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Iron deficiency (ID) is the most common nutritional disorder worldwide. It is often observed in patients with chronic diseases, such as heart failure (HF), chronic kidney disease (CKD), inflammatory bowel disease (IBD) and cancer. ID is associated with poor clinical outcome, including poor performance, reduced quality of life, as well as increased hospitalization and mortality. The aim of this review is to provide an overview about the role of ID in chronic diseases (HF, CKD, IBD, cancer) regarding their current definitions and clinical relevance; diagnostic accuracy of iron parameters in chronic inflammatory conditions and its potential as prognostic markers. Due to different definitions and guideline recommendations of ID, various laboratory parameters for ID diagnostic exist and there is no general consensus about the definition of ID and its treatment. Still, a general trend can be observed across all investigated indications of this review (HF, CKD, IBD, cancer) that serum ferritin and transferrin saturation (TSAT) are the two parameters mentioned most often and emphasized in all guidelines to define ID and guide treatment. The most commonly used threshold values for the diagnosis of ID are TSAT of < 20% and serum ferritin of < 100–300 µg/L. Noteworthy, both TSAT and particularly ferritin are frequently applied, but both may vary due to inflammatory conditions. Studies showed that TSAT is less affected by inflammatory processes and may therefore be more accurate and reliable than serum ferritin, particularly in conditions with elevated inflammatory state. A low iron status and particularly a low TSAT value was associated with a poor outcome in all investigated indications, with the strongest evidence in HF patients. Routine surveillance of iron status in these groups of patients with chronic conditions is advisable to detect ID early. Depending on the inflammatory state, TSAT < 20% may be the more accurate diagnostic marker of ID than ferritin. Moreover, TSAT may also be the more reliable estimate for the prognosis, particularly in HF.

Aims Many European healthcare providers struggle to adopt multidisciplinary, integrated care pathways for people with heart failure (HF) as recommended by the European Society of Cardiology. PRO‐HF (Program to Optimize Heart Failure Patient Pathways) was developed to help clinicians identify strengths, gaps, and shortcomings in their HF pathways and support tailored interventions to optimize pathways and enhance patient care. We report initial findings from baseline assessments of HF pathway characteristics and challenges from 10 hospitals in six European countries (France, Ireland, Portugal, Spain, The Netherlands, and United Kingdom). Methods and results Baseline assessments were holistic appraisals of full HF services to calibrate current status and development needs and assist management teams in prioritizing improvement projects. Assessments were performed using a comprehensive checklist of measures covering the HF patient journey from diagnosis to ongoing follow‐up. These included a digital survey sent to full HF care teams and one‐to‐one interviews. The digital survey focused on four key areas (HF outpatient clinic; remote patient management; efficient device implantation and inpatient pathways; and network maximization) and 16 dimensions of excellence. Priority areas and themes for action identified in baseline assessments were (i) provision of HF specialist care; (ii) data capture and analysis; (iii) institutional care protocols; (iv) hospital‐wide strategies; and (v) multidisciplinary teams (MDTs). Suboptimal specialist care of emergency inpatients was an issue at all hospitals and prioritized at 8/10. Availability and accessibility of data on patients, activities, and outcomes was an issue at all hospitals and prioritized by 4/10. A lack of clear protocols, templates, and tools for some HF activities created variability in patient care (e.g., HF specialist consultations, diagnostic testing, follow‐up appointments, medications, and device eligibility) and inefficient use of clinician time. This made it difficult to initiate new technologies (e.g., remote patient monitoring) due to the risk of overburdening staff. MDTs were frequently understaffed. Multiple interventions were identified to address gaps and shortcomings that could be tailored to specific needs of individual hospitals (e.g., inpatient pathway optimization, creation/optimization of HF outpatient clinics, development of an HF performance dashboard, enhancement of protocol adherence, streamlining cardiac resynchronisation therapy pathways, and MDT coordination). Conclusions PRO‐HF provides a valuable opportunity to identify gaps and significant shortcomings in HF pathways in European hospitals. Preliminary findings from hospitals that have initiated suggested changes to address these challenges are encouraging, though longer‐term follow‐up from more hospitals is needed to confirm the impact of PRO‐HF on HF pathway optimization and patient care.

Background Recent clinical studies suggest that inflammatory mediators have huge potential in individualized therapy and in efficacy screening and can be utilized as biomarkers for a plethora of pathological conditions. The standard approach for detecting and measuring these inflammatory mediators is via blood samples. Nevertheless, there is no scientific report providing solid evidence on the most suitable blood compartment that will give the optimal inflammatory mediator measurement, or regarding the diurnal variation of circulating mediators. In this study, we present the biological variability of circulating cytokines and chemokines from healthy individuals (mean age 59 years) assessed by a novel membrane-based assay. Methods Fifteen males and an equal number of females (all above 50 years) with no known inflammatory condition were selected. Through a planar method, named Proteome Profiler™, improved with fluorescence readout into a semi-quantitative multiplex assay, a screening of 36 inflammatory mediators was performed in serum and plasma of morning and afternoon blood withdrawals. Results The multiplex analysis revealed that the physiological variability of several circulating inflammatory mediators was relatively small within a cohort of 30 healthy aging subjects. There was no substantial gender effect in the inflammatory mediator profile. On the contrary, most of the cytokine/chemokine values measured in the afternoon collection were found to be higher compared to the morning ones, particularly in plasma. Conclusions In this study we provide evidence that circulating cytokine and chemokine levels of healthy individuals are elevated when blood is sampled in the afternoon compared to the morning, as influenced by the circulating cortisol levels. Furthermore, we report significant differences between cytokine/chemokine levels measured in serum and plasma. Our results provide essential information for future studies that will focus on examining circulating inflammatory mediator differences between healthy and diseased individuals.

In the HOMAGE (Heart Omics in AGEing) trial, spironolactone reduced serum concentrations of procollagen Type I C‐terminal propeptide (PICP), a fibrosis biomarker, in patients at risk of heart failure. To elucidate the underlying mechanisms, multidimensional analyses including proteomics were conducted. Olink cardiovascular and inflammation panels (n = 276 proteins) were measured in plasma from 488 HOMAGE participants at baseline, 1 month, and 9 months after randomization. Proteins associated with PICP changes were identified using machine learning algorithms (MLAs). Selected candidates were further analyzed in patients with heart failure and preserved ejection fraction (Aldo‐DHF trial). Linear regression and mediation analyses assessed which MLA‐selected proteins mediated spironolactone's effects on PICP. MLAs consistently linked PICP reduction to changes in biomarkers of collagen (e.g., decreased COL1A1), fatty acid metabolism (e.g., increased FABP4), immune function (e.g., increased CCL24 and IL6RA, and decreased FLT3L), neurological function (e.g., increased DNER), cell–matrix interactions (e.g., increased galectin‐9 [GAL9] and decreased thrombospondin‐2 [THBS2]), and reduced NT‐proBNP. Mediation analysis suggested that changes in GAL9 and THBS2 were associated with spironolactone‐induced PICP reduction, which was confirmed in Aldo‐DHF patients. This study raises the hypothesis that spironolactone inhibits collagen synthesis via inflammatory, metabolic, and extracellular matrix pathways, and particularly through modulation of GAL9 and THBS2. In HOMAGE, 276 plasma proteins were profiled using Olink panels. Machine learning algorithms identified galectin‐9 (GAL9), thrombospondin‐2 (THBS2), and NT‐proBNP as predictors of changes in procollagen type I C‐terminal propeptide (PICP) after spironolactone treatment. Decreasing THBS2 and increasing GAL9 were associated with PICP reduction in HOMAGE and Aldo‐DHF patients, suggesting a potential mediating role of these proteins in fibrosis modulation .

Abstract Aims Inter-atrial block (IAB), a marker of electrical atrial dysfunction, is associated with an increased risk of atrial fibrillation (AF) and adverse events in various populations. The prognostic impact of IAB in heart failure (HF) with preserved ejection fraction (HFpEF) remains unknown. The aim of this study is to determine the prevalence of IAB and the association of IAB and AF with adverse events in HFpEF across different healthcare settings. Methods and results To identify electrical atrial dysfunction, baseline ECG's and medical history were analysed in HFpEF patients in an ambulatory setting and after recent HF hospitalisation. Patients were categorised into (i) HFpEFNo IAB, (ii) HFpEFIAB, or (iii) HFpEFAF. Adverse events included HF hospitalisation, cardiac/sudden death and a composite of both. The ambulatory cohort included 372 patients [mean age 75 ± 7 years, 252 (68%) females]. The recently hospitalised cohort included 132 patients [mean age 81 ± 10 years, 80 (61%) females]. Ambulatory patients included 17 (4%) HFpEFnoIAB, 114 (31%) HFpEFIAB and 241 (65%) HFpEFAF, while recently hospitalised patients included 31 (23%), 73 (55%) and 28 (21%), respectively. After 33 months of follow-up of ambulatory patients, composite endpoints occurred in 0 (0%) HFpEFnoIAB, 12 (11%) HFpEFIAB [HR 4.1 (95% CI 0.5–522.6)] and 59 (24%) HFpEFAF patients [HR 10.1 (95% CI 1.5–1270.4), P < 0.001]. Recently hospitalised patients showed a similar trend, with composite endpoints in 10 (32%) HFpEFnoIAB, 31 (42%) HFpEFIAB (HR 1.5 [95% CI 0.7–3.1]) and 22 (79%) HFpEFAF (HR 3.8 [95% CI 1.8–8.1], P < 0.001). Conclusions Progressive stages of electrical atrial dysfunction appeared to be prognostic markers of adverse outcomes in ambulatory and recently hospitalised patients with HFpEF. Ambulatory patients with HFpEF and no early stages of electrical atrial dysfunction showed to be at very low risk for adverse outcomes. Whether such patients benefit less strict management remains to be investigated.

Aims Cardiac resynchronization therapy (CRT) requires intensive, complex, and multidisciplinary care for heart failure (HF) patients. Due to limitations in time, resources, and coordination of care, in current practice, this is often incomplete. We evaluated the effect of the introduction of a CRT‐care pathway (CRT‐CPW) on clinical outcome and costs. Methods and results The CRT‐CPW focused on structuring CRT patient selection, implantation, and follow‐up management. To facilitate and guarantee quality, checklists were introduced. The CRT‐CPW was implemented in the Maastricht University Medical Centre in 2014. Physician‐led usual care was restructured to a nurse‐led care pathway. A retrospective comparison of data from CRT patients receiving usual care (2012–2014, 222 patients) and patients receiving care according to CRT‐CPW (2015–2018, 241 patients) was performed. The primary outcome was the composite of all‐cause mortality and HF hospitalization. Hospital‐related costs of cardiovascular care after CRT implantation were analysed to address cost‐effectiveness of the CRT‐CPW. Demographics were comparable in the usual care and CRT‐CPW groups. Kaplan–Meier estimates of the occurrence of the primary endpoint showed a significant improvement in the CRT‐CPW group (25.7% vs. 34.7%, hazard ratio 0.56; confidence interval 0.40–0.78; P < 0.005), at 36 months of follow‐up. The total costs for cardiology‐related hospitalizations were significantly reduced in the CRT‐CPW group [€17 698 (14 192–21 195) vs. 19 933 (16 980–22 991), P < 0.001]. Bootstrap cost‐effectiveness analyses showed that implementation of CRT‐CPW would be an economically dominant strategy in 90.7% of bootstrap samples. Conclusions The introduction of a novel multidisciplinary, nurse‐led care pathway for CRT patients resulted in significant reduction of the combination of all‐cause mortality and HF hospitalizations, at reduced cardiovascular‐related hospital costs.

Aims Diagnosis of heart failure with preserved ejection fraction (HFpEF) can be challenging. This study aimed to evaluate the potential of a webtool to enhance the scoring accuracy when applying the complex HFA‐PEFF and H2FPEF algorithms, which are commonly used for diagnosing HFpEF. Methods and results We developed an online tool, the HFpEF calculator, that enables the automatic calculation of current HFpEF algorithms. We assessed the accuracy of manual vs. automatic scoring, defined as the percentage of correct scores, in a cohort of cardiologists with varying clinical experience. Cardiologists scored eight online clinical cases using a triple cross‐over design (i.e. two manual–two automatic–two manual–two automatic). Data were analysed in study completers (n = 55, 29% heart failure specialists, 42% general cardiologists, and 29% cardiology residents). Manually calculated scores were correct in 50% (HFA‐PEFF: 50% [50–75]; H2FPEF: 50% [38–50]). Correct scoring improved to 100% using the HFpEF calculator (HFA‐PEFF: 100% [88–100], P < 0.001; H2FPEF: 100% [75–100], P < 0.001). Time spent on clinical cases was similar between scoring methods (±4 min). When corrections for faulty algorithm scores were displayed, cardiologists changed their diagnostic decision in up to 67% of cases. At least 67% of cardiologists preferred using the online tool for future cases in clinical practice. Conclusions Manual calculation of HFpEF diagnostic algorithms is often inaccurate. Using an automated webtool to calculate HFpEF algorithms significantly improved correct scoring. This new approach may impact the eventual diagnostic decision in up to two‐thirds of cases, supporting its routine use in clinical practice.

Background In Europe, more than 15 million people live with heart failure (HF). It imposes an enormous social, organizational and economic burden. As a reaction to impending impact on healthcare provision, different country-specific structures for HF-care have been established. The aim of this report is to provide an overview and compare the HF-care approaches of Germany, Ireland, the Netherlands and the UK, and to open the possibility of learning from each other’s experience. Methods A mixed methods approach was implemented that included a literature analysis, interviews and questionnaires with HF-patients and caregivers, and expert interviews with representatives from healthcare, health service research and medical informatics. Results The models of HF-care in all countries analyzed are based on the European Society of Cardiology guidelines for diagnosis and treatment of HF. Even though the HF-models differed in design and implementation in practice, key challenges were similar: (i) unequal distribution of care between urban and rural areas, (ii) long waiting times, (iii) unequal access to and provision of healthcare services, (iv) information and communication gaps and (v) inadequate implementation and financing of digital applications. Conclusion Although promising approaches exist to structure and improve HF-care, across the four countries, implementation was reluctant to embrace novel methods. A lack of financial resources and insufficient digitalization making it difficult to adopt new concepts. Integration of HF-nurses seems to be an effective way of improving current models of HF-care. Digital solutions offer further opportunities to overcome communication and coordination gaps and to strengthen self-management skills.

The integration of clinical research data across various institutions faces hurdles due to differing definitions, inconsistent terminologies, and inadequate support for interoperable metadata. While biomedical ontologies offer valuable tools for structuring clinical data, they have not yet been fully utilized for creating comprehensive metadata descriptors, such as variable semantics, statistical summaries, and governance elements essential for data discovery and alignment. We present the Clinical Metadata Exploration Ontology (CMEO) that builds upon well-established ontologies to provide a cohesive representation of study designs, data elements, exploratory statistics, and data reuse permissions. CMEO facilitates semantic querying for study exploration and comparison of data elements across studies, particularly when individual-level data cannot be shared. We demonstrate its utility using metadata from five studies: four heart-failure studies and one wearable-based type 1 diabetes study. After serializing, we executed SPARQL queries that operationalized study-level discovery, variable alignment across studies, and governance-constrained reuse. This FAIR-compliant, metadata-driven integration across heterogeneous sources enables scalable, privacy-conscious research and underpins federated clinical data exploration.

School-based intervention studies promoting a healthy lifestyle have shown favorable immediate health effects. However, there is a striking paucity on long-term follow-ups. The aim of this study was therefore to assess the 3 yr-follow-up of a cluster-randomized controlled school-based physical activity program over nine month with beneficial immediate effects on body fat, aerobic fitness and physical activity. Initially, 28 classes from 15 elementary schools in Switzerland were grouped into an intervention (16 classes from 9 schools, n = 297 children) and a control arm (12 classes from 6 schools, n = 205 children) after stratification for grade (1st and 5th graders). Three years after the end of the multi-component physical activity program of nine months including daily physical education (i.e. two additional lessons per week on top of three regular lessons), short physical activity breaks during academic lessons, and daily physical activity homework, 289 (58%) participated in the follow-up. Primary outcome measures included body fat (sum of four skinfolds), aerobic fitness (shuttle run test), physical activity (accelerometry), and quality of life (questionnaires). After adjustment for grade, gender, baseline value and clustering within classes, children in the intervention arm compared with controls had a significantly higher average level of aerobic fitness at follow-up (0.373 z-score units [95%-CI: 0.157 to 0.59, p = 0.001] corresponding to a shift from the 50th to the 65th percentile between baseline and follow-up), while the immediate beneficial effects on the other primary outcomes were not sustained. Apart from aerobic fitness, beneficial effects seen after one year were not maintained when the intervention was stopped. A continuous intervention seems necessary to maintain overall beneficial health effects as reached at the end of the intervention. ControlledTrials.com ISRCTN15360785.