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At least 19 records

Effects of hindlimb unweighting on the mechanical and structure properties of the rat abdominal aorta

Previous studies have shown that hindlimb unweighting of rats, a model of microgravity, reduces evoked contractile tension of peripheral conduit arteries. It has been hypothesized that this diminished contractile tension is the result of alterations in the mechanical properties of these arteries (e.g., active and passive mechanics). Therefore, the purpose of this study was to determine whether the reduced contractile force of the abdominal aorta from 2-wk hindlimb-unweighted (HU) rats results from a mechanical function deficit resulting from structural vascular alterations or material property changes. Aortas were isolated from control (C) and HU rats, and vasoconstrictor responses to norepinephrine (10(-9)-10(-4) M) and AVP (10(-9)-10(-5) M) were tested in vitro. In a second series of tests, the active and passive Cauchy stress-stretch relations were determined by incrementally increasing the uniaxial displacement of the aortic rings. Maximal Cauchy stress in response to norepinephrine and AVP were less in aortic rings from HU rats. The active Cauchy stress-stretch response indicated that, although maximum stress was lower in aortas from HU rats (C, 8.1 +/- 0.2 kPa; HU, 7.0 +/- 0.4 kPa), it was achieved at a similar hoop stretch. There were also no differences in the passive Cauchy stress-stretch response or the gross vascular morphology (e.g., medial cross-sectional area: C, 0.30 +/- 0.02 mm(2); HU, 0.32 +/- 0.01 mm(2)) between groups and no differences in resting or basal vascular tone at the displacement that elicits peak developed tension between groups (resting tension: C, 1.71 +/- 0.06 g; HU, 1.78 +/- 0.14 g). These results indicate that HU does not alter the functional mechanical properties of conduit arteries. However, the significantly lower active Cauchy stress of aortas from HU rats demonstrates a true contractile deficit in these arteries.

Non-NASA Center↗

A Novel Technique for the Treatment of Type 2 Endoleak After Endovascular Aortic Repair: Sac Embolization with Balloon Occlusion of the Aorta (SEBOA)

Purpose: We presented a new method of sac embolization using n-butyl-cyanoacrylate (NBCA) with balloon occlusion of the aorta (SEBOA) that can facilitate decreasing flow rate of the involved branches with the goal of type 2 endoleak resolution after endovascular aortic repair (EVAR). Technique: This technique is demonstrated in six patients who required type 2 endoleak treatment including previous technical failure. A transarterial approach was performed in four patients and transabdominal direct puncture in two. Technical success was defined as complete embolization of both involved branches and sac on postoperative CT. Sacography under balloon occlusion of the aorta demonstrated decreased flow rate of the all involved branches in all patients. SEBOA was performed using 25 or 33% of NBCA diluted with lipiodol. Technical success was obtained in 3 of 6 patients, and one major complication was observed with adhesion of NBCA to the microcatheter resulting in foreign body retention. Conclusion: SEBOA may help solve the difficulty of type 2 endoleak treatment after EVAR as decreased flow rate of the involved branches under balloon occlusion of the aorta was achieved in all patients. However, protocols regarding concentration of NBCA or using other embolic materials are needed to improve the success rate.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Prophylactic Occlusion Balloon Placement in the Abdominal Aorta Combined with Uterine or Ovarian Artery Embolization for the Prevention of Cesarean Hysterectomy Due to Placenta Accreta: A Retrospective Study

Objective: To evaluate the outcomes of uterine-conserving surgery with the occlusion balloon technique followed by uterine or ovarian artery embolization (OAE) in women with placenta accreta. Methods: A total of 31 consecutive patients, who were diagnosed with placenta accreta through grayscale ultrasonography or magnetic resonance imaging prenatally, were retrospectively analyzed in our hospital between October 2015 and September 2017. All of the women underwent a Cesarean section combined with prophylactic placement of a balloon catheter in the abdominal aorta followed by uterine artery embolization (UAE) or OAE when necessary. Results: Technical success was achieved in 31 cases (100%), including successful catheterization and inflation of balloons. The uterus was conserved in 30 (96.77%) patients. The estimated blood loss, packed RBC transfused, and the operation time were 1906.45 ± 1117.64 ml, 4(0–6) U, and 88.68 ± 28.35 min, respectively. Out of all of the patients, we found nine cases of bleeding after the release of the balloon. Among these patients, six cases originated from the ovarian arteries and three cases originated from uterine arteries. Further embolization was performed through catheterization. The mean fetal radiation exposure was 4.33 ± 0.79 mGy. Conclusions: Prophylactic abdominal aorta balloon occlusion followed by UAE or OAE can effectively control postpartum hemorrhaging with reduced blood loss, transfusion requirements, and hysterectomy rates in patients with placenta accreta.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Histologic Analysis with the Newly Designed Exoskeleton Seal{sup ®} Stent-Graft in the Porcine Abdominal Aorta

Purpose: To investigate the technical feasibility of a novel exoskeleton Seal{sup ®} stent-graft and analyze early histologic changes in the porcine abdominal aorta. Materials and Methods: Six pigs received an abdominal stent-graft (Group I), and six received an iliac branch stent-graft (Group II). Groups were subdivided as follows: Group Ia, which received three bifurcated main-body stent-grafts; Group Ib, which received three bifurcated main-body stent-grafts with both iliac graft-stents; Group IIa, which received three simple uni-iliac tapered stent-grafts; and Group IIb, which received three uni-iliac tapered tapered stent-grafts with right straight limb and left branched limb. Statistical analyses were performed with the Wilcoxon signed-rank test and mixed-model regression analysis. Results: The primary technical success rate (< 24 h) was 83% because of two acute thromboses in the lumen of the stented abdominal aorta immediately after stent-graft placement. At 4 weeks, late thrombosis occurred in two pigs. Higher mean neointimal hyperplasia areas (23.5% vs. 16.2%; P = .047), neointimal hyperplasia thicknesses (545.5 μm vs. 422.2 μm; P = .001), and degrees of collagen deposition (2.71 vs. 2.33; P = .002) were observed at the bare-metal stent-graft compared with the proximal exoskeleton portion of the stent-graft, with no significant differences between the patent and occluded groups or among the four types of stent-grafts. Conclusions: The exoskeleton stent-graft demonstrates 66% of patency rate during 1-month follow-up due to four cases of thromboses; however, the endothelialization on the junction of proximal graft showed no significant differences between the patent and occluded groups. Further studies should investigate long-term outcomes with prolonged neointimal hyperplasia.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Accelerating massively parallel hemodynamic models of coarctation of the aorta using neural networks

Comorbidities such as anemia or hypertension and physiological factors related to exertion can influence a patient’s hemodynamics and increase the severity of many cardiovascular diseases. Observing and quantifying associations between these factors and hemodynamics can be difficult due to the multitude of co-existing conditions and blood flow parameters in real patient data. Machine learning-driven, physics-based simulations provide a means to understand how potentially correlated conditions may affect a particular patient. Here, we use a combination of machine learning and massively parallel computing to predict the effects of physiological factors on hemodynamics in patients with coarctation of the aorta. We first validated blood flow simulations against in vitro measurements in 3D-printed phantoms representing the patient’s vasculature. We then investigated the effects of varying the degree of stenosis, blood flow rate, and viscosity on two diagnostic metrics – pressure gradient across the stenosis (ΔP) and wall shear stress (WSS) - by performing the largest simulation study to date of coarctation of the aorta (over 70 million compute hours). Using machine learning models trained on data from the simulations and validated on two independent datasets, we developed a framework to identify the minimal training set required to build a predictive model on a per-patient basis. We then used this model to accurately predict ΔP (mean absolute error within 1.18 mmHg) and WSS (mean absolute error within 0.99 Pa) for patients with this disease.

59 BASIC BIOLOGICAL SCIENCES↗

HAND transcription factors cooperatively specify the aorta and pulmonary trunk

Congenital heart defects (CHDs) affecting the cardiac outflow tract (OFT) constitute a significant cause of morbidity and mortality. The OFT develops from migratory cell populations which include the cardiac neural crest cells (cNCCs) and secondary heart field (SHF) derived myocardium and endocardium. The related transcription factors HAND1 and HAND2 have been implicated in human CHDs involving the OFT. Although Hand1 is expressed within the OFT, Hand1 NCC-specific conditional knockout mice (H1CKOs) are viable. Here we show that these H1CKOs present a low penetrance of OFT phenotypes, whereas SHF-specific Hand1 ablation does not reveal any cardiac phenotypes. Further, HAND1 and HAND2 appear functionally redundant within the cNCCs, as a reduction/ablation of Hand2 on an NCC-specific H1CKO background causes pronounced OFT defects. Double conditional Hand1 and Hand2 NCC knockouts exhibit persistent truncus arteriosus (PTA) with 100% penetrance. NCC lineage-tracing and Sema3c in situ mRNA expression reveal that Sema3c-expressing cells are mis-localized, resulting in a malformed septal bridge within the OFTs of H1CKO;H2CKO embryos. Interestingly, Hand1 and Hand2 also genetically interact within the SHF, as SHF H1CKOs on a heterozygous Hand2 background exhibit Ventricular Septal Defects (VSDs) with incomplete penetrance. Previously, we identified a BMP, HAND2, and GATA-dependent Hand1 OFT enhancer sufficient to drive reporter gene expression within the nascent OFT and aorta. Using these transcription inputs as a probe, we identify a novel Hand2 OFT enhancer, suggesting that a conserved BMP-GATA dependent mechanism transcriptionally regulates both HAND factors. These findings support the hypothesis that HAND factors interpret BMP signaling within the cNCCs to cooperatively coordinate OFT morphogenesis.

59 BASIC BIOLOGICAL SCIENCES↗

Influence of flow and pressure on wave propagation in the canine aorta.

Data on wave speed acquired from 20 anesthetized dogs showed that the thoracic aorta was essentially nondispersive for small artificially generated pressure waves traveling in the downstream or the upstream direction and having frequencies between 40 and 120 Hz. The amplitude of these waves decayed exponentially with the distance traveled. Theoretical studies are cited which have shown that changes in wave speed due to variations in pressure and flow produce marked nonlinear effects in hemodynamics.

Histand, M. B.↗

Hydroelastic effects in the aorta bifurcation zone

The mechanical behavior of the vessels and blood is mathematically analyzed at the point of aortic bifurcation using a homogeneous single layer channel as a model of the aorta. Allowance is made for the fact that the aortic intima is considerably less rigid than the other layers. For analysis of blood flow in the major arteries, the blood is treated as a viscous Newtonian fluid whose movements are described by Navier-Stokes equations and a continuity equation. Blood flow dynamics at the aortic bifurcation are discussed on the basis of the results.

Volmir, A. S.↗

Evidence that simulated microgravity may alter the vascular nonreceptor tyrosine kinase second messenger pathway

Simulated microgravity (hind limb unweighting; HU) reduces maximal contractile capacity to norepinephrine (NE) but not 5-hydroxytryptamine (5-HT) in the rat abdominal aorta of male Wistar rats. Our earlier study showed that voltage-operated calcium channels, the MAPK pathway [1], and vasoconstrictive prostaglandins contribute to the NE-induced contraction of control (C) but not HU, aorta rings. Genistein, a general tyrosine kinase inhibitor, caused a significant reduction in vascular contractility in C but not HU arteries. The present study explored the role of protein kinase C (PKC) and extracellular receptor-activated kinase 1 and 2 (ERK1/2) in the HU-induced vascular hyporesponsiveness to NE. Microgravity was simulated in Wistar rats by 20 day HU. The abdominal aorta was removed from control and HU rats, cut into 3 mm rings, and mounted in tissue baths to measure isometric contraction. Protein levels were determined using Western blot analysis. PD98059, a selective MAPKK inhibitor, caused a marked inhibition of NE-induced contraction in both C and HU arteries. Calphostin C, a PKC inhibitor, completely abolished the contractile response to NE in both C and HU tissues. Phosphorylated (activated) ERK1/2 protein mass was greater in C, compared to HU, aortas, and was reduced by genistein only in C tissues. MAPK total protein levels in the rat aorta were increased in the HU-treated, compared to C, animals. These results indicate that PKC represents an early transduction step in the contractile response to NE in the rat abdominal aorta. That inhibition of the step immediately before activation of MAPK reduced contraction in both C and HU tissues, while general tyrosine kinase inhibition with genistein blocked only the control responses, suggests that a nonreceptor tyrosine kinase may be involved in HU-induced vascular hyporesponsiveness to NE.

Non-NASA Center↗

Comparison of Chimney Technique and Single-Branched Stent Graft for Treating Patients with Type B Aortic Dissections that Involved the Left Subclavian Artery

Objective: To compare the short-term efficiency of two different endovascular repairs for type B aortic dissection involving the left subclavian artery. Methods: From February 2013 to March 2016, a cohort of 43 patients with TBADs involving the LSA underwent thoracic endovascular aortic repair (TEVAR) in two departments, consisting of 22 (Group A) with chimney grafts (CGs) and 21 (Group B) with single-branched stent graft (SBSG). Results of the two groups in perioperative and follow-up period (≥ 3 months) were comparatively analyzed, especially on aortic remodeling. Results: Endoluminal repair of the two groups was successfully carried out. The median follow-up period was 19 months (range, 3–43 months) in Group A and 12 months in Group B (range, 6–32 months). During the TEVAR, one CG compression occurred in Group A and one type I endoleak in Group B. During follow-up, four complications occurred in Group A (two CGs occlusion, one type I endoleak and one death from dissecting aneurysm rupture), compared with two occurred in Group B (one sidearm graft twist and one death from myocardial infarction). Complete thrombosis of the false lumen (FL) in thoracic aorta was revealed in 83.3% (15/18) cases in Group A and 89.5% (17/19) in Group B. Partial thrombosis of the FL was revealed in 16.7% (3/18) cases in Group A and 10.5% (2/19) in Group B. In the abdominal aorta, complete thrombosis of the FL was noted in 23.1% (3/13) cases in Group A and 36.4% (4/11) in Group B. Partial thrombosis of the FL was revealed in 76.9% (10/13) cases in Group A and 63.6% (7/11) in Group B. Significant true lumen re-expansion and false lumen regression were observed in different levels of the descending aorta by computed tomography angiography (CTA) in both Groups A and B (P < 0.05). No significant diametric changes of abdominal aorta were found during follow-up in both groups. Conclusions: For patients with TBADs involving the LSA, the chimney technique and the SBSG revealed comparable results. Further evaluation of more patients with longer follow-up is needed to substantiate these results.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Silenced long non-coding RNA activated by DNA damage elevates microRNA-495-3p to suppress atherosclerotic plaque formation via reducing Krüppel-like factor 5

Objective: Atherosclerosis (AS) is an inflammatory disease and the formation of atherosclerotic plaque plays a critical role in AS progression. We aimed to investigate the effect of long non-coding RNA (lncRNA) activated by DNA damage (NORAD)/microRNA-495-3p (miR-495-3p)/Krüppel-like factor 5 (KLF5) axis on atherosclerotic plaque formation. Methods: The ApoE{sup −/-} mice were fed a high-fat diet to construct AS mouse models and the modeled mice were treated with altered NORAD, miR-495-3p or KLF5. NORAD, miR-495-3p and KLF5 expression in mouse aorta tissues were evaluated, and the levels of inflammatory factors, oxidative stress factors, endothelial function indices and blood lipid in mice were all determined. The atherosclerotic plaque area, lipid deposition area, collagen fibers and CD68 expression in mouse aorta tissues were assessed. The regulatory relation between NORAD and miR-495-3p, and the target relation between miR-495-3p and KLF5 were confirmed. Results: NORAD and KLF5 were increased whereas miR-495-3p was decreased in atherosclerotic mouse aortas. Inhibited NORAD or elevated miR-495-3p suppressed inflammation, oxidative stress, endothelial dysfunction, blood lipid level, atherosclerotic plaque area, collagen fibers and CD68 expression in atherosclerotic mouse aortas. Effects of elevated miR-495-3p on atherosclerotic mice could be reversed by up-regulation of KLF5. NORAD served as a sponge of miR-495-3p and miR-495-3p directly targeted KLF5. Conclusion: Silenced NORAD elevated miR-495-3p to suppress atherosclerotic plaque formation via reducing KLF5. Findings in our research may be helpful for exploring molecular mechanisms of AS.

60 APPLIED LIFE SCIENCES↗

Cardiovascular Responses to Simulated Spaceflight: Molecular Signatures and Surrogate Outputs to Measure CVD Risk

During extended space missions beyond low Earth orbit, astronauts will encounter prolonged periods of weightlessness and low dose space radiation. Previous studies have shown that exposure to small doses of high LET radiation (< 50 cGy) can lead to both short-term and long-term alterations in heart function, structure and underlying molecular mechanisms. In this study, we aim to identify the molecular signature associated with the cardiovascular response to simulated galactic cosmic radiation (5-ion GCR) alone or in combination with simulated weightlessness at time intervals relevant to mission length and recovery. Additionally, we aim to determine whether sex impacts cardiovascular responses to these spaceflight factors. Our overarching goal is to enhance our understanding of the cardiovascular risks associated with extended space missions and the clinical endpoints they suggest. We hypothesize that exposure to simulated space radiation leads to enduring alterations in the transcriptome, redox signaling and cytokine environment of cardiovascular tissue, some which have known links with reduced cardiovascular performance, aging, and increased risk of cardiovascular disease (CVD). Furthermore, we posit that simulated space radiation exposure in combination with simulated microgravity exacerbates cardiovascular deficits compared to single factor exposure. Female and male C57BL/6J mice, aged 23-24 weeks, were exposed to a single dose of 5, 15, or 50 cGy of 5-ion GCR, or sham-treated (0 cGy). Euthanasia was performed at 14 days and ~4 months post-irradiation. Hearts, aorta and blood plasma were collected shortly thereafter. RNA-sequencing of left ventricles at ~4 months post-GCR exposure revealed sex differences in the heart transcriptome with a few genes showing radiation-dependent changes in expression levels. Notably, some of the differentially expressed genes in 15 and 50 cGy GCR groups are known to play roles in the development of CVD. Analysis of protein levels of a subset of inflammatory cytokines in the heart indicated sex differences but no differences between sham and 50 cGy groups. Results also showed correlations among differentially expressed genes and a subset of inflammatory cytokines, with some correlations altered by GCR exposure. These findings suggest that GCR exposure can modify protein and gene networks linked to inflammation and CVD progression. In the aorta, telomere lengths were comparable across treatment groups sexes. Mitochondrial copy number is a biomarker for mitochondrial function with decreased copy numbers associated with cardiometabolic disease traits. Mitochondrial copy numbers of aorta also showed no sex nor dose differences. In a second study, mice underwent one week of simulated microgravity by hindlimb unloading (HU) and then exposed to a single dose of 15 cGy of 5-ion GCR. HU was conducted for an additional two weeks following GCR exposure. Single factor exposure groups (HU or GCR only) also were included in the study. Euthanasia was then performed and the same tissues were collected. Protein levels of select inflammatory cytokines in the heart showed sex-dependent differences in expression. In the aorta, telomere lengths and mitochondrial copy number also showed sex differences. In summary, our results indicate differences between sexes in biomarkers related to cardiovascular health. Exposure to 5-ion GCR or HU, alone or in combination, did not result in changes in most of the cardiovascular biomarkers that were examined. However, in the heart, simulated space radiation at doses of 15 and 50 cGy led to long-term alterations in the expression levels of a small group of genes known to be associated with the progression of CVD. The long-term transcriptomic changes resulting from exposure to simulated space radiation should be carefully investigated to mitigate adverse cardiovascular events during and after deep space missions. Our results also highlight the importance of sex-specific strategies in monitoring and maintaining cardiovascular health during and after deep space missions.

cardiovascular↗

Design, synthesis, and antihypertensive activity of new pyrimidine derivatives endowing new pharmacophores

A new series of achiral pyrimidine derivatives based on nifedipine-like structure was designed and synthesized. These pyrimidyl derivatives contained hydrazine, hydrazones, acetohydrazide, differently substituted benzylidene functionalities, benzosulfohydrazine, various heterocycles such as pyrazole, pyrazolidinedione, thiazoline, and thiazolidinone rings, and fused ring systems such as triazolopyrimidine and pyrimidotriazine rings. Compounds 5a, 5b, 11b, 8b, 9b–d, and 15b showed a decrease in mean arterial rabbit blood pressure (MABP) ranging from 51.4 to 78.2 mmHg in rabbits in comparison with nifedipine-treated rabbits. Among these derivatives, compounds 5a, 5b, 9b, and 9c were found to exhibit calcium channel blockade activity on preparations of rabbit aortae. They exhibited relaxation in the range of 89.2% to 74.4% in comparison to nifedipine (57.6%) as well as a decrease in heart rate. Histopathological effect of compounds 5a,b on the expression of endothelial nitric oxide synthase (eNOS) was also examined on rat aorta. An intense expression of eNOS immune staining in aortic endothelium was seen for compound 5b indicating that it lowered blood pressure via activation of eNOS expression in aorta.

60 APPLIED LIFE SCIENCES↗

Liver metastases of neuroendocrine tumors: is it possible to diagnose different histologic subtypes depending on multiphasic CT features?

Purpose: To assess and compare the multiphasic computed tomography (CT) features of neuroendocrine tumor (NET) liver metastases and to investigate the possibility to predict the histologic subtype of the primary tumor. Materials and methods: Between January 2013 and December 2017 patients with biopsy proven NET with at least one liver metastasis who underwent multiphasic CT were enrolled in this study. All cases were acquired using a standardized multiphasic liver CT protocol, arterial, portal, and hepatic venous phases were obtained. Images were retrospectively analyzed in consensus by two abdominal radiologists blinded to clinical data and histologic subtype. The size, number, and location of lesions were noted. Enhancement patterns of each lesion on arterial, portal, and hepatic venous phases were assessed. For quantitative analysis, CT attenuation of tumors, liver parenchyma, and aorta were measured using a circular region of interest (ROI) on arterial, portal, and hepatic venous phases for reflecting the blood supply of the tumor. Tumor-to-aorta and tumor-to-liver ratio were calculated in all three phases. Differences between subtypes of NET liver metastases were studied using ROC analysis of clustered data. Results: A total of 255 neuroendocrine tumor liver metastases divided into 101 (39.6%) pancreatic, 60 (23.5%) gastroenteric and 94 (36.8%) lung NET liver metastases were analyzed. Contrast enhancement of lesions was homogeneous in 78% of patients (n = 199), which was significantly more frequent in patients with pancreatic group than in those with gastroenteric origin (n = 90, 89.1% vs. n = 28, 46.7%; p < 0.001). Gastroenteric NET metastases frequently showed heterogeneous enhancement, which was significantly higher than in the other two groups (50% vs. 3% and 2%). With respect to the location of the primary tumor, the difference in enhancement patterns of the liver lesions was statistically significant (p < 0.001). Pancreatic NET metastases were mostly hyperdense on arterial images and isodense on portal and hepatic venous phase images (79.2%, n = 80). Gastroenteric NET metastases were mostly hyperdense on arterial phase images and hypodense on portal and hepatic venous phase images (n = 28, 46.7%). The most frequent pattern for lung NET metastases was hypoattenuation on all three phase images (n = 44, 46.8%). ROC analysis of clustered data revealed statistically significant differences between pancreatic NET liver metastases, gastroenteric NET liver metastases, and lung NET liver metastases in terms of tumor-to-aorta (T–A) ratio and tumor-to-liver (T–L) ratio (p < 0.001). Conclusion: We observed statistically significant differences in multiphasic CT features (enhancement pattern, T–A ratio, and T–L ratio) between histologic subtypes of NET liver metastases. As the difference in histological subtypes of NET liver metastases results in a different prognosis and different management strategy, these CT features might help to identify the primary tumor when it is not known to ensure accurate tumor staging and to provide optimal treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗