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Aims: Two key echocardiographic parameters that are currently used to diagnose heart failure (HF) with preserved ejection fraction (HFpEF) are left atrial volume index (LAVi) and left ventricular mass index (LVMi). We investigated whether patients' characteristics, biomarkers, and co‐morbidities are associated with these parameters and whether the relationships differ between patients with HFpEF or HF with reduced ejection fraction (HFrEF). Methods: We consecutively enrolled 831 outpatients with typical signs and symptoms of HF and elevated N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) levels and categorized patients based upon left ventricular ejection fraction (LVEF): LVEF < 40% (HFrEF), LVEF between 40% and 50% (HF with mid‐range ejection fraction), and LVEF ≥ 50% (HFpEF). The study includes consecutively enrolled HF patients from an HF outpatient clinic at a tertiary medical centre in the Netherlands. All patients underwent baseline characterization, laboratory measurements, and echocardiography. Results: Four hundred sixty‐nine patients had HFrEF, 189 HF with mid‐range ejection fraction, and 173 HFpEF. The patients with HFrEF were rather male [HFrEF: 323 (69%); HFpEF: 80 (46%); P < 0.001], and the age was comparable (HFrEF 67 ± 13; HFpEF 70 ± 14; P = 0.069). In HFpEF, more patients had hypertension [190 (40.5%); 114 (65.9%); P < 0.001], higher body mass indices (27 ± 8; 30 ± 7; P < 0.001), and atrial fibrillation [194 (41.4); 86 (49.7); P = 0.029]. The correlation analyses showed that in HFrEF patients, LAVi was significantly associated with age (β 0.293; P < 0.001), male gender (β 0.104; P = 0.042), body mass index (β −0160; P = 0.002), diastolic blood pressure (β −0.136; P < 0.001), New York Heart Association (β 0.174; P = 0.001), atrial fibrillation (β 0.381; P < 0.001), galectin 3 (β 0.230; P < 0.001), NT‐proBNP (β 0.183; P < 0.001), estimated glomerular filtration rate (β −0.205; P < 0.001), LVEF (β −0.173; P = 0.001), and LVMi (β 0.337; P < 0.001). In HFpEF patients, only age (β 0.326; P < 0.001), atrial fibrillation (β 0.386; P < 0.001), NT‐proBNP (β 0.176; P = 0.036), and LVMi (β 0.213; P = 0.013) were associated with LAVi. Conclusions: Although LVMi and LAVi are hallmark parameters to diagnose HFpEF, they only correlate with a few characteristics of HF and mainly with atrial fibrillation. In contrast, in HFrEF patients, LAVi relates strongly to several other HF parameters. These findings underscore the complexity in visualizing the pathophysiology of HFpEF and question the relation between cardiac structural remodeling and the impact of co‐morbidities. [ABSTRACT FROM AUTHOR]

Aims: Evidence on the association of macrophage‐ and neutrophil‐related blood biomarkers with clinical outcome in heart failure patients is limited, and, with the exception of C‐reactive protein, no data exist on their temporal evolution. We aimed to investigate whether temporal patterns of these biomarkers are related to clinical outcome in patients with stable chronic heart failure (CHF). Methods and Results: In 263 patients with CHF, we performed serial plasma measurements of scavenger receptor cysteine‐rich type 1 protein M130 (CD163), tartrate‐resistant acid phosphatase type 5 (TRAP), granulins (GRN), spondin‐1 (SPON1), peptidoglycan recognition protein 1 (PGLYRP1), and tissue factor pathway inhibitor (TFPI). The Cardiovascular Panel III (Olink Proteomics AB, Uppsala, Sweden) was used. During 2.2 years of follow‐up, we collected 1984 samples before the occurrence of the composite primary endpoint (PE) or censoring. For efficiency, we selected 567 samples for the measurements (all baseline samples, the last two samples preceding the PE, and the last sample before censoring in event‐free patients). The relationship between repeatedly measured biomarker levels and the PE was evaluated by joint models. Mean (±standard deviation) age was 67 ± 13 years; 189 (72%) were men; left ventricular ejection fraction (%) was 32 ± 11. During follow‐up, 70 (27%) patients experienced the PE. Serially measured biomarkers predicted the PE in a multivariable model adjusted for baseline clinical characteristics [hazard ratio (95% confidence interval) per 1‐standard deviation change in biomarker]: CD163 [2.07(1.47–2.98), P < 0.001], TRAP [0.62 (0.43–0.90), P = 0.009], GRN [2.46 (1.64–3.84), P < 0.001], SPON1 [3.94 (2.50–6.50), P < 0.001], and PGLYRP1 [1.62 (1.14–2.31), P = 0.006]. Conclusions: Changes in plasma levels of CD163, TRAP, GRN, SPON1, and PGLYRP1 precede adverse cardiovascular events in patients with CHF. [ABSTRACT FROM AUTHOR]

Background: Information on the pathophysiological differences between heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF) is needed OBJECTIVES: The purpose of this study was to establish biological pathways specifically related to HFrEF and HFpEF.Methods: The authors performed a network analysis to identify unique biomarker correlations in HFrEF and HFpEF using 92 biomarkers from different pathophysiological domains in a cohort of 1,544 heart failure (HF) patients. Data were independently validated in 804 patients with HF. Networks were enriched with existing knowledge on protein-protein interactions and translated into biological pathways uniquely related to HFrEF, HF with a midrange ejection fraction, and HFpEF.Results: In the index cohort (mean age 74 years; 34% female), 718 (47%) patients had HFrEF (left ventricular ejection fraction [LVEF] <40%) and 431 (27%) patients had HFpEF (LVEF ≥50%). A total of 8 (12%) correlations were unique for HFrEF and 6 (9%) were unique to HFpEF. Central proteins in HFrEF were N-terminal B-type natriuretic peptide, growth differentiation factor-15, interleukin-1 receptor type 1, and activating transcription factor 2, while central proteins in HFpEF were integrin subunit beta-2 and catenin beta-1. Biological pathways in HFrEF were related to DNA binding transcription factor activity, cellular protein metabolism, and regulation of nitric oxide biosynthesis. Unique pathways in patients with HFpEF were related to cytokine response, extracellular matrix organization, and inflammation. Biological pathways of patients with HF with a midrange ejection fraction were in between HFrEF and HFpEF.Conclusions: Network analysis showed that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarker profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization. (The BIOlogy Study to TAilored Treatment in Chronic Heart Failure [BIOSTAT-CHF]; EudraCT 2010-020808-29). [ABSTRACT FROM AUTHOR]

Introduction:Heart failure (HF) has become the cardiovascular epidemic of the century and now imposes an immense burden on health care systems. While our understanding of the pathophysiology of HF has increased dramatically, the translation of knowledge into clinical practice has been disappointing. Metabolic dysfunction in HF has been studied for eight decades, but these efforts have not resulted in effective therapies. This paucity in clinical translation probably results from the variable contribution of metabolic dysfunction to the underlying heart disease. A major unmet need in cardiac drug development is therefore the ability to identify a homogeneous subset of patients in whom HF is driven by a specific mechanism that can be targeted. Areas covered:The available literature was evaluated to describe maladaptive metabolic perturbations that occur in failing hearts and may cause metabolic inflexibility, oxidative stress and cardiac energy depletion. Furthermore, the potential utility of various biomarkers and molecular imaging techniques to detect and quantify specific metabolic dysfunctions in HF were compared. Finally, the authors propose ways to utilize these techniques to select patients for specific metabolic interventions. Expert commentary:Metabolic dysfunction is among the most promising therapeutic targets in HF. Meticulous patient-selection with molecular imaging techniques and specific biomarkers appears indispensable for the effective translation of decades of scientific knowledge into clinical therapeutics. [ABSTRACT FROM PUBLISHER]

Heart failure has become the cardiovascular epidemic of the century. The European Journal of Heart Failure is dedicated to the advancement of knowledge in the field of heart failure management. In 2012 and 2013, several pioneering scientific discoveries and paradigm-shifting clinical trials have been published. In the current paper, we will discuss the most significant novel insights into the pathophysiology, diagnosis, and treatment of heart failure that were published during this period. All relevant research areas are discussed, including pathophysiology, co-morbidities, arrhythmias, biomarkers, clinical trials, and device therapy, including left ventricular assist devices. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains a major medical problem, and the European Journal of Heart Failure is dedicated to publishing research further investigating its pathophysiology and diagnosis in order to help clinicians alleviate symptoms and improve patient outcomes.1 This review reports on important studies in the field of HF published in 2011. All research areas are addressed, including experimental studies, biomarkers, clinical trials, arrhythmias, and new insights into the role of device therapy. [ABSTRACT FROM AUTHOR]

Background The prognostic impact of reduced glomerular filtration rate (GFR) in chronic heart failure (CHF) is increasingly recognised, but little is known about tubular damage in these patients. Objective To investigate the prevalence of tubular damage, and its association with GFR, and prognosis in patients with CHF. Methods and results In 90 patients with CHF, GFR and effective renal plasma flow (ERPF) were measured ([125I]iothalamate and [131I]hippuran clearances). The tubular markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as well as urinary albumin excretion were determined in 24 h urine collections. Mean GFR was 78±26 ml/min/1.73 m². Urinary NGAL (175 (70-346) µg/g creatinine (gCr)), NAG (12 (6-17) U/gCr) and KIM-1 (277 (188-537) ng/gCr) levels were increased compared with 20 healthy controls (all p<0.001). Urinary NAG, but not NGAL or KIM-1 correlated with GFR (r=-0.34, p=0.001) and ERPF (r=-0.29, p=0.006). Both NAG (r=0.21, p=0.048) and KIM-1 (r=0.23, p=0.033) correlated with plasma N-terminal pro-brain natriuretic peptide levels. Both urinary KIM-1 (HR=1.15 (95% CI 1.02 to 1.30) per 100 ng/gCr increase, p=0.025) and NAG (HR=1.42 (95% CI 1.02 to 1.94) per 5 U/gCr increase, p=0.039), were associated with an increased risk of death or heart failure hospitalisations, independent of GFR. Conclusion Tubular damage, as indicated by increased urinary concentrations of NGAL, NAG and KIM-1 is common in patients with CHF and mildly reduced GFR. Both urinary KIM-1 and NAG showed prognostic information additional to GFR. These findings suggest an important role for tubular damage and tubular markers in cardiorenal interaction in heart failure. [ABSTRACT FROM AUTHOR]

BACKGROUND: The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD). METHODS: Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCHDM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] =12), NT-proBNP (N-terminal pro-B-type natriuretic peptide =125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T =14 ng/L; hs-cTnI =31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NTproBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated. RESULTS: The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358). CONCLUSIONS: Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer.Methods: HF was induced by inflicting large anterior myocardial infarction in APCmin mice, which are prone to developing precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was used in which an infarcted or sham-operated heart was transplanted into a recipient mouse while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-myocardial infarction proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and patients with HF. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large, prospective general population cohort.Results: The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4-fold in APCmin mice (all P<0.0001). The severity of left ventricular dysfunction and fibrotic scar strongly correlated with tumor growth ( P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and paraoxonase 1) that were elevated in human patients with chronic HF (n=101) compared with healthy subjects (n=180; P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (n=8319) were predictive of new-onset cancer (n=1124) independently of risk factors for cancer (age, smoking status, and body mass index).Conclusions: We demonstrate that the presence of HF is associated with enhanced tumor growth and that this is independent of hemodynamic impairment and could be caused by cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer. [ABSTRACT FROM AUTHOR]