Increased Tissue Microarray Matrix Metalloproteinase Expression Favors Proteolysis in Thoracic Aortic Aneurysms and Dissections

Recent years have witnessed the emergence of novel technologies that enable less invasive endovascular treatment of descending thoracic aortic disease (TAD). This has occurred against a backdrop of improved identification of various disease processes and better results with open surgical repair. The natural history of the specific acute aortic syndromes that affect the descending thoracic aorta has also been described with more clarity and has become more commonly recognized. This is in part secondary to the widespread availability and application of advanced imaging technologies that permit precise diagnoses. As data are accumulating, these pathological processes involving the descending thoracic aorta are no longer thought of as simply variants of one another but as distinct entities with well-defined clinical behavior. As the technology for endovascular repair continues to mature and its utilization increases, there is a need for a careful assessment of the current state of medical management, traditional open therapy, and evolving endovascular treatment of distinct thoracic aortic pathologies. The purpose of this scientific statement is to present a contemporary review of the various pathological processes that affect the descending thoracic aorta: Aneurysms, dissections, intramural hematomas (IMHs), penetrating atherosclerotic ulcers (PAUs), and aortic transections. These disorders will be considered in detail, with an exploration of the natural history, available treatment options, and controversies regarding management. Current intervention criteria will be reviewed with respect to both open surgical repair and endovascular treatment. Our goal is to provide the healthcare professional with a better understanding of the pathophysiology of the various disease processes that involve the descending thoracic aorta and to review current outcomes and technical pitfalls associated with these therapies to facilitate strong, evidence-based decision making in the care of these patients. Treatment of descending TAD involves complex, exigent decision making in an era of evolving technology. Survival data for nonoperative …

Objective To explore the experience and management of intraoperative care of patients with aneurysm of thoracic aorta and aortic dissecting aneurysm treated with endovascular aneurysm repair and blood vessel bypass (the hybrid operation). Methods Ten patients with aneurysm of thoracic aorta and aortic dissecting aneurysm were treated with the hybrid operation in catheter lab. During the operation, nurses and doctors cooperated connivantly. Following measures were carried out to ensure the smooth operation and prevent the occurrence of complications: life signs were monitored carefully and medicines and equipments were prepared fully. Results 10 patients with aneurysm of thoracic aorta and aortic dissecting aneurysm underwent the hybrid operation successfully without no complications. Conclusions It was safe and effective to carry out the hybrid operation for patients with aneurysm of thoracic aorta and aortic dissecting aneurysm by strict management and specialist nurses raining. Skilled collaboration and strict life signs monitoring was pivotal to ensure the success of the hybrid operation. Key words: Thoracic aorta aneurysm; Aortic dissecting aneurysm; Endovascular aneurysm repair; Hybrid operation; Intervention nursing management

Evolving Experience of Percutaneous Management of Type B Aortic Dissection

Disintegrin-like and Metalloproteinase with Thrombospondin Motifs (ADAMTS) proteins that are fundamentally located in the extracellular matrix (ECM) have critical roles on different cellular processes by altering the ECM architecture. It has been known that expression of some members of these proteinases increases in aneurismal and dissectional aortic tissue. The purpose of this study is to investigate ADAMTS1, 5, 16 and tissue inhibitors of metalloproteinases-1, -2 (TIMP-1, -2) levels in aortic tissue obtained from patients with thoracic aortic aneurysms and dissections and to achieve new insights about the function of ADAMTS family members. We investigated ADAMTS1, 5, and 16 expression in human thoracic aortic aneurysms (TAA) (n = 22), thoracic aortic dissections (TAD) (n = 12), and thoracic aortas from age-matched control organ donors (n = 6) (a total number of 34 cases and 6 controls). The expression levels of ADAMTS proteins were determined by Western blot technique using anti-ADAMTS1, ADAMTS5, ADAMTS16, TIMP-1 and TIMP-2 antibodies. ADAMTS1, 5, and 16 protein expressions were significantly higher in thoracic aortic aneurysm and dissection tissues compared to control aortic tissues. Furthermore, TIMP-1 protein levels decreased in TAA and TAD tissues, TIMP-2 did not change. Under the light of our findings, increased expression of ADAMTS1, 5, and 16 proteins may promote deceleration in thoracic aortic aneurysm progression. This is the first study that demonstrates ADAMTS5 and ADAMTS16 proteolytic activity in aneurysm and dissection.

Transforming growth factor (TGF)-β/Smad signaling pathway in aortic dissection patients and normal subjects has not been previously described. The present study was designed to evaluate the TGF-β/Smad signaling expressions in the patients with acute type A aortic dissection in comparison with those in the patients with thoracic aortic aneurysm and with coronary artery disease, and (or) the healthy subjects. Consecutive surgical patients for acute type A aortic dissection (20 patients), aortic aneurysm (nine patients) or coronary artery disease (20 patients) were selected into this study. Blood samples (4 ml) were obtained from the right radial arterial indwelling catheter after systemic heparinization prior to the start of cardiopulmonary bypass in the operating room. Twenty-one young healthy volunteers without underlying health issues who donated forearm venous blood samples (4 ml) were taken as control. The surgical specimens of the aortic tissues were obtained immediately after they were severed during the operations of the replacement of the aorta in the patients with aortic dissection or aortic aneurysm. In patients receiving coronary artery bypass grafting, the tiny aortic tissues were taken when the punch holes of the proximal anastomosis on the anterior wall of the ascending aorta were made. The aortic tissues were for RNA, protein, or supernatant preparations until detection of TGF-β1 mRNA by quantitative real-time reverse transcription polymerase chain reaction, of TGF-β1, TGF-β receptor I, Smad2/3, Smad4 and Smad7 by Western blot, and of TGF-β1 by enzyme-linked immunosorbent assay, respectively. In particular, the linear correlations of the relative grayscales between different proteins of each group, and those correlations between the quantitative TGF-β1 by enzyme-linked immunosorbent assay and the time interval from the onset to surgery or the maximal dimensions of the aorta of the aortic dissection group were assessed. Quantitative real-time reverse transcription polymerase chain reaction showed that TGF-β1 mRNA were upregulated in all surgical groups (1.59 ± 0.33 vs. 1.45 ± 0.34 vs. 1.48 ± 0.48, P > 0.05). Western blot revealed that the expressions of TGF-β1, TGF-β receptor I, Smad2/3, Smad4 and Smad7 were positive in the aortic tissues of all three investigated groups. Of the quantitative relative grayscales, a significant reverse correlation was noted between TGF-β1 and Smad2/3 (Y = -0.8552X + 1.6417, r = -0.759, P < 0.0001), and a close direct correlation between Smad4 and Smad7 (Y = 0.5905X + 0.2805, r = 0.781, P < 0.0001) in the Aortic Dissection Group. In the Aortic Aneurysm Group, Smad4 and Smad7 were also closely correlated (Y = 0.5228X + 0.1642, r = 0.727, P = 0.026), and in the Coronary Artery Disease Group, TGF-β1 and Smad7 were much significantly correlated (Y = 0.5301X + 0.5758, r = 0.917, P = 0.004). By enzyme-linked immunosorbent assay, TGF-β1 level of the aortic tissue was lower in the aortic dissection than in the aortic aneurysm and coronary artery disease groups with no statistical significance (319.52 ± 129.21 pg/mg protein vs. 324.09 ± 49.70 pg/mg protein vs. 304.15 ± 29.39 pg/mg protein, P > 0.05). The plasma TGF-β1 levels were 1158.30 ± 11.54 pg/ ml, 1170.27 ± 8.26 pg/ml, 1225.00 ± 174.42 pg/mL and 1160.25 ± 13.01 pg/mL in the four groups, respectively, showing significant intergroup differences (P < 0.05). No significant correlation was found between the aortic or plasma TGF-β1 levels and the time interval from the onset to surgery or the maximal dimensions of the aorta in the patients of the aortic dissection group. Aortic dissection, aortic aneurysm and atheroslerosis might be associated with an enhanced TGF β/Smad signaling function, with aortic dissection exhibiting a less prominent upregulation. It might have implications for downstream signal activation presumably translating into matrix degradation in the condition of aortic dissection in comparison to matrix deposition in aortic aneurysm and coronary artery disease.

Aortic diseases are relatively rare but are associated with high morbidity and mortality. Emergency physicians (EPs) should consider aortic disease in all patients with pain in the torso, particularly those with other diverse or seemingly unconnected complaints. This review summarizes the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes for patients with abdominal aortic aneurysms (AAAs), thoracic aortic aneurysms (TAAs), and aortic dissection. Figures show a transverse image of an AAAs with a transmural hematoma, a three-dimensional computed tomographic angiogram (CTA) rendering of a thoracic aneurysm associated with a bicuspid aortic valve in the typical ascending aortic location, a chest x-ray film demonstrating prominent and blurred aortic knob due to TAA, acute aortic dissection subtypes, an electrocardiogram and transesophageal echocardiography of a patient with acute ascending aortic dissection, magnetic resonance images of a patient with dissection of the proximal descending aorta, CT representations of a type A dissection involving a dilated ascending aorta and a type B dissection involving the descending thoracic aorta, and a decision algorithm for evaluation and treatment of a suspected aortic dissection. Tables list normal aortic dimensions by CTA and echocardiography, average annual rate of expansion and rupture of AAA based on current diameter, and the etiology of TAA. Key words: AAA, aorta, aortic dissection, ascending aortic dissection, descending aortic dissection, intimal tear, intramural hematoma, thoracic aortic aneurysm

The pathogenesis of thoracic aortic aneurysm and dissection (TAAD) is complex and incompletely understood. The hallmarks of the disease process are aortic inflammatory cell infiltration and protease mediated elastic fiber disruption. In a study recently published in Clinical Science (2018) 132 (6), 655-668), Liu et al explore the mechanism through which aortic vascular smooth cells and macrophages participate in TAAD using a mouse model. The authors propose that interleukin-3 (IL-3) released from aortic vascular smooth cells is central to the disease process. IL-3 stimulated matrix metalloproteinase 12 (MMP12) release from macrophages via mitogen activated protein kinase pathways. MMP12 is a protease known to be involved in both aortic aneurysm and dissection. IL-3 knockout mice had significantly reduced aortic wall MMP12, and reduced protease activity. This was associated with protection against TAAD.

Background Dissection and other complications of ascending aortic aneurysms are potentially life-threatening. Several factors may be implicated in aneurysm progression and dissection. The role of tissue microRNAs may be of interest. Purpose To examine how serum biomarkers and tissue expression of microRNAs are associated with thoracic aortic aneurysms and dissection. Methods We compared three groups of patients; 21 patients with aneurysm of the aortic root, ascending aorta or aortic arch undergoing scheduled repair, 11 patients with acute Stanford type A aortic dissection who underwent emergency surgery and 18 patients with normal aortic diameter undergoing other cardiac surgery (control group). Prior to surgery, peripheral blood samples were obtained from patients, to assess osteoprotegerin and adiponectin levels with the ELISA method. Tissue samples from ascending aortic wall were obtained from patients during surgery. Following appropriate storage and homogenization, tissue Matrix Metalloproteinases (MMPs) 2 and 9 were measured with the ELISA method, while tissue microRNAs 29 and 195 were measured using qrtPCR, after RNA extraction. Results There was no significant difference among control, aneurysm and dissection groups in terms of age (62±10 years vs 66±12 years vs 59±12 years, p=0.052), gender distribution (77.8% male vs 81% male vs 90% male, p=0.28) or BMI (28.51±2.92 kg/m2 vs 25.72±3.09 kg/m2 vs 27.02±3.2 kg/m2, p=0.76). There was also no difference among control, aneurysm and dissection groups regarding hypertension (72% vs 62% vs 73%, p=0.73), diabetes mellitus (22% vs 19% vs 36%, p=0.54), smoking (44% vs 29% vs 46%, p=0.09) or dyslipidemia (78% vs 43% vs 55%, p=0.08). The groups of control subjects, aneurysms and dissections did not differ in osteoprotegerin [44 (28, 52) pmol/l vs 31 (28, 37) pmol/l vs 45 (24, 71) pmol/l, p=0.17], adiponectin [6,65 (2,39, 9,79) μg/ml vs 5,28 (2,34, 6,98) μg/ml vs 4,13 (2,49, 7,52) μg/ml, p=0.43], tissue MMP2 [0.97 (0.42, 27.66) ng/ml vs 9.12 (1.72, 61.49) ng/ml vs 2.51 (0.22, 235.72) ng/ml, p=0.34] and tissue MMP9 levels [0.96 (0.29, 8.56) ng/ml vs 10.31 (1.18, 25.58) ng/ml vs 2.76 (0.63, 54.83) ng/ml, p=0.09] (Figure 1). Importantly, tissue expression of mir29 was 2.11-fold higher in the dissection group (p=0.001) and 2.99-fold higher in the aneurysm group (p&amp;lt;0.001) compared to the control group. Tissue expression of mir195 was 2.72-fold higher in the dissection group (p&amp;lt;0.001) and 2.00-fold lower in the aneurysm group (p=0.08) compared to the control group (Figure 2). Conclusions These findings highlight the role of epigenetic modifications through altered microRNA tissue expression in aortic wall synthesis, extracellular matrix degradation and progress of aneurysm formation and dissection. The exact role of microRNA expression in aortic dilatation and dissection, as well as their role as potential biomarkers, merit further validation. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

<h2>Abstract</h2><h3>Background</h3> Thoracic aortic aneurysms (TAA) and aortic dissections (AD) are recognized as one of the leading causes of death in developed countries. Although mortality decreases if at-risk individuals are diagnosed early on through screening, many fail to seek the proper preventive interventions timely. Genetic predisposition, smoking, and hypertension are well-known risk factors for highly lethal aortic aneurysmal rupture or dissection. Hypothyroidism has also been extensively described in the literature as a possible risk factor directly related to the origin of thoracic aortic aneurysm and dissection. Numerous studies have proposed a pathophysiological role for hypothyroidism in the development of TAA and AD, although this role is still not fully understood. <h3>Objective</h3> This scoping review sought human and animal studies to examine the relationship between hypothyroidism and thoracic aortic diseases. <h3>Methods</h3> A search in PubMed, Web of Science, and Scopus using the terms "aortic dissection," "aorta," "aortic aneurysm," and "hypothyroidism" yielded 907 articles, and only nine were relevant to this study topic and criteria. <h3>Results</h3> The included articles discuss thoracic aortic diseases as potential risk factors for thoracic aortic aneurysm and dissection. A low thyroid hormone level might be a negative prognostic indicator after acute aortic dissection. <h3>Conclusion</h3> Establishing a link between hypothyroidism and thoracic aortic diseases could improve clinical practice through the development of screening strategies for thyroid function in patients with thoracic aortic diseases, thereby reducing postoperative mortality rates.

BackgroundThoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype–phenotype correlations within families of the patients with TAAD.Methods51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan–Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery.Results and discussionIn 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35–46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45–57, p = 0.0083). This effect was also found when the ‘genotype-positive’ group was restricted to probands with ‘likely causative’ variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27–47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group).ConclusionsThis study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0870-4) contains supplementary material, which is available to authorized users.

Thoracic aortic aneurysm (TAA) is a life-threatening condition that predisposes to aortic dissection (AD), yet its underlying pathophysiologic mechanisms remain poorly understood. Tandem mass tag-based quantitative proteomics of plasma from type A AD patients was performed to identify dysregulated proteins. The β-aminopropionitrile-induced mouse model was used to experimentally recapitulate TAA progression, with disease mechanisms further characterized through RNA sequencing transcriptomics, complemented by comprehensive molecular analyses including immunohistochemistry, immunofluorescence, western blot, co-immunoprecipitation, and bioinformatics integration. Integrin αV and integrin αL were significantly downregulated proteins in plasma samples from patients with type A AD. Integrin αV abundantly expressed in the aortic media, particularly in smooth muscle cells (SMCs), with significantly reduced expression after dissection. Pharmacologic inhibition of integrin αV with cilengitide or SB273005 markedly aggravated ascending TAA development, accompanied by severe disorganization and loss of elastic fibers. Bulk RNA sequencing revealed that integrin αV inhibition exacerbated proinflammatory responses during TAA progression. Inhibiting integrin αV disrupted the SMC transition to a contractile phenotype, whereas STAT1 negatively regulated integrin αV-mediated SMC phenotypic modulation. These findings identify integrin αV as a promising molecular target for TAA intervention. However, they also highlight concerns regarding the clinical use of integrin αV inhibitors, which are currently under investigation in cancer trials because they may increase the risk of TAA or AD development.

Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH-sponsored program that collects information about individuals with genetically triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross-sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD <50 years). Women comprised 32% of 1,449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD <50 years, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR = 0.65, P < 0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi; OR = 0.68, P < 0.05). As in BAV, other genetically triggered aortic diseases such as FTAAD and TAAD <50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events.

We thank Del Porto et al. [1] for their valuable comments on our letter to the editor [2]. Expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is increased in patients with aortic aneurysms and dissections, and an imbalance between them is regarded as an underlying pathomechanism [3]. A 1:1 molecular ratio between MMPs and TIMPs maintains the structural integrity of the aorta by regulating the degradation and synthesis of the extracellular matrix [3,4]. Although MMP-12 has been implicated in many pathological processes, such as aortic aneurysms and dissections, atherosclerotic plaque progression, emphysema and cancer, it is regarded as a specific marker of aortic dissection [4,5]. Even though there is no specific TIMP for MMP-12, it is conceivable that evaluating TIMPs as well as the MMP/TIMP ratio could be helpful in determining the mechanism underlying aortic dissections and the usefulness of new markers more precisely.None declared.

23 - Endovascular management of aortic and thoracic aneurysms

Objective To evaluate the clinical significance of the change of serum matrix metalloproteinases (MMP)-1,-2,-3 and -9 in acute and chronic aortic diseases and acute myocardial ischemia.Methods The blood serum levels of MMP-1,-2,-3 and -9 were detected in 30 patients with acute aortic dissection,19 patients with chronic aortic dissection,19 patients with aortic aneurysm and in 12 patients with acute myocardial ischemia,as well as in 16 healthy individuals who served as the control group.Serum MMP levels were measured by using an ELISA technique.Results There were significantly higher levels of MMP-3 in patients with acute myocardial ischemia as compared to acute aortic dissection ( [19.10 ± 3.11 ] μg/L vs [11.89 ± 1.31 ] μg/L,P =0.02).Significantly lower levels of MMP-1 were found in healthy controls compared to the groups of patients ( [1.30 ± 0.56 ] μg/L vs [2.99 ± 0.78 ] μg/L in acute aortic dissection,P =0.03,[3.12 ±0.78] μg/L in chronic dissection,P =0.02,[3.01 ± 1.01 ] μg/L in thoracic aortic aneurysm,P =0.03 and [5.01 ± 0.98 ] μg/L in acute myocardial ischemia,P =0.01 ).Higher levels of M MP-1 and MMP-3 were detected on males.There was a positive correlation between MMP-1 and increasing age ( r =0.38,P ＜ 0.05 ).In patients operated for acute type A aortic dissection,the levels of MMP-1,MMP-3 and MMP-9 increased immediately after surgery,while the levels of MMP-2 decreased.Twenty-four hours after surgery levels of MMP-1,-2 and -9 were almost equal to the preoperative ones( P ＞ 0.05 ).Conclusion Measurement of serum MMP levels in thoracic aortic disease and acute myocardial ischemia is a simple and relatively rapid laboratory test that could be used as a biochemical indicator of aortic disease or acute myocardial ischemia,when evaluated in combination with imaging techniques. Key words: Matrix metalloproteinases; Thoracic aortic diseases; Myocardial ischemia