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none 18 si The implementation of new surgical techniques offers chances but carries risks. Usually, several years pass before a critical appraisal and a balanced opinion of a new treatment method are available and rely on the evidence from the literature and expert's opinion. The frozen elephant trunk (FET) technique has been increasingly used to treat complex pathologies of the aortic arch and the descending aorta, but there still is an ongoing discussion within the surgical community about the optimal indications. This paper represents a common effort of the Vascular Domain of EACTS together with several surgeons with particular expertise in aortic surgery, and summarizes the current knowledge and the state of the art about the FET technique. The majority of the information about the FET technique has been extracted from 97 focused publications already available in the PubMed database (cohort studies, case reports, reviews, small series, meta-analyses and best evidence topics) published in English. Shrestha, M.; Bachet, J.; Bavaria, J.; Carrel, T.P.; De Paulis, R.; Di Bartolomeo, R.; Etz, C.D.; Grabenwöger, M.; Grimm, M.; Haverich, A.; Jakob, H.; Martens, A.; Mestres, C.A.; Pacini, D.; Resch, T.; Schepens, M.; Urbanski, P.P.; Czerny, M. Shrestha, M.; Bachet, J.; Bavaria, J.; Carrel, T.P.; De Paulis, R.; Di Bartolomeo, R.; Etz, C.D.; Grabenwöger, M.; Grimm, M.; Haverich, A.; Jakob, H.; Martens, A.; Mestres, C.A.; Pacini, D.; Resch, T.; Schepens, M.; Urbanski, P.P.; Czerny, M.

Bicuspid aortic valve (BAV) is the most common heart valve malformation, and it may be associated with the development of long-term complications, such as aortic stenosis (AS) secondary to valvular calcification and aortic insufficiency (AI), with or without ascending aortic aneurysm (AAA). This study was performed at the Institute of Cardiovascular Diseases, Timişoara, Romania, from 2015 through 2018 and included a total of 105 patients with BAV. Out of the 105 BAV patients, 14 displayed AAA, alongside either AS or AI, and were selected undergo aortic valve replacement (AVR) alongside surgical replacement or aortoplasty of the ascending aorta, and the elastic fiber loss in the ascending aortic wall was evaluated for each patient. Two surgical interventions used alongside AVR in BAV patients with AAA and AS or AI were compared in this study: reduction ascending aortoplasty (RAA) and ascending aorta replacement (AAR). Postoperative follow-ups have shown RAA is useful short-term but that, in contrast to AAR, it leads to aortic redilatation over time. These results can contribute to a major future meta-analysis with the goal of improving the current clinical practice guidelines for BAV aortopathy.

Senescence of smooth muscle cells (SMCs) has a crucial role in the pathogenesis of abdominal aortic aneurysm (AAA), a disease of vascular degeneration. Perturbation of cellular ribosomal DNA (rDNA) transcription triggers nucleolar stress response. Previously we demonstrated that induction of nucleolar stress in SMCs elicited cell cycle arrest via the ataxia-telangiectasia mutated (ATM)/ATM- and Rad3-related (ATR)-p53 axis. However, the specific roles of nucleolar stress in vascular degeneration remain unexplored. In the present study, we demonstrated for the first time that in both human and animal AAA tissues, there were non-coordinated changes in the expression of RNA polymerase I machinery components, including a downregulation of transcription initiation factor-IA (TIF-IA). Genetic deletion of TIF-IA in SMCs in mice (smTIF-IA-/-) caused spontaneous aneurysm-like lesions in the aorta. In vitro, induction of nucleolar stress triggered a non-canonical DNA damage response, leading to p53 phosphorylation and a senescence-like phenotype in SMCs. In human AAA tissues, there was increased nucleolar stress in medial cells, accompanied by localized DNA damage response within the nucleolar compartment. Our data suggest that perturbed rDNA transcription and induction of nucleolar stress contribute to the pathogenesis of AAA. Moreover, smTIF-IA-/- mice may be a novel animal model for studying spontaneous AAA-like vascular degenerations.

The ascending aorta dilatation in the bicuspid aortic valve (BAV) patients is often attributed to congenital abnormalities of the aortic wall, but it may be related to hemodynamic disturbances in the course of BAV disease. At present, ascending aortic diameter is used as almost sole but weak predictor of aortic dissection and rupture in BAV. We examined the association between aortic wall mechanics and severity of aortic valve disease including different cusps fusion patterns using conventional echocardiography and tissue Doppler imaging (TDI). We prospectively studied 106 BAV patients: 72 with right-left (R-L) coronary cusp fusion were matched 1:1 to 34 patients with right-noncoronary (R-N) cusp fusion obtaining 34 pairs of patients. Peak systolic radial velocity and acceleration of the ascending aortic wall, measured by TDI, were used as an index of hemodynamic stress imposed on the aorta. Paired analysis showed higher aortic wall radial velocity (4.71 ± 1.61 cm/s vs. 3.33 ± 1.44 cm/s, p = 0.001) and acceleration (1.08 ± 0.46 m/s2 vs. 0.80 ± 0.34 m/s2, p = 0.015) in-R-L compared to R-N fusion. Pearson correlation showed association of ascending tubular aortic diameter with age (r = 0.258, p = 0.012), weight (r = 0.323, p = 0.001), peak aortic valve gradient (r = 0.386, p = 0.0001), aortic root diameter (r = 0.439, p

Aortic diameter measurements play a crucial role for the indication of aortic root surgery in Marfan patients. However, for magnetic resonance angiography (MRA)-derived measurements, there is no consensus on whether the aortic wall should be included or excluded in the aortic diameter. The purpose of this retrospective study was to compare the reliability of non-contrast bright blood MRA aortic inner-to-inner and outer-to-outer edge measurements in patients with Marfan syndrome. Forty Marfan patients underwent ECG-gated balanced steady-state free-precession MRA of the aorta at 1.5 T. Two readers independently performed inner and outer measurements at different aortic levels. They rated the image quality of the delineation of both inner and outer vessel wall edges on a four-point scale. MRA-derived diameters of the sinuses of Valsalva were compared with echocardiography-derived diameters. Aortic vessel wall delineation score was rated higher at all levels for inner than for outer vessel walls (p

Formation of aortic aneurysms as a consequence of augmented transforming growth factor β (TGF-β) signaling and vascular smooth muscle cell (VSMC) dysfunction is a potentially lethal complication of Marfan syndrome (MFS). Here, we examined VSMC senescence in patients with MFS and explored the potential mechanisms that link VSMC senescence and TGF-β. Tissue was harvested from the ascending aorta of control donors and MFS patients, and VSMCs were isolated. Senescence-associated β-galactosidase (SA-β-gal) activity and expression of senescence-related proteins (p53, p21) were significantly higher in aneurysmal tissue from MFS patients than in healthy aortic tissue from control donors. Compared to control-VSMCs, MFS-VSMCs were larger with higher levels of both SA-β-gal activity and mitochondrial reactive oxygen species (ROS). In addition, TGF-β1 levels were much higher in MFS- than control-VSMCs. TGF-β1 induced VSMC senescence through excessive ROS generation. This effect was suppressed by Mito-tempo, a mitochondria-targeted antioxidant, or SC-514, a NF-κB inhibitor. This suggests TGF-β1 induces VSMC senescence through ROS-mediated activation of NF-κB signaling. It thus appears that a TGF-β1/ROS/NF-κB axis may mediate VSMC senescence and aneurysm formation in MFS patients. This finding could serve as the basis for a novel strategy for treating aortic aneurysm in MFS.

Background Ascending aortic aneurysms constitute an important hazard for individuals with a bicuspid aortic valve (BAV). However, the processes that degrade the aortic wall in BAV disease remain poorly understood. Methods We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-s-galactosidase activity, p16Ink4a and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged BAV aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies. Findings We uncovered SMCs at varying depths of cellular senescence within BAV- and tricuspid aortic valve (TAV)-associated aortic aneurysms. Senescent SMCs were also abundant in non-aneurysmal BAV aortas but not in non-aneurysmal TAV aortas. Multivariable analysis revealed that BAV disease independently associated with SMC senescence. Furthermore, SMC senescence was heightened at the convexity of aortas associated with right-left coronary cusp fusion. Aged BAV SMCs had a pronounced collagenolytic SASP. Moreover, senescent SMCs in the aortic wall were enriched with surface-localized MMP1 and surrounded by weakly birefringent collagen fibrils. The senescent-collagenolytic SMC phenotype depended on p38 MAPK signaling, which was chronically activated in BAV aortas. Interpretation We have identified a cellular senescence-collagen destruction axis in at-risk ascending aortas. This novel “seno-destructive” SMC phenotype could open new opportunities for managing BAV aortopathy. Fund Canadian Institutes of Health Research, Lawson Health Research Institute, Heart and Stroke Foundation of Ontario/Barnett-Ivey Chair.

Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy. Myocardin related transcription factor A (MRTFA, MKL1) is a multifaceted transcription factor, regulating diverse biological processes. However, a detailed understanding of the mechanistic role of MKL1 in AAA has yet to be elucidated. In this study, we showed induced MKL1 expression in thoracic and abdominal aneurysmal tissues, respectively in both mice and humans. MKL1 global knockout mice displayed reduced AAA formation and aortic rupture compared with wild-type mice. Both gene deletion and pharmacological inhibition of MKL1 markedly protected mice from aortic dissection, an early event in Angiotensin II (Ang II)-induced AAA formation. Loss of MKL1 was accompanied by reduced senescence/proinflammation in the vessel wall and cultured vascular smooth muscle cells (VSMCs). Mechanistically, a deficiency in MKL1 abolished AAA-induced p38 mitogen activated protein kinase (p38MAPK) activity. Similar to MKL1, loss of MAPK14 (p38α), the dominant isoform of p38MAPK family in VSMCs suppressed Ang II-induced AAA formation, vascular inflammation, and senescence marker expression. These results reveal a molecular pathway of AAA formation involving MKL1/p38MAPK stimulation and a VSMC senescent/proinflammatory phenotype. These data support targeting MKL1/p38MAPK pathway as a potential effective treatment for AAA., Graphical abstract Image 1, Highlights • MKL1 expression is induced in both thoracic and abdominal aneurysmal tissues. • Genetic ablation and pharmacological inhibition of MKL1 protect mice from aortic dissection and AAA induced by Ang II. • Depletion of MKL1 in mice suppresses Ang II-induced vascular inflammation and senescence. • Depletion of MKL1 blunts the activation of p38MAPK and STAT3 pathways. • Loss of MAPK14 in VSMCs suppresses Ang II-induced AAA formation, vascular inflammation, and senescence marker expression.

The present study evaluated our modified technique for placing a valve one size larger for Biological Bentall (Bio-Bentall) with a stented valve using a double sawing ring technique with a comparison to classical Bio-Bentall with a stent-less valve. Between December 2001 and July 2017, 44 patients (10 stent-less and 34 stented) with Bio-Bentall were included in this study. The early and mid-term surgical outcomes and re-operation free rates, including the structural valve deterioration (SVD) rate, were investigated. The mean follow-up duration was 69 months. There were two in-hospital mortalities in the stent-less group and one in the stented group, showing no significant difference. The survival at 1, 5 and 10 years was 80%, 50% and 30% in the stent-less group and 85%, 77% and 71% in the stented group, respectively, with a significant difference. There were no cases of SVD occurrence in either group. Freedom from re-operation at 1, 5 and 10 years was 100% at all points in the stent-less group and 100%, 96% and 96% in the stented group, respectively, without significance. The mean pressure gradient through the aortic valve according to the most recent echocardiogram was 8.1 mmHg in the stent-less group and 15.8 mmHg in the stented group, without significance. Our modified technique for Bio-Bentall showed a feasible short- and mid-term survival compared to classical stent-less Bio-Bentall. Both techniques had a good outcome concerning SVD occurrence and the re-operation-free rate with a low-pressure gradient in the aortic position.

Introduction: Abdominal aortic aneurysm represents a local pathological dilatation of the abdominal aorta. It is caused by structural weakness of aortic wall but there are many other risk factors that may positively correlate with incidence of AAA like hypertension, smoking, male gender, older age, family history etc. Aim: The purpose of the study was to evaluate the correlation of atherosclerotic risk factors and the size of aortic aneurysm in patients that were admitted for the surgical treatment at the Clinic for cardiovascular surgery in Sarajevo during period 2016-2019. Methods: The study was designed as a retrospective study with one group of patients that was conducted at the Clinical Center of the University of Sarajevo at the Clinic for Cardiovascular Surgery. It included 150 patients, 126 males and 24 females, all of them with infrarenal localization of AAA. From medical records we have collected relevant anamnestic data (age, gender, positive family history, diabetes mellitus, hypertension, hyperlipidemia, smoking, alcohol consumption and obesity). The size of aneurysm was determined by both ultrasound and CT arteriography. The data are processed in the Statistical Package for Social Sciences Ver. 22.0. The results are tabulated or graphically showed, and level of statistical significance was set at p

BACKGROUND AND PURPOSE: Abdominal aortic aneurysm (AAA) is a degenerative disease affecting human health, but there are no safe and effective medications for AAA therapy. Cycloastragenol (CAG), derived from Astragali Radix, has various pharmacological effects. However, whether CAG can protect against AAA remains elusive. In this study, we investigated whether CAG has an inhibitory effect on AAA and its related mechanism. EXPERIMENTAL APPROACH: The AAA mouse model was induced by incubating the abdominal aorta with elastase. CAG was administered by gavage at different doses beginning on the same day or 14 days after inducing AAA to explore its preventive or therapeutic effects respectively. The preventive effects of CAG on AAA were verified in another AAA mouse model induced by angiotensin II in ApoE(−/−) mouse. In vitro experiments were implemented on rat vascular smooth muscle cells (VSMCs) stimulated by TNF‐α. KEY RESULTS: Compared to the control AAA model group, CAG (125 mg·kg(−1) body weight day(−1)) reduced the incidence of AAA, the dilatation of aorta and elastin degradation in media in both mouse models of AAA. CAG suppressed the inflammation, oxidation, phenotype switch and apoptosis in TNF‐α‐stimulated VSMCs, ameliorated the expression and activity of MMPs and decreased the activation of the ERK/JNK signalling pathway. CAG also inhibited the degradation of elastin in TNF‐α‐stimulated VSMCs. CONCLUSION AND IMPLICATIONS: CAG presents protective effects against AAA through down‐regulation of the MAPK signalling pathways and thus attenuates inflammation, oxidation, VSMC phenotype switch and apoptosis and the expression of MMPs as well as increasing elastin biosynthesis.

Increasing researches suggest that inflammatory response is involved in vascular remodeling, which plays an important role in the development of aortic dissection. Glucocorticoids have been widely used in the clinical practice due to its powerful and effective anti-inflammatory property. However, the potential relationship between glucocorticoids and aortic dissection was still obscure. This study sought to elucidate the effect of glucocorticoids on the development and progression of aortic dissection, and the potential mechanism involved. Serum cortisol in aortic dissection patients was significantly higher than that in non-ruptured aortic aneurysm patients and healthy volunteers by radioimmunoassay. In modified C57BL/6 mouse model of aortic dissection, glucocorticoids reduced the incidence of aortic dissection and protected the collagen from degradation. Furthermore, glucocorticoids inhibited the TNF-α secretion of THP-1 monocytes, decreased the migration, phenotype switch from contractile type to synthetic type, and the apoptosis of human aortic smooth muscle cells induced by TNF-α. Finally, TNF-sRII was identified as an important cytokine in cellular interaction that participated in vascular remodeling by targeting the p38 MAPK-HSP27 pathway. These results indicate that glucocorticoids inhibit the incidence of aortic dissection by decreasing the TNF-α secretion and increasing the uncombined TNF-sRII, positively participating in vascular remodeling., Highlights • Glucocorticoids participate in the vascular remodeling of aortic dissection mediated by soluble TNF-RII. • Soluble TNF-RII may be used as a potential and attractive target for the intervention of aortic dissection in the future. In clinical study, we found the serum cortisol in aortic dissection patients was significantly higher than that in non-ruptured aortic aneurysm patients and healthy volunteers. In modified C57BL/6 mouse model, we found glucocorticoids reduced the incidence of aortic dissection, and protected the collagen from degradation. Furthermore, glucocorticoids inhibited the TNF-α secretion of macrophages, decreased the migration, the phenotype switch from contractile type to synthetic type, and the apoptosis of human aortic smooth muscle cells induced by TNF-α. In general, glucocorticoids participate the vascular remodeling of aortic dissection via the p38 MAPK-HSP27 pathway mediated by TNF-sRII.

© The Author(s) 2017. The influence of an aortic aneurysm on blood flow waveforms is well established, but how to exploit this link for diagnostic purposes still remains challenging. This work uses a combination of experimental and computational modelling to study how aneurysms of various size affect the waveforms. Experimental studies are carried out on fusiform-type aneurysm models, and a comparison of results with those from a one-dimensional fluid–structure interaction model shows close agreement. Further mathematical analysis of these results allows the definition of several indicators that characterize the impact of an aneurysm on waveforms. These indicators are then further studied in a computational model of a systemic blood flow network. This demonstrates the methods’ ability to detect the location and severity of an aortic aneurysm through the analysis of flow waveforms in clinically accessible locations. Therefore, the proposed methodology shows a high potential for non-invasive aneurysm detectors/monitors.

Aortic dissection is a disease whereby an injury in the wall of the aorta leads to the creation of a true lumen and a false lumen separated by an intimal flap which may contain multiple communicating tears between the lumina. It has a high associated morbidity and mortality, but at present, the timing of surgical intervention for stable type B dissections remains an area of debate. Detailed knowledge of haemodynamics may yield greater insight into the long-term outcomes for dissection patients by providing a greater understanding of pressures, wall shear stress and velocities in and around the dissection. In this paper, we aim to gather further insight into the complex haemodynamics in aortic dissection using medical imaging and computational fluid dynamics modelling. Towards this end, several computer models of the aorta of a patient presenting with an acute Stanford type B dissection were created whereby morphometric parameters related to the dissection septum were altered, such as removal of the septum, and the variation of the number of connecting tears between the lumina. Patient-specific flow data acquired using 2D PC-MRI in the ascending aorta were used to set the inflow boundary condition. Coupled zero-dimensional (Windkessel) models representing the distal vasculature were used to define the outlet boundary conditions and tuned to match 2D PC-MRI flow data acquired in the descending aorta. Haemodynamics in the dissected aorta were compared to those in an equivalent ‘healthy aorta’, created by virtually removing the intimal flap (septum). Local regions of increased velocity, pressure, wall shear stress and alterations in flow distribution were noted, particularly in the narrow true lumen and around the primary entry tear. The computed flow patterns compared favourably with those obtained using 4D PC-MRI. A lumped-parameter heart model was subsequently used to show that in this case there was an estimated 14 % increase in left ventricular stroke work with the onset of dissection. Finally, the effect of secondary connecting tears (i.e. those excluding the primary entry and exit tears) was also studied, revealing significant haemodynamic changes when no secondary tears are included in the model, particularly in the true lumen where increases in flow over \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$+200\,\%$$\end{document}+200% and drops in peak pressure of 18 % were observed.

In this study, we assessed whether the down-regulation of Yes-associated protein (YAP) is involved in the pathogenesis of extracellular matrix (ECM) mechanical stress-induced Stanford type A aortic dissection (STAAD). Human aortic samples were obtained from heart transplantation donors as normal controls and from STAAD patients undergoing surgical replacement of the ascending aorta. Decreased maximum aortic wall velocity, ECM disorders, increased VSMC apoptosis, and YAP down-regulation were identified in STAAD samples. In a mouse model of STAAD, YAP was down-regulated over time during the development of ECM damage, and increased VSMC apoptosis was also observed. YAP knockdown induced VSMC apoptosis under static conditions in vitro, and the change in mechanical stress induced YAP down-regulation and VSMC apoptosis. This study provides evidence that YAP down-regulation caused by the disruption of mechanical stress is associated with the development of STAAD via the induction of apoptosis in aortic VSMCs. As STAAD is among the most elusive and life-threatening vascular diseases, better understanding of the molecular pathogenesis of STAAD is critical to improve clinical outcome.

In the present study we aimed to identify novel mechanisms and therapeutics for thoracic aortic aneurysm (TAA) in Fbn1C1039G/+ Marfan Syndrome (MFS) mice. The expression of mature/active TGFβ and its downstream effector NOX4 were upregulated while tetrahydrobiopterin (H4B) salvage enzyme dihydrofolate reductase (DHFR) was downregulated in Fbn1C1039G/+ mice. In vivo treatment with anti-TGFβ completely attenuated NOX4 expression, restored DHFR protein abundance, reduced ROS production, recoupled eNOS and attenuated aneurysm formation. Intriguingly, oral administration with folic acid (FA) to recouple eNOS markedly alleviated expansion of aortic roots and abdominal aortas in Fbn1C1039G/+ mice, which was attributed to substantially upregulated DHFR expression and activity in the endothelium to restore tissue and circulating levels of H4B. Notably, circulating H4B levels were accurately predictive of tissue H4B bioavailability, and negatively associated with expansion of aortic roots, indicating a novel biomarker role of circulating H4B for TAA. Furthermore, FA diet abrogated TGFβ and NOX4 expression, disrupting the feed-forward loop to inactivate TGFβ/NOX4/DHFR/eNOS uncoupling axis in vivo and in vitro, while PTIO, a NO scavenger, reversed this effect in cultured human aortic endothelial cells (HAECs). Besides, expression of the rate limiting H4B synthetic enzyme GTP cyclohydrolase 1 (GTPCHI), was downregulated in Fbn1C1039G/+ mice at baseline. In cultured HAECs, RNAi inhibition of fibrillin resulted in reduced GTPCHI expression, while this response was abrogated by anti-TGFβ, indicating TGFβ-dependent downregulation of GTPCHI in response to fibrillin deficiency. Taken together, our data for the first time reveal that uncoupled eNOS plays a central role in TAA formation, while anti-TGFβ and FA diet robustly abolish aneurysm formation via inactivation of a novel TGFβ/NOX4/DHFR/eNOS uncoupling/TGFβ feed-forward pathway. Correction of fibrillin deficiency is additionally beneficial via preservation of GTPCHI function.

Introduction : Type 2 endoleaks (T2E) occur in 10 to 20% of patients after endovascular abdominal aortic aneurysm repair (EVAR) and remain a significant clinical issue. Aim: To evaluate the efficacy and clinical outcomes of transarterial treatment of persistent type II endoleaks after EVAR using the liquid embolic Onyx. Material and methods From February 2012 to August 2015 transarterial T2E embolization was attempted in 22 patients (21 men, median age: 73, range: 62–88 years). Indications for treatment included an increase in the diameter of the aneurysm sac above 5 mm and a persistent endoleak observed for more than 6 months. Mean time from EVAR to endoleak treatment was 43 months (range: 2–125 months). Results: Primary technical success was achieved in 17 (77.3%) patients and secondary technical success in 81.8%, with 0% in-hospital mortality. The mean procedure time was 95 ±48 min, with an average fluoroscopy time of 54 ±25 min. The mean amount of Onyx used was 7.5 ±6.6 ml. Clinical success was seen in 17/21 patients with follow-up imaging (80.9%). Mean follow-up time was 17 months (range: 3–38 months). Conclusions : Onyx has been shown to effectively stabilize previous aneurysm growth as a result of the T2E in the majority of our patients. Transarterial embolization of T2E can be significantly improved as compared to previously reported results by using liquid embolic polymers such as Onyx.

Degeneration of elastic lamina and vascular calcification are common features of vascular pathology such as aortic aneurysms. We tested whether dual therapy with targeted nanoparticles (NPs) can remove mineral deposits (by delivery of a chelating agent, ethylene diamine tetraacetic acid (EDTA)) and restore elastic lamina (by delivery of a polyphenol, pentagalloyl glucose (PGG)) to reverse moderate aneurysm development. EDTA followed by PGG NP delivery led to reduction in macrophage recruitment, matrix metalloproteinase (MMP) activity, elastin degradation and calcification in the aorta as compared to delivery of control blank NPs. Such dual therapy restored vascular elastic lamina and improved vascular function as observed by improvement in circumferential strain. Therefore, dual targeted therapy may be an attractive option to remove mineral deposits and restore healthy arterial structures in moderately developed aneurysms.

Introduction Dilatation of the ascending aorta is a common finding in Tetralogy of fallot (TOF). We sought to provide aortic dimensions in children and adolescents after corrected TOF obtained by contrast-enhanced cardiac-magnetic-resonance angiography (CE-CMRA) that could serve as reference values. Materials and methods We enrolled 101 children and adolescents (56 male) with a median age of 10.9 years. All patients underwent CE-CMRA imaging using a 3-dimensional spoiled gradient-echo-sequence. Aortic diameters were measured at the level of the aortic valve (AV), aortic sinus (AS), sino-tubular junction (STJ) and the ascending aorta (AA) and compared with normal values obtained from literature. Sex-specific aortic dimensions are given as percentile curves as well as z scores. Furthermore CMR volumetric and functional parameters as well as clinical and anamnestic data were analyzed to identify parameters that are associated with aortic dilatation. Results Diameters for aortic size for males were 3.6 + 16.6*BSA0.5 at the AV level, 7.0 + 19.5*BSA0.5 at the AS level, 7.0 + 14.4*BSA0.5 at the STJ level and 7.3 + 15.5*BSA0.5 at the AA level. Diameters for females were 5.8 + 14.1*BSA0.5 at the AV level, 7.2 + 17.6*BSA0.5 at the AS level, 5.2 + 15.4*BSA0.5 at the STJ level and 2.0 + 17.8*BSA0.5 at the AA level. All diameters in TOF patients were larger compared with normal values. The postoperative interval and age at examination were the only parameters associated with aortic size at all measured levels. Conclusion We provide CE-CMRA data of aortic dimensions in children and adolescents after correction of TOF. Our data might be useful for an estimation of the “normal” aortic size in this patient cohort and can serve as a basis for future longitudinal studies adding prognostic data.

Peroxisome proliferator-activated receptor γ agonists have been shown to inhibit angiotensin II (AngII)-induced experimental abdominal aortic aneurysms. Macrophage infiltration to the vascular wall is an early event in this pathology, and therefore we explored the effects of the peroxisome proliferator-activated receptor γ agonist pioglitazone on AngII-treated macrophages. Using microarray-based expression profiling of phorbol ester-stimulated THP-1 cells, we found that a number of aneurysm-related gene changes effected by AngII were modulated following the addition of pioglitazone. Among those genes, polycystic kidney disease 1 (PKD1) was significantly up-regulated (multiple testing corrected p < 0.05). The analysis of the PKD1 proximal promoter revealed a putative early growth response 1 (EGR1) binding site, which was confirmed by chromatin immunoprecipitation (ChIP) and quantitative PCR. Further analysis of publicly available ChIP-sequencing data revealed that this putative binding site overlapped with a conserved EGR1 binding peak present in 5 other cell lines. Quantitative real-time PCR showed that EGR1 suppressed PKD1, while AngII significantly up-regulated PKD1, an effect counteracted by pioglitazone. Conversely, in EGR1 short hairpin RNA lentivirally transduced THP-1 cells, reduced EGR1 led to a significant up-regulation of PKD1, especially after treatment with pioglitazone. In vivo, deficiency of Egr1 in the haematopoietic compartment of mice completely abolished the incidence of CaCl2-induced aneurysm formation.

Wrapping and graft replacement are two optional procedures for the treatment of dilated ascending aorta at the time of aortic valve replacement (AVR). Wrapping is considered less invasive. The aim of this study was to compare the short- and long-term clinical outcomes as well as the long-term quality of life in patients undergoing these two procedures.This study enrolled 40 consecutive patients with dilated ascending aorta who had undergone either wrapping (WAA group, n=20) or replacement (RAA group, n=20) of the ascending aorta at the time of AVR. Short-term outcomes, long-term deaths, and aortic events were evaluated, as was quality of life using the SF-36 Short Form. Long-term maximal proximal aortic diameter was also obtained.There were no early deaths in either group. Pump time was shorter, and transfusion (55% vs. 95%, p=0.035) and postoperative atrial fibrillation (5% vs. 30%, p=0.036) rates were lower, in the WAA than in the RAA group. At a mean follow-up of 4.9 years, the overall 5 year survival rates in the WAA and RAA groups were 78.1% and 87.5%, respectively. There were no significant between group differences in SF-36 scores in any subcategory of this survey. Long-term maximal aortic diameter remained stable in both groups. Both surgical interventions for dilated ascending aorta at the time of AVR yield favorable and comparable results in patients with suitable anatomy. Furthermore, we found no differences in quality of life between these procedures.

To evaluate the feasibility of using contrast medium (CM) of low and ultra-low volumes and injection rates in aortic CT angiography (CTA) through the joint application of single-source dual-energy CT (ssDECT) and adaptive statistical iterative reconstruction (ASIR).120 patients with known or suspected aortic dissection underwent aortic CTA and were equally divided into 3 groups. Conventional 120-kVp scan with a CM volume of 70 ml and an injection rate of 5 ml sGroups B and C had equivalent subjective scores and CT values as Group A, whereas they had higher or equivalent contrast-to-noise ratios. Group B had 40.1% and 30% reductions on CM volume and injection rate, respectively, than Group A. Group C further resulted in 19.2% and 22% lesser CM volume and injection rate than Group B. The average effective radiation doses for the study groups were 22.5-24.5% lower than the control group.With the aid of ASIR and ssDECT for aortic CTA, it is feasible to adopt low and ultra-low CM volumes and injection rates while obtaining good quality images. Advances in knowledge: Low and ultra-low CM volumes and injection rates are feasible in CTA through the joint application of ssDECT and ASIR.

Oxidative stress plays an important role in the formation of abdominal aortic aneurysm (AAA), and we have recently established a causal role of uncoupled eNOS in this severe human disease. We have also shown that activation of NADPH oxidase (NOX) lies upstream of uncoupled eNOS. Therefore, identification of the specific NOX isoforms that are required for eNOS uncoupling and AAA formation would ultimately lead to novel therapies for AAA. In the present study, we used the Ang II infused hph-1 mice to examine the roles of NOX isoforms in the development of AAA. We generated double mutants of hph-1-NOX1, hph-1-NOX2, hph-1-p47phox, and hph-1-NOX4. After two weeks of Ang II infusion, the incidence rate of AAA substantially dropped from 76.5% in Ang II infused hph-1 mice (n=34) to 11.1%, 15.0%, 9.5% and 0% in hph-1-NOX1 (n=27), hph-1-NOX2 (n=40), hph-1-p47phox (n=21), and hph-1-NOX4 (n=33) double mutant mice, respectively. The size of abdominal aortas of the four double mutant mice, determined by ultrasound analyses, was significantly smaller than the hph-1 mice. Aortic nitric oxide and H4B bioavailabilities were markedly improved in the double mutants, while superoxide production and eNOS uncoupling activity were substantially diminished. These effects seemed attributed to an endothelial specific restoration of dihydrofolate reductase expression and activity, deficiency of which has been shown to induce eNOS uncoupling and AAA formation in both Ang II-infused hph-1 and apoE null animals. In addition, over-expression of human NOX4 N129S or T555S mutant newly identified in aneurysm patients increased hydrogen peroxide production, further implicating a relationship between NOX and human aneurysm. Taken together, these data indicate that NOX isoforms 1, 2 or 4 lies upstream of dihydrofolate reductase deficiency and eNOS uncoupling to induce AAA formation. These findings may promote development of novel therapeutics for the treatment of the disease by inhibiting NOX signaling., Graphical abstract fx1, Highlights • Double mutants of hph-1-NOX1, hph-1-NOX2, hph-1-p47phox and hph-1-NOX4 had diminished AAA. • The attenuation of AAA is via recovery of endothelial DHFR and recoupling of eNOS. • Human NOX4 mutants N129S and T555S found in aneurysm patients produced more H2O2. • Targeting NOX signaling may represent a novel therapeutic strategy for aortic aneurysms.

// Jen-Chun Wang 1, 2 , Wu-Chien Chien 3, 4, * , Chi-Hsiang Chung 3, 4, 5 , Wen-I Liao 1 , Chang-Huei Tsao 3, 6 , Yung-Fu Wu 3 and Shih-Hung Tsai 1, * 1 Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 2 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 3 Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 4 School of Public Health, National Defense Medical Center, Taipei, Taiwan 5 Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan 6 Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Shih-Hung Tsai, email: tsaishihung@yahoo.com.tw Wu-Chien Chien, email: chienwu@mail.ndmctsgh.edu.tw Keywords: aortic aneurysm, malignancy, transforming growth factor-β, Marfan syndrome, fibrillin Received: March 15, 2017 Accepted: August 06, 2017 Published: August 11, 2017 ABSTRACT Background: Cardiovascular disease and malignancy have numerous similarities and possible interactions, as these diseases share several risk factors, epidemiological features and biological signaling pathways. Data regarding the risk of malignancy in patients with aortic aneurysm (AA) are scarce. We aimed to determine whether patients with AA have an increased risk of malignancy. Materials and Methods: The data for the nationwide population-based retrospective cohort study described herein were obtained from the Taiwan National Health Insurance Research Database (NHIRD). We selected adult patients who had been newly diagnosed with AA and were followed up between 2000 and 2010. We excluded patients who had been diagnosed with AA and malignancy prior to the date of the AA diagnosis. The control cohort was selected from individuals who had no history of AA and was selected with 1:4 matching according to co-morbidities and medication history. The outcome was a diagnosis of malignancy and the cumulative incidence of AA. Results: A total of 10,933 patients diagnosed with AA were identified. The patients with an AA had a significantly higher cumulative risk of developing malignancies in subsequent years than the patients without an AA (log rank test < 0.001). Similarly, patients with malignancies had a significantly higher cumulative risk of developing an AA in subsequent years than patients without malignancies (log rank test < 0.001). Conclusions: Patients with an AA were shown to have a substantially increased risk of developing a variety of malignancies compared with patients without AAs. Healthcare professionals should be aware of this increased risk when treating patients with AAs.

Hypertension and abdominal aortic aneurysm (AAA) are severe cardiovascular diseases with incompletely defined molecular mechanisms. In the current study we generated dihydrofolate reductase (DHFR) knockout mice for the first time to examine its potential contribution to the development of hypertension and AAA, as well as the underlying molecular mechanisms. Whereas the homozygote knockout mice were embryonically lethal, the heterozygote knockout mice had global reduction in DHFR protein expression and activity. Angiotensin II infusion into these animals resulted in substantially exaggerated elevation in blood pressure and development of AAA, which was accompanied by excessive eNOS uncoupling activity (featured by significantly impaired tetrahydrobiopterin and nitric oxide bioavailability), vascular remodeling (MMP2 activation, medial elastin breakdown and adventitial fibrosis) and inflammation (macrophage infiltration). Importantly, scavenging of mitochondrial reactive oxygen species with Mito-Tempo in vivo completely abrogated development of hypertension and AAA in DHFR knockout mice, indicating a novel role of mitochondria in mediating hypertension and AAA downstream of DHFR deficiency-dependent eNOS uncoupling. These data for the first time demonstrate that targeting DHFR-deficiency driven mitochondrial dysfunction may represent an innovative therapeutic option for the treatment of AAA and hypertension. Keywords: Dihydrofolate reductase, Angiotensin II, Hypertension, Abdominal aortic aneurysm, Endothelial nitric oxide synthase, Mitochondria