Biomarker and transcriptomics profiles of serum selenium concentrations in patients with heart failure are associated with immunoregulatory processes.

BACKGROUND: Low selenium concentrations are associated with worse outcomes in heart failure (HF). However, the underlying pathophysiologic mechanisms remain incompletely understood. Therefore, we aimed to contrast serum selenium concentrations to blood biomarker and transcriptomic profiles in patients with HF. METHODS: Circulating biomarkers, whole blood transcriptomics and serum selenium measurements in a cohort of 2328 patients with HF were utilized. Penalized linear regression and gene expression analysis were used to assess biomarker and transcriptomics profiles, respectively. As a proof-of-principle, potential causal effects of selenium on excreted cytokines concentrations were investigated using human peripheral blood mononuclear cells (PBMCs). RESULTS: Mean selenium levels were 60.6 µg/L in Q1 and 122.0 µg/L in Q4. From 356 biomarkers and 20 clinical features, the penalized linear regression model yielded 44 variables with <5 % marginal false discovery rate as predictors of serum selenium. Biomarkers associated positively with selenium concentrations included: epidermal growth factor receptor (EGFR), IFN-gamma-R1, CD4, GDF15, and IL10. Biomarkers associated negatively with selenium concentrations included: PCSK9, TNFSF13, FGF21 and PAI. Additionally, 148 RNA transcripts were found differentially expressed between high and low selenium status (Padj.<0.05; log-fold-change<|0.25|). Enrichment analyses of the selected biomarkers and RNA transcripts identified similar enriched processes, including regulation processes of leukocyte differentiation and activation, as well as cytokines production. The mRNA expression of two selenoproteins (MSRB1 and GPX4) were strongly correlated with serum selenium, while GPX4, SELENOK, and SELENOS were associated with prognosis. In the in-vitro setting, PBMCs supplemented with selenium showed significantly lower abundance of several (pro-)inflammatory cytokines. CONCLUSION: These data suggest that immunoregulation is an important mechanism through which selenium might have beneficial roles in HF. The beneficial effects of higher serum selenium concentrations are likely because of global immunomodulatory effects on the abundance of cytokines. MSRB1 and GPX4 are potential modulators of and should be pursued in future research.

Micronutrient deficiencies in heart failure: Mitochondrial dysfunction as a common pathophysiological mechanism?

Heart failure is a devastating clinical syndrome, but current therapies are unable to abolish the disease burden. New strategies to treat or prevent heart failure are urgently needed. Over the past decades, a clear relationship has been established between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilization, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these perturbations result in progressive depletion of cardiac adenosine triphosphate (ATP) and cardiac energy deprivation. Increasing the delivery of energy substrates (e.g., fatty acids, glucose, ketones) to the mitochondria will be worthless if the mitochondria are unable to turn these energy substrates into fuel. Micronutrients (including coenzyme Q10, zinc, copper, selenium and iron) are required to efficiently convert macronutrients to ATP. However, up to 50% of patients with heart failure are deficient in one or more micronutrients in cross-sectional studies. Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing myocardium away from an "an engine out of fuel" to "a defective engine on a path to self-destruction." This summary of evidence suggests that supplementation with micronutrients-preferably as a package rather than singly-might be a potential therapeutic strategy in the treatment of heart failure patients.

High selenium levels associate with reduced risk of mortality and new-onset heart failure: data from PREVEND.

AIM: To elucidate the relationship between serum selenium levels and the risk of mortality and new-onset heart failure (HF) in the general adult population. METHODS AND RESULTS: Selenium was measured in a Dutch cohort and a retrospective analysis of prospectively assessed data was performed. Main outcome measures were all-cause mortality and incidence of new-onset HF separately, and combined as a composite endpoint. Serum selenium was measured in 5973 subjects and mean selenium concentration was 84.6 (±19.5) µg/L. Mean age was 53.6 (±12.1) years and 3103 subjects (52%) were female. Median follow-up was 8.4 years. Selenium levels associated positively with female sex, higher total cholesterol and glucose concentrations, and associated negatively with incidence of anaemia, iron deficiency, current smoking, increased C-reactive protein levels, and higher body mass index. Univariate analysis on all subjects showed no association of continuous selenium concentrations, per 10 µg/L increase, with the composite endpoint (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.87-1.06, p = 0.407). However, significant interaction with smoking status was observed. In non-smoking subjects (n = 4288), continuous selenium concentrations were independently associated with reduced mortality risk (HR 0.87, 95% CI 0.79-0.96, p = 0.005), lower risk of new-onset HF (HR 0.82, 95% CI 0.69-0.96, p = 0.017), as well as reduced risk of the composite endpoint (HR 0.86, 95% CI 0.79-0.94, p = 0.001). In smoking subjects, no associations were found. CONCLUSION: Serum selenium was independently associated with multiple indicators of the metabolic syndrome. In addition, high selenium levels were independently associated with reduced mortality and new-onset HF in non-smokers. Well-powered interventional studies are necessary to evaluate the potential benefit of repleting selenium, especially in non-smoking subjects.

A Clinical Tool to Predict Low Serum Selenium in Patients with Worsening Heart Failure.

Selenium is an essential micronutrient, and a low selenium concentration (<100 µg/L) is associated with a poorer quality of life and exercise capacity, and an impaired prognosis in patients with worsening heart failure. Measuring selenium concentrations routinely is laborious and costly, and although its clinical utility is yet to be proven, an easy implemented model to predict selenium status is desirable. A stepwise multivariable logistic regression analysis was performed using routinely measured clinical factors. Low selenium was independently predicted by: older age, lower serum albumin, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function, and the presence of orthopnea and iron deficiency. A 10-points risk-model was developed, and a score of ≥6 points identified >80% of patients with low selenium (sensitivity of 44%, specificity of 80%). Given that selenium and iron overlap in their physiological roles, we evaluated the shared determinants and prognostic associates. Both deficiencies shared similar clinical characteristics, including the model risk factors and, in addition, a low protein intake and high levels of C-reactive protein. Low selenium was associated with a similar or worse prognosis compared to iron deficiency. In conclusion, although it is difficult to exclude low selenium based on clinical characteristics alone, we provide a prediction tool which identifies heart failure patients at higher risk of having a low selenium status.

Selenium and outcome in heart failure.

AIMS: Severe deficiency of the essential trace element selenium can cause myocardial dysfunction although the mechanism at cellular level is uncertain. Whether, in clinical practice, moderate selenium deficiency is associated with worse symptoms and outcome in patients with heart failure is unknown. METHODS AND RESULTS: BIOSTAT-CHF is a multinational, prospective, observational cohort study that enrolled patients with worsening heart failure. Serum concentrations of selenium were measured by inductively coupled plasma mass spectrometry. Primary endpoint was a composite of all-cause mortality and hospitalization for heart failure; secondary endpoint was all-cause mortality. To investigate potential mechanisms by which selenium deficiency might affect prognosis, human cardiomyocytes were cultured in absence of selenium, and mitochondrial function and oxidative stress were assessed. Serum selenium concentration (deficiency) was <70 µg/L in 485 (20.4%) patients, who were older, more often women, had worse New York Heart Association class, more severe signs and symptoms of heart failure and poorer exercise capacity (6-min walking test) and quality of life (Kansas City Cardiomyopathy Questionnaire). Selenium deficiency was associated with higher rates of the primary endpoint [hazard ratio (HR) 1.23; 95% confidence interval (CI) 1.06-1.42] and all-cause mortality (HR 1.52; 95% CI 1.26-1.86). In cultured human cardiomyocytes, selenium deprivation impaired mitochondrial function and oxidative phosphorylation, and increased intracellular reactive oxygen species levels. CONCLUSIONS: Selenium deficiency in heart failure patients is independently associated with impaired exercise tolerance and a 50% higher mortality rate, and impaired mitochondrial function in vitro, in human cardiomyocytes. Clinical trials are needed to investigate the effect of selenium supplements in patients with heart failure, especially if they have low plasma concentrations of selenium.

Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function.

AIMS: Iron deficiency is common in patients with heart failure and associated with a poor cardiac function and higher mortality. How iron deficiency impairs cardiac function on a cellular level in the human setting is unknown. This study aims to determine the direct effects of iron deficiency and iron repletion on human cardiomyocytes. METHODS AND RESULTS: Human embryonic stem cell-derived cardiomyocytes were depleted of iron by incubation with the iron chelator deferoxamine (DFO). Mitochondrial respiration was determined by Seahorse Mito Stress test, and contractility was directly quantified using video analyses according to the BASiC method. The activity of the mitochondrial respiratory chain complexes was examined using spectrophotometric enzyme assays. Four days of iron depletion resulted in an 84% decrease in ferritin (P < 0.0001) and significantly increased gene expression of transferrin receptor 1 and divalent metal transporter 1 (both P < 0.001). Mitochondrial function was reduced in iron-deficient cardiomyocytes, in particular ATP-linked respiration and respiratory reserve were impaired (both P < 0.0001). Iron depletion affected mitochondrial function through reduced activity of the iron-sulfur cluster containing complexes I, II and III, but not complexes IV and V. Iron deficiency reduced cellular ATP levels by 74% (P < 0.0001) and reduced contractile force by 43% (P < 0.05). The maximum velocities during both systole and diastole were reduced by 64% and 85%, respectively (both P < 0.001). Supplementation of transferrin-bound iron recovered functional and morphological abnormalities within 3 days. CONCLUSION: Iron deficiency directly affects human cardiomyocyte function, impairing mitochondrial respiration, and reducing contractility and relaxation. Restoration of intracellular iron levels can reverse these effects.