Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation.

Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.

Splenic monocytes drive pathogenic subretinal inflammation in age-related macular degeneration.

Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1+ splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD.

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-ß pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-ß pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-ß pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Safety of Continuing Anticoagulation Prior to Cardiac Catheterization in Pediatric Patients: A Los Angeles Center Experience.

This is the first report specifically describing outcomes of pediatric patients who underwent cardiac catheterization while on uninterrupted anticoagulation. One hundred forty-four cardiac catheterizations were identified that met inclusion criteria at our institution from 11/2014 to 10/2019. The median age and weight of the patients were 6.3 [0.01-20.9] years and 19.3 [2.1-172.5] kg, respectively. Seventy-eight (54%) catheterizations involved inpatients. The most common cardiac diagnoses among the cohort were single ventricle (n = 41), conotruncal defects (n = 37), and structurally normal heart (n = 16). The most common indications for anticoagulation were arterial/venous thrombus (n = 45), Fontan physiology (n = 32), and mechanical valve thrombus prophylaxis (n = 27). The anticoagulation medications used were warfarin (n = 57), heparin (n = 52), enoxaparin (n = 25), fondaparinux (n = 5), rivaroxaban (n = 2), and both heparin and warfarin (n = 3). Interventions were performed in 96 cases (67%). The median length of the procedure was 122.5 [15-760] minutes, and the median time to achieve hemostasis was 18.0 [range: 5-76, IQR: 13-25] minutes. Adverse events were present in 11 cases (7.6%), and of those only 2 cases (1.4%) were bleeding-related complications. Our single-center data suggest that performing cardiac catheterization on pediatric patients while on uninterrupted anticoagulation is safe and does not substantially increase the risk of bleeding complications based on a cohort of patients that varied in age, size, diagnosis, medical complexity, and type of intervention performed. Patients on warfarin therapy for a mechanical valve are most likely to benefit from this practice, as the ability to continue warfarin therapy avoids the need for bridging and other interruption-related complications.

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model.

OBJECTIVE: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-ß deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. METHODS: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. RESULTS: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. INTERPRETATION: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952-966.

Characteristics and outcomes of acute COVID-19 infection in paediatric and young adult patients with underlying cardiac disease.

OBJECTIVE: To describe outcomes of acute coronavirus disease 2019 in paediatric and young adult patients with underlying cardiac disease and evaluate the association between cardiac risk factors and hospitalisation. STUDY DESIGN: We conducted a retrospective single-institution review of patients with known cardiac disease and positive severe acute respiratory syndrome coronavirus 2 RT-PCR from 1 March, 2020 to 30 November, 2020. Extracardiac comorbidities and cardiac risk factors were compared between those admitted for coronavirus disease 2019 illness and the rest of the cohort using univariate analysis. RESULTS: Forty-two patients with a mean age of 7.7 ± 6.7 years were identified. Six were 18 years of age or more with the oldest being 22 years of age. Seventy-six percent were Hispanic. The most common cardiac diagnoses were repaired cyanotic (n = 7, 16.6%) and palliated single ventricle (n = 7, 16.6%) congenital heart disease. Fourteen patients (33.3%) had underlying syndromes or chromosomal anomalies, nine (21%) had chronic pulmonary disease and eight (19%) were immunosuppressed. Nineteen patients (47.6%) reported no symptoms. Sixteen (38.1%) reported only mild symptoms. Six patients (14.3%) were admitted to the hospital for acute coronavirus disease 2019 illness. Noncardiac comorbidities were associated with an increased risk of hospitalisation (p = 0.02), particularly chronic pulmonary disease (p = 0.01) and baseline supplemental oxygen requirement (p = 0.007). None of the single ventricle patients who tested positive required admission. CONCLUSIONS: Hospitalisations for coronavirus disease 2019 were rare among children and young adults with underlying cardiac disease. Extracardiac comorbidities like pulmonary disease were associated with increased risk of hospitalisation while cardiac risk factors were not.

25-Hydroxycholesterol amplifies microglial IL-1ß production in an apoE isoform-dependent manner.

BACKGROUND: Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models. METHODS: We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-ß plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry. RESULTS: We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-ß plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1ß is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1ß secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1ß release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity. CONCLUSION: 25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1ß-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.

Routine Surveillance Catheterization is Useful in Guiding Management of Stable Fontan Patients.

We developed a Fontan surveillance catheterization protocol as part of routine assessment of stable patients 10 years after Fontan completion. The surveillance catherization includes hemodynamic assessment with inhaled nitric oxide, angiography, liver biopsy, and transcatheter intervention if indicated. We aimed to describe hemodynamic and liver biopsy findings, response to pulmonary vasoreactivity testing, rates of transcatheter intervention, and changes in medical therapy following surveillance catheterization in stable Fontan patients. A single-center retrospective review of Fontan patients undergoing surveillance catheterization between November 2014 and May 2019 was performed. Liver biopsies were independently scored by two pathologists. Sixty-three patients underwent surveillance catheterization (mean age 14.6 ± 3.0 years). The mean Fontan pressure was 11.8 ± 2.1 mmHg. The mean cardiac index was 2.9 ± 0.6 L/min/m2. In the 51 patients who underwent pulmonary vasoreactivity testing, there was a significant decrease in median pulmonary vascular resistance (1.8 [range 0.8-4.1] vs 1.4 [range 0.7-3.0] Wood units × m2; p < 0.001). The mean cardiac index increased (3.0 ± 0.6 vs 3.2 ± 0.7 L/min/m2, p = 0.009). The Fontan pressure did not change significantly. Fifty-seven patients underwent liver biopsy, and all but one showed fibrosis. Nineteen patients (33.3%) demonstrated bridging fibrosis or cirrhosis. Twenty-five patients underwent 34 transcatheter interventions. Pulmonary artery or Fontan stent placement was performed in 19 patients. Phosphodiesterase type 5 inhibitors were initiated in nine patients following surveillance catheterization. Routine surveillance catheterization with liver biopsy in adolescent Fontan patients reveals information that can guide interventional and medical management. Further long-term follow-up and assessment are indicated to assess the benefit of these interventions.

Stent treatment of ostial branch pulmonary artery stenosis: initial and medium-term outcomes and technical considerations to avoid and minimise stent malposition.

OBJECTIVE: Stenting of ostial pulmonary artery stenosis presents several unique challenges. These include difficulty in defining anatomy and need for precise stent placement in order to avoid missing the ostial stenosis or jailing either the contralateral branch pulmonary artery or the ipsilateral upper lobe branch. DESIGN: A retrospective review of outcomes was conducted in 1.5 or 2-ventricle patients who underwent stent placement for ostial branch pulmonary artery stenosis. Specific catheterisation lab techniques were reviewed. RESULTS: Forty-seven branch pulmonary arteries underwent stent placement for ostial stenosis in 43 patients. The median age and weight were 3.7 (0.3-18.1) years and 14.2 (5.6-70.0) kg, respectively. Three (2-8) angiographic projections were needed to profile the ostial stenosis. Open-cell stents were used in 23 and stents were modified in 5 cases. Following stent implantation, the minimum diameter improved from 3.6 (0.8-10.5) to 8.1 (4.2-16.5) mm (p < 0.001). The gradient improved from 21 (0-66) to 4 (0-27) mmHg (p < 0.001). Stent malposition occurred in eight (17%) of the stents placed. Five migrated distally causing suboptimal ostial coverage necessitating placement of a second stent in four. Three migrated proximally and partially jailed the contralateral pulmonary artery. Intentional jailing of the upper lobe branch occurred in four additional cases. At a follow-up of 2.4 (0.3-4.9) years, 15 stents underwent further dilation and 1 had a second stent placed within the exiting stent. CONCLUSION: Ostial branch pulmonary artery stenosis may require additional angiography to accurately define the ostial stenosis. Treatment with stents is effective but carries high rates of stent malposition.

Further percutaneous dilation of a Melody® valve in the mitral position to accommodate somatic growth in a small child: lessons learned.

A 15-month-old child underwent percutaneous expansion of a Melody transcatheter pulmonary valve in the mitral position to accommodate growth after initial surgical implantation during infancy, but transiently decompensated after valvuloplasty owing to stent malformation. The Melody valve in the mitral position of small patients can be further expanded by percutaneous dilation, but there are a number of potential complications and technical improvements to consider.

Elevated Pulmonary Artery Pressure, Not Pulmonary Vascular Resistance, is an Independent Predictor of Short-Term Morbidity Following Bidirectional Cavopulmonary Connection.

Single ventricle palliation relies on the pulmonary vasculature accommodating non-pulsatile systemic venous return. Mean pulmonary artery pressure (MPAP) and indexed pulmonary vascular resistance (PVRi) are two measures that impact pulmonary blood flow following bidirectional cavopulmonary connection (BCPC). The purpose of the study was to determine which hemodynamic features are associated with adverse outcomes after BCPC. Pre-operative hemodynamic data and post-operative morbidity and mortality in 250 patients undergoing BCPC at a single center from 2008 to 2014 were reviewed. Patients were then separated into 5 physiologic states based on MPAP, PVRi, and degree of pulmonary to systemic blood flow (Qp:Qs). There were 9 (3.6%) deaths, and 49 patients (20%) sustained major morbidity. An ROC curve identified MPAP > 16 mmHg as an inflection point. Pre-BCPC sildenafil and oxygen use, ventricular dysfunction, and MPAP > 16 mmHg (OR 4.1 [95% CI 1.8-9.2]) were independently associated with morbidity. MPAP > 16 mmHg (OR 6.7 [95% CI 1.6-28]) and pre-BCPC oxygen use were associated with hospital mortality. PVRi was not associated with morbidity or mortality. Of the five physiologic states, patients with high MPAP, low PVRi, and low Qp:Qs fared the worst, with the highest risk of major morbidity (OR 8.6 [3.0-24.9]) and highest risk of mortality (OR 8.0 [1.5-41.3]) when compared to their reference groups (low MPAP, low PVRi). Elevated MPAP, need for pre-operative oxygen support, sildenafil use, and systemic ventricular systolic dysfunction predict morbidity following BCPC. Specifically, patients with elevated MPAP not due to elevated PVRi or pulmonary blood flow had the highest risk of morbidity and mortality.

Unmasking the borderline coarctation: the utility of isoproterenol in the paediatric cardiac catheterisation laboratory.

BACKGROUND: One indication for intervention in coarctation of the aorta is a peak-to-peak gradient >20 mmHg. Gradients may be masked in patients under general anaesthesia and may be higher during exercise. Isoproterenol was given during cardiac catheterisation to simulate a more active physiologic state. OBJECTIVES: We aimed to describe the haemodynamic effects of isoproterenol in patients with coarctation and the impact of intervention on the elicited gradients. METHODS: A retrospective study was performed on two-ventricle patients who underwent cardiac catheterisation for coarctation with isoproterenol testing. RESULTS: 25 patients received isoproterenol before and after intervention. With isoproterenol, the mean diastolic (p=0.0015) and mean arterial (p=0.0065) blood pressures proximal to the coarctation decreased significantly. The mean systolic, diastolic, and mean arterial blood pressures distal to the coarctation decreased significantly (p20 mmHg. Post intervention, the median gradient decreased to 2 (0-29) mmHg, versus baseline, p=0.005, and with isoproterenol it decreased to 8 (0-27) mmHg, versus pre-intervention isoproterenol, p<0.0001. There were significant improvements in the gradients by Doppler (<0.0001) and by blood pressure cuff (p=0.0313). The gradients on isoproterenol best correlated with gradients by blood pressure cuff in the awake state (R2=0.76, p<0.0001). CONCLUSIONS: Isoproterenol can be a useful tool to assess the significance of a coarctation and the effectiveness of an intervention. Percutaneous interventions can effectively reduce the gradients elicited by isoproterenol.

Long-term outcomes and re-interventions following balloon aortic valvuloplasty in pediatric patients with congenital aortic stenosis: A single-center study.

OBJECTIVES: To describe long-term risk of mortality, aortic insufficiency (AI), and re-intervention following balloon aortic valvuloplasty (BAV) in pediatric patients and to identify risk factors for re-intervention. BACKGROUND: Few studies report long-term outcomes following BAV in infants and children. METHODS: Kaplan-Meier estimates and proportional hazards regression were used in a retrospective study of 154 patients undergoing BAV from 1993 to 2013. RESULTS: Seventy-six (49%) patients were neonates. Aortic stenosis (AS) gradients were reduced by 38 ± 19 mm Hg. Moderate or severe AI developed acutely in 19 (12%) patients. Estimates of fifteen-year transplant-free survival were 85% (95%CI: 73-92%) in neonates, 94% (95%CI: 80-96%) in infants, and 100% in older patients. Neonates had an elevated long-term risk of AI (P < 0.001) and left heart re-interventions (P = 0.02). At 15 years, an estimated 32% (95%CI: 15-50%) of neonates and 44% (95%CI: 20-65%) of non-neonates remained free from re-intervention; an estimated 45% (95% CI: 26-63%) of neonates and 62% (95% CI: 40-77%) of non-neonates remained free of aortic valve replacement (AVR). Neonatal age, additional left heart lesions, higher pre- and post-dilation gradients, and acute AI were associated with LVOT re-interventions. Post-dilation gradient ≥30 mm Hg and acute AI were associated with AVR. Patients with moderate or severe acute AI but a residual AS gradient <30 mm Hg had a greater risk of AVR compared to patients with a residual AS gradient ≥30 mm Hg but mild or less AI (HR: 2.98 [95% CI: 1.01-8.77]). CONCLUSIONS: While post-BAV survival is excellent, long-term risks of AI and re-intervention are significant. Acute AI is a more strongly associated with AVR than residual AS. © 2016 Wiley Periodicals, Inc.

Tailoring stents to fit the anatomy of unique vascular stenoses in congenital heart disease.

BACKGROUND: Unique and small anatomical features often preclude the use of available vascular stents in pediatric patients with congenital heart disease (CHD). OBJECTIVES: To report our experience and outcomes tailoring stents to fit unique anatomy, particularly in small children and infants with CHD. METHODS: Stent tailoring techniques included trimming, folding, and flaring. Patients receiving a tailored stent November 2002 to February 2015 were included in a retrospective analysis. RESULTS: Forty-one tailored stents were implanted in 30 patients with median age and weight of 0.8 years (6 days to 17 years) and 8.1 kg (2.9-47.9 kg). Thirty stents were placed intraoperatively and 11 percutaneously. Sites included branch pulmonary arteries (BPA; n = 32), pulmonary veins (n = 6), SVC (n = 1), and the ventricular septum (n = 2). Twenty-three (56%) stents were trimmed with or without folding to avoid jailing of side branches, 16 (39%) stents were folded or flared with or without trimming to avoid excessive proximal protrusion, and two (5%) stents were folded back at both ends for implantation in ventricular septal defects. Final stent lengths were 6-15 mm. Minimal vessel diameters increased from 2.8 ± 1.4 mm to 6.7 ± 2.6 mm (P < 0.001). Complications included two intraoperative BPA tears, three pinhole balloon leaks, two intraoperative stent dislodgements, one transient heart block, and one lung reperfusion injury. Follow-up catheterization included 36 re-dilations and implantation of four additional stents over a median of 4.1 years. In-stent restenosis was the indication in 25 (69.4%) re-interventions. CONCLUSION: Tailored stents can be safely implanted to fit unique anatomy in small patients. Re-interventions can effectively treat restenosis and accommodate ongoing vessel growth.

Reduction in Radiation Dose in a Pediatric Cardiac Catheterization Lab Using the Philips AlluraClarity X-ray System.

The objective of this study was to compare radiation doses and imaging quality using Philips AlluraClarity (Philips Healthcare, Best, The Netherlands) X-ray system and an older generation reference system. AlluraClarity is a new generation fluoroscopy system designed to reduce radiation without compromising image quality, but reports of its use in pediatric patients are limited. Dose area products (DAP, mGy cm2) and DAP/kg were compared in patients catheterized using Allura Xper and AlluraClarity systems over a year of use for each. Randomly selected studies from each system were assessed for image quality. The 430 patients imaged with Clarity were larger than the 332 imaged with Xper (median BSA: 0.74 vs. 0.64 m2, p = 0.06), and median total fluoroscopic times (TFT) were similar (15.8 vs. 16.1 min, p = 0.37). Median DAPs were 8661 mGy cm2 (IQR: 18,300 mGy cm2) and 4523 mGy cm2 (IQR: 11,596 mGy cm2) with Xper and Clarity, respectively (p < 0.001). There was a reduction in median DAP in all procedure categories. After adjustment for BSA, TFT, and procedure type, using Clarity was associated with a 57.5% (95% CI 51.5-62.8%, p < 0.001) reduction in DAP for all procedures. Reductions did not significantly differ by weight (<10 kg, 10-40 kg, ≥ 40 kg). There was an adjusted percent reduction in DAP for each procedure category ranging from 39.0% (95% CI 25.6-50.1%, p < 0.001) for cardiac biopsies with or without coronary angiography to 67.6% (95% CI 61.2-72.8%, p < 0.001) for device occlusions. Mean overall imaging quality scores (4.3 ± 0.8 with Clarity vs. 4.4 ± 0.6 with Xper, p = 0.62) and scores based on specific quality parameters were similar in the two groups. Use of AlluraClarity substantially reduced radiation doses compared to the older generation reference system without compromising imaging quality in a pediatric cardiac catheterization lab.

APOE Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration.

Contrary to Alzheimer's disease (AD), the APOE2 allele increases and the APOE4 allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most common APOE3 allele. The underlying mechanism for this association with AMD and the reason for the puzzling difference with AD are unknown. We previously demonstrated that pathogenic subretinal mononuclear phagocytes (MPs) accumulate in Cx3cr1-deficient mice due to the overexpression of APOE, interleukin-6, and CC chemokine ligand 2 (CCL2). We here show using targeted replacement mice expressing the human APOE isoforms (TRE2, TRE3, and TRE4) that MPs of TRE2 mice express increased levels of APOE, interleukin-6, and CCL2 and develop subretinal MP accumulation, photoreceptor degeneration, and exaggerated choroidal neovascularization similar to AMD. Pharmacological inhibition of the cytokine induction inhibited the pathogenic subretinal inflammation. In the context of APOE-dependent subretinal inflammation in Cx3cr1(GFP/GFP) mice, the APOE4 allele led to diminished APOE and CCL2 levels and protected Cx3cr1(GFP/GFP) mice against harmful subretinal MP accumulation observed in Cx3cr1(GFP/GFP)TRE3 mice. Our study shows that pathogenic subretinal inflammation is APOE isoform-dependent and provides the rationale for the previously unexplained implication of the APOE2 isoform as a risk factor and the APOE4 isoform as a protective factor in AMD pathogenesis. SIGNIFICANCE STATEMENT: The understanding of how genetic predisposing factors, which play a major role in age-related macular degeneration (AMD), participate in its pathogenesis is an important clue to decipher the pathomechanism and develop efficient therapies. In this study, we used transgenic, targeted replacement mice that carry the three human APOE isoform-defining sequences at the mouse APOE chromosomal location and express the human APOE isoforms. Our study is the first to show how APOE2 provokes and APOE4 inhibits the cardinal AMD features, inflammation, degeneration, and exaggerated neovascularization. Our findings reflect the clinical association of the genetic predisposition that was recently confirmed in a major pooled analysis. They emphasize the role of APOE in inflammation and inflammation in AMD.

The Valeo stent: a pre-mounted, open-cell, large stent for use in small children with CHD.

OBJECTIVES: The aim of the present study was to determine the outcomes of using the Valeo stent (Bard Peripheral Vascular, Tempe, Arizona, United States of America) in small children with CHD. BACKGROUND: Stenting vascular stenoses is safe and effective in adults and older children with CHD but is limited in smaller children. The design of the Valeo stent addresses these limitations but has not been extensively described. METHODS: Bench testing was conducted to determine the maximum diameter of the stent, foreshortening, and side-cell diameter. A retrospective analysis of Valeo stents implanted between October, 2012 and October, 2014 was performed. Patient profile, pre-implant/post-implant catheterization data, and stent geometry were reviewed. RESULTS: Bench testing: medium and large Valeo stents can be dilated up to 13 mm and 20 mm diameters, respectively. Side-cells are dilatable up to 12 mm. Valeo stents are of low profile - delivered through 6- or 7-Fr sheaths - and show minimal foreshortening. Retrospective analysis: a total of 81 stents were implanted in 61 patients with CHD. The median weight was 15.3 kg, and the median age was 58.9 months. Stents were implanted in the pulmonary artery, systemic vein, aorta, and pulmonary vein. Overall, mean vessel diameters increased from 4.1 to 7.7 mm (121.7%). There was effective mean gradient reduction: 3.7-0.5 mmHg (63%) in the venous systems, 28.2-12.5 mmHg (63.7%) in the pulmonary arteries, and 17.4-4 mmHg (77.1%) in the aorta. The mean stent foreshortening was 2.5%, and the mean recoil was 5.9%. Side-cells that crossed other vessels were dilated in four cases, and stents were re-mounted onto different-sized balloons in seven cases. CONCLUSIONS: The features of the Valeo stent, such as low profile, large maximum diameter, open-cell design, minimal foreshortening, and recoil, make it suitable for treating vascular stenoses in small children with CHD.

Risk of congenital heart defects in the offspring of smoking mothers: a population-based study.

OBJECTIVES: To conduct a population-based study examining the occurrence of congenital heart defects (CHDs) in relation to maternal smoking during the first trimester of pregnancy. STUDY DESIGN: This retrospective case-control study used Washington State birth certificates from 1989 to 2011 and linked hospital discharge International Classification of Diseases, 9th revision, codes to identify singleton nonsyndromic CHD cases and determine maternal prenatal smoking status. We calculated ORs from multivariate logistic regression models to compare maternal first-trimester smoking status (any and daily number of cigarettes) among 14,128 cases, both overall and by phenotype, and 60,938 randomly selected controls frequency matched on birth year. RESULTS: Offspring of mothers reporting cigarette use in the first trimester of pregnancy were more likely to be born with a CHD (aOR 1.16 [1.08-1.24]) independent of demographic characteristics and other prenatal risk factors for CHDs. Maternal smoking was most strongly associated with pulmonary valve anomalies (aOR 1.48 [95% CI: 1.15-1.90]), pulmonary artery anomalies (aOR 1.71 [1.40-2.09]), and isolated atrial septal defects (aOR 1.22 [1.08-1.38]). The association between maternal smoking and CHDs was stronger with increasing number of daily cigarettes and among older (35+ years) mothers compared with younger mothers. CONCLUSIONS: We provide evidence that maternal smoking during pregnancy is a risk factor for select CHD phenotypes. Maternal smoking may account for 1.4% of all CHDs. New findings include a strong dose-dependence of the association and augmented risk in older mothers.

Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner.

Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low-density lipoprotein receptor (LDLR) has a high affinity for apoE, and is the only member of its receptor family to demonstrate an apoE isoform specific binding affinity (E4>E3>>E2). Evidence suggests that a functional interaction between apoE and LDLR influences the risk of CVD and AD. We hypothesize that the differential cognitive effects of the apoE isoforms are a direct result of their varying interactions with LDLR. To test this hypothesis, we have employed transgenic mice that express human apoE2, apoE3, or apoE4, and either human LDLR (hLDLR) or no LDLR (LDLR(-/-)). Our results show that plasma and brain apoE levels, cortical cholesterol, and spatial memory are all regulated by isoform-dependent interactions between apoE and LDLR. Conversely, both anxiety-like behavior and cued associative memory are strongly influenced by APOE genotype, but these processes appear to occur via an LDLR-independent mechanism. Both the lack of LDLR and the interaction between E4 and the LDLR were associated with significant impairments in the retention of long term spatial memory. Finally, levels of hippocampal apoE correlate with long term spatial memory retention in mice with human LDLR. In summary, we demonstrate that the apoE-LDLR interaction affects regional brain apoE levels, brain cholesterol, and cognitive function in an apoE isoform-dependent manner.

Blocking the interaction between apolipoprotein E and Aß reduces intraneuronal accumulation of Aß and inhibits synaptic degeneration.

Accumulation of ß-amyloid (Aß) in the brain is a key event in Alzheimer disease pathogenesis. Apolipoprotein (Apo) E is a lipid carrier protein secreted by astrocytes, which shows inherent affinity for Aß and has been implicated in the receptor-mediated Aß uptake by neurons. To characterize ApoE involvement in the intraneuronal Aß accumulation and to investigate whether blocking the ApoE/Aß interaction could reduce intraneuronal Aß buildup, we used a noncontact neuronal-astrocytic co-culture system, where synthetic Aß peptides were added into the media without or with cotreatment with Aß12-28P, which is a nontoxic peptide antagonist of ApoE/Aß binding. Compared with neurons cultured alone, intraneuronal Aß content was significantly increased in neurons co-cultured with wild-type but not with ApoE knockout (KO) astrocytes. Neurons co-cultured with astrocytes also showed impaired intraneuronal degradation of Aß, increased level of intraneuronal Aß oligomers, and marked down-regulation of several synaptic proteins. Aß12-28P treatment significantly reduced intraneuronal Aß accumulation, including Aß oligomer level, and inhibited loss of synaptic proteins. Furthermore, we showed significantly reduced intraneuronal Aß accumulation in APPSW/PS1dE9/ApoE KO mice compared with APPSW/PS1dE9/ApoE targeted replacement mice that expressed various human ApoE isoforms. Data from our co-culture and in vivo experiments indicate an essential role of ApoE in the mechanism of intraneuronal Aß accumulation and provide evidence that ApoE/Aß binding antagonists can effectively prevent this process.