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.

Sexual dimorphism in selenium deficiency is associated with metabolic syndrome and prevalence of heart disease.

BACKGROUND: Serum selenium levels have been associated with the incidence of heart failure (HF) and signs of the metabolic syndrome. In addition, notable differences have been reported between males and females in food intake and micronutrient metabolism, possibly explaining different health outcomes. OBJECTIVE: Our objective was to elucidate sex-specific, cross-sectional phenotypic differences in the association of serum selenium concentrations with parameters of metabolic syndrome and HF. METHODS: We investigated data from individuals from a community-based cohort (PREVEND; N = 4288) and heart failure cohort (BIOSTAT-CHF; N = 1994). In both populations, cross-sectional analyses were performed for potential interaction (p < 0.1) between sex and serum selenium with overlapping signs and clinical parameters of the metabolic syndrome and HF. RESULTS: Baseline selenium levels of the total cohort were similar between PREVEND (85.7 µg/L) and BIOSTAT-CHF (89.1 µg/L). Females with lower selenium levels had a higher BMI and increased prevalence of diabetes than females with higher selenium, in both PREVEND (pinteraction < 0.001; pinteraction = 0.040, resp.) and BIOSTAT-CHF (pinteraction = 0.021; pinteraction = 0.024, resp.), while opposite associations were observed for males. Additionally, in females, but not in males, lower selenium was associated with a higher prevalence of myocardial infarction (MI) in PREVEND (pinteraction = 0.021) and BIOSTAT-CHF (pinteraction = 0.084). CONCLUSION: Lower selenium was associated with a higher BMI and increased prevalence of diabetes in females, opposite to males, and was also associated with more MI in females. Interventional studies are needed to validate this observation.

Dosing of losartan in men versus women with heart failure with reduced ejection fraction: the HEAAL trial.

AIMS: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit. METHODS AND RESULTS: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66 years and 30% of patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high- vs. low-dose losartan for the composite outcome of all-cause death or all-cause hospitalization: 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women; interaction P = 0.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III/IV, and estimated glomerular filtration rate <60 mL/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe heart failure symptoms. CONCLUSIONS: Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g. kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders.

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.

Conceptual Considerations for Device-Based Therapy in Acute Decompensated Heart Failure: DRI2P2S.

Acute decompensated heart failure remains the most common cause of hospitalization in older adults, and studies of pharmacological therapies have yielded limited progress in improving outcomes for these patients. This has prompted the development of novel device-based interventions, classified mechanistically based on the way in which they intend to improve central hemodynamics, increase renal perfusion, remove salt and water from the body, and result in clinically meaningful degrees of decongestion. In this review, we provide an overview of the pathophysiology of acute decompensated heart failure, current management strategies, and failed pharmacological therapies. We provide an in depth description of seven investigational device classes designed to target one or more of the pathophysiologic derangements in acute decompensated heart failure, denoted by the acronym DRI2P2S. Dilators decrease central pressures by increasing venous capacitance through splanchnic nerve modulation. Removers remove excess fluid through peritoneal dialysis, aquaphoresis, or hemodialysis. Inotropes directly modulate the cardiac nerve plexus to enhance ventricular contractility. Interstitial devices enhance volume removal through lymphatic duct decompression. Pushers are novel descending aorta rotary pumps that directly increase renal artery pressure. Pullers reduce central venous pressures or renal venous pressures to increase renal perfusion. Selective intrarenal artery catheters facilitate direct delivery of short acting vasodilator therapy. We also discuss challenges posed in clinical trial design for these novel device-based strategies including optimal patient selection and appropriate end points to establish efficacy.

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.

A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF.

AIMS: Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure. METHODS: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence-based medical therapy. In the follow-up phase, uptitration to guideline-recommended doses was encouraged. CONCLUSION: By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure.

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency.

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research.

Finerenone : third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease.

INTRODUCTION: The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF), and attenuate progression of diabetic kidney disease. However, their use is limited by the fear of inducing hyperkalemia, especially in patients with renal dysfunction. Finerenone is a novel nonsteroidal MRA, with higher selectivity toward the mineralocorticoid receptor (MR) compared to spironolactone and stronger MR-binding affinity than eplerenone. AREAS COVERED: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of finerenone. EXPERT OPINION: The selectivity and greater binding affinity of finerenone to the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with HF and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease and diabetic kidney disease, showed promising results. Phase III trials will have to show whether finerenone might become the third-generation MRA for the treatment of HF and diabetic kidney disease.

Decongestion in acute heart failure.

Congestion is a major reason for hospitalization in acute heart failure (HF). Therapeutic strategies to manage congestion include diuretics, vasodilators, ultrafiltration, vasopressin antagonists, mineralocorticoid receptor antagonists, and potentially also novel therapies such as gut sequesterants and serelaxin. Uncertainty exists with respect to the appropriate decongestion strategy for an individual patient. In this review, we summarize the benefit and risk profiles for these decongestion strategies and provide guidance on selecting an appropriate approach for different patients. An evidence-based initial approach to congestion management involves high-dose i.v. diuretics with addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade with thiazide diuretics or natriuretic doses of mineralocorticoid receptor antagonists. Vasopressin antagonists may improve aquaresis and relieve dyspnoea. If diuretic strategies are unsuccessful, then ultrafiltration may be considered. Ultrafiltration should be used with caution in the setting of worsening renal function. This review is based on discussions among scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from 30 November to 1 December 2012.

Vasodilators in the treatment of acute heart failure: what we know, what we don't.

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice.

Effect of intensive versus moderate lipid lowering on endothelial function and vascular responsiveness to angiotensin II in stable coronary artery disease.

Recent evidence has demonstrated that intensive lipid-lowering therapy with a high-dose statin provides significant clinical benefit beyond moderate lipid-lowering therapy. However, dose-dependent effects of short-term statin therapy on vascular function have not been demonstrated. We studied endothelial function and vascular responsiveness to angiotensin II in patients who had coronary artery diseased and were randomized to receive low- or high-dose atorvastatin (10 or 80 mg, respectively) or placebo. Internal thoracic artery segments were obtained during coronary bypass surgery and studied in vitro. Endothelium-dependent vasodilation was increased with atorvastatin therapy (p = 0.035) but was significantly increased further in patients who received 80 mg compared with those who received 10 mg of atorvastatin (p = 0.05). Endothelium improvement was accompanied by decreased vascular response to angiotensin II (p = 0.039). These findings suggest a mechanism for the clinical benefit of intensive lipid-lowering treatment in coronary heart disease.