Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis

Rationale: Patients with chronic kidney disease (CKD) have an exceedingly high cardiovascular risk; which further increases in patients on peritoneal dialysis (PD). The pathophysiological role of reactive metabolites accumulating in CKD such as glucose degradation products (GDP) is uncertain. Objective: Delineating the impact of GDP present in PD fluids in accelerated vasculopathy development in patients with CKD. Methods and Results: Omental and parietal peritoneal tissues were obtained from 107 children with CKD prior to dialysis, and 90 children on chronic PD with PD fluids containing very low or high concentrations of GDP. Omental arterioles, protected from local PD fluid exposure by surrounding fat, were microdissected for multi-omics analyses. High-GDP exposed omental arterioles exhibited three-fold higher advanced glycation endproduct concentrations and upregulated genes involved in cell death/apoptosis and suppressed genes related to cell viability/survival, cytoskeleton organization and immune response biofunctions. Vasculopathy associated canonical pathways concordantly regulated on gene- and protein level with high-GDP exposure included cell death/proliferation, apoptosis, cytoskeleton organization, metabolism and detoxification, cell junction signaling, and immune response. Parietal peritoneal arterioles of patients exposed to high-GDP fluids exhibited lumen narrowing compared to patients with CKD5 and patients on low-GDP PD, intima thickness was increased. Protein quantification verified increased proapoptotic activity and cytoskeleton disintegration, single-molecule-localization microscopy demonstrated arteriolar endothelial zonula occludens-1 (ZO-1) disruption. Absolute and per endoluminal surface length, arteriolar endothelial cell counts inversely correlated with GDP exposure, caspase-3, TGF-ß induced pSMAD2/3, interleukin-6, ZO-1 abundance and lumen narrowing. In vitro, 3,4-dideoxyglucosone-3-ene reduced lamin-A/C and membrane ZO-1 assembly, increased pSMAD2/3, and ionic and 4- and 10kDa permeability of arterial endothelial cells. Conclusions: Our findings indicate a fundamental role of GDP in PD associated vasculopathy, exerted by endothelial cell junction and cytoskeleton disruption, and induction of apoptosis. They should redirect the focus of research and intervention on targeting reactive metabolite overload in CKD and PD.

Chronic exposure to diesel exhaust may cause small airway wall thickening without lumen narrowing: a quantitative computerized tomography study in Chinese diesel engine testers

Background Diesel exhaust (DE) is a major source of ultrafine particulate matters (PM) in ambient air and contaminates many occupational settings. Airway remodeling assessed using computerized tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural changes of small airways caused by chronic DE exposure is unknown. Wall and lumen areas of 6th and 9th generations of four candidate airways were quantified using end-inhalation CT scans in 78 diesel engine testers (DET) and 76 non-DETs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response relationship. Results Environmental monitoring and CCAM showed a much higher PM exposure in DETs, which was associated with higher wall area and wall area percent for 6th generation of airways. However, no reduction in lumen area was identified. No study subjects met spirometry diagnosis of airway obstruction. This suggested that small airway wall thickening without lumen narrowing may be an early feature of airway remodeling in DETs. The effect of DE exposure status on wall area percent did not differ by lobes or smoking status. Although the trend test was of borderline significance between categorized CCAM and wall area percent, subjects in the highest CCAM category has a 14% increase in wall area percent for the 6th generation of airways compared to subjects in the lowest category. The impact of DE exposure on FEV1 can be partially explained by the wall area percent with mediation effect size equal to 20%, Pperm = 0.028). Conclusions Small airway wall thickening without lumen narrowing may be an early image feature detected by CT and underlie the pathology of lung injury in DETs. The pattern of changes in small airway dimensions, i.e., thicker airway wall without lumen narrowing caused by occupational DE exposure was different to that (i.e., thicker airway wall with lumen narrowing) seen in our previous study of workers exposed to nano-scale carbon black aerosol, suggesting constituents other than carbon cores may contribute to such differences. Our study provides some imaging indications of the understanding of the pulmonary toxicity of combustion derived airborne particulate matters in humans.

Vasa Vasorum Lumen Narrowing in Brain Vascular Hyalinosis in Systemic Hypertension Patients Who Died of Ischemic Stroke

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of the vasa vasorum and oxidative stress. Transmission electron microscopy revealed endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. The siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott–Aldrich syndrome protein (a regulator of actin polymerization). Spontaneously hypertensive stroke-prone rats also exhibited lesions indicative of brain vascular hyalinosis, the endothelial cell protrusion into the lumen of the vasa vasorum, and endocytosis in vasa vasorum endothelial cells. We propose that endocytosis-dependent endothelial cell bulge protrusion narrows the vasa vasorum, resulting in ischemic oxidative damage to cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients.

Vasa vasorum lumen narrowing in brain vascular hyalinosis in systemic hypertension patients with ischemic stroke

Ischemic stroke is a major cause of death among patients with systemic hypertension. The narrowing of the lumen of the brain vasculature contributes to the increased incidence of stroke. While hyalinosis represents the major pathological lesions contributing to the vascular lumen narrowing and stroke, the pathogenic mechanism of brain vascular hyalinosis has not been well characterized. Thus, the present study examined the postmortem brain vasculature of human patients who died of ischemic stroke due to systemic hypertension. Hematoxylin and eosin staining and immunohistochemistry showed the occurrence of brain vascular hyalinosis with infiltrated plasma proteins along with the narrowing of vasa vasorum and oxidative stress. Transmission electron microscopy revealed the endothelial cell bulge protrusion into the vasa vasorum lumen and the occurrence of endocytosis in the vasa vasorum endothelium. The treatment of cultured microvascular endothelial cells with adrenaline also promoted the formation of the bulge as well as endocytic vesicles. siRNA knockdown of sortin nexin-9 (a mediator of clathrin-mediated endocytosis) inhibited the adrenaline-induced endothelial cell bulge formation. Adrenaline promoted protein-protein interactions between sortin nexin-9 and neural Wiskott–Aldrich Syndrome protein (a regulator of actin polymerization). We propose that endocytosis-depending endothelial cell bulge narrows the vasa vasorum, resulting in ischemic oxidative damage to the cerebral vessels, the formation of hyalinosis, the occurrence of ischemic stroke, and death in systemic hypertension patients.

Perfusion and plaque evaluation to predict recurrent stroke in symptomatic middle cerebral artery stenosis

Background and purposeWe investigated the baseline demographics of patients with severe unilateral atherosclerotic stenosis of the middle cerebral artery (MCA) using multimodal MRI and evaluated the haemodynamic impairments and plaque characteristics of patients who had a recurrent stroke.Materials and methodsWe retrospectively recruited consecutive patients with severe unilateral atherosclerotic MCA stenosis who underwent arterial spin labelling (ASL) with postlabelling delay (PLD) of 1.5 and 2.5 s, and vessel wall MRI. For each PLD, cerebral blood flow (CBF) maps were generated. Hypoperfusion volume ratio (HVR) from 2 PLD CBF was calculated. An HVR value ≥50% was considered as severe HVR. Plaque areas, plaque burden, plaque length and remodelling index were measured. Plaque enhancement at maximal lumen narrowing site were graded. Baseline clinical and imaging characteristics were compared between patients with (event+) and without (event−) 1 year ischaemic events.ResultsForty-three patients (47.23±12.15 years; 28 men) were enrolled in this study. Seven patients had an HVR ≥50%. During the 1-year follow-up, 7 patients had experienced a recurrent stroke. HVR were significantly higher in the event+ than event− (53.17%±29.82% vs 16.9%±15.57%, p=0.0002), whereas no significant difference was detected in plaque areas, plaque burden, remodelling index, plaque length and plaque enhancement grade. The multivariable analysis revealed that a severe HVR was significantly associated with a recurrent stroke (Odds ratio=12.93, 95% confidence interval 1.57 to 106.24, p=0.017) after adjusted by hypertension and smoking.ConclusionHVR obtained from two PLD ASL may be a useful imaging predictor of recurrent stroke.

Carotid Artery Stenting Using a Closed-Cell Stent-in-Stent Technique for Unstable Plaque

Purpose: To examine whether carotid artery stenting (CAS) of stenoses with unstable plaque using a closed-cell stent-in-stent technique prevents plaque protrusion. Materials and Methods: Between December 2014 and August 2018, 35 consecutive patients (mean age 75.8 years; 29 men) with carotid artery stenosis (20 symptomatic) and unstable plaque diagnosed by magnetic resonance imaging were prospectively analyzed. Mean diameter stenosis was 83.5%. All CAS procedures were performed with stent-in-stent placement of Carotid Wallstents using an embolic protection device and conservative postdilation. The technical success rate, incidence of plaque protrusion, ischemic stroke rate within 30 days, and new ipsilateral ischemic lesions on diffusion-weighted imaging (DWI) within 48 hours after CAS were prospectively assessed. Follow-up outcomes included the incidences of ipsilateral stroke and restenosis. Results: The technical success rate was 100%. No plaque protrusion or stroke occurred in any patient. New ischemic lesions were observed on DWI in 10 (29%) patients. During the mean 11.6-month follow-up, no ipsilateral strokes occurred. Two (6%) patients developed asymptomatic restenosis recorded as 53% lumen narrowing and occlusion, respectively. Conclusion: CAS using a closed-cell stent-in-stent technique for unstable plaque may be useful for preventing plaque protrusion and ischemic complications.

Transition From Phasic to Tonic Contractility in Airway Smooth Muscle After Birth: An Experimental and Computational Modeling Study

Fetal airway smooth muscle (ASM) exhibits phasic contractile behavior, which transitions to a more sustained “tonic” contraction after birth. The timing and underlying mechanisms of ASM transition from a phasic to a tonic contractile phenotype are yet to be established. We characterized phasic ASM contraction in preterm (128 day gestation), term (∼150 day gestation), 1–4 month, 1 yr, and adult sheep (5yr). Spontaneous phasic activity was measured in bronchial segments as amplitude, frequency, and intensity. The mechanism of phasic ASM contraction was investigated further with a computational model of ASM force development and lumen narrowing. The computational model comprised a two-dimensional cylindrical geometry of a network of contractile units and the activation of neighboring cells was dependent on the strength of coupling between cells. As expected, phasic contractions were most prominent in fetal airways and decreased with advancing age, to a level similar to the level in the 1–4 month lambs. Computational predictions demonstrated phasic contraction through the generation of a wave of activation events, the magnitude of which is determined by the number of active cells and the strength of cell–cell interactions. Decreases in phasic contraction with advancing age were simulated by reducing cell–cell coupling. Results show that phasic activity is suppressed rapidly after birth, then sustained at a lower intensity from the preweaning phase until adulthood in an ovine developmental model. Cell–cell coupling is proposed as a key determinant of phasic ASM contraction and if reduced could explain the observed maturational changes.