Effect of TEVAR Combined with Drugs and Drug Therapy Alone on the Efficacy and Safety of Stable Standford B Aortic Dissection.

Objective: Stanford type B aortic dissection is a condition in which the intima of the aorta tears, and TEVAR is an interventional treatment to manage this dissection through intimal repair. To evaluate the medium-term clinical efficacy of endovascular repair (TEVAR) for Aortic dissection and drug Conservative management for Stanford B Aortic dissection aneurysms and further explore whether the former is superior to drug Conservative management in the medium-term efficacy. Methods: The clinical data of 70 patients with stable Standford type B Aortic dissection admitted to our hospital from March 2016 to March 2020 were retrospectively analyzed. They were divided into the treatment group (n = 47) and the control group (n = 23). The control group patients were treated solely with medication, while the treatment group patients were treated with TEVAR on the basis of the control group patients. The treatment efficacy and safety of the two groups of patients were compared and analyzed. All patients will be followed up once a month for 12 months after discharge and every 2 months thereafter (for a total of 3 years). Results: The findings highlight the need to carefully weigh the benefits and harms in the treatment of Stanford type B aortic dissection, especially when considering TEVAR surgery. Future research should focus on reducing postoperative complications to optimize treatment strategies and improve overall patient outcomes.TEVAR surgery significantly reduces hospital mortality, but is also associated with significantly increased postoperative complications, emphasizing the complexity of treatment decisions. This finding provides critical information about weighing the risks and survival benefits of surgery, helping medical teams and patients make informed treatment choices. The hospital mortality rate of patients in the treatment group was 12.77%, while the hospital mortality rate of patients in the control group was 21.74%. The difference between the two groups was statistically significant (P < .05). The incidence of postoperative complications in the treatment group was 23.40%, while the control group did not experience any major complications. The difference between the two groups was statistically significant (P < .05). The mortality rate of patients in the treatment group within 30 days of discharge was 0%, while the mortality rate of patients in the control group within 30 days of discharge was 11.11%. The difference between the two groups was statistically significant (P < .05). The Kaplan Meier curve showed that the survival rates at 3 years of the control and treatment groups were 56.52% and 95.12%, respectively. The log-rank test showed a statistical difference between the two groups. Univariate and multivariate regression analysis showed that postoperative neurological complications (HR = 32.41; P = .00) and preoperative Aortic valve regurgitation (HR = 3.91; P = .00) were risk factors for medium-term death. Conclusion: The TEVAR combination drug is a safe and effective treatment for stable Stanford B Aortic dissection. It can reduce mortality. Compared with drug treatment, it has obvious advantages in medium-term treatment effects. Early rising for high-risk patients can make them have better long-term outcomes. Limitations of the study include its retrospective nature and the use of data from only a single medical center, which may limit the external generalizability of the results.

Cordycepin suppresses vascular inflammation, apoptosis and oxidative stress of arterial smooth muscle cell in thoracic aortic aneurysm with VEGF inhibition.

BACKGROUND: Thoracic aortic aneurysm (TAA) is a type of common and serious vascular disease, in which inflammation, apoptosis and oxidative stress are strongly involved in the progression. Cordycepin, a bioactive compound from Cordyceps militaris, exhibits anti-inflammatory and anti-oxidative activities. This study aimed to address the role and mechanism of cordycepin in TAA. METHODS: The thoracic aortas were perivascularly administrated with calcium chloride (CaCl2), and human aortic smooth muscle cells (HASMCs) were incubated with angiotensin II (Ang II) to simulate the TAA model in vivo and in vitro, respectively. The effect and mechanism of cordycepin in TAA were explored by hematoxylin and eosin (HE) staining, immunohistochemistry (IHC), immunofluorescence (IF), western blot, biochemical test, cell counting kit-8 (CCK-8), and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assays. RESULTS: Cordycepin improved the CaCl2-induced the aneurysmal alteration and disappearance of normal wavy elastic structures of the aorta tissues, TAA incidence and thoracic aortic diameter in rats, and Ang II-induced the cell viability of HASMCs. Cordycepin reversed the CaCl2-induced the relative protein expression of cleaved caspase 9, cleaved caspase 3, interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1ß, and the relative levels of glutathione (GSH), malonaldehyde (MDA) and reactive oxygen species (ROS) in vivo, or Ang II-induced these changes in vitro. Mechanically, cordycepin reduced the relative protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), cluster of differentiation 31 (CD31) and endothelial nitric oxide synthase (eNOS) in the Ang II-induced HASMCs. Correspondingly, overexpression of VEGF increased the levels of the indicators involved in apoptosis, inflammation and oxidative stress, which were antagonized with the cordycepin incubation in the Ang II-induced HASMCs. CONCLUSION: Cordycepin inhibited apoptosis, inflammation and oxidative stress of TAA through the inhibition of VEGF.

Attenuation of Smooth Muscle Cell Phenotypic Switching by Angiotensin 1-7 Protects against Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) involves extracellular matrix (ECM) remodeling of the aortic wall, leading to reduced biomechanical support with risk of aortic dissection and rupture. Activation of the renin-angiotensin system, and resultant angiotensin (Ang) II synthesis, is critically involved in the onset and progression of TAA. The current study investigated the effects of angiotensin (Ang) 1-7 on a murine model of TAA. Male 8-10-week-old ApoEKO mice were infused with Ang II (1.44 mg/kg/day) and treated with Ang 1-7 (0.576 mg/kg/day). ApoEKO mice developed advanced TAA in response to four weeks of Ang II infusion. Echocardiographic and histological analyses demonstrated increased aortic dilatation, excessive structural remodelling, perivascular fibrosis, and inflammation in the thoracic aorta. Ang 1-7 infusion led to attenuation of pathological phenotypic alterations associated with Ang II-induced TAA. Smooth muscle cells (SMCs) isolated from adult murine thoracic aorta exhibited excessive mitochondrial fission, oxidative stress, and hyperproliferation in response to Ang II. Treatment with Ang 1-7 resulted in inhibition of mitochondrial fragmentation, ROS generation, and hyperproliferation. Gene expression profiling used for characterization of the contractile and synthetic phenotypes of thoracic aortic SMCs revealed preservation of the contractile phenotype with Ang 1-7 treatment. In conclusion, Ang 1-7 prevented Ang II-induced vascular remodeling and the development of TAA. Enhancing Ang 1-7 actions may provide a novel therapeutic strategy to prevent or delay the progression of TAA.

Endovascular Repair of the Thoracic Aorta Combined with Drug Therapy in Acute Uncomplicated Type B Aortic Dissection.

Objective: This study was to evaluate the clinical efficacy of thoracic endovascular aortic repair (TEVAR) combined with Best Medical Therapy (BMT) in acute uncomplicated type B aortic dissection (TBAD). Methods: Using the random method, 90 patients admitted to our hospital between January 2018 and January 2020 with acute uncomplicated TBAD were randomly divided into a control group and a study group, with 45 cases in each of the groups. The effectiveness of BMT combined with TEVAR treatment was compared. Results: The incidence of recent adverse reactions did not differ significantly between the two groups. Compared to the control group, the 1-year survival rate and 2-year survival rate of patients in the study group were considerably higher. In order to examine the relationship between survival and time, the Kaplan-Meier curve was used. Both groups reached the median survival time after 24 months of follow-up. The expected survival time of the study group was longer than that of the control group. False lumen thrombosis or absence of thrombus was significantly more prevalent in the study group than in the control group. Conclusion: For patients with acute uncomplicated TBAD, BMT combined with TEVAR can significantly improve the long-term survival rate and increase the expected survival time.

Construction of a high-throughput aorta smooth muscle-on-a-chip for thoracic aortic aneurysm drug screening.

Thoracic aortic aneurysm (TAA), in which arteries enlarge asymptomatically over time until dissection or rupture occurs, is a serious health risk. The mainstay of TAA treatment remains surgical repair due to the lack of effective drugs. The complex etiology and pathogenesis of TAA, including hemodynamic alterations and genetic factors, lead to inaccuracies in preclinical models for drug screening. Previously, our group designed an aorta smooth muscle-on-a-chip to emulate human aorta physiology and pathophysiology and screened three promising therapeutic drugs targeting mitochondrial dynamics in TAA. On this foundation, we updated the one-channel chip to an eighteen-well chip platform with four polydimethylsiloxane layers. Benefiting from this high-throughput chip, we rapidly screened multiple drugs simultaneously using distinct cell lines in vitro. In addition, we observed the abnormal activation of hypoxia-inducible factor 1-alpha (HIF-1alpha) in aortas from TAA patients by Western blot and bioinformatics analyses. Intriguingly, this phenomenon was replicated only when smooth muscle cells (SMCs) were strained on the chip. We then screened seven specific HIF-1alpha inhibitors and selected the two most effective drugs (2-methoxyestradiol and digoxin) by quantitative PCR and colorimetric methods. The results demonstrated that these two drugs can improve respiratory chain function and rescue the SMC contractile phenotype, showing applicability for the clinical treatment of TAA. This high-throughput aorta smooth muscle-on-a-chip will become a potential preclinical model for TAA drug screening.

National Adherence to Medical Management of Aortic Aneurysms.

OBJECTIVES: The purpose of this study was to describe levels of adherence to guideline-based medical management in patients with aortic aneurysms, using an analogous population with coronary artery disease as a comparator. Adherence among those with aortic aneurysms has never been studied. METHODS: Adult patients with an aortic aneurysm or coronary artery disease diagnosed between 2004 and 2018 in the Optum Clinformatics deidentified Datamart were queried. Aneurysms were subclassified as thoracic, abdominal, or both. Receipt of an antihypertensive or antihyperlipidemic was determined through pharmacy claims. Adherence was determined as receipt of the indicated pharmacologic(s) after a diagnosis of aneurysm or coronary artery disease. Adherence was compared between those with aneurysms and coronary disease using univariable logistic regression. RESULTS: After exclusions, 194,144 patients with an aortic aneurysm and 3,946,782 with coronary artery disease were identified. Overall adherence was low (45.0%) and differed significantly by aneurysm subtype: highest in isolated thoracic (45.9%) and lowest in isolated abdominal aneurysms (42.6%). Adherence levels declined significantly after 1 year by about 15% in each aneurysm subtype. All subtypes of aneurysm had a significantly lower odds of adherence compared to those with coronary disease with odds ranging from 0.61 in those with isolated abdominal aneurysms to 0.80 with isolated thoracic aneurysms. CONCLUSIONS: Adherence among those with aortic aneurysms is very low, differs by subtype, and declines with time. Levels of adherence in those with aortic aneurysms is significantly lower compared to those with coronary artery disease. This should prove a reasonable target for implementation initiatives.

Patient-derived microphysiological model identifies the therapeutic potential of metformin for thoracic aortic aneurysm.

BACKGROUND: Thoracic aortic aneurysm (TAA) is the permanent dilation of the thoracic aortic wall that predisposes patients to lethal events such as aortic dissection or rupture, for which effective medical therapy remains scarce. Human-relevant microphysiological models serve as a promising tool in drug screening and discovery. METHODS: We developed a dynamic, rhythmically stretching, three-dimensional microphysiological model. Using patient-derived human aortic smooth muscle cells (HAoSMCs), we tested the biological features of the model and compared them with native aortic tissues. Drug testing was performed on the individualized TAA models, and the potentially effective drug was further tested using ß-aminopropionitrile-treated mice and retrospective clinical data. FINDINGS: The HAoSMCs on the model recapitulated the expressions of many TAA-related genes in tissue. Phenotypic switching and mitochondrial dysfunction, two disease hallmarks of TAA, were highlighted on the microphysiological model: the TAA-derived HAoSMCs exhibited lower alpha-smooth muscle actin expression, lower mitochondrial membrane potential, lower oxygen consumption rate and higher superoxide accumulation than control cells, while these differences were not evidently reflected in two-dimensional culture flasks. Model-based drug testing demonstrated that metformin partially recovered contractile phenotype and mitochondrial function in TAA patients' cells. Mouse experiment and clinical investigations also demonstrated better preserved aortic microstructure, higher nicotinamide adenine dinucleotide level and lower aortic diameter with metformin treatment. INTERPRETATION: These findings support the application of this human-relevant microphysiological model in studying personalized disease characteristics and facilitating drug discovery for TAA. Metformin may regulate contractile phenotypes and metabolic dysfunctions in diseased HAoSMCs and limit aortic dilation. FUNDING: This work was supported by grants from National Key R&D Program of China (2018YFC1005002), National Natural Science Foundation of China (82070482, 81771971, 81772007, 51927805, and 21734003), the Science and Technology Commission of Shanghai Municipality (20ZR1411700, 18ZR1407000, 17JC1400200, and 20YF1406900), Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), and Shanghai Municipal Education Commission (Innovation Program 2017-01-07-00-07-E00027). Y.S.Z. was not supported by any of these funds; instead, the Brigham Research Institute is acknowledged.

An assessment of the current medical management of thoracic aortic disease: A patient-centered scoping literature review.

Thoracic aortic aneurysm and dissection are complex diagnoses that require management by multidisciplinary providers using a variety of medical therapies, surgical interventions, and lifestyle modifications. Pharmacological agents, such as ß-blockers (atenolol) and angiotensin II type 1 receptor blockers (losartan), have been mainstay treatments for several years, and research from the past decade has continued to evaluate these and other medication classes to further improve patient morbidity and mortality. Combination ß- and renin-aldosterone-angiotensin blockade, statins, metformin, antioxidants, and vitamins have been evaluated as therapeutics in both thoracic and abdominal aortic aneurysms, as well as the effects of various antibiotics (ie, fluoroquinolones and tetracyclines) and benefits of lifestyle modifications (eg, diet and exercise) and enhanced patient-centered care and treatment adherence. In addition, as our understanding of the genetic, biochemical, and pathophysiological mechanisms behind these diseases expands, so do potential targets for future therapeutic research (eg, interleukins, matrix metalloproteases, and mast cells). This review incorporates the major meta-analyses, systematic and generalized reviews, and clinical trials published from 2010 through 2021 that focus on these topics in thoracic aortic aneurysms (and abdominal aneurysms when thoracic literature is scarce). Several key ongoing clinical trials, case studies, and in vivo/in vitro studies are also mentioned. Furthermore, we discuss current gaps in the literature and the abundance of clinical evidence for some interventions in abdominal aneurysms with few thoracic correlates, thus indicating a need for investigation of these subjects in the latter.

Dexamethasone attenuated thoracic aortic aneurysm and dissection in vascular smooth muscle cell Tgfbr2-disrupted mice with CCL8 suppression.

NEW FINDINGS: What is the central question of this study? What is the relationship of chemokine (C-C motif) ligand 8 (CCL8) to thoracic aortic aneurysm and dissection (TAAD) formation in postnatal mice with vascular smooth muscle cell (VSMC) Tgfbr2 disruption, and is dexamethasone a potential treatment? What is the main finding and its importance? CCL8 was associated with the formation of TAAD in VSMC Tgfbr2-disrupted mice. Dexamethasone reduced TAAD formation and inhibited mitogen-activated protein kinase (p-p38) and nuclear factor-κB (p-p65) signalling pathways. CCL8 might be an important promoter of aortic inflammation. Dexamethasone provided potential therapeutic effects in TAAD treatment. ABSTRACT: Aortic inflammation plays a vital role in initiation and progression of thoracic aortic aneurysm and dissection (TAAD). Disturbance of the transforming growth factor-ß (TGF-ß) signalling pathway is believed to be one of the pathogenic mechanisms of TAAD. Initially, Myh11-CreERT2 .Tgfbr2f/f male mice were used to build a TAAD mouse model, and bioinformatic analyses revealed enriched inflammatory signal pathways and upregulated chemokine (C-C motif) ligand 8 (CCL8). So we hypothesized that vascular smooth muscle cell (VSMC) Tgfbr2 disruption in postnatal mice results in aortic inflammation associated with CCL8 secretion. Real-time quantitative PCR and serum enzyme-linked immunosorbent assay (ELISA) results confirmed that CCL8 expression began to increase after VSMC Tgfbr2 disruption. Next, we cultured mouse thoracic aortas ex vivo, and observed that the protein expression of CCL8 in culture supernatants was increased by ELISA. Subsequently, the co-localization of CCL8 with α-smooth muscle actin or CD68 was found to be significantly increased by immunofluorescence. Then, dexamethasone (DEX) was used to treat TAAD in VSMC Tgfbr2-disrupted mice; the results of histochemical, immunofluorescence and immunohistochemical staining indicated that DEX therapy reduced CCL8 secretion, inflammatory cell recruitment, aortic medial thickening, elastic fibre fragmentation, extracellular matrix degradation and contractile apparatus impairment, and thereby ameliorated TAAD formation. Western blotting showed that mitogen-activated protein kinase and nuclear factor-κB signalling pathways in aorta were overactivated after VSMC Tgfbr2 disruption, but inhibited by DEX therapy. Altogether, CCL8 might be an important promoter in TAAD formation of VSMC Tgfbr2-disrupted mice, and DEX provided potential therapeutic effects in TAAD treatment.

Legumain Is an Endogenous Modulator of Integrin αvß3 Triggering Vascular Degeneration, Dissection, and Rupture.

BACKGROUND: The development of thoracic aortic dissection (TAD) is closely related to extracellular matrix degradation and vascular smooth muscle cell (VSMC) transformation from contractile to synthetic type. LGMN (legumain) degrades extracellular matrix components directly or by activating downstream signals. The role of LGMN in VSMC differentiation and the occurrence of TAD remains elusive. METHODS: Microarray datasets concerning vascular dissection or aneurysm were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes. Four-week-old male Lgmn knockout mice (Lgmn-/-), macrophage-specific Lgmn knockout mice (LgmnF/F;LysMCre), and RR-11a-treated C57BL/6 mice were given BAPN (ß-aminopropionitrile monofumarate; 1 g/kg/d) in drinking water for 4 weeks for TAD modeling. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Cell interaction was examined in macrophage and VSMC coculture system. The reciprocity of macrophage-derived LGMN with integrin αvß3 in VSMCs was tested by coimmunoprecipitation assay and colocalization analyses. RESULTS: Microarray datasets from the Gene Expression Omnibus database indicated upregulated LGMN in aorta from patients with TAD and mice with angiotensin II-induced AAA. Elevated LGMN was evidenced in aorta and sera from patients with TAD and mice with BAPN-induced TAD. BAPN-induced TAD progression was significantly ameliorated in Lgmn-deficient or inhibited mice. Macrophage-specific deletion of Lgmn alleviated BAPN-induced extracellular matrix degradation. Unbiased profiler polymerase chain reaction array and Gene Ontology analysis displayed that LGMN regulated VSMC phenotype transformation. Macrophage-specific deletion of Lgmn ameliorated VSMC phenotypic switch in BAPN-treated mice. Macrophage-derived LGMN inhibited VSMC differentiation in vitro as assessed by macrophages and the VSMC coculture system. Macrophage-derived LGMN bound to integrin αvß3 in VSMCs and blocked integrin αvß3, thereby attenuating Rho GTPase activation, downregulating VSMC differentiation markers and eventually exacerbating TAD development. ROCK (Rho kinase) inhibitor Y-27632 reversed the protective role of LGMN depletion in vascular dissection. CONCLUSIONS: LGMN signaling may be a novel target for the prevention and treatment of TAD.

Inflammatory Thoracic Aortic Aneurysm in a Patient with Advanced Lung Adenocarcinoma Treated with Pembrolizumab.

A 57-year-old man with lung adenocarcinoma was treated with chemotherapy and immune checkpoint blockade. After two cycles of carboplatin, pemetrexed, and pembrolizumab, he developed a persistent fever. Chest computed tomography (CT) suggested inflammation of the aortic wall. We treated the patient with corticosteroids. After four cycles of carboplatin, pemetrexed, and pembrolizumab, chest CT showed an aneurysm in the ascending aorta. We diagnosed him with inflammatory thoracic aortic aneurysm induced by pembrolizumab and performed surgical replacement of the ascending aorta. Although this might be a very rare case, we should be aware of aortitis as a potential adverse effect of pembrolizumab.

Dexamethasone reduces the formation of thoracic aortic aneurysm and dissection in a murine model.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with no effective pharmaceutical therapies currently available. Inflammation plays a key role in the progression of aneurysms. Dexamethasone (DEX), a synthetic glucocorticoid, has showed alleviating effects on cells in vitro from TAAD patients. Here we performed a study aiming at investigating the protective role of DEX in a ß-aminopropionitrile monofumarate (BAPN)-induced TAAD mouse model. DEX (dose: 0.04 mg/kg/day) treatment significantly reduced the aortic diameter and inhibited TAAD formation. DEX reduced infiltration of macrophages and neutrophils, apoptosis of vascular smooth muscle cells (VSMCs), expression of metalloproteinase 2/9, and extracellular matrix degradation in BAPN-treated TAAD mice. Furthermore, DEX therapy downregulated the expression of p-p65 in macrophages and VSMCs, which suggested that DEX might ameliorate BAPN-induced TAAD by suppressing NF-κB signaling. Therefore, DEX therapy attenuates the progression of BAPN-induced TAAD murine model and could be used as an effective adjuvant therapy for treating TAAD.

Comparison of mid-term outcomes of endovascular repair and medical management in patients with acute uncomplicated type B aortic dissection.

OBJECTIVES: To further assess the early and mid-term outcomes of thoracic endovascular aortic repair (TEVAR) in patients with acute uncomplicated type B aortic dissection (TBAD) compared with those receiving best medical treatment (BMT). METHODS: Between February 2008 and March 2018, 357 consecutive patients with acute uncomplicated TBAD were retrospectively analyzed. Among them, 191 patients underwent TEVAR, and 166 received BMT. After propensity score matching, we obtained 145 matched pairs for analysis. RESULTS: In the matched population, the 30-day mortality between the TEVAR group and the BMT group showed no statistically significant difference, whereas the early adverse events rates in the TEVAR group were significantly greater than that of the BMT group (P = .003). Freedom from all-cause mortality in the TEVAR group was significantly greater than that of the BMT group (TEVAR: 91.9% at 5 years, BMT: 82.2% at 5 years, P = .028). Freedom from aortic-related mortality in the TEVAR group was significantly greater than that of the BMT group (TEVAR: 94.1% at 5 years, BMT: 86.1% at 5 years, P = .044). Multivariable Cox-hazard regression analysis demonstrated that the older age (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.08, P = .013), BMT (HR, 2.33; 95% CI, 1.08-5.05, P = .032), and the distance between the primary entry tear and the left subclavian artery <2.0 cm (HR, 2.30; 95% CI, 1.06-4.99, P = .035) were the significant risk factors for all-cause death. Given death as a competing factor, the cumulative incidence of rupture in the BMT group was significantly greater than that of the TEVAR group (BMT: 13.7% at 5 years, TEVAR: 5.1% at 5 years, P = .024). CONCLUSIONS: Despite more complications in the early stage, TEVAR was associated with decreased risk of late death and had fewer late aortic ruptures compared with BMT in patients with acute uncomplicated TBAD. Therefore, TEVAR may be considered as the first option to improve the late outcomes in these patients.

Captopril versus atenolol to prevent expansion rate of thoracic aortic aneurysms: rationale and design.

Thoracic aortic aneurysms are correlated with significant mortality and morbidity. No therapy, however, is effective at limiting aneurysm expansion and preventing rupture. Angiotensin-converting enzyme inhibitors can reduce the wall shear stress and inflammation, both of which play vital roles in the expansion of the aneurysm. A total of 636 patients will be randomized into one of three parallel arms, receiving captopril, atenolol or placebo. The primary end point will be the rate of change in the absolute diameter of the aortic root and ascending aorta on MRI of the aorta after 36 months. The trial will investigate the efficacy of angiotensin-converting enzyme inhibitors versus beta-blocker therapy in reducing the growth rate of thoracic aortic aneurysms and rupture. Trial registration number: NCT04224675.

Transforming Growth Factor-ß and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment.

Thoracic aortic aneurysms (TAAs) are permanent pathological dilatations of the thoracic aorta, which can lead to life-threatening complications, such as aortic dissection and rupture. TAAs frequently occur in a syndromic form in individuals with an underlying genetic predisposition, such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Increasing evidence supports an important role for transforming growth factor-ß (TGF-ß) and the renin-angiotensin system (RAS) in TAA pathology. Eventually, most patients with syndromic TAAs require surgical intervention, as the ability of present medical treatment to attenuate aneurysm growth is limited. Therefore, more effective medical treatment options are urgently needed. Numerous clinical trials investigated the therapeutic potential of angiotensin receptor blockers (ARBs) and ß-blockers in patients suffering from syndromic TAAs. This review highlights the contribution of TGF-ß signaling, RAS, and impaired mechanosensing abilities of aortic VSMCs in TAA formation. Furthermore, it critically discusses the most recent clinical evidence regarding the possible therapeutic benefit of ARBs and ß-blockers in syndromic TAA patients and provides future research perspectives and therapeutic implications.

Clevidipine as a therapeutic and cost-effective alternative to sodium nitroprusside in patients with acute aortic syndromes.

BACKGROUND: Sodium nitroprusside is the preferred agent for the treatment of high blood pressure during acute aortic syndrome if blood pressure remains elevated after heart rate control with beta-blockers. The increasing cost of sodium nitroprusside in the USA led us to assess the efficacy and safety of intravenous clevidipine, a calcium channel blocker with quick onset of action, short half-life and significantly lower costs than sodium nitroprusside, in patients presenting with acute aortic syndrome. METHODS: We performed a retrospective chart review of consecutive patients admitted to the Cleveland Clinic Cardiac Intensive Care Unit from 2013-2016 with a diagnosis of acute aortic syndrome. Patients who received intravenous sodium nitroprusside were compared with those receiving intravenous clevidipine. The primary outcome was a significant difference in blood pressure at one, three and six hours. Secondary outcomes included time to achieving blood pressure target and in hospital mortality with rates of hypotension and bradycardia as safety endpoints. RESULTS: A total of 85 patients with suspected acute aortic pathology received clevidipine and 50 received sodium nitroprusside. Clinical and demographic characteristics were similar in both groups, except for a higher incidence of abdominal aortic aneurysm in the clevidipine group and for a trend towards higher use of labetalol in the clevidipine group. There were no significant differences in blood pressure or heart rate at one, three and six hours after starting either infusion. The rates of hypotension, bradycardia and in-hospital mortality did not differ. Time to achieve blood pressure control were also similar between groups. CONCLUSION: Intravenous clevidipine appears to be a safe and effective alternative to sodium nitroprusside for the management of high blood pressure during acute aortic dissection. In the USA, clevidipine could represent a cost effective therapy providing similar outcomes than sodium nitroprusside.

Short term follow-up of a patient with uncomplicated type B aortic dissection under dabigatran treatment.

This case report illustrates the follow-up of a 57-year-old female with a type B aortic dissection (AD) under dabigatran treatment. The patient had been operated on 8 years earlier due to type A AD. The aortic valve was repaired and a 26-mm polyester fiber graft was applied to the ascending aorta and the aortic arch. In computerized tomography scans taken after the procedure, a dissection flap extending from the descending aorta to the iliac arteries was seen, but the patient was asymptomatic and no further surgery was performed. The patient was subsequently diagnosed with atrial fibrillation. A CHA2DS2VASc score of 3 was recorded and dabigatran treatment was initiated. The aortic aneurysm and dissection were followed up via computed tomography and echocardiography at regular intervals, and at 6 months no progression was seen. No thromboembolic or hemorrhagic events were observed. To our knowledge, this is the first case report of dabigatran treatment for a patient with a type B AD. Based on this case, the use of dabigatran would appear to be safe in a patient with an uncomplicated type B AD, but the results of this case need to be confirmed with extended follow-up and additional patients.

Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.

Comparison of type B dissection by open, endovascular, and medical treatments.

OBJECTIVE: This study aimed to address the shortcomings of previous clinical trials that were inadequate to prove the superiority of thoracic endovascular aortic repair (TEVAR) in managing type B aortic dissection (TBAD) over open surgery (OS) or best medical treatment (BMT). The comparative effectiveness of these three treatments was analyzed using data of the National Inpatient Sample, a large U.S. database including patients from 4378 hospitals. METHODS: Adult patients diagnosed with a primary or secondary TBAD in the years 2005 to 2012 were included for analysis. Patients who had aortic aneurysm or received cardioplegia, valve repair, or operations on vessels of the heart were excluded. A three-category propensity score was created by using a multinomial logistic regression model, a three-way matching algorithm for 1:1:1 matching was applied, and a parallel outcome comparison between the three matched treatment groups was performed. RESULTS: Of a total of 54,971 patients included in the study, we matched 17,211 into three equal-size treatment groups (OS, 5755; TEVAR, 5695; BMT, 5761). No significant difference in the 22 baseline covariates was found in the matched cohort. We found TEVAR to have a much lower mortality rate than OS (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.46-0.79) or BMT (OR, 0.62; 95% CI, 0.47-0.83). Mortality rates between OS and BMT were similar (OR, 0.97; 95% CI, 0.74-1.27). We also found TEVAR to have a lower complication rate, shorter hospitalization, and lower medical cost compared with OS. CONCLUSIONS: TEVAR is superior to BMT or OS for treatment of TBAD in terms of mortality, complications, and cost.

Rapamycin attenuates a murine model of thoracic aortic aneurysm by downregulating the miR-126-3p mediated activation of MAPK/ERK signalling pathway.

Thoracic aortic aneurysm (TAA) is fatal diseases, which leads to aortic rupture and sudden death. Blood pressure-lowering drugs are ineffective for most of the patients. Our previous study demonstrated the inhibition of endothelial secreted miR-126-3p by rapamycin ameliorate the aneurysmal phenotype of smooth muscle cells (SMCs) in vitro. Hence, this study aimed to evaluate the modulation and mechanism of miR-126-3p in a murine model of TAA (Fbn1C1039G/+). Our results showed that noticeable disturbed flow (DF) was observed in the aorta of Fbn1C1039G/+ mice, and the expression of miR-126-3p was significantly increased under the DF in the cell chamber. This finding was also confirmed by tests in the corresponding DF area of the human aortic aneurysm tissue. Constant rapamycin administration significantly ameliorates the incidence and severity of Fbn1C1039G/+ mice characterized by decreased aortic media degradation, macrophage infiltration and MMP2/9 expression in the aortic wall. Mechanistic studies showed that rapamycin attenuates TAA progression by inhibiting miR-126-3p through ERK1/2 inactivation.