Pathogenesis and management of Brugada syndrome in schizophrenia: A scoping review.

CONTEXT: Excess cardiovascular morbidity and an increased prevalence of sudden cardiac death (SCD) contributes to premature mortality in schizophrenia. Brugada syndrome (BrS) is an important but underrecognized cause of SCD. It is more commonly seen in schizophrenia than in general population controls. METHODS: We conducted a scoping review to describe the pathogenesis of BrS in schizophrenia and to identify the psychotropic medications that increase the risk of unmasking BrS and associated ventricular arrhythmias resulting in SCD. FINDINGS: Schizophrenia and BrS share similar calcium channel abnormalities, which may result in aberrant myocardial conductivity. It remains uncertain if there is a genetic pre-disposition for BrS in a subset of patients with schizophrenia. However, the unmasking of Brugada ECG patterns with the use of certain antipsychotics and antidepressants increases the risk of precipitating SCD, independent of QT prolongation. CONCLUSIONS AND FUTURE DIRECTIONS: Specific cardiology assessment and interventions may be required for the congenital or unmasked Brugada ECG pattern in schizophrenia. The current long-term standard of care for BrS is an implantable cardioverter defibrillator (ICD), but post-implantation psychological effects must be considered. Careful use of antipsychotic and other psychotropic medications is necessary to minimize proarrhythmic effects due to impact on cardiac sodium and calcium ion channels. When prescribing such drugs to patients with schizophrenia, clinicians should be mindful of the potentially fatal unmasking of Brugada ECG patterns and how to manage it. We present recommendations for psychiatrists managing this patient population.

Serum BTP concentrations are not affected by hepatic dysfunction.

BACKGROUND: Beta Trace Protein (BTP) is a promising marker of glomerular filtration rate (GFR). Equations to estimate GFR using BTP have been proposed. Very little is known about BTP's production and metabolism. It has been hypothesized that the liver metabolizes certain BTP isoforms. As such, hepatic dysfunction may influence serum levels independently of GFR. This would impact on the accuracy and precision of GFR estimates using BTP. The purpose of this study was to assess the impact of cirrhosis on serum BTP concentrations. METHODS: BTP, cystatin C (cysC) and creatinine (Cr) were measured in 99 cirrhotic subjects and in matched controls. BTP/cysC and Cr/cysC ratios were compared between cases and controls. This was repeated after stratification by Child Pugh category. Comparisons of ratios between Child Pugh category A and combined B and C case subjects were also performed. RESULTS: There were no differences in BTP/cysC ratios between cases and controls for the entire cohort (0.80 vs 0.79) or for any of the Child Pugh categories (p > 0.10). There were significant differences between cases (1.09) and controls (0.73) for the BTP/Cr ratios (p < 0.001). The BTP/Cr ratio was higher in those with more advanced cirrhosis as compared to those with less severe cirrhosis (1.20 vs 1.03, p < 0.01). There were no differences in BTP/cysC ratios between those with less severe and more advanced cirrhosis (p = 0.25). CONCLUSIONS: This study suggests that hepatic dysfunction does not influence serum BTP levels and argues against a significant role for the liver in BTP metabolism. Confirmation in a larger group of patients with advanced cirrhosis is required.

Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36.

Tubulointerstitial fibrosis is a hallmark of advanced diabetic kidney disease that is linked to a decline in renal function, however the pathogenic mechanisms are poorly understood. Microparticles (MPs) are 100-1000 nm vesicles shed from injured cells that are implicated in intercellular signalling. Our lab recently observed the formation of MPs from podocytes and their release into urine of animal models of type 1 and 2 diabetes and in humans with type 1 diabetes. The purpose of the present study was to examine the role of podocyte MPs in tubular epithelial cell fibrotic responses. MPs were isolated from the media of differentiated, untreated human podocytes (hPODs) and administered to cultured human proximal tubule epithelial cells (PTECs). Treatment with podocyte MPs increased p38 and Smad3 phosphorylation and expression of the extracellular matrix (ECM) proteins fibronectin and collagen type IV. MP-induced responses were attenuated by co-treatment with the p38 inhibitor SB202190. A transforming growth factor beta (TGF-ß) receptor inhibitor (LY2109761) blocked MP-induced Smad3 phosphorylation and ECM protein expression but not p38 phosphorylation suggesting that these responses occurred downstream of p38. Finally, blockade of the class B scavenger receptor CD36 completely abrogated MP-mediated p38 phosphorylation, downstream Smad3 activation and fibronectin/collagen type IV induction. Taken together our results suggest that podocyte MPs interact with proximal tubule cells and induce pro-fibrotic responses. Such interactions may contribute to the development of tubular fibrosis in glomerular disease.

High glucose increases the formation and pro-oxidative activity of endothelial microparticles.

AIMS/HYPOTHESIS: Individuals with diabetes exhibit increases in circulating endothelial microparticles (eMPs, also referred to as endothelial microvesicles), which are associated with endothelial dysfunction and a heightened risk of cardiovascular complications. We have shown that eMPs are markers and mediators of vascular injury although their role in diabetes is unclear. We hypothesised that the composition and biological activity of eMPs are altered in response to high glucose exposure. We assessed the effects of high glucose on eMP formation, composition and signalling in cultured HUVECs. METHODS: eMPs were isolated from the media of HUVECs cultured under conditions of normal glucose (eMPNG), high glucose (eMPHG) or osmotic control of L-glucose (eMPLG). eMP size, concentration and surface charge were assessed by nanoparticle tracking analysis and flow cytometry. eMP protein composition was assessed by liquid chromatography-tandem mass spectrometry, and eMP-mediated effects on coagulation, reactive oxygen species (ROS) production and vessel function were assessed. RESULTS: Exposure of HUVECs to high glucose for 24 h caused a threefold increase in eMP formation, increased mean particle size (269 ± 18 nm vs 226 ± 11 nm) and decreased surface charge. Compared with eMPNG or eMPLG, eMPHG possessed approximately threefold greater pro-coagulant activity, stimulated HUVEC ROS production to a greater extent (~250% of eMPNG) and were more potent inhibitors of endothelial-dependent relaxation. Proteomic analysis of eMPs identified 1212 independent proteins of which 68 were exclusively found in eMPHG. Gene ontology analysis revealed that eMPHG-exclusive proteins were associated with signalling pathways related to blood coagulation, cell signalling and immune cell activation. CONCLUSIONS/INTERPRETATION: Our results indicate that elevated glucose is a potent stimulus for eMP formation that also alters their molecular composition leading to increased bioactivity. Such effects may contribute to progressive endothelial injury and subsequent cardiovascular complications in diabetes.

Microparticle Formation in Peritoneal Dialysis: A Proof of Concept Study.

BACKGROUND: Injury to the mesothelial layer of the peritoneal membrane during peritoneal dialysis (PD) is implicated in loss of ultrafiltration capacity, but there are no validated biomarkers for mesothelial cell injury. Microparticles (MPs) are 0.1 to 1.0 µm membrane vesicles shed from the cell surface following injury and are sensitive markers of tissue damage. Formation of MPs in the peritoneal cavity during PD has not been reported to date. METHODS: We designed a single-center, proof of concept study to assess whether peritoneal solution exposure induces formation of mesothelial MPs suggestive of PD membrane injury. We examined MP levels in PD effluents by electron microscopy, nanoparticle tracking analysis (NTA), flow cytometry, procoagulant activity, and Western blot. RESULTS: NTA identified particles in the size range of 30 to 900 nm, with a mean of 240 (SE: 10 nm). MP levels increased in a progressive manner during a 4-hour PD dwell. Electron microscopy confirmed size and morphology of vesicles consistent with characteristics of MPs as well as the presence of mesothelin on the surface. Western blot analysis of the MP fraction also identified the presence of mesothelin after 4 hours, suggesting that MPs found in PD effluents may arise from mesothelial cells. CONCLUSIONS: Our results suggest that MPs are formed and accumulate in the peritoneal cavity during PD, possibly as a stress response. Assessing levels of MPs in PD effluents may be useful as a biomarker for peritoneal membrane damage.

CONTEXTE: Les lésions causées à la couche mésothéliale de la membrane péritonéale au cours d'une dialyse péritonéale (DP) sont impliquées dans la perte de capacité d'ultrafiltration. Toutefois, il n'existe aucun biomarqueur validé permettant la détection de ces lésions. Les microparticules (MP) sont des vésicules membranaires de 0,1 à 1,0 µm qui se détachent de la surface des cellules à la suite des lésions. Les microparticules sont sensibles aux marqueurs de dommages tissulaires. À ce jour, la formation de microparticules dans la cavité péritonéale au cours de la DP n'a pas été observée. MÉTHODOLOGIE: Nous avons conçu une étude de preuve de concept que nous avons menée dans un seul centre. Nous voulions déterminer si l'exposition à la solution de dialyse péritonéale induisait la formation de microparticules mésothéliales, ce qui pourrait indiquer la présence de dommages membranaires provoqués par la DP. Nous avons mesuré les taux de microparticules dans les effluents de la DP par microscopie électronique, par analyse du suivi individuel de particules (Nanoparticle Tracking Analysis­NTA), en cytométrie de flux, par la mesure de l'activité pro-coagulante et par Western Blot. RÉSULTATS: L'analyse par NTA a identifié des particules allant de 30 à 900 nanomètres, dont le diamètre moyen était de 240 ±10 nanomètres. Les taux de MP ont augmenté d'une façon progressive au cours des quatre heures que durait la DP. La microscopie électronique a confirmé la taille et la morphologie de vésicules conformes aux caractéristiques des MP, de même que la présence de mésothéline en surface. L'analyse par Western Blot de fragments de MP a également indiqué la présence de mésothéline après 4 heures, ce qui suggère que les microparticules recueillies dans les effluents de dialyse pourraient provenir de cellules mésothéliales. CONCLUSIONS: Nos résultats suggèrent que des microparticules sont formées au cours de la DP et qu'elles s'accumulent dans la cavité péritonéale, possiblement en réponse au stress. Par conséquent, la mesure des taux de microparticules dans les effluents de DP pourrait s'avérer un bon biomarqueur pour indiquer la présence de lésions dans la membrane péritonéale.

Human endothelial colony-forming cells protect against acute kidney injury: role of exosomes.

The administration of certain progenitor cells is protective in experimental acute kidney injury (AKI), and mechanisms may involve the release of paracrine factors. Endothelial colony-forming cells (ECFCs) are endothelial precursor cells with a high proliferative capacity and pro-angiogenic potential. We examined the effects of human umbilical cord blood-derived ECFCs and their extracellular vesicles in a mouse model of ischemic AKI and in cultured human umbilical vein endothelial cells subjected to hypoxia/reoxygenation. In mice with ischemic AKI, administration of ECFCs (i.v.) at the time of reperfusion significantly attenuated increases in plasma creatinine, tubular necrosis, macrophage infiltration, oxidative stress, and apoptosis, without cell persistence in the kidneys. In cultured human umbilical vein endothelial cells, hypoxia/reoxygenation stimulated apoptosis. This effect was inhibited by incubation with conditioned medium or exosomes (40- to 100-nm diameter) derived from ECFCs, but not by microparticles (100- to 1000-nm diameter) or vesicle-depleted conditioned medium. Administration of exosomes (i.v.) directly to mice with ischemic AKI attenuated renal injury, as assessed by plasma creatinine, tubular necrosis, and apoptosis. Taken together, these studies indicate protective effects of human cord blood-derived ECFCs in experimental AKI and suggest that ECFC-derived exosomes may mediate the protective response via inhibition of endothelial cell apoptosis.