Fluoropyrimidine Cardiotoxicity: Time for a Contemporaneous Appraisal

Introduction

Fluoropyrimidines (FPDs) are a fundamental component of many chemotherapy regimens. Cardiotoxic adverse events (AEs) such as angina, ischemia, arrhythmias, and cardiomyopathy associated with 5-fluorouracil (5-FU) and capecitabine (CAPE) have been sparingly described in studies, primarily through case reports. Data from the 1990s revealed an estimated incidence of 0.5% to 19%, with cardiovascular fatalities occurring in ≤28%. The current use of FPDs includes multiple dosing regimens, oral or intravenous delivery, and administration with additional cardiotoxic therapies. As such, it is imperative to better define the cardiotoxicity risk in the modern treatment era. We comprehensively evaluated the incidence, prevalence, and ascertainment of cardiovascular risk factors and disease within ECOG-ACRIN (Eastern Cooperative Group Cancer Research Group – American College of Radiology Imaging Network) Cancer Research Group clinical trials incorporating 5-FU and CAPE.

Distinct memory CD4+ T-cell subsets mediate immune recognition of Epstein Barr virus nuclear antigen 1 in healthy virus carriers

CD4+ T cells, specific for transforming latent infection with the Epstein Barr virus (EBV), consistently recognize the nuclear antigen 1 of EBV (EBNA1). EBNA1-specific effector CD4+ T cells are primarily T-helper 1 (TH1) polarized. Here we show that most healthy EBV carriers have such IFN-secreting EBNA1-specific CD4+ T cells at a frequency of 0.03% of circulating CD4+ T cells. In addition, healthy carriers have a large pool of CD4+ T cells that proliferated in response to EBNA1 and consisted of distinct memory-cell subsets. Despite continuous antigen presence due to persistent EBV infection, half of the proliferating EBNA1-specific CD4+ T cells belonged to the central-memory compartment (TCM). The remaining EBNA1-specific CD4+ T cells displayed an effector-memory phenotype (TEM), of which a minority rapidly secreted IFN upon stimulation with EBNA1. Based on chemokine receptor analysis, all EBNA1-specific TCM CD4+ T cells were TH1 committed. Our results suggest that protective immune control of chronic infections, like EBV, includes a substantial reservoir of TCM CD4+ TH1 precursors, which continuously fuels TH1-polarized effector cells.     

Seriously ill hospitalized patients’ perspectives on the benefits and harms of two models of hospital CPR discussions

Objective

To describe seriously ill patients’ perspectives on expert-endorsed approaches for hospital cardiopulmonary resuscitation (CPR) discussions.

Methods

We created two videos depicting a hospital doctor discussing CPR with a seriously ill patient. One depicted a values-based approach with a doctor's recommendation, and one an information-focused approach without a recommendation. During semi-structured interviews, 20 seriously ill hospitalized patients viewed and commented on both videos. We conducted a thematic analysis to describe benefits and harms of specific discussion components.

Results

Half of participants reported no preference between the videos; 35% preferred the information-focused, and 15% the values-based. Participants’ reactions to the discussion components varied. They identified both benefits and harms with components in both videos, though most felt comfortable with all components (range, 60–65%) except for the doctor's recommendation in the values-based video. Only 40% would feel comfortable receiving a recommendation, while 65% would feel comfortable with the doctor eliciting their CPR preference as in the information-focused video, p = 0.03.

Conclusion

Participants’ reactions to expert-endorsed discussion components varied. Most would feel uncomfortable receiving a doctor's recommendation about CPR.

Practice implications

Participants’ varied reactions suggest the need to tailor CPR discussions to individual patients. Many patients may find doctor's recommendations to be problematic.     

Digoxin Benefit Varies by Risk of Heart Failure Hospitalization: Applying the Tufts MC HF Risk Model

Background

Digoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization.

Abnormalities in 3-Dimensional Left Ventricular Mechanics With Anthracycline Chemotherapy Are Associated With Systolic and Diastolic Dysfunction

Objectives

The objective of this study was to evaluate the changes in three-dimensional (3D) speckle-tracking echocardiography–derived measures of mechanics and their associations with systolic and diastolic dysfunction after anthracyclines.

PPARγ Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission

PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction.     

FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice

Alcohol withdrawal is associated with hypothalamic–pituitary–adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a co-chaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.