Epigenetics and Heart Failure.

Epigenetics refers to changes in phenotypes without changes in genotypes. These changes take place in a number of ways, including via genomic DNA methylation, DNA interacting proteins, and microRNAs. The epigenome is the second dimension of the genome and it contains key information that is specific to every type of cell. Epigenetics is essential for many fundamental processes in biology, but its importance in the development and progression of heart failure, which is one of the major causes of morbidity and mortality worldwide, remains unclear. Our understanding of the underlying molecular mechanisms is incomplete. While epigenetics is one of the most innovative research areas in modern biology and medicine, compounds that directly target the epigenome, such as epidrugs, have not been well translated into therapies. This paper focuses on epigenetics in terms of genomic DNA methylation, such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications. These appear to be more dynamic than previously anticipated and may underlie a wide variety of conditions, including heart failure. We also outline possible new strategies for the development of novel therapies.

Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood.

BACKGROUND: Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. OBJECTIVES: To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. METHODS: The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N=80 women) and DNA methylation (N=93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. RESULTS: U-As concentrations, ranging 10-1251µg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. CONCLUSIONS: Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap.

The effects of arsenic exposure on blood pressure and early risk markers of cardiovascular disease: Evidence for population differences.

BACKGROUND: Exposure to inorganic arsenic has been identified as a risk factor for elevated blood pressure and cardiovascular disease. Our aim with this study was to elucidate effects of arsenic on blood pressure and early risk markers of cardiovascular disease in a population with efficient arsenic metabolism that can modify other arsenic-related health effects. METHODS: The study included 225 women in the northern Argentinean Andes. Exposure to arsenic was assessed by the sum of arsenic metabolite concentrations in urine. Blood pressure was measured in the supine position. Blood samples were collected for measurement of hemoglobin, homocysteine, triglycerides, apolipoproteins A and B, and cytokines in separated plasma. RESULTS: The median arsenic concentration in urine was 200 µg/L (range 22-545 µg/L). Unexpectedly, urinary arsenic concentrations were inversely associated with both systolic (p=0.081), and diastolic (p=0.002) blood pressure, and with the ratio of apolipoproteins B/A (p<0.001). There was no clear sign of increased inflammation, measured as cytokine concentrations, in relation to arsenic. Furthermore, urinary arsenic was associated with low hemoglobin concentrations (p<0.001). CONCLUSIONS: Our results show that arsenic exposure was not associated with elevated levels of early risk markers for cardiovascular disease in this population. This provides evidence that the effects of arsenic on risk of cardiovascular disease differ between populations, which needs to be taken into account in risk assessment.

Effect of zinc supplementation on immune and inflammatory responses in pediatric patients with shigellosis.

BACKGROUND: Several studies showed benefits of long-term zinc supplementation on the incidence, severity, and duration of diarrhea and on the incidence of respiratory infections. Prolonged zinc supplementation also improves cell-mediated immunity in severely malnourished children. OBJECTIVE: We studied the effect of short-term zinc supplementation on intrinsic and specific immune and inflammatory responses in moderately malnourished children with acute shigellosis. DESIGN: A randomized, double-blind, placebo-controlled trial was conducted in Shigella-infected children aged 12-59 mo. Elemental zinc (20 mg) and a multivitamin containing vitamins A and D, thiamine, riboflavin, nicotinamide, and calcium at twice the recommended dietary allowance were given daily for 2 wk to the zinc group (n = 28), whereas the multivitamin alone was given to the control group (n = 28). Standard antibiotic therapy was given to all patients. RESULTS: Serum zinc concentrations increased in both groups during convalescence; however, zinc supplementation showed a significant effect. The lymphocyte proliferation response in the zinc group increased relative to that in the control group (P = 0.002), but no significant effects were seen on concentrations of cytokines (interleukin 2 and interferon gamma) released from mitogen-stimulated mononuclear cells or on concentrations of cytokines (interleukin 2, interferon gamma, and interleukin 1beta) in feces. Among the antigen [lipopolysaccharide and invasion plasmid-encoded antigen (Ipa)]-specific antibodies, plasma Ipa-specific immunoglobulin G responses at day 30 were significantly higher in the zinc group than in the control group. However, the 2 groups did not differ significantly in the other antigen-specific responses in plasma and stool. CONCLUSION: A 14-d course of zinc supplementation during acute shigellosis increases the lymphocyte proliferation response and the Ipa-specific immunoglobulin G response.

Arsenic-associated oxidative stress, inflammation, and immune disruption in human placenta and cord blood.

BACKGROUND: Arsenic (As) exposure during pregnancy induces oxidative stress and increases the risk of fetal loss and low birth weight. OBJECTIVES: In this study we aimed to elucidate the effects of As exposure on immune markers in the placenta and cord blood, and the involvement of oxidative stress. METHODS: Pregnant women were enrolled around gestational week (GW) 8 in our longitudinal, population-based, mother-child cohort in Matlab, an area in rural Bangladesh with large variations in As concentrations in well water. Women (n = 130) delivering at local clinics were included in the present study. We collected maternal urine twice during pregnancy (GW8 and GW30) for measurements of As, and placenta and cord blood at delivery for assessment of immune and inflammatory markers. Placental markers were measured by immunohistochemistry, and cord blood cytokines by multiplex cytokine assay. RESULTS: In multivariable adjusted models, maternal urinary As (U-As) exposure both at GW8 and at GW30 was significantly positively associated with placental markers of 8-oxoguanine (8-oxoG) and interleukin-1ß (IL-1ß); U-As at GW8, with tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ); and U-As at GW30, with leptin; U-As at GW8 was inversely associated with CD3+ T cells in the placenta. Cord blood cytokines (IL-1ß, IL-8, IFNγ, TNFα) showed a U-shaped association with U-As at GW30. Placental 8-oxoG was significantly positively associated with placental proinflammatory cytokines. Multivariable adjusted analyses suggested that enhanced placental cytokine expression (TNFα and IFNγ) was primarily influenced by oxidative stress, whereas leptin expression appeared to be mostly mediated by As, and IL-1ß appeared to be influenced by both oxidative stress and As. CONCLUSION: As exposure during pregnancy appeared to enhance placental inflammatory responses (in part by increasing oxidative stress), reduce placental T cells, and alter cord blood cytokines. These findings suggest that effects of As on immune function may contribute to impaired fetal and infant health.

Influenza in outpatient ILI case-patients in national hospital-based surveillance, Bangladesh, 2007-2008.

BACKGROUND: Recent population-based estimates in a Dhaka low-income community suggest that influenza was prevalent among children. To explore the epidemiology and seasonality of influenza throughout the country and among all age groups, we established nationally representative hospital-based surveillance necessary to guide influenza prevention and control efforts. METHODOLOGY/PRINCIPAL FINDINGS: We conducted influenza-like illness and severe acute respiratory illness sentinel surveillance in 12 hospitals across Bangladesh during May 2007-December 2008. We collected specimens from 3,699 patients, 385 (10%) which were influenza positive by real time RT-PCR. Among the sample-positive patients, 192 (51%) were type A and 188 (49%) were type B. Hemagglutinin subtyping of type A viruses detected 137 (71%) A/H1 and 55 (29%) A/H3, but no A/H5 or other novel influenza strains. The frequency of influenza cases was highest among children aged under 5 years (44%), while the proportions of laboratory confirmed cases was highest among participants aged 11-15 (18%). We applied kriging, a geo-statistical technique, to explore the spatial and temporal spread of influenza and found that, during 2008, influenza was first identified in large port cities and then gradually spread to other parts of the country. We identified a distinct influenza peak during the rainy season (May-September). CONCLUSIONS/SIGNIFICANCE: Our surveillance data confirms that influenza is prevalent throughout Bangladesh, affecting a wide range of ages and causing considerable morbidity and hospital care. A unimodal influenza seasonality may allow Bangladesh to time annual influenza prevention messages and vaccination campaigns to reduce the national influenza burden. To scale-up such national interventions, we need to quantify the national rates of influenza and the economic burden associated with this disease through further studies.