Candidate circulating biomarkers for the cardiovascular disease continuum

The early identification of susceptibility to adverse cardiovascular outcomes and risk stratification amongst asymptomatic individuals, as well as amongst those with overt disease continues to be one of the major priorities of clinically-orientated research in the field of atherothrombosis. Available data from epidemiological studies indicate that traditional risk factors do not fully explain the predisposition to cardiovascular disease, its dynamics in different population groups and treatment responses. The pressing need for the development and clinical implementation of new markers of atherothrombotic disease has fuelled rapidly expanding research into cardiac biomarkers. This review outlines the main principles of biomarker qualification that have entered clinical practice, as well as an overview of the development of targeted biomarkers across the cardiovascular "continuum". We discuss in detail the evidence from epidemiological and clinical studies advocating the potential clinical use of the most promising candidate plasma biomarkers (more specifically, C-reactive protein, coagulation and inflammatory mediators and natriuretic peptides). Such an application of biomarkers to aid clinical risk assessment would be important in our efforts to improve risk stratification of subjects at risk of cardiovascular events.     

Pharmacogenomics of metabolic effects of rosiglitazone

INTRODUCTION: Thiazolidinediones are increasingly used drugs for the treatment of Type 2 diabetes. The individual response to thiazolidinedione therapy, ranging from the variable degree of metabolic improvement to harmful side-effects, is empirical, yet the underlying mechanisms remain elusive. In order to assess the pharmacogenomic component of thiazolidinediones' metabolic action, we compared the effect of rosiglitazone in two genetically defined models of metabolic syndrome, polydactylous (PD) and BN.SHR4 inbred rat strains, with their insulin-sensitive, normolipidemic counterpart, the Brown Norway (BN) rat. MATERIALS & METHODS: 5-month-old male rats were fed a high-fat diet for 4 weeks, and the experimental groups received rosiglitazone (0.4 mg/100 g body weight) during the last 2 weeks of high-fat diet feeding. We assessed metabolic and morphometric profiles, oxidative stress parameters and gene expression in white adipose tissue. RESULTS: In many followed parameters, we observed genetic background-specific effects of rosiglitazone administration. The mass and the sensitivity of visceral adipose tissue to insulin-stimulated lipogenesis increased with rosiglitazone treatment only in PD, correlating with a PD-specific significant increase in expression of prostaglandin D2 synthase. The glucose tolerance was enhanced in all strains, although fasting plasma glucose was increased by rosiglitazone in BN and BN.SHR4. Among the markers of lipid peroxidation, we observed the rosiglitazone-driven increase of plasma-conjugated dienes only in BN.SHR4. The genes with genotype-specific expression change included ADAM metallopeptidase domain 7, aquaporin 9, carnitine palmitoyltransferase 1B, caveolin 1, catechol-O-methyl transferase, leptin and prostaglandin D2 synthase 2. CONCLUSION: Rosiglitazone's effects on lipid deposition and insulin sensitivity of peripheral tissues are largely dependent on the genetic background it acts upon.     

Influence of Plasma Cholesterol and Triglyceride Concentrations and Eritoran (E5564) Micelle Size on its Plasma Pharmacokinetics and Ex Vivo Activity Following Single Intravenous Bolus Dose Into Healthy Female Rabbits

Purpose Eritoran (E5564) is a glycophospholipid that acts as a toll-like receptor 4 (TLR4) antagonist that is being tested as a treatment for severe sepsis and septic shock. In the blood, eritoran binds to plasma lipoproteins altering its pharmacokinetic and pharmacodynamic (PD) effects in vivo. The purpose of this study was to determine the influence of changes in plasma cholesterol and triglyceride concentrations on the plasma pharmacokinetics and ex vivo activity of eritoran following single intravenous bolus dosing of eritoran to healthy female rabbits fed either a regular chow diet or a cholesterol-enriched diet. This was done with eritoran administered as stable micelle formulations of mean hydrodynamic diameters of 8 or 27 nm). Methods Female New Zealand White rabbits were fed a standard diet for 7 days and then randomly assigned either a regular chow diet [regular-diet (n = 9)] or a cholesterol-enriched diet [cholesterol-diet (n = 12)] for an additional 7 days. Following feeding of these diets a single intravenous bolus dose of eritoran (0.5 mg/kg) formulated into either “small micelles” (8 nm in diameter) or “large micelles” (27 nm in diameter) was administered to regular-fed and cholesterol-fed rabbits. Serial blood samples were obtained prior to eritoran administration and at the following times post injection: 0.083 (5 min), 1, 2, 4, 8, 10, 24, 48 and 72 h. Plasma was analyzed for eritoran concentrations using LC/MS/MS. Total plasma cholesterol (TC) and triglyceride (TG) levels were quantified using enzymatic kits. Plasma eritoran pharmacokinetic (PK) parameters were estimated by non-compartmental analysis using the WinNonlin nonlinear estimation program. To analyze PD activity, whole blood obtained at 0.083 (5 min), 2, 24, 48 and 72 h following eritoran administration was assessed for ex vivo activity by measuring the ability of 1 and 10 ng/ml LPS to elicit TNF-α release. Results Total plasma cholesterol and triglyceride levels were significantly higher in cholesterol-fed rabbits compared to the rabbits fed a regular chow diet. Diet had no effect on the estimated plasma PK parameters. However, PD activity of both small and large micelle eritoran as measured by an ex vivo challenge dose of 1 ng/ml LPS was reduced in blood of cholesterol-fed rabbits compared to normal-fed rabbits. Comparison of PK parameters for small and large micelles indicated that small micelles had increased AUC_{0–72 h}, decreased plasma clearance and increased initial concentration (measured at 5 min post administration) compared to the large micelle formulation. Consistent with this observation, eritoran formulated into small micelles had significantly greater ex vivo activity than large micelles and was independent of TC and TG concentrations. Conclusions These findings suggest that plasma pharmacokinetics and activity of eritoran maybe influenced by eritoran micelle size and plasma TC and TG concentrations.     

Genetic Variation in Human Vitamin C Transporter Genes in Common Complex Diseases

Adequate plasma, cellular, and tissue vitamin C concentrations are required for maintaining optimal health through suppression of oxidative stress and optimizing functions of certain enzymes that require vitamin C as a cofactor. Polymorphisms in the vitamin C transporter genes, compromising genes encoding sodium-dependent ascorbate transport proteins, and also genes encoding facilitative transporters of dehydroascorbic acid, are associated with plasma and tissue cellular ascorbate status and hence cellular redox balance. This review summarizes our current knowledge of the links between variations in vitamin C transporter genes and common chronic diseases. We conclude that emerging genetic knowledge has a good likelihood of defining future personalized dietary recommendations and interventions; however, further validations through biological studies as well as controlled dietary trials are required to identify predictive and actionable genetic biomarkers. We further advocate the need to consider genetic variation of vitamin C transporters in future clinical and epidemiologic studies on common complex diseases.     

COVID-19 Vaccine-Related Axillary and Cervical Lymphadenopathy in Patients with Current or Prior Breast Cancer and Other Malignancies: Cross-Sectional Imaging Findings on MRI,CT, and PET-CT

Breast radiologists are increasingly seeing patients with axillary adenopathy related to COVID-19 vaccination. Vaccination can cause levels I–III axillary as well as cervical lymphadenopathy. Appropriate management of vaccine-related adenopathy may vary depending on clinical context. In patients with current or past history of malignancy, vaccine-related adenopathy can be indistinguishable from nodal metastasis. This article presents imaging findings of oncology patients with adenopathy seen in the axilla or neck on cross-sectional imaging (breast MRI, CT, or PET-CT) after COVID-19 vaccination. Management approach and rationale is discussed, along with consideration on strategies to minimize false positives in vaccinated cancer patients. Time interval between vaccination and adenopathy seen on breast MRI, CT, or PET-CT is also reported.