Obliteration Of Arteries Research Articles

Hypusine Signaling Promotes Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Rationale: The ubiquitous polyamine spermidine is essential for cell survival and proliferation. One important function of spermidine is to serve as a substrate for hypusination, a posttranslational modification process that occurs exclusively on eukaryotic translation factor 5A (eIF5A) and ensures efficient translation of various gene products. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of the small pulmonary arteries (PAs) caused by excessive proliferation of PA smooth muscle cells (PASMCs) and suppressed apoptosis. Objectives: To characterize the role of hypusine signaling in PAH. Methods: Molecular, genetic, and pharmacological approaches were used both invitro and invivo to investigate the role of hypusine signaling in pulmonary vascular remodeling. Measurements and Main Results: Hypusine forming enzymes-deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH)-and hypusinated eukaryotic translation factor 5A are overexpressed in distal PAs and isolated PASMCs from PAH patients and animal models. In vitro, inhibition of DHPS using N1-guanyl-1,7-diaminoheptane or shRNA resulted in a decrease in PAH-PASMC resistance to apoptosis and proliferation. In vivo, inactivation of one allele of Dhps targeted to smooth muscle cells alleviates PAH in mice, and its pharmacological inhibition significantly decreases pulmonary vascular remodeling and improves hemodynamics and cardiac function in two rat models of established PAH. With mass spectrometry, hypusine signaling is shown to promote the expression of a broad array of proteins involved in oxidative phosphorylation, thus supporting the bioenergetic requirements of cell survival and proliferation. Conclusions: These findings support inhibiting hypusine signaling as a potential treatment for PAH.

Iodixanol as a New Contrast Agent for Cyanoacrylate Embolization: A Preliminary In Vivo Swine Study.

N-butyl cyanoacrylate (NBCA) is a lipophilic, permanent embolic glue that must be opacified for fluoroscopic guidance. Empirically, lipophilic Lipiodol Ultra Fluid® (LUF) has been added to produce a single-phase physically stable mixture. Varying the dilution ratio allows control of glue polymerization kinetics. LUF is far more costly than water-soluble iodinated contrast agents (ICAs). Our purpose was to evaluate whether a water-soluble nonionic iso-osmolar ICA could be used instead. We embolized both renal arteries of six swine using 1:3 NBCA-LUF or NBCA-iodixanol in 1:1, 1:3, and 1:7 ratios. We used both micro-computed tomography to assess the distality of glue penetration and indexed cast ratio and histology to assess distality, arterial obliteration, vessel-wall damage, and renal-parenchyma necrosis. Glue-LUF produced significantly greater indexed cast ratio and renal-artery ROI values and a significantly shorter cast-to-capsule distance. The injected volume was significantly greater with 1:7 iodixanol than with the other mixtures. No significant differences were found for histological evidence of artery obliteration, vessel-wall damage, or renal-parenchyma necrosis. This is the first study dealing with ICA alone as a contrast agent for cyanoacrylate embolization, compared to LUF. More research is needed to determine whether water-soluble nonionic iodinated agents can be used for human NBCA embolization given the good safety profile, availability, and low cost of ICA.

The EPOR/CD131 heteroreceptoragonist has an endothelioprotective effect against the background of pulmonary hypertension caused by monocrotalin

Introduction: The abnormal increase in pulmonary pressure observed in pulmonary arterial hypertension (PAH) is a consequence of increased pulmonary vascular resistance due to progressive loss and obliteration of pulmonary arteries. The initial trigger is a combination of factors that lead to endothelial damage and impaired vascular regeneration. Aim: research the possibilities of pharmacological correction of pulmonary arterial hypertension induced by monocrotalin using the EPOR/CD131 heteroreceptor agonist with the laboratory code EP-11-3.
 Materials and Methods: The study of pharmacological activity on a model of monocrotaline induced PAH was carried out on male Sprague-Dawley rats weighing 180-220 grams. Monocrotaline (MCT) pulmonary hypertension was simulated in 30 animals using subcutaneous injection of MCT at a dose of 60 mg/kg. Seven days after the injection of MCT, the administration of the studied compounds began. The erythropoietin derivative with the laboratory code EP-11-3 and pHBSP administered subcutaneously at a dose of 25 mcg/kg once every 3 days for 21 days.
 Results: On the model of monocrotalin-induced PAH, it was shown that the erythropoietin derivative with the laboratory code EP-11-3 has a pronounced endothelioprotective effect, reducing the coefficient of endothelial dysfunction, statistically significantly increasing the expression of VEGF-R2 mRNA and reducing the expression of SDF-1 mRNA, reducing the concentrations of CT-1 and PNP, and reducing the signs of remodeling of the heart and pulmonary vessels.
 Conclusion: Erythropoietin derivative with laboratory code EP-11-3 has an endothelioprotective effect and reduces the manifestations of vascular remodeling in pulmonary hypertension caused by monocrotalin.

Abstract 17836: ATP Citrate Lyase Coordinates Lipid Synthesis and Expression Cell Cycle Regulating Genes to Promote Vascular Remodeling in Pulmonary Arterial Hypertension

INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of distal pulmonary arteries (PAs) due to enhanced proliferation, suppressed apoptosis and increased migration of PA smooth muscle cells (PASMCs). Like cancer cells, this abnormal phenotype of PASMCs is driven by epigenetic reprogramming and fueled by a metabolic shift towards glycolysis. ATP-Citrate Lyase (ACLY) is a nuclear-cytosolic enzyme that converts citrate to acetyl-CoA, which serves as substrate for histone acetyltransferases regulating gene expression and as a building block for lipid synthesis (required for proliferating cells to generate membrane). ACLY has recently emerged as a key player and therapeutic target in cancer. However, its role in PAH is unknown. METHODS/RESULTS: ACLY, p-ACLY (active form) expression and its nuclear localization were increased in distal PAs and PASMCs from PAH patients (WB and IF, p<0.01). Similar results were observed in the Sugen/Hypoxia (Su/Hx) animal models. In vitro , ACLY inhibition (BMS, siRNA) decreases PAH-PASMCs proliferation (PLK1; Ki67; p<0,01) and survival (Survivin; Annexin-V; p<0.01). These effects were accompanied with a decreased glycolysis (PFKBP3, p-PDH) and increased OCR/ECAR (Seahorse). Moreover, ACLY inhibition decreases the PAH-PASMCs migratory potential. Using RNA-Seq, we demonstrated that inhibition of ACLY downregulates genes associated with cell division and lipid synthesis. Further experiments revealed that ACLY promotes nuclear acetyl-CoA production favoring acetylation of H3K27, H3K9, H4, and GCN5-mediated transcriptional activation of genes responsible for cell cycle progression. Accordingly, we demonstrated that GCN5 inhibition decreases proliferation and survival of PAH-PASMCs (Ki67, AnnexinV). In vivo , Acly loss-of-function targeted to SMCs conferred protection against Su/HX-induced PAH in mice (echo and RHC). Accordingly, pharmacological inhibition of ACLY using BMS-303141 or Bempedoic Acid improved hemodynamics (RVSP, mPAP, SV, TPR, p<0.05) and vascular remodeling (EVG, p<0.05) in Su/Hx rats with established PAH. CONCLUSION: We demonstrated that ACLY inhibition may represent a novel therapeutic avenue to improve vascular remodeling in PAH.

P374 THE BAD COUSIN OF PULMONARY EMBOLISM: PRIMARY PULMONARY ARTERY SARCOMA

Abstract A young man of 29 years presented to the Emergency Room reporting worsening dyspnea for about 2 weeks. He had never had previous cardiovascular disease nor had risk factors for them. Hemodynamics were stable, but arterial blood gases showed hypocapnic hypoxia. The ECG revealed a S1Q3T3 pattern, incomplete right bundle branch block and signs of right ventricular overload. D–dimer was 4493 ng/ml. CT pulmonary angiogram (CTPA) showed massive bilateral embolism with thrombotic material in the right ventricle (RV) and almost complete obliteration of pulmonary trunk and main pulmonary arteries; moreover, there were subpleural nodularities in upper pulmonary lobes. Echocardiogram showed a dilated and hypokinetic RV, moderate tricuspid regurgitation with a sPAP of 80 mmHg, thrombotic pulmonary trunk obliteration and floating thrombi adhered to the tricuspid valve. UFH therapy was started. After ten days, there was no improvement in clinical status, echocardiography and CTPA. So, we decided to perform mechanical thrombectomy. In addition to thrombotic material, fibrous tissue was extracted and histologically analyzed. At the end of the procedure, the patient became hemodynamically unstable (BP 80/40 mmHg and HR 130 bpm) with dyspnea and tachypnea. ABG showed mixed acidosis. Right ventricular function worsened due to high afterload for the persistence of thrombotic material in the pulmonary trunk, defining a picture of obstructive shock. We started fibrinolysis (with rtPA), enoximone and norepinephrine, but asystole occurred and the patient eventually died. The histological examination revealed that the mass was a pleomorphic rhabdomyosarcoma of the pulmonary artery. Primary pulmonary artery sarcoma is an extremely rare and histologically heterogeneous disease. It develops mainly from great pulmonary arteries and then it grows up in the lumen of vessels. It may involve pulmonary valve and RV and invade pulmonary parenchyma and loco–regional lymph nodes. Diagnosis is challenging, because it simulates pulmonary embolism in clinical, echocardiographic and radiological presentation. Suspicion may arise from lack of benefit from anticoagulant therapy. Nodular pulmonary infiltrates are typical. There are two surgical approaches: pneumectomy or endarterectomy (as palliation). Prognosis is poor: mean survival of 1,5 month without therapy and 10 months with pneumectomy. In addition to the progression of the disease, death can occur for obstructive shock, as in our patient.

MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL FEATURES OF PLACENTA AND PLACENTAL FACTOR IN WOMEN WITH ISOLATED CONGENITAL HEART DEFECTS IN NEWBORN

Introduction. Congenital heart defects (CHD) in fetus can affect the course of pregnancy, cause changes in the functioning of the pregnant woman's systems and metabolic and hemodynamic disorders. The relevance of the problems CHD is primarily due to their high frequency in newborns (5-9 per 1,000 live births) depending on geographical differences and the significant share among multiple congenital malformations and the need for surgical treatment in the neonatal period. Placenta, as one of the least studied human organs, plays not only a crucial role in the process of organogenesis, but also in the "programming" of human health after fetal and newborn periods. For today, it’s important to determine the association between the CHD and placental abnormalities, the nature and consequences of which need further study.Objective. To study morphological and immunohistochemical features of placental structures in parturients with isolated congenital heart defects in the newborn.Material and methods. Over the period 2020-2021, 90 pregnant women aged 17 to 39 years (mean age 28.36±5.08) who gave birth at 37-41 weeks, and their placents, of which 30 had different forms of CHD in the newborn, were examined on a hospital-based sample. Patients were divided into two groups: the study - women with CHD in the newborn, and control - somatically healthy motherswith healthy children. Given the different etiologies of cardiovascular defects in fetus, as well as the presence of different risk factorsfor their occurrence, in order to minimize their impact on the emergence of isolated CHD, considered appropriate selection criteria for pregnant women with non-syndromic forms of cardiovascular defects, as the presence of genetic syndrome can affect intrauterine fetaldevelopment, which makes it impossible to determine a single effect of CHD development. The selection criteria in this study included:somatically healthy woman, unburdened pregnancy, natural insemination (without using of reproductive technologies), the presence of isolated heart disease in the fetus, confirmed by a cardiologist using echocardiography. Organometric, macroscopic, general histological and immunohistochemical methods were used to study placental morphology and placental factors.Results. Analyzing the data on the morphological features of placentas from women with CHD in the newborn, we should note the presence of circulatory disorders in 60% of cases, namely multiple infarcts, complete or partial obliteration of arteries and arterioles with perivascular fibrosis (in the stem villi – 15%, intermediate – 10%, terminal - 10%), reduced number of fetal vessels in the terminal villiand syncytiocapillary membranes, abrupt vasodilation of intermediate villi. Complete or partial replacement of villous epithelium by fibrinoid masses in 20% was also detected. Immunohistochemical study of placental growth factor showed less pronounced expression in syncytia, decidual sheath and stromal cells (1-2 points) compared with control (2-3 points).Conclusions. The revealed morphological and immunohistochemical changes in the placental barrier at different levels refer to the damage of maternal and fetal placenta structures of parturients with isolated neonatal heart disease, which lead to impaired stromalvascular processes with reduced perfusion. This confirms the world data on the presence of placental-cardiac axis and can be a predictor of CHD at the early stages of placental structure study, as well as in further prediction of the child's health.

Chronic thromboembolic pulmonary hypertension resulting in decompensated right heart failure

Chronic thromboembolic pulmonary hypertension is a notoriously underdiagnosed cause of severe pulmonary hypertension. It is a form of precapillary pulmonary hypertension (PH) that results from intraluminal thrombus organization and fibrous formation which ultimately results in the complete obliteration of pulmonary arteries, resulting in increased pulmonary vascular resistance which leads to the development of pulmonary hypertension and as a result right heart failure. The mechanism involves the narrowing of the pulmonary artery which increases blood pressure within the lungs and impairs blood flow which increases the workload of the right side of the heart ultimately causing right heart failure. Pulmonary hypertension can also cause arrhythmias, blood clots, and bleeding in the lungs. Even though CTEPH is a deadly condition, among all forms of pulmonary hypertension, CTEPH is the only curable form. Echocardiography is the initial assessment tool for suspected PH. A right heart catheterization may be performed to confirm the presence of pulmonary hypertension. Confirmation of CTEPH requires a V/Q scan. Although ventilation/perfusion scintigraphy has a major role in the evaluation of patients with suspected CTEPH, nowadays CTA chest is being used widely as it produces much better-quality images compared to V/Q scan. Without treatment, the prognosis is very poor. Out of three treatment modalities such as; pulmonary endarterectomy (PEA) surgery, balloon pulmonary angioplasty (BPA), and medical therapy, surgery is the gold standard. The physician must be familiar with the disease entity, early diagnosis, and appropriate treatment to improve survival. Here we present a literature review on this topic.

Abstract 10202: DNA-PKcs: A Novel Therapeutic Target in Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular obliteration of small pulmonary arteries (PAs), notably due to excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs). Accumulating evidence indicates that PAH-PASMCs have acquired an over-efficient DNA damage response (DDR) ensuring sensing, signaling, and repair of DNA damages, accounting for their enhanced capacity to survive and proliferate under stressful conditions. DNA-dependent protein kinase (DNA-PK) is a pivotal component of the DNA repair machinery which plays an instrumental role in the overall survival and proliferation of cancer cells. Based on similarities between PAH and cancer cells, we thus hypothesized that increased expression of DNA-PK contributes to vascular remodeling in PAH. Methods and Results: Using Western blot (WB) and immunohistochemistry, we found that expression and activity of DNA-PK were increased in PAH-PASMCs (n=6) compared to controls (n=6, p<0.01). Similarly, DNA-PK was significantly up-regulated in distal PAs from PAH animal models (i.e. MCT rats and Su/Hx rats and mice, n=5/group, p<0.01). In vitro, the pharmacological inhibition of DNA-PK using AZD-7648 or Nedisertib attenuates PAH-PASMC proliferation (Ki67 and EdU labeling, MCM2, PLK1, and PNCA by WB; p<0.05) and resistance to apoptosis (AnnexinV labeling, Survivin by WB)(n=5 cell lines; p<0.05). These effects were associated with reduced expression of gH2AX. As assessed by echocardiography and right heart catheterization, treatment with AZD7648 improved pulmonary hemodynamics (RVSP, mPAP, and TPR) and right ventricular function (CO, PAT/PET, TAPSE) in Su/Hx mice with established PAH (n=10/group; all p<0.01). Accordingly, pulmonary vascular remodeling (EVG) and the proportion of PCNA-positive PASMCs were reduced in AZD7648-treated Su/Hx mice when compared to vehicle-treated Su/Hx mice (p<0.001). Conclusions: We showed for the first time that DNA-PK is overexpressed in human and experimental PAH and contributes to the pro-proliferative and anti-apoptotic phenotype of PAH-PASMCs.

What next and what to expect?

What next and what to expect? A 17-year-old female presented with painless progressive loss of vision in both eyes (OU) with multiple episodes of syncope and postural giddiness for 1 month. On ocular examination, best-corrected visual acuity (BCVA) was 1/60 in the right eye (OD) and finger counting close to the face in the left eye (OS); intraocular pressure was within normal limits in both the eyes. Slit-lamp examination revealed corkscrew conjunctival vessels [Fig. 1a), anterior chamber (AC) cells 1(+), and iris neovascularization. Pupils were mid-dilated and sluggishly reacting to light. Fundus examination revealed hyperemia and neovascularization of the disc, dilated retinal veins with a beaded appearance, patches of retinal whitening over the macula and peripapillary area, and arterio-venous (AV) anastomosis [Fig. 1b and 1c]. What is the Next Step? Systemic examination Computed tomography (CT)-angiography Fundus fluorescein angiography and optical coherence tomography All of the above Findings On systemic examination, the radial artery pulse could not be felt, and the carotid pulsations were felt very feebly on both sides. The pulse rate measured in the right popliteal artery was 80/min. Blood pressure (BP) was not recordable in the upper limbs. BP recorded in the right lower leg was 150/90 mm Hg. CT angiography revealed severe luminal narrowing involving the left common carotid artery and left subclavian artery at the ostial level, and juxta-ostial narrowing of the right brachiocephalic trunk with multiple enhancing collateral channels noted in the neck [Fig. 1d-f].Figure 1: (a) Slit-lamp photography showing corkscrew conjunctival vessels, (b) and (c) fundus images showing neovascularization of the disc, dilated retinal veins with beaded appearance, patches of retinal whitening over the macula and peripapillary area, and arterio-venous anastomosis, computed tomography (CT) angiography image showing (d) narrowing of the right brachiocephalic trunk (yellow arrow), (e) narrowing of the left common carotid artery (yellow arrow), (f) stenosed left subclavian artery, minimal contrast filled vessel seen (yellow arrow)Proliferative retinopathy in both eyes was treated with pan-retinal photocoagulation (PRP) and one intravitreal injection of bevacizumab (Avastin) in OS. She received oral prednisolone for the systemic condition. Subsequently, she underwent phacoemulsification with foldable intraocular lens implantation in OU. She had a BCVA of 20/120 in OD and 20/400 in OS at the last follow-up visit. Diagnosis: Takayasu arteritis (TA) with Takayasu retinopathy Correct Answer: B Discussion TA is a chronic inflammatory disease affecting the large and medium-sized vessels, predominantly in the aorta and its main branches leading to the arterial wall thickening, fibrosis, stenosis, and thrombus formation resulting in cerebral and ocular ischemia.[1] Ophthalmic features in TA result from either due to the obliteration of arteries causing ischemic ocular changes (hypotensive retinopathy) or due to renal artery stenosis causing uncontrolled hypertension (hypertensive retinopathy).[2] Manifestations due to retinal hypoxia are microaneurysms, AV anastomosis, retinal vein occlusion, proliferative retinopathy, cataract, neovascular glaucoma, ocular ischemic syndrome, ischemic optic neuropathy, optic atrophy, retinal detachment, etc.[3] Statement of ethics Written informed consent for publication (including the images) has been obtained from the parent of the patient. All procedures carried out were in accordance with the tenets of the Declaration of Helsinki. Institute Ethics Committee approval is not required for a case report according to Indian council of medical research guidelines. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Artemisinin and Its Derivate Alleviate Pulmonary Hypertension and Vasoconstriction in Rodent Models.

Background Pulmonary arterial hypertension (PAH) is a complex pulmonary vasculature disease characterized by progressive obliteration of small pulmonary arteries and persistent increase in pulmonary vascular resistance, resulting in right heart failure and death if left untreated. Artemisinin (ARS) and its derivatives, which are common antimalarial drugs, have been found to possess a broad range of biological effects. Here, we sought to determine the therapeutic benefit and mechanism of ARS and its derivatives treatment in experimental pulmonary hypertension (PH) models. Methods Isolated perfused/ventilated lung and isometric tension measurements in arteries were performed to test pulmonary vasoconstriction and relaxation. Monocrotaline (MCT) and hypoxia+Su5416 (SuHx) were administered to rats to induce severe PH. Evaluation methods of ARS treatment and its derivatives in animal models include echocardiography, hemodynamics measurement, and histological staining. In vitro, the effect of these drugs on proliferation, viability, and hypoxia-inducible factor 1α (HIF1α) was examined in human pulmonary arterial smooth muscle cells (hPASMCs). Results ARS treatment attenuated pulmonary vasoconstriction induced by high K+ solution or alveolar hypoxia, decreased pulmonary artery (PA) basal vascular tension, improved acetylcholine- (ACh-) induced endothelial-dependent relaxation, increased endothelial nitric oxide (NO) synthase (eNOS) activity and NO levels, and decreased levels of NAD(P)H oxidase subunits (NOX2 and NOX4) expression, NAD(P)H oxidase activity, and reactive oxygen species (ROS) levels of pulmonary arteries (PAs) in MCT-PH rats. NOS inhibitor, L-NAME, abrogated the effects of ARS on PA constriction and relaxation. Furthermore, chronic application of both ARS and its derivative dihydroartemisinin (DHA) attenuated right ventricular systolic pressure (RVSP), Fulton index (right ventricular hypertrophy), and vascular remodeling of PAs in the two rat PH models. In addition, DHA inhibited proliferation and migration of hypoxia-induced PASMCs. Conclusions In conclusion, these results indicate that treatment with ARS or DHA can inhibit PA vasoconstriction, PASMC proliferation and migration, and vascular remodeling, as well as improve PA endothelium-dependent relaxation, and eventually attenuate the development and progression of PH. These effects might be achieved by decreasing NAD(P)H oxidase generated ROS production and increasing eNOS activation to release NO in PAs. ARS and its derivatives might have the potential to be novel drugs for the treatment of PH.

Recurrent postpartum hemorrhage at subsequent pregnancy in patients with prior uterine artery embolization: angiographic findings and outcomes of repeat embolization.

To evaluate angiographic findings and outcomes of uterine artery embolization (UAE) for recurrent postpartum hemorrhage (PPH) in a subsequent pregnancy in patients with a history of prior UAE. Between March 2004 and February 2021, UAE was performed for PPH with gelatin sponge slurry in 753 patients. Among these, 13 underwent repeat UAE for recurrent PPH after subsequent delivery. The causes of PPH, angiographic findings, hemostasis, and adverse events were evaluated. The causes of recurrent PPH included retained placental tissue (n = 9) and uterine atony (n = 4). On angiography, unilateral or bilateral uterine arteries were obliterated due to prior UAE in 10 patients (76.9%). The uterine collateral vessels were embolized (anterior division of the internal iliac artery [n = 10], round ligament [n = 5], and ovarian [n = 4] artery). In the remaining three patients with recanalized or patent (not embolized at prior UAE) uterine arteries, both uterine arteries were embolized. Immediate hemostasis was achieved in nine patients (69.2%). The remaining four patients (30.8%) with obliterated uterine arteries required hysterectomy. There were three mild adverse events (pelvic pain [n = 2] and fever [n = 1]). UAE with gelatin sponge slurry frequently causes permanent uterine artery obliteration. In cases of recurrent PPH occurring in subsequent pregnancy, repeat UAE may be less likely to achieve hemostasis (69.2%). 1. UAE with gelatin sponge slurry frequently caused permanent uterine artery obliteration.2. In recurrent PPH occurring in subsequent pregnancy, the repeat UAE may be less likely to achieve hemostasis than initial UAE.

Surgical Treatment of Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension.

Venous thromboembolism clinically presents as deep venous thrombosis or acute pulmonary embolism and is globally recognized as the third most frequent acute cardiovascular syndrome after myocardial infarction and stroke. Although pulmonary embolism does not typically cause severe pulmonary hypertension in the acute setting, thrombus organization and fibrosis can lead to stenosis or obliteration of pulmonary arteries in a minority of patients, which in turn result in severe pulmonary hypertension and right heart failure. This disease is labeled chronic thromboembolic pulmonary hypertension and can occur after a single episode or multiple ones of pulmonary embolism. The cornerstone of pulmonary embolism treatment is medical therapy, whereas systemic thrombolytic therapy has to be considered for patients with hemodynamic instability. Given the current acceptable short-term surgical mortality, the potential of first-line surgical embolectomy as an alternative to medical thrombolysis has gained momentum as far as pulmonary embolism treatment is concerned. In contrast to pulmonary embolism, bilateral complete pulmonary endarterectomy under short deep hypothermic circulatory arrest intervals is the treatment of choice against chronic thromboembolic pulmonary hypertension, given patients' operability. Pulmonary endarterectomy is suggested in every operable patient when the operation is offered by an experienced multidisciplinary team, including at least one experienced surgeon. Surgical embolectomy should also be limited to large institutions since it also requires an experienced heart team. This review concerns a thorough discussion regarding surgical treatment of pulmonary embolism and chronic thromboembolic pulmonary hypertension. Eligibility criteria, operation-related complications and postoperative outcomes are discussed in detail.

Abstract 10759: Atp Citrate Lyase: An Attractive Target at the Nexus of Metabolic and Epigenetic Alterations in Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of distal pulmonary arteries (PAs). As in cancer, excessive proliferation and resistance to apoptosis of PA resident cells (especially PA smooth muscle cells, PASMCs), fueled by metabolic aberrations (metabolic shift toward glycolysis) and interconnected global changes in the epigenetic landscape is a pivotal component of severe PA remodeling, for which current pharmacotherapies have limited efficacy. ATP Citrate Lyase (ACLY), a nuclear cytosolic enzyme that converts citrate to Acetyl-CoA, has recently emerged as a key player and therapeutic target in cancer by favoring Warburg effect, lipid synthesis and chromatin remodeling. However, its role in PAH is unknown. We hypothesized that ACLY is upregulated in PAH and supports the abnormal phenotype of PAH-PASMCs. Methods/Results: Increased expression and nuclear localization of ACLY were observed in lungs and isolated PASMCs from PAH patients compared to controls (n=10, p<0.05; immunoblot and immunofluorescence). Similarly, ACLY was upregulated in PAH animal models (Su/Hx rats and mice). We found that pharmacological or molecular (siRNA) inhibition of ACLY impedes PAH-PASMC bioenergetics (as assessed by TMRM, expression of glycolytic enzymes and seahorse) and decreased P300-dependent histone H3 and H4 acetylation. Consistently, inhibition of ACLY was accompanied by 1) a decrease in proliferation (Ki67 labeling, n=8, p<0.05), 2) an increase in apoptosis (Annexin V and TMRM, n=8, p<0.05) and 3) a downregulation of P300-regulated pro-proliferative/anti-apoptotic factors (western blot of PCNA, Survivin, PLK1 and STAT3). In vivo, inhibition of ACLY using ETC-1002 in both male and female Su/Hx-challenged rats with established PAH resulted in a significant improvement in pulmonary vascular remodeling and right ventricular function (RVSP, mPAP, TAPSE, S-Wave, SV by echocardiography and catheterization). Furthermore, we found that inactivation of Acly targeted to smooth muscle cells confers protection in a gene-dosage-dependent manner against Su/Hx-induced PAH in mice. Conclusion: We demonstrated that the inhibition of ACLY is a novel and attractive therapeutic strategy to reverse PAH.

Viabahn Open Rebranching Technique combined with hybrid debranching technique help preventing renal artery obliteration and renal dysfunction aggravation in the treatment of thoracoabdominal aortic aneurysms

OBJECTIVE: Hybrid debranching technique combined with conventional open surgery and endovascular repair was an effective treatment for thoracoabdominal aortic aneurysm (TAAA). We propose a new technique to reduce the time of RA anastomosis. MATERIALS AND METHODS: The hybrid staged operation procedure was evaluated in the period of 2013 and 2017 in three academic centers. The bilateral renal artery anastomosis in the experimental group used VORTEC technique. In the control group, the bilateral renal artery reconstruction was performed by conventional artificial blood vessel anastomosis. Primary outcome was technical success, the time of renal artery anastomosis, and major complications. Long term follow-up up to 7 years was evaluated as well. RESULTS: In total 57 patients were enrolled. Compared with the control group, there was a statistical difference in the mean time of left RA anastomosing (19.8 vs 4.6 min, p<0.001) and the right RA anastomosing (20.5 vs 4.6 min, p<0.001) in the experimental group. While the aggravation of renal dysfunction occurred in 12 patients in 1 year after the stage surgery, and there was a statistical difference between the experimental group and the control group (4 vs 8, p=0.025). CONCLUSION: The VORTEC technique could help reducing the time of RA anastomosing and get lower complication rate and better effect during long-term follow up.

Overexpression of Msx1 in Mouse Lung Leads to Loss of Pulmonary Vessels Following Vascular Hypoxic Injury.

Pulmonary arterial hypertension (PAH) is a progressive lung disease caused by thickening of the pulmonary arterial wall and luminal obliteration of the small peripheral arteries leading to increase in vascular resistance which elevates pulmonary artery pressure that eventually causes right heart failure and death. We have previously shown that transcription factor Msx1 (mainly expressed during embryogenesis) is strongly upregulated in transformed lymphocytes obtained from PAH patients, especially IPAH. Under pathological conditions, Msx1 overexpression can cause cell dedifferentiation or cell apoptosis. We hypothesized that Msx1 overexpression contributes to loss of small pulmonary vessels in PAH. In IPAH lung, MSX1 protein localization was strikingly increased in muscularized remodeled pulmonary vessels, whereas it was undetectable in control pulmonary arteries. We developed a transgenic mouse model overexpressing MSX1 (MSX1OE) by about 4-fold and exposed these mice to normoxic, sugen hypoxic (3 weeks) or hyperoxic (100% 02 for 3 weeks) conditions. Under normoxic conditions, compared to controls, MSX1OE mice demonstrated a 30-fold and 2-fold increase in lung Msx1 mRNA and protein expression, respectively. There was a significant retinal capillary dropout (p < 0.01) in MSX1OE mice, which was increased further (p < 0.03) with sugen hypoxia. At baseline, the number of pulmonary vessels in MSX1OE mice was similar to controls. In sugen-hypoxia-treated MSX1OE mice, the number of small (0–25 uM) and medium (25–50 uM) size muscularized vessels increased approximately 2-fold (p < 0.01) compared to baseline controls; however, they were strikingly lower (p < 0.001) in number than in sugen-hypoxia-treated control mice. In MSX1OE mouse lung, 104 genes were upregulated and 67 genes were downregulated compared to controls. Similarly, in PVECs, 156 genes were upregulated and 320 genes were downregulated from siRNA to MSX1OE, and in PVSMCs, 65 genes were upregulated and 321 genes were downregulated from siRNA to MSX1OE (with control in the middle). Many of the statistically significant GO groups associated with MSX1 expression in lung, PVECs, and PVSMCs were similar, and were involved in cell cycle, cytoskeletal and macromolecule organization, and programmed cell death. Overexpression of MSX1 suppresses many cell-cycle-related genes in PVSMCs but induces them in PVECs. In conclusion, overexpression of Msx1 leads to loss of pulmonary vessels, which is exacerbated by sugen hypoxia, and functional consequences of Msx1 overexpression are cell-dependent.

The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension characterized by the presence of fibrotic intraluminal thrombi and causing obliteration of the pulmonary arteries. Although both endothelial cell (EC) dysfunction and inflammation are linked to CTEPH pathogenesis, regulation of the basal inflammatory response of ECs in CTEPH is not fully understood. Therefore, in the present study, we investigated the role of the nuclear factor (NF)-κB pro-inflammatory signaling pathway in ECs in CTEPH under basal conditions. Basal mRNA levels of interleukin (IL)-8, IL-1β, monocyte chemoattractant protein-1 (MCP-1), C-C motif chemokine ligand 5 (CCL5), and vascular cell adhesion molecule-1 (VCAM-1) were upregulated in CTEPH-ECs compared to the control cells. To assess the involvement of NF-κB signaling in basal inflammatory activation, CTEPH-ECs were incubated with the NF-κB inhibitor Bay 11-7085. The increase in pro-inflammatory cytokines was abolished when cells were incubated with the NF-κB inhibitor. To determine if NF-κB was indeed activated, we stained pulmonary endarterectomy (PEA) specimens from CTEPH patients and ECs isolated from PEA specimens for phospho-NF-κB-P65 and found that especially the vessels within the thrombus and CTEPH-ECs are positive for phospho-NF-κB-P65. In summary, we show that CTEPH-ECs have a pro-inflammatory status under basal conditions, and blocking NF-κB signaling reduces the production of inflammatory factors in CTEPH-ECs. Therefore, our results show that the increased basal pro-inflammatory status of CTEPH-ECs is, at least partially, regulated through activation of NF-κB signaling and potentially contributes to the pathophysiology and progression of CTEPH.

Preclinical Investigation of Trifluoperazine as a Novel Therapeutic Agent for the Treatment of Pulmonary Arterial Hypertension.

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.

Preoperative obliteration of choroidal arteries in the treatment of large hypervascular tumors in the lateral ventricle

BackgroundRemoval of large hypervascular tumors in the lateral ventricle still poses a surgical challenge. These tumors are usually fed from choroidal arteries, and vascular control is typically performed late during the removal. We aimed to evaluate the clinical efficacy of our strategy for persistent preoperative obliteration of feeders from the choroidal arteries to manage large hypervascular tumors in the lateral ventricle.MethodsWe retrospectively analyzed six patients with hypervascular tumors in the lateral ventricle. We first attempted to obstruct feeders using endovascular treatment, and, if unavailable, performed initial microsurgical occlusion through the temporal horn for the staged tumor removal. ResultsIn all patients, feeder obliteration was successfully performed; the anterior choroidal arteries were occluded by the endovascular treatment and microsurgical occlusion in one and five patients, respectively, while the lateral posterior choroidal arteries were occluded via endovascular treatment in four patients. No patients had permanent symptoms due to feeder obliteration, and tumor devascularization was achieved at the mean rate of 69.9%. During the tumor removal, the mean blood loss volume was 253 ml. No postoperative hemorrhage had occurred, and all patients scored ≤ 2 on the modified Rankin Scale at six months post-removal.ConclusionsAlthough further studies are warranted, persistent feeder obliteration of choroidal arteries could be an effective treatment strategy against large hypervascular tumors in the lateral ventricle.

Outcomes in Severe Upper GI Hemorrhage from Dieulafoy's Lesion with Monitoring of Arterial Blood Flow.

Dieulafoy's lesion (DL) is a rare but increasingly recognized cause of severe upper GI hemorrhage (SUGIH). There is little consensus regarding the endoscopic approach to management of bleeding from DL. Our purposes were to compare 30-day outcomes of patients with SUGIH from DL with Doppler endoscopic probe (DEP) monitoring of blood flow and guided treatment versus standard visually guided hemostasis (VG). Eighty-two consecutive DL patients with SUGIH were identified in a large CURE Hemostasis database from previous prospective cohort studies and two recent RCTs at two university-based medical centers. 30-day outcomes including rebleeding, surgery, angiography, death, and severe medical complications were compared between the two treatment groups. 40.2% of DL bleeds occurred in inpatients. 43.9% of patients had cardiovascular disease, and 48.7% were taking medications associated with bleeding. For the entire cohort, 41.3% (26/63) of patients treated with VG had a composite 30-day outcome as compared to 10.5% (2/19) of patients treated with DEP (p = 0.017). Rebleeding occurred within 30days in 33.3% and 10.5% of those treated with VG and DEP, respectively (p = 0.051). After propensity score matching, the adjusted 30-day composite outcome occurred in 39.0% in the VG group compared to 2.6% in the DEP group (p < 0.001). Adjusted 30-day rebleeding occurred in 25.3% in the VG group versus 2.6% in the DEP group (p < 0.001). DL patients with SUGIH were frequently inpatients and had severe cardiovascular comorbidities and recurrent bleeding. Lesion arterial blood flow monitoring and obliteration are an effective way to treat bleeding from DL which reduces negative 30-day clinical outcomes.

Chronic thromboembolic pulmonary hypertension - still evolving.

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension (PH). The disease is still underdiagnosed, and the true prevalence is unknown. CTEPH is characterized by intraluminal non-resolving thrombus organization and fibrous stenosis, or complete obliteration of pulmonary arteries, promoted by progressive remodeling of the pulmonary vasculature. One consequence of this is an increase in pulmonary vascular resistance and pressure, resulting in PH and progressive right heart failure, leading to death if left untreated.Endovascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients. PEA surgery is the only technique that can potentially cure CTEPH disease, especially in patients with fresh or organized thrombi of the proximal branches of pulmonary arteries. However, not all patients are eligible for PEA surgery. Recent research has provided evidence suggesting balloon pulmonary angioplasty (BPA) and targeted medical therapy as additional promising available treatments options for inoperable CTEPH and recurrent/persistent PH after PEA surgery.Studies on BPA have shown it to improve pulmonary hemodynamics, symptoms, exercise capacity and RV function in inoperable CTEPH. Subsequently, BPA has developed into an essential component of the modern era of CTEPH treatment. Large randomized controlled trials have demonstrated varying significant improvements with targeted medical therapy in technically inoperable CTEPH patients. Thus, treatment of CTEPH requires a comprehensive multidisciplinary assessment, including an experienced PEA surgeon, PH specialist, BPA interventionist and CTEPH-trained radiologist at expert centers. In this comprehensive review, we address the latest developments in the fast-evolving field of CTEPH. These include advancements in imaging modalities and developments in operative and interventional techniques, which have widened the range of patients who may benefit from these procedures. The efficacy and safety of targeted medical therapies in CTEPH patients are also discussed. As the treatment options for CTEPH improve, hybrid management involving multiple treatments in the same patient may become a viable option in the near future.