Intimal Fibrosis Research Articles

A new way to treat proximal deep venous thrombosis using E-selectin inhibition

ObjectiveThere is an inter-relationship between thrombosis and inflammation. Previously, we have shown the importance of P-selectin in thrombogenesis and thrombus resolution in many preclinical animal models. The role of E-selectin has been explored in rodent models and in a small pilot study of clinical calf vein deep venous thrombosis. The purpose of this study was to determine the role of E-selectin in thrombosis in a primate model of proximal iliac vein thrombosis, a model close to the human condition. MethodsIliac vein thrombosis was induced with a well-characterized primate model. Through a transplant incision, the hypogastric vein and iliac vein branches were ligated. Thrombus was induced by balloon occlusion of the proximal and distal iliac vein for 6 hours. The balloons were then deflated, and the primates recovered. Starting on postocclusion day 2, animals were treated with the E-selectin inhibitor GMI-1271, 25 mg/kg subcutaneously, once daily until day 21 (n = 4). Nontreated control animals received no treatment (n = 5). All animals were evaluated by magnetic resonance venography (MRV); evaluation of vessel area by ultrasound, protein analysis, hematology (complete blood count), and coagulation tests (bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, and thromboelastography) were performed at baseline, day 2, day 7, day 14, and day 21 with euthanasia. In addition, platelet function and CD44 expression on leukocytes were determined. ResultsE-selectin inhibition by GMI-1271 significantly increased vein recanalization by MRV vs control animals on day 14 (P < .05) and day 21 (P < .0001). GMI-1271 significantly decreased vein wall inflammation by MRV with gadolinium vein wall enhancement vs control also on day 14 (P < .0001) and day 21 (P < .0001). The thromboelastographic measure of clot strength (maximum amplitude) showed significant decreases in animals treated with GMI-1271 vs controls at day 2 (P < .05) and day 7 (P < .05). Animals treated with GMI-1271 had significant vessel area increase by day 21 vs controls (P < .05) by ultrasound. Vein wall intimal thickening (P < .001) and intimal fibrosis (P < .05) scores were significantly decreased in GMI-1271-treated animals vs controls. Importantly, no significant differences in hematology or coagulation test results were noted between all groups, suggesting that E-selectin inhibition carries no bleeding potential. GMI-1271 did not affect platelet function or aggregation or CD44 expression on leukocytes. In addition, no episodes of bleeding were noted in either group. ConclusionsThis study suggests that E-selectin modulates venous thrombus progression and that its inhibition will increase thrombus recanalization and decrease vein wall inflammation, without affecting coagulation. The use of an E-selectin inhibitor such as GMI-1271 could potentially change how we treat deep venous thrombosis.

Pathological abnormalities in splenic vasculature in non-cirrhotic portal hypertension: Its relevance in the management of portal hypertension.

BACKGROUNDPortal hypertension (PH) is associated with changes in vascular structure and function of the portosplenomesenteric system (PSMS). This is referred to as portal hypertensive vasculopathy. Pathological abnormalities of PSMS has been described in the literature for cirrhotic patients. Raised portal pressure and hyperdynamic circulation are thought to be the underlying cause of this vasculopathy. In view of this, it is expected that pathological changes in splenic and portal vein similar to those reported in cirrhotic patients with PH may also be present in patients with non-cirrhotic PH (NCPH).AIMTo investigate pathological abnormalities of splenic vein in patients with NCPH, and suggest its possible implications in the management of PH.METHODSA prospective observational study was performed on 116 patients with NCPH [Extrahepatic portal vein obstruction (EHPVO): 53 and non-cirrhotic portal fibrosis (NCPF): 63] who underwent proximal splenorenal shunt (PSRS), interposition shunt or splenectomy with devascularization in JIPMER, Pondicherry, India, a tertiary level referral center, between 2011-2016. All patients were evaluated by Doppler study of PSMS, computed tomography porto-venogram and upper gastrointestinal endoscopy. An acoustic resonance forced impulse (ARFI) scan and abdomen ultrasound were done for all cases to exclude cirrhosis. Intraoperative and histopathological assessment of the harvested splenic vein was performed in all. The study group was divided into delayed and early presentation based on the median duration of symptoms (i.e. 108 mo).RESULTSThe study group comprising of 116 patients [77 (66%) females and 39 (34%) males] with NCPH had a median age of 22 years. Median duration of symptoms was 108 mo. The most common presentation in both EHPVO and NCPF patients was upper gastrointestinal bleeding (hematemesis and melena). The ARFI scan revealed a median score of 1.2 (1.0-1.8) m/s for EHPVO and 1.5 (0.9-2.8) m/s for NCPF. PSRS was performed in 84 patients (two of whom underwent interposition PSRS using a 10 mm Dacron graft); splenoadrenal shunt in 9; interposition mesocaval shunt in 5; interposition 1st jejunal to caval shunt in 1 patient and devascularization with splenectomy in 17 patients. Median pre-splenectomy portal pressure was 25 (range: 15-51) mm Hg. In 77% cases, the splenic vein was abnormal upon intraoperative assessment. Under macroscopic examination, wall thickening was observed in 108 (93%), venous thrombosis in 32 (28%) and vein wall calcification in 27 (23%) cases. Upon examination under a surgical magnification loupe, 21 (18%) patients had intimal defects in the splenic vein. Histopathological examination of veins was abnormal in all cases. Medial hypertrophy was noted in nearly all patients (107/116), while intimal fibrosis was seen in 30%. Ninety one percent of patients with intimal fibrosis also had venous thrombosis. Vein wall calcification was found in 22%, all of whom had intimal fibrosis and venous thrombosis. The proportion of patients with pathological abnormalities in the splenic vein were significantly greater in the delayed presentation group as compared to the early presentation group.CONCLUSIONPathological changes in the splenic vein similar to those in cirrhotic patients with PH are noted in NCPH. We recommend that PH in NCPH be treated as systemic and pulmonary hypertension equivalent in the gastrointestinal tract, and that early aggressive therapy be initiated to reduce portal pressure and hemodynamic stress to avoid potential lethal effects.

Characteristics of Pulmonary Vascular Remodeling in a Porcine Model of Shunt-Associated Pulmonary Arterial Hypertension.

Lung biopsy is the gold standard for evaluating pathological changes in the pulmonary vascular bed. Knowing the distribution characteristics of pulmonary vascular lesions can improve the accuracy of lung biopsy. To investigate the distribution characteristics of pulmonary vascular remodeling, a reliable porcine model of shunt-associated pulmonary arterial hypertension (PAH) was established. Twenty piglets were randomly divided into the experimental group (n = 10) and the control group (n = 10). A modified Blalock-Taussig shunt (MBTS, left innominate artery to main pulmonary artery) was created surgically in the experimental group. Three months later, an invasive catheter was used to obtain hemodynamic parameters, and lung biopsy was performed to assess the remodeling of pulmonary vascular bed. MBTS was successfully implemented in six piglets. There's no significant difference in hemodynamic parameters of the two groups before the shunt. However, these parameters and right ventricular hypertrophy index of the experimental group were significantly increased after three months shunting. Pathological changes in the experimental group, including thickening of pulmonary artery media, intimal fibrosis, and right ventricular hypertrophy, were observed. Furthermore, the percentage of media thickness and medial area of the experimental group were significantly higher than control group. Histopathology showed that vascular remodeling of the lung was inhomogeneous and that the lateral lesion was more severe than other segments. These results indicated that MBTS could be used to establish a reliable porcine model of shunt-associated PAH and that multisite detection with different segments should be applied to assess the severity of pulmonary vascular remodeling.

Takayasu arteritis: a rare case scenario

Takayasu’s arteritis (TA), commonly known as “Pulseless disease”, is rare granulomatous arteritis, which affects large and medium-sized arteries, especially the aorta and its branches. Other arteries that can be affected are proximal portions of pulmonary, coronary, and renal arteries. Initially, mononuclear cell infiltrates in the adventitia leading to granuloma formation, followed by disruption of the elastic layer and subsequent massive medial and intimal fibrosis. These lesions result in segmental stenosis, occlusion, dilatation, and aneurysmal formation in the affected vessels. Diminished or absent pulses are present in 84-96% of patients, associated with limb claudication and blood pressure discrepancies between the two arms. The symptoms are secondary to the involved artery, and it may evolve into a life-threatening condition. The involvement of the carotid artery leads to ophthalmic artery hypoperfusion and causes the ocular ischemic syndrome. It usually affects young females during the second and the third decades of life but rare cases have been reported in children as young as 24 months of age. Although females are more likely to be affected in TA, males are also affected. In adults approximately 80% of patients with TA are women, although the female-to-male ratio varied from 9:1 in reports from Japan, 6.9:1 in Mexico to 1.2:1 in Israel. Aim of our report is to describe the case of a young female of 14 years of age. She presented with arterial hypertension and respiratory distress. CT Angiography showed Type IIb Takayasu Arteritis. ECHO revealed dilated cardiomyopathy with grade III diastolic dysfunction with decreased ejection fraction up to 20-25%. She was treated with steroids, anti-hypertensive drugs, and diuretics.

An automatic diagnostic system of coronary artery lesions in Kawasaki disease using intravascular optical coherence tomography imaging.

Intravascular optical coherence tomography (IV-OCT) is a light-based imaging modality with high resolution, which employs near-infrared light to provide tomographic intracoronary images. Morbidity caused by coronary heart disease is a substantial cause of acute coronary syndrome and sudden cardiac death. The most common intracoronay complications caused by coronary artery disease are intimal hyperplasia, calcification, fibrosis, neovascularization and macrophage accumulation, which require efficient prevention strategies. OCT can provide discriminative information of the intracoronary tissues, which can be used to train a robust fully automatic tissue characterization model based on deep learning. In this study, we aimed to design a diagnostic model of coronary artery lesions. Particularly, we trained a random forest using convolutional neural network features to distinguish between normal and diseased arterial wall structure. Then, based on the arterial wall structure, fully convolutional network is designed to extract the tissue layers in normal cases, and pathological tissues regardless of lesion type in pathological cases. Then, the type of the lesions can be characterized with high precision using our previous model. The results demonstrate the robustness of the model with the approximate overall accuracy up to 90%.

Microangiopathic Lesions in IgA Nephropathy: A Cohort Study

Renal arteriolar microangiopathic lesions may occur in immunoglobulin A nephropathy (IgAN), but their role in disease progression remains unclear. We sought to understand the prevalence and character of microangiopathic lesions in IgAN and their role in disease progression. A retrospective cohort study. In this study, we enrolled a Chinese cohort with 944 adult patients with IgAN who had been followed up for at least 1 year. Renal arteriolar microangiopathic lesions. Composite kidney end point event defined as a>50% reduction in estimated glomerular filtration rate, end-stage kidney disease, or death. All kidney biopsies were independently reviewed by 2 investigators. Renal arteriolar microangiopathic lesions were detected using light microscopy. Multivariable Cox regression analysis was used to test the association between microangiopathic lesions and the outcomes. Overall, 194 (20.6%) patients had renal arteriolar microangiopathic lesions. Patients with microangiopathic lesions presented with higher blood pressures, more severe proteinuria, and lower estimated glomerular filtration rates (allP<0.001) than patients without microangiopathic lesions. After a median follow-up of4.2 years, 75 (38.7%) patients with microangiopathic lesions and 83 (11.1%) patients without these lesions reached the composite kidney end point (P<0.001). In a multivariable Cox regression model adjusting for clinical and pathologic variables available at thetime of biopsy, the presence of microangiopathic lesions was an independent risk factor for kidney failure (HR, 1.95; 95% CI, 1.34-2.83; P<0.001). Renal vascular sclerosis (arterial intimal fibrosis or arteriolar hyalinosis) was not a risk factor for kidney disease progression (P= 0.5). A single Chinese center's experience, retrospective study, most patients were not tested for hemolytic markers (for example, haptoglobin level, lactate dehydrogenase level, and schistocytes). Renal arteriolar microangiopathic lesions are frequent in IgAN and their presence is independently associated with progression to kidney failure. If confirmed in other patient cohorts, such lesions could be considered for inclusion in formal classification schemes of IgAN.

Management of Saphenous Vein Graft Disease in Patients with Prior Coronary Artery Bypass Surgery.

In this review, we summarize the pathogenesis of saphenous venous graft (SVG) failure in patients following coronary artery bypass graft (CABG) surgery. We also provide an update on various aspects of prevention and management of SVG failure. Application of perioperative measures and medical therapies to promote SVG patency is crucial to optimize clinical outcomes in patients following CABG. Percutaneous coronary intervention (PCI) of SVG disease is fraught with complications, with the highest risk being no-reflow and periprocedural myocardial infarction due to distal embolization of microemboli. Minimizing this risk with use of distal embolic protection when feasible and understanding the role of adjunctive pharmacotherapies is critical in reducing the risk of adverse cardiac events. The long-term patency of SVGs remains a contemporary challenge and is adversely affected by thrombotic occlusion, intimal fibrosis, and accelerated atherosclerosis. Prevention of SVG failure is multifactorial. Use of perioperative measures, medical therapies, and PCI techniques to promote SVG patency is vital to optimize outcomes in patients following CABG. Further prospective trials are needed to define the optimal medical and surgical therapy to maintain short- and long term SVG patency.

Cerebellar Atrophy and Neurocognitive Disorder as Primary Presentation of Antiphospholipid Syndrome in a Young Male

Antiphospholipid syndrome (APS) is a multisystem autoimmunedisorder characterized by arterial or venous thrombosis and pregnancymorbidity in the presence of antiphospholipid antibodies(aPL).1 It can be primary or secondary. Primary antiphospholipid syndromeoccurs in the absence of any other related disease. Secondaryantiphospholipid syndrome occurs with other autoimmune diseases,such as systemic lupus erythematosus.The presence of aPL can be demonstrated in one of three ways:the presence of anticardiolipin antibodies (aCL), β 2-glycoprotein Iantibodies (GPI), or lupus anticoagulant antibodies (LA).1 To meetclassification criteria for antiphospholipid syndrome, patients shouldhave one clinical criterion, either vascular thrombosis (venous orarterial) or pregnancy morbidity (at least one fetal death or pretermdelivery or three or more unexplained, consecutive, spontaneouspregnancy losses) and one laboratory criterion, the presence of aPLantibodies need to be seen twice and at least 12 weeks apart for confirmation.Neurological manifestations are common in APS and areattributed mainly to vascular thrombosis and aPL-induced neuronaltissue injury. The most common neurological presentation is an ischemiccerebrovascular accident (CVA) or transient ischemic attack(TIA). However, clinical presentations including cognitive dysfunction,headaches, seizures, and psychosis may be atypical in some cases,which makes diagnosis more difficult.2In our case, a male patient initially presented with a neurocognitivedisorder, dementia, cerebral atrophy, and seizure of unknown etiology.A diagnosis of APS was made after a brain biopsy revealed microinfarctsand intimal fibrosis and an aPL antibody test was positive.

Histopathologic Findings on Implantation Renal Allograft Biopsies Correlate With Kidney Donor Profile Index and 30-Day Serum Creatinine

BackgroundThe Kidney Donor Profile Index (KDPI) provides a numerical estimate of deceased donor kidney quality. The KDPI uses 10 donor factors but it does not consider histopathologic findings. We examined whether the KDPI and its component donor factors correlate with the degree of histopathologic changes seen in implantation renal allograft biopsies. MethodsAll deceased donor kidney transplants at our institution from July 1, 2016 to March 15, 2017 that had an implantation biopsy were included. The biopsies were graded based on the Banff criteria for interstitial fibrosis, tubular atrophy, arterial intimal fibrosis, and arteriolar hyalinosis, as well as percent glomerulosclerosis. Linear and logistic regression were used to assess the correlation between histopathologic findings and KDPI and the ability of these variables to predict 30-day serum creatinine (SCr) and delayed graft function (DGF). ResultsOne hundred thirty-four recipients from 107 donors were included. All histopathologic features examined correlated significantly with KDPI, with arteriolar hyalinosis correlating most strongly. Arteriolar hyalinosis was also associated with the most component donor factors of the KDPI. Histopathologic findings alone or in combination with KDPI predicted 30-day SCr but not DGF. Using the KDPI in combination with degree of interstitial fibrosis and tubular atrophy was the best predictor of 30-day SCr. ConclusionHistopathologic changes seen in implantation renal allograft biopsies correlate with KDPI and predict 30-day SCr. Using a combination of donor histopathologic findings and KDPI may be the best predictor of short-term graft function.

Calciphylaxis and its diagnosis: A review.

Calciphylaxis also known as Calcific uremic arteriolopathy (CUA), is a rare fatal complication usually associated with end-stage renal disease (ESRD). It is characterized by skin ulceration and necrosis leading to significant pain. The disease calciphylaxis is pathological state resulting in accumulation of calcium content in medial wall of small blood vessels along with the fibrotic changes in intima. The aetiopathogenesis of this disease, small vessel vasculopathy, remains complicated, and unclear. It is believed that development of calciphylaxis depends on medial calcification, intimal fibrosis of arterioles and thrombotic occlusion. The disease is rare, life-threatening medical condition that occurs mostly in population with kidney disease or in patients on dialysis. Skin biopsy and radiographic features are helpful in the diagnosis of calciphylaxis, but negative results do not necessarily exclude the diagnosis. This article highlights steps undertaking in the diagnosis of calciphylaxis.

Reliability of deceased-donor procurement kidney biopsy images uploaded in United Network for Organ Sharing.

Prior studies demonstrate poor agreement among pathologists' interpretation of kidney biopsy slides. Reliability of representative images of these slides uploaded to the United Network of Organ Sharing (UNOS) web portal for clinician review has not been studied. We hypothesized high agreement among pathologists' image interpretation, since static images eliminate variation induced by viewing different areas of movable slides. To test our hypothesis, we compared the assessments of UNOS-uploaded images recorded in standardized forms by three pathologists. We selected 100 image sets, each having at least two images from kidneys of deceased donors. Weighted Cohen's kappa was used for inter-rater agreement. Mean (SD) donor age was 50 (13). Acute tubular injury had kappas of 0.12, 0.14, and 0.19; arteriolar hyalinosis 0.16, 0.27, and 0.38; interstitial inflammation 0.30, 0.33, and 0.49; interstitial fibrosis 0.28, 0.32, and 0.67; arterial intimal fibrosis 0.34, 0.42, and 0.59; tubular atrophy 0.35, 0.41, and 0.52; glomeruli thrombi 0.32, 0.53, and 0.85; and global glomerulosclerosis 0.68, 0.70, and 0.77. Pathologists' agreement demonstrated kappas of 0.12 to 0.77. The lower values raise concern about the reliability of using images. Although further research is needed to understand how uploaded images are used clinically, the field may consider higher-quality standards for biopsy photomicrographs.

A NOVEL MUTATION IN A PATIENT WITH PULMONARY VENO-OCCLUSIVE DISEASE MASQUERADING AS PULMONARY ARTERIAL HYPERTENSION

A NOVEL MUTATION IN A PATIENT WITH PULMONARY VENO-OCCLUSIVE DISEASE MASQUERADING AS PULMONARY ARTERIAL HYPERTENSION

VOLUMETRIC ASSESSMENT OF INTRACORONARY PATHOLOGICAL FORMATIONS USING OCT IMAGING IN KAWASAKI DISEASE

Kawasaki disease (KD) can lead to coronary artery aneurysms with subsequent intimal hyperplasia, neovascularization, fibrosis, calcification, and macrophage accumulation. Intracoronary Optical Coherence Tomography (OCT) was found promising for characterization of coronary artery tissue layers in KD patients. Cross-sectional OCT images of coronary arteries play a crucial role to estimate the thickness variations of arterial wall layers, but the visualization is limited on a 2D plane. Automatic volumetric assessment of pathological formations of each tissue would be of high interest to quantify pathological formations. Hence, the goal of this study is to perform automatic registration of 2D OCT cross-sections for volumetric analysis of pathological formations in KD patients. In this study, 26 OCT cross-sectional pullbacks were obtained from different pediatric patients with KD using ILUMIEN ® OCT system. Each pullback sequence consists of ∼100 images per patient. We designed a model to compound 2D images of coronary artery tissues using a Convolutional Neural Network (CNN). CNNs were found to be very effective techniques to extract automatically specific and discriminative attributes of various tissues from OCT images. A fully-automated tissue classification model is used to characterize intima, media, neovascularization, fibrosis, and calcification using CCN and deep learning algorithms. Similarity between deep features extracted from different coronary artery tissues is used for registration. Paired t-test is applied between every two consequent frames of each pullback to validate tissue alignment before and after applying CNN-based registration. Alpha is set to 0.05 and significant difference was observed if the p-value was less than 0.05. The 3D models (figure) show a good alignment of intracoronary tissue layers and pathological formations with very low p-values (-log10 (p-value) = 34.35 ± 26.41 and significant difference of 0.03 ± 0.01 for all patient’s pullback). We applied our technique to create 3D reconstruction and analyze volume variations of coronary artery layers and pathological formations caused by KD on coronary artery tissues. By doing so, we can create an automated diagnostic framework providing clinicians with an operator-independent diagnosis of histological coronary lesions. From a visual 3D rendering of qualitative findings, we can generate a quantitative diagnostic output. This study contributes to estimate volumetric variations of various pathological formations caused by KD on coronary artery tissue layers. A visual 3D rendering of qualitative findings, together with a quantitative diagnostic report can greatly enhance patient care and management.

A retrospective analysis of treatment of wounds caused by calciphylaxis: Hyperbaric oxygen therapy with and without sodium thiosulfate

Calciphylaxis, or calcific uremic arteriolopathy, is a rare, but devastating condition with a mortality approaching 80% in the United States, often seen in patients with chronic kidney disease. It is characterized by calcification and intimal fibrosis with arteriolar stenosis and subsequent thrombosis. Skin changes such as livedo reticularis, tender papules, and violaceous plaques result and progress to necrotic ulceration. Management of calciphylaxis includes maintenance of normal levels of calcium, phosphorus and parathyroid hormone, and optimization of hemodialysis and nutritional status. In our cohort, aggressive wound management coupled with sodium thiosulfate and hyperbaric oxygen therapy (HBOT) has achieved improvement in rates of healing for recalcitrant wounds associated with calciphylaxis but limited evidence for the efficacy of either treatment exists. We conducted a retrospective analysis of 94 patients treated for calciphylaxis at a Wound and Hyperbaric Center at an academic institution between 2000 and 2017 who were considered for HBOT. We assessed whether response to therapy as measured by wound healing varied among patients who received sodium thiosulfate, hyperbaric oxygen treatment, both therapies, or neither therapy. We found HBOT to be beneficial in healing compared to no therapy - 81.7% or 36 of 44 patients with complete or substantial resolution of their wounds vs. neither therapy - 11.4% or 3 of 26 patients. We found sodium thiosulfate to be beneficial in healing compared to neither therapy - 66.6% or 2 of 3 patients with complete or substantial resolution of their wounds vs. no therapy. We found combined HBOT & sodium thiosulfate to be more beneficial in healing compared to either therapy alone and to neither therapy - 86.3% or 19 of 22 patients with complete or substantial resolution of wounds. Given the dramatic clinical improvement, HBOT in combination with sodium thiosulfate has an important adjunctive role in the treatment of calciphylaxis.

An Update on Calciphylaxis.

Calciphylaxis, also known as calcific uremic arteriolopathy and uremic small artery disease with medial wall calcification and intimal hyperplasia, is a multifactorial cutaneous vascular disease characterized by chronic, painful, non-healing wounds that occur frequently in patients with chronic kidney disease, predominantly in those with end-stage renal disease. The pathogenesis remains unclear, and the development of calciphylaxis lesions depends on medial calcification, intimal fibrosis of arterioles and thrombotic occlusion. Despite an increase in reports of calciphylaxis in the literature and clinical recognition of demographic characteristics and risk factors associated with calciphylaxis, it remains a poorly understood disease with high morbidity and mortality. In this review, we analyze and summarize the clinical manifestations, pathogenesis and pathophysiology, histopathology, differential diagnosis, diagnostic workup and treatment modalities for calciphylaxis. Because of the lack of consensus regarding the optimal approach to and treatment of this disorder, a high degree of clinical suspicion, early diagnosis, and multimodal and multidisciplinary treatment in collaboration with dermatology, nephrology, wound care, nutrition and pain management specialties may improve survival in patients with calciphylaxis.

Histopathological evaluation of aortic coarctation after conventional balloon angioplasty in neonates.

Optimal management strategy for native aortic coarctation in neonates and young infants is still a matter of debate. The surgical procedure, histopathologic research, and clinical outcome in 15 neonates who underwent surgery after successful balloon angioplasty is the basis of this study. Between 01 October, 2014 and 01 August, 2017, we enrolled 15 patients with native aortic coarctation for this study. These patients had complications regarding recoarctation, following balloon angioplasty intervention at our institute and other centres. Surgically extracted parts were examined histopathologically and patient's data were collected retrospectively.ResultThe reasons for recurrence of recoarctation after balloon angioplasty are as follows: patients with higher preoperative echocardiographic gradients had recoarctation earlier, neointimal proliferation, aortic intimal fibrosis at the region of ductal insertion, and ductal residual tissue debris after balloon angioplasty. No repeat intervention was required in the 15 patients who underwent surgery followed by balloon angioplasty. Early mortality was seen in one patient after surgery. Postoperative complication in the surgical group occurred in the form of chylothorax in one patient. In centres in which the neonatal ICU is inexperienced, balloon angioplasty is particularly recommended. In developing neonatal clinics, balloon angioplasty, when performed on patients at their earliest possible age, delays actual corrective operation to a later date, which in turn provides less risky surgical outcomes in infants who are gaining weight, growing, and do not have any haemodynamic complaints.

Selecting living donors for uterus transplantation: lessons learned from two transplantations resulting in menstrual functionality and another attempt, aborted after organ retrieval.

To contribute to establishing donor selection criteria based on our experience with two successful living-donor human uterus transplantations (UTx) and an aborted attempt. This interventional study included three patients with uterine agenesis, aged 23, 34, and 23years, scheduled for UTx, and their uterus-donating mothers, aged 46, 61, and 46years, respectively. Interventions included preoperative investigations, donor surgery, back-table preparation, and recipient surgery. Preoperative imaging, surgical data, histopathology, menstrual pattern, and uterine blood flow were the main outcome measures. In the first case (46-year-old mother/23-year-old daughter), donor/recipient surgery took 12.12/5.95h. Regular spontaneous menstruations started 6-week post-transplantation, continuing at 24-28-day intervals throughout the 6-month observation period. Repeated follow-up cervical biopsies showed no signs of rejection. In the second case (61-year-old donor), surgery lasted 13.10h; attempts to flush the retrieved uterus failed due to extreme resistance of the left uterine artery (UA) and inability to perfuse the right UA. Transplantation was aborted to avoid graft vessel thrombosis or insufficient blood flow during potential pregnancy. Histopathology revealed intimal fibrosis and initial sclerosis (right UA), extensive intimal fibrosis (parametric arterial segments), and subtotal arterial stenosis (myometrial vascular network). In the third case (46-year-old mother/23-year-old daughter), donor/recipient surgery took 9.05/4.52h. Menstruations started 6-week post-transplantation. Repeated cervical biopsies showed no signs of rejection during the initial 12-week follow-up period. Meticulous preoperative evaluation of potential living uterus donors is essential. This may include selective contrast-enhanced UA angiograms and limitation of donor age, at least in donors with risk factors for atherosclerosis. ClinicalTrials.gov Identifier: NCT03048396.

Pulmonary veno-occlusive disease: An important consideration in patients with pulmonary hypertension.

Pulmonary veno-occlusive disease is a rare subcategory of pulmonary arterial hypertension (WHO Group 1). The disease is poorly understood and difficult to diagnose; it has no definitive cure to date. These patients present with nonspecific symptoms, including dyspnea, exercise intolerance, and weakness. Chest x-rays sometimes differ from idiopathic pulmonary arterial hypertension and may demonstrate alveolar infiltrates and pleural effusions. High resolution computed tomography scans reveal ground glass opacities, interlobular septal thickening, and lymphadenopathy. Echocardiography can estimate the level of pulmonary artery pressures; right heart catheterization is needed for complete hemodynamic characterization of these patients. Lung biopsies demonstrate remodeling of the venules and small veins with intimal and adventitial fibrosis. This can result in total venous occlusion and subsequent recanalization. Similar changes occur in the small arteries and arterioles but are less pronounced than the venous changes. There is no effective medical therapy for these patients, and treatment with the pulmonary arterial hypertension specific medications often causes acute deterioration with pulmonary edema. The recent discovery of the biallelic mutations of the EIF2AK4 gene as an etiology for heritable form of pulmonary veno-occlusive disease increases our understanding of the disease pathogenesis and potentially identifies a future approach to treatment. Without definitive treatment, the prognosis is very poor, and the life expectancy of these patients is much shorter than patients with pulmonary arterial hypertension. These patients need early referral to transplantation centers.

Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary veno-occlusive disease

Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD. Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models. PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models). Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.

Pulmonary venous remodeling in COPD‐pulmonary hypertension and idiopathic pulmonary arterial hypertension

Pulmonary vascular arterial remodeling is an integral and well-understood component of pulmonary hypertension (PH). In contrast, morphological alterations of pulmonary veins in PH are scarcely described. Explanted lungs (n = 101) from transplant recipients with advanced chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary arterial hypertension (IPAH) were analyzed for venous vascular involvement according to a pre-specified, semi-quantitative grading scheme, which categorizes the intensity of venous remodeling in three groups of incremental severity: venous hypertensive (VH) grade 0 = characterized by an absence of venous vascular remodeling; VH grade 1 = defined by a dominance of either arterialization or intimal fibrosis; and VH grade 2 = a substantial composite of arterialization and intimal fibrosis. Patients were grouped according to clinical and hemodynamic characteristics in three groups: COPD non-PH, COPD-PH, and IPAH, respectively. Histological specimens were examined by a cardiovascular pathologist blinded to clinical and hemodynamic data. Pathological alterations of pulmonary veins were present in all hemodynamic groups, with the following incidences of VH grade 0/1/2: 34/66/0% in COPD non-PH; 19/71/10% in COPD-PH; and 11/61/28% in IPAH. In COPD, explorative correlation analysis of venous remodeling suggested a modest positive correlation with systolic and mean pulmonary artery pressure (P = 0.032, respectively) and an inverse modest correlation with diffusion capacity for carbon monoxide (P = 0.027). In addition, venous remodeling correlated positively with the degree of arterial remodeling (P = 0.014). In COPD-PH and IPAH, advanced forms of pulmonary venous remodeling are present, emphasizing that the disease is not exclusively restricted to arterial lesions. In addition, venous remodeling may be related to the hemodynamic severity, but more rigorous analysis is required to clearly define potential relationships.