models B to D indicated the AD group, where models B and C presented a proximal primary entry with the false lumen (FL) lengths of 15 and 20 cm, respectively, and model D presented a 20 cm FL with a proximal primary entry and a distal reentry. All the aortic models were connected to a mock circulation loop to attain the realistic flow and pressure status. The flow distribution rate (FDR) of the aortic branches was calculated. Doppler ultrasound was applied to visualize the AD structure and to attain the velocity of flow in both the true and false lumens. Several sections of the AD were stained with hematoxylin and eosin for histologic evaluation after the experiment. RESULTS: This study demonstrated that higher pressures were found for the AD group compared with the control group. The mean systolic pressures at the inlet of models A to D were 113.34±0.81, 120.58±0.52, 117.76±0.82, and 115.87±0.42 mm Hg, respectively. The FDRs of the celiac artery in models A to D were 8.65%, 8.32%±0.15%, 7.87%±0.13%, and 8.03%±0.21%, respectively. By ultrasound visualization, the velocity of the flow at the entry to the FL in the AD group ranged in 10 to 92 cm/s. The dissection flap presented pulsatile movement, especially in the models B and C which contained 1 primary entry without distal reentries. Histological examinations indicated that AD was located between the intimal and medial layers. CONCLUSIONS: Our ex vivo models demonstrated that the configuration of the dissected aorta influenced the pressure distribution. Moreover, the dissection flap affected the FDR of the aortic branches that possibly inducing malperfusion syndrome.

NCOR1 maintains the homeostasis of vascular smooth muscle cells and protects against aortic aneurysm.

Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays critical roles in the pathogenesis of aortic aneurysm (AA). The function of nuclear receptor corepressor1 (NCOR1) in regulation of VSMC phenotype and AA is unclear. Herein, using smooth muscle NCOR1 knockout mice, we demonstrated that smooth muscle NCOR1 deficiency decreased both mRNA and protein levels of contractile genes, impaired stress fibers formation and RhoA pathway activation, reduced synthesis of elastin and collagens, and induced the expression and activity of MMPs, manifesting a switch from contractile to degradative phenotype of VSMCs. NCOR1 modulated VSMC phenotype through 3 different mechanisms. First, NCOR1 deficiency increased acetylated FOXO3a to inhibit the expression of Myocd, which downregulated contractile genes. Second, deletion of NCOR1 derepressed NFAT5 to induce the expression of Rgs1, thus impeding RhoA activation. Third, NCOR1 deficiency increased the expression of Mmp12 and Mmp13 by derepressing ATF3. Finally, a mouse model combined apoE knockout mice with angiotensin II was used to study the role of smooth muscle NCOR1 in the development of AA. The results showed that smooth muscle NCOR1 deficiency increased the incidence of aortic aneurysms and exacerbated medial degeneration in angiotensin II-induced AA mouse model. Collectively, our data illustrated that NCOR1 interacts with FOXO3a, NFAT5, and ATF3 to maintain contractile phenotype of VSMCs and suppress AA development. Manipulation of smooth muscle NCOR1 may be a potential approach for AA treatment.

Clinical characteristics and placental pathology analysis of 14 cases of pregnancy with aortic dissection/aortic aneurysm / 中华病理学杂志

Objective: To investigate the pathological changes of placenta in pregnant women with aortic dissection/aneurysm and their relationship with clinical features. Methods: The placental samples of 14 pregnant women with aortic dissection/aneurysm diagnosed from January 2012 to October 2021 and 10 normal placental samples of pregnant women from January 2021 to December 2021 at Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, China were selected. Routine H&E staining and immunohistochemistry were used to analyze the histological features under light microscope. The clinical data were also analyzed. Results: The age of 14 pregnant patients with aortic dissection/aneurysm for placental examination ranged from 22 to 38 years (median, 28 years). The gestational ages ranged from 22 to 39 weeks (median, 34 weeks). The pregnancy of second trimester was noted in 2 cases, and the third trimester in 12 cases. All cases were singleton pregnancy. Seven cases were Stanford type A aortic dissection, 6 cases were Stanford type B aortic dissection, and one case was aortic root aneurysm. Four of the pregnant women underwent aortic dissection surgery after caesarean section, three underwent caesarean section after aortic dissection surgery, and seven underwent both caesarean section and aortic dissection procedures. Among the newborns, 2 cases were full-term birth, and 12 cases were premature birth. Twelve cases had alive newborns, and 2 cases stillbirths. Fetal/placental weight ratio (FPR)<10th percentile was in 5 cases and FPR>90th percentile in one case. Compared with the normal group, accelerated villus maturation and distal villus dysplasia were more frequently found in pregnancy with aortic dissection group (P<0.05). There was no significant difference in villi infarction and decidua vascular lesions between the two groups (P>0.05), nor was there correlation between the type of aortic dissection and distal villus dysplasia and accelerated villus maturation of placentas (P>0.05). The number of villous interstitial blood vessels in the placentas of pregnancy with aortic dissection group was significantly fewer than that in the normal control group (P<0.01). Conclusions: There are considerable pathological changes in the placentas of pregnant women with aortic dissection/aneurysm. The main histological features are accelerated villus maturation and distal villus dysplasia, which are manifestations of villous ischemia and hypoxia, and also a part of the placental pathological manifestations of maternal vascular dysperfusion.

Phospholipase Cε insufficiency causes ascending aortic aneurysm and dissection.

Phospholipase Cε (PLCε) is a phospholipase C isoform with a wide range of physiological functions. It has been implicated in aortic valve disorders, but its role in frequently associated aortic disease remains unclear. To determine the role of PLCε in thoracic aortic aneurysm and dissection (TAAD) we used PLCε-deficient mice, which develop aortic valve insufficiency and exhibit aortic dilation of the ascending thoracic aorta and arch without histopathological evidence of injury. Fourteen days of infusion of Plce1+/+ and Plce1-/- mice with angiotensin II (ANG II), which induces aortic dilation and dissection, led to sudden death secondary to ascending aortic dissection in 43% of Plce1-/- versus 5% of Plce1+/+ mice (P < 0.05). Medial degeneration and TAAD were detected in 80% of Plce1-/- compared with 10% of Plce1+/+ mice (P < 0.05) after 4 days of ANG II. Treatment with ANG II markedly increased PLCε expression within the ascending aortic adventitia. Total RNA sequencing demonstrated marked upregulation of inflammatory and fibrotic pathways mediated by interleukin-1ß, interleukin-6, and tumor necrosis factor-α. In silico analysis of whole exome sequences of 258 patients with type A dissection identified 5 patients with nonsynonymous PLCE1 variants. Our data suggest that PLCε deficiency plays a role in the development of TAAD and aortic insufficiency.NEW & NOTEWORTHY We describe a novel phenotype by which PLCε deficiency predisposes to aortic valve insufficiency and ascending aortic aneurysm, dissection, and sudden death in the setting of ANG II-mediated hypertension. We demonstrate PLCE1 variants in patients with type A aortic dissection and aortic insufficiency, suggesting that PLCE1 may also play a role in human aortic disease. This finding is of very high significance because it has not been previously demonstrated that PLCε directly mediates aortic dissection.

Medial degeneration and atherosclerosis show discrete variance around the circumference of ascending aorta aneurysms.

Medial degeneration is the most common histological finding in ascending aortic aneurysms with lesser but significant involvement by atherosclerosis. The overall extent and severity can be potentially underrated because of their uneven distribution and macroscopic inconspicuousness of medial degeneration. This study aims to compare the distribution of degenerative and atherosclerotic lesions around ascending aorta circumference, also considering aortic valve cuspidity. We evaluated 88 cases of resected ascending aortae, 25 with a tricuspid aortic valve and 63 with a malformed aortic valve, oriented by a cardiac surgeon and sent for pathological examination. We applied the consensus documents from 2015 and 2016 for microscopic evaluation of aortic specimens. The medial degeneration and atherosclerosis were graded semi-quantitatively for each aortic quadrant: convexity, anterior wall, concavity, and posterior wall. Nearly all quadrants showed at least mild medial degeneration; more severe findings of medial degeneration and atherosclerosis were in the aneurysms associated with the tricuspid valve. In the aneurysms with the tricuspid aortic valve, there was more frequent and more severe atherosclerosis at the concavity than at the anterior wall (p = .046); the frequency and severity of medial degeneration did not differ significantly. The aneurysms with a malformed aortic valve showed more severe medial degeneration at the concavity compared to the convexity (p = .011); atherosclerosis was less common and did not show any significant differences. More than half of the samples also revealed at least a one-grade (mostly one-grade) difference among the quadrants in individual cases for both atherosclerosis and medial degeneration. Extreme differences were rare except for atherosclerosis in the tricuspid group. The results revealed only slight overall differences around the aortic circumference, with concavity being the most susceptible. Still, thanks to occurring inter- and intraindividual variability, the examination of all quadrants seems meaningful not to miss the most severe changes and to underscore the findings.

Ascending aortic aneurysm associated with lymphoplasmacytic thoracic aortitis mimics acute type A intramural hematoma - case report.

INTRODUCTION: Lymphoplasmacytic thoracic aortitis is still underrecognized cause of thoracic aortic aneurysm. CASE REPORT: We herein report a case of symptomatic inflammatory ascending aortic aneurysm and pericarditis diagnosed on CT scan as acute type A intramural hematoma. Patient underwent emergency supracoronary ascending aorta replacement with a prosthetic graft. Marked inflammatory thickening of aneurysm wall was the intraoperative finding. Histopathologic examination of the excised aortic tissue showed inflammation with lymphoplasmacytic pattern of aortitis. CONCLUSION: This case demonstrates that lymphoplasmacytic aortitis may mimic symptoms and radiological findings of intramural hematoma.

High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease.

Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.

Matricellular proteins: Potential biomarkers and mechanistic factors in aortic aneurysms.

Aortic aneurysms, including thoracic aortic aneurysms and abdominal aortic aneurysms, are life-threatening macrovascular diseases with high mortality. The already known key mechanisms implicated in aortic aneurysm pathogenesis involve the remodeling of the extracellular matrix and a set of cellular responses, such as inflammation, oxidative stress and vascular smooth muscle cell dysfunction. Matricellular proteins constitute a group of nonstructural extracellular proteins that link the interaction between cells and their extracellular microenvironment and have been widely reported in different diseases, including aortic aneurysms. In the present review, we summarize the role of various matricellular proteins in the pathogenesis and progression of aortic aneurysms, as well as address the possibility of using these proteins as biomarkers and pathogenic factors, to highlight their clinical significance in aortic aneurysms.