Progression Of Aortic Disease Research Articles

Effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve-related aortopathy

AimsThe aim of this study is to evaluate the effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve (BAV)-related aortopathy and ascending phenotype. MethodsConsecutive paediatric patients (≤16 years) with BAV and ascending aorta (AsAo) dilation (z-score > 3) were enrolled in this observational retrospective cohort study. Patients receiving prophylactic treatment with either atenolol (0.5 to 1.0 mg/kg/daily) or losartan (0.7 to 1.4 mg/kg/daily) were compared with those who did not receive medical prophylaxis (control group). The primary outcome of interest was the annual rate of change in maximal AsAo diameter z-score in the treatment and control groups. ResultsFrom a cohort of 1005 patients, 120 (mean age 11.3 ± 4.5 years, 82% males) fulfilled the inclusion criteria and were included in the study. Patients in the treatment and control group had similar age, sex, family history of BAV, BAV morphology, and baseline AsAo diameter. During a median follow-up of 7.1 years (interquartile range 3.8–10.2), no differences were observed in the annual growth rate of aortic diameter z-score between patients on treatment and controls. The prevalence of aortic diameter progression was similar in the treatment and control groups, and treatment with atenolol or losartan was not associated with a lower rate of aortic disease progression. ConclusionsThe findings revealed no significant difference in the annual aortic growth rate between treated and untreated patients. Larger cohort studies or, ideally, randomized clinical controlled trials are needed to validate these findings.

Blood flow assessment technology in aortic surgery: a narrative review.

Blood flow assessment is an emerging technique that allows for assessment of hemodynamics in the heart and blood vessels. Recent advances in cardiovascular imaging technologies have made it possible for this technique to be more accessible to clinicians and researchers. Blood flow assessment typically refers to two techniques: measurement-based flow visualization using echocardiography or four-dimensional flow magnetic resonance imaging (4D flow MRI), and computer-based flow simulation based on computational fluid dynamics modeling. Using these methods, blood flow patterns can be visualized and quantitative measurements of mechanical stress on the walls of the ventricles and blood vessels, most notably the aorta, can be made. Thus, blood flow assessment has been enhancing the understanding of cardiac and aortic diseases; however, its introduction to clinical practice has been negligible yet. In this article, we aim to discuss the clinical applications and future directions of blood flow assessment in aortic surgery. We then provide our unique perspective on the technique's translational impact on the surgical management of aortic disease. Articles from the PubMed database and Google Scholar regarding blood flow assessment in aortic surgery were reviewed. For the initial search, articles published between 2013 and 2023 were prioritized, including original articles, clinical trials, case reports, and reviews. Following the initial search, additional articles were considered based on manual searches of the references from the retrieved literature. In aortic root pathology and ascending aortic aneurysms, blood flow assessment can elucidate postoperative hemodynamic changes after surgical reconfiguration of the aortic valve complex or ascending aorta. In cases of aortic dissection, analysis of blood flow can predict future aortic dilatation. For complicated congenital aortic anomalies, surgeons may use preoperative imaging to perform "virtual surgery", in which blood flow assessment can predict postoperative hemodynamics for different surgical reconstructions and assist in procedural planning even before entering the operating room. Blood flow assessment and computational modeling can evaluate hemodynamics and flow patterns by visualizing blood flow and calculating biomechanical forces in patients with aortic disease. We anticipate that blood flow assessment will become an essential tool in the treatment planning and understanding of the progression of aortic disease.

Comparison of open thoracoabdominal repair for chronic aortic dissections and aneurysms

ObjectiveAortic dissection is common in patients undergoing open surgical repair of thoracoabdominal aortic aneurysms (TAAAs). Most often, dissection is chronic and is associated with progressive aortic dilatation. Because contemporary outcomes in chronic dissection are not clearly understood, we compared patient characteristics and outcomes after open TAAA repair between patients with chronic dissection and those with non-dissection aneurysm. MethodsWe retrospectively analyzed data from 3470 open TAAA repairs performed in a single practice. Operations were for non-dissection aneurysm in 2351 (67.8%) and chronic dissection in 1119 (32.2%). Outcomes included operative mortality and adverse events, a composite variable comprising operative death and persistent (present at discharge) stroke, paraplegia, paraparesis, and renal failure necessitating dialysis. Logistic regression identified predictors of operative mortality and adverse events. Time-to-event analyses examined survival, death, repair failure, subsequent progressive repair, and survival free of failure or subsequent repair. ResultsCompared with patients with non-dissection aneurysm, those with chronic dissection were younger, had fewer atherosclerotic risk factors, and were more likely to have heritable thoracic aortic disease and undergo extent II repair. The operative mortality rate was 8.5% (n = 296) overall and was higher in non-dissection aneurysm patients (n = 217; 9.2%) than in chronic dissection patients (n = 79; 7.1%; P = .03). Adverse events were less frequent (P = .01) in patients with chronic dissection (n = 145; 13.0%), 22 (2.0%) of whom had persistent paraplegia. Chronic dissection was not predictive of operative mortality (P = .5) or adverse events (P = .6). Operative mortality and adverse events, respectively, were independently predicted by emergency repair (odds ratio [OR], 3.46 and 2.87), chronic kidney disease (OR, 1.74 and 1.81), extent II TAAA repair (OR, 1.44 and 1.73), increasing age (OR, 1.04/year and 1.04/year), and increasing aortic cross-clamp time (OR, 1.02/minutes and 1.02/minutes). Patients with chronic dissection had lower 10-year unadjusted mortality (42% vs 69%) but more frequent repair failure (5% vs 3%) and subsequent repair for progressive aortic disease (11% vs 5%) than patients with non-dissection aneurysm (P < .001); these differences were no longer statistically significant after adjustment. ConclusionsOutcomes of open TAAA repair vary by aortic disease type. Emergency repairs and atherosclerotic diseases most commonly occur in patients with non-dissection aneurysm and independently predict operative mortality. Repair of chronic dissection is associated with low rates of adverse events, including operative mortality and persistent paraplegia, along with reasonable late survival and good durability. However, patients with chronic dissection tend to more commonly undergo subsequent repair to treat progressive aortic disease, which emphasizes the need for robust long-term imaging surveillance protocols.

The geometric evolution of aortic dissections: Predicting surgical success using fluctuations in integrated Gaussian curvature.

Clinical imaging modalities are a mainstay of modern disease management, but the full utilization of imaging-based data remains elusive. Aortic disease is defined by anatomic scalars quantifying aortic size, even though aortic disease progression initiates complex shape changes. We present an imaging-based geometric descriptor, inspired by fundamental ideas from topology and soft-matter physics that captures dynamic shape evolution. The aorta is reduced to a two-dimensional mathematical surface in space whose geometry is fully characterized by the local principal curvatures. Disease causes deviation from the smooth bent cylindrical shape of normal aortas, leading to a family of highly heterogeneous surfaces of varying shapes and sizes. To deconvolute changes in shape from size, the shape is characterized using integrated Gaussian curvature or total curvature. The fluctuation in total curvature (δK) across aortic surfaces captures heterogeneous morphologic evolution by characterizing local shape changes. We discover that aortic morphology evolves with a power-law defined behavior with rapidly increasing δK forming the hallmark of aortic disease. Divergent δK is seen for highly diseased aortas indicative of impending topologic catastrophe or aortic rupture. We also show that aortic size (surface area or enclosed aortic volume) scales as a generalized cylinder for all shapes. Classification accuracy for predicting aortic disease state (normal, diseased with successful surgery, and diseased with failed surgical outcomes) is 92.8±1.7%. The analysis of δK can be applied on any three-dimensional geometric structure and thus may be extended to other clinical problems of characterizing disease through captured anatomic changes.

Abstract 18753: Dynamic Phenotypic Transition of Smooth Muscle Cells During Human Ascending Thoracic Aortic Disease Progression: From Compensation in Aortic Aneurysm to Decompensation in Aortic Dissection

Introduction: Although ascending thoracic aortic aneurysm (ATAA) and ascending thoracic aortic dissection (ATAD) share common pathologic features of aortic degeneration, the specific elements that lead to rapid disease progression in ATAD remain poorly understood. We examined the molecular and cellular dynamics in smooth muscle cells (SMCs) of aortic tissues from ATAA and ATAD patients and further examined mechanisms in a mouse model. Methods: Single-cell RNA sequencing (scRNA-seq) analyses were performed in ascending aortic tissues from individuals without aortic disease (n=8), patients with ATAA without dissection (n=9), and patients with acute ATAD (n=9). Further, scRNA-seq and scATAC-seq were performed in ascending aortic tissues from mice infused with angiotensin II (AngII) or control mice; scRNA-seq analyses were performed on SMC-specific Tgfbr2 -/- mice. Results: Six SMC subtypes were identified in human aortic tissues. Cluster proportion and trajectory analyses indicated a profound SMC transition from contractile in control to extracellular matrix (ECM)-contractile phenotype in ATAA, however, was reduced in ATAD tissues. Instead, ATAD showed significant SMC transition to inflammatory phenotype. Consistently, many genes in ECM organization and muscle contraction, collectively termed compensatory response, were upregulated in ATAA but downregulated in ATAD tissues compared with controls, whereas inflammatory response and cell death pathway genes were significantly upregulated in ATAD compared with control and ATAA tissues. Cell-cell interaction, regulatory network, and motif analysis suggested that TGF-beta-MEF2C signaling contributed to the induction of the ECM-contractile SMC phenotype. MEF2C + SMCs exhibited the capacity of transition towards ECM-producing SMCs in both mouse and human aorta. SMC-specific Tgfbr2 -/- mice showed compromised SMC transition to ECM-producing phenotype. Conclusions: Our study reveals SMC phenotypic transitions to ECM-producing SMCs in ATAA and to inflammatory and pro-death SMCs in ATAD, which represent a compensatory response in ATAA and a decompensatory status in ATAD. TGF-beta-MEF2C, a novel regulatory axis, promoted the compensatory response in SMCs of the ascending aorta.

Unraveling the role of TGFβ signaling in thoracic aortic aneurysm and dissection using Fbn1 mutant mouse models

Although abnormal TGFβ signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, its precise role in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to elucidate the role of TGFβ signaling in three Fbn1 mutant mouse models representing a range of aortic disease from microdissection (without aneurysm) to aneurysm (without rupture) to aneurysm and rupture. Results indicated that reduced TGFβ signaling and increased mast cell proteases were associated with microdissection. In contrast, increased abundance of extracellular matrix proteins, which could be reporters for positive TGFβ signaling, were associated with aneurysm. Marked reductions in collagens and fibrillins, and increased TGFβ signaling, were associated with aortic rupture. Our data indicate that TGFβ signaling performs context-dependent roles in the pathogenesis of thoracic aortic disease.

Three-Dimensional Characterization of Aortic Root Motion by Vascular Deformation Mapping

The aorta is in constant motion due to the combination of cyclic loading and unloading with its mechanical coupling to the contractile left ventricle (LV) myocardium. This aortic root motion has been proposed as a marker for aortic disease progression. Aortic root motion extraction techniques have been mostly based on 2D image analysis and have thus lacked a rigorous description of the different components of aortic root motion (e.g., axial versus in-plane). In this study, we utilized a novel technique termed vascular deformation mapping (VDM(D)) to extract 3D aortic root motion from dynamic computed tomography angiography images. Aortic root displacement (axial and in-plane), area ratio and distensibility, axial tilt, aortic rotation, and LV/Ao angles were extracted and compared for four different subject groups: non-aneurysmal, TAA, Marfan, and repair. The repair group showed smaller aortic root displacement, aortic rotation, and distensibility than the other groups. The repair group was also the only group that showed a larger relative in-plane displacement than relative axial displacement. The Marfan group showed the largest heterogeneity in aortic root displacement, distensibility, and age. The non-aneurysmal group showed a negative correlation between age and distensibility, consistent with previous studies. Our results revealed a strong positive correlation between LV/Ao angle and relative axial displacement and a strong negative correlation between LV/Ao angle and relative in-plane displacement. VDM(D)-derived 3D aortic root motion can be used in future studies to define improved boundary conditions for aortic wall stress analysis.

Aortic valve replacement for moderate aortic stenosis during mitral surgery improves survival free from severe stenosis.

Optimal management of moderate aortic stenosis during surgery for another indication is unclear. We assessed the effects of surgical aortic valve replacement for moderate aortic stenosis during mitral surgery. An institutional mitral surgery database was queried for patients with preoperative moderate aortic stenosis. Patients were stratified by whether they underwent concomitant surgical aortic valve replacement. Morbidity was analyzed using Student's t tests, Wilcoxon rank sum, chi-squared, and Fisher's exact tests. Survival was analyzed using Kaplan-Meier estimation and Cox regression. Of 85 mitral surgery recipients with moderate aortic stenosis from 2012 to 2019, 62 (73%) underwent concomitant surgical aortic valve replacement. Surgical aortic valve replacement recipients were more likely to have bicuspid (11% vs. 0%, p = 0.019) or rheumatic (18% vs. 0%, p = 0.019) aortic valves, and to undergo mitral repair (32% vs. 9%, p = 0.028). Groups did not differ with respect to mitral etiology, New York Heart Association class, or cardiac intervention history (p > 0.05). Postoperatively, groups had similar stroke and gastrointestinal bleed rates (3% vs. 0% and 2% vs. 0% in the surgical aortic valve replacement vs. no surgical aortic valve replacement group respectively, both p > 0.99). Five-year survival free from severe aortic stenosis was higher in the surgical aortic valve replacement group (66% vs. 17%, p = 0.002). Surgical aortic valve replacement protected against the composite of death and progression to severe aortic stenosis at 5 years (hazard ratio: 0.32, p = 0.003). Surgical aortic valve replacement for moderate aortic stenosis at time of mitral surgery is a well-tolerated strategy to reduce aortic disease progression.

Fenestrated Endovascular Aortic Repair After Failed Endovascular Aortic Repair.

Fenestrated endovascular aortic repair (FEVAR) is technically more challenging when performed after a failing EVAR procedure (FEVAR after EVAR). This study aims to assess the technical outcome of FEVAR after EVAR and to identify factors that may influence complication rates. A retrospective observational study was conducted at a single department of vascular and endovascular surgery. The rate of FEVAR after EVAR compared to primary FEVAR is reported. Complication and primary unconnected fenestration (PUF) rates as well as survival were assessed for the FEVAR after EVAR cohort. PUF rates and operating time were also compared to all primary FEVAR patients. Patient characteristics and technical factors such as number of fenestrations or use of a steerable sheath were assessed as possible influencers on technical success when performing FEVAR after EVAR. Two hundred and nine fenestrated devices were implanted during the study period (2013 to April 2020). Thirty-five patients (16.7% of all FEVAR patients) had undergone FEVAR after EVAR and were included in the study. Overall survival at last follow-up (20.2±19.1 months) was 82.9% in FEVAR after EVAR patients. Rates of technical failure dropped significantly after 14 procedures (42.9% vs. 9.5%; p=0.03). Primary unconnected fenestrations were seen in 3 cases of FEVAR after EVAR (8.6%) and 14 of 174 primary FEVAR cases (8.0%; p>0.99). Operating time for FEVAR after EVAR was significantly higher than for primary FEVAR (301.1±110.5 minutes vs. 253.9±103.4 minutes; p=0.02). The availability of a steerable sheath was a significant predictor of reduced risk of PUFs, whereas age and gender, number of fenestrations or suprarenal fixation of the failed EVAR did not significantly influence PUF rates. Fewer technical complications were seen over the study period in FEVAR after EVAR patients. While rates of PUFs were not different from primary FEVAR, operating time was significantly longer in patients undergoing FEVAR for failed EVAR. Fenestrated EVAR can be a valuable and safe tool to treat patients with progression of aortic disease or type Ia endoleak after EVAR but may be more complex to achieve than primary FEVAR. This retrospective study assesses the technical outcome of fenestrated endovascular aortic repair (fenestrated EVAR; FEVAR) after prior EVAR. While rates of primary unconnected fenestrations were not different from primary FEVAR, operating time was significantly longer in patients undergoing FEVAR for failed EVAR. Fenestrated EVAR after prior EVAR may be technically more challenging than primary FEVAR procedures, but could be performed with equally good results in this patient cohort. FEVAR offers a feasible treatment option for patients with progression of aortic disease or type Ia endoleak after EVAR.

Biomechanical and transcriptional evidence that smooth muscle cell death drives an osteochondrogenic phenotype and severe proximal vascular disease in progeria.

Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process in proximal elastic arteries that was less evident in distal muscular arteries. Changes in aortic structure and function were then associated with changes in transcriptomics assessed via both bulk and single cell RNA sequencing, which suggested a novel sequence of progressive aortic disease: adverse extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotype that results in an accumulation of proteoglycans that thickens the aortic wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased central artery pulse wave velocity is known to drive left ventricular diastolic dysfunction, the primary diagnosis in progeria children. It appears that mechanical stresses above ~ 80kPa initiate this progressive aortic disease process, explaining why elastic lamellar structures that are organized early in development under low wall stresses appear to be nearly normal whereas other medial constituents worsen progressively in adulthood. Mitigating early mechanical stress-driven smooth muscle cell loss/phenotypic modulation promises to have important cardiovascular implications in progeria patients.

Global proteomic analysis reveals lysine succinylation contributes to the pathogenesis of aortic aneurysm and dissection

Protein lysine succinylation is a recently discovered posttranslational modification. This study examined the role of protein lysine succinylation in the pathogenesis of aortic aneurysm and dissection (AAD). 4D label-free LC-MS/MS analysis was used to perform the global profiles of succinylation in aortas obtained from 5 heart transplant donors, 5 patients with thoracic aortic aneurysm (TAA), and 5 patients with thoracic aortic dissection (TAD). In comparison to normal controls, we detected 1138 succinylated sites from 314 proteins in TAA, and 1499 sites from 381 proteins in TAD. Among these, 120 differentially succinylated sites from 76 proteins overlapped between TAA and TAD (|log2FC| > 0.585, p < 0.05). These differentially modified proteins were mainly localized in the mitochondria and cytoplasm, and were primarily involved in diverse energy metabolic processes, including carbon metabolism, amino acid catabolism, and β-oxidation of fatty acids. By establishing an in vitro model of lysine succinylation in vascular smooth muscle cells, we observed changes in the activities of three key metabolic enzymes (PKM, LDHA, and SDHA). These findings suggest that succinylation potentially contributes to the pathogenesis of aortic diseases, and presents a valuable resource for investigating the functional roles and regulatory mechanisms of succinylation in AAD. SignificanceAAD are interrelated life-threatening diseases associated with high morbidity and mortality. Although we discovered that lysine succinylation was significantly up-regulated in the aorta tissues of patients with AAD, its role in the progression of aortic diseases is largely unknown. We conducted a 4D label-free LC-MS/MS analysis and identified 120 differentially succinylated sites on 76 proteins that overlapped between TAA and TAD as compared to normal controls. Lysine succinylation may contribute to the pathogenesis of AAD by regulating energy metabolism pathways. The proteins containing succinylated sites could be served as potential diagnostic markers and therapeutic targets for aortic diseases.

Abstract 15325: Dynamic Change From Mitochondrial Compensation to Mitochondrial Failure During Aortic Disease Progression and Dissection Formation

Introduction: Ascending thoracic aortic aneurysm (ATAA) progression to dissection (ATAD) is associated with a high risk of mortality. Since the specific molecular and cellular changes leading to dissection are poorly understood, we compared transcriptome profiles of aortic smooth muscle cells (SMCs) between ATAD, ATAA, and controls. Methods: We performed single-cell RNA sequencing (scRNA-seq) of ascending aorta tissues from patients with acute ATAD (dissected and non-dissected areas were collected separately, 3 women, 5 men) and ATAA without dissection (3 women, 4 men), and from control subjects without aortic diseases (transplant donors, 3 women, 5 men). SMCs clusters were analyzed and immunofluorescence staining was performed to confirm expression of key genes. Mice exposed to β-aminopropionitrile monofumarate (BAPN) starting at P21 were used to investigate the changes of mitochondria-related genes during disease progression in undissected mice. Results: Compared with controls, SMCs in ATAA exhibited an adaptive response characterized by upregulation of a subset of focal adhesion and contractile genes and a pro-fibroblast phenotype. These expression changes were decreased in SMCs in ATAD, which instead exhibited significant increases in genes for inflammatory response, glycolysis, senescence and cell death. Additionally, mitochondrial genes including tricarboxylic acid (TCA) cycle genes (e.g. SDHB , FH , and MDH2 ) and mitochondria genome genes (e.g. MT-ND4 , MT-CO2 , and MT-CYB ), exhibited increased expression in ATAAs, and downregulated in ATADs. Immunofluorescence staining of corresponding proteins confirmed some key findings. Consistent with human data, scRNA-seq showed increased mitochondria-related genes in SMCs in BAPN mouse model at P35 when aneurysms form, which were decreased in the proximal aortic tissues after the onset of dissection deaths in surviving mice at P42. Conclusions: Our data suggest a dynamic change from mitochondrial compensation to failure with progression from normal to aortic aneurysms to dissections, which ultimately increases cell death pathways.

Increases in hydraulic conductance and solute permeability in a mouse model of ascending thoracic aortic aneurysm

Large elastic arteries, such as the aorta, contain concentric layers of elastic laminae composed mainly of the extracellular matrix protein elastin. The structure of the elastic laminae could affect transmural mass transport and contribute to aortic disease progression. We studied the effects of a genetic mutation (LoxM292R/+, referred to as MU) in mice associated with ascending thoracic aortic aneurysm (TAA) on the mass transport and elastic laminae structure. Solute absent fluid flux and hydraulic conductance through the ascending aortic wall were not significantly different between groups, however solute present fluid flux, hydraulic conductance, solute flux, and solute permeability of 4 kDa FITC-dextran were significantly increased in the MU group, indicating that movement of small molecules into the aortic wall is facilitated in MU mice. Quantification from light microscopy images of the ascending aorta showed no significant differences in wall thickness, or inner elastic lamina fenestration size and density, but an increase in the number of elastic laminae breaks in the MU group. Ultrastructural comparisons from transmission electron micrographs suggest less dense and disorganized elastic laminae in MU aorta that may also contribute to the transport differences. Our results provide an initial investigation into the connections between mass transport and elastic laminae structure, specifically in a genetic mouse aneurysm model, which can be further used to understand TAA pathology and develop treatment strategies.

Thoracic Aortic Dilation: Implications for Physical Activity and Sport Participation.

Thoracic aortic dilatation is a progressive condition that results from aging and many pathological conditions (i.e., connective tissue, inflammatory, shear stress disorders, severe valvular heart disease) that induce degenerative changes in the elastic properties, leading to the loss of elasticity and compliance of the aortic wall. Mild aortic root enlargement may be also observed in athletes and is considered as a normal adaptation to regular exercise training. On the other hand, high-intensity physical activity in individuals with a particular genetic substrate, such as those carrying gene variants associated with Marfan syndrome or other inherited aortopathies, can favor an excessive aortic enlargement and trigger an acute aortic dissection. The evaluation of the aortic valve and aortic root diameters, as well as the detection of a disease-causing mutation for inherited aortic disease, should be followed by a tailored decision about sport eligibility. In addition, the risk of aortic complications associated with sport in patients with genetic aortic disease is poorly characterized and is often difficult to stratify for each individual athlete. This review aims to describe the relationship between regular physical activity and aortic dilation, focusing on patients with bicuspid aortic valve and inherited aortic disease, and discuss the implications in terms of aortic disease progression and sport participation.

Impact of genotype on the progression of aortic disease in patients with Marfan syndrome and Loeys-Dietz syndrome

Marfan and Loeys-Dietz syndromes are connective tissue disorders characterized by high clinical variability. The major morbidity and mortality in both syndromes relate to the dilatation of the aorta predisposing to aortic tear. We investigated the putative relationship between the genotype, aortic growth speed and the occurrence of severe cardio vascular events (prophylactic surgery of the aortic root, aortic dissection or related death). We have performed a retrospective study of 102 patients with pathogenic variants in FBN1, TGFβR1 and R2 and SMAD3 genes followed at a Marfan reference center in France. The average age at the start of the study was 13.8 years and data were collected over 5 years. The FBN1 variants were classified as haploinsufficient (HI) or dominant negative (DN). Aortic diameters and aortic dilatation at the level of the Valsalva sinuses were assessed by echocardiography. No overall aortic growth difference was found between Marfan and Loeys-Dietz syndrome (1,14 vs. 1,11 mm/year, P = 0,74), neither between HI and DN groups (1,12 vs. 1,01 mm/year, P = 0,36). However, patients with a SMAD 3 mutation seem to have lower aortic growth than those in the TGFβ group (0,91 vs. 1,34 mm/year, P = 0,36). No difference concerning Valsalva sinus Z score evolution was found between these groups. We didn’t find any differences concerning the occurrence of cardio vascular events between Marfan and Loeys Dietz syndrome and their genetics subgroups. Aortic growth in men was significantly faster than in women (1,23 vs. 0,91 mm/year, P = 0,005). Marfan syndrome and Loeys-Dietz, as well as their genetics subgroups should be monitored similarly for the development of aortic root aneurysm. Like other phenotypic characteristics of these syndromes, the cardio vascular manifestations present a high variability among patients and a correlation genotype/phenotype is not informative for patient care. A possible exception is the TGFβ group, which may grow faster.

Outcomes of intramural hematoma involving the ascending aorta and extending into the descending thoracic aorta.

The optimal treatment of intramural hematoma (IMH) involving the ascending aorta remains controversial. This study aimed to analyze the results of the management of patients with acute IMH involving the ascending aorta and extending into the descending thoracic aorta, to compare outcomes of descending thoracic endovascular aortic repair (TEVAR) with that of medical therapy (MT), and to assess the risk factors associated with adverse aortic events. We retrospectively analyzed all patients diagnosed with acute IMH involving the ascending aorta and extending into the descending thoracic aorta from January 2012 to December 2019. The primary end points during follow-up were aortic disease-related death and adverse aorta-related events that required surgical or endovascular treatment, such as aortic rupture, the progression of aortic disease, or endoleak. We identified a total of 135 patients with acute IMH involving the ascending aorta and extending into the descending thoracic aorta, of whom 104 underwent descending TEVAR (group 1) and 31 were managed with MT (group 2). Freedom from adverse aorta-related events at 1, 3, and 5years was significantly higher for patients who underwent descending TEVAR compared with those managed with MT (89.2%, 88.2%, and 84.0% vs 74.2%, 74.2%, and 74.2%, respectively; P= .026). The 1-, 3-, and 5-year survival rates for patients in the descending TEVAR group was 100%, 100%, and 100%, respectively, which was significantly higher than the survival of the MT group: 93.5%, 93.5%, and 81.9%, respectively (P= .002). On a univariate analysis among patients receiving MT, those who suffered adverse aorta-related events showed a higher prevalence of renal insufficiency (55.6% vs 9.1%; P= .003). In MT patients, multivariate analysis showed that renal insufficiency was the only independent risk factor associated with adverse aorta-related events (hazard ratio, 8.691; 95% confidence interval, 2.056-36.737; P= .003). Based on our study, compared with MT, descending TEVAR might be the more favorable treatment for patients with IMH involving the ascending aorta and extending into the descending thoracic aorta. Patients with renal insufficiency are more likely to experience adverse aorta-related events, which implies the need for subsequent intervention or an increased risk of mortality. The risk factor would be helpful for clinical decision-making.

Association of sleep apnoea risk and aortic enlargement in Marfan syndrome

BackgroundMarfan syndrome (MFS) is a connective tissue disorder characterised by complex aortic pathology and a high prevalence of obstructive sleep apnoea (OSA). OSA produces intrathoracic transmural stresses that may accelerate...

Characterizing the cardiovascular phenotype of a new zebrafish model of Marfan syndrome

Abstract Background Marfan syndrome (MFS) is a rare disease caused by a defect in the fibrillin-1 gene (FBN1), with potentially severe cardiovascular manifestations. MFS patients are particularly susceptible to a progressive aortic dilation leading to potential dissection and wall rupture. No causal treatment for the disease is available and current medical treatment is aimed at slowing aortic disease progression to minimize severe complications. When indicated, surgical repair of the aortic defect is performed. Although these strategies have clearly led to improved survival, some patients still present with fatal complications. Purpose To generate a new flexible zebrafish model of MFS to gain a better understanding of the underlying pathophysiological mechanisms and to find new treatment options. Methods We used the CRISPR/Cas9 method to disrupt the 3 fibrillin genes in zebrafish (fbn1, fbn2a, and fbn2b). The Tg(kdrl:EGFP) reporter was used to visualize cardiovascular structure by fluorescent microscopy up to 8 days post fertilization (dpf). A subset of embryos was treated with the myosin inhibitor 2,3-butanedione monoxime (BDM). Results We found that zebrafish lacking fbn1 and/or fbn2a do not show any detectable phenotype during development. No evidence of induction of genetic compensation was found in these mutant lines. Zebrafish deficient in fbn2b however do show strong phenotypes, including fully penetrant finfold atrophy (Fig. 1A-B and E, arrowhead). On average 50% of homozygous fbn2b mutant (fbn2b−/−) zebrafish embryos show endocardial detachment (Fig. 1C-D; a:atrium, v:ventricle), leading to vascular embolism, pericardial edema (Fig. 1B, arrow), loss of blood flow, and ultimately death at 7–9 dpf. Interestingly, fbn2b−/− without endocardial detachment survive normally, but develop a dilated bulbus arteriosus phenotype during larval stages (Fig. 1F-G, arrow; 1H: diameter during minimal and maximal distension, *: P&amp;lt;0.05 and ***: P&amp;lt;0.001 by Sidak's post-test after Two-Way ANOVA). This anatomical structure is strongly related to the aortic root in humans, which is the predominant location of aortic dilation in MFS. All fbn2b−/− embryos show abnormal early development of the caudal vein as a cavernous structure lacking vessel integrity (Fig. 2, arrowheads). This phenotype resolves in embryos retaining normal blood flow. We found that fbn2b−/− embryos raised in BDM to inhibit blood flow show a more severe caudal vein phenotype than wild-type (WT) controls (Fig. 2, yellow line: severe vascular dilation). Conclusion Loss of fbn2b, but not the other fibrillin genes, in zebrafish results in cardiovascular manifestations overlapping with MFS. These data indicate that fbn2b−/− zebrafish can be a relevant model to explore the mechanisms leading from fibrillin deficiency to the cardiovascular symptoms observed in MFS. Our preliminary results suggest that there is an interplay between fibrillin deficiency and biomechanical signaling. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Fund Baillet Latour Grant for Medical Research Figure 1. Phenotype of fbn2b−/− larvaeFigure 2. Effect of blood flow in fbn2b−/−

Tryptophan Catabolism and Inflammation: A Novel Therapeutic Target For Aortic Diseases.

Aortic diseases are the primary public health concern. As asymptomatic diseases, abdominal aortic aneurysm (AAA) and atherosclerosis are associated with high morbidity and mortality. The inflammatory process constitutes an essential part of a pathogenic cascade of aortic diseases, including atherosclerosis and aortic aneurysms. Inflammation on various vascular beds, including endothelium, smooth muscle cell proliferation and migration, and inflammatory cell infiltration (monocytes, macrophages, neutrophils, etc.), play critical roles in the initiation and progression of aortic diseases. The tryptophan (Trp) metabolism or kynurenine pathway (KP) is the primary way of degrading Trp in most mammalian cells, disturbed by cytokines under various stress. KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), etc. Depends on the cell types, these metabolites can elicit both hyper- and anti-inflammatory effects. Accumulating evidence obtained from various animal disease models indicates that KP contributes to the inflammatory process during the development of vascular disease, notably atherosclerosis and aneurysm development. This review outlines current insights into how perturbed Trp metabolism instigates aortic inflammation and aortic disease phenotypes. We also briefly highlight how targeting Trp metabolic pathways should be considered for treating aortic diseases.

Inflammasomes in the Pathophysiology of Aortic Disease.

Aortic diseases comprise aneurysms, dissections, and several other pathologies. In general, aging is associated with a slow but progressive dilation of the aorta, along with increased stiffness and pulse pressure. The progression of aortic disease is characterized by subclinical development or acute presentation. Recent evidence suggests that inflammation participates causally in different clinical manifestations of aortic diseases. As of yet, diagnostic imaging and surveillance is mainly based on ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Little medical therapy is available so far to prevent or treat the majority of aortic diseases. Endovascular therapy by the introduction of covered stentgrafts provides the main treatment option, although open surgery and implantation of synthetic grafts remain necessary in many situations. Because of the risks associated with surgery, there is a need for identification of pharmaceutical targets interfering with the pathophysiology of aortic remodeling. The participation of innate immunity and inflammasome activation in different cell types is common in aortic diseases. This review will thus focus on inflammasome activities in vascular cells of different chronic and acute aortic diseases and discuss their role in development and progression. We will also identify research gaps and suggest promising therapeutic targets, which may be used for future medical interventions.