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Aims: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF)., Methods and Results: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death., Conclusions: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2)., Methods: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values., Results: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P < 0.001), but not sST2 (P = 0.165). Over a median 2.0-year follow-up (1.5-2.5), 1717 patients (21%) died, and 1298 (16%) died from cardiovascular causes; 2255 patients (28%) were hospitalized for HF over 1.8 years (0.9-2.1). NT-proBNP, hs-TnT and sST2 predicted the three end points regardless of COPD status. The best cut-offs from receiver-operating characteristics analysis were higher in patients with COPD than in those without. Patients with all three biomarkers higher than or equal to end-point- and COPD-status-specific cut-offs were also those with the worst prognosis., Conclusions: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Objectives: The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories., Background: Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain., Methods: Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m 2 ), normal weight (BMI 18.5-24.9 kg/m 2 ), overweight (BMI 25-29.9 kg/m 2 ), and mildly (BMI 30-34.9 kg/m 2 ), moderately (BMI 35-39.9 kg/m 2 ), or severely (BMI ≥40 kg/m 2 ) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death., Results: The study population included 12,763 patients (mean age 66 ± 12 years; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (β = -0.174 for 1 kg/m 2 ; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men., Conclusions: NT-proBNP maintains its independent prognostic value up to 40 kg/m 2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients., Competing Interests: Funding Support and Author Disclosures Dr Januzzi is supported in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; has received grant support from Novartis Pharmaceuticals, Roche Diagnostics, Abbott, Singulex and Prevencio; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Boehringer Ingelheim, Janssen, and Takeda. Dr Richards has sat on advisory boards and/or received speakers honoraria, travel support, and/or grants from Novartis, Roche Diagnostics, Abbott Laboratories, Thermo Fisher, and Critical Diagnostics. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the Advisory Board/ Steering Committee/Executive Committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, WebMD Global LLC, Radcliffe Group Ltd, and Corpus. Dr Latini has received grant support and travel reimbursements from Roche Diagnostics. Dr Brunner-La Rocca reports unrestricted research grants and consulting fees from Roche Diagnostics, as well as unrestricted research grants from Novartis and GlaxoSmithKline outside this work. Dr Bayes-Genis has received grant support from Roche Diagnosis, lecture honoraria from Roche Diagnostics and Critical Diagnostics, and consulting income from Roche Diagnostics, Critical Diagnostics, and Novartis. Dr Lupón has received lecture honoraria from Roche Diagnostics and Critical Diagnostics. The University Medical Centre Groningen, which employs Drs De Boer and Meems, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche, outside the submitted work. Dr Gaggin has received grant support from Roche and Portola; consulting income from Roche Diagnostics, Amgen, and Ortho Clinical; and research payments for clinical endpoint committees for EchoSense and Radiometer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) and soluble suppression of tumorigenesis-2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers., Methods and Results: Individual data from 5301 patients with chronic HF and NT-proBNP, hs-TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60-69 years (n = 1628, 31%), 70-79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT-proBNP 1564 ng/L, hs-TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT-proBNP and hs-TnT, but not sST2. The best NT-proBNP and hs-TnT cut-offs for 1-year and 5-year all-cause and cardiovascular mortality and 1- to 12-month HF hospitalization increased with age, while the best sST2 cut-offs did not. When stratifying patients according to age- and outcome-specific cut-offs, this stratification yielded independent prognostic significance over NT-proBNP levels only, or the composite of NT-proBNP and hs-TnT, and improved risk prediction for most endpoints. Finally, absolute NT-proBNP, hs-TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables., Conclusions: Soluble ST2 is less influenced by age than NT-proBNP or hs-TnT; all these biomarkers predict outcome regardless of age. The use of age- and outcome-specific cut-offs of NT-proBNP, hs-TnT and sST2 allows more accurate risk stratification than NT-proBNP alone or the combination of NT-proBNP and hs-TnT., (© 2019 European Society of Cardiology.)

Aims: Whether prevalence and mortality of patients with heart failure with preserved or mid-range (40-49%) ejection fraction (HFpEF and HFmREF) are similar to those of heart failure with reduced ejection fraction (HFrEF), as reported in some epidemiologic studies, remains highly controversial. We determined and compared characteristics and outcomes for patients with HFpEF, HFmREF, and HFrEF in a prospective, international, multi-ethnic population., Methods and Results: Prospective multi-centre longitudinal study in New Zealand (NZ) and Singapore. Patients with HF were assessed at baseline and followed over 2 years. The primary outcome was death from any cause. Secondary outcome was death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF, and HFrEF. Of 2039 patients enrolled, 28% had HFpEF, 13% HFmrEF, and 59% HFrEF. Compared with HFrEF, patients with HFpEF were older (62 vs. 72 years), more commonly female (17% vs. 48%), and more likely to have a history of hypertension (61% vs. 78%) but less likely to have coronary artery disease (55% vs. 41%). During 2 years of follow-up, 343 (17%) patients died. Adjusting for age, sex, and clinical risk factors, patients with HFpEF had a lower risk of death compared with those with HFrEF (hazard ratio 0.62, 95% confidence interval 0.46-0.85). Plasma (NT-proBNP) was similarly related to mortality in both HFpEF, HFmrEF, and HFrEF independent of the co-variates listed and of ejection fraction. Results were similar for the composite endpoint of death or HF and were consistent between Singapore and NZ., Conclusion: These prospective multinational data showed that the prevalence of HFpEF within the HF population was lower than HFrEF. Death rate was comparable in HFpEF and HFmrEF and lower than in HFrEF. Plasma levels of NT-proBNP were independently and similarly predictive of death in the three HF phenotypes., Trial Registration: Australian New Zealand Clinical Trial Registry (ACTRN12610000374066).

Aim: To investigate the relationship between heart rate and survival in patients with heart failure (HF) and coexisting atrial fibrillation (AF)., Methods and Results: Patients with AF included in the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) meta-analysis were the main focus of this analysis (3259 patients from 17 studies). The outcome was all-cause mortality at 3 years. Heart rate was analysed as a categorical (tertiles; T1 ≤77 b.p.m., T2 78-98 b.p.m., T3 ≥98 b.p.m.) and continuous variable. Cox proportional hazard models were used to compare the risk of all-cause death between tertiles of baseline heart rate. Patients in the highest tertile were more often female, less likely to have an ischaemic aetiology or diabetes, had a lower ejection fraction but higher blood pressure and New York Heart Association (NYHA) class. Higher heart rate was associated with higher mortality in patients with sinus rhythm (SR) but not in those in AF. In patients with heart failure and reduced ejection fraction (HF-REF) and AF, death rates per 100 patient years were lowest in the highest heart rate tertile (T1 18.9 vs. T3 15.9) but this difference was not statistically significant (P = 0.10). In patients with heart failure and preserved ejection fraction (HF-PEF), death rates per 100 patient years were highest in the highest heart rate tertile (T1 14.6 vs. T3 16.0, P = 0.014). However, after adjustment for other important prognostic variables, higher heart rate was no longer associated with higher mortality in HF-PEF (or HF-REF)., Conclusions: In this meta-analysis of patients with HF, heart rate does not have the same prognostic significance in patients in AF as it does in those in SR, irrespective of ejection fraction or treatment with beta-blocker., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Heart failure (HF) with preserved ejection fraction (EF) accounts for a substantial proportion of cases of HF, and to date no treatments have clearly improved outcome. There are also little data comparing HF cohorts of differing ethnicity within the Asia-Pacific region., Methods: The Singapore Heart Failure Outcomes and Phenotypes (SHOP) study and Prospective Evaluation of Outcome in Patients with Heart Failure with Preserved Left Ventricular Ejection Fraction (PEOPLE) study are parallel prospective studies using identical protocols to enroll patients with HF across 6 centers in Singapore and 4 in New Zealand. The objectives are to determine the relative prevalence, characteristics, and outcomes of patients with HF and preserved EF (EF ≥50%) compared with those with HF and reduced EF, and to determine initial data on ethnic differences within and between New Zealand and Singapore. Case subjects (n = 2,500) are patients hospitalized with a primary diagnosis of HF or attending outpatient clinics for management of HF within 6 months of HF decompensation. Control subjects are age- and gender-matched community-based adults without HF from Singapore (n = 1,250) and New Zealand (n = 1,073). All participants undergo detailed clinical assessment, echocardiography, and blood biomarker measurements at baseline, 6 weeks, and 6 months, and are followed over 2 years for death or hospitalization. Substudies include vascular assessment, cardiopulmonary exercise testing, retinal imaging, and cardiac magnetic resonance imaging., Conclusions: The SHOP and PEOPLE studies are the first prospective multicenter studies defining the epidemiology and interethnic differences among patients with HF in the Asia-Oceanic region, and will provide unique insights into the pathophysiology and outcomes for these patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims: To describe changes in heart failure (HF) epidemiology in New Zealand between 1988 and 2008 using the number of days alive and out of hospital after a first hospitalization for HF, and to use these data to evaluate the overall impact of changing patterns of hospitalization and survival., Methods and Results: We performed a population analysis of all HF hospitalization and mortality data from 1 January 1988 to 31 December 2008 in New Zealand. The main outcome measures were: days alive and out of hospital, age standardized hospitalization rates, and mortality after an index hospitalization for HF. The number of days alive and out of hospital at 2 years increased by 2 months over the two decades of the study (from 448.8 to 511.3 days). Age standardized index HF hospitalization rates increased from 1988 to 1999, and declined thereafter, current rates are 106.9/100 000 for women and 174.3/100 000 for men. Patient age at index admission progressively increased, and hospital length of stay decreased. Mortality rates progressively decreased until 2000, but there has been no further decrease since then. Total hospital days have decreased up to 2008., Conclusion: There have been major changes in the epidemiology of HF in New Zealand between 1988 and 2008, during which time there have been important changes in HF management. Despite increasing age, hospitalization rates are now declining and patients with HF are surviving longer out of hospital and with fewer hospital days. These results support the need for continued emphasis on delivery of effective community-based care for patients with this long-term condition.

Background: The urocortins are emerging as potentially important contributors to neurohumoral regulation of the circulation with recent reports attributing a powerful array of hemodynamic, renal, and neurohumoral effects to the urocortins in cardiac failure. These peptides also seem to have cardioprotective effects in the setting of ischemia-reperfusion. Little is known concerning the plasma concentrations of the urocortins in health and disease. We have investigated plasma urocortin 1 as a potential diagnostic marker of heart failure and documented its relationships to symptoms, measures of cardiac function, and concurrent levels of other circulating neurohormones., Methods and Results: In 299 patients with recent onset dyspnea or peripheral edema presenting to primary care, plasma urocortin 1 and other vasoactive hormones were assayed, and echocardiography was performed. Heart failure was present in 74 patients (25%) according to predefined diagnostic criteria. Urocortin 1 levels were increased in patients with heart failure and were related to functional class, clinical signs of heart failure, echocardiographic indicators of left ventricular dimensions and function, plasma creatinine, and concurrent circulating levels of plasma natriuretic peptides, adrenomedullin, and endothelin 1., Conclusions: Plasma urocortin 1 is elevated in heart failure (in proportion to the degree of cardiac dysfunction) in concert with the generalized neurohormonal activation seen in this condition. Urocortin levels predict heart failure independent of age, history of previous myocardial infarction, diabetes, hypertension, fractional shortening, and N-terminal prohormone brain natriuretic peptide levels.

Objective: The study objective was to more precisely evaluate the link between the pseudonormal mitral filling pattern and death by way of systematic review and meta-analysis., Methods: Patients with heart failure (HF) and coronary artery disease (CAD) were included. Online databases were searched for prospective studies of patients with HF and CAD who had comprehensive echocardiography. Mortality in patients with pseudonormal filling was compared with restrictive filling and other nonrestrictive filling patterns, including normal and abnormal relaxation. Review Manager Version 4.2.7 software was used for the analysis., Results: Seven studies (5 HF and 2 CAD) were identified, and 887 patients (244 deaths) were included. The pseudonormal filling pattern conferred a 4-fold increase in odds of death compared with abnormal relaxation/normal (odds ratio 4.46; 95% confidence interval, 2.87-6.92). Outcome was similar when restrictive filling was compared with pseudonormal filling (odds ratio 1.16; 95% confidence interval, 0.78-1.74). Death was the main outcome measure., Conclusion: This literature-based meta-analysis, pooling results from 7 prospective studies, demonstrates the 4-fold increase in odds of death associated with pseudonormal filling compared with abnormal relaxation/normal. The pseudonormal filling pattern and restrictive filling pattern are associated with similar risk of death. These data further support the need for a comprehensive assessment of diastolic filling, including assessment for pseudonormal filling, as part of routine echocardiographic risk stratification in patients with HF and CAD.

Background: Although brain natriuretic peptide (BNP) and E/Ea are closely related in heart failure (HF) patients and may be helpful to guide HF therapy, the response of E/Ea to changes in BNP over several weeks of intensive HF treatment optimisation is unknown. This study was designed to investigate this relationship., Methods and Results: In 17 patients with decompensated HF, treatment was titrated to reduce the NT-proBNP level to <200pg/mL over 10 weeks. Paired NT-proBNP measurements and echocardiograms were performed at two weekly intervals during the study. Treatment titration was associated with a reduction in E/Ea (17.6+/-6.8S.D. to 13.7+/-5.0S.D., p=0.018) in keeping with the reduction in NT-proBNP (median 603 [S.E. 561] to 311 [S.E. 235], p=0.045). This relationship remained in those who responded to titration (reduction in NT-proBNP of >or=50%), and those who did not. The overall change in E/Ea was similar to the changes observed in NT-proBNP in each group however there appeared to be temporal differences in the changes in E/Ea and NT-proBNP., Conclusion: This pilot study demonstrates that the E/Ea decreases after NT-proBNP guided HF therapy. E/Ea may be a complementary target for HF therapy optimisation; this hypothesis should be further evaluated in larger scale randomised trials.

Aims: Brain natriuretic peptide (BNP), left ventricular (LV) systolic function, and mitral filling pattern (MFP) are prognostic indicators in patients with heart failure (HF). This study evaluated the potential role of E/Ea for predicting cardiovascular (CV) events in patients with suspected HF. This non-invasive measure of LV filling pressure has been shown to predict outcome in more advanced HF, but not in mild HF in the community., Methods and Results: Two hundred and twenty-eight elderly symptomatic general practice patients (dyspnoea/oedema) were recruited and underwent clinical evaluation, NT-proBNP assay, and comprehensive echocardiography. The Kaplan-Meier analysis of time to first CV hospitalization or CV death was performed for 1 year after presentation according to nominated thresholds of LV systolic function, NT-proBNP, MFP, and E/Ea ratio. Mean age was 70.3 +/- 7.3 years, mean NT-proBNP was 111.4 +/- 185.8, and 148 (65%) were female. Twenty-six patients (11%) experienced a CV event within 18 months of baseline (6 deaths and 20 admissions). Time to first CV event predicted by NT-proBNP (P < 0.0001), MFP (P = 0.009), and E:Ea (P = 0.0076), but not EF (P = 0.098). When NT-proBNP was elevated, E:Ea >15 identified a group of patients with lower survival (P < 0.0001)., Conclusion: Both E/Ea and NT-proBNP predicted hospitalization and when used in a two-step approach (NT-proBNP first, followed by E/Ea), the combination of both (elevated NT-proBNP and elevated E/Ea) identified those patients at highest risk, thus supporting a complementary approach for echocardiography and NT-proBNP in patients with HF symptoms.

Background and Objective: Doppler echocardiographic assessment of diastolic filling provides a non-invasive estimate of left ventricular (LV) filling pressure and the most advanced diastolic filling grade, the restrictive filling pattern (RFP), has been linked to prognosis in patients post acute myocardial infarction (AMI) and with heart failure (HF). There remains some uncertainty about the prognostic role of RFP in patients with varied levels of systolic function. The objective of this collaboration is to determine whether the presence of RFP offers additional prognostic information over LV systolic function, symptoms or other clinical factors in patients post AMI or with HF., Methods: The Meta-analysis Research Group in Echocardiography (MeRGE) has been established in order to test this through two individual patient meta-analyses. Prospective studies that enrolled patients with either established HF or post AMI and included Doppler-echocardiography and outcome data will be merged into two large datasets (3739 AMI patients and 3540 HF patients) in order to evaluate the independent effects of RFP upon total and cardiovascular mortality using Kaplan-Meier survival analysis methods and Cox proportional hazards model for multi-variate analysis. Survival will be examined within different bands of LV systolic function based upon ejection fraction (EF)., Implications: This unique dataset will provide a very large cohort of patients, which will be adequately powered to provide new and prognostically important information to further aid risk stratification in these two high-risk patient groups.

Background: Two recent literature-based meta-analyses revealed that restrictive filling pattern (RFP) was associated with a 4-fold increase in the risk of death in patients with heart failure (HF) and postacute myocardial infarction (AMI). This similar but unique analysis evaluated the link between RFP and morbidity., Methods and Results: Prospective echocardiographic studies of patients post-AMI and with HF that reported HF morbidity were identified. Events (post-AMI: development of HF; HF: HF readmission) were compared between patients with and without RFP in both patient groups. Review Manager version 4.2.7 software was used for the analysis. Twelve post-AMI studies (1286 patients, 271 events) and 5 HF studies (647 patients, 176 events) were identified. RFP was associated with HF readmission in the HF patients (OR 2.96 [2.02-4.33] and development of HF post-AMI (OR 10.10 [7.02-14.51]). The event rate in the RFP group was the same regardless of disease category (49% post-AMI, 42% HF); however, RFP was less prevalent in the post-AMI group (22% versus 39%)., Conclusions: This literature-based meta-analysis confirms that RFP is a powerful predictor of HF hospitalization in patients with HF and especially the development of HF post-AMI. This is an important prognostic sign and should be incorporated into routine clinical practice.

Background: Several studies have reported that the presence of a restrictive filling pattern (RFP) is associated with poor outcome in patients with heart failure (HF). These studies, of variable sample size, have involved different HF patient groups with variable associated mortality rates and follow-up times, and while powered for effects on combined end-points such as death or hospital admission, many were underpowered to reliably determine the overall effect of the RFP on total mortality. Consequently, we performed a meta-analysis to determine the mortality associated with RFP in patients with HF., Methods: We searched several online medical databases for prospective studies of patients with HF. All authors were requested to confirm their data. All-cause mortality was compared between RFP and non-restrictive filling patterns (Non-RFP). Review Manager version 4.2.7 software was used for the analysis., Results: 3024 patients in 27 studies were identified (379 idiopathic cardiomyopathy, 2645 mixed aetiology HF). Average follow-up was between 3 months and 5 years. 1284 (42%) patients had RFP at baseline. 688 deaths occurred and the overall odds ratio for death was 4.36 (CI 3.60, 5.04); idiopathic group: 6.65 (CI 3.86, 11.47); mixed aetiology group: 4.10 (CI 3.34, 5.04). The overall odds ratio for death/transplantation was 4.87 (CI 4.04, 5.86); idiopathic group: 7.62 (CI 4.50, 12.92); mixed aetiology group: 4.56 (CI 3.74, 5.56)., Conclusions: Restrictive filling pattern is associated with a four-fold increase in mortality in patients with HF and thus should be an important part of the echocardiographic assessment of such patients.

Background: Atrial fibrillation (AF) and congestive heart failure (HF) often coexist, but there is conflicting data regarding the association of AF with outcome in HF. To examine this further we have evaluated the prognostic effect of AF in two complementary CHF populations; a population based data set of 55,106 patients admitted to hospital with CHF, and a cohort of 197 patients recruited after a hospital admission with HF into a management clinical trial., Methods: Firstly, data for all hospital admissions in New Zealand from 1988 to 1997 were obtained. Using coding data, 55,106 first admissions for HF were identified, the presence of AF was determined by secondary diagnosis coding, and all cause mortality was obtained. Secondly, patients enrolled in the Auckland Heart Failure Management Study were evaluated for the presence or absence of AF, and for all cause mortality at three years., Results: Mortality at 30 days, 6 and 12 months was significantly lower for AF patients compared to sinus rhythm (SR) in the national admissions cohort. In the clinical trial cohort the presence of AF was also associated with lower three-year mortality, although this difference was not seen when the groups were stratified by Doppler mitral filling pattern (a restrictive filling pattern was associated with reduced longevity compared to SR, non-restrictive or AF)., Conclusions: This data shows that the presence of AF in two general HF populations in New Zealand is not associated with an adverse prognosis. HF severity, and in particular a restrictive filling pattern, remain powerful predictors of mortality.

Objective: Heart failure is associated with poor prognosis and the differentiation of patients on the basis of diastolic filling patterns helps to identify several groups of patients with incrementally higher risk. However, this is reliant on accurate definition of filling patterns. The aim of this study was to compare preload reduction with contrast-enhanced pulmonary venous Doppler recordings for the correct assessment of diastolic filling pattern., Methods: In all, 20 patients with heart failure and 25 healthy volunteers were studied on 2 separate days. Preload reduction was achieved with the Valsalva maneuver (nonstandardized and standardized) and sublingual nitroglycerin. Responses were compared among the 3 methods and the filling patterns obtained on each day with the various methods compared., Results: Although pulmonary venous Doppler improved the diastolic classification over mitral Doppler, preload reduction resulted in better classification and improved sensitivity, specificity, and positive and negative predictive values. No advantage was observed for either the standardized Valsalva or pharmacologic preload reduction., Conclusion: Preload reduction is an essential part of the assessment of diastolic filling grade in patients with heart failure as it can identify pseudonormal filling (mildly increased filling pressures), reversible restrictive filling (high filling pressures), and nonreversible restrictive filling pattern (very high filling pressures).

Aims: Wall motion score index (WMSI) is an important prognostic indicator in heart failure (HF) patients but requires endocardial visualisation. This study evaluated the role tissue harmonic imaging (THI) and contrast opacification (LVO) for improving endocardial visualisation and the determination of WMSI in HF patients., Methods and Results: Thirty-one HF patients and 30 controls underwent apical echocardiography with fundamental imaging (FUND), THI and THI with contrast agent (Levovist). Visualisation and motion were graded in the six segments from each of the apical two and four chamber views. Both THI and LVO reduced the percentage of non-visualised segments (FUND 13.6%, THI 5.6%, LVO 2.8%, p=0.01) in the controls, but in HF patients, only THI improved visualisation (% segments not visualised FUND 9.7%, THI 3.5%, LVO 4.8%, p=0.06). The anterior and lateral walls were the least well visualised with FUND, but improved with LVO (anterior p=0.0026, lateral p=0.0003). No improvement was seen in the inferior wall (p=0.30) or septum (p=0.2). WMSI was similar by all methods and negatively correlated with ejection fraction (FUND r=-0.69, THI r=-0.74, LVO r=-0.77, all p<0.001)., Conclusion: THI improved endocardial visualisation in all subjects and LVO offered additional benefit in the controls, but not in HF patients. Regional endocardial visualisation was inconsistent. Thus, both patient factors and wall segment site need to be considered when using contrast agents for endocardial visualisation.

The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart failure are unknown. The potential of plasma amino-terminal C-type natriuretic peptide (N-CNP) as a marker of cardiac function was investigated in symptomatic patients. In 305 patients with recent-onset dyspnea and/or peripheral edema, presenting to primary care, assay of plasma amino-terminal C-type natriuretic peptide and other plasma vasoactive hormones was conducted together with echocardiography. Heart failure was diagnosed in 77 (of the 305) patients by rigorous application of predefined criteria. Plasma amino-terminal C-type natriuretic peptide concentrations were elevated in patients with heart failure, and by univariate analysis were related to age, renal function, and other hormones. On multivariate analysis, tertile of plasma N-CNP interacted with tertile of plasma amino-terminal B-type natriuretic peptide to predict heart failure independent of age, gender, renal function, or echocardiographic left ventricular fractional shortening. N-CNP showed significant relations to concurrent plasma CNP, atrial natriuretic peptide (ANP), N-ANP, B-type (or brain) natriuretic peptide (BNP), N-BNP, endothelin-1, and adrenomedullin but not to echocardiographic indicators of left ventricular systolic function. Plasma amino-terminal C-type natriuretic peptide is elevated in heart failure and is related to other plasma hormones in heart failure. These findings suggest a possible compensatory response from the peripheral vasculature to heart failure by an endothelium-based vasodilator peptide and mandate further exploration of the role of C-type natriuretic peptide in this condition.

Aims: To investigate the effects of tissue harmonic imaging (THI) and contrast chamber opacification (LVO) upon measurement variability and reproducibility of echocardiographic left ventricular (LV) volume and ejection fraction (EF) measurements in patients with heart failure (HF)., Background: Echocardiography is often used in HF patients to determine LV volumes and EF. However, current echo methods are variable and may not be applicable for repeat testing in individual patients. THI and LVO have both been shown to improve endocardial visualisation, but it remains to be determined whether this results in better measurement reproducibility., Methods: Thirty-one HF patients and 30 control subjects underwent echocardiography on two separate days. LV volumes were measured under four different imaging conditions: fundamental, THI, LVO and LVO with ECG-triggered Power Doppler. Chamber opacification, pulmonary transit time (PTT), endocardial enhancement, reproducibility and bias were assessed., Results: Chamber opacification was inferior and the PTT longer in the HF patients. PTT was related to LV volumes, EF, jugular venous pressure and mitral filling pattern. THI improved endocardial visualisation, and although LVO improved endocardial visualisation in the controls, it offered no benefit over THI in the HF patients. LV volumes and EF were different for each method and THI was the least variable method for repeat measurements., Conclusions: THI improved endocardial visualisation and was the least variable of the techniques. LVO offered no further advantage in patients with HF and thus cannot be routinely advocated and since LV volumes and EF were different for each, these methods are neither comparable nor interchangeable for follow-up assessments.

Background: Recent studies have investigated specific strategies for heart failure management. None has involved collaboration between primary and secondary care. Potential gains for patients may result from collaborative strategies., Objective: To assess the effect of an integrated management approach for patients with heart failure on general practice., Methods: The study design was a cluster randomized controlled trial of integrated primary/ secondary care compared with usual care for heart failure patients. The study took place at Auckland Hospital, New Zealand and involved 197 patients admitted with an episode of heart failure. Patients were randomized to management group or control group (who received "usual" care). Management group patients received early clinical review, education sessions, a personal diary for medications and weight, and regular clinical follow-up alternating between GP and hospital clinic. Follow-up was for 12 months., Results: Patients visited GPs frequently (median 14 visits, range 0-40), with no statistical difference between the two groups. Heart failure was the most common reason for consulting the GP. There was no relationship between GP consultations and patients' attendance at the study clinic, or hospital admissions. Management group GPs and patients expressed a high level of satisfaction., Conclusion: GP consultation rates were not affected by the programme. Further research will determine if general practice based programmes result in further gains.

Objectives: The purpose of this study was to determine the effect of amino-terminal pro-brain natriuretic peptide (N-BNP) on the diagnostic accuracy of heart failure (HF) in primary care., Background: The accurate diagnosis of patients with suspected HF presenting in primary care is difficult. Amino-terminal pro-brain natriuretic peptide is present in high levels in cardiac dysfunction and may improve the diagnostic accuracy of HF in primary care., Methods: The Natriuretic Peptides in the Community Study was a prospective, randomized controlled trial of the effect of N-BNP on the accuracy of HF diagnosis. Patients presenting to their general practitioner (GP) with symptoms of dyspnea and/or peripheral edema were included. The GPs formulated an initial diagnosis based on clinical assessment. All patients underwent a full cardiologic assessment that included echocardiography and N-BNP. Each patient was randomized to the BNP group (GP received the N-BNP result) or the control group (GP did not receive the N-BNP result). Patients were then reviewed by their GP, and their diagnosis was reviewed. The primary end point was the accuracy of the GPs' diagnoses compared with the panel standard., Results: A total of 305 patients were included; mean age was 72 years, 65% were female. Seventy-seven patients met the panel criteria for HF. The diagnostic accuracy improved 21% in the BNP group and 8% in the control group (p = 0.002). The main impact of N-BNP measurement on diagnostic accuracy was the GPs' correctly ruling out HF. The number needed to diagnose by N-BNP measurement was seven patients., Conclusion: This study demonstrates that N-BNP measurement significantly improves the diagnostic accuracy of HF by GPs over and above customary clinical review.

Objectives: We sought to investigate whether pseudonormal (PN) filling was associated with death or hospital admission in patients with congestive heart failure (CHF)., Background: The high mortality rate associated with CHF is related to many clinical and echocardiographic variables. In particular, a short mitral deceleration time and restrictive diastolic filling predict death and/or hospital admission. We hypothesized that differentiating patients with nonrestrictive filling might identify an intermediate PN group that may be associated with intermediate risk., Methods: A total of 115 patients admitted to the hospital for exacerbation of CHF symptoms underwent pre-discharge Doppler echocardiography to determine mitral inflow (before and after preload reduction) and pulmonary venous return. Patients were followed up for one year, and all-cause mortality and re-admission data were analyzed., Results: The classification of filling patterns was: abnormal relaxation (AR) in 46 (40%) patients, pseudonormal (PN) filling in 42 (36.5%) patients and restrictive filling pattern (RFP) in 27 (23.4%) patients. When comparing the RFP group with the AR group, all-cause mortality was higher (38.4% vs. 17.4%, p = 0.033), hospital admission was higher (70.3% vs. 54.3%, p = 0.073), death/hospital admission was higher (77.8% vs. 56.5%, p = 0.02), CHF hospital admission was higher (40.7% vs. 15.2%, p = 0.01) and death/CHF hospital admission was higher (62.9% vs. 26.1%, p = 0.0005). Mortality in the PN group was not significantly different from that in the two other groups, but re-admissions were higher than the AR group (76.2% vs. 54.3%, p = 0.006), as was death/re-admission (78.6% vs. 56.5%, p = 0.004) and death/CHF re-admission (47.6% vs. 26.1%, p = 0.03). Re-admissions in the PN and RFP groups were comparable., Conclusions: In a general hospital population of older patients with CHF, PN filling was associated with hospital admission rates similar to those seen with restrictive filling. The combined end point of death/CHF hospital admission was similar for restrictive filling and AR. Measurement of these variables is easy to add to routine clinical echocardiography and may provide important prognostic information in a wide range of patients with CHF.

Background: Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids. Methods and findings: We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments. Conclusions: There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease. Anthony G B Walters and colleagues assess cardiovascular outcomes fifty years after antenatal exposure to betamethasone, in long-term follow-up of a randomised double-blind, placebo-controlled trial. Author summary: Why was this study done?: Antenatal corticosteroids (ANC) are given to pregnant persons at risk of preterm birth to reduce the risk of death and breathing difficulty for their offspring. Animal studies have shown later adverse effects of ANC on offspring, particularly on their cardiovascular health in adulthood. There is little robust evidence about long-term effects in humans. This study aimed to provide evidence about the long-term effects of ANC on offspring cardiovascular health in adulthood. What did the researchers do and find?: We assessed participants at 50 years of age who had been exposed to ANC or placebo during the first randomised clinical trial of this treatment. We compared cardiovascular disease and cardiovascular risk factors between those exposed to ANC and placebo in 424 participants (46% of those still alive), using a questionnaire and routinely collected administrative data. We found no differences in cardiovascular outcomes between those exposed to ANC and those who were not. What do these findings mean?: There is no evidence that ANC has adverse effects on the cardiovascular health outcomes of offspring up to 50 years of age. The main limitation was the follow-up rate of less than 50% and the use of health questionnaires and routinely collected data rather than in-person assessments. [ABSTRACT FROM AUTHOR]

Abstract: Background: Meta-analyses are increasingly used to summarise observational data however a literature meta-analysis (LMA) may give different results to the corresponding individual patient meta-analysis (IPMA). This study compares the published results of equivalent LMAs and IPMAs, highlighting factors that can affect the results and therefore impact on clinical interpretation of meta-analyses. Method: Univariate results from published meta-analyses of prospective observational outcome data were compared, as were the number of studies, patients and length of follow-up. The absolute difference in survival was calculated. The association between severe diastolic dysfunction (RFP) and death post acute myocardial infarction (AMI) and in chronic heart failure (HF) were used as clinical examples. Results: The IPMA hazard ratio was lower that the LMA odds ratio: AMI hazard ratio 2.67 (95% confidence interval 2.23 to 3.20), odds ratio 4.10 (3.38 to 4.99); HF hazard ratio 2.42 (2.06 to 2.83), odds ratio 4.36 (3.60 to 5.04). The IPMAs contained most of the studies from the LMAs as well as additional unpublished data, and a longer length of follow-up was available in the IPMAs (AMI 3.7 vs 2.6 yr, HF 4.0 vs 1.5yr). Restricting analysis to the same studies in both the LMA and IPMA resulted in a similar difference in effect sizes between methods to those found in the published analyses. Conclusions: The result of a meta-analysis is affected by whether study level or individual patient data have been used, and the variant of analysis that is required. Awareness and consideration of these factors is important for clinical interpretation of meta-analyses. [Copyright &y& Elsevier]