Search

Objective: The aim of this study was to evaluate the roles of fibroblast growth factor 21 (FGF21) in heart failure patients with reduced ejection fraction and its association with Heart Failure with reduced Ejection Fraction (HFrEF)., Methods: The level of FGF21 was measured by enzyme-linked immunosorbent assay (ELISA) in 199 subjects enrolled in this study, including 128 subjects with HFrEF and 71 control subjects. The mean follow-up time was 13.36 months. The left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) percentage were evaluated by the 2D echocardiography. Serum brain natriuretic peptide (BNP) was measured in the routine clinical laboratory., Results: The serum FGF21 level was evidently higher in patients with HFrEF than in the control group (228.72 ± 24.04 vs. 171.60 ± 12.98, p < 0.001). After 1 year of follow-up, 61 patients (47.66%) with heart failure were readmitted to the hospital, including 8 deaths (13.11%). The AUC of the receiver operating characteristic (ROC) curve for the predictive value of FGF21 for prognosis was 0.964. Kaplan-Meier analysis results showed that there were significant differences in the 1-year mortality and heart failure readmission events between the grouped subjects. A poor prognosis was correlated with the serum level of FGF21, BNP, LVEDD, and LVEF, which was confirmed by the univariate Cox analysis., Conclusion: FGF21 was independently associated with an increased risk of mortality and readmission HFrEF patients. Therefore, FGF21 has the potential to be a biomarker for the progression of HFrEF in patients., Competing Interests: There are no conflicts of interest., (Copyright © 2022 Liuzhang Fan et al.)

Background: The relationship between the benefits of empagliflozin in heart failure with reduced ejection fraction (HFrEF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) has not been reported., Objectives: The authors sought to evaluate the relationship between NT-proBNP and empagliflozin effects in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)., Methods: Patients with HFrEF were randomly assigned to placebo or empagliflozin 10 mg daily. NT-proBNP was measured at baseline, 4 weeks, 12 weeks, 52 weeks, and 100 weeks. Patients were divided into quartiles of baseline NT-proBNP., Results: Incidence rates for each study outcome were 4- to 6-fold higher among those in the highest versus lowest NT-proBNP quartiles (≥3,480 vs <1,115 pg/mL). Study participants with higher NT-proBNP had 2- to 3-fold total hospitalizations higher than the lowest NT-proBNP quartile. Empagliflozin reduced risk for major cardiorenal events without heterogeneity across NT-proBNP quartiles (primary endpoint P interaction  = 0.94; renal composite endpoint P interaction  = 0.71). Empagliflozin treatment significantly reduced NT-proBNP at all timepoints examined; by 52 weeks, the adjusted mean difference from placebo was 13% (P < 0.001). An NT-proBNP in the lowest quartile (<1,115 pg/mL) 12 weeks after randomization was associated with lower risk for subsequent cardiovascular death or heart failure hospitalization regardless of baseline concentration. Treatment with empagliflozin resulted in 27% higher adjusted odds of an NT-proBNP concentration of <1,115 pg/mL by 12 weeks compared with placebo (P = 0.01)., Conclusions: In EMPEROR-Reduced, higher baseline NT-proBNP concentrations were associated with greater risk for adverse heart failure or renal outcomes, but empagliflozin reduced risk regardless of baseline NT-proBNP concentration. The NT-proBNP concentration after treatment with empagliflozin better informs subsequent prognosis than pretreatment concentrations. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures The EMPEROR-Reduced trial was supported by Boehringer Ingelheim and Eli Lilly and Company. Dr Januzzi is supported in part by the Hutter Family Professorship at Harvard Medical School; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in Clinical Endpoint Committees/Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. Dr Zannad has recently received Steering Committee or Advisory Board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius. Dr Anker has received fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; and has received grant support from Abbott and Vifor Pharma. Dr Butler is a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, V-Wave Limited, and Vifor. Dr Filippatos has lectured for and/or has Committee Member contributions in trials sponsored by Medtronic, Vifor, Servier, Novartis, Bayer, Amgen, and Boehringer Ingelheim. Dr Pocock is a consultant for Boehringer Ingelheim. Dr Ferreira is a consultant for Boehringer Ingelheim. Dr Sattar has consulted for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Novo Nordisk, Novartis, Sanofi, and Pfizer; and has received grant support from Boehringer Ingelheim. Drs Vedin and Schnee, Mr Cotton, and Ms Iwata are employees of Boehringer Ingelheim Pharmaceuticals. Dr Packer has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Lilly, Novartis, ParatusRx, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: The sodium glucose co-transporter 2 inhibitors have demonstrated favorable effects on cardiovascular and renal disease; however, they may also increase low-density lipoprotein cholesterol (LDL-C). There are limited data directly comparing the effects of sodium glucose co-transporter 2inhibitors on serum lipids to other antihyperglycemic therapies. In this post-hoc analysis of the CANA-HF trial, we sought to compare the effects of canagliflozin to sitagliptin in patients with type 2 diabetes mellitus (T2DM) and heart failure and reduced ejection fraction (HFrEF). The CANA-HF trial was a prospective, randomized controlled study that compared the effects of canagliflozin 100 mg daily to sitagliptin 100 mg daily on cardiorespiratory fitness in patients with HFrEF and T2DM. Of the 36 patients enrolled in CANA-HF, 35 patients had both baseline and 12-weeks serum lipids obtained via venipuncture. The change in LDL-C from baseline to 12 weeks was 5 (-12.5 to 19.5) mg/dL versus -8 (-19 to -1) mg/dL (P = 0.82) and triglyceride levels was -4 (-26 to 9) mg/dL and -10.5 (-50 to 29.3) mg/dL (P = 0.52) for canagliflozin and sitagliptin, respectively. No significant differences were found between canagliflozin and sitagliptin for total cholesterol, high-density lipoprotein cholesterol or non-HDL-C (P > 0.5 for all). These data suggest that compared with sitagliptin, canagliflozin may not increase LDL-C in patients with T2DM and HFrEF., Competing Interests: A. Abbate has served as consultant to Janssen. S. Carbone is supported by a Career Development Award 19CDA34660318 from the American Heart Association and by the Clinical and Translational Science Awards Program UL1TR002649 from National Institutes of Health to Virginia Commonwealth University. The remaining authors reports no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with ageing in HFrEF potentially leading to targeted therapies in this vulnerable population., Methods and Results: From a panel of 363 cardiovascular biomarkers available in 1611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged >75 vs. <65 years. Second, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly vs. younger patients. After adjustment, multiple test correction [false discovery rate (FDR) 1%], and cross-validation, 27/363 biomarkers were associated with older age, 22 positively and 5 negatively. The biomarkers that were positively associated with older age were associated with tumour cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumourigenesis. Among the 27 biomarkers, WFDC2 (WAP four-disulphide core domain protein 2)-that broadly functions as a protease inhibitor-was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed., Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumour cell regulation were activated, while pathways associated with tumour proliferation functions were down-regulated. These findings may help in a better understanding of the ageing processes in HFrEF and identify potential therapeutic targets., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Inflammation is one of the principal triggering mechanisms for left ventricular fibrosis and remodeling in heart failure, leading to adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, is assumed to play a significant role in the fibrotic response to inflammation. Left ventricular mass index (LVMI) is a parameter of the prefibrotic inflammatory phase of heart failure preceding remodeling. The present study aimed to investigate the prognostic value of the sST2/LVMI ratio in heart failure with reduced ejection fraction., Methods: This was a prospective cohort study. A total of 45 consecutive patients with heart failure with reduced ejection fraction, treated between September 2015 and December 2016, were enrolled. The sST2/LVMI ratio was measured at baseline. The primary endpoint was a composite of cardiovascular mortality and readmission for heart failure. The prognostic impact of the sST2/LVMI ratio was evaluated using a multivariable Cox proportional hazards regression model., Results: Forty-five patients were enrolled in this study. Their average age was 48 ± 14 years, and approximately 20% of them were men. Patients were followed for 9 months, during which the primary outcome occurred in 15 patients. Kaplan-Meier analysis showed that patients with a high sST2/LVMI ratio (≥ 0.39) had shorter event-free survival than those with intermediate (between 0.39 and 0.24) and low ratios (< 0.24) (log-rank, P = 0.022). The fully adjusted multivariable Cox regression analysis showed that the sST2/LVMI ratio was positively associated with the composite outcome in patients with heart failure with reduced ejection fraction after adjusting for confounders (hazard ratio 1.64, 95% confidence interval 1.06 to 2.54). By subgroup analysis, a stronger association was found with age between 40 and 55 years, systolic blood pressure < 115 or ≥ 129 mmHg, diastolic blood pressure < 74 mmHg, hematocrit < 44.5%, and interventricular septum thickness ≥ 8.5 mm., Conclusion: In patients with heart failure with reduced ejection fraction, the relationship between the sST2/LVMI ratio and the composite outcome was linear. A higher baseline ratio of sST2/LVMI was associated with an increased risk of cardiovascular mortality and heart failure rehospitalization in the short-term follow-up., (© 2021. The Author(s).)

Background: The endogenous lipid molecule sphingosine-1-phosphate (S1P) has received attention in the cardiovascular field due to its significant cardioprotective effects, as revealed in animal studies. The purpose of our study was to identify the distribution characteristics of S1P in systolic heart failure patients and the prognostic value of S1P for long-term prognosis., Methods: We recruited 210 chronic systolic heart failure patients from June 2014 to December 2015. Meanwhile 54 healthy people in the same area were selected as controls. Plasma S1P was measured by liquid chromatography-tandem mass spectrometry. Patients were grouped according to the baseline S1P level quartiles, and restricted cubic spline plots described the association between S1P and all-cause death. Cox proportional hazard analysis was used to determine the relationship between category of S1P and all-cause death., Results: Compared with the control group, the plasma S1P in chronic heart failure patients demonstrated a higher mean level (1.269 μmol/L vs 1.122 μmol/L, P = 0.006) and a larger standard deviation (0.441 vs 0.316, P = 0.022). Based on multivariable Cox regression with restricted cubic spline analysis, a non-linear and U-shaped association between S1P levels and the risk of all-cause death was observed. After a follow-up period of 31.7 ± 10.3 months, the second quartile (0.967-1.192 μml/L) with largely normal S1P levels had the lowest all-cause mortality and either an increase (adjusted HR = 2.368, 95%CI 1.006-5.572, P = 0.048) or a decrease (adjusted HR = 0.041, 95%CI 0.002-0.808, P = 0.036) predicted a worse prognosis. The survival curves showed that patients in the lowest quartile and highest quartile were at a higher risk of death., Conclusions: Plasma S1P levels in systolic heart failure patients are related to the long-term all-cause mortality with a U-shaped correlation., Trial Registration: CHiCTR, ChiCTR-ONC-14004463. Registered 20 March 2014.

To determine (a) whether chronic heart failure with reduced ejection fraction (HFrEF) is associated with increased glycocalyx shedding; (b) whether glycocalyx shedding in HFrEF with left ventricular dyssynchrony is related to inflammation, endothelial dysfunction and/or redox stress and is ameliorated by cardiac resynchronisation therapy. Glycocalyx shedding has been reported to be increased in heart failure and is a marker of increased mortality. Its role in dyssynchronous systolic heart failure and the effects of cardiac resynchronisation therapy (CRT) are largely unknown. Twenty-six patients with dyssynchronous HFrEF were evaluated before and 6 months after CRT insertion. Echocardiographic septal to posterior wall delay (SPWD) assessed intra-ventricular mechanical dyssynchrony, and quality of life, integrity of nitric oxide (NO) signalling, inflammatory and redox-related biomarkers were measured. Glycocalyx shedding was quantitated via plasma levels of the glycocalyx component, syndecan-1. Syndecan-1 levels pre-CRT were inversely correlated with LVEF (r = - 0.45, p = 0.02) and directly with SPWD (r = 0.44, p = 0.02), QOL (r = 0.39, p = 0.04), plasma NT-proBNP (r = 0.43, p = 0.02), and the inflammatory marker, symmetric dimethylarginine (SDMA) (r = 0.54, p = 0.003). On multivariate analysis, syndecan-1 levels were predicted by SPWD and SDMA (β = 0.42, p = 0.009 and β = 0.54, p = 0.001, respectively). No significant correlation was found between syndecan-1 levels and other markers of endothelial dysfunction/inflammatory activation. Following CRT there was no significant change in syndecan-1 levels. In patients with dyssynchronous HFrEF, markers of glycocalyx shedding are associated with the magnitude of mechanical dyssynchrony and elevation of SDMA levels and inversely with LVEF. However, CRT does not reverse this process.

Background: Secondary mitral regurgitation (sMR) drives adverse cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF). Progression in severity over time contributes to a transition towards more advanced HF stages. Early identification of patients at risk for sMR progression remains challenging. We therefore sought to assess a broad spectrum of neurohumoral biomarkers in patients with HFrEF to explore their ability to predict progression of sMR., Methods: A total of 249 HFrEF patients were enrolled. Biomarkers encompassing key neurohumoral pathways in heart failure were sampled at baseline, and sMR progression was assessed over 3 years of follow-up., Results: Of 191 patients with nonsevere sMR at baseline, 18% showed progressive sMR within three years after study enrolment. Progression of sMR was associated with higher levels of MR-proADM (adj.OR 2.25, 95% CI 1.29-3.93; P = .004), MR-proANP (adj.OR 1.84, 95% CI 1.14-3.00; P = .012), copeptin (adj.OR 1.66, 95% CI 1.04-2.67; P = .035) and CT-pro-ET1 (adj.OR 1.68, 95% CI 1.06-2.68; P = .027) but not with NT-proBNP (P = .54)., Conclusion: Increased plasma levels of neurohumoral cardiac biomarkers are predictors of sMR progression in patients with HFrEF and add easily available incremental prognostic information for risk stratification. Importantly, NT-proBNP was not useful to predict progressive sMR in the present analysis. On the contrary, MR-proANP, primarily produced in the atria, copeptin partly triggered by intra-cardiac and intra-arterial pressures and MR-proADM, a marker of forward failure and peripheral released vasoactive CT-proET1, increase based on a progressive loading burden by sMR and may thus serve as better predictors of sMR progression., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: The aim of this study is research relation of serum neopterin level with mortality and morbidity due to systolic HF and also its role in diagnosis of patients with systolic HF. Material and methods: Eighty-one patients with systolic heart failure (HF group) and eighty-one age- and gender-matched healthy subjects (the control group) were enrolled in the study. Echocardiographic examination was performed accordingly. At the beginning of the study, serum B type natriuretic peptide (BNP), neopterin, and high sensitive C-reactive protein (hs-CRP) were measured accordingly. The subjects were followed for one year then after. Mortality rate and number of hospitalisation due to HF were recorded. Results: Age and gender distribution over the groups were statistically similar ( p  > .05). LVEF of the control and HF groups were 62 ± 3 and 27 ± 3%, respectively ( p  < .001). Average neopterin value of HF group was significantly higher than that of the control group ( p  < .001). Both hs-CRP and BNP values were well correlated to neopterin values ( p  = .667 and .778, respectively). There was a significant correlation between number of hospitalisation and neopterin values among patients in HF group ( p  = .008). Also among HF group, neopterin value of patients died within first year of follow-up ( n  = 29) was higher than that of patients survived beyond first year ( n  = 52 and p  = .011). Conclusions: Neopterin is a biomarker reflecting ongoing inflammatory process in deteriorating heart. High level of serum neopterin concentrations was associated with mortality and morbidity in systolic HF.

High-density lipoprotein (HDL) confers protection against cardiovascular disease partly attributable to its robust anti-oxidant activities, which is largely impaired in diabetic conditions. In this study, we analyzed the anti-oxidant activity of HDL, as represented by the arylesterase activity of paraoxonase 1 (PON1) in HDL particles, in 216 consecutive HF patients with (n = 79) or without (n = 137) type 2 diabetes, and age- and gender-matched 112 diabetic and 189 non-diabetic non-HF controls. We found arylesterase activity was significantly decreased in patients with than without HF, and was further decreased when comorbid with diabetes. After adjusting for conventional risk factors and apolipoprotein A-I levels, arylesterase activity remained correlated positively with left ventricular ejection fraction in diabetic (r = 0.325, P = 0.020) but not non-diabetic patients (r = 0.089, P = 0.415), and negatively with NT-proBNP and NYHA functional class in both subgroups. In regression analyses, a higher risk of HF was observed in diabetic than non-diabetic patients when having low arylesterase activities. In conclusion, our data demonstrate that impaired serum arylesterase activity in patients with HF is further reduced when comorbid with diabetes. The relationship of impaired arylesterase activity to HF is especially enhanced in diabetic patients.

Background: Growth differentiation factor-15 (GDF-15) is a stress-inducible cytokine and member of the transforming growth factor-β cytokine superfamily that refines prognostic assessment in subgroups of patients with heart failure (HF). We evaluated its role in HF patients with chronic kidney disease (CKD, estimated glomerular filtration rate <60 mL/min/1.73 m 2 )., Methods: A total of 358 patients with stable systolic HF were followed for a median of 1121 (interquartile range, 379-2600) days. Comprehensive evaluation including B-type natriuretic peptide (BNP) and GDF-15 testing was performed at study entry; the analysis was stratified according to kidney function., Results: Patients with CKD (33.8%) were older, had more often diabetes, and were less often treated with angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB). GDF-15 was associated with estimated glomerular filtration rate, whereas BNP was associated with left ventricular-end diastolic diameter and ejection fraction (P < 0.01). During follow-up, 244 patients (68.2%) experienced an adverse outcome (death, urgent transplantation, implantation of mechanical circulatory support). In patients with HF and CKD, the Cox proportional hazard model identified BNP, GDF-15, sex, systolic blood pressure, sodium, total cholesterol, and ACEi/ARB treatment as significant variables associated with an adverse outcome (P < 0.05). In multivariable analysis, BNP was replaced by GDF-15. Net reclassification improvement confirmed prognostic superiority of the model encompassing GDF-15 (GDF-15, sodium, total cholesterol, ACEi/ARB treatment) compared with the model without GDF-15 (BNP, sex, sodium, ACEi/ARB treatment), net reclassification improvement 0.62, P = 0.005. In contrast, in patients with HF and normal kidney function, BNP remained superior to GDF-15 in a multivariable model., Conclusions: In patients with systolic HF and CKD, GDF-15 is more strongly associated with adverse outcomes than the conventionally used BNP., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Activated leukocytes may contribute to the development and progression of heart failure (HF). We investigated the predictive value of circulating levels of stable and readily detectable markers reflecting both monocyte/macrophage and T-cell activity, on clinical outcomes in HF patients with reduced ejection fraction (HFrEF)., Methods: The association between baseline plasma levels of soluble CD163 (sCD163), macrophage migration inhibitory factor (MIF), granulysin, soluble interleukin-2 receptor (sIL-2R), and activated leukocyte cell adhesion molecule (ALCAM) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anemia, enrolled in the Reduction of Events by darbepoetin alfa in Heart Failure (RED-HF) trial. Modifying effects and interaction with darbepoetin alfa treatment were also assessed., Results: All leukocyte markers, except granulysin, were associated with the primary outcome and all-cause death in univariate analysis (all p < 0.01) and remained significantly associated in multivariable analysis adjusting for conventional clinical variables (e.g. age, gender, BMI, NYHA class, creatinine, LVEF, etiology) and CRP. However, after final adjustment for TnT and NT-proBNP no associations were found with outcomes. No interaction with darbepoetin alpha treatment was observed for any marker., Conclusions: Leukocyte activation markers sCD163, MIF, sIL-2R, and ALCAM were associated with adverse outcome in patients with HFrEF, but add little as prognostic markers on top of established biochemical risk markers., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00358215 .

Background: Circulating concentrations of N-terminal fragment of the prohormone of brain natriuretic peptide (NT-proBNP) are influenced by age and common age-related comorbidities, such as renal dysfunction. Therefore, utility of NT-proBNP for prediction of prognosis in the aged has been questioned. We aimed to investigate the prognostic value of NT-proBNP across age classes in a cohort of patients with chronic systolic HF., Methods and Results: We enrolled 2364 consecutive outpatients with HF and left ventricular ejection fraction ≤50%. Patients were classified according to age quartiles, and a very elderly subgroup was identified, aged ≥85 years. After baseline assessment (including NT-proBNP testing), patients were followed-up for the composite of cardiovascular death, heart transplantation or ventricular assistance device implantation (primary outcome) and for all-cause death (secondary outcome). Patients in the fourth quartile (Q4, age ≥ 77 years, n = 638) and in the very elderly subgroup (age ≥ 85 years, n = 153), had higher NT-proBNP (p < .001 vs Q1). NT-proBNP was independently associated with primary and secondary outcome at 1- and 5-years follow-up in the whole population, as well as in Q4 and in the very elderly subgroup (all p < .05). Compared to the whole population, Q4 and very elderly had higher NT-proBNP cut-off for prediction of 1-year primary (4188 and 9729 ng/l, respectively vs 3710 ng/l) and secondary outcome (4296 and 7634 ng/l, respectively vs 3056 ng/l)., Conclusions: NT-proBNP predicts mortality in elderly and very elderly patients with chronic systolic HF, both at mid- and long-term follow-up. Higher NT-proBNP prognostic cut-off should be considered in the aged HF population., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Procalcitonin (PCT) is an excellent marker of sepsis but was not extensively studied in cardiology. The present study investigated PCT plasma concentration in patients with chronic heart failure with reduced ejection fraction (HFrEF) and its prognostic value during 24-month follow-up., Material and Methods: Study group consisted of 130 patients with HFrEF (LVEF ≤ 45%) and 32 controls. PCT level was assessed on admission in all patients. Telephone follow-up was performed every three months over a period of 2 years. Endpoints were death of all causes and readmission for HFrEF exacerbation., Results: HFrEF patients had significantly higher PCT concentration than controls (166.95 versus 22.15 pg/ml; p < 0.001). Individuals with peripheral oedema had increased PCT comparing to those without oedema (217.07 versus 152.12 pg/ml; p < 0.02). In ROC analysis, PCT turned out to be a valuable diagnostic marker of HFrEF (AUC 0.91; p < 0.001). Kaplan-Meier survival curves revealed that patients with PCT in the 4th quartile had significantly lower probability of survival than those with PCT in the 1st and 2nd quartiles. In univariate, but not multivariate, analysis, procalcitonin turned out to be a significant predictor of death during 24-month follow-up. (HR 1.002; 95% CI 1.000-1.003; p < 0.03)., Conclusions: Elevated PCT concentration may serve as another predictor of worse outcome in patients with HFrEF.

Introduction: Mechanisms of maintenance of both atrial fibrillation and structural left ventricular disease are known to include fibrosis. Galectin-3, a biomarker of fibrosis, is elevated both in patients with heart failure and persistent atrial fibrillation. We sought to find whether galectin-3 has a prognostic value in patients with heart failure and a reduced left ventricular ejection fraction undergoing ablation of persistent atrial fibrillation., Methods: Serum concentrations of galectin-3 were determined in a consecutive series of patients with an ejection fraction ≤40%, addressed for ablation of persistent atrial fibrillation. Responders to ablation were patients in sinus rhythm and with an ejection fraction ≥50% at 6 months. A combined endpoint of heart failure hospitalization, transplantation and/or death was used at 12 months., Results: Seventy-five patients were included (81% male, age 63±10 years, ejection fraction 34±7%, galectin-3 21±12 ng/mL). During follow-up, eight patients were hospitalized for decompensated heart failure, 1 underwent heart transplantation, and 4 died; 50 patients were considered as responders to ablation. After adjustment, galectin-3 level independently predicted both 6-month absence of response to ablation (OR = 0.89 per unit increase, p = 0.002). Patients with galectin-3 levels <26 had a 95% 1-year event-free survival versus 46% in patients with galectin-3 ≥26 ng/mL (p<0.0001)., Conclusions: Galectin-3 levels independently predict outcomes in patients with reduced left ventricular systolic function addressed for ablation of persistent AF, and may be of interest in defining the therapeutic strategy in this population., Competing Interests: The authors have declared that no competing interests exist.

Background The Seattle heart failure model or the cardiac and comorbid conditions (3C-HF) scores may help define patient risk in heart failure. Direct comparisons between them or versus N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) have never been performed. Methods Data from consecutive patients with stable systolic heart failure and 3C-HF data were examined. A subgroup of patients had the Seattle heart failure model data available. The endpoints were one year all-cause or cardiovascular death. Results The population included 2023 patients, aged 68 ± 12 years, 75% were men. At the one year time-point, 198 deaths were recorded (10%), 124 of them (63%) from cardiovascular causes. While areas under the curve were not significantly different, NT-proBNP displayed better reclassification capability than the 3C-HF score for the prediction of one year all-cause and cardiovascular death. Adding NT-proBNP to the 3C-HF score resulted in a significant improvement in risk prediction. Among patients with Seattle heart failure model data available ( n = 798), the area under the curve values for all-cause and cardiovascular death were similar for the Seattle heart failure model score (0.790 and 0.820), NT-proBNP (0.783 and 0.803), and the 3C-HF score (0.770 and 0.800). The combination of the 3C-HF score and NT-proBNP displayed a similar prognostic performance to the Seattle heart failure model score for both endpoints. Adding NT-proBNP to the Seattle heart failure model score performed better than the Seattle heart failure model alone in terms of reclassification, but not discrimination. Conclusions Among systolic heart failure patients, NT-proBNP levels had better reclassification capability for all-cause and cardiovascular death than the 3C-HF score. The inclusion of NT-proBNP to the 3C-HF and Seattle heart failure model score resulted in significantly better risk stratification.

Background: Plasma extracellular RNAs have recently garnered interest as biomarkers in heart failure (HF). Most studies in HF focus on single extracellular RNAs related to phenotypes and outcomes, and few describe their functional roles. We hypothesized that clusters of plasma microRNAs (miRNAs) associated with left ventricular (LV) remodeling in human HF would identify novel subsets of genes involved in HF in animal models., Methods and Results: We prospectively measured circulating miRNAs in 64 patients with systolic HF (mean age, 64.8 years; 91% men; median LV ejection fraction, 26%) with serial echocardiography (10 months apart) during medical therapy. We defined LV reverse remodeling as a 15% reduction in LV end-systolic volume index. Using principal components analysis, we identified a component associated with LV reverse remodeling (odds ratio=3.99; P =0.01) that provided risk discrimination for LV reverse remodeling superior to a clinical model (C statistic, 0.58 for a clinical model versus 0.71 for RNA-based model). Using network bioinformatics, we uncovered genes not previously widely described in HF regulated simultaneously by >2 miRNAs. We observed increased myocardial expression of these miRNAs during HF development in animals, with downregulation of target gene expression, suggesting coordinate miRNA-mRNA regulation. Target mRNAs were involved in autophagy, metabolism, and inflammation., Conclusions: Plasma miRNAs associated with LV reverse remodeling in humans are dysregulated in animal HF and target clusters of genes involved in mechanisms implicated in HF. A translational approach integrating human HF, bioinformatics, and model systems may uncover novel pathways involved in HF., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00351390., (© 2018 American Heart Association, Inc.)

Background: Acute heart failure (AHF) is one of the leading causes of admission to emergency department (ED); severe hypoxemic AHF may be treated with noninvasive ventilation (NIV). Despite the demonstrated clinical efficacy of NIV in relieving symptoms of AHF, less is known about the hyperacute effects of bilevel positive airway pressure (BiPAP) ventilation on hemodynamics of patients admitted to ED for AHF. We therefore aimed to assess the effect of BiPAP ventilation on principal hemodynamic, respiratory, pulse oximetry, and microcirculation indexes in patients admitted to ED for AHF, needing NIV., Methods: Twenty consecutive patients admitted to ED for AHF and left ventricular systolic dysfunction, needing NIV, were enrolled in the study; all patients were treated with NIV in BiPAP mode. The following parameters were measured at admission to ED (T 0 , baseline before treatment), 3 hours after admission and initiation of BiPAP NIV (T 1 ), and after 6 hours (T 2 ): arterial blood oxygenation (pH, partial pressure of oxygen in the alveoli/fraction of inspired oxygen ratio, Paco 2 , lactate concentration, HCO 3- ), hemodynamics (tricuspid annular plane systolic excursion, transpulmonary gradient, transaortic gradient, inferior vena cava diameter, brain natriuretic peptide [BNP] levels), microcirculation perfusion (end-tidal CO 2 [etco 2 ], peripheral venous oxygen saturation [SpvO 2 ])., Results: All evaluated indexes significantly improved over time (analysis of variance, P < .001 in quite all cases.)., Conclusions: The BiPAP NIV may rapidly ameliorate several hemodynamic, arterial blood gas, and microcirculation indexes in patients with AHF and left ventricular systolic dysfunction.

Study Objectives: Subjective versus objective sleepiness in heart failure (HF) remains understudied; therefore, we sought to examine the association of these measures and interrelationships with biochemical markers., Methods: Participants with stable systolic HF recruited from a clinic-based program underwent attended polysomnography, Multiple Sleep Latency Testing, questionnaire data collection including Epworth Sleepiness Scale (ESS), and morning phlebotomy for biochemical markers. Linear regression was used to assess the association of mean sleep latency (MSL) and ESS (and other reported outcomes) with adjustment of age or body mass index or left ventricular ejection fraction (LVEF) (beta coefficients, 95% confidence interval) and also with biochemical markers (beta coefficients, 95% confidence interval)., Results: The final analytic sample comprised 26 participants: 52 ± 14 years with apnea-hypopnea index (AHI): 34 ± 27, LVEF: 34 ± 12%, MSL: 7 ± 5 minutes and ESS: 7 (5, 10). There was no significant association of MSL and ESS (-0.36, -0.81 to 0.09, P = .11), AHI, or other questionnaire-based outcomes in adjusted analyses. Although statistically significant associations of ESS and biomarkers were not observed, there were associations of MSL and cortisol (μg/dL) [-0.05: -0.08, -0.01, P = .012] and interleukin-6 (pg/mL) [-0.11: -0.18, -0.04, P = .006], which persisted in adjusted models., Conclusions: In systolic HF, although overall objective sleepiness was observed, this was not associated with subjective sleepiness (ie, a discordance was identified). Differential upregulation of systemic inflammation in objective sleepiness was observed, findings not observed with subjective sleepiness. These findings suggest that underlying mechanistic pathways of inflammation may provide the explanation for dissonance of objective and subjective sleepiness symptoms in HF, thus potentially informing targeted diagnostic and therapeutic approaches., Commentary: A commentary on this article appears in this issue on page 1369., (© 2017 American Academy of Sleep Medicine)

Circulating cardiodepressant factors were found to mediate cardiac dysfunction in patients with sepsis and acute systolic heart failure. To investigate the presence of circulating cardiodepressant factors in patients with Takotsubo Cardiomyopathy (TC), plasma samples were collected from 4 patients with TC, 3 with septic shock, 5 with acute systolic heart failure and 4 healthy controls and injected intraperitoneally in mice. The cardiodepressant effects are measured with transthoracic echocardiography. Plasma injection from control and TC subjects had no effects on left ventricle ejection fraction (LVEF) whereas plasma from the other two groups induced a significant reduction in LVEF. At difference than sepsis and acute heart failure, TC is not characterized by the presence of soluble cardiodepressant factors. Myocardial dysfunction in TC may be mediated by a neurocardiogenic mechanism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: Renal dysfunction (RD) is associated with increased morbidity and mortality in heart failure (HF). At present, no specific treatment for patients with RD, to prevent progression of HF, has been developed. How different hormone axes-and thereby potential treatment options-are affected by RD in HF warrants further investigations., Methods and Results: Patients with left ventricular ejection fraction (LVEF) <0.45% were enrolled prospectively from an outpatient HF clinic. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR), and patients were grouped by eGFR: eGFR group I, ≥90 mL/min/1.73 m 2 ; eGFR group II, 60-89 mL/min/1.73 m 2 ; and eGFR group III, ≤59 mL/min/1.73 m 2 . Multivariate linear regression models were developed to evaluate the associations between eGFR groups and hormones. A total of 149 patients participated in the study. Median age was 69 [interquartile range (IQR): 64-73] and 26% were female; LVEF was 33% (IQR: 27-39), 78% were in functional class II-III, median eGFR was 74 (54-89) mL/min/1.73 m 2 , and median N-terminal pro-brain natriuretic peptide was 1303 pg/mL (IQR: 441-2740). RD was associated with increased aldosterone, parathyroid hormone (PTH), and copeptin concentrations (P < 0.05 for all) after adjustment for traditional confounders and medical treatment., Conclusions: RD is associated with increased concentrations of aldosterone, PTH, and copeptin in systolic HF outpatients. Our results underscore the importance of treatment with mineralocorticoid receptor antagonist in systolic HF in particular in patients with RD and suggest that vasopressin and parathyroid receptor antagonism are potential treatment options in HF patients with known RD., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: Sphingosine-1-Phosphate (S1P) is a bioactive sphingolipid with important functions in immunity, inflammation and cardiovascular biology. S1P is associated with prevalence and severity of coronary artery disease and myocardial infarction. However, its relevance in ischemic cardiomyopathy is unknown. We aimed to investigate associations of plasma S1P and other sphingolipids with the extent of heart failure in patients with ischemic heart disease., Methods and Results: 74 patients with ischemic heart disease were investigated in this observational study. Plasma concentrations of S1P, C16 ceramide and sphingomyelin (SM) were measured using liquid chromatography/tandem mass-spectrometry and associated with objective (echocardiography) and subjective (dyspnea) signs of heart failure. Plasma S1P and SM but not C16 ceramide concentrations were negatively associated with left ventricular ejection fraction (LVEF) and dyspnea (ranked by New York Heart Association; LVEF: S1P standardized coefficient beta: -0.25; 95%CI: -273 to -13nM, p=0.03; SM beta: -0.24; 95%CI: -16,310 to -413nM, p=0.04; NYHA: S1P beta: -0.3; 95%CI: -174 to -26nM, p=0.009; SM beta: -0.46; 95%CI: -13,462 to -5013nM, p<0.001). ROC analysis revealed that S1P and SM predicted impaired LVEF with optimal cut-off levels below 843nM and 77μM, respectively., Conclusion: S1P is associated with the impairment of LVEF and dyspnea. Considering the major effects of S1P on cardiac and vascular functions in experimental models, we put forward the hypothesis that S1P is causally involved in the pathophysiology of heart failure. Interfering pharmacologically with S1P receptors may have an impact on ischemic cardiomyopathy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: While abnormal left ventricular (LV) global longitudinal strain (GLS) has been described in patients with heart failure with preserved ejection fraction (HFpEF), its prevalence and clinical significance are poorly understood., Methods and Results: Patients enrolled in the RELAX trial of sildenafil in HFpEF (LV ejection fraction ≥50%) in whom two-dimensional, speckle-tracking LV GLS was possible (n = 187) were analysed. The distribution of LV GLS and its associations with clinical characteristics, LV structure and function, biomarkers, exercise capacity and quality of life were assessed. Baseline median LV GLS was -14.6% (25th and 75th percentile, -17.0% and -11.9%, respectively) and abnormal (≥ - 16%) in 122/187 (65%) patients. Patients in the tertile with the best LV GLS had lower N-terminal pro-brain natriuretic peptide (NT-proBNP) [median 505 pg/mL (161, 1065) vs. 875 pg/mL (488, 1802), P = 0.008) and lower collagen III N-terminal propeptide (PIIINP) levels [median 6.7 µg/L (5.1, 8.1) vs. 8.1 µg/L (6.5, 10.5), P = 0.001] compared with the tertile with the worst LV GLS. There was also a modest linear relationship with LV GLS and log-transformed NT-proBNP and PIIINP (r = 0.29, P < 0.001 and r = 0.19, P = 0.009, respectively). We observed no linear association of LV GLS with Minnesota Living with Heart Failure scores, 6-min walk distance, peak oxygen consumption, or expiratory minute ventilation/carbon dioxide excretion slope., Conclusions: Impaired LV GLS is common among HFpEF patients, indicating the presence of covert systolic dysfunction despite normal LV ejection fraction. Impaired LV GLS was associated with biomarkers of wall stress and collagen synthesis and diastolic dysfunction but not with quality of life or exercise capacity, suggesting other processes may be more responsible for these aspects of the HFpEF syndrome., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: Venous congestion has become increasingly recognized as a potential contributor to end-organ dysfunction in heart failure. Elevated I-FABP, which is excreted specifically from damaged intestinal epithelial cells, has been found in patients with abdominal hypertension and intestinal ischemia. We hypothesize that elevated intestinal fatty acid-binding protein (I-FABP) levels would identify patients with more advanced heart failure who have venous and intestinal congestion., Methods: Baseline serum I-FABP levels were measured in 69 acute decompensated heart failure (ADHF) patients admitted to the intensive care unit for invasive hemodynamic monitoring and tailored medical therapy. Comprehensive echocardiography examinations were performed in all study patients, and clinical outcomes (death, cardiac transplant or left ventricular assist device placement) were assessed., Results: The median circulating I-FABP level was 853pg/ml (interquartile range: 533 to 1448pg/ml). Age, gender, race, and baseline comorbidities were comparable between patients with low and high I-FABP levels. Although there were no significant correlations between I-FABP levels and invasively-measured hemodynamic parameters nor echocardiographic parameters, patients with higher I-FABP levels (≥853g/ml) had significantly worse clinical outcomes compared to those with lower I-FABP levels (<853pg/ml, P=0.025)., Conclusion: Circulating I-FABP levels had no association with invasively-measured hemodynamic parameters, but were associated with adverse clinical outcomes in patients with ADHF with systolic dysfunction., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objectives: To define the role of single or serial measurement of endothelin 1 (ET-1) for prognostication beyond traditional and modern markers of risk in heart failure (HF)., Methods: In total, 115 patients with chronic systolic HF were followed for 10 months. Clinical assessment and ET-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), highly sensitive troponin I (hsTnI), soluble ST2 (sST2), and galectin 3 were measured at each visit., Results: Elevated ET-1 was associated with worse HF, lower right ventricular function, higher pulmonary pressure, and higher left atrial volume index despite similar left ventricular function. ET-1 correlated with angiotensin-converting enzyme inhibitor use. A model containing traditional risk factors, ET-1, NT-proBNP, hsTnI, and sST2 best predicted cardiovascular events, and ET-1 improved reclassification. In an adjusted time-integrated model, percent time spent with ET-1 of 5.90 pg/mL or less was predictive of fewer cardiovascular events (odds ratio, 0.75; 95% confidence interval, 0.62-0.91). ET-1 reduction over time was associated with a lower rate of cardiovascular events compared with increasing or stable ET-1 (24.4% vs 50.0%)., Conclusions: ET-1 may be a unique predictor of HF prognosis, complementing other biomarkers in a multimarker profile. Serial measurement of ET-1 may provide additional prognostic information., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Introduction: The characteristics and outcomes of patients hospitalized with acute systolic heart failure (HF) and normal admission B-type natriuretic peptide (BNP) has not been previously explored., Methods: Using the ESCAPE trial data, we compared patients with acute HF and left ventricular ejection fraction (LVEF) ≤30% who have either normal or elevated BNP on the day of hospitalization. The study endpoints were 30-day and 6-month mortality, all-cause rehospitalization and rehospitalization for HF., Results: Among 347 patients with acute systolic HF, 43 had normal (mean 50.6pg/mL) and 304 had elevated admission BNP (mean 1144pg/mL). Compared with patients with elevated BNP, those with normal admission BNP were younger (51.5 vs. 56.8years, P=0.01), with higher body mass index (33.6 vs. 28.7kg/m 2 , P<0.0001), lower frequency of ischemic etiology for heart disease (20.9% vs. 51.7%, P<0.001), lower blood urea nitrogen (29.1 vs. 36.3mg/dL, P=0.005) and creatinine (1.34 vs. 1.52mg/dL, P=0.038) levels, higher LVEF (25.5% vs. 19.1%, P=0.018), higher cardiac index (2.34 vs. 1.96, P=0.013), and better diastolic function evident by lower E/A ratio (1.73 vs. 2.67, P=0.001) and longer deceleration of E velocity (166 vs. 141ms, P=0.028). There was no difference between patients with normal or elevated admission BNP with regards to the degree of congestion. There were no differences between both groups in post-discharge hard endpoints such as 30-day (P=0.101) and 6-month (P=0.143) mortality, rehospitalization for any cause (P=0.992) or for HF (P=0.763)., Conclusion: Patients hospitalized with acute systolic HF and normal admission BNP had no significant differences in the degree of congestion and post-discharge outcomes compared with those with elevated BNP. A normal BNP in this instance was not valuable for diagnostic or prognostic purposes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Urocortin 1 (UCN1) has vasodilator, diuretic, and natriuretic effects, and its expression increases in heart failure (HF). Adrenomedullin (ADM) increases cardiac output and lowers blood pressure in healthy men and in patients with heart failure. The aim of the study was to determine UCN1 and ADM levels in patients with HF, to evaluate the relationship of UCN1 and ADM with various clinical parameters, and to assess UCN1 and ADM as diagnostic markers in HF, in comparison with pro-brain natriuretic peptide (pro-BNP)., Methods: We investigated serum levels of UCN1, ADM, and pro BNP in 86 consecutive patients with systolic HF [ejection fraction (EF) ≤45%] and 85 healthy controls. Serum UCN1, ADM, and pro-BNP levels were measured with the ELISA method. Transthoracic echocardiography was performed to determine left ventricular EF and pulmonary artery systolic pressure., Results: UCN1 and ADM levels were higher in HF patients (446.2±145.7 pg/mL, p<0.001; 87.9±4.2 pg/mL, p<0.001 respectively). UCN1 was positively correlated with pro-BNP (r=0.963, p<0.001), ADM (r=0.915, p<0.001), and NYHA (r=0.879, p<0.001); ADM was positively correlated with pro-BNP (r=0.956, p<0.001) and NYHA (r=0.944, p<0.001). Receiver operating characteristic curves yielded an area under the curve of 1.00 (p<0.001) for UCN1, 1.00 (p<0.001) for ADM, and 0.99 (p<0.001) for pro-BNP in the diagnosis of HF., Conclusion: UCN1 and ADM increase with worsening HF and left ventricular dysfunction. They may be used as diagnostic biomarkers in systolic HF, but the incremental value of measuring UCN1 and ADM in patients tested for pro-BNP is questionable.

Background: Among various cardiac autoantibodies (AAbs), those recognizing the β 1 -adrenergic receptor (β 1 AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption., Objectives: The goal of this study was to investigate the role of β 1 AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy., Methods: Peripheral blood samples were drawn at enrollment in patients with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; <6 months). The presence of IgG and IgG3-β 1 AR-AAb was determined, and echocardiograms were assessed, at baseline and 6 months. Patients were followed up for ≤48 months., Results: Among the 353 patients who had blood samples adequate for the analysis, 62 (18%) were positive for IgG3-β 1 AR-AAbs (IgG3 group), 58 (16%) were positive for IgG but not IgG3 (non-IgG3 group), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. Left ventricular end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other groups (left ventricular end-diastolic diameter, p < 0.01; left ventricular end-systolic diameter, p = 0.03). At 6 months, LVEF was significantly higher in the IgG3 group (p = 0.007). Multiple regression analysis showed that IgG3-β 1 AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In patients with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had a lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint., Conclusions: IgG3-β 1 AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Functional status is one of the main concerns in the management of heart failure (HF). Recently, the FAIR-HF and CONFIRM-HF trials showed that correcting anaemia using intravenous iron supplementation improved functional variables in patients with absolute or relative iron deficiency. Relative iron deficiency is supposed to be a marker of HF severity, as ferritin concentration increases with advanced stages of HF, but little is known about the impact of absolute iron deficiency (AID)., Aims: To study the impact of AID on functional variables and survival in patients with chronic systolic HF., Methods: One hundred and thirty-eight non-anaemic patients with chronic systolic HF were included retrospectively. Patients were divided into two groups according to iron status: the AID group, defined by a ferritin concentration<100μg/L and the non-AID group, defined by a ferritin concentration≥100μg/L. Functional, morphological and biological variables were collected, and survival was assessed., Results: Patients in the AID group had a poorer 6-minute walking test (342 vs. 387m; P=0.03) and poorer peak exercise oxygen consumption (13.8 vs. 16.0mL/min/kg; P=0.01). By multivariable analysis, ferritin<100μg/L was associated with impaired capacity of effort, assessed by peak exercise oxygen consumption. By multivariable analysis, there was no difference in total mortality between groups, with a mean follow-up of 5.1±1.1 years., Conclusions: The poorer functional evaluations in iron-deficient patients previously reported are not caused by the merging of two different populations (i.e. patients with absolute or relative iron deficiency). Our study has confirmed that non-anaemic HF patients with AID have poorer peak oxygen consumption. However, AID has no impact on the survival of these patients., (Copyright © 2017. Published by Elsevier Masson SAS.)

Background: Heart failure (HF) patients with diabetes (DM) have an adverse prognosis and reduced functional capacity, which could be associated with cardiac fibrosis, increased chamber stiffness and reduced left ventricular (LV) contractile reserve. Galectin-3 (Gal-3) and fibulin-1 are circulating biomarkers potentially reflecting cardiac fibrosis. We hypothesize that plasma levels of Gal-3 and fibulin-1 are elevated in HF patients with DM and are associated with reduced LV contractile reserve in these patients., Methods: A total of 155 patients with HF with reduced ejection fraction underwent a low-dose dobutamine echocardiography and blood sampling for biomarker measurements. Patients were classified according to history of DM and an oral glucose tolerance test (OGTT) as: normal glucose tolerance (NGT) (n = 70), impaired glucose tolerance (IGT) (n = 25) and DM (n = 60)., Results: Galectin-3 levels were elevated in DM patients as compared to non-diabetic patients (P = 0.02), while higher fibulin-1 levels were observed in HF patients with IGF and DM (P = 0.07). Reduced LV contractile reserve was associated with increasing Gal-3 levels (β = -0.19, P = 0.03) although, this association was attenuated after adjustment for estimated glomerular filtration rate (P = 0.66). Fibulin-1 was not associated with LV contractile reserve (P = 0.71)., Conclusions: Galectin-3 and fibulin-1 levels were elevated in HF patients with impaired glucose metabolism. However, reduced LV contractile reserve among HF patients with DM does not to have an independent impact on plasma Gal-3 and fibulin-1 levels.

Objective: Excessive activated proinflammatory cytokines may promote extracellular matrix alterations which induce adverse left ventricular remodeling in systolic heart failure (SHF). We sought to identify whether high-sensitivity C-reactive protein (hsCRP) levels were independently associated with SHF., Methods: In our retrospective case-control study, 2236 subjects were included, and 260 patients had SHF. Blood sample collection, clinical laboratory tests, electrocardiogram and echocardiography examinations were performed. The questionnaires were completed by professional interviews., Results: In 2236 subjects, the prevalence rate of SHF were 1.7, 1.8, 8.4 and 32.6% between hsCRP concentrations (<1 mg/L, ≥1 to <3 mg/L, ≥3 to <10 mg/L and ≥10 mg/L, respectively) (p=0.000). hsCRP concentrations (<1 mg/L, ≥1 to <3 mg/L, ≥3 to <10 mg/L and ≥10 mg/L) were associated in a linear trend with N-terminal pro-brain natriuretic peptide (NT-proBNP, p=0.000) and left ventricular ejection fraction (LVEF, p=0.000). hsCRP was also significantly related to NT-proBNP, LVEF and SHF (r=0.232, p=0.000; r=-0.358, p=0.000 and r=0.413, p=0.000, respectively). In logistic regression model, after adjusting for heart failure risk factors, compared with the low concentration of hsCRP (<1 mg/L), the high concentration of hsCRP (≥10 mg/L) was significantly independently associated with SHF (odds ratio = 10.78 [1.303 to 89.10], p=0.027)., Conclusion: Low to high concentration of hsCRP showed a linear trend association with SHF. A high concentration of hsCRP was independently associated with SHF., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Cardiac amyloidosis is an infiltrative cardiomyopathy that is challenging to diagnose. We hypothesized that the novel biomarkers hepatocyte growth factor (HGF), galectin-3 (GAL-3), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) would be elevated in cardiac amyloidosis and may be able to discriminate from non-cardiac systemic amyloidosis or other cardiomyopathies with similar clinical or morphologic characteristics., Methods: Patients were selected from the Vanderbilt Main Heart Registry according to the following groups: (1) amyloid light-chain (AL) cardiac amyloidosis (n = 26); (2) transthyretin (ATTR) cardiac amyloidosis (n = 7); (3) left ventricular hypertrophy (LVH) (n = 45); (4) systolic heart failure (n = 42); and (5) non-cardiac systemic amyloidosis (n = 7). Biomarkers were measured in stored plasma samples. Biomarkers' discrimination performance in predicting AL cardiac amyloidosis (i.e., Concordance index) was reported. A survival analysis was used to explore the relationship between HGF levels and mortality among AL cardiac amyloidosis patients., Results: HGF levels were markedly elevated in patients with AL cardiac amyloidosis (median = 622, interquartile range (IQR): 299-1228 pg/mL) compared with the other groups, including those with non-cardiac systemic amyloidosis (median = 134, IQR: 94-163 pg/mL, p < 0.001). HGF was not a specific marker for ATTR amyloidosis. Gal-3 was elevated in all groups with amyloidosis but could not differentiate between those with and without cardiac involvement. There was no difference in IL-6 or VEGF between those with AL cardiac amyloidosis compared to other groups (p = 0.13 and 0.057, respectively)., Conclusions: HGF may be a specific marker that distinguishes AL cardiac amyloidosis from other cardiomyopathies with similar clinical or morphologic characteristics. Further studies are necessary to determine whether HGF levels predict the likelihood of survival.

Objective: To elucidate the prevalence and role of β1 adrenergic receptor autoantibodies (β1AR-AAb) belonging to the immunoglobulin (Ig)G3 subclass in patients with heart failure (HF) treated with β-adrenergic blockers., Background: Several cardiac AAbs have been reported to be present in sera from patients with dilated cardiomyopathy and other etiologies. Among AAbs, those recognizing β1AR-AAbs show agonist-like effects, have detrimental effects on cardiomyocytes, and may induce persistent myocardial damage., Methods: We quantify total IgG and IgG3 subclass β1AR-AAb in subjects with chronic stable HF with long-term follow-up., Results: In our study cohort of 121 subjects, non-IgG3-β1AR-AAb and IgG3-β1AR-AAb were found to be positive in 20 (17%) and 26 patients (21%), respectively. The positive rate of IgG3-β1AR-AAb was significantly higher for those with nonischemic compared with ischemic HF etiology (27% vs 8%, P = .01), but the positive rate for non-IgG3-β1AR-AAb was similar between the 2 groups (18% vs 16%, respectively, P = NS). There were no significant differences in clinical and echocardiographic measures among total β1AR-AAb negative, non-IgG3-β1AR-AAb positive, and IgG3-β1AR-AAb positive groups at baseline. During 2.2 ± 1.2 years of follow-up, we observed similar rates of the composite endpoint of all-cause mortality, cardiac transplantation, or hospitalization resulting from HF between total IgG-β1AR-AAb negative and positive patients. However, the composite endpoint events were significantly more common in the patients without than in those with IgG3-β1AR-AAb (P = .048, log-rank test)., Conclusions: Presence of IgG3-β1AR-AAb, not total IgG, was associated with paradoxically more favorable outcomes in our cohort of patients with chronic systolic HF largely treated by β-blockers., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Both renal function and serum sodium level are well-known prognostic markers in heart failure (HF) patients. We investigated the prognostic value of the renal impairment (RI) stratified by the serum sodium level in systolic HF patients.The Clinical Characteristics and Outcomes in Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (the COAST) Study enrolled hospitalized systolic HF patients (ejection fraction<45%) in South Korea, Taiwan, and China. Twelve-month mortality was stratified according to the renal function and serum sodium level.Of 1462 enrolled patients, 716 patients (49%) had RI (GFR<60 mL/min/1.73 m), and they had higher 12-month mortality than those without RI (22.8% vs. 10.9%, P<0.001). Furthermore, 676 patients (46%) had low sodium level defined as Na

Background: Galectin-3 predicts prognosis in heart failure (HF) and may help to select HF patients in need of intensified therapy., Methods: This retrospective post hoc analysis included 219 patients from the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-HF) and 631 patients from Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) with HF who had reduced ejection fraction and available galectin-3 plasma concentrations. The interaction between galectin-3, β-blockers, renin-angiotensin system (RAS) blockade, and spironolactone on outcome was evaluated in TIME-CHF and validated in GISSI-HF. End points were all-cause mortality and the composite of mortality with HF hospitalization or any hospitalization., Results: High galectin-3 concentrations were associated with adverse outcome in both cohorts and remained significantly associated with death after multivariate adjustment [hazard ratio 2.42 (95% CI 1.17-5.01), P = 0.02, in TIME-CHF; 1.47 (1.02-2.10), P = 0.04, in GISSI-HF). In TIME-CHF, patients with low galectin-3 plasma concentrations had a better prognosis when β-blockers were up-titrated, whereas patients with high galectin-3 plasma concentrations did not (interaction P < 0.05 for mortality and death with or without hospitalization). Opposite trends were seen for RAS blockade but were not statistically significant. Patients with high galectin-3 plasma concentrations had neutral prognosis when receiving spironolactone, whereas patients with low galectin-3 plasma concentrations had worse prognosis when receiving spironolactone (interaction P < 0.10 for death with or without hospitalization). In the GISSI-HF validation cohort, these interactions were confirmed for β-blockers (P < 0.05 for all end points) and consistent for RAS blockade (P < 0.10 for death with or without hospitalization), but inconsistent for spironolactone., Conclusions: Galectin-3 is a mediocre prognostic marker, and galectin-3 concentrations interact with the treatment effect of β-blockers and possibly RAS blockade in patients with systolic HF., (© 2015 American Association for Clinical Chemistry.)

Objectives: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) appears to be involved in atherosclerotic plaque vulnerability and rupture. In this study, we aimed to evaluate the utility of serum LOX-1 levels in the diagnosis and assessment of left ventricular systolic HF and LOX-1’s relationship with serum pro-brain natriuretic peptide (NT-proBNP)., Design and Settings: This was a cross-sectional study of all eligible patients admitted to the department of cardiology of the University Hospital between July 2011 and April 2012., Methods: Fifty-five patients with a diagnosis of systolic heart failure and 25 patients without systolic HF were enrolled in this study. Serum C-reactive protein, NT-proBNP, and LOX-1 were studied., Results: Serum LOX-1 and NT-proBNP levels were significantly higher in the heart failure group and showed a positive correlation with NT-proBNP and negative correlations with left ventricular ejection fraction (EF). In addition, LOX-1 levels in patients with ischaemic cardiomyopathy were significantly higher, while they were similar in patients with dilated cardiomyopathy compared to control subjects., Conclusion: Our study demonstrates the utility of the serum LOX-1 levels in the diagnosis of left ventricular systolic heart failure. LOX-1 may have a place in the diagnosis of heart failure, in particular in patients with ischaemic cardiomyopathy.

Background: Elevated levels of aldosterone are a modifiable contributor to clinical worsening in heart failure with reduced ejection fraction (HFrEF). Endothelin-1 (ET-1), which is increased in HFrEF, induces pulmonary endothelial aldosterone synthesis in vitro. However, whether transpulmonary aldosterone release occurs in humans or aldosterone relates to functional capacity in HFrEF is not known. Therefore, we aimed to characterize ET-1 and transpulmonary aldosterone levels in HFrEF and determine if aldosterone levels relate to peak volume of oxygen uptake (pVO2)., Methods: Data from 42 consecutive HFrEF patients and 18 controls referred for invasive cardiopulmonary exercise testing were analyzed retrospectively., Results: Radial ET-1 levels (median [interquartile range]) were higher in HFrEF patients compared with controls (17.5 [11.5-31.4] vs 11.5 [4.4-19.0] pg/ml, p = 0.04). A significant ET-1 transpulmonary gradient (pulmonary arterial [PA] - radial arterial levels) was present in HFrEF (p < 0.001) but not in controls (p = 0.24). Compared with controls, aldosterone levels (median [interquartile range]) were increased in HFrEF patients in the PA (364 [250-489] vs 581 [400-914] ng/dl, p < 0.01) and radial compartments (366 [273-466] vs 702 [443-1223] ng/dl, p < 0.001). Akin to ET-1, a transpulmonary increase (median [interquartile range]) in aldosterone concentration was also observed between controls and HFrEF patients at rest (7.5 [-54 to 40] vs 61.6 [-13.6 to 165] ng/dl, p = 0.01) and peak exercise (-20.7 [-39.6 to 79.1] vs 25.8 [-29.2 to 109.3] ng/dl, p = 0.02). The adjusted pVO2 correlated inversely with aldosterone levels at peak activity in the PA (r = -0.31, p = 0.01) and radial artery (r = -0.32, p = 0.01)., Conclusions: These data provide preliminary evidence in support of increased transpulmonary aldosterone levels in HFrEF and suggest an inverse relationship between circulating aldosterone and pVO2. Future prospective studies are needed to characterize the functional effects of transpulmonary and circulating aldosterone on cardiac reserve capacity in HFrEF., (Published by Elsevier Inc.)

Introduction: Atrial fibrillation (AF) is a common arrhythmia in heart failure (HF). Recent studies have shown that serum cancer antigen-125 (CA-125) levels are elevated in HF, and high levels of CA-125 in HF patients with sinus rhythm have been shown to be associated with the development of new onset AF. However, the relation between CA-125 levels and the presence of AF in HF is unknown. In this study we investigated whether plasma CA-125 levels in patients with systolic HF could predict the presence of AF., Methods: The study was a retrospective cohort design including 205 stable systolic HF patients who were selected during outpatient clinic visits and who had CA-125 measurement and an electrocardiogram within the last one month before admittance to cardiology clinic. Patients were classified into two groups based on the presence of AF (n = 67) or sinus rhythm (n = 138)., Results: The mean age of the patients was 68 ± 11 years. CA-125 levels were significantly higher in patients with AF than patients with SR [33 (3-273) vs 102 (7-296) U/ml, P < 0.001]. CA-125 level, presence of right ventricular dilatation, pericardial effusion, moderate to severe TR and MR, and left atrial diameter were found to be associated with the presence of AF in univariate analysis. In a multivariate logistic regression model, only the CA-125 level remained associated. Also, according to the ROC curve analysis, the optimal cut-off level of CA-125 for predicting AF was ≥ 91 U/mL with a specificity of 84% and a sensitivity of 54%., Conclusion: We have shown that the CA-125 levels can be used to predict AF in patients with systolic HF.

Patients with heart failure (HF) have evidence of chronic systemic inflammation. Whether inflammation contributes to the exercise intolerance in patients with HF is, however, not well established. We hypothesized that the levels of C-reactive protein (CRP), an established inflammatory biomarker, predict impaired cardiopulmonary exercise performance, in patients with chronic systolic HF. We measured CRP using high-sensitivity particle-enhanced immunonephelometry in 16 patients with ischemic heart disease (previous myocardial infarction) and chronic systolic HF, defined as a left ventricular ejection fraction ≤ 50% and New York Heart Association class II-III symptoms. All subjects with CRP >2 mg/L, reflecting systemic inflammation, underwent cardiopulmonary exercise testing using a symptom-limited ramp protocol. CRP levels predicted shorter exercise times (R = -0.65, p = 0.006), lower oxygen consumption (VO2) at the anaerobic threshold (R = -0.66, p = 0.005), and lower peak VO2 (R = -0.70, p = 0.002), reflecting worse cardiovascular performance. CRP levels also significantly correlated with an elevated ventilation/carbon dioxide production slope (R = +0.64, p = 0.008), a reduced oxygen uptake efficiency slope (R = -0.55, p = 0.026), and reduced end-tidal CO2 level at rest and with exercise (R = -0.759, p = 0.001 and R = -0.739, p = 0.001, respectively), reflecting impaired gas exchange. In conclusion, the intensity of systemic inflammation, measured as CRP plasma levels, is associated with cardiopulmonary exercise performance, in patients with ischemic heart disease and chronic systolic HF. These data provide the rationale for targeted anti-inflammatory treatments in HF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Gas exchange abnormalities are part of the heart failure (HF) syndrome and growing interest raised on possible biomarkers of alveolar-capillary unit damage. The present pilot single-center study sought to investigate the prognostic values of circulating surfactant protein type B (SP-B) in a cohort of systolic HF patients., Methods: One hundred and fifty-one HF stable outpatients and 37 healthy subjects underwent a full clinical assessment, including pulmonary function and lung diffusion for carbon monoxide (DLco), maximal cardiopulmonary exercise test and measurements for both circulating immature and mature forms of SP-B. Study end-points were hospitalization due to HF worsening and cardiovascular mortality., Results: Immature SP-B, but not the mature form, was significantly higher in HF patients than in controls and was independently related to DLco, peak oxygen uptake and ventilatory efficiency. During the follow-up (median: 995 days; interquartile range: 739-1247 days), 97 patients experimented at least one HF hospitalization and 9 died for cardiovascular causes. At univariate analysis immature SP-B levels were significantly related to both cardiovascular death (p=0.033) and HF hospitalization (p<0.001). At multivariate analysis, immature SP-B levels remained independently associated to HF hospitalization (hazard ratio: 2.304; 95% confidence interval 1.858-3.019; p<0.001)., Conclusions: Present data confirm a strong relationship between circulating immature SP-B levels, gas exchange abnormalities and exercise limitations in stable HF as well as they are consistent with the use of immature SP-B in HF clinical risk assessment. Larger prospective studies are needed to confirm its prognostic role as well as to evaluate whether immature SP-B plasma concentration varies in response to specific treatment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The aim of this study was to evaluate the association of fibroblast growth factor (FGF)-23 with clinical and laboratory findings, the prognostic value of FGF-23, and the relationship between angiotensin-converting enzyme inhibitor (ACEi) therapy, FGF-23 levels, and outcomes in patients with chronic systolic heart failure (HF)., Background: FGF-23 is a bone-derived hormone regulating mineral metabolism. Higher FGF-23 levels are associated with an increased risk of cardiovascular mortality or HF development. Mechanisms leading to increased FGF-23 and its prognostic value have not been thoroughly studied in HF., Methods: FGF-23 was measured in 369 patients (mean age 59 ± 11 years, 84% male) with systolic HF. Patients were followed for adverse events (e.g., death, urgent heart transplantation, ventricular assist device implantation)., Results: Tricuspid regurgitation severity, chronic kidney disease (CKD), alkaline phosphatase concentrations, inferior vena cava dilation, and absence of ACEi therapy were independently associated with FGF-23. FGF-23 was independently associated with outcomes in patients without CKD (hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.14 to 1.78), but not in CKD patients (HR: 1.12, 95% CI: 0.87 to 1.45). In patients without CKD and with FGF-23 in the highest tertile, ACEi therapy was associated with a lower risk of adverse events (HR: 0.42, 95% CI: 0.21 to 0.81), whereas no association was seen in the remaining patients (HR: 1.18, 95% CI: 0.52 to 2.70)., Conclusions: In systolic HF, elevated FGF-23 is an independent predictor of adverse events, particularly in patients with preserved renal function. The association of FGF-23 with adverse events likely reflects early alterations of renal hemodynamics and renin-angiotensin system activation. Increased FGF-23 may identify a subset of HF patients benefiting from ACEi therapy., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked., Objectives: To identify the prevalence of ID in a HF clinic and evaluate whether ID is associated with increased plasma concentrations of different cardiovascular biomarkers that carry a poor prognosis., Methods: We prospectively included 149 patients with systolic HF referred to an outpatients HF clinic. ID was defined as ferritin<100 μg/L or ferritin 100-300 μg/L and Tranferin-saturation<0.20. Five different cardiovascular biomarkers were analyzed on frozen plasma., Results: The patients had a median age of 70 (Interquartile range: 64-75) years, 25% were females, 29% were in functional class III-IV and LVEF was 32 (27-39) %. The prevalence of ID was 45% (95%-confidence interval (CI): 37-53%). In multivariate analyses, ID was not associated with plasma concentrations of troponin I, NT-proBNP, MR-proANP, chromogranin A or copeptin (P>0.05 for all) but with plasma concentrations of hs-CRP (odds ratio: 2.03, 95%-CI: 1.02-4.02, P=0.043)., Conclusion: ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Both impaired left ventricular (LV) global longitudinal strain (GLS) and increased plasma concentrations of natriuretic peptides(NP) are associated with a poor outcome in heart failure (HF). Increased levels of NP reflect increased wall stress of the LV. However, little is known about the relationship between LV GLS and NP. This aim of this study was to evaluate the relationship between the echocardiographic measure LV GLS and plasma levels of NP., Methods: We prospectively included 149 patients with verified systolic HF at the baseline visit in an outpatient HF clinic. LV GLS was assessed by two dimension speckle tracking and plasma concentrations of N-terminal-pro-brain-natriuretic-peptide (NT-proBNP) and pro-atrial-natriuretic-peptide (proANP) were analysed., Results: The patients had a median age of 70 years, 28.2 % were females, 26.5 % were in functional class III-IV, median left ventricular ejection fraction (LVEF) was 33 % and median LV GLS was -11 %. LV GLS was associated with increased plasma concentrations of NT-proBNP and proANP in multivariate logistic regression (NT-proBNP: Odds RatioGLS: 7.25, 95 %-CI: 2.48-21.1, P < 0.001 and proANP: Odds RatioGLS: 3.26, 95-%-CI: 1.28-8.30, P = 0.013) and linear regression (NT-proBNP: βGLS: 1.19, 95 %-CI: 0.62-1.76, P < 0.001 and proANP: βGLS: 0.42, 95-%-CI: 0.11-0.72, P = 0.007) models after adjustment for traditional confounders (age, gender, body-mass-index, atrial fibrillation, renal function) and left atrial volume index., Conclusion: Impaired LV GLS is associated with increased plasma concentrations of NP and our data suggest that left ventricular myocardial mechanics estimated by LV GLS reflects myocardial wall stress in chronic systolic HF.

Objective: Osteoprotegerin (OPG) may predict progression of chronic congestive heart failure (CHF) with increased mortality and play an important role in the development of pulmonary arterial hypertension (PAH). Mounting evidence suggests that PAH developed during CHF is not solely caused by a "passive" increase from the left ventricular enddiastolic pressure, but rather a "reactive" response from contributing lung endothelial dysfunction and vascular remodelling, a pathological process that can be significantly influenced by endothelial progenitor cells (EPCs).This study aims to examine whether circulating EPCs from patients with CHF are affected and if OPG could be implicated during disease progression., Methods: In this study EPCs were isolated, cultured, and quantified from patients of CHF with (n = 20) or without PAH (n=40) as measured by right heart catheterization. Serum levels of OPG and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were analysed and correlated with EPCs., Results: A significant decrease in circulating EPCs (39.3 ?9.1 vs 67.1 ?10.5 EPCs/x200 field; P <0.05) was found in CHF patients who developed PAH compared to those without PAH. Both OPG (551.90 +/- 49.83 vs. 312.29 +/- 31.12 pg/ml; P<0.05) and NT-pro BNP (2,946.50 +/- 1,434.50 vs. 1,328.20 +/- 811.90; P < 0.05) were also significantly elevated in CHF patients with PA H. Circulating level of OPG correlated inversely with EPCs (r = -0.45, P = 0.037) but positively with mPAP (r =0.53, P=0.011)., Conclusions: Our study demonstrates that OPG elevation and EPC depletion are associated with CHF patients who have developed PAH. The inverse relationship of circulating OPG with EPCs suggests a possible mechanism for OPG in the development of pulmonary vascular dysfunction, thus worsening prognosis for CHF patients.