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Abstract 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: Diuretic resistance is common and results in poor outcome. Spot urine sodium (UrNa) is suggested as a tool to tailor diuretics and improve efficacy of therapy. We prospectively evaluate the prevalence of diuretic resistance, predictors of low spot-UrNa and the prognostic value of spot-UrNa in an unselected ADHF population. Methods: Patients admitted for ADHF and treated with iv diuretics were included. Spot-UrNa was collected 2 h after administration of an IV diuretic bolus. The main endpoint was a composite of HF re-hospitalizations and all-cause mortality at 90 days follow-up. Results: 143 patients were included in this study (median age 81 [75 – 85] years, 55 % male), of which 50 % were newly diagnosed with HF. Low spot-UrNa was independently associated with worse renal function, low serum sodium, and systolic blood pressure, previous loop diuretic and SGLT2i use and loop diuretic administered dose. Both absolute spot-UrNa (HR 0.87, 95 % CI 0.79 – 0.95, P=0.003 per 10 mmol/L increase) and a urinary sodium ≥ 100 mmol/l (HR=0.51, 95 % CI 0.27 – 0.97, P=0.04) significantly predicted the composite endpoint. This association was no longer significant after correction for confounders. Patients with low spot-UrNa attained longer IV diuretic treatment and a higher cumulative IV diuretic dose. Conclusions: Spot-UrNa is prevalent and occurs more often in patients with more progressed cardio-renal disease. Spot-UrNa significantly predicts 90-day HF hospital-free survival in ADHF. Further studies are needed evaluating the effect of UrNa guided diuretic treatment on clinical endpoints.

Abstract Aims Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline‐directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real‐world TITRATE‐HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long‐term outcomes in patients with de novo, chronic, and worsening HF. Methods and results A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow‐up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF‐related hospitalizations, HF‐related urgent visits with a need for intravenous diuretics, all‐cause mortality, and cardiovascular mortality. Conclusions TITRATE‐HF is a real‐world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.

Abstract 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

Abstract Aims Hyperkalaemia is observed frequently in heart failure (HF) patients and is associated with an impaired prognosis and underuse of mineralocorticoid receptor antagonists (MRAs). However, the effects of serum potassium on prescription of the full guideline recommended daily dose of 50 mg in real‐world daily practice are unknown. Therefore, we investigated serum potassium and its association with the prescribed MRA dose in a large cohort of chronic HF patients. Methods and results A total of 5346 patients with chronic HF with a left ventricular ejection fraction ≤40% from 34 Dutch outpatient HF clinics between 2013 and 2016 were analysed on serum potassium and MRA (spironolactone and eplenerone) dose. Data were stratified by potassium as a serum potassium level 5.0 mmol/L. Multivariable logistic regression models were used to assess the association between serum potassium and MRA dose and to adjust for potential confounders. Mean serum potassium was 4.4 ± 0.5 mmol/L and hyperkalaemia (serum potassium >5.0 mmol/L) was present in 399 patients (7.5%). MRA was used in 3091 patients (58.1%). Patients with hyperkalaemia significantly less often received ≥100% of the target dose (50 mg) compared with patients with a serum potassium between 4.0–5.0 mmol/L and

Introduction This study aimed to evaluate the use and dose of loop diuretics (LDs) across the entire ejection fraction (EF) spectrum in a large, ‘real-world’ cohort of chronic heart failure (HF) patients.Methods A total of 10 366 patients with chronic HF from 34 Dutch outpatient HF clinics were analysed regarding diuretic use and diuretic dose. Data regarding daily diuretic dose were stratified by furosemide dose equivalent (FDE)>80 mg or ≤80 mg. Multivariable logistic regression models were used to assess the association between diuretic dose and clinical features.Results In this cohort, 8512 (82.1%) patients used diuretics, of which 8179 (96.1%) used LDs. LD use was highest among HF with reduced EF (HFrEF) patients (81.1%) followed by HF with mild-reduced EF (76.1%) and HF with preserved ejection fraction EF (73.8%, p80 mg, across all HF categories. Renal impairment was associated with a higher FDE across the entire EF spectrum.Conclusion In this large registry of real-world HF patients, LD use was highest among HFrEF patients. Advanced symptoms, diabetes mellitus and worse renal function were significantly associated with a higher diuretic dose regardless of left ventricular ejection fraction.

Abstract 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

Abstract 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

Abstract 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

Aims: Implementation of guideline-recommended pharmacological treatment in heart failure (HF) patients remains challenging. In 2021, the European Heart Failure Association (HFA) published a consensus document in which patient profiles were created based on readily available patient characteristics and suggested that treatment adjusted to patient profile may result in better individualized treatment and improved guideline adherence. This study aimed to assess the distribution of these patient profiles and their treatment in a large real-world chronic HF cohort.Methods and results: The HFA combined categories of heart rate, blood pressure, presence of atrial fibrillation, chronic kidney disease, and hyperkalemia into eleven phenotypic patient profiles. A total of 4,455 patients with chronic HF and a left ventricular ejection fraction ≤40% with complete information on all characteristics were distributed over these profiles. In total, 1,640 patients (36.8%) could be classified into one of the HFA profiles. Three of these each comprised >5% of the population and consisted of patients with a heart rate >60 beats per minute with normal blood pressure (>90/60 mmHg) and no hyperkalemia.Conclusion: Nearly forty percent of a real-world chronic HF population could be distributed over the eleven patient profiles as suggested by the HFA. Phenotype-specific treatment recommendations are clinically relevant and important to further improve guideline implementation.

Abstract Mortality in type 2 diabetes, is determined not only by classical complications, but also by comorbidities, and is linked to hyperglycaemia and apparent even in prediabetes. We aimed to comprehensively investigate, in a population-based cohort, health burden defined as the presence of comorbidities in addition to classical complications and cardiometabolic risk factors, in not only type 2 diabetes but also prediabetes. Such population-based study has not been performed previously. Extensive phenotyping was performed in 3,410 participants of the population-based Maastricht Study (15.0% prediabetes and 28.6% type 2 diabetes) to assess presence of 17 comorbidities, six classical complications, and ten cardiometabolic risk factors. These were added up into individual and combined sum scores and categorized. Group differences were studied with multinomial regression analyses adjusted for age and sex. Individuals with type 2 diabetes and prediabetes, as compared to normal glucose metabolism (NGM), had greater comorbidities, classical complications, cardiometabolic risk factors and combined sum scores (comorbidities sum score ≥ 3: frequencies (95% CI) 61.5% (57.6;65.4) and 41.2% (36.5;45.9) vs. 25.4% (23.5;27.4), p-trend

Abstract Aims Heart failure (HF) represents a clinical syndrome resulting from different aetiologies and degrees of heart diseases. Among these, a key role is played by primary heart muscle disease (cardiomyopathies), which are the combination of multifactorial environmental insults in the presence or absence of a known genetic predisposition. The aim of the Maastricht Cardiomyopathy registry (mCMP‐registry; NCT04976348) is to improve (early) diagnosis, risk stratification, and management of cardiomyopathy phenotypes beyond the limits of left ventricular ejection fraction (LVEF). Methods and results The mCMP‐registry is an investigator‐initiated prospective registry including patient characteristics, diagnostic measurements performed as part of routine clinical care, treatment information, sequential biobanking, quality of life and economic impact assessment, and regular follow‐up. All subjects aged ≥16 years referred to the cardiology department of the Maastricht University Medical Center (MUMC+) for HF‐like symptoms or cardiac screening for cardiomyopathies are eligible for inclusion, irrespective of phenotype or underlying causes. Informed consented subjects will be followed up for 15 years. Two central approaches will be used to answer the research questions related to the aims of this registry: (i) a data‐driven approach to predict clinical outcome and response to therapy and to identify clusters of patients who share underlying pathophysiological processes; and (ii) a hypothesis‐driven approach in which clinical parameters are tested for their (incremental) diagnostic, prognostic, or therapeutic value. The study allows other centres to easily join this initiative, which will further boost research within this field. Conclusions The broad inclusion criteria, systematic routine clinical care data‐collection, extensive study‐related data‐collection, sequential biobanking, and multi‐disciplinary approach gives the mCMP‐registry a unique opportunity to improve diagnosis, risk stratification, and management of HF and (early) cardiomyopathy phenotypes beyond the LVEF limits.

Abstract Aims The prevalence and the natural course of iron deficiency (ID) in acute heart failure (AHF) are still unclear. We investigated the prevalence of ID in unselected patients admitted with AHF on admission, at discharge and up to 3 months thereafter. Methods and results In this prospective, multicentre, observational study, 742 patients admitted with AHF were enrolled. The main study outcome was the percentage of patients with ID (ferritin

Abstract Aims Although diabetes mellitus (DM) is a common co‐morbidity in chronic heart failure (HF) patients, European data on concurrent HF and DM treatment are lacking. Therefore, we have studied the HF treatment of patients with and without DM. Additionally, with the recent breakthrough of sodium–glucose cotransporter 2 (SGLT2) inhibitors in the field of HF, we studied the potential impact of this new drug in a large cohort of HF patients. Methods and results A total of 7488 patients with chronic HF with a left ventricular ejection fraction

Abstract Aims This study aimed to assess the sex‐specific distribution of heart failure (HF) with preserved, mid‐range, and reduced ejection fraction across three health care settings. Methods and results In this descriptive observational study, we retrieved the distribution of HF types [with reduced ejection fraction (HFrEF), mid‐range ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF)] for men and women between 65 and 79 years of age in three health care settings from a single country: (i) patients with screening‐detected HF in the high‐risk community (i.e. those with shortness of breath, frailty, diabetes mellitus, and chronic obstructive pulmonary disease) from four screening studies, (ii) patients with confirmed HF from primary care derived from a single observational study, and (iii) patients with confirmed HF from outpatient cardiology clinics participating in a registry. Among 1407 patients from the high‐risk community, 288 had screen‐detected HF (15% HFrEF, 12% HFmrEF, 74% HFpEF), and 51% of the screen‐detected HF patients were women. In both women (82%) and men (65%), HFpEF was the most prevalent HF type. In the routine general practice population (30 practices, 70 000 individuals), among the 160 confirmed HF cases, 35% had HFrEF, 23% HFmrEF, and 43% HFpEF, and in total, 43% were women. In women, HFpEF was the most prevalent HF type (52%), while in men, this was HFrEF (41%). In outpatient cardiology clinics (n = 34), of the 4742 HF patients (66% HFrEF, 15% HFmrEF, 20% HFpEF), 36% were women. In both women (56%) and men (71%), HFrEF was the most prevalent HF type. Conclusions Both HF types and sex distribution vary considerably in HF patients of 65–79 years of age among health care settings. From the high‐risk community through to general practice to the cardiology outpatient setting, there is a shift in HF type from HFpEF to HFrEF and a decrease in the proportion of HF patients that are women.

Abstract Background Needs assessment tools can facilitate healthcare professionals in timely recognition of palliative care needs. Despite the increased attention for implementation of such tools, most studies provide little or no attention to the context of implementation. The aim of this study was to explore factors that contribute positively and negatively to timely screening of palliative care needs in advanced chronic heart failure. Methods Qualitative study using individual interviews and focus groups with healthcare professionals. The data were analysed using a deductive approach. The Consolidated Framework for Implementation Research was used to conceptualise the contextual factors. Results Twenty nine healthcare professionals with different backgrounds and working in heart failure care in the Southern and Eastern parts of the Netherlands participated. Several factors were perceived to play a role, such as perception and knowledge about palliative care, awareness of palliative care needs in advanced chronic heart failure, perceived difficulty when and how to start palliative care, limited acceptance to treatment boundaries in cardiology, limited communication and collaboration between healthcare professionals, and need for education and increased attention for palliative care in advanced chronic heart failure guidelines. Conclusions This study clarified critical factors targeting patients, healthcare professionals, organisations to implement a needs assessment tool for timely recognition of palliative care needs in the context of advanced chronic heart failure. A multifaceted implementation strategy is needed which has attention for education, patient empowerment, interdisciplinary collaboration, identification of local champions, chronic heart failure specific guidelines and culture.

Background Hospitalisations for heart failure are frequent and costly, linked with a lower quality of life, and lead to higher morbidity and mortality. Home hospitalisation interventions could be a substitute for in-hospital stays to reduce the burden on patients. The current study aims to investigate patient-reported satisfaction and usability in combination with the safety of a digital health-supported home hospitalisation intervention for heart failure patients. Methods We conducted an international, multicentre, single-arm, interventional study to investigate the feasibility and safety of a digital health-supported home hospitalisation platform. Patients with acute decompensation of known and well-assessed chronic heart failure with an indication for hospital admission were included. The primary outcome was patient satisfaction. Secondary outcomes were usability, adherence, and safety. Results A total number of 66 patients were included, of which the data of 65 patients (98.5%) was analysed. A total of 86.1% of patients reported being very satisfied or totally satisfied. No patients reported to be not satisfied with the home hospitalisation intervention. The patients reported a sufficient usability score (mean score: 75.8% of 100%) for the digital health-supported home hospitalisation platform. The adherence to the daily measurements of blood pressure and weight was very high, whereas the adherence to the daily interaction with the eCoach was lower (69.3%). In 7 patients (10.8%), a conversion from home hospitalisation to regular hospitalisation was needed. Furthermore, 6 patients (9.2%) had rehospitalisation within 30 days after the end of the home hospitalisation intervention. Conclusion A digitally supported home hospitalisation intervention is feasible. This study demonstrates high patient satisfaction and sufficiently high usability scores. The safety outcomes are comparable with traditional heart failure hospitalisations. This indicates that digitally supported home hospitalisation could be an alternative to in-hospital care for all age groups, yet further research is needed to prove the (cost-) effectiveness.

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P

Background: Cognitive impairment (CI) is common in patients with heart failure (HF) and impacts treatment adherence and other aspects of patient life in HF. Recognition of CI in patients with HF is therefore important. We aimed to develop a risk model with easily available patient characteristics, to identify patients with HF who are at high risk to be cognitively impaired and in need for further cognitive investigation. Methods & results: The risk model was developed in 611 patients ≥ 60 years with HF from the TIME-CHF trial. Fifty-six (9 %) patients had CI (defined as Hodkinson Abbreviated Mental Test ≤ 7). We assessed the association between potential predictors and CI with least-absolute-shrinkage-and-selection-operator (LASSO) regression analysis. The selected predictors were: older age, female sex, NYHA class III or IV, Charlson comorbidity index ≥ 6, anemia, heart rate ≥ 70 bpm and systolic blood pressure ≥ 145 mmHg. A model that combined these variables had a c-statistic of 0.70 (0.63–0.78). The model was validated in 155 patients ≥ 60 years with HF from the ECHO study. In the validation cohort 51 (33 %) patients had CI (defined as a Mini Mental State Exam ≤ 24). External validation showed an AUC of 0.56 (0.46–0.66). Conclusions: This risk model with easily available patient characteristics has poor predictive performance in external validation, which may be due to case-mix variation. These findings underscore the need for active screening and standardized assessment for CI in patients with HF.

Objectives Predicting the presence or absence of coronary artery disease (CAD) is clinically important. Pretest probability (PTP) and CAD consortium clinical (CAD2) model and risk scores used in the guidelines are not sufficiently accurate as the only guidance for applying invasive testing or discharging a patient. Artificial intelligence without the need of additional non-invasive testing is not yet used in this context, as previous results of the model are promising, but available in high-risk population only. Still, validation in low-risk patients, which is clinically most relevant, is lacking.Design Retrospective cohort study.Setting Secondary outpatient clinic care in one Dutch academic hospital.Participants We included 696 patients referred from primary care for further testing regarding the presence or absence of CAD. The results were compared with PTP and CAD2 using receiver operating characteristic (ROC) curves (area under the curve (AUC)). CAD was defined by a coronary stenosis >50% in at least one coronary vessel in invasive coronary or CT angiography, or having a coronary event within 6 months.Outcome measures The first cohort validating the memetic pattern-based algorithm (MPA) model developed in two high-risk populations in a low-risk to intermediate-risk cohort to improve risk stratification for non-invasive diagnosis of the presence or absence of CAD.Results The population contained 49% male, average age was 65.6±12.6 years. 16.2% had CAD. The AUCs of the MPA model, the PTP and the CAD2 were 0.87, 0.80, and 0.82, respectively. Applying the MPA model resulted in possible discharge of 67.7% of the patients with an acceptable CAD rate of 4.2%.Conclusions In this low-risk to intermediate-risk population, the MPA model provides a good risk stratification of presence or absence of CAD with a better ROC compared with traditional risk scores. The results are promising but need prospective confirmation.

Abstract Background Patients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The “Heart OMics in AGEing” (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial. Methods Protein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes. Results Twenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05). Conclusions Amongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.

Background Interatrial block (IAB) has been associated with supraventricular arrhythmias and stroke, and even with sudden cardiac death in the general population. Whether IAB is associated with life‐threatening arrhythmias (LTA) and sudden cardiac death in dilated cardiomyopathy (DCM) remains unknown. This study aimed to determine the association between IAB and LTA in ambulant patients with DCM. Methods and Results A derivation cohort (Maastricht Dilated Cardiomyopathy Registry; N=469) and an external validation cohort (Utrecht Cardiomyopathy Cohort; N=321) were used for this study. The presence of IAB (P‐wave duration>120 milliseconds) or atrial fibrillation (AF) was determined using digital calipers by physicians blinded to the study data. In the derivation cohort, IAB and AF were present in 291 (62%) and 70 (15%) patients with DCM, respectively. LTA (defined as sudden cardiac death, justified shock from implantable cardioverter‐defibrillator or anti‐tachypacing, or hemodynamic unstable ventricular fibrillation/tachycardia) occurred in 49 patients (3 with no IAB, 35 with IAB, and 11 patients with AF, respectively; median follow‐up, 4.4 years [2.1; 7.4]). The LTA‐free survival distribution significantly differed between IAB or AF versus no IAB (both P

Abstract Aims Whether and how iron deficiency (ID) impacts patients with heart failure (HF) with preserved ejection fraction (HFpEF) remain unclear. The aim of our study was to investigate the impact of ID on functional status, exercise capacity, and prognosis in HFpEF. Methods and results The study population consisted of 300 HFpEF patients. ID was defined as serum ferritin

Abstract Aims Global longitudinal strain (GLS) has become an alternative to left ventricular ejection fraction (LVEF) to determine systolic function of the heart. The absence of cut‐off values is one of the limitations preventing full clinical implementation. The aim of this study is to determine a cut‐off value of GLS for an increased risk of adverse events in individuals with a normal LVEF. Methods and results Echocardiographic images of 502 subjects (52% female, mean age 48 ± 15) with an LVEF ≥ 55% were analysed using speckle tracking‐based GLS. The primary endpoint was cardiovascular death or cardiac hospitalization. The analysis of Cox models with splines was performed to visualize the effect of GLS on outcome. A cut‐off value was suggested by determining the optimal specificity and sensitivity. The median GLS was −22.2% (inter‐quartile range −20.0 to −24.9%). In total, 35 subjects (7%) had a cardiac hospitalization and/or died because of cardiovascular disease during a follow‐up of 40 (5–80) months. There was a linear correlation between the risk for adverse events and GLS value. Subjects with a normal LVEF and a GLS between −22.9% and −20.9% had a mildly increased risk (hazard ratio 1.01–2.0) for cardiac hospitalization or cardiovascular mortality, and the risk was doubled for subjects with a GLS of −20.9% and higher. The optimal specificity and sensitivity were determined at a GLS value of −20.0% (hazard ratio 2.49; 95% confidence interval: 1.71–3.61). Conclusions There is a strong correlation between cardiac adverse events and GLS values in subjects with a normal LVEF. In our single‐centre study, −20.0% was determined as a cut‐off value to identify subjects at risk. A next step should be to integrate GLS values in a multi‐parametric model.

Abstract Background Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce. Methods A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models. Results We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83–2.63), p = 0.18. Conclusion In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.

Abstract Backgrounds The role of right ventricular (RV) and atrial (RA) structure and function, in the increased heart failure risk in (pre)diabetes is incompletely understood. The purpose of this study is to investigate the associations between (pre)diabetes and RV and RA structure and function, and whether these are mediated by left ventricular (LV) alterations or pulmonary pressure. Methods Participants of the Maastricht Study; a population-based cohort study (426 normal glucose metabolism (NGM), 142 prediabetes, 224 diabetes), underwent two-dimensional and tissue Doppler echocardiography. Multiple linear regression analyses with pairwise comparisons of (pre)diabetes versus NGM, adjusted for cardiovascular risk factors, and mediation analyses were used. Results In general, differences were small. Nevertheless, in individuals with prediabetes and diabetes compared to NGM; RA volume index was lower (both p

Background This cross‐sectional study evaluated associations between structural and functional measures of left ventricular diastolic function and cardiorespiratory fitness (CRF) in a well‐characterized population‐based cohort stratified according to glucose metabolism status. Methods and Results Six hundred seventy‐two participants from The Maastricht Study (mean±SD age, 61±9 years; 17.4% prediabetes and 25.4% type 2 diabetes mellitus) underwent both echocardiography to determine left atrial volume index, left ventricular mass index, maximum tricuspid flow regurgitation, average e′ and E/e′ ratio; and submaximal cycle ergometer test to determine CRF as maximum power output per kilogram body mass. Associations were examined with linear regression adjusted for cardiovascular risk and lifestyle factors, and interaction terms. After adjustment, in normal glucose metabolism but not (pre)diabetes, higher left atrial volume index (per 1 mL/m2), left ventricular mass index (per 1 g/m2.7), maximum tricuspid regurgitation flow (per 1 m/s) were associated with higher CRF (maximum power output per kilogram body mass; β in normal glucose metabolism 0.015 [0.008–0.023], Pinteraction (pre)diabetes 0.10; for left atrial volume index, left ventricular mass index, maximum tricuspid regurgitation flow, respectively). Furthermore, after adjustment, in all individuals, higher average E/e′ ratio (per unit), but not average e′, was associated with lower CRF (normal glucose metabolism −0.044 [−0.071 to −0.016]), Pinteraction >0.10). Conclusions In this population‐based study, structural and functional measures of left ventricular diastolic function were independently differentially associated with CRF over the strata of glucose metabolism status. This suggests that deteriorating left ventricular diastolic function, although of small effect, may contribute to the pathophysiological process of impaired CRF in the general population. Moreover, the differential effects in these structural measures may be the consequence of cardiac structural adaptation to effectively increase CRF in normal glucose metabolism, which is absent in (pre)diabetes.

Objective Heart failure is a growing challenge to healthcare systems worldwide. Technological solutions have the potential to improve the health of patients and help to reduce costs. Acceptability is a prerequisite for the use and a successful implementation of new disruptive technologies. This qualitative study aimed to explore determinants that influence the acceptance of patients and their informal caregivers regarding a patient-oriented digital decision-making solution—a doctor-at-home system.Design We applied a semistructured design using an interview guide that was based on a theoretical framework influenced by established acceptance theories. The interviews were analysed using a content analysis.Setting A multicentred study in four European countries.Participants We interviewed 49 patients and 33 of their informal caregivers. Most of the patients were male (76%) and aged between 60 and 69 years (43%). Informal caregivers were mostly female (85%). The majority of patients (55%) suffered from heart failure with mild symptoms.Results Four main categories emerged from the data: needs and expectations, preferences regarding the care process, perceived risk and trust. Participants expressed clear wishes and expectations regarding a doctor-at-home, especially the need for reassurance and support in the management of heart failure. They were receptive to changes to the current healthcare processes. However, trust was identified as an important basis for acceptance and use. Finally, perceived risk for decision-making errors is a crucial topic in need of attention.Conclusion Patients and informal caregivers see clear benefits of digitalisation in healthcare. They perceive that an interactive decision-making system for patients could empower and enable effective self-care. Our results provide important insights for development processes of patient-centred decision-making systems by identifying facilitators and barriers for acceptance. Further research is needed, especially regarding the influence and mitigation of patients and informal caregivers’ perceived risks.

The vast majority of acute heart failure episodes are characterized by increasing symptoms and signs of congestion with volume overload. The goal of therapy in those patients is the relief of congestion through achieving a state of euvolaemia, mainly through the use of diuretic therapy. The appropriate use of diuretics however remains challenging, especially when worsening renal function, diuretic resistance and electrolyte disturbances occur. This position paper focuses on the use of diuretics in heart failure with congestion. The manuscript addresses frequently encountered challenges, such as (i) evaluation of congestion and clinical euvolaemia, (ii) assessment of diuretic response/resistance in the treatment of acute heart failure, (iii) an approach towards stepped pharmacologic diuretic strategies, based upon diuretic response, and (iv) management of common electrolyte disturbances. Recommendations are made in line with available guidelines, evidence and expert opinion.

Normal brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels are helpful in excluding chronic heart failure in the ambulatory setting, although they have been studied less well and possibly less accurately than in acute care. They may also be of help in screening patients at risk to intervene and reduce the development of heart failure. Natriuretic peptides are also excellent prognostic markers of chronic heart failure, but the clinical value of such prognostic information is less clear. One possible application for this information is guiding medical therapy in chronic heart failure. Many studies have investigated this approach, but results are mixed and do not clearly show improvement in outcome. Still, it may be that in patients with reduced ejection fraction and few comorbidities, measuring NT-proBNP to uptitrate medication improves prognosis.

Background During uncomplicated pregnancy, left ventricular remodeling occurs in an eccentric way. In contrast, during preeclamptic gestation, the left ventricle hypertrophies concentrically, concurrent with loss in circulatory volume and increased blood pressure. Concentric cardiac structure persists in a substantial proportion of women and may be associated with pressure and volume load after preeclampsia. We hypothesize that low volume load, as indicated by plasma volume (PV) after preeclampsia and increased pressure load, is associated with remote concentric remodeling. Methods and Results In this longitudinal cohort study, we included 100 formerly preeclamptic women. Two visits were performed: at 0.8 years postpartum and at 4.8 years postpartum. During visit 1, we measured blood pressure and PV (I125 dilution technique, low PV ≤48 mL/kg lean body mass). During the second visit, we assessed cardiac geometry by cardiac ultrasound. Concentric remodeling was defined as relative wall thickness >0.42 and left ventricular mass index ≤95 g/m2. We adjusted multivariable analysis for primiparity, systolic blood pressure, PV mL/kg lean body mass, and antihypertensive medication at visit 1. Low PV is associated with remote concentric remodeling (odds ratio [OR], 4.37; 95% CI, 1.06–17.40; and adjusted OR, 4.67; 95% CI, 1.02–21.42). Arterial pressure load (systolic, diastolic, and mean arterial pressure) is also associated with development of concentric remodeling (OR, 1.15 [95% CI, 0.99–1.35]; OR, 1.24 [95% CI, 0.98–1.58]; and OR, 1.20 [95% CI, 0.98–1.47], respectively). Conclusions In former preeclamptic women, development toward left ventricular concentric remodeling is associated with low volume load and increased pressure load.

BackgroundChronic diseases are increasingly prevalent in Western countries. Once hospitalised, the chance for another hospitalisation increases sharply with large impact on well-being of patients and costs. The pattern of readmissions is very complex, but poorly understood for multiple chronic diseases.MethodsThis cohort study of administrative discharge data between 2009-2014 from 21 tertiary hospitals (eight USA, five UK, four Australia, four continental Europe) investigated rates and reasons of readmissions to the same hospital within 30 days after unplanned admission with one of the following chronic conditions; heart failure; atrial fibrillation; myocardial infarction; hypertension; stroke; chronic obstructive pulmonary disease (COPD); bacterial pneumonia; diabetes mellitus; chronic renal disease; anaemia; arthritis and other cardiovascular disease. Proportions of readmissions with similar versus different diseases were analysed.ResultsOf 4,901,584 admissions, 866,502 (17.7%) were due to the 12 chronic conditions. In-hospital, 43,573 (5.0%) patients died, leaving 822,929 for readmission analysis. Of those, 87,452 (10.6%) had an emergency 30-day readmission, rates ranged from 2.8% for arthritis to 18.4% for COPD. One third were readmitted with the same condition, ranging from 53% for anaemia to 11% for arthritis. Reasons for readmission were due to another chronic condition in 10% to 35% of the cases, leaving 30% to 70% due to reasons other than the original 12 conditions (most commonly, treatment related complications and infections). The chance of being readmitted with the same cause was lower in the USA, for female patients, with increasing age, more co-morbidities, during study period and with longer initial length of stay.ConclusionReadmission in chronic conditions is very common and often caused by diseases other than the index hospitalisation. Interventions to reduce readmissions should therefore focus not only on the primary condition but on a holistic consideration of all the patient's comorbidities.

Abstract Introduction We examined the role of hemodynamic dysfunction in cognition by relating cerebral blood flow (CBF), measured with arterial spin labeling (ASL), to cognitive functioning, in patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (MRI; ie, possible vascular cognitive impairment [VCI]). Methods We included 439 participants (124 HF; 75 COD; 127 possible VCI; 113 reference participants) from the Dutch multi‐center Heart–Brain Study. We used pseudo‐continuous ASL to estimate whole‐brain and regional partial volume‐corrected CBF. Neuropsychological tests covered global cognition and four cognitive domains. Results CBF values were lowest in COD, followed by VCI and HF, compared to reference participants. This did not explain cognitive impairment, as we did not find an association between CBF and cognitive functioning. Discussion We found that reduced CBF is not the major explanatory factor underlying cognitive impairment in patients with hemodynamic dysfunction along the heart–brain axis.

There is limited evidence on the relationships of preference for end-of-life life-sustaining treatments [LSTs] and diagnostic contexts like heart failure [HF] or cancer, and patient attitudes toward and perceived susceptibility to use advance directives [ADs]. Thus, this study aimed to compare attitudes and perceived susceptibility between HF patients and community-dwelling patients with cancer, and examine the associations of these variables with their preference for each LST (cardiopulmonary resuscitation [CPR], ventilation support, hemodialysis, and hospice care). Secondary data were obtained from 36 outpatients with HF (mean age, 65.44 years; male, 69.4%) and 107 cancer patients (mean age, 67.39 years; male, 32.7%). More patients with HF preferred CPR than cancer patients (41.7% and 15.9%, χ2 = 8.88, P = 0.003). Attitudes and perceived susceptibility were similar between the two diagnostic cohorts. HF patients and those with more positive attitudes had greater odds of preferring CPR (odds ratio [OR] = 3.02, confidence interval [CI] = 1.19, 7.70) and hospice care (OR = 1.14, CI = 1.06, 1.23), respectively. HF diagnosis and AD attitudes increased the preference for CPR and hospice care, respectively. This suggests that it is important to gain positive attitudes toward ADs and consider diagnostic context to facilitate informed decision-making for LSTs.

Abstract Background The costs for treating coronary artery disease (CAD) are high worldwide. We performed a prespecified analyses of cost-effectiveness of three therapeutic strategies for multivessel CAD. Methods From May 1995 to May 2000, a total of 611 patients were randomly assigned to coronary artery bypass graft (CABG), n = 203; percutaneous coronary intervention (PCI), n = 205; or medical treatment (MT), n = 203. This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALYs) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the three treatment options produced significant improvements in QALYs. After 5 years, PCI and CABG had better QALYs results compared with MT. The ICER results favored CABG and PCI, and favored PCI over CABG in 61% of the drawings. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusions At 5-year follow-up, the three treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of cost-effectiveness after 5 years of follow-up among the three treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT. Trial registration ISRCTN, ISRCTN66068876, Registered 06/10/1994, http://www.controlled-trials.com/ISRCTN66068876

Background: Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are. Here, we provide an overview of the design and protocol. Methods: The Heart-Brain Study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling. In subsets of participants we assess Alz­heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines. Results and Conclusions: The Heart-Brain Study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor.

Extracellular matrix protein turnover may play an important role in left atrial (LA) remodelling. The aim is to investigate the associations between matrix metalloproteinase (MMPs), tissue inhibitor of metalloproteinase (TIMP-1) and LA volume index (LAVI) and if these associations are independent of TIMP-1 levels. Participants from The Hoorn Study, a population-based cohort study (n = 674), underwent echocardiography. Serum MMPs (i.e., MMP-1, MMP-2, MMP-3, MMP-9, and MMP-10) and TIMP-1 levels were measured with ELISA. Multiple linear regression analyses were used. MMP-1 levels were not associated with LAVI. Higher MMP-2 levels were associated with larger LAVI (regression coefficient per SD increase in MMP (95% CI); 0.03 (0.01; 0.05). Higher MMP-3 and MMP-9 levels were associated with smaller LAVI; −0.04 (−0.07; −0.01) and −0.04 (−0.06; −0.02) respectively. Only in women were higher MMP-10 levels associated with larger LAVI; 0.04 (0.00; 0.07, p-interaction 0.04). Additionally, only in women were higher TIMP-1 levels associated with smaller LAVI; −0.05 (−0.09; −0.01, p-interaction 0.03). The associations between MMPs and LAVI were independent of TIMP-1 levels. In conclusion, serum MMPs are associated with LAVI, independent of CVD risk factors and TIMP-1 levels. In addition, these associations differ according to sex and within MMP subgroups. This shows that the role of MMPs in LA remodelling is complex.

BACKGROUND:Normal high sensitivity cardiac troponin (hs-cTn) assays rule out acute myocardial infarction (AMI) with great accuracy, but additional non-invasive testing is frequently ordered. This observational study evaluates whether clinical characteristics can contribute to risk stratification and could guide referral for additional testing. METHODS:918 serial patients with acute chest pain and normal hs-cTnT levels were prospectively included. Major adverse cardiac events (MACE) and non-invasive test results were assessed during one-year follow-up. Patients were classified as low and high risk based on clinical characteristics. RESULTS:MACE occurred in 6.1% of patients and mainly comprised revascularizations (86%). A recent abnormal stress test, suspicious history, a positive family history and higher baseline hs-cTnT levels were independent predictors of MACE with odds ratios of 16.00 (95%CI:6.25-40.96), 16.43 (6.36-42.45), 2.33 (1.22-4.42) and 1.10 (1.01-1.21), respectively. Absence of both recent abnormal stress test and suspicious history identified 86% of patients. These patients were at very low risk for MACE (0.4% in 30-days and 2.3% in one-year). Despite this, the majority (287/345 = 83%) of additional tests were performed in low risk patients, with

Approximately one third of patients treated with cardiac resynchronization therapy do not derive any detectable benefit. In these patients, acute invasive hemodynamic evaluation can be used for therapy optimization. This report describes the use of systematic invasive hemodynamic measurements for clinical decision making in a patient who experienced severe ventricular arrhythmias and clinical deterioration following a biventricular upgrade.

BackgroundThe prognostic value of the change in heart rate from the supine to upright position (∆HR) in patients with chronic heart failure (HF) is unknown. Methods and Results∆HR was measured in patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME‐CHF) who were in sinus rhythm and had no pacemaker throughout the trial (n=321). The impact of ∆HR on 18‐month outcome (HF hospitalization‐free survival) was assessed. In addition, the prognostic effect of changes in ∆HR between baseline and month 6 on outcomes in the following 12 months was determined. A lower ∆HR was associated with a higher risk of death or HF hospitalization (hazard ratio 1.79 [95% confidence interval {95% CI} 1.19‐2.75] if ∆HR ≤3 beats/min [bpm], P=0.004). In the multivariate analysis, lower ∆HR remained an independent predictor of death or HF hospitalization (hazard ratio 1.75 [95% CI, 1.18‐2.61] if ∆HR ≤3 bpm, P=0.004) along with ischemic HF etiology, lower estimated glomerular filtration rate, presence and extent of rales, and no baseline β‐blocker use. In patients without event during the first 6 months, the change in ∆HR from baseline to month 6 predicted death or HF hospitalization during the following 12 months (hazard ratio=2.13 [95% CI 1.12–5.00] if rise in ∆HR

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.