Tumor biomarkers:association with heart failure outcomes

Background: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. Objectives: To explore the association between tumor biomarkers and HF outcomes. Methods: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumor biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1, and AFP. Results: During a median follow-up of 21 months, 555 (27%) patients reached the primary endpoint of all-cause mortality. CA125, CYFRA 21-1, CEA, and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P<0.001, P for trend <0.001), and were respectively associated with a hazard ratio of 1.17 (95% CI 1.12 – 1.23; P<0.0001), 1.45 (95% CI 1.30 – 1.61; P<0.0001), 1.19 (95% CI 1.09 – 1.30; P =0.006), and 1.10 (95% CI 1.05 – 1.16; P<0.001)for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, hemoglobin, and beta-blocker). All tumor biomarkers (except AFP) had significant associations with secondary endpoints (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality, and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a non-inferior AUC compared to NT-proBNP (0.68) for all-cause mortality (P =0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC =0.71) improved the predictive value of the model for all-cause mortality (P =0.0002 compared to NT-proBNP). Conclusions: Several established tumor biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumor biomarkers are also dysregulated in HF

The Effect of Aggressive Versus Conventional Lipid-lowering Therapy on Markers of Inflammatory and Oxidative Stress

Purpose Recent trial results are in favor of aggressive lipid lowering using high dose statins in patients needing secondary prevention. It is unclear whether these effects are solely due to more extensive lipid lowering or the result of the potentially anti-inflammatory properties of statins. We aimed to determine whether aggressive compared with conventional statin therapy is more effective in reducing systemic markers of inflammation and oxidative stress. Materials and methods This was a multi-centre, double-blind, placebo-controlled trial. Patients with previous cardiovascular disease, who did not achieve low density lipoprotein (LDL) cholesterol levels <2.6 mmol/l on conventional statin therapy (simvastatin 40 mg) were randomized to continue with simvastatin 40 mg or to receive atorvastatin 40 mg for 8 weeks and thereafter atorvastatin 80 mg for the final 8 weeks (aggressive treatment). Lipids, C-reactive protein, soluble cellular adhesion molecules, neopterin, von Willebrand Factor, and antibodies against oxidized LDL were measured at baseline and after 16 weeks. Results Lipid levels decreased significantly in the aggressive treatment group (LDL-C reduction 20.8%; P <0.001), whereas a slight increase was observed in the conventional group (LDL-C increase 3.7%; P = 0.037). A significant reduction in antibodies against oxidized LDL was seen in the aggressive (13.4%; P <0.001) and the conventional (26.8%; P <0.001) group, but there was no difference between groups (P = 0.25). Furthermore, no significant differences in change in other biomarkers was observed between both groups. Conclusions This study does not support the hypothesis that a more profound reduction in inflammatory and oxidative stress contributes to the benefits of aggressive statin therapy

Effects of eight neuropsychiatric copy number variants on human brain structure

peer reviewedMany copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions. © 2021, The Author(s)

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Serial right ventricular endomyocardial biopsy in rapid-onset severe heart failure due to giant cell myocarditis

Giant cell myocarditis (GCM) is a serious condition that warrants immediate diagnosis and treatment. It often presents as rapidly progressive heart failure and/or malignant ventricular arrhythmias. Here, we describe a 34-year-old patient with myasthenia gravis who presented with GCM 2 weeks after resection of a thymoma. A cardiac biopsy confirming the diagnosis was done within 3 days after admission. After institution of an aggressive immunosuppressive drug regimen, implantation of an implantable cardioverter defibrillator, and intensive cardiac rehabilitation, the patient recovered dramatically. In control biopsies after 4 weeks and 6 months, no more giant cells were found. We conclude that, in the case of nonischemic acute heart failure in young patients, a biopsy should be performed as soon as possible to prevent an unfavourable outcome of this often fatal disease. (c) 2006 Elsevier Inc. All rights reserved

Follow-up care by a genetic counsellor for relatives at risk for cardiomyopathies is cost-saving and well-appreciated: a randomised comparison

Increasing numbers of patient relatives at risk of developing dilated or hypertrophic cardiomyopathy (DCM/HCM) are being identified and followed up by cardiologists according to the ACC/ESC guidelines. However, given limited healthcare resources, good-quality low-cost alternative approaches are needed. Therefore, we have compared conventional follow-up by a cardiologist with that provided at a cardiogenetic clinic (CGC) led by a genetic counsellor. Phenotype-negative first-degree relatives at risk for DCM/HCM were randomly assigned to see either a cardiologist or to attend a CGC. Uptake and resource use were recorded. For 189 participants, we evaluated quality of care experienced, patient satisfaction and perceived personal control (PPC) using validated questionnaires and estimated the average cost difference of these two modes of care. Maximum patient satisfaction scores were achieved more frequently at the CGC (86% vs 45%, P <0.01). In terms of follow-up care provided, the genetic counsellor did not perform worse than the cardiologist (95% vs 59%, P <0.01). The genetic counsellor more often enquired about the relative-at risk's health (100% vs 65%, P <0.01) and family health (97% vs 33%, P <0.01), measured blood pressure (98% vs 29%, P <0.01) and gave disease-specific information (77% vs 52%, P <0.01). Although PPC scores were equal in both groups, the average cost per patient of CGC follow-up was 25% lower. Follow-up of phenotype-negative relatives at risk for DCM/HCM at a CGC led to greater patient satisfaction and is well-appreciated at lower cost. CGC care is a good alternative to conventional cardiological follow-up for this growing group of patient

Skin autofluorescence is elevated in patients with stable coronary artery disease and is associated with serum levels of neopterin and the soluble receptor for advanced glycation end products

Aims: To investigate whether skin autofluorescence (AF), a non-invasive marker for advanced glycation end products (AGEs), is elevated in stable coronary artery disease (sCAD) and to investigate its relationship with serum levels of the soluble receptor for AGEs (sRAGE), neopterin and C-reactive protein (CRP). Methods and results: Skin AF and serum levels of sRAGE, neopterin and CRP were assessed in 63 sCAD patients (mean age: 64.7 +/- 10.5 years), comprising 78% males, 19% subjects with diabetes, and 22% current smokers and in 33 (mean age: 63.4 +/- 10.0 years) healthy non-diabetic and non-smoking age and gender matched controls. Skin AF was significantly increased in sCAD compared with controls, irrespective of diabetes, current smoking and renal function. Levels of sRAGE (standardized beta: 0.43 (explaining 17% of variance in skin AF); P <0.001), neopterin (beta: 0.36 (11%); P = 0.003) and glucose (beta: 0.29 (8%); P = 0.0011) as well as current smoking (beta: 0.26 (6%); P = 0.024) were independently associated with skin AF (R(2) 0.42), whereas the association of gender, former smoking, body mass index, CRP, lipids, creatinine clearance and pulse pressure with skin AF was not significant in this model. Conclusion: These data demonstrate that skin AF is elevated in sCAD and is related to sRAGE and neopterin, making it an easily applicable tool to improve our understanding of inflammatory and oxidative stress in cardiovascular disease. (C) 2007 Elsevier Ireland Ltd. All rights reserved

Atherosclerotic plaque characteristics are not associated with future cardiovascular events in patients undergoing iliofemoral endarterectomy

Background: Plaque characteristics such as intraplaque hemorrhage (IPH) have been associated with secondary cardiovascular events (CVE) in patients undergoing carotid endarterectomy. In addition, carotid plaques containing macrophage infiltration or a large lipid core size were associated with less restenosis. It is currently unknown whether iliofemoral plaque histopathologic characteristics are predictive for secondary CVE in patients with peripheral arterial disease undergoing iliofemoral endarterectomy. The aim of this study was to examine the association between iliofemoral atherosclerotic plaque characteristics and secondary CVE in patients undergoing iliofemoral endarterectomy. Methods: There were 497 patients with iliofemoral atherosclerotic disease who underwent primary endarterectomy of the iliac or femoral artery from 2002 to 2013 included. All specimen were uptaken in the Athero Express biobank and 7 histologic plaque characteristics were analyzed: calcification, collagen, fat content, IPH, macrophages, smooth muscle cells, and vessel density. The composite CVE consisted of myocardial infarction, cerebrovascular accident, peripheral (re-)interventions, and cardiovascular death. Multivariate Cox regression models were used to examine the association between plaque and the composite end point during a follow-up period of 3 years. Results: Of the 497 patients, 225 (46.4%) experienced a composite CVE within 3 years after the initial surgery. Calcified plaques were univariably associated with composite CVE (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.00-1.73; P =.049). After correction for confounders, multivariable analyses showed no association between calcified plaques and composite CVE (HR, 1.13; 95% CI, 0.85-1.50; P =.413). IPH was not predictive of secondary CVE (HR, 1.02; 95% CI, 0.79-1.33; P =.867). Conclusions: In this cohort of patients with peripheral arterial disease undergoing iliofemoral endarterectomy, investigated atherosclerotic plaque characteristics were not independently associated with secondary CVE during follow-up