Proteomics identifies lipocalin-2 in neonatal inflammation associated with cerebrovascular alteration in mice and preterm infants.

Staphylococcus (S.) epidermidis is the most common nosocomial coagulase-negative staphylococci infection in preterm infants. Clinical signs of infection are often unspecific and novel markers to complement diagnosis are needed. We investigated proteomic alterations in mouse brain after S. epidermidis infection and in preterm infant blood. We identified lipocalin-2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. We further proved that LCN2 protein expression was associated with endothelial cells but not astrocyte reactivity. By combining network analysis and differential expression approaches, we identified LCN2 linked to blood C-reactive protein levels in preterm infants born <28 weeks of gestation. Blood LCN2 levels were associated with similar alterations of cytokines and chemokines in both infected mice and human preterm infants with increased levels of C-reactive protein. This experimental and clinical study suggests that LCN2 may be a marker of preterm infection/inflammation associated with cerebrovascular changes and neuroinflammation.

Transcriptome network analysis links perinatal Staphylococcus epidermidis infection to microglia reprogramming in the immature hippocampus.

Staphylococcus epidermidis (S. epidermidis) is the most common nosocomial pathogen in preterm infants and associated with increased risk of cognitive delay, however, underlying mechanisms are unknown. We employed morphological, transcriptomic and physiological methods to extensively characterize microglia in the immature hippocampus following S. epidermidis infection. 3D morphological analysis revealed activation of microglia after S. epidermidis. Differential expression combined with network analysis identified NOD-receptor signaling and trans-endothelial leukocyte trafficking as major mechanisms in microglia. In support, active caspase-1 was increased in the hippocampus and using the LysM-eGFP knock-in transgenic mouse, we demonstrate infiltration of leukocytes to the brain together with disruption of the blood-brain barrier. Our findings identify activation of microglia inflammasome as a major mechanism underlying neuroinflammation following infection. The results demonstrate that neonatal S. epidermidis infection share analogies with S. aureus and neurological diseases, suggesting a previously unrecognized important role in neurodevelopmental disorders in preterm born children.

Association of N-Acetyl Asparagine with QTc in Diabetes: A Metabolomics Study.

Changes in the cardio-metabolomics profile and hormonal status have been associated with long QT syndrome, sudden cardiac death and increased mortality. The mechanisms underlying QTc duration are not fully understood. Therefore, an identification of novel markers that complement the diagnosis in these patients is needed. In the present study, we performed untargeted metabolomics on the sera of diabetic patients at a high risk of cardiovascular disease, followed up for 2.55 [2.34-2.88] years (NCT02431234), with the aim of identifying the metabolomic changes associated with QTc. We used independent weighted gene correlation network analysis (WGCNA) to explore the association between metabolites clusters and QTc at T1 (baseline) and T2 (follow up). The overlap of the highly correlated modules at T1 and T2 identified N-Acetyl asparagine as the only metabolite in common, which was involved with the urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine. This analysis was confirmed by applying mixed models, further highlighting its association with QTc. In the current study, we were able to identify a metabolite associated with QTc in diabetic patients at two chronological time points, suggesting a previously unrecognized potential role of N-Acetyl asparagine in diabetic patients suffering from long QTc.

Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation.

BACKGROUND AND PURPOSE: Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders with considerably increased risk in male infants born preterm and with neonatal infection. Here, we investigated the role of postnatal immune activation on hippocampal synaptopathology by targeting Reelin+ cells in mice with ASD-like behaviours. EXPERIMENTAL APPROACH: C57/Bl6 mouse pups of both sexes received lipopolysaccharide (LPS, 1 mg·kg-1 ) on postnatal day (P) 5. At P45, animal behaviour was examined by marble burying and sociability test, followed by ex vivo brain MRI diffusion kurtosis imaging (DKI). Hippocampal synaptogenesis, number and morphology of Reelin+ cells, and mRNA expression of trans-synaptic genes, including neurexin-3, neuroligin-1, and cell-adhesion molecule nectin-1, were analysed at P12 and P45. KEY RESULTS: Social withdrawal and increased stereotypic activities in males were related to increased mean diffusivity on MRI-DKI and overgrowth in hippocampus together with retention of long-thin immature synapses on apical dendrites, decreased volume and number of Reelin+ cells as well as reduced expression of trans-synaptic and cell-adhesion molecules. CONCLUSION AND IMPLICATIONS: The study provides new insights into sex-dependent mechanisms that may underlie ASD-like behaviour in males following postnatal immune activation. We identify GABAergic interneurons as core components of dysmaturation of excitatory synapses in the hippocampus following postnatal infection and provide cellular and molecular substrates for the MRI findings with translational value.

[Management of coronary perforations during angioplasty]. / Gestione delle perforazioni coronariche durante angioplastica coronarica.

Coronary perforation represents a terrible complication of percutaneous coronary intervention (PCI) which, if not promptly recognized and treated, can lead to catastrophic consequences for the patient. Hence, acquisition of the basic techniques for the treatment of coronary perforations is critical for the interventional cardiologist in order to safely perform PCIs. Although the incidence of coronary perforations remains low during PCI, it is possible to recognize some subgroups of patients and some types of coronary lesions, such as chronic coronary total occlusions, that are associated with increased risk. The treatments currently available depend on the type and site of coronary perforation, therefore timely recognition is of paramount importance in order to be able to quickly establish the most appropriate treatment.

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice.

Background:Staphylococcus epidermidis is the most common nosocomial infection and the predominant pathogen in late-onset sepsis in preterm infants. Infection and inflammation are linked to neurological and developmental sequelae and bacterial infections increase the vulnerability of the brain to hypoxia-ischemia (HI). We thus tested the hypothesis that S. epidermidis exacerbates HI neuropathology in neonatal mice. Methods: Male and female C57Bl/6 mice were injected intraperitoneally with sterile saline or 3.5 × 107 colony-forming units of S. epidermidis on postnatal day (PND) 4 and then subjected to HI on PND5 (24 h after injection) or PND9 (5 d after injection) by left carotid artery ligation and exposure to 10% O2. White and gray matter injury was assessed on PND14-16. In an additional group of animals, the plasma, brain, and liver were collected on PND5 or PND9 after infection to evaluate cytokine and chemokine profiles, C5a levels and C5 signaling. Results: HI induced 24 h after injection of S. epidermidis resulted in greater gray and white matter injury compared to saline injected controls in males, but not in females. Specifically, males demonstrated increased gray matter injury in the cortex and striatum, and white matter loss in the subcortical region, hippocampal fimbria and striatum. In contrast, there was no potentiation of brain injury when HI occurred 5 d after infection in either sex. In the plasma, S. epidermidis-injected mice demonstrated increased levels of pro- and anti-inflammatory cytokines and chemokines and a reduction of C5a at 24 h, but not 5 d after infection. Brain CCL2 levels were increased in both sexes 24 h after infection, but increased only in males at 5 d post infection. Conclusion: Ongoing S. epidermidis infection combined with neonatal HI increases the vulnerability of the developing brain in male but not in female mice. These sex-dependent effects were to a large extent independent of expression of systemic cytokines or brain CCL2 expression. Overall, we provide new insights into how systemic S. epidermidis infection affects the developing brain and show that the time interval between infection and HI is a critical sensitizing factor in males.

Sex Differences in Long-Term Outcomes in Patients With Deferred Revascularization Following Fractional Flow Reserve Assessment: International Collaboration Registry of Comprehensive Physiologic Evaluation.

Background Sex-specific differences may influence prognosis after deferred revascularization following fractional flow reserve (FFR) measurement. This study sought to investigate the sex differences in long-term prognosis of patients with deferred revascularization following FFR assessment. Methods and Results A total of 879 patients (879 vessels) with deferred revascularization with FFR >0.75 who underwent FFR and coronary flow reserve measurements were enrolled from 3 countries (Korea, Japan, and Spain). Long-term outcomes were assessed in 649 men and 230 women by the patient-oriented composite outcome (POCO, a composite of any death, any myocardial infarction, and any revascularization). We applied inverse-probability weighting based on propensity scores to account for differences at baseline between women and men (age, hyperlipidemia, diabetes mellitus, diameter stenosis, lesion length, multivessel disease, FFR, coronary flow reserve. The median follow-up duration was 1855 days (745-1855 days). Median FFR values were 0.88 (0.83-0.93) in men and 0.89 (0.85-0.94) in women, respectively. The occurrences of POCO were significantly high in men compared with that in women (10.5% versus 4.2%, P=0.007). Kaplan-Meier analysis revealed that women had a significantly lower risk of POCO (χ2=7.2, P=0.007). Multivariate COX proportional hazards regression analysis revealed that age, male, diabetes mellitus, diameter stenosis, lesion length, and coronary flow reserve were independent predictors of POCO. After applying IPW, the hazard ratio of males for POCO was 2.07 (95% CI, 1.07-4.04, P=0.032). Conclusions This large multinational study reveals that long-term outcome differs between women and men in favor of women after FFR-guided revascularization deferral. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT02186093.

Optical coherence tomography evaluation of the absorb bioresorbable scaffold performance for overlap versus non-overlap segments in patients with coronary chronic total occlusion: insight from the GHOST-CTO registry.

The Absorb bioresorbable vascular scaffold (BVS) promised to avoid some of the disadvantages of its metal predecessors. Even though it has been taken off the market, limited data is available about its use in coronary chronic total occlusion (CTO) and its performance in overlap segments, which would be of special research interest due to its large thickness. This data is still pertinent since the platform of bioresorbable devices has not been abandoned, with several companies working on it. We aimed to compare healing and performance between overlap (OL) and non-overlap regions (NOL) of CTO lesions treated with BVS, using optical coherence tomography (OCT). Fourteen patients with overlapping BVS were included from the GHOST-CTO registry, resulting in 25 OL and 38 NOL regions. OCT based parameters were compared between OL and NOL groups at baseline (post-implantation) and 12-month follow-up. The mean age was 61.7 ± 7.2 years and 12 (86%) were males. Twelve (86%) patients underwent PCI for stable coronary artery disease and 2 (14%) had unstable angina. At 12-month follow-up, mean lumen area decreased in both NOL and OL regions, but the decrease was significantly larger in the OL region (NOL - 0.7 ± 1.33 vs. OL - 2.4 ± 1.54 mm2; p = 0.002). Mean scaffold area increased in both regions, but increased significantly more in NOL ( + 1.1 ± 1.54 vs. + 0.4 ± 1.16 mm2; p = 0.016). The percent of uncovered struts was lower in the OL group (5.0 ± 6.6% vs. 3.75 ± 8.7%, p = 0.043), whereas the percentage of malapposed struts was similar (0.3 ± 0.5% vs. 0.7 ± 2.3%, p = 0.441). Neointimal hyperplasia (NIH) was more pronounced in the OL region (0.13 ± 0.04 vs. 0.24 ± 0.10 mm2, p = 0.001). The OL and NOL segments showed comparable healing in terms of coverage and malapposition. However, NIH was more prominent in OL region. The long-term clinical implications of these findings needs further evaluation. The present study provides important insights for future development of BVS technology.

Recanalization of Chronic Total Occlusions in Patients With vs Without Chronic Kidney Disease: The Impact of Contrast-Induced Acute Kidney Injury.

BACKGROUND: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is associated with high contrast volumes, which can be particularly deleterious in patients with chronic kidney disease (CKD). We aimed to study the outcomes of CTO PCI in subjects with vs without CKD, and the impact of contrast-induced acute kidney injury (CI-AKI). METHODS: This multicentre registry included patients who underwent CTO PCI at 5 centres. CI-AKI was defined as an increase in serum creatinine ≥0.3 mg/dL or ≥50% from baseline within 72 hours. Study endpoints were CI-AKI, and all-cause death and target-lesion failure (TLF: cardiac death, target-vessel myocardial infarction, or target-lesion revascularization) on follow-up. RESULTS: Study population included 1092 patients (CKD n = 214, no CKD n = 878). Patients with CKD had more comorbidities and adverse angiographic features, compared with subjects without CKD. Patients with CKD experienced lower technical (79% vs 87%, P = 0.001) and procedural (79% vs 86%, P = 0.008) success rates. CI-AKI developed in 9.1% (CKD 15.0% vs no CKD 7.8%, P = 0.001). Rates of in-hospital need for dialysis were 0.5% vs 0%, respectively (P = 0.03). Patients with CKD had higher 24-month rates of all-cause death (11.2% vs 2.7%, P < 0.001) and new need for dialysis (1.1% vs 0.1%, P = 0.03), but similar TLF rates (12.4% vs 10.5%, P = 0.47). CI-AKI was not an independent predictor of all-cause death or TLF. CONCLUSIONS: CTO PCI in patients with CKD is associated with lower success rates and higher incidence of CI-AKI. The need for dialysis both in-hospital and on follow-up is infrequent. Although patients with CKD suffer higher rates of all-cause death, TLF rates are similar regardless of CKD status.

Impact of Incomplete Revascularization on Long-Term Outcomes Following Chronic Total Occlusion Percutaneous Coronary Intervention.

We aimed to evaluate the impact of incomplete revascularization (ICR) on long-term outcomes of patients undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Consecutive patients undergoing CTO PCI at 4 centers were included. Baseline SYNTAX score (bSS: low [≤ 22], intermediate [>22 and <33], high [≥33]), residual SYNTAX score (rSS: 0, >0 and ≤8, >8), and SYNTAX revascularization index (SRI: 100 × (bSS-rSS)/bSS: 100%, 50% to 99%, <50%) were calculated. The primary end point was major adverse cardiac events (MACEs; cardiac death, any myocardial infarction, any revascularization) on follow-up. Multivariable Cox regression analysis was conducted to identify predictors of MACEs. Overall, 686 patients were included (low bSS: n = 437; intermediate bSS: n = 187; high bSS: n = 62). Occlusion complexity, crossing strategies, and procedural success rates were similar across groups. The degree of ICR increased with higher bSS categories (rSS was 2.5 ± 4.7 in low vs 6.2 ± 9.3 in intermediate vs 9.1 ± 12.2 in high bSS, p <0.001). The SRI followed a similar pattern. Median follow-up was 781 (369 to 1,217) days. Three-year MACE rates increased with higher bSS and rSS, and decreasing SRI categories (bSS: low 19.4% vs intermediate 25.9% vs high 33.3%, p = 0.02), which was driven by a higher incidence of repeat revascularization. Compared with an rSS = 0, both an rSS >0 and ≤8 (hazard ratio 2.06, p = 0.004) and an rSS >8 (hazard ratio 3.19, p <0.001) were independent predictors of MACEs. Similar findings were observed when the SRI was entered in a separate model. In conclusion, even a mild degree of ICR is associated with a higher incidence of MACEs on long-term follow-up after CTO PCI.

Long-Term Outcomes of Percutaneous Coronary Intervention for Chronic Total Occlusion in Patients Who Have Undergone Coronary Artery Bypass Grafting vs Those Who Have Not.

BACKGROUND: We aimed to investigate the procedural and long-term outcomes of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) in patients who had undergone previous coronary artery bypass grafting (CABG) vs those who had not, and to evaluate the role of the Registry of CrossBoss and Hybrid procedures in France, the Netherlands, Belgium, and United Kingdom (RECHARGE) score in predicting acute and long-term outcomes. METHODS: We compiled a multicentre registry of consecutive patients undergoing CTO PCI at 7 centres between January 2009 and April 2017. The primary end point was target-vessel failure (TVF), a composite of cardiac death, target-vessel myocardial infarction, and target-vessel revascularization on follow-up. RESULTS: Overall, 2058 patients were included (patients who underwent CABG, n = 401; CABG-naïve patients, n = 1657). Patients who had undergone CABG were older and had a higher prevalence of comorbidities and higher occlusion complexity (RECHARGE score, 3.6 ± 1.3 vs 1.8 ± 1.2; P < 0.001). Antegrade dissection/re-entry techniques and the retrograde approach were used more frequently in patients who had undergone CABG. Procedural metrics were worse, and technical (82% vs 88%; P = 0.001) and procedural (81% vs 87%; P = 0.001) success was lower in patients who had undergone CABG. They also experienced a higher rate of major complications (3.7% vs 1.5%; P = 0.004). The RECHARGE score was inversely associated with technical success (P < 0.001). Median follow-up was 377 days (interquartile range, 277-766 days). The 24-month TVF rate was higher in patients who had undergone CABG than in CABG-naïve patients (16.1% vs 9.0%; P < 0.001). On multivariable analysis, the RECHARGE score (hazard ratio, 1.61; P < 0.001) remained an independent predictor of TVF, together with longer total stent length and not using a drug-eluting stent. CONCLUSIONS: Compared with CABG-naïve patients, CTO PCI in patients who had undergone CABG shows higher procedural complexity, worse success rates, and higher adjusted risk of TVF on follow-up.

Outcomes of a novel thin-strut bioresorbable-polymer sirolimus-eluting stent in patients with chronic total occlusions: A multicenter registry.

BACKGROUND: We aimed to evaluate the mid-term outcomes of a novel thin-strut bioresorbable-polymer sirolimus-eluting stent (BP-SES) in chronic total occlusion (CTO) percutaneous coronary intervention (PCI), as compared with durable-polymer everolimus-eluting stents (EES). METHODS: We compiled a multicenter registry of patients undergoing CTO recanalization followed by BP-SES or EES implantation. The primary endpoint was the incidence of target-lesion failure (TLF, a composite of cardiac death, target-vessel myocardial infarction, and target-lesion revascularization) at one year. Propensity score matching (PSM) was used to adjust for case mix. RESULTS: Overall, 413 patients were included (BP-SES n = 242, EES n = 171). PSM resulted in 131 matched pairs, which represented the subject of the main analysis. Antegrade wire escalation was the most successful crossing technique (66% vs. 63%, p = 0.98) in both the BP-SES and EES groups, respectively. Procedural success rates were similar between groups (BP-SES 96% vs. EES 93%, p = 0.24). At one-year follow-up, there were no differences in the primary endpoint of TLF (5.7% vs. 8.3%, p = 0.44), and in cardiac death (0.9% vs. 2.8%, p = 0.32), target-vessel myocardial infarction (0.9% vs 1.9%, p = 0.57), target-lesion revascularization (3.7% vs 3.7%, p = 0.99), or stent thrombosis (0.9% vs. 1.9%, p = 0.57), in BP-SES vs. EES, respectively. CONCLUSIONS: Patients undergoing CTO PCI with BP-SES suffer a low rate of TLF at one-year follow-up, which is similar to that of subjects treated with durable-polymer EES.

Severe Kawasaki disease in a 3-month-old patient: a case report.

BACKGROUND: Kawasaki disease is a multi-system vasculitis which usually occurs in children under 5 years of age. In infants under three months of age, it is very rare and usually associated with a high incidence of incomplete or atypical forms, often unresponsive to treatment. This condition increases the risk of cardiovascular complications such as coronary artery aneurysms. CASE PRESENTATION: We describe a 3-month-old infant who developed early and severe aneurysms in three coronary arteries despite a timely administration of intravenous immunoglobulins, followed by three days of intravenous methylprednisolone. CONCLUSION: This case report underlines that the development of coronary artery aneurysm correlates with a delayed diagnosis and treatment, incomplete or atypical forms of the disease, and additionally the severity of clinical presentation, especially in cases of very young infants below 3 months of age. Our case is notable because of the very young age of the patient, the severity of clinical presentation with an early development of coronary artery aneurysms and the unresponsiveness to the therapy.