Narrowing Down the Symptomatology of Isolated Vascular Rings in Children.

Vascular rings may cause respiratory or gastrointestinal symptoms due to compression of the trachea and/or esophagus. Advances in imaging have enabled early detection in asymptomatic patients posing new management dilemmas. Surgery is expected to relieve symptoms, although this has not been well studied. We sought to evaluate the presence and pattern of symptoms associated with vascular rings before surgical intervention and to detail symptom resolution after surgery. A 10-year retrospective review of patients diagnosed with an isolated vascular ring was performed between January 2010 and December 2019. 100 patients were identified; 35 double aortic arch (DAA) and 65 right aortic arch and left ligamentum arteriosum (RALL). 73 patients were symptomatic on presentation; 47 had respiratory, 5 had gastrointestinal, and 21 had both types of symptoms. Surgical repair was performed in 75 patients; 74 were symptomatic. Respiratory symptoms were more likely in patients with preoperative tracheal narrowing (p < 0.001). Moderate-severe respiratory symptoms led to surgery in RALL patients (OR 10.6, p = 0.0001). DAA patients were more likely to undergo surgery (p < 0.001) irrespective of symptom severity. At a median post-surgical follow-up of 4 months, there was a significant reduction in symptom burden (p < 0.001), except for asthma symptoms (p = 0.131). Symptom resolution was not dependent on the vascular ring anatomy (p = 0.331) or the age at operation (p = 0.158). Vascular rings are typically accompanied by respiratory symptoms and less commonly GI symptoms, both of which resolve in most patients after surgery. Those who present predominantly with asthma-like symptoms may not achieve resolution after surgery.

Cardiac surgical outcomes of patients with heterotaxy syndrome.

Objectives: The study objectives were to analyze the outcomes of pediatric patients with heterotaxy syndrome undergoing cardiovascular surgery and to determine the predictors of mortality. Methods: A retrospective analysis of 82 patients diagnosed with heterotaxy syndrome who underwent cardiovascular surgery between January 2008 and December 2017 was performed. Univariate and multivariable Cox regression analyses to determine risk factors for mortality and Kaplan-Meier analysis for survival were performed. Results: Patient mortality in the cohort was 34% (28/82), including 36% (20/55) for single ventricle palliation and 30% (8/27) for biventricular repair. At 5 years, the probability of survival did not differ between the groups by log-rank testing (P = .829). Multivariable analysis found extracorporeal membrane oxygenation support (hazard ratio, 10.4; 95% confidence interval, 4.3-25.4; P < .001), total anomalous pulmonary venous return (hazard ratio, 4.3; 95% confidence interval, 1.7-10.8; P = .002), and birth weight 2.5 kg or less (hazard ratio, 2.4; 95% confidence interval, 1.0-5.4; P = .041) to be independent risk factors for mortality in all-comers. Pulmonary vein stenosis was a univariate predictor of mortality among all patients with heterotaxy (hazard ratio, 3.0; 95% confidence interval, 1.4-6.4; P = .005) and in the subgroup of patients with single ventricles (hazard ratio, 4.0; 95% confidence interval, 1.7-9.7; P = .002). Overall survival was 66% (54/82) at a median follow-up time of 2.2 years (0.4-4.1) from the initial surgery. Conclusions: Outcomes of children with heterotaxy syndrome, irrespective of the operative pathway, remain suboptimal in the current era. Risk factors for mortality in this population include birth weight 2.5 kg or less, extracorporeal membrane oxygenation, pulmonary vein stenosis, and total anomalous pulmonary venous return, which may help to further optimize surgical decision making. Multiorgan system involvment is frequently encountered in these patients.

Hybrid strategy in neonates with ductal-dependent systemic circulation and multiple risk factors.

OBJECTIVE: The study objective was to analyze outcomes of the hybrid strategy for ductal-dependent systemic circulation consisting of bilateral pulmonary artery banding with or without ductal stenting followed by delayed Norwood-type palliation or comprehensive stage II operation in high-risk neonates. METHODS: A retrospective analysis was performed between December 2017 and March 2021. Thirty high-risk neonates underwent palliation with bilateral pulmonary artery banding: 11 with prostaglandin therapy and 19 with ductal stenting. Median (range) age and body weight of patients at hybrid stage I were 3 days (0-43) and 2.9 kg (1.1-4.2), respectively. Operative and interstage mortality, morbidity, and reintervention rates were assessed. RESULTS: Overall survival was 70% (21/30) at a median follow-up time of 9 months (range, 0-37) from hybrid stage I. Operative survival for hybrid stage I was 90% (27/30), of which 2 patients received palliative care, and there was 1 interstage death (4%, 1/27). After hybrid stage I, 37% of patients had a reintervention, and 3% (n = 1) used extracorporeal membrane oxygenation before the next stage of repair. Five patients are awaiting second-stage operation, and 9 patients are awaiting Fontan completion. CONCLUSIONS: High-risk neonates with hypoplastic left heart syndrome or its variants can be successfully palliated using the hybrid strategy and bridged to a delayed Norwood or comprehensive stage II operation with satisfactory survival. This operative approach is a promising alternative pathway for neonates deemed to be high risk due to multiple preoperative risk factors.

Macrophage IL-1ß promotes arteriogenesis by autocrine STAT3- and NF-κB-mediated transcription of pro-angiogenic VEGF-A.

Peripheral artery disease (PAD) leads to considerable morbidity, yet strategies for therapeutic angiogenesis fall short of being impactful. Inflammatory macrophage subsets play an important role in orchestrating post-developmental angiogenesis, but the underlying mechanisms are unclear. Here, we find that macrophage VEGF-A expression is dependent upon the potent inflammatory cytokine, IL-1ß. IL-1ß promotes pro-angiogenic VEGF-A165a isoform transcription via activation and promoter binding of STAT3 and NF-κB, as demonstrated by gene-deletion, gain-of-function, inhibition, and chromatin immunoprecipitation assays. Conversely, IL-1ß-deletion or inhibition of STAT3 or NF-κB increases anti-angiogenic VEGF-A165b isoform expression, indicating IL-1ß signaling may also direct splice variant selection. In an experimental PAD model of acute limb ischemia, macrophage IL-1ß expression is required for pro-angiogenic VEGF-A expression and for VEGF-A-induced blood flow recovery via angio- or arteriogenesis. Though further study is needed, macrophage IL-1ß-dependent transcription of VEGF-A via STAT3 and NF-κB may have potential to therapeutically promote angiogenesis in the setting of PAD.

Association Between Exogenous Nitric Oxide Given During Cardiopulmonary Bypass and the Incidence of Postoperative Kidney Injury in Children.

OBJECTIVE: To compare the incidence and severity of acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass and the administration of exogenous nitric oxide in children. DESIGN: A retrospective cohort study. SETTING: A single institution, university hospital. PARTICIPANTS: All children younger than 18 years of age who underwent surgery with cardiopulmonary bypass. INTERVENTIONS: Medical records of all eligible patients between January 4, 2017, and June 28, 2019, were reviewed. Patients were divided into two groups based on whether they received exogenous nitric oxide. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was a change in serum creatinine level, defined as the difference between the preoperative creatinine and peak postoperative creatinine. The secondary endpoint was the incidence and severity of postoperative AKI. A difference-in-difference method using fixed-effect multiple linear regression was carried out to compare the difference in maximum serum creatinine changes between the control and intervention groups. Five hundred ninety-one patients were included in the analysis: 298 (50.5%) in the control group and 293 (49.5%) in the intervention group. Control and intervention groups did not vary significantly in terms of baseline characteristics except for bypass time. After adjusting for all baseline variables, there was no statistically significant difference in the increase in serum creatinine between the control and the intervention groups (0.01 [95% CI: -0.03, 0.05], p = 0.545). CONCLUSIONS: This single-center, retrospective, cohort study found no change in the incidence and severity of postoperative AKI after the administration of nitric oxide into the cardiopulmonary bypass circuit in children.

Statins Disrupt Macrophage Rac1 Regulation Leading to Increased Atherosclerotic Plaque Calcification.

OBJECTIVE: Calcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1ß (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1ß mRNA, and increased Rac1-dependent IL-1ß protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1ß expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2). CONCLUSIONS: Statins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1ß signaling axis.

Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1ß Production.

OBJECTIVE: The calcium composition of atherosclerotic plaque is thought to be associated with increased risk for cardiovascular events, but whether plaque calcium itself is predictive of worsening clinical outcomes remains highly controversial. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. APPROACH AND RESULTS: Here, we identify Rac2 as a major inflammatory regulator of signaling that directs plaque osteogenesis. In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage interleukin-1ß (IL-1ß) expression, which in turn is a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs. Calcified coronary arteries from patients revealed decreased Rac2 expression but increased IL-1ß expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1ß levels. Moreover, we found that elevated IL-1ß was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden. CONCLUSIONS: Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1ß expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.

Chemokine-coupled ß2 integrin-induced macrophage Rac2-Myosin IIA interaction regulates VEGF-A mRNA stability and arteriogenesis.

Myeloid cells are important contributors to arteriogenesis, but their key molecular triggers and cellular effectors are largely unknown. We report, in inflammatory monocytes, that the combination of chemokine receptor (CCR2) and adhesion receptor (ß2 integrin) engagement leads to an interaction between activated Rac2 and Myosin 9 (Myh9), the heavy chain of Myosin IIA, resulting in augmented vascular endothelial growth factor A (VEGF-A) expression and induction of arteriogenesis. In human monocytes, CCL2 stimulation coupled to ICAM-1 adhesion led to rapid nuclear-to-cytosolic translocation of the RNA-binding protein HuR. This activation of HuR and its stabilization of VEGF-A mRNA were Rac2-dependent, and proteomic analysis for Rac2 interactors identified the 226 kD protein Myh9. The level of induced Rac2-Myh9 interaction strongly correlated with the degree of HuR translocation. CCL2-coupled ICAM-1 adhesion-driven HuR translocation and consequent VEGF-A mRNA stabilization were absent in Myh9(-/-) macrophages. Macrophage VEGF-A production, ischemic tissue VEGF-A levels, and flow recovery to hind limb ischemia were impaired in myeloid-specific Myh9(-/-) mice, despite preserved macrophage recruitment to the ischemic muscle. Micro-CT arteriography determined the impairment to be defective induced arteriogenesis, whereas developmental vasculogenesis was unaffected. These results place the macrophage at the center of ischemia-induced arteriogenesis, and they establish a novel role for Myosin IIA in signal transduction events modulating VEGF-A expression in tissue.