Medium-Term Results of Balloon Valvuloplasty of Native Pulmonary Valve Stenosis with and without Supravalvular Obstruction in Childhood

Objectives: Factors influencing results of balloon valvuloplasty (BVP) of pulmonary valve stenosis (PS) in children are investigated. Background: BVP has become the standard of care for PS, medium-term results are not uniform and depend on various preconditions. Methods: We analysed the medium-term results of BVP of PS in children in an observational, single centre study. Need for additional procedure was defined as outcome after initial BVP. Results: We included 143 children (83 female) at a median (IQR) age of 2.6 (0.26–9.24) months and body weight of 5 (3.4–8) kg at BVP with a follow–up of 5.04 (1.6–10.2) years. We used balloon size of 10 (9–14) mm and maximal balloon pressure of 4 (3.5–10) atm, resulting in balloon–to–pulmonary annulus ratio of 1.28 (1.2–1.4). Systolic pressure gradient of PS was reduced with BVP (43.5 mmHg vs. 14.0 mmHg, p < 0.001) and confirmed by echocardiography (68.0 mmHg vs. 25.0 mmHg, p < 0.001) day 1 post procedure. Pulmonary BVP with associated supravalvular PS resulted in a relevant reduction of systolic pressure gradient in 23 of 31 patients (74.2%). Early additional procedure was necessary in 14 patients (9.8%) after 0.2 (0.1–0.7) years due to residual PS (n = 13) and infective endocarditis (n = 1). Factors for additional procedures were associated supravalvular PS with a higher residual pressure gradient, but not genetic syndrome. During further follow–up of 5.04 (1.6–10.2) years no further additional procedures were needed. Conclusions: Pulmonary BVP of native pulmonary valve stenosis leads to excellent medium-term results, even in 3 of 4 infants with associated supravalvular obstruction sufficient pressure relief can be obtained. Keywords Pediatric; catheter; congenital; pulmonary balloon valvuloplast

Different evolutionary potential in host ants of the genus Proformica and their slavemaking ant Rossomyrmex (Hymenoptera: Formicidae)

El parasitismo es reconocido como uno de los principales conductores de la evolución. Cada organismo involucrado en ese tipo de relación presenta un potencial evolutivo, que puede medirse como diversidad genética, que depende a su vez de factores como su capacidad de dispersión, el flujo génico y el tamaño, estructura y composición de sus poblaciones. El potencial evolutivo condiciona también la posibilidad de adaptación local entre parásito y hospedador. En las hormigas esclavistas la adaptación local entre parásito y hospedador puede medirse mediante las similitudes en la composición de hidrocarburos (CHCs) de la cutícula. Las hormigas del género Rossomyrmex parasitan, es decir asaltan y esclavizan, a hormigas del género Proformica. En este trabajo se aportan nuevos datos genéticos de dos de las tres especies hospedadoras estudiadas por nosotros, y se ponen en común con otros ya publicados para analizar las características genéticas y biológicas de estos tres sistemas hospedador-parásito. Estos sistemas presentan rangos variables de distribución (fragmentados y continuos), diversidad genética, potencial evolutivo y adaptación local. La distribución geográfica (fragmentada o continua) influye decisivamente en la estructura de las poblaciones de Proformica, más que la composición del hormiguero. Cuando comparamos los potenciales evolutivos de hospedador y parásito, también hay variabilidad en este factor, conduciendo a diferentes resultados de adaptación local en las diferentes parejas hospedador-parásito. Por todo ello, se considera que las especies de estos géneros constituyen un modelo de interés, en el que se podrían hacer estudios comparativos para conocer qué procesos han conducido a diferentes salidas evolutivas durante la carrera de armamentos hospedador-parásito.Parasitism is known to be one of the main drivers of evolution. Each organism involved in this relationship has an evolutionary potential that can be measured as its genetic diversity. This feature, in turn, depends on factors such as the dispersal ability, genetic flow and size, structure and composition of its populations. The evolutionary potential also constrains local adaptation between parasite and host. In slave-making ants, this local adaptation can be measured as the similitude in the cuticular hydrocarbon (CHCs) composition. Ants of the genus Rossomyrmex parasitize by raiding and enslaving ants from the genus Proformica. In this study we report new genetic data on two of the three host species studied by us, which together with previous published data enable us to analyze the genetic and biological characteristics of the different host-parasite systems. These systems show variable ranges of distribution (fragmented and continuous), genetic diversity, evolutionary potential and local adaptation. The geographic distribution (fragmented or continuous) strongly influences the population structure of Proformica in comparison with nest composition. We also found differences in the evolutionary potential when comparing host and parasite species, being local adaptation different for each host-parasite system. All these results suggest that the ants of both genera constitute interesting model systems for the comparative study of the processes leading to different evolutionary outcomes in the host-parasite arms-race

Deletion of the myeloid endothelin-B receptor confers long-term protection from angiotensin II-mediated renal, retinal &amp; vascular injury

International audienceThe endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ETB) receptors (LysM-CreEdnrblox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-CreEdnrblox/lox and littermate controls (Ednrblox/lox) for six weeks. Unexpectedly, LysM-CreEdnrblox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-CreEdnrblox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-CreEdnrblox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-CreEdnrblox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ETB signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-CreEdnrblox/lox mice than in controls. At six weeks, macrophages from LysM-CreEdnrblox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrblox/lox mice. Thus, myeloid cell ETB receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages

Podocytes maintain high basal levels of autophagy independent of mTOR signaling

While constant basal levels of macroautophagy/autophagy are a prerequisite to preserve long-lived podocytes at the filtration barrier, MTOR regulates at the same time podocyte size and compensatory hypertrophy. Since MTOR is known to generally suppress autophagy, the apparently independent regulation of these two key pathways of glomerular maintenance remained puzzling. We now report that long-term genetic manipulation of MTOR activity does in fact not influence high basal levels of autophagy in podocytes either in vitro or in vivo. Instead we present data showing that autophagy in podocytes is mainly controlled by AMP-activated protein kinase (AMPK) and ULK1 (unc-51 like kinase 1). Pharmacological inhibition of MTOR further shows that the uncoupling of MTOR activity and autophagy is time dependent. Together, our data reveal a novel and unexpected cell-specific mechanism, which permits concurrent MTOR activity as well as high basal autophagy rates in podocytes. Thus, these data indicate manipulation of the AMPK-ULK1 axis rather than inhibition of MTOR as a promising therapeutic intervention to enhance autophagy and preserve podocyte homeostasis in glomerular diseases

Mild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells

Cancer and cardiovascular disease (CVD) share common risk factors such as dyslipidemia, obesity and inflammation. However, the role of pro-atherogenic environment and its associated low-grade inflammation in tumor progression remains underexplored. Here we show that feeding C57BL/6J mice with a non-obesogenic high fat high cholesterol diet (HFHCD) for two weeks to induce mild dyslipidemia, increases the pool of circulating Ly6Chi monocytes available for initial melanoma development, in an IL-1β-dependent manner. Descendants of circulating myeloid cells, which accumulate in the tumor microenvironment of mice under HFHCD, heighten pro-angiogenic and immunosuppressive activities locally. Limiting myeloid cell accumulation or targeting VEGF-A production by myeloid cells decrease HFHCD-induced tumor growth acceleration. Reverting the HFHCD to a chow diet at the time of tumor implantation protects against tumor growth. Together, these data shed light on cross-disease communication between cardiovascular pathologies and cancer

The endothelin B receptor plays a crucial role in the adhesion of neutrophils to the endothelium in sickle cell disease

Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ETB receptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ETB function was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients

A novel role for myeloid endothelin-B receptors in hypertension

International audienceAIMS:Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype.METHODS AND RESULTS:In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies.CONCLUSION:Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension

A novel role for myeloid endothelin-B receptors in hypertension

International audienceAIMS:Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype.METHODS AND RESULTS:In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies.CONCLUSION:Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension

VII. Discours

Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. Methods: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. Results: Six survey rounds comprising 65–79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders–Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. Discussion: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders–Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration

Autophagy protein 5 controls flow-dependent endothelial functions

Dysregulated autophagy is associated with cardiovascular and metabolic diseases, where impaired flow-mediated endothelial cell responses promote cardiovascular risk. The mechanism by which the autophagy machinery regulates endothelial functions is complex. We applied multi-omics approaches and in vitro and in vivo functional assays to decipher the diverse roles of autophagy in endothelial cells. We demonstrate that autophagy regulates VEGF-dependent VEGFR signaling and VEGFR-mediated and flow-mediated eNOS activation. Endothelial ATG5 deficiency in vivo results in selective loss of flow-induced vasodilation in mesenteric arteries and kidneys and increased cerebral and renal vascular resistance in vivo. We found a crucial pathophysiological role for autophagy in endothelial cells in flow-mediated outward arterial remodeling, prevention of neointima formation following wire injury, and recovery after myocardial infarction. Together, these findings unravel a fundamental role of autophagy in endothelial function, linking cell proteostasis to mechanosensing