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.

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.

ACE2 deficiency inhibits thoracic aortic dissection by enhancing SIRT3 mediated inhibition of inflammation and VSCMs phenotypic switch.

BACKGROUND: Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in ß-aminopropionitrile fumarate (BAPN)-induced TAD. METHODS: A mouse model of TAD induced by BAPN and IL-1ß -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. RESULTS: We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. CONCLUSION: ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

PUM2 regulates the formation of thoracic aortic dissection through EFEMP1.

Thoracic aortic dissection (TAD) is a severe cardiovascular disease attributed to the abnormal phenotypic switch of vascular smooth muscle cells (VSMCs). We found that the RNA-binding protein PUM2 and the fibulin protein EFEMP1 were significantly decreased at the TAD anatomical site. Therefore, we constructed expression and silencing vectors for PUM2 and EFEMP1 to analyze differential expression. Overexpression of PUM2 inhibited VSMC proliferation and migration. Western blot analysis indicated that PUM2 overexpression in VSMCs upregulated α-SMA and SM22α and downregulated OPN and MMP2. Immunofluorescence demonstrated that PUM2 and EFEMP1 were co-expressed in VSMCs. Immunoprecipitation confirmed that PUM2 bound to EFEMP1 mRNA to promote EFEMP1 expression. An Ang-II-induced aortic dissection mouse model showed that PUM2 impedes the development of aortic dissection in vivo. Our study demonstrates that PUM2 inhibits the VSMC phenotypic switch to prevent aortic dissection by targeting EFEMP1 mRNA. These findings could assist the development of targeted therapy for TAD.

A harmful MYH11 variant detected in a family with thoracic aortic dissection and patent ductus arteriosus.

Thoracic aortic dissection (TAD) is an important cause of sudden cardiac death and is characterized by high morbidity, mortality, and a poor prognosis. Patent ductus arteriosus (PDA) is a common congenital heart disease. The pathogenesis of both TAD and PDA has been reported to be related to genetic factors. The MYH11 gene, which encodes myosin heavy chain 11, has been reported in individuals with both TAD and PDA. Herein, we first detected a harmful MYH11 missense variant (c. T3728C, p. L1243P) in a TAD and PDA family. This missense variant co-segregated with the TAD/PDA phenotype in this family of four individuals, providing evidence of its harmfulness. Histopathological examinations revealed the presence of fragmented, broken, and lessened elastic fibers and the deposition of proteoglycans in the median of aortic dissection. Moreover, the immunofluorescence results showed that the labeled MYH11 protein in the tissue of the aortic dissection was weaker than that in the normal aorta. We present this familial case to stress the necessity of postmortem genetic testing in such cases among forensic practices. Identifying those culprit gene variants can direct effective genetic counseling and personalized health management in family members (especially first-degree relatives) with high-risk genotypes.

Tomo-seq identifies NINJ1 as a potential target for anti-inflammatory strategy in thoracic aortic dissection.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening disease caused by an intimal tear in the aorta. The histological characteristics differ significantly between the tear area (TA) and the distant area. Previous studies have emphasized that certain specific genes tend to cluster at the TA. Obtaining a thorough understanding of the precise molecular signatures near the TA will assist in discovering therapeutic strategies for TAD. METHODS: We performed a paired comparison of the pathological patterns in the TA with that in the remote area (RA). We used Tomo-seq, genome-wide transcriptional profiling with spatial resolution, to obtain gene expression signatures spanning from the TA to the RA. Samples from multiple sporadic TAD patients and animal models were used to validate our findings. RESULTS: Pathological examination revealed that the TA of TAD exhibited more pronounced intimal hyperplasia, media degeneration, and inflammatory infiltration compared to the RA. The TA also had more apoptotic cells and CD31+α-SMA+ cells. Tomo-seq revealed four distinct gene expression patterns from the TA to the RA, which were inflammation, collagen catabolism, extracellular matrix remodeling, and cell stress, respectively. The spatial distribution of genes allowed us to identify genes that were potentially relevant with TAD. NINJ1 encoded the protein-mediated cytoplasmic membrane rupture, regulated tissue remodeling, showed high expression levels in the tear area, and co-expressed within the inflammatory pattern. The use of short hairpin RNA to reduce NINJ1 expression in the beta-aminopropionitrile-induced TAD model led to a significant decrease in TAD formation. Additionally, it resulted in reduced infiltration of inflammatory cells and a decrease in the number of CD31+α-SMA+ cells. The NINJ1-neutralizing antibody also demonstrated comparable therapeutic effects and can effectively impede the formation of TAD. CONCLUSIONS: Our study showed that Tomo-seq had the advantage of obtaining spatial expression information of TAD across the TA and the RA. We pointed out that NINJ1 may be involved in inflammation and tissue remodeling, which played an important role in the formation of TAD. NINJ1 may serve as a potential therapeutic target for TAD.

Pulsatile Deformations of a Conformable Descending Thoracic Aortic Endograft in Aneurysm, Dissection, and Blunt Traumatic Aortic Injury Patients.

PURPOSE: This study presents analytic techniques to quantify cardiac pulsatility-induced deformations of thoracic aortic endografts in patients with thoracic aortic aneurysm (TAA), dissection (TAD), and blunt thoracic aortic injury (BTAI) after thoracic endovascular aortic repair (TEVAR). TECHNIQUE: We analyzed 19 image data sets from 14 patients treated for TAA, TAD, and BTAI with cardiac-gated post-TEVAR CTs. Systolic and diastolic geometric models were constructed and diametric, axial, and bending deformations were quantified. For patients with cardiac-gated pre-op scans, the damping of pulsatile diametric distension was computed. Maximum localized diametric distension was 2.4±1.0%, 4.2±1.7%, and 5.5±1.6%, and axial deformation was 0.0±0.1%, -0.1±0.3%, and 1.1±0.6% in the endografts of TAA, TAD, and BTAI cohorts, respectively. Diametric distension damping from pre- to post-TEVAR was ~50%. Diametric and bending deformations were localized at certain axial positions on the endograft, and the inner curve bends more than the centerline, especially adjacent to overlapping regions. CONCLUSION: The presented techniques support investigation of multi-axial endograft deformations between disease causes and geometric locations on the device. Discretized quantification of deformation is needed to define device fatigue testing conditions and predict device durability in patients. CLINICAL IMPACT: This study demonstrates analytic techniques to quantify discretized deformation of thoracic endografts. Cardiac-resolved computed tomography is sometimes acquired for surgical planning and follow-up, however, the dynamic data are not typically used to quantify pulsatile deformations. Our analytic techniques extract the centerline and surface geometry of the stented thoracic aorta during the cardiac cycle, which are used to quantify diametric, axial, and bending deformations to provide better understanding of device durability and impact on the native anatomy.

Accurate Embolization for Endoleak after F-TEVAR of Thoracic Aortic Dissection by Detachable Coils.

OBJECTIVES: To evaluate the efficacy and clinical outcomes of accurate embolization of endoleaks after fenestrated thoracic endovascular aortic repair (F-TEVAR) for thoracic aortic dissections. METHODS: Twenty patients with endoleaks (17 type I and 3 type II) after fenestrated thoracic endovascular aortic repair (F-TEVAR) were embolized using detachable and ordinary coils. We assessed the success rate and complications of the operation, and its effects, through clinical and CT follow-up. RESULTS: The mean clinical follow-up duration was 25.68 ± 11.07 months (3-44 months). During follow-up, all endoleaks were completely embolized and aortic remodeling was improved. Secondary endoleaks occurred in four patients who were embolized twice. No other complications or death were reported. CONCLUSION: Embolization using detachable and ordinary coils is effective and safe for the treatment of endoleaks after fenestrated thoracic endovascular aortic repair.

EphrinB2 promotes the human aortic smooth muscle cell growth and migration via mediating F-actin remodeling.

OBJECTIVES: To evaluate the potential effect of EphrinB2 in human thoracic aortic dissection (TAD) and to illustrate the mechanisms governing the role of EphrinB2 in the growth of human aortic smooth muscle cells (HASMC). METHODS: In the study, EphrinB2 expression was investigated by qRT-PCR and immunohistochemistry in 12 pairs of TAD and adjacent human tissues. HASMCs were used for in vitro experiments. Next, EphrinB2 overexpression and depletion in HASMCs were established by EphrinB2-overexpressing vectors and small interfering RNA, respectively. The transfection efficiency was evaluated by qRT-PCR and Western blot. The effects of overexpression and depletion of EphrinB2 on cell proliferation, migration, and invasion were tested in vitro. Cell Counting Kit-8, flow cytometry and transwell migration/invasion, and wound healing assay were used to explore the function of EphrinB2 on HASMC cell lines. The relationship between EphrinB2 and F-actin was assessed by Western blot, immunofluorescence, and Co-IP. RESULTS: We found that EphrinB2 was a prognostic biomarker of TAD patients. Moreover, EphrinB2 expression negatively correlated to aortic dissection tissues, and disease incidence of males, suggesting that EphrinB2 might act as a TAD suppressor by promoting proliferation or decreasing apoptosis in HASMC. Next, over-expression of EphrinB2 in HASMC lines drove cell proliferation, migration, and invasion, and inhibited apoptosis while knockdown EphrinB2 showed the opposite phenomenon, respectively. Furthermore, the level of F-actin in mRNA, protein, and distribution in HASMC cell lines highly matched with the expression of EphrinB2, which indicated that EphrinB2 could mediate the HASMC cytoskeleton via inducing F-actin. CONCLUSIONS: In conclusion, our results first provided the pivotal role of EphrinB2 in HASMC proliferation initiated by mediating F-actin and demonstrated a prognostic biomarker and the potential targets for therapy to prevent thoracic aortic dissection.

[Latest Findings on the Pathogenic Mechanisms of Thoracic Aortic Dissection].

Thoracic aortic dissection (TAD) is a cardiovascular disease entailing a high lethality between 65% and 85%. Surgery-assissed implant/interventional stenting is the prevailing treatment of TAD. However, surgical treatment can cause severe postoperative complications and patients incur a relatively higher risk of postoperative mortality. Since the pathogenic mechanism underlying TAD is not clear, effective medication therapies are still not available. In recent years, along with advances in single-cell sequencing and other molecular biological technologies, there have been prelimiary findings suggesting the special role of dysfunctional vascular smooth muscle cells (VSMCs) in the pathogenesis and development of TAD. Furthermore, the molecular mechanisms regulating the dysfunction of VSMCs have been initially explored. It is expected that these new findings will contribute to the development of new strategies to prevent TAD and lead to new ideas for the identifiction of potential drug therapeutic targets. Herein, we summarized the critical role of dysfunctional VSMCs in the pathogenesis and development of TAD and presented in detail the biological factors and the related molecular mechanisms that regulate the dysfunction of VSMCs. We hope this review will provide a reference for further investigation into the central role of dysfunctional VSMCs in the pathogenesis and development of TAD and exploration for effective molecular drug targets for TAD.

Single-cell transcriptomic analysis reveals differential cell subpopulations and distinct phenotype transition in normal and dissected ascending aorta.

BACKGROUND: Acute thoracic aortic dissection (ATAD) is a fatal condition characterized by tear of intima, formation of false lumen and rupture of aorta. However, the subpopulations of normal and dissected aorta remain less studied. METHODS: Single-cell RNA sequencing was performed including 5 patients with ATAD and 4 healthy controls. Immunohistochemistry and immunofluorescence were used to verify the findings. RESULTS: We got 8 cell types from human ascending aorta and identified 50 subpopulations including vascular smooth muscle cells (VSMCs), endothelial cells, fibroblasts, neutrophils, monocytes and macrophages. Six transmembrane epithelial antigen of prostate 4 metalloreductase (STEAP4) was identified as a new marker of synthetic VSMCs. CytoTRACE identified subpopulations with higher differentiation potential in specified cell types including synthetic VSMCs, enolase 1+ fibroblasts and myeloid-derived neutrophils. Synthetic VSMCs-derived C-X-C motif chemokine ligand 12 (CXCL12) might interact with neutrophils and fibroblasts via C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), respectively, which might recruit neutrophils and induce transdifferentitation of fibroblasts into synthetic VSMCs. CONCLUSION: We characterized signatures of different cell types in normal and dissected human ascending aorta and identified a new marker for isolation of synthetic VSMCs. Moreover, we proposed a potential mechanism that synthetic VSMCs might interact with neutrophils and fibroblasts via CXCL12-CXCR4/ACKR3 axis whereby deteriorating the progression of ATAD, which might provide new insights to better understand the development and progression of ATAD.

The Effect of Intravenous and Oral Beta-Blocker Use in Patients with Type B Thoracic Aortic Dissection.

BACKGROUND: Beta-blockers have become the cornerstone for medical management in patients with chronic type B aortic dissection (TBAD). However, the effect of being on and/or receiving intravenous beta-blockers during hospitalization on outcomes of surgical repair of TBAD is not fully described. We sought to investigate this association during open surgical repair (OSR) and endovascular (Endo) intervention for nontraumatic TBAD. METHODS: The Premier Healthcare Database was inquired (June/2009-March/2015). Patients with nontraumatic isolated TBAD were identified via ICD-9-CM diagnosis and procedural codes. Patients with codes that indicated TAAD were excluded. In-hospital mortality, cardiac complications (CHF, MI, arrythmia) and stroke were evaluated. Log binomial regression analyses with bootstrapping were performed to assess the relative risk of adverse outcomes. RESULTS: A total of 1,752 were admitted for OSR (54.3%) and Endo (45.7%) TBAD repair. Use of oral beta blocker (BB) was 16.0% in OSR and 56.4% in Endo groups. In each arm, patients on BB were more likely to be diabetic, on aspirin or statin and more likely to receive additional IV BB than nonBB patients. There was no significant difference in age, sex, race, or prior history of CHF between BB and nonBB groups. Mortality was proportionally lower in patients on BB in OSR group (7.9% vs. 16.7%; P = 0.006) and Endo (3.3% vs. 9.2%; P < 0.001). The adjusted relative risk for mortality and stroke were significantly lower in oral BB recipients compared with none [aRR (95% CI): 0.53 (0.32-0.90) and 0.46 (0.25-0.87); both P ≤ 0.02]. IV metoprolol was the only IV BB that reduced mortality [aRR (95% CI): 0.62 (0.46-0.85); P = 0.003]. A dose of ≤10 mg was associated with significant mortality reduction: 6.3% (3.0-9.5%) compared with 8.1% (4.6-11.6%) in no IV BB group. Cardiac complications were not affected by BB use. CONCLUSIONS: For patients with nontraumatic TBAD, use of oral BB was associated with significant protection against in-hospital mortality and stroke following repair. Metoprolol was the only Intravenous BB type associated with improved survival. Further research is warranted to elucidate the effect of beta-blockers on the long-term surgical outcomes of TBAD.

Systemic immune-inflammation index predicted short-term outcomes in ATAD patients undergoing surgery.

OBJECTIVE: Systemic immune-inflammation index (SII) is a biomarker that reflect systemic inflammation. We aimed to assess the value of SII in prediction of short-term outcomes in acute type A aortic dissection (ATAD) patients undergoing surgery. METHOD: All patients underwent surgery for ATAD at our institution from 2018 to 2020 (n = 324) were retrospectively reviewed and divided into low SII (<1582.6 × 109 /L) and high SII (≥1582.6 × 109 /L) group according to optimal cut-off values defined by receiver operating characteristic curve. Cox regression and Kaplan-Meier analyses were performed to illustrate the correlation between SII and postoperative short-outcomes, including 30-day mortality and main complications after surgery. RESULTS: In total, 48 (14.8%) patients died in 30 days after ATAD surgery. And multivariable Cox analysis demonstrated that high preoperative SII was closely related with 30-day mortality (hazard ratio: 3.532, 95% confidence interval: 1.719-7.255, p = .001). Furthermore, Kaplan-Meier analysis illustrated that the short-term mortality rate increased significantly in high SII group (p < .001). In addition, the incidence of main postoperative complications including major adverse cardiovascular events (p = .001) and multiorgan failure (p = .002) were higher in high SII group. However, the length of intensive unit stay (p = .909) and hospital stay (p = .836) presented no difference in two groups. CONCLUSION: The study indicated that SII was an available biomarker to predict postoperative short-term prognosis, but not length of stay in intensive care unit and hospital in ATAD patients. And SII may be applied to risk stratification and patient selection in ATAD patients before surgery.

Is There Enough Evidence to Support the Role of Glycosaminoglycans and Proteoglycans in Thoracic Aortic Aneurysm and Dissection?-A Systematic Review.

Altered proteoglycan (PG) and glycosaminoglycan (GAG) distribution within the aortic wall has been implicated in thoracic aortic aneurysm and dissection (TAAD). This review was conducted to identify literature reporting the presence, distribution and role of PGs and GAGs in the normal aorta and differences associated with sporadic TAAD to address the question; is there enough evidence to establish the role of GAGs/PGs in TAAD? 75 studies were included, divided into normal aorta (n = 51) and TAAD (n = 24). There is contradictory data regarding changes in GAGs upon ageing; most studies reported an increase in GAG sub-types, often followed by a decrease upon further ageing. Fourteen studies reported changes in PG/GAG or associated degradation enzyme levels in TAAD, with most increased in disease tissue or serum. We conclude that despite being present at relatively low abundance in the aortic wall, PGs and GAGs play an important role in extracellular matrix maintenance, with differences observed upon ageing and in association with TAAD. However, there is currently insufficient information to establish a cause-effect relationship with an underlying mechanistic understanding of these changes requiring further investigation. Increased PG presence in serum associated with aortic disease highlights the future potential of these biomolecules as diagnostic or prognostic biomarkers.

Cause-specific mortality of type B aortic dissection and assessment of competing risks of mortality.

OBJECTIVE: Natural history studies of type B aortic dissection (TBAD) commonly report all-cause mortality. Our aim was to determine cause-specific mortality in TBAD and to evaluate the clinical characteristics associated with aorta-related and nonaorta-related mortality. METHODS: Clinical and administrative records were reviewed for patients with acute TBAD between 1995 and 2017. Demographics, comorbidities, presentation, and initial imaging findings were abstracted. Cause of death was ascertained through a multimodality approach using electronic health records, obituaries, social media, Social Security Death Index, and state mortality records. Causes of death were classified as aorta related, nonaorta related, or unknown. A Fine-Gray multivariate competing risk regression model for subdistribution hazard ratio was employed to analyze the association of clinical characteristics with aorta-related and nonaorta-related mortality. RESULTS: A total of 275 individuals met inclusion criteria (61.1 ± 13.7 years, 70.9% male, 68% white). Mean survival after discharge was 6.3 ± 4.7 years. Completeness of follow-up Clark C index was 0.87. All-cause mortality was 50.2% (n = 138; mean age, 70.1 ± 14.6 years) including an in-hospital mortality of 8.4%. Cause-specific mortality was aorta related, nonaorta related, and unknown in 51%, 43%, and 6%, respectively. Compared with patients with nonaorta-related mortality, patients with aorta-related mortality were younger at acute TBAD (69.5 ± 11.2 years vs 61.6 ± 15.5 years; P = .001), underwent more descending thoracic aortic repairs (19.4% vs 45.8%; P = .002), and had a shorter survival duration (5.7 ± 3.9 vs 3.4 ± 4.5 years; P = .002). There was clear variation in cause of death by each decade of life, with higher aorta-related mortality among those younger than 50 years and older than 70 years and a stepwise increase in nonaorta-related mortality with each increasing decade (P < .001). All-cause mortality at 1 year, 3 years, and 10 years was 15%, 24%, and 57%, respectively. After accounting for competing risks, the cumulative incidence of aorta-related mortality at 1 year, 3 years, and 10 years was 8.9%, 16.5%, and 27.2%, respectively, and that of nonaorta-related mortality was 2.7%, 7.2%, and 29%, respectively. A maximum descending thoracic aortic diameter >4 cm was associated with an increase in hazard of aorta-related mortality by 84% (subdistribution hazard ratio, 1.84; 95% confidence interval, 1.03-3.28) on multivariate competing risk regression analysis. CONCLUSIONS: TBAD is associated with high 10-year mortality. Those at risk for aorta-related mortality have a clinical phenotype different from that of individuals at risk for nonaorta-related mortality. This information is important for building risk prediction models that account for competing mortality risks and to direct optimal and individualized surgical and medical management of TBAD.

Management of Descending Thoracic Aortic Diseases: Similarities and Differences Among Cardiovascular Guidelines.

Cardiovascular societies have developed recommendations regarding the management of thoracic aortic diseases. While improvements in treatment have been observed during the past decade in regard to patient selection, thoracic endovascular aortic repair (TEVAR) and associated techniques, and high-volume centralization, the broad expansion of TEVAR has raised considerations about its indications, appropriateness, limitations, and application. The aim of this systematic review was to assess the similarities and differences among current cardiovascular societies' guidelines for the management of thoracic aortic diseases. The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched from January 2009 to May 2020. The initial search identified 990 articles. After exclusion of duplicate or inappropriate articles, the final analysis included 5 articles from cardiovascular societies published between 2010 and 2020. Selected controversial topics were analyzed, including diagnosis, imaging, spinal cord ischemia prevention, and management of the most important thoracic aortic pathologies. The analysis included data concerning the therapeutic approach in acute and chronic type B aortic dissection, penetrating aortic ulcer, intramural hematoma, thoracic aortic aneurysm, and traumatic aortic injury, as well a discussion of inflammatory aneurysms, aortitis, and genetic syndromes. The review presents consistent and controversial recommendations, as well as "gray zone" issues that need further investigation. There was significant overlap and agreement among the 5 societies regarding the management of thoracic aortic diseases. Especially in dissection and aneurysm management, TEVAR has established its role as the treatment of choice. However, robust evidence is still needed in many aspects of the management of thoracic aortic pathologies.

Vitamin B Mitigates Thoracic Aortic Dilation in Marfan Syndrome Mice by Restoring the Canonical TGF-ß Pathway.

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms have been correlated with TAA severity in MFS patients. However, the detailed relationship between the folate-methionine cycle and MFS pathogenesis remains unclear. Fbn1C1039G/+ mice were reported to be a disease model of MFS. To study the role of the folate-methionine cycle in MFS, Fbn1C1039G/+ mice were treated orally with methionine or vitamin B mixture (VITB), including vitamins B6, B9, and B12, for 20 weeks. VITB reduced the heart rate and circumference of the ascending aorta in Fbn1C1039G/+ mice. Our data showed that the Mtr and Smad4 genes were suppressed in Fbn1C1039G/+ mice, while VITB treatment restored the expression of these genes to normal levels. Additionally, VITB restored canonical transforming-growth factor ß (TGF-ß) signaling and promoted Loxl1-mediated collagen maturation in aortic media. This study provides a potential method to attenuate the pathogenesis of MFS that may have a synergistic effect with drug treatments for MFS patients.

Downregulation of HDAC1 suppresses media degeneration by inhibiting the migration and phenotypic switch of aortic vascular smooth muscle cells in aortic dissection.

Although much progress has been made in the diagnosis and treatment of thoracic aortic dissection (TAD), the overall morbidity and mortality rates of TAD are still high. Therefore, the molecular pathogenesis and etiology of TAD need to be elucidated. In this study, we found that histone deacetylase 1 (HDAC1) expression is dramatically higher in the aortic wall of patients with TAD (than that in a normal group) and negatively correlates with the levels of the vascular smooth muscle cell (SMC) contractile-phenotype markers. Knockdown of HDAC1 upregulated both smooth muscle 22 α (SM22α) and α-smooth muscle actin (α-SMA) in platelet-derived growth factor (PDGF)-BB-treated and -untreated SMCs. In addition, the knockdown of HDAC1 markedly decreased SMC viability and migration in contrast to the control group under the conditions of quiescence and PDGF-BB treatment. We also showed that the expression of polycystic kidney disease 1 (PKD1) is decreased in the aortic wall of patients with TAD and negatively correlates with HDAC1 expression. Overexpressed PKD1 obviously increased SM22α and α-SMA expression and reduced the viability and migration of SMCs, but these effects were attenuated by HDAC1. Furthermore, we demonstrated that HDAC1 serves as an important modulator of the migration and phenotypic switch of SMCs by suppressing the PKD1- mammalian target of the rapamycin signaling pathway. HDAC1 downregulation inhibited media degeneration and attenuated the loss of elastic-fiber integrity in a mouse model of TAD. Our results suggest that HDAC1 might be a new target for the treatment of a macrovascular disease such as TAD.

Readmissions after acute type B aortic dissection.

OBJECTIVE: Acute type B aortic dissection can be treated with medical management alone, open surgical repair, or thoracic endovascular aortic repair (TEVAR). The nationwide burden of readmissions after acute type B aortic dissection has not been comprehensively assessed. METHODS: We analyzed adults with a hospitalization due to acute type B aortic dissection between January 1, 2010, and December 31, 2014, in the Nationwide Readmissions Database. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify hospitalizations with a primary diagnosis code for thoracic or thoracoabdominal aortic dissection. The primary outcome was nonelective 90-day readmission. Predictors of readmission were determined using hierarchical logistic regression. RESULTS: The study population consisted of 6937 patients with unplanned admissions for type B aortic dissections from 2010 through 2014. Medical management alone was the treatment for 62.6% of patients, 21.0% had open surgical repair, and 16.4% underwent TEVAR. Nonelective 90-day readmission rate was 25.1% (23.6% with medical management alone, 26.9% with open repair, and 28.7% with TEVAR; P < .001). An additional 4.7% of patients were electively readmitted. The most common cause for nonelective readmission was new or recurrent arterial aneurysm or dissection (24.8%). Of those with unplanned readmissions, 5.2% underwent an aortic procedure. The mortality rate during nonelective readmission was 5.0%, and the mean cost of the rehospitalization was $22,572 ± $41,598. CONCLUSIONS: More than one in four patients have a nonelective readmission 90 days after hospitalization for acute type B aortic dissection. Absolute rates of readmission varied by initial treatment received but were high irrespective of the initial treatment. The most common cause of readmission was aortic disease, particularly among those treated with medication alone. Further research is required to determine potential interventions to decrease these costly and morbid readmissions, including the role of multidisciplinary aortic teams.

Insulin-like growth factor-binding protein 3 inhibits angiotensin II-induced aortic smooth muscle cell phenotypic switch and matrix metalloproteinase expression.

NEW FINDINGS: What is the central question of this study? Insulin-like growth factor 1 and its major binding protein insulin-like growth factor binding protein 3 (IGFBP3) are involved in collagen deregulation in several cardiovascular diseases: what is the role of IGFBP3 in thoracic aortic dissection and does it regulate aortic smooth muscle cells' phenotypic switch? What is the main finding and its importance? IGFBP3 inhibits aortic smooth muscle cells' phenotypic switch from a contractile to a synthetic phenotype, decreases matrix metalloproteinase 9 activation and suppresses elastin degradation. These findings provide a better understanding of the pathogenesis of thoracic aortic dissection. ABSTRACT: Thoracic aortic dissection (TAD) is characterized by aortic media degeneration and is a highly lethal disease. An aortic smooth muscle cell (AoSMC) phenotypic switch is considered a key pathophysiological change in TAD. Insulin-like growth factor binding protein 3 (IGFBP3) was found to be downregulated in aortic tissues of TAD patients. The present work aimed to study the function of IGFBP3 in AoSMCs' phenotypic switch and matrix metalloproteinase (MMP) expression. We established a mouse model of TAD by angiotensin (Ang) II infusion to ß-aminopropionitrile-administrated mice, and found decreased IGFBP3 expression accompanied by aortic dilatation and elastin degradation in vivo. Further, mouse (m)AoSMCs were isolated from mouse thoracic aorta and treated with Ang II. Ang II induced downregulation of IGFBP3 in vitro. To further study the function of IGFBP3, primary mAoSMCs were infected with adenovirus expressing IGFBP3 followed by Ang II induction. Enforced upregulation of IGFBP3 decreased MMP9 expression and activation as well as increasing tissue inhibitor of metalloproteinase (TIMP) 1 expression in Ang II-induced mAoSMCs. No difference was observed in MMP2 and TIMP3 expression. IGFBP3 suppressed subsequent Ang II-induced elastin degradation in vitro. IGFBP3 inhibited Ang II-induced mAoSMCs' phenotypic switch as evidenced by increased smooth muscle actin α-2 (ACTA2) and myosin heavy chain 11 (MYH11) expression and decreased secreted phosphoprotein 1 (SPP1) and vimentin expression. Taken together, the present study demonstrates the role of IGFBP3 in preserving AoSMCs' contractile state and reducing MMP9 activation and thus promoting elastic fibre synthesis, which provides a better understanding of the pathogenesis of TAD.