Aging differentially modulates the Wnt pro-survival signalling pathways in vascular smooth muscle cells.

We previously reported pro-survival effects of Wnt3a and Wnt5a proteins in vascular smooth muscle cells (VSMCs). Wnt5a achieved this through induction of Wnt1-inducible signalling pathway protein-1 (WISP-1) consequent to ß-catenin/CREB-dependent, TCF-independent, signalling. However, we found that as atherosclerosis advances, although Wnt5a protein was increased, WISP-1 was reduced. We hypothesized this disconnect could be due to aging. In this study, we elucidate the mechanism underlying Wnt3a pro-survival signalling and demonstrate the differential effect of age on Wnt3a- and Wnt5a-mediated survival. We show Wnt3a protein was expressed in human atherosclerotic coronary arteries and co-located with macrophages and VSMCs. Meanwhile, Wnt3a stimulation of primary mouse VSMCs increased ß-catenin nuclear translocation and TCF, but not CREB, activation. Wnt3a increased mRNA expression of the pro-survival factor WISP-2 in a TCF-dependent manner. Functionally, ß-catenin/TCF inhibition or WISP-2 neutralization significantly impaired Wnt3a-mediated VSMC survival. WISP-2 was upregulated in human atherosclerosis and partly co-localized with Wnt3a. The pro-survival action of Wnt3a was effective in VSMCs from young (2 month) and old (18-20 month) mice, whereas Wnt5a-mediated rescue was impaired with age. Further investigation revealed that although Wnt5a induced ß-catenin nuclear translocation in VSMCs from both ages, CREB phosphorylation and WISP-1 upregulation did not occur in old VSMCs. Unlike Wnt5a, pro-survival Wnt3a signalling involves ß-catenin/TCF and WISP-2. While Wnt3a-mediated survival was unchanged with age, Wnt5a-mediated survival was lost due to impaired CREB activation and WISP-1 regulation. Greater understanding of the effect of age on Wnt signalling may identify targets to promote VSMC survival in elderly patients with atherosclerosis.

Corticosteroids for the treatment of Kawasaki disease in children.

BACKGROUND: Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in the developed world. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids. OBJECTIVES: To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. Corticosteroids may be given alone or in conjunction with other accepted KD treatments. Secondary objectives include the effect of steroids on mortality, the time taken for laboratory parameters to normalise, the duration of acute symptoms (such as fever), the long-term impact of steroid use and evaluating their safety in KD and their efficacy in relevant population subgroups. SEARCH METHODS: The Cochrane Vascular Information Specialist searched Cochrane Vascular's Specialised Register (25 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) in the Cochrane Library (searched 25 November 2016). Trial registries were also searched for details of ongoing or unpublished studies. SELECTION CRITERIA: We selected randomised trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroid and different durations of treatment. DATA COLLECTION AND ANALYSIS: MJS and GMC independently selected studies, assessed evidence quality and extracted data. This process was overseen by AJW. MAIN RESULTS: Seven trials consisting of 922 participants were included in this analysis. Trials ranged from 32 to 242 participants. On pooled analysis, corticosteroids reduced the subsequent occurrence of coronary artery abnormalities (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.18 to 0.46; 907 participants; 7 studies; I² = 55%) without resultant serious adverse events (no events, 737 participants) and mortality (no events, 915 participants). In addition, corticosteroids reduced the duration of fever (mean difference (MD) -1.65 days, 95% CI -3.31 to 0.00; 210 participants; 2 studies; I² = 88%), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD -2.80 days, 95% CI -4.38 to -1.22; 178 participants; 1 study) and length of hospital stay (MD -1.41 days, 95% CI -2.36 to -0.46; 39 participants; 1 study). No studies detailed outcomes beyond 24 weeks. Subgroup analysis showed some potential groups that may benefit more than others; however, further randomised controlled trials are required before this can be the basis for clinical action.Evidence quality was graded according to the GRADE system. Evidence was considered high quality for the incidence of serious adverse events, mortality and time for laboratory parameters to normalise. Evidence was considered moderate for the incidence of coronary artery abnormalities due to potential inconsistencies in data geography and patient benefits according to grouping. Evidence was moderate for duration of clinical symptoms (fever, rash) due to potential subjectivity in measurement. Evidence was moderate for length of hospital stay as only one study recorded this outcome. This means that we are reasonably confident that the true effect is close to that estimated in this work. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that use of steroids in the acute phase of KD can be associated with improved coronary artery abnormalities, shorter duration of hospital stay and a decreased duration of clinical symptoms. High-quality evidence shows reduced inflammatory marker levels. There were insufficient data available regarding incidence of adverse effects attributable to steroids, mortality and long-term (> 1 year) coronary morbidity. Certain groups, including those based in Asia, those with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use, especially with decreasing rates of heart problems, but more tests are needed to answer these questions. Evidence presented in this study suggests that treatment with a long course of steroids should be considered for all children diagnosed with KD until further studies are performed.

Clinical Predictors of Pacemaker Implantation in Patients with Syncope Receiving Implantable Loop Recorder with or without ECG Conduction Abnormalities.

BACKGROUND: Implantable loop recorders (ILR) allow prolonged cardiac rhythm monitoring and improved diagnostic yield in syncope patients. Predictive factors for pacemaker (PM) implantation in the ILR population with unexplained syncope have not been adequately investigated. In this single center, retrospective, observational study we investigated factors that predict PM implantation in this population. METHODS: We retrospectively analyzed our ILR database of patients aged over 18 years who underwent ILR implantation for unexplained syncope between January 2009 and June 2013. Patient case notes were examined for demographics, history, electrocardiogram (ECG) abnormalities, investigations, and events during follow-up. The primary end-point was the detection of a symptomatic or asymptomatic bradycardia requiring PM implantation. RESULTS: During a period of 4.5 years, 200 patients were implanted with ILR for unexplained syncope, of who n = 33 (16.5%) had clinically significant bradycardia requiring PM implantation. After multivariable analysis, history of injury secondary to syncope was found to be the strongest independent predictor for PM implantation (odds ratio [OR]:9.1; P < 0.001; 95% confidence interval [CI]: (3.26-26.81). Other significant predictors included female sex, PR interval > 200msec, and age >75 years. In patients without conduction abnormalities on the ECG, history of injury secondary to syncope was found to be the strongest independent predictor for PM implantation (OR: 8.16; P = 0.00027; 95% [CI]: (2.67-26.27). CONCLUSIONS: A history of injury secondary to syncope and female sex were independent predictive factors for bradycardia necessitating PM implantation in patients receiving an ILR for syncope with or without ECG conduction abnormalities.