Nanoplastics can cause severe malformations in chicken embryos. To improve our understanding of the toxicity of nanoplastics to embryos, we have studied their biodistribution in living chicken... Show moreNanoplastics can cause severe malformations in chicken embryos. To improve our understanding of the toxicity of nanoplastics to embryos, we have studied their biodistribution in living chicken embryos. We injected the embryos in the vitelline vein at stages 18–19. We injected polystyrene nanoparticles (PS-NPs) tagged with europium- or fluorescence. Their biodistribution was tracked using inductively-coupled plasma mass spectrometry on tissue lysates, paraffin histology, and vibratome sections analysed by machine learning algorithms. PS-NPs were found at high levels in the heart, liver and kidneys. Furthermore, PS-NPs crossed the endocardium of the heart at sites of epithelial-mesenchymal transformation; they also crossed the liver endothelium. Finally, we detected PS-NPs in the allantoic fluid, consistent with their being excreted by the kidneys. Our study shows the power of the chicken embryo model for analysing the biodistribution of nanoplastics in embryos. Such experiments are difficult or impossible in mammalian embryos. These findings are a major advance in our understanding of the biodistribution and tissue-specific accumulation of PS-NPs in developing animals. Show less
Ge, Y.; Roon, L. van; Chen, H.S.; Methorst, R.; Paton, M.; DeRuiter, M.C.; ... ; Jongbloed, M.R.M. 2023
The cardiac autonomic nervous system is crucial in controlling cardiac function, such as heart rate and cardiac contractility, and is divided into sympathetic and parasympathetic branches. Normally... Show moreThe cardiac autonomic nervous system is crucial in controlling cardiac function, such as heart rate and cardiac contractility, and is divided into sympathetic and parasympathetic branches. Normally, there is a balance between these two branches to maintain homeostasis. However, cardiac disease states such as myocardial infarction, heart failure, and hypertension can induce the remodeling of cells involved in cardiac innervation, which is associated with an adverse clinical outcome.Although there are vast amounts of data for the histological structure and function of the cardiac autonomic nervous system, its molecular biological architecture in health and disease is still enigmatic in many aspects. Novel technologies such as single-cell RNA sequencing (scRNA-seq) hold promise for the genetic characterization of tissues at single-cell resolution. However, the relatively large size of neurons may impede the standardized use of these techniques. Here, this protocol exploits droplet-based single-nucleus RNA sequencing (snRNA-seq), a method to characterize the biological architecture of cardiac sympathetic neurons in health and disease. A stepwise approach is demonstrated to perform snRNA-seq of the bilateral superior cervical (SCG) and stellate ganglia (StG) dissected from adult mice.This method enables long-term sample preservation, maintaining an adequate RNA quality when samples from multiple individuals/experiments cannot be collected all at once within a short period of time. Barcoding the nuclei with hashtag oligos (HTOs) enables demultiplexing and the trace-back of distinct ganglionic samples post sequencing. Subsequent analyses revealed successful nuclei capture of neuronal, satellite glial, and endothelial cells of the sympathetic ganglia, as validated by snRNA-seq. In summary, this protocol provides a stepwise approach for snRNA-seq of sympathetic extrinsic cardiac ganglia, a method that has the potential for broader application in studies of the innervation of other organs and tissues. Show less
Background Inflammation around the tendons of interosseous muscles of the hand (interosseous tendon inflammation) was recently observed with MRI for the first time in patients with rheumatoid... Show moreBackground Inflammation around the tendons of interosseous muscles of the hand (interosseous tendon inflammation) was recently observed with MRI for the first time in patients with rheumatoid arthritis and in at-risk individuals with detectable anti-citrullinated protein antibodies, generating the hypothesis that interosseous tendon inflammation precedes clinical arthritis. To better understand the role of interosseous tendon inflammation during the development of rheumatoid arthritis, we studied the frequency of interosseous tendon inflammation in healthy individuals and in those with arthralgia that was suspected of progressing to rheumatoid arthritis (ie, clinically suspect arthralgia) and the association of interosseous tendon inflammation with other symptoms of inflamed joint tissues and with clinical arthritis development.Methods Adult (age >= 18 years) patients who presented with clinically suspect arthralgia and symptom-free (control) individuals underwent contrast-enhanced hand MRI. MRIs were evaluated for interosseous tendon inflammation on the radial and ulnar sides of the second to fifth metacarpophalangeal joints, and for synovitis, tenosynovitis, and osteitis using the rheumatoid arthritis MRI scoring system. Patients with clinically suspect arthralgia were followed up for clinical arthritis development. The presence of local tenosynovium was examined using immunohistochemistry for anti-CD55 and anti-CD68 on tissue from the hands of three embalmed bodies donated for scientific research. The primary outcome for the cross-sectional part of the study was the presence of interosseous tendon inflammation on MRI. The primary outcome for the longitudinal part of the study was development of clinical arthritis.Findings Between April 3, 2012, and May 20, 2020, 667 patients with clinically suspect arthralgia (mean age 44 years [SD 13], 504 [76%] were women and 163 [24%] were men) underwent contrast-enhanced hand MRI. Between Nov 1, 2013, and Nov 30, 2014, 193 symptom-free controls were recruited (mean age 50 years [SD 16], 136 [70%] were women and 57 [30%] were men). Two (1%) of 193 symptom-free controls had interosseous tendon inflammation. Immunohistochemistry of cadaveric hand tissues showed no tenosynovium surrounding interosseous tendons. At inclusion, 67 (10%) of 667 patients with clinically suspect arthralgia had interosseous tendon inflammation (p<00001 vs symptom-free controls). Interosseous tendon inflammation occurred more frequently if synovitis (odds ratio [OR] 22 [95% CI 12-42]), or tenosynovitis (OR 97 [55-170]), was present at metacarpophalangeal joints. A three-dimensional MRI reconstruction suggested confluency of interosseous tendon inflammation with metacarpophalangeal-flexor-tenosynovitis. 91 (16%) of 558 patients with clinically suspect arthralgia developed clinical arthritis during follow-up (median total follow-up 253 months [95% CI 251-255]). Patients with clinically suspect arthralgia with interosseous tendon inflammation had a higher risk of developing clinical arthritis (hazard ratio [HR] 45 [28-72]), which was attenuated but still significant after adjusting for concomitant synovitis, tenosynovitis, or osteitis (HR 17 [102-28]).Interpretation Interosseous tendon inflammation is almost absent in symptom-free individuals but occurs in people with clinically suspect arthralgia, in whom it correlates with symptoms and is associated with the development of clinical arthritis. The absence of local tenosynovium suggests that interosseous tendon inflammation arises from expanding local subclinical inflammation in the pre-arthritis phase of rheumatoid arthritis. Show less
Staal, A.H.J.; Cortenbach, K.R.G.; Gorris, M.A.J.; Woude, L.L. van der; Srinivas, M.; Heijmen, R.H.; ... ; Kimmenade, R.R.J. van 2023
Background: Bicuspid aortic valve (BAV) is associated with ascending aorta aneurysms and dissections. Presently, genetic factors and pathological flow patterns are considered responsible for... Show moreBackground: Bicuspid aortic valve (BAV) is associated with ascending aorta aneurysms and dissections. Presently, genetic factors and pathological flow patterns are considered responsible for aneurysm formation in BAV while the exact role of inflammatory processes remains unknown.Methods: In order to objectify inflammation, we employ a highly sensitive, quantitative immunohistochemistry approach. Whole slides of dissected, dilated and non-dilated ascending aortas from BAV patients were quantitatively analyzed.Results: Dilated aortas show a 4-fold increase of lymphocytes and a 25-fold increase in B lymphocytes in the adventitia compared to non-dilated aortas. Tertiary lymphoid structures with B cell follicles and helper T cell expansion were identified in dilated and dissected aortas. Dilated aortas were associated with an increase in M1-like macrophages in the aorta media, in contrast the number of M2-like macrophages did not change significantly.Conclusion: This study finds unexpected large numbers of immune cells in dilating aortas of BAV patients. These findings raise the question whether immune cells in BAV aortopathy are innocent bystanders or contribute to the deterioration of the aortic wall. Show less
Dakkak, Y.J.; Dijk, B.T. van; Jansen, F.P.; Wisse, L.J.; Reijnierse, M.; Helm-van Mil, A.H.M. van der; DeRuiter, M.C. 2022
MRI-detected inflammation around the extensor tendons of metacarpophalangeal (MCP-) joints is prevalent in RA and poses a markedly increased risk of RA development when present in arthralgia... Show moreMRI-detected inflammation around the extensor tendons of metacarpophalangeal (MCP-) joints is prevalent in RA and poses a markedly increased risk of RA development when present in arthralgia patients. Such inflammation is called 'peritendinitis' since anatomy literature reports no presence of a tenosynovial sheath at these tendons. However, the presence or absence of tenosynovium at these extensor tendons has never been studied. Therefore, an anatomical and histological study of extensor tendons at the MCP-joints of three embalmed human hands was performed. Immunohistochemical staining showed the presence of markers for synovial macrophages and fibroblast-like synoviocytes bordering a natural dorsal space next to the extensor tendon, suggesting the presence of a synovial lining. This implies that contrast-enhancement on MRI around extensor tendons at MCP-joints observed in early RA and pre-RA likely represents tenosynovitis and that inflammation of this synovial tissue is an early feature of RA. Show less
In fetal aortic stenosis (AS), it remains challenging to predict left ventricular development over the course of pregnancy. Myocardial organization, differentiation and fibrosis could be potential... Show moreIn fetal aortic stenosis (AS), it remains challenging to predict left ventricular development over the course of pregnancy. Myocardial organization, differentiation and fibrosis could be potential biomarkers relevant for biventricular outcome. We present four cases of fetal AS with varying degrees of severity and associate myocardial deformation on fetal ultrasound with postmortem histopathological characteristics. During routine fetal echocardiography, speckle tracking recordings of the cardiac four-chamber view were performed to assess myocardial strain as parameter for myocardial deformation. After pregnancy termination, postmortem cardiac specimens were examined using immunohistochemical labeling (IHC) of key markers for myocardial organization, differentiation and fibrosis and compared to normal fetal hearts. Two cases with critical AS presented extremely decreased left ventricular (LV) strain on fetal ultrasound. IHC showed overt endocardial fibro-elastosis, which correlated with pathological fibrosis patterns in the myocardium and extremely disturbed cardiomyocyte organization. The LV in severe AS showed mildly reduced myocardial strain and less severe disorganization of the cardiomyocytes. In conclusion, the degree of reduction in myocardial deformation corresponded with high extent to the amount of pathological fibrosis patterns and cardiomyocyte disorganization. Myocardial deformation on fetal ultrasound seems to hold promise as a potential biomarker for left ventricular structural damage in AS. Show less
Snoep, M.C.; Aliasi, M.; Meeren, L.E. van der; Jongbloed, M.R.M.; DeRuiter, M.C.; Haak, M.C. 2021
Impaired placentation is an important contributing factor to intra-uterine growth restriction and pre-eclampsia in fetuses with congenital heart defects (CHD). These pregnancy complications occur... Show moreImpaired placentation is an important contributing factor to intra-uterine growth restriction and pre-eclampsia in fetuses with congenital heart defects (CHD). These pregnancy complications occur more frequently in pregnancies with fetal CHD. One of the most important factors influencing the life of children with CHD is neurodevelopmental delay, which seems to start already in utero. Delayed neurodevelopment in utero may be correlated or even (partly) explained by impaired placentation in CHD cases. This systematic review provides an overview of published literature on placental development in pregnancies with fetal CHD. A systematic search was performed and the Newcastle-Ottawa scale was used to access data quality. Primary outcomes were placenta size and weight, vascular and villous architecture, immunohistochemistry, angiogenic biomarkers and/or placental gene expression. A total of 1161 articles were reviewed and 21 studies were included. Studies including CHD with a genetic disorder or syndrome and/or multiple pregnancies were excluded. Lower placental weight and elevated rates of abnormal umbilical cord insertions were found in CHD. Cases with CHD more frequently showed microscopic placental abnormalities (i.e. abnormal villous maturation and increased maternal vascular malperfusion lesions), reduced levels of angiogenic biomarkers and increased levels of anti-angiogenic biomarkers in maternal serum and umbilical cord blood. Altered gene expression involved in placental development and fetal growth were found in maternal serum and CHD placentas. In conclusion, abnormal placentation is found in CHD. More extensive studies are needed to elucidate the contribution of impaired placentation to delayed neurodevelopment in CHD cases. Show less
Kruithof, B.P.T.; Pol, V. van de; T. los; Lodder, K.; Gourabi, B.M.; DeRuiter, M.C.; ... ; Marsan, N.A. 2021
Calcific aortic valve disease (CAVD) is a common progressive disease of the aortic valves, for which no medical treatment exists and surgery represents currently the only therapeutic solution. The... Show moreCalcific aortic valve disease (CAVD) is a common progressive disease of the aortic valves, for which no medical treatment exists and surgery represents currently the only therapeutic solution. The development of novel pharmacological treatments for CAVD has been hampered by the lack of suitable test-systems, which require the preservation of the complex valve structure in a mechanically and biochemical controllable system. Therefore, we aimed at establishing a model which allows the study of calcification in intact mouse aortic valves by using the Miniature Tissue Culture System (MTCS), an ex vivo flow model for whole mouse hearts. Aortic valves of wild-type mice were cultured in the MTCS and exposed to osteogenic medium (OSM, containing ascorbic acid, beta-glycerophosphate and dexamethasone) or inorganic phosphates (PI). Osteogenic calcification occurred in the aortic valve leaflets that were cultured ex vivo in the presence of PI, but not of OSM. In vitro cultured mouse and human valvular interstitial cells calcified in both OSM and PI conditions, revealing in vitro-ex vivo differences. Furthermore, endochondral differentiation occurred in the aortic root of ex vivo cultured mouse hearts near the hinge of the aortic valve in both PI and OSM conditions. Dexamethasone was found to induce endochondral differentiation in the aortic root, but to inhibit calcification and the expression of osteogenic markers in the aortic leaflet, partly explaining the absence of calcification in the aortic valve cultured with OSM. The osteogenic calcifications in the aortic leaflet and the endochondral differentiation in the aortic root resemble calcifications found in human CAVD. In conclusion, we have established an ex vivo calcification model for intact wild-type murine aortic valves in which the initiation and progression of aortic valve calcification can be studied. The in vitro-ex vivo differences found in our studies underline the importance of ex vivo models to facilitate pre-clinical translational studies. Show less
Background Fecal incontinence is a multifactorial problem and its etiology is complex. Various therapies are available and different success rates have been described. The aim of this study was to... Show moreBackground Fecal incontinence is a multifactorial problem and its etiology is complex. Various therapies are available and different success rates have been described. The aim of this study was to assess the effectiveness and safety of non-dynamic graciloplasty in patients with passive fecal incontinence. Methods We retrospectively studied charts of patients with fecal incontinence treated with graciloplasty at our institution from November 2015 until June 2018. Patients were included according to the following criteria: (1) presence of predominantly passive fecal incontinence and (2) presence of a lax perineal body. Primary outcome was the effectiveness, defined as a significant reduction or absence of the complaints of passive fecal incontinence at 3, 6 and 12 months after surgery. Second, we studied the safety of the procedure evaluating the complications within 30 days after surgery. Results Thirty-one patients met the inclusion criteria. Twenty-six of them, in addition to passive incontinence as the main symptom, had some degree of fecal urgency. The median age at the first visit to the outpatient clinic was 64.0 years (IQR 52-68). Most patients were female (n = 29, 94%). At 3 months after graciloplasty, 71% (22 of 31) of patients were successfully treated for their passive fecal incontinence. At 6 months, the success rate of the graciloplasty increased to 77%. At 12 months among the patients who were still seen in the clinic, the success rate was 58% (18/31). Two patients cancelled follow-up visits after 3 months, because of failure to control symptoms in 1 case. After 6 months, 9 patients were given the choice to do telephone follow-up only. Of these 11 patients without in-person follow-up, 10 were contacted 1 year after surgery and in 7 of them, the graciloplasty was effective in controlling their passive fecal incontinence for an overall success rate of 80% (25/31). Of the 26 patients with mixed passive and urge incontinence, 6 (23%) still complained of urge incontinence at 1 year. Of these patients with persistent urge incontinence, 6 underwent sacral nerve stimulation which was successful in 4. Two serious complications occurred within 30 days. A rectal perforation requiring temporary colostomy and a recto-vaginal fistula which was successfully repaired. Conclusion Non-dynamic graciloplasty is an effective treatment for passive fecal incontinence. Differentiation based on subtypes of fecal incontinence might be important for a pattern-specific approach to treatment. More research is necessary to determine the right indications for more invasive treatments of fecal incontinence. Show less
Whilst knowledge regarding the pathophysiology of congenital heart disease (CHDs) has advanced greatly in recent years, the underlying developmental processes affecting the cardiac outflow tract ... Show moreWhilst knowledge regarding the pathophysiology of congenital heart disease (CHDs) has advanced greatly in recent years, the underlying developmental processes affecting the cardiac outflow tract (OFT) such as bicuspid aortic valve, tetralogy of Fallot and transposition of the great arteries remain poorly understood. Common among CHDs affecting the OFT, is a large variation in disease phenotypes. Even though the different cell lineages contributing to OFT development have been studied for many decades, it remains challenging to relate cell lineage dynamics to the morphologic variation observed in OFT pathologies. We postulate that the variation observed in cellular contribution in these congenital heart diseases might be related to underlying cell lineage dynamics of which little is known. We believe this gap in knowledge is mainly the result of technical limitations in experimental methods used for cell lineage analysis. The aim of this review is to provide an overview of historical fate mapping and cell tracing techniques used to study OFT development and introduce emerging technologies which provide new opportunities that will aid our understanding of the cellular dynamics underlying OFT pathology. Show less
Background: Patients with a bicuspid aortic valve (BAV) are at risk of developing valve deterioration and aortic dilatation. We aimed to investigate whether blood biomarkers are associated with... Show moreBackground: Patients with a bicuspid aortic valve (BAV) are at risk of developing valve deterioration and aortic dilatation. We aimed to investigate whether blood biomarkers are associated with disease stage inpatients with BAV.Methods: Serum levels of high sensitivity C-reactive protein (hsCRP), high sensitivity troponin T (hsTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and total transforming growth factor-beta 1 (TGF-beta 1) were measured in adult BAV patients with valve dysfunction or aortic pathology. Age-matched general population controls were included for TGF beta-1 measurements. Correlation analyses and multivariable linear regression were used to determine the association between (2log-transformed) biomarker levels and aortic valve regurgitation, aortic valve stenosis, aortic dilatation, or left ventricular function.Results: hsCRP and hsTnT were measured in the total group of 183 patients (median age 34 years, 25th-75th percentile 23-46), NT-proBNP in 162 patients, and TGF-beta 1 beta in 108 patients. Elevated levels of NT-proBNP were found in 20% of the BAV patients, elevated hsTnT in 6%, and elevated hsCRP in 7%. Higher hsTnT levels were independently associated with aortic regurgitation [odds ratio per doubling (OR2log) 1.34, 95% CI 1.01;1.76] and higher NT-proBNP levels with aortic valve maximal velocity (beta(2log) 0.17, 95%CI 0.07;028) and aortic regurgitation (OR2log 1.41, 95%CI 1.11;1.79). Both BAV patients with (9.9 +/- 2.7 ng/mL) and without aortic dilatation (10.4 +/- 2.9 ng/mL) showed lower TGF-beta 1 levels compared to general population controls (n = 85, 11.8 +/- 3.2 ng/mL).Conclusions: Higher NT-proBNP and hsTNT levels were associated with aortic valve disease in BAV patients. TGF-beta 1 levels were lower in BAV patients than in the general population, and not related to aortic dilatation. Longitudinal data are needed to further investigate the prognostic value of biomarkers in these patients. (C) 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. Show less
Patients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The... Show morePatients with a congenital bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, have an increased risk of developing thoracic aneurysms and aortic dissection. The mechanisms underlying BAV-associated aortopathy are poorly understood. This study examined BAV-associated aortopathy in Nos3(-/-) mice, a model with congenital BAV formation. A combination of histological examination and in vivo ultrasound imaging was used to investigate aortic dilation and dissections in Nos3(-/-) mice. Moreover, cell lineage analysis and single-cell RNA sequencing were used to observe the molecular anomalies within vascular smooth muscle cells (VSMCs) of Nos3(-/-) mice. Spontaneous aortic dissections were found in ascending aortas located at the sinotubular junction in similar to 13% of Nos3(-/-) mice. Moreover, Nos3(-/-) mice were prone to developing aortic dilations in the proximal and distal ascending aorta during early adulthood. Lower volumes of elastic fibres were found within vessel walls of the ascending aortas of Nos3(-/-) mice, as well as incomplete coverage of the aortic inner media by neural crest cell (NCC)-derived VSMCs. VSMCs of Nos3(-/-) mice showed downregulation of 15 genes, of which seven were associated with aortic aneurysms and dissections in the human population. Elastin mRNA was most markedly downregulated, followed by fibulin-5 expression, both primary components of elastic fibres. This study demonstrates that, in addition to congenital BAV formation, disrupted endothelial-mediated nitric oxide (NO) signalling in Nos3(-/-) mice also causes aortic dilation and dissection, as a consequence of inhibited elastic fibre formation in VSMCs within the ascending aorta. Show less
Background: Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require... Show moreBackground: Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require detailed knowledge of the spatial location and distribution of cardiac autonomic nerves, however, there are controversies on this subject in humans.Objective: To provide a systematic overview of current knowledge on human anatomy of the cardiac autonomic nervous system.Results: In contrast to the often claimed assumption that human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1-T4 or T5, there is ample evidence indicating involvement of cervical spinal segment C8 and thoracic spinal segments below T5. Whether cervical ganglia besides the stellate ganglion play a role in transmission of cardiac sympathetic signals is unclear. Similarly, there is debate on the origin of cardiac nerves from different thoracic ganglia. Most human studies report thoracic cardiac nerves emerging from the first to fourth thoracic paravertebral ganglia; others report contributions from the fifth, sixth and even the seventh thoracic ganglia. There is no agreement on the precise composition of nerve plexuses at the cardiac level. After years of debate, it is generally accepted that the vagal nerve contributes to ventricular innervation. Vagal distribution appears higher in atria, whereas adrenergic fibers exceed the number of vagal fibers in the ventricles.Conclusion: Anatomy of the human cardiac autonomic nervous system is highly variable and likely extends beyond generally assumed boundaries. This information is relevant for thoracic epidural anesthesia and procedures targeting neuronal modulation of cardiac sympathetic innervation. Show less
The 19th century Russian surgeon Nikolay Ivanovich Pirogov believed passionately in the importance of anatomy for surgeons. His interest in anatomy began as a medical student in Moscow. After... Show moreThe 19th century Russian surgeon Nikolay Ivanovich Pirogov believed passionately in the importance of anatomy for surgeons. His interest in anatomy began as a medical student in Moscow. After graduating in 1828 Pirogov entered the postgraduate German-Baltic University of Dorpat (now Tartu in the Republic of Estonia) where he studied anatomy and surgery. After completing his study, he remained to research the consequences of ligation of the aorta in a series of animal experiments, which formed the core of his doctoral thesis. He wanted to determine the feasibility of aortic ligation as a treatment for patients with an aneurysm of the aorta or iliac artery. He discovered that success was only likely when the aorta was ligated between the two mesenteric arteries and the ligature gradually tightened, an approach surgically difficult in humans. Pirogov then spent 2 years at the Charite Hospital in Berlin before returning to Russia. In 1841, he was appointed Professor of Applied Anatomy and Surgery at the Imperial Medico-Surgical Academy in Saint Petersburg. He instituted the teaching of microscopy and histology to the medical curriculum and in 1846 formed the Institute for Applied Anatomy within the academy, where in addition to teaching medical students future teachers of anatomy in Russia were trained. Pirogov published extensively on anatomy, including several anatomical atlases, the most notable his three-dimensional atlas of topographical anatomy published in four volumes between 1852 and 1859. Today Pirogov's contributions to anatomy are remembered in a number of anatomical structures named after him. Clin. Anat., 33:714-730, 2020. (c) 2019 Wiley Periodicals, Inc. Show less
Rationale: After cardiac damage, excessive neurite outgrowth (sympathetic hyperinnervation) can occur, which is related to ventricular arrhythmias/sudden cardiac death. Post-damage reactivation of... Show moreRationale: After cardiac damage, excessive neurite outgrowth (sympathetic hyperinnervation) can occur, which is related to ventricular arrhythmias/sudden cardiac death. Post-damage reactivation of epicardium causes epicardium-derived cells (EPDCs) to acquire a mesenchymal character, contributing to cardiac regeneration. Whether EPDCs also contribute to cardiac re/hyperinnervation, is unknown.Aim: To investigate whether mesenchymal EPDCs influence cardiac sympathetic innervation.Methods and results: Sympathetic ganglia were co-cultured with mesenchymal EPDCs and/or myocardium, and neurite outgrowth and sprouting density were assessed. Results showed a significant increase in neurite density and directional (i.e. towards myocardium) outgrowth when ganglia were co-cultured with a combination of EPDCs and myocardium, as compared to cultures with EPDCs or myocardium alone. In absence of myocardium, this outgrowth was not directional. Neurite differentiation of PC12 cells in conditioned medium confirmed these results via a paracrine effect, in accordance with expression of neurotrophic factors in myocardial explants co-cultured with EPDCs. Of interest, EPDCs increased the expression of nerve growth factor (NGF) in cultured, but not in fresh myocardium, possibly due to an "ischemic state" of cultured myocardium, supported by TUNEL and Hif1 alpha expression. Cardiac tissues after myocardial infarction showed robust NGF expression in the infarcted, but not remote area.Conclusion: Neurite outgrowth and density increases significantly in the presence of EPDCs by a paracrine effect, indicating a new role for EPDCs in the occurrence of sympathetic re/hyperinnervation after cardiac damage. Show less
ObjectivesIn congenital heart malformations with pulmonary stenosis to atresia an abnormal lateral ductus arteriosus to left pulmonary artery connection can lead to a localised narrowing (pulmonary... Show moreObjectivesIn congenital heart malformations with pulmonary stenosis to atresia an abnormal lateral ductus arteriosus to left pulmonary artery connection can lead to a localised narrowing (pulmonary ductal coarctation) or even interruption We investigated embryonic remodelling and pathogenesis of this area.Material and methodsNormal development was studied in WntCre reporter mice (E10.0-12.5) for neural crest cells and Nkx2.5 immunostaining for second heart field cells. Data were compared to stage matched human embryos and a VEGF120/120 mutant mouse strain developing pulmonary atresia.ResultsNormal mouse and human embryos showed that the mid-pharyngeal endothelial plexus, connected side-ways to the 6th pharyngeal arch artery. The ventral segment formed the proximal pulmonary artery. The dorsal segment (future DA) was solely surrounded by neural crest cells. The ventral segment had a dual outer lining with neural crest and second heart field cells, while the distal pulmonary artery was covered by none of these cells. The asymmetric contribution of second heart field to the future pulmonary trunk on the left side of the aortic sac (so-called pulmonary push) was evident. The ventral segment became incorporated into the pulmonary trunk leading to a separate connection of the left and right pulmonary arteries. The VEGF120/120 embryos showed a stunted pulmonary push and a variety of vascular anomalies.SummarySide-way connection of the DA to the left pulmonary artery is a congenital anomaly. The primary problem is a stunted development of the pulmonary push leading to pulmonary stenosis/atresia and a subsequent lack of proper incorporation of the ventral segment into the aortic sac. Clinically, the aberrant smooth muscle tissue of the ductus arteriosus should be addressed to prohibit development of severe pulmonary ductal coarctation or even interruption of the left pulmonary artery. Show less
Background: Although tenosynovitis in the hands is associated with rheumatoid arthritis (RA), it is unknown whether tenosynovitis of the forefoot is associated with RA.Purpose: To determine the... Show moreBackground: Although tenosynovitis in the hands is associated with rheumatoid arthritis (RA), it is unknown whether tenosynovitis of the forefoot is associated with RA.Purpose: To determine the anatomy of tendon sheaths of the forefoot and the relationship between MRI-detected tenosynovitis at metatarsophalangeal (MTP) joints and RA.Materials and Methods: Fourteen forefeet of donated bodies were examined at flexor tendons and extensor tendons for the presence and course of tendon sheaths. In the prospective study between June 2013 and March 2016, newly presenting patients with RA, patients with other early arthritides, and healthy control participants all underwent MRI of unilateral MTP joints 1-5. MRI studies were scored by two independent readers for tenosynovitis, synovitis, and bone marrow edema. The association between the presence of these features and RA was examined by using logistic regression.Results: Macroscopically, all extensor and flexor tendons crossing MTP joints demonstrated sheaths surrounding tendons. Microscopically, a synovial sheath was present. MRI evaluation was performed in 634 participants: 157 newly presenting patients with RA (109 women; mean age, 59 years 6 11 [standard deviation]), 284 patients with other early arthritides (158 women; mean age, 56 years 6 17), and 193 healthy control participants (136 women; mean age, 50 years 6 16). MRI-detected tenosynovitis was associated with RA, both when compared with patients with other arthritides (odds ratio [OR], 2.5; 95% confidence interval [CI]: 1.7, 3.9; P < .001) and healthy control participants (OR, 46; 95% CI: 14, 151; P < .001). The association was OR of 2.4 (95% CI: 1.5, 3.8; P < .001) for flexor tendons and OR of 3.1 (95% CI: 1.9, 5.2; P < .001) for extensor tendons. The sensitivity of tenosynovitis in RA was 65 of 157 (41%; 95% CI: 35%, 50%). The specificity for RA was 63 of 284 (78%; 95% CI: 72%, 82%) compared with other arthritides, and three of 193 (98%; 95% CI: 96%, 99%) compared with healthy control participants.Conclusion: Tendons at metatarsophalangeal joints are surrounded by tenosynovium. MRI-detected tenosynovitis at metatarsophalangeal joints was specific for rheumatoid arthritis when compared with findings in patients with other arthritides and findings in healthy control participants. (C) RSNA, 2020 Show less
Grewal, N.; Gittenberger-de Groot, A.C.; Thusen, J. von der; Wisse, L.J.; Bartelings, M.M.; DeRuiter, M.C.; ... ; Poelmann, R.E. 2020
Background: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in... Show moreBackground: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in the tricuspid aortic valve (TAV) and the BAV populations as a reference for future studies on aortopathy and related syndromes. Methods: Non-dilated TAV and BAV ascending aortic wall samples were collected, including 60 TAV (embryonic-70 years) and 32 BAV specimens (fetal-72 years, categorized in eight age groups. Results: In TAV, intimal development starts in the neonatal phase. After birth, the thickness of the medial layer increases significantly by increase of elastic lamellae up to and including the "young child" phase stabilizing afterwards. The BAV shows already prenatal intimal thickening becoming significantly thinner after birth subsequently stabilizing. In BAV, increase in elastic lamellae is seen between the young child and the adolescent phases, stabilizing afterwards. Conclusions: Vascular development in TAV is described in three phases: maturation, stabilization, and degeneration. For BAV, the development can be described in two phases: maturation (already prenatally) and degeneration. After birth, the development of the aorta is characterized by degeneration, leading to weakening of the ascending aortic wall and increasing the risk of aortopathy. Show less
Grewal, N.; Gittenberger-de Groot, A.C.; Thusen, J. von der; Wisse, L.J.; Bartelings, M.M.; DeRuiter, M.C.; ... ; Poelmann, R.E. 2020
