KLF15 maintains contractile phenotype of vascular smooth muscle cells and prevents thoracic aortic dissection by interacting with MRTFB.

Thoracic aortic dissection (TAD) is a highly dangerous cardiovascular disorder caused by weakening of the aortic wall, resulting in a sudden tear of the internal face. Progressive loss of the contractile apparatus in vascular smooth muscle cells (VSMCs) is a major event in TAD. Exploring the endogenous regulators essential for the contractile phenotype of VSMCs may aid the development of strategies to prevent TAD. Krüppel-like factor 15 (KLF15) overexpression was reported to inhibit TAD formation; however, the mechanisms by which KLF15 prevents TAD formation and whether KLF15 regulates the contractile phenotype of VSMCs in TAD are not well understood. Therefore, we investigated these unknown aspects of KLF15 function. We found that KLF15 expression was reduced in human TAD samples and ß-aminopropionitrile monofumarate-induced TAD mouse model. Klf15KO mice are susceptible to both ß-aminopropionitrile monofumarate- and angiotensin II-induced TAD. KLF15 deficiency results in reduced VSMC contractility and exacerbated vascular inflammation and extracellular matrix degradation. Mechanistically, KLF15 interacts with myocardin-related transcription factor B (MRTFB), a potent serum response factor coactivator that drives contractile gene expression. KLF15 silencing represses the MRTFB-induced activation of contractile genes in VSMCs. Thus, KLF15 cooperates with MRTFB to promote the expression of contractile genes in VSMCs, and its dysfunction may exacerbate TAD. These findings indicate that KLF15 may be a novel therapeutic target for the treatment of TAD.

S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages.

BACKGROUND: S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection. METHODS: Biotin-switch assay combined with liquid chromatography-tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and Apoe-/- mice infused with angiotensin II. Angiotensin II-induced aortic aneurysm model and ß-aminopropionitrile-induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis. RESULTS: Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and Apoe-/- mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-κB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis. CONCLUSIONS: SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-κB signaling pathway-dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.

Asiatic acid alleviates vascular remodeling in BAPN-induced aortic dissection through inhibiting NF-κB p65/CX3CL1 signaling.

Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong anti-inflammatory properties. Yet, its effects on ß-aminopropionitrile (BAPN)-triggered AD have not been clearly established. The objective is to determine whether AA attenuates adverse aortic remodeling in BAPN-induced AD and clarify potential molecular mechanisms. In vitro studies, RAW264.7 cells pretreated with AA were challenged with lipopolysaccharide (LPS), and then the vascular smooth muscle cells (VSMCs)-macrophage coculture system was established to explore intercellular interactions. To induce AD, male C57BL/6J mice at three weeks of age were administered BAPN at a dosage of 1 g/kg/d for four weeks. To decipher the mechanism underlying the effects of AA, RNA sequencing analysis was conducted, with subsequent validation of these pathways through cellular experiments. AA exhibited significant suppression of M1 macrophage polarization. In the cell coculture system, AA facilitated the transformation of VSMCs into a contractile phenotype. In the mouse model of AD, AA strikingly prevented the BAPN-induced increases in inflammation cell infiltration and extracellular matrix degradation. Mechanistically, RNA sequencing analysis revealed a substantial upregulation of CX3CL1 expression in BAPN group but downregulation in AA-treated group. Additionally, it was observed that the upregulation of CX3CL1 negated the beneficial impact of AA on the polarization of macrophages and the phenotypic transformation of VSMCs. Crucially, our findings revealed that AA is capable of downregulating CX3CL1 expression, accomplishing this by obstructing the nuclear translocation of NF-κB p65. The findings indicate that AA holds promise as a prospective treatment for adverse aortic remodeling by suppressing the activity of NF-κB p65/CX3CL1 signaling pathway.

ß-Aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice.

BACKGROUND: ß-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice. METHODS: BAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to BAPN dose, and mouse strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, the ascending and descending thoracic aortas were harvested after 1 week of BAPN administration before the appearance of overt pathology. RESULTS: BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-SMA (α-smooth muscle actin). One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the 2 aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. CONCLUSIONS: BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.

The AORTA Gene score for detection and risk stratification of ascending aortic dilation.

BACKGROUND AND AIMS: This study assessed whether a model incorporating clinical features and a polygenic score for ascending aortic diameter would improve diameter estimation and prediction of adverse thoracic aortic events over clinical features alone. METHODS: Aortic diameter estimation models were built with a 1.1 million-variant polygenic score (AORTA Gene) and without it. Models were validated internally in 4394 UK Biobank participants and externally in 5469 individuals from Mass General Brigham (MGB) Biobank, 1298 from the Framingham Heart Study (FHS), and 610 from All of Us. Model fit for adverse thoracic aortic events was compared in 401 453 UK Biobank and 164 789 All of Us participants. RESULTS: AORTA Gene explained more of the variance in thoracic aortic diameter compared to clinical factors alone: 39.5% (95% confidence interval 37.3%-41.8%) vs. 29.3% (27.0%-31.5%) in UK Biobank, 36.5% (34.4%-38.5%) vs. 32.5% (30.4%-34.5%) in MGB, 41.8% (37.7%-45.9%) vs. 33.0% (28.9%-37.2%) in FHS, and 34.9% (28.8%-41.0%) vs. 28.9% (22.9%-35.0%) in All of Us. AORTA Gene had a greater area under the receiver operating characteristic curve for identifying diameter ≥ 4 cm: 0.836 vs. 0.776 (P < .0001) in UK Biobank, 0.808 vs. 0.767 in MGB (P < .0001), 0.856 vs. 0.818 in FHS (P < .0001), and 0.827 vs. 0.791 (P = .0078) in All of Us. AORTA Gene was more informative for adverse thoracic aortic events in UK Biobank (P = .0042) and All of Us (P = .049). CONCLUSIONS: A comprehensive model incorporating polygenic information and clinical risk factors explained 34.9%-41.8% of the variation in ascending aortic diameter, improving the identification of ascending aortic dilation and adverse thoracic aortic events compared to clinical risk factors.

Gut microbial metabolite trimethylamine N-oxide induces aortic dissection.

Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 µM vs. 1.85, IQR: 1.40 to 3.35 µM; p < 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or ß-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The in vitro experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The in vivo BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management.

Early matrix softening contributes to vascular smooth muscle cell phenotype switching and aortic dissection through down-regulation of microRNA-143/145.

Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection.

Cannabidiol protects against acute aortic dissection by inhibiting macrophage infiltration and PMAIP1-induced vascular smooth muscle cell apoptosis.

Acute aortic dissection (AAD) progresses rapidly and is associated with high mortality; therefore, there remains an urgent need for pharmacological agents that can protect against AAD. Herein, we examined the therapeutic effects of cannabidiol (CBD) in AAD by establishing a suitable mouse model. In addition, we performed human AAD single-cell RNA sequencing and mouse AAD bulk RNA sequencing to elucidate the potential underlying mechanism of CBD. Pathological assays and in vitro studies were performed to verify the results of the bioinformatic analysis and explore the pharmacological function of CBD. In a ß-aminopropionitrile (BAPN)-induced AAD mouse model, CBD reduced AAD-associated morbidity and mortality, alleviated abnormal enlargement of the ascending aorta and aortic arch, and suppressed macrophage infiltration and vascular smooth muscle cell (VSMC) apoptosis. Bioinformatic analysis revealed that the pro-apoptotic gene PMAIP1 was highly expressed in human and mouse AAD samples, and CBD could inhibit Pmaip1 expression in AAD mice. Using human aortic VSMCs (HAVSMCs) co-cultured with M1 macrophages, we revealed that CBD alleviated HAVSMCs mitochondrial-dependent apoptosis by suppressing the BAPN-induced overexpression of PMAIP1 in M1 macrophages. PMAIP1 potentially mediates HAVSMCs apoptosis by regulating Bax and Bcl2 expression. Accordingly, CBD reduced AAD-associated morbidity and mortality and mitigated the progression of AAD in a mouse model. The CBD-induced effects were potentially mediated by suppressing macrophage infiltration and PMAIP1 (primarily expressed in macrophages)-induced VSMC apoptosis. Our findings offer novel insights into M1 macrophages and HAVSMCs interaction during AAD progression, highlighting the potential of CBD as a therapeutic candidate for AAD treatment.

miR-485-3p targets SIRT1 in vascular smooth muscle cells mediating the occurrence of aortic dissection.

Studies have demonstrated a close correlation between MicroRNA and the occurrence of aortic dissection (AD). However, the molecular mechanisms underlying this relationship have not been fully elucidated and further exploration is still required. In this study, we found that miR-485-3p was significantly upregulated in human aortic dissection tissues. Meanwhile, we constructed in vitro AD models in HAVSMCs, HAECs and HAFs and found that the expression of miR-485-3p was increased only in HAVSMCs. Overexpression or knockdown of miR-485-3p in HAVSMCs could regulate the expression of inflammatory cytokines IL1ß, IL6, TNF-α, and NLRP3, as well as the expression of apoptosis-related proteins BAX/BCL2 and Cleaved caspase3/Caspase3. In the in vivo AD model, we have observed that miR-485-3p regulates vascular inflammation and apoptosis, thereby participating in the modulation of AD development in mice. Based on target gene prediction, we have validated that SIRT1 is a downstream target gene of miR-485-3p. Furthermore, by administering SIRT1 agonists and inhibitors to mice, we observed that the activation of SIRT1 alleviates vascular inflammation and apoptosis, subsequently reducing the incidence of AD. Additionally, functional reversal experiments revealed that overexpression of SIRT1 in HAVSMCs could reverse the cell inflammation and apoptosis mediated by miR-485-3p. Therefore, our research suggests that miR-485-3p can aggravate inflammation and apoptosis in vascular smooth muscle cells by suppressing the expression of SIRT1, thereby promoting the progression of aortic dissection.

HSPB6 Deficiency Promotes the Development of Aortic Dissection and Rupture.

To better understand the pathogenesis of acute type A aortic dissection, high-sensitivity liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS)-based proteomics and phosphoproteomics approaches were used to identify differential proteins. Heat shock protein family B (small) member 6 (HSPB6) in aortic dissection was significantly reduced in human and mouse aortic dissection samples by real-time PCR, western blotting, and immunohistochemical staining techniques. Using an HSPB6-knockout mouse, we investigated the potential role of HSPB6 in ß-aminopropionitrile monofumarate-induced aortic dissection. We found increased mortality and increased probability of ascending aortic dissection after HSPB6 knockout compared with wild-type mice. Mechanistically, our data suggest that HSPB6 deletion promoted vascular smooth muscle cell apoptosis. More importantly, HSPB6 deletion attenuated cofilin activity, leading to excessive smooth muscle cell stiffness and eventually resulting in the development of aortic dissection and rupture. Our data suggest that excessive stiffness of vascular smooth muscle cells caused by HSPB6 deficiency is a new pathogenetic mechanism leading to aortic dissection.

Iron deficiency affects oxygen transport and activates HIF1 signaling pathway to regulate phenotypic transformation of VSMC in aortic dissection.

BACKGROUND: Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration.This experiment aims to explore how iron deficiency (ID) affects the function of vascular smooth muscle cell (VSMC) and participates in the occurrence and development of AD by regulating gene expression. METHODS: The relationship between iron and AD was proved by Western-blot (WB) and immunostaining experiments in human and animals. Transcriptomic sequencing explored the transcription factors that were altered downstream. WB, flow cytometry and immunofluorescence were used to demonstrate whether ID affected HIF1 expression through oxygen transport. HIF1 signaling pathway and phenotypic transformation indexes were detected in cell experiments. The use of the specific HIF1 inhibitor PX478 further demonstrated that ID worked by regulating HIF1. RESULTS: The survival period of ID mice was significantly shortened and the pathological staining results were the worst. Transcriptomic sequencing indicated that HIF1 was closely related to ID and the experimental results indicated that ID might regulate HIF1 expression by affecting oxygen balance. HIF1 activation regulates the phenotypic transformation of VSMC and participates in the occurrence and development of AD in vivo and in vitro.PX478, the inhibition of HIF1, can improve ID-induced AD exacerbation.

Unveiling cellular and molecular aspects of ascending thoracic aortic aneurysms and dissections.

Ascending thoracic aortic aneurysm (ATAA) remains a significant medical concern, with its asymptomatic nature posing diagnostic and monitoring challenges, thereby increasing the risk of aortic wall dissection and rupture. Current management of aortic repair relies on an aortic diameter threshold. However, this approach underestimates the complexity of aortic wall disease due to important knowledge gaps in understanding its underlying pathologic mechanisms.Since traditional risk factors cannot explain the initiation and progression of ATAA leading to dissection, local vascular factors such as extracellular matrix (ECM) and vascular smooth muscle cells (VSMCs) might harbor targets for early diagnosis and intervention. Derived from diverse embryonic lineages, VSMCs exhibit varied responses to genetic abnormalities that regulate their contractility. The transition of VSMCs into different phenotypes is an adaptive response to stress stimuli such as hemodynamic changes resulting from cardiovascular disease, aging, lifestyle, and genetic predisposition. Upon longer exposure to stress stimuli, VSMC phenotypic switching can instigate pathologic remodeling that contributes to the pathogenesis of ATAA.This review aims to illuminate the current understanding of cellular and molecular characteristics associated with ATAA and dissection, emphasizing the need for a more nuanced comprehension of the impaired ECM-VSMC network.

Risk assessment for aortic dissection in Turner syndrome: The role of the aortic growth rate.

OBJECTIVE: The risk of aortic dissection (AoD) is increased in Turner syndrome (TS) but predicting those at risk is difficult. Based on scarce evidence, preventive aortic surgery is recommended when aortic diameter increases >5 mm/year. To investigate the aortic growth rate in TS and TS-related conditions associated with aortic growth. We also reported our experience of women who suffered aortic dissection (AoD), and who had preventive aortic replacement. METHODS: 151 adult TS were retrospectively identified. Women who had more than one transthoracic echocardiogram (TTE) after age 16 years were included in the aortic growth study. Aortic diameters at sinuses of Valsalva (SoV) and ascending aorta (AA) were analysed by two experts. RESULTS: 70/151 women had more than one TTE (interscan interval 4.7 years). Mean aortic growth was 0.13 ± 0.59 mm/year at SoV and 0.23 ± 0.82 mm/year at AA. Known risk factors for aortic dilatation and TS-related conditions were not associated with aortic growth. 4/151 women experienced AoD (age 25±8 years): two had paired scans for aortic growth, which was 0.67 mm/year at both SoV and AA in the first woman, and 11 mm/year (SoV) and 4 mm/year (AA) in the second. Only 1/4 of women with AoD survived; she used a TS cardiac-alert card to inform emergency personnel about her risk of AoD. 5/151 had a preventive aortic replacement, but one died post-operatively. CONCLUSIONS: Mean aortic growth in our TS population was increased compared to non-TS women and was not associated with currently known risk factors for AoD, suggesting that aortic growth rate itself could be a useful variable to stratify who is at risk for AoD.

Association of triglyceride-glucose index with the risk of incident aortic dissection and aneurysm: a large-scale prospective cohort study in UK Biobank.

BACKGROUND: Triglyceride-glucose (TyG) index is an emerging surrogate indicator of insulin resistance, which has been demonstrated as a risk factor for various cardiovascular diseases including coronary syndrome, in-stent restenosis, and heart failure. However, association of TyG index with incident aortic dissection (AD) and aortic aneurysm (AA) remains to be investigated. METHODS: This study included 420,292 participants without baseline AD/AA from the large-scale prospective UK Biobank cohort. The primary outcome was incident AD/AA, comprising AD and AA. Multivariable-adjusted Cox proportional hazards regression models and restricted cubic spline (RCS) analyses were applied to assess the relationship between TyG index and the onset of AD/AA. In addition, the association between TyG index and incident AD/AA was examined within subgroups defined by age, gender, smoking status, drinking status, diabetes, hypertension, and BMI. RESULTS: Over a median follow-up period of 14.8 (14.1, 15.5) years, 3,481 AD/AA cases occurred. The incidence of AD/AA rose along with elevated TyG index. RCS curves showed a linear trend of TyG index with risk of incident AD/AA. TyG index was positively associated with risk of incident AD/AA after adjusting for age, gender, smoking status, drinking status, BMI, hypertension, LDL-c, and HbA1c, with adjusted HRs of 1.0 (reference), 1.20 (95% CI 1.08-1.35), 1.21 (95% CI 1.08-1.35), and 1.30 (95% CI 1.16-1.45) for TyG index quartiles 2, 3, and 4, respectively. Especially, participants in the highest TyG index quartile had highest risk of developing AA, with an adjusted HR of 1.35 (95% CI 1.20-1.52). CONCLUSIONS: TyG index is independently associated with a higher risk of incident AD/AA, indicating the importance of using TyG index for risk assessment of AD/AA, especially for AA.

Comparison of open thoracoabdominal repair for chronic aortic dissections and aneurysms.

OBJECTIVE: Aortic 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. METHODS: We 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. RESULTS: Compared 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. CONCLUSIONS: Outcomes 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.

Endovascular treatment for thoracic aortic disease from the Global Registry for Endovascular Aortic Treatment.

OBJECTIVE: Global Registry for Endovascular Aortic Treatment (GREAT) is an international prospective multicenter registry collecting real-world data on performance of W. L. Gore thoracic and abdominal aortic endografts. This analysis evaluated the long-term differences in patient survival and device performance in patients undergoing thoracic endovascular aortic repair (TEVAR) for any thoracic aortic pathology. METHODS: From August 2010 to October 2016, 5014 patients were enrolled in GREAT. The population of interest was comprised of only patients treated for thoracic aortic pathologies. Through 5 years, primary outcomes were all-cause and aortic-related mortality, stroke, aortic rupture, endoleaks, migration, fracture, compression, paraplegia, and any reintervention through 5 years, grouped by pathology. Secondary outcomes were reintervention rate and freedom from serious device- and aortic-related events. RESULTS: The 578 patients with thoracic aortic pathologies enrolled in GREAT and identified for this analysis were categorized by common pathologies: thoracic aneurysm (n = 239), thoracic dissection (n = 203), arch (n = 26), and other (n = 110). The mean age of this population was 66.1 ± 12.8 years, and 64.7% were male. Procedure survival was 99.7%. In the overall group, at index procedure to 30 days and 31 days to 5 years, Kaplan-Meier estimates of freedom from all-cause mortality were 99.6% and 66.4%, respectively, and for aortic-related mortality were 97.7% and 94.6%, respectively. Aortic rupture rate was 0.5% (n = 3) at 30 days and 1.4% (n = 8) through 5 years. Stroke and spinal cord ischemic events were 1.9% (n = 11) and 1.6% (n = 9) at 30 days and at 5 years were 3.6% (n = 20), 0.5% (n = 3), respectively. Reinterventions were required in 7.3% (n = 42) at 30 days and 12.4% (n = 69) through 5 years. The number of patients with endoleaks at 30 days was 2.1% (n = 12): n = 3 (1.1%) for each of types IA, 1B, and II; n = 2 (0.3%) for type III; and n = 4 (0.7%) for unspecified. Through 5 years, the percentage of patients was 8.3% (n = 40): n = 15 (3.1%) for type IA; n = 10 (2.1%) for type IB; n = 11 (2.3%) for type II; and n = 9 (1.9%) for unspecified. One patient (0.2%) had stent migration at 30 days (aneurysm group); none were reported through 5 years. There were no incidents of stent compression or fracture from index procedure through 5 years. CONCLUSIONS: Data herein demonstrates durability and support for treatment of thoracic aortic disease with the GORE TAG conformable thoracic stent graft, including no incidents of stent compression/fracture and high freedom from aortic-related mortality. The planned analysis of follow-up to 10 years in GREAT will be beneficial.

Volumetric analysis in primary and residual type B aortic dissection treated with stented-assisted balloon-induced intimal disruption and relamination technique can predict aortic reintervention.

OBJECTIVE: The aim of this study was to investigate the mid-term results of stented-assisted balloon-induced intimal disruption and relamination (STABILISE) in patients with aortic dissection with the implementation of volumetric analysis. METHODS: This was a single-center retrospective analysis of prospectively collected data. From May 2017 to September 2022, 42 patients underwent STABILISE for acute complicated or subacute high-risk aortic dissection. STABILISE was completed with distal extended endovascular aortic repair in 24 patients. A computed tomography scan was performed at baseline, before hospital discharge, and at 1, 3, and 5 years. Perfused total aortic, true lumen, and false lumen volumes were assessed for thoracic, visceral, and aorto-iliac segment. The ratio between false lumen and total volume was named perfusion dissection index (PDI). Complete remodeling was defined as PDI = 0, and positive remodeling as PDI ≤0.1. RESULTS: Technical success was 97.6%. No 30-day deaths, spinal cord injuries, or retrograde dissections were observed. Mean follow-up was 44 ± 19.4 months. Thoracic diameter was lower at last available computed tomography scan (36.7 vs 33.0 mm; P = .01). Aortic growth >5 mm was observed in 9.5% of the patients. Thoracic and visceral aortic complete remodeling were 92.8% and 83.3%, respectively, with no difference between acute and subacute group. Distal extended endovascular aortic repair significantly increased complete remodeling in the aorto-iliac segment, compared with STABILISE alone (69.6% vs 21.4%; P < .001). Freedom from vascular reinterventions at 3 years was 83.1% (95% confidence interval, 71.5%-96.6%). Total PDI ≤0.1 at first postoperative control was a predictor of vascular reinterventions (P < .0001). CONCLUSIONS: STABILISE is a safe and feasible technique associated with high mid-term rates of complete remodeling in the thoracic and visceral aorta. Volumetric analysis allows the quantification of aortic remodeling and represents a predictor of aortic reinterventions.

Natural history and long-term outcomes of medically managed Type B intramural hematoma.

OBJECTIVE: Type B intramural hematoma (IMH) is often managed medically, yet may progress to dissection, aneurysmal dilation, or rupture. The aim of this study was to report the natural history of medically managed Type B IMH, and factors associated with progression. METHODS: We reviewed patients with medically managed Type B IMH between January 1995 to December 2022 at a single center. Any patients with immediate surgical or endovascular intervention were excluded. Demographic profiles, comorbidities, imaging, and follow-up details were reviewed. Patients were divided into two groups: Group 1 had isolated IMH, and Group 2 had IMH along with aneurysm or dissection at the time of presentation. On follow-up, progression was defined as degeneration to aneurysm/dissection or increase in the thickness of IMH in Group 1. In Group 2, progression was an increase in the size of aneurysm or development of new dissection. RESULTS: Of 104 patients with Type B IMH during the study period, 92 were medically managed. The median age was 77 years, and 45 (48.9%) were females. Comorbidities included hypertension (83.7%), hypercholesterolemia (44.6%), and active smoking (47.8%). Mean Society for Vascular Surger comorbidity score was 6.3. Mean IMH thickness and aortic diameter at presentation were 8.9 mm and 38.3 mm, respectively. Median follow-up was 55 months. Overall survival at 1 year and 5 years was 85.8% and 61.9%, respectively. During follow-up, 19 patients (20.7%) required intervention, more common in Group 2 (Group 1, 8/66; 12.3% vs Group 2, 11/26; 42.3%; P = .001). This resulted in higher freedom from intervention in Group 1 at 1 year (93.5% vs 62.7%) and 5 years (87.5% vs 51.1%; P < .001). Indication for intervention was dissection (n = 4), aneurysm (n = 12), and progression of IMH (n = 3). In Group 1, progression was seen in 25 (37.9%), three (4.5%) remained stable, 29 (43.9%) had complete resolution of IMH, and nine patients were lost to follow-up. In Group 2, 11 patients (42.3%) had progression, seven (26.9%) remained stable, and eight were lost to follow-up. IMH thickness at presentation >7.2 mm is associated with both increased odds of progression (odds ratio, 3.3; 95% confidence interval, 1.2-11.1; P = .03) and intervention (odds ratio, 5.5; 95% confidence interval, 1.3-36.9; P = .03) during the follow-up. CONCLUSIONS: Although many patients with Type B IMH managed medically stabilize or regress, progression or need for intervention can occur in up to 40% of cases. This is associated with the presence of aneurysm, dissection, and IMH thickness. Long-term follow-up is mandatory as late interventions occur, particularly for higher risk patients.

Extended thoracic endovascular aortic repair is optimal therapy in acute complicated type B dissection.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) represents optimal therapy for complicated acute type B aortic dissection (aTBAD). Persistent knowledge gaps remain, including the optimal length of aortic coverage, impact on distal aortic remodeling, and fate of the dissected abdominal aorta. METHODS: Review of the Emory Aortic Database identified 92 patients who underwent TEVAR for complicated aTBAD from 2012 to 2018. Standard TEVAR covered aortic zones 3 and 4 (from the left subclavian to the mid-descending thoracic aorta). Extended TEVAR fully covered aortic zones 3 though 5 (from the left subclavian to the celiac artery). Long-term imaging, clinical follow-up, and overall and aortic-specific mortality were reviewed. RESULTS: Extended TEVAR (n = 52) required a greater length of coverage vs standard TEVAR (n = 40) (240 ± 32 mm vs 183 ± 23 mm; P < .01). In-hospital mortality occurred in 5.4% of patients (7.7% vs 2.5%; P = .27) owing to mesenteric malperfusion (n = 3) or rupture (n = 2). The overall incidences of postoperative stroke, transient paraparesis, paraplegia, and dialysis were 5.4% (3.9% vs 7.5%; P = .38), 3.2% (5.8% vs 0%; P = .18), 0%, and 0% respectively, equivalent between groups. Follow-up was 96.6% complete to a mean of 6.1 years (interquartile range, 3.5-8.6 years). There were significantly higher rates of complete thrombosis or obliteration of the entire thoracic false lumen after Extended TEVAR (82.2% vs 51.5%; P = .04). Distal aortic reinterventions were less frequent after extended TEVAR (5.8% vs 20%; P = .04). Late aorta-specific survival was 98.1% after extended TEVAR vs 92.3% for standard TEVAR (P = .32). CONCLUSIONS: Extended TEVAR for complicated aTBAD is safe, results in a high rate of total thoracic false lumen thrombosis/obliteration, and reduces distal reinterventions. Longer-term follow-up will be needed to demonstrate a survival benefit compared to limited aortic coverage.

Five-year outcomes of endovascular treatment for aortic dissection from the Global Registry for Endovascular Aortic Treatment.

OBJECTIVE: The Global Registry for Endovascular Aortic Treatment (GREAT) is an International prospective multicenter registry collecting real-world data on performance of Gore aortic endografts. The purpose was to analyze the long-term outcomes and patient survival rates, as well as device performance in patients undergoing thoracic endovascular aortic repair for acute and chronic and complicated or uncomplicated type B aortic dissection (TBAD). METHODS: From August 2010 to October 2016, 5014 patients were enrolled in the GREAT registry. The study population were patients treated with thoracic endovascular aortic repair for TBAD through 5-year follow-up (days 0-2006). The primary outcomes for this analysis were all-cause and aortic-related mortality, stroke, aortic rupture, endoleaks, migration, fracture, compression, and any reintervention through 5 years. RESULTS: We identified 265 patients. The mean age was 60.9 ± 11.9 years (range, 19-84 years; 211 males [79.6%]). Devices used were the Gore TAG and Conformable Gore TAG Thoracic Endoprosthesis. There were 228 patients (86.0%) who underwent primary endovascular treatment (144 off-label [54.3%]); 22 (8.3%) underwent reintervention after prior endovascular procedure and 15 (5.7%) underwent reintervention after prior open procedure. Kaplan-Meier estimated freedom from all-cause mortality at 5 years was 71.1%. Freedom from aortic-related mortality through 5 years was 95.8%. There was no significant difference in freedom from all-cause mortality during the follow-up period in complicated or uncomplicated disease. At 30 days and through 5 years, respectively, for all the following outcomes, the aortic rupture rate was 1.1% (n = 3) and 1.9% (n = 5). The stroke rate was 1.1% (n = 3) and 4.2% (n = 11). The spinal cord ischemic event rate was 1.5% (n = 4) and 2.6% (n = 7). Reinterventions were required in 6.4% (n = 17) and 21.1% (n = 56) of patients. The need for conversion to open repair was 0.4% (n = 1) and 2.6% (n = 7). Additional graft placement was required in 3 patients (1.1%) and 16 patients (6.0%). The endoleak rate at 30 days was 3.4% (n = 9); type IA (n = 1 [0.4%]), type IB (n = 4 [1.5%]), type II (n = 1 [0.4%]), type III (n = 1 [0.4%]), and unspecified (n = 4 [1.6%]). Through 5 years, the endoleak rate was 12.1% (n = 32); type IA (n = 7 [2.6%]), type IB (n = 10 [3.8%]), type II (n = 9 [3.4%]), type III (n = 2 [0.8%]), and unspecified (n = 12 [4.5%]). There were no cases of stent migration, compression or fracture through 5 years. CONCLUSIONS: Results at the 5-year follow-up demonstrate that the use of the Gore TAG and Conformable Gore TAG Thoracic Endoprosthesis can be supported in treatment of TBAD (acute, chronic, complicated, and uncomplicated). These data demonstrate strong device durability, beneficial patient outcomes, and support for the treatment of thoracic aortic dissection with an endovascular approach. Complete 10-year follow-up in GREAT as planned will be advantageous.