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Background: The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach., Methods and Results: We measured 25 known SASP proteins among 2248 PHFS (Penn HF Study) participants using the SOMAScan V4 assay. We extracted the common variance in these proteins to generate SASP factor scores and assessed the relationship between these SASP factor scores and (1) all-cause death and (2) the composite of death or HF hospital admission. We also assessed the relationship of each SASP factor to 4746 other proteins, correcting for multiple comparisons, followed by pathway analyses. Two SASP factors were identified. Both factors were associated with older age, lower estimated glomerular filtration rate, and more advanced New York Heart Association class, among other clinical variables. Both SASP factors exhibited a significant positive association with the risk of death independent of the Meta-Analysis of Global-Group in Chronic HF score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. The 2 identified SASP factors were associated with 1201 and 1554 proteins, respectively, belonging to various pathways including the coagulation system, complement system, acute phase response signaling, and retinoid X receptor-related pathways that regulate cell metabolism., Conclusions: Increased SASP components are independently associated with adverse outcomes in HF. Biologic pathways associated with SASP are predominantly related to coagulation, inflammation, and cell metabolism.

Background: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear., Methods and Results: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort., Conclusions: KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.

Background: The relationship of serial NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurements with changes in cardiac features and outcomes in heart failure (HF) remains incompletely understood. We determined whether common clinical covariates impact these relationships., Methods and Results: In 2 nationwide observational populations with HF, the relationship of serial NT-proBNP measurements with serial echocardiographic parameters and outcomes was analyzed, further stratified by HF with reduced versus preserved left ventricular ejection fraction, inpatient versus outpatient enrollment, age, obesity, chronic kidney disease, atrial fibrillation, and attainment of ≥50% guideline-recommended doses of renin-angiotensin system inhibitors and β-blockers. Among 1911 patients (mean±SD age, 65.1±13.4 years; 26.6% women; 62% inpatient and 38% outpatient), NT-proBNP declined overall, with more rapid declines among inpatients, those with obesity, those with atrial fibrillation, and those attaining ≥50% guideline-recommended doses. Each doubling of NT-proBNP was associated with increases in left ventricular volume (by 6.1 mL), E/e' (transmitral to mitral annular early diastolic velocity ratio) (by 1.4 points), left atrial volume (by 3.6 mL), and reduced left ventricular ejection fraction (by -2.1%). The effect sizes of these associations were lower among patients with HF with preserved ejection fraction, atrial fibrillation, or advanced age ( P interaction <0.001). A landmark analysis identified that an SD increase in NT-proBNP over 6 months was associated with a 27% increase in the risk of the composite event of HF hospitalization or all-cause death between 6 months and 2 years (adjusted hazard ratio, 1.27 [95% CI, 1.15-1.40]; P <0.001)., Conclusions: The relationships between NT-proBNP and structural/functional remodeling differed by age, presence of atrial fibrillation, and HF phenotypes. The association of increased NT-proBNP with increased risk of adverse outcomes was consistent in all subgroups.

Background: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction., Methods and Results: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P =3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P =0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P =0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission., Conclusions: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Background: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization., Methods and Results: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P <0.0001), growth differentiation factor-15 (sHR, 1.68; P <0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P <0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P <0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death., Conclusions: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Background Data on rehospitalizations for heart failure (HF) in Asia are scarce. We sought to determine the burden and predictors of HF (first and recurrent) rehospitalizations and all-cause mortality in patients with HF and preserved versus reduced ejection fraction (preserved EF, ≥50%; reduced EF, <40%), in the multinational ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registry. Methods and Results Patients with symptomatic (stage C) chronic HF were followed up for death and recurrent HF hospitalizations for 1 year. Predictors of HF hospitalizations or all-cause mortality were examined with Cox regression for time to first event and other methods for recurrent events analyses. Among 1666 patients with HF with preserved EF (mean age, 68±12 years; 50% women), and 4479 with HF with reduced EF (mean age, 61±13 years; 22% women), there were 642 and 2302 readmissions, with 28% and 45% attributed to HF, respectively. The 1-year composite event rate for first HF hospitalization or all-cause death was 11% and 21%, and for total HF hospitalization and all-cause death was 17.7 and 38.7 per 100 patient-years in HF with preserved EF and HF with reduced EF, respectively. In HF with preserved EF, consistent independent predictors of these clinical end points included enrollment as an inpatient, Southeast Asian location, and comorbid chronic kidney disease or atrial fibrillation. The same variables were predictive of outcomes in HF with reduced EF except atrial fibrillation, and also included Northeast Asian location, older age, elevated heart rate, decreased systolic blood pressure, diabetes, smoking, and non-usage of beta blockers. Conclusions One-year HF rehospitalization and mortality rates were high among Asian patients with HF. Predictors of outcomes identified in this study could aid in risk stratification and timely interventions. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01633398.

Aims: Anthracycline chemotherapy (AC) for breast cancer can cause cancer therapy‐related cardiac dysfunction (CTRCD) with resultant heart failure, traditionally defined as a reduction in left ventricular (LV) ejection fraction on echocardiography. In recent years, global longitudinal systolic strain (GLS) has been used to identify subclinical cardiac dysfunction prior to development of overt CTRCD. Recent harmonized guidelines have incorporated GLS into definitions for CTRCD to identify cardiac dysfunction and inform decisions regarding cardioprotective strategies. Methods and results: We evaluated subclinical dysfunction in breast cancer patients treated with AC and determined the echocardiographic and patient factors associated with significant GLS changes. One hundred fourteen HER2 negative patients treated with AC were prospectively recruited and underwent serial echocardiograms (LVEF and LVGLS) at three time points (prior to AC, 3 months, and 1 year). CTRCD was defined as an asymptomatic reduction in LVEF of 10% or symptomatic drop of 5% to LVEF <53%. Subclinical LV dysfunction was defined as a reduction of ≥10% in GLS compared with baseline, recognizing that this cut off identified an 'at risk cohort' rather than patients with established CTRCD. No participant demonstrated CTRCD by reduction in LVEF. Forty‐three patients (38%) demonstrated a ≥10% relative reduction in GLS at 12 months; 20/43 (47%) had a reduced absolute GLS to <16%, and were older, had hypertension, increased LV mass, lower baseline e′ velocity and GLS. GLS ≥20.5% at baseline yielded a sensitivity of 79% and specificity of 87% for a normal GLS (i.e., ≥16%) at 1 year despite a ≥10% reduction from baseline. Conclusions: We present a stepwise evaluation for subclinical LV dysfunction using both a relative reduction in GLS combined with an absolute reduction in GLS. We believe our findings may re‐stratify patients with a high baseline GLS into a lower risk group despite transient relative GLS decrements ≥10%. [ABSTRACT FROM AUTHOR]

Aims: Soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt‐1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. Methods and results: ELISA assays for sFlt‐1, PlGF and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt‐1 or PlGF levels were genotyped. sFlt‐1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All‐cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt‐1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt‐1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt‐1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57–16.1; p < 0.001) in PEOPLE, independent of age, NT‐proBNP, ischaemic aetiology, diabetic status and beta‐blocker therapy. Conclusions: Plasma sFlt‐1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF. [ABSTRACT FROM AUTHOR]

Aim: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. Methods and results: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age‐ and sex‐matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi‐block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross‐referenced with small‐molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60–71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)‐8 and IL‐6 were possible targets related to lower EF and worsening renal function. Conclusion: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF. [ABSTRACT FROM AUTHOR]

The article discusses the HF-REVERT trial, which is the first trial to test the efficacy and safety of an antisense oligonucleotide (ASO) in heart failure (HF). The trial focuses on patients with reduced left ventricular ejection fraction (LVEF) after a myocardial infarction (MI). The ASO being tested, CDR132L, suppresses microRNA (miR)-132-3p, which is known to exacerbate adverse cardiac remodeling. The primary endpoint of the trial is the change in echocardiographic left ventricular end-systolic volume index at 6 months. The article highlights the potential of manipulating non-coding RNAs as a new therapeutic strategy for HF. [Extracted from the article]

Aims: We investigated titration patterns of angiotensin‐converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta‐blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all‐cause mortality/heart failure (HF) hospitalization] in a real‐world population with HF with reduced ejection fraction (HFrEF). Methods and results: Participants with HFrEF (left ventricular ejection fraction <40%) from a prospective multi‐centre study were examined for use and dose [relative to guideline‐recommended maintenance dose (GRD)] of ACEis/ARBs and beta‐blockers at baseline and 6 months. 'Stay low' was defined as <50% GRD at both time points, 'stay high' as ≥50% GRD, and 'up‐titrate' and 'down‐titrate' as dose trajectories. Among 1110 patients (mean age 63 ± 13 years, 16% women, 26% New York Heart Association Class III/IV), 714 (64%) were multi‐ethnic Asians from Singapore and 396 were from New Zealand (mainly European ethnicity). Baseline use of either ACEis/ARBs or beta‐blockers was high (87%). Loop diuretic was prescribed in >80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta‐blockers. At 6 months, a large majority remained in the 'stay low' category, one third remained in 'stay high', whereas 10–16% up‐titrated and 4–6% down‐titrated. Patients with lower (vs. higher) N‐terminal pro‐beta‐type natriuretic peptide levels were more likely to be up‐titrated or be in 'stay high' for ACEis/ARBs and beta‐blockers (P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of 'staying low' (all P < 0.005) for prescribed doses of ACEis/ARBs and beta‐blockers. Adjusted for inverse probability weighting, ≥100% GRD for ACEis/ARBs [hazard ratio (HR) = 0.42; 95% confidence interval (CI) 0.24–0.73] and ≥50% GRD for beta‐blockers (HR = 0.58; 95% CI 0.37–0.90) (vs. Nil) were associated with lower hazards for 1 year composite outcome. Country of enrolment did not modify the associations of dose categories with 1 year composite outcome. Higher medication doses were associated with greater improvements in QoL. Conclusions: Although HF medication use at baseline was high, most patients did not have these medications up‐titrated over 6 months. Multiple clinical factors were associated with changes in medication dosages. Further research is urgently needed to investigate the causes of lack of up‐titration of HF therapy (and its frequency), which could inform strategies for timely up‐titration of HF therapy based on clinical and biochemical parameters. [ABSTRACT FROM AUTHOR]

B This article refers to 'Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation' by K. Oyama I et al i ., published in this issue on pages 832-841. b The incidence and prevalence of atrial fibrillation (AF), by far the most common cardiac arrhythmia, has risen over the last 30 years. Therefore, this data set offers no internal comparison of AF and sinus rhythm with respect to the performance of the three markers in predicting HF hospitalization or HF death. [Extracted from the article]

Aims: To define plasma concentrations, determinants, and optimal prognostic cut‐offs of soluble suppression of tumorigenesis‐2 (sST2), high‐sensitivity cardiac troponin T (hs‐cTnT), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) in women and men with chronic heart failure (HF). Methods and results: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs‐cTnT, and NT‐proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all‐cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs‐cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT‐proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut‐off was lower in women for sST2 (28 vs. 31 ng/mL) and hs‐cTnT (22 vs. 25 ng/L), while NT‐proBNP cut‐off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex‐specific cut‐offs improved risk prediction compared with the use of previously standardized prognostic cut‐offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs‐cTnT than sST2 or NT‐proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex‐specific cut‐off of hs‐cTnT for the endpoint of 5 year cardiovascular death. Conclusions: In patients with chronic HF, concentrations of sST2 and hs‐cTnT, but not of NT‐proBNP, are lower in women. Lower sST2 and hs‐cTnT and higher NT‐proBNP cut‐offs for risk stratification could be used in women. [ABSTRACT FROM AUTHOR]

Aims: The importance of iron deficiency (ID) in heart failure with preserved ejection fraction (HFpEF) is unknown. In HF with reduced ejection fraction (HFrEF), ID is reported as an independent predictor of mortality in HF although not all published studies agree. Different definitions of ID have been assessed, and the natural history of untreated ID not established, which may explain the conflicting results. This study aimed to assess the relationship between ID and mortality in HFpEF, clarify which definition of ID correlates best with outcomes in HFrEF, and determine the prognostic importance of change in ID status over time. Methods and results: Analyses were conducted on data from 1563 patients participating in a prospective international cohort study comparing HFpEF with HFrEF. Plasma samples from baseline and 6 month visits were analysed for the presence of ID. Two ID definitions were evaluated: IDFerritin = 'ferritin < 100 mcg/L or ferritin 100–300 mcg/L + transferrin saturation < 20%' and IDTsat = 'transferrin saturation < 20%'. The risk of all‐cause mortality and death/HF hospitalization associated with baseline ID (IDFerritin or IDTsat) and change in ID status at 6 months (persistent, resolving, developing, or never present) was estimated in multivariable Cox proportional hazards models. Of 1563 patients, 1115 (71%) had HFrEF and 448 (29%) HFpEF. Prevalence of ID was similar in HFpEF and HFrEF (58%). Patients with ID were more likely to be female, diabetic, and have a higher co‐morbid burden than patients without ID. ID by either definition did not confer independent risk for either all‐cause mortality or death/HF hospitalization for patients with HFpEF [IDFerritin hazard ratio (HR) 0.65 (95% confidence interval 0.40–1.05), P = 0.08; IDTsat HR 1.16 (0.72–1.87), P = 0.55]. In the overall study cohort (HFrEF + HFpEF) and HFrEF subgroup, IDFerritin was inferior to IDTsat in prediction of all‐cause mortality [overall cohort: HR 1.21 (0.95–1.53), P = 0.12 vs. HR 1.95 (1.52–2.51), P < 0.01; HFrEF: HR 1.12 (0.85–1.48), P = 0.43 vs. HR 1.57 (1.15–2.14), P < 0.01]. Persistence of IDTsat at 6 months was strongly associated with poor outcomes compared with never having IDTsat [HR 2.22 (1.42–3.46), P < 0.01] or having IDTsat at baseline self‐resolve by 6 months [HR 1.40 (1.06–1.86), P = 0.02]. Conclusions: Iron deficiency is equally prevalent in HFpEF and HFrEF but is negatively prognostic only in HFrEF. The natural history of ID is important; persistent ID is strongly associated with mortality whereas resolution is not. IDTsat is the superior definition of ID and should inform future trials investigating the efficacy of intravenous iron replacement in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Calcium is widely used in conjunction with vitamin D to prevent osteoporosis. The use of calcium supplementation is also promoted for its potential benefits in lowering the risk for metabolic syndromes and cancers. However, the causal link between calcium and various health outcomes remains unclear. This review focuses on the evidence from 24 Mendelian randomization (MR) studies that were designed to minimize bias from confounding and reverse causation. These MR studies evaluated the effect of lifelong genetically higher serum calcium levels on various health outcomes. Overall, available MR studies found no conclusive effects of serum calcium levels on bone mineral density and fracture, ischemic stroke and heart failure, cancers, type 2 diabetes, Parkinson disease, or offspring birth weight. However, a higher serum calcium concentration was reported to have estimated causal effects on increased risks for coronary artery disease (especially myocardial infarction), migraine, renal colic, allergy/adverse effect of penicillin, and reduced risks for osteoarthrosis and osteoarthritis. In conclusion, supplementation of calcium in individuals from the general population is not predicted to influence the risk of most investigated diseases to date. Moreover, long‐term high serum calcium concentrations may result in adverse health outcomes. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

New biomarkers are being evaluated for their ability to advance the management of patients with heart failure. Despite a large pool of interesting candidate biomarkers, besides natriuretic peptides virtually none have succeeded in being applied into the clinical setting. In this review, we examine the most promising emerging candidates for clinical assessment and management of patients with heart failure. We discuss high‐sensitivity cardiac troponins (Tn), procalcitonin, novel kidney markers, soluble suppression of tumorigenicity 2 (sST2), galectin‐3, growth differentiation factor‐15 (GDF‐15), cluster of differentiation 146 (CD146), neprilysin, adrenomedullin (ADM), and also discuss proteomics and genetic‐based risk scores. We focused on guidance and assistance with daily clinical care decision‐making. For each biomarker, analytical considerations are discussed, as well as performance regarding diagnosis and prognosis. Furthermore, we discuss potential implementation in clinical algorithms and in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

B This article refers to 'Urinary peptides in heart failure: a link to molecular pathophysiology' by T. He I et al i ., published in this issue on pages 1875-1887. b Proteomic screening of blood and/or urine is gaining prominence as a method to aid discovery of candidate biomarkers to elucidate the molecular basis of disease along with potential applications in clinical diagnosis, risk stratification and treatment decision-making. Urinary peptides in heart failure - the need for care with pees and cues However, whether or not filtration of larger molecular weight peptides out of urine samples (post-sample dilution in SDS containing buffers) also removes bound smaller peptides that could provide extra information remains unknown. [Extracted from the article]