Association between low selenoprotein P concentrations and anaemia in hospitalized heart failure patients.

AIMS: Heart failure (HF) patients with anaemia tend to have a worse outcome, with increased hospitalization rates, decreased exercise tolerance, and higher mortality compared to those without anaemia. Limited research exists on the association between selenium deficiency and anaemia specifically in HF patients, despite previous findings of a correlation in different populations. The BIOSTAT-CHF study demonstrated that higher selenium levels in HF patients were associated to a lower risk of anaemia and iron deficiency. This study investigates the relationship between selenoprotein P (SELENOP) concentrations, a major contributor and functional biomarker of selenium transport, and anaemia, Hb levels, and iron status in hospitalized HF patients. METHODS AND RESULTS: SELENOP was analysed in 320 hospitalized HF subjects, with complete data available for 310 subjects. The relationships between continuous SELENOP concentrations and 1) Hb concentrations, 2) anaemia (Hb < 115 g/L (women), <130 g/L (men)), and 3) iron status (as measured by transferrin receptor 1 (TfR1) which increases in iron deficiency) were evaluated using multivariable logistic and linear regression models. Additionally, SELENOP concentrations in the lowest quartile were related to anaemia, haemoglobin, and iron state in multivariable logistic and linear models. The mean age of the study population was 75.0 ± 11.6 years, and 30% were women. Anaemia was present in 133 subjects (42.9%). SELENOP concentrations were positively correlated with haemoglobin concentrations (0.238; P < 0.001) and negatively with TfR1 concentrations (-0.238, P < 0.001). In multivariable regression models, higher SELENOP concentrations were associated with higher Hb concentrations (B = 3.23; P = 0.002) and lower TfR1 concentrations (B = -0.20; P < 0.001). Furthermore, SELENOP deficiency was associated with lower Hb concentrations (B = -7.64: P = 0.001), higher TfR1 concentrations (B = 0.31; P = 0.003), and higher odds of anaemia in HF patients (odds ratio 2.17; 95% confidence interval 1.23-3.82; P = 0.008). CONCLUSIONS: In hospitalized heart failure patients, lower concentrations of SELENOP were associated with higher prevalence of anaemia.

Selenoprotein P deficiency is associated with higher risk of incident heart failure.

INTRODUCTION: Selenium deficiency has been associated with mortality, cardiovascular disease and worsened prognosis in heart failure (HF). In a recent population-based study, high selenium levels were shown to be associated with reduced mortality and reduced incidence of HF, but only in non-smokers. Here, we aimed to examine if selenoprotein P (SELENOP), a main selenium carrier protein, is associated with incident HF. MATERIALS AND METHODS: SELENOP concentrations were measured in plasma of 5060 randomly selected subjects from the population-based prospective cohort "Malmö Preventive Project" (n = 18240) using an ELISA approach. Exclusion of subjects with prevalent HF (n = 230) and subjects with missing data on co-variates included in the regression analysis (n = 27) resulted in complete data for 4803 subjects (29.1% women, mean age 69.6 ± 6.2 years, 19.7% smokers). Cox regression models adjusted for traditional risk factors were used to analyse SELENOP's association with incident HF. Further, subjects within the quintile with the lowest SELENOP concentrations were compared to subjects in the remaining quintiles. RESULTS: Each 1 standard deviation increment in SELENOP levels was associated with lower risk of incident HF (n = 436) during a median follow-up period of 14.7 years (hazard ratio (HR) 0.90; CI95% 0.82-0.99; p = 0.043). Further analyses showed that subjects in the lowest SELENOP quintile were at the highest risk of incident HF when compared to quintiles 2-5 (HR 1.52; CI95% 1.21-1.89; p = 2.5 × 10-4). CONCLUSION: Low selenoprotein P levels are associated with a higher risk of incident HF in a general population. Further studies are warranted.

Selenoprotein-P Deficiency Predicts Cardiovascular Disease and Death.

Selenoprotein-P (SELENOP) is the main carrier of selenium to target organs and reduces tissue oxidative stress both directly and by delivering selenium to protective selenoproteins. We tested if the plasma concentration of SELENOP predicts cardiovascular morbidity and mortality in the primary preventive setting. SELENOP was measured from the baseline exam in 2002-2006 of the Malmö Preventive Project, a population-based prospective cohort study, using a validated ELISA. Quintiles of SELENOP concentration were related to the risk of all-cause mortality, cardiovascular mortality, and a first cardiovascular event in 4366 subjects during a median (interquartile range) follow-up time of 9.3 (8.3-11) years using Cox proportional Hazards Model adjusting for cardiovascular risk factors. Compared to subjects in the lowest quintile of SELENOP, the risk of all three endpoints was significantly lower in quintiles 2-5. The risk (multivariate adjusted hazard ratio, 95% CI) decreased gradually with the lowest risk in quintile 4 for all-cause mortality (0.57, 0.48-0.69) (p < 0.001), cardiovascular mortality (0.52, 0.37-0.72) (p < 0.001), and first cardiovascular event (0.56, 0.44-0.71) (p < 0.001). The lower risk of a first cardiovascular event in quintiles 2-5 as compared to quintile 1 was significant for both coronary artery disease and stroke. We conclude that the 20% with lowest SELENOP concentrations in a North European population without history of cardiovascular disease have markedly increased risk of cardiovascular morbidity and mortality, and preventive selenium supplementation studies stratified for these subjects are warranted.

Targeting tachykinin receptors in neuroblastoma.

Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma.

Modulation of circulating vasoactive peptides and extracellular matrix proteins are two novel mechanisms in the cardioprotective action of acarbose.

BACKGROUND: Acarbose, an alpha-glucosidase inhibitor, unexpectedly reduced the incidence of hypertension and cardiovascular endpoints in the STOP-NIDDM study. Based on the growing evidence of a link between vasoregulatory peptides and metabolic traits, we hypothesized that changes of the Glycemic Index by acarbose may modulate vasoregulatory peptide levels via regulation of postprandial metabolism. METHODS: Subjects with type 2 diabetes and with metabolic syndrome were treated with acarbose (12 weeks, 300mg/d) in a double-blind, placebo-controlled, cross-over intervention. Changes in fasting and postprandial levels of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM), WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as well as fasting and postprandial glucose/insulin levels in the liquid meal test were assessed. RESULTS: Acarbose strongly decreased postprandial insulin concentrations in subjects with metabolic syndrome (P=0.004), and postprandial glucose excursions in both groups. Postprandial MR-proANP and CT-proET-1 levels increased after acarbose treatment (P<0.01 and P<0.05, respectively) in subjects with metabolic syndrome only. No effect of acarbose treatment on MR-prADM was observed in both groups. All three peptides were correlated with each over, but neither with insulin sensitivity in euglycemic clamps, nor with adiponectin levels. WISP1 decreased after acarbose treatment in subjects with metabolic syndrome. CONCLUSIONS: Plasma MR- proANP and CT-proET-1 concentrations, but not MR-prADM concentrations, were affected by treatment with acarbose over 12 weeks. Our findings provide new possible mechanisms of acarbose action in diabetes and metabolic syndrome.

The decrease in gamma-tocopherol in plasma and lipoprotein fractions levels off within two days of vitamin E supplementation.

The effects of vitamin E supplementation on alpha- and gamma-tocopherol concentrations were studied in plasma and lipoprotein fractions of five healthy volunteers taking 1000 IU/day of RRR alpha-tocopherol for 4 days. Although plasma alpha-tocopherol increased, gamma-tocopherol decreased. Compared with baseline, gamma-/alpha-tocopherol ratios decreased from 48 h onward (P < 0.001). They all leveled off within 48 h. From 12 h onward, gamma-/alpha-tocopherol ratios were higher in VLDL and IDL than in LDL and HDL, indicating that gamma-tocopherol is better maintained in triglyceride-rich lipoprotein fractions. These data suggest that vitamin E supplementation exceeding 2 days does not further decrease gamma-tocopherol concentrations.