Journal: Eur J Heart Fail

Sorted by: date / impact
Abstract

Relationship between Body-Mass Index, Cardiovascular Biomarkers and Incident Heart Failure.

Suthahar N, Meems LMG, Groothof D, Bakker SJL, ... van Veldhuisen DJ, de Boer RA
Background
There are limited data examining whether body-mass index (BMI) influences the association between cardiovascular biomarkers and incident heart failure (HF).
Methods and results
Thirteen biomarkers representing key HF domains were measured: N-terminal-pro-B-type natriuretic peptide (NT-proBNP), mid-regional-pro-A-type natriuretic peptide (MR-proANP), cardiac troponin-T (cTnT), C-reactive protein, procalcitonin, galectin-3, C-terminal pro-endothelin-1 (CT-pro-ET-1), mid-regional pro-adrenomedullin, plasminogen activator inhibitor-1, copeptin, renin, aldosterone and cystatin-C. Associations of biomarkers with BMI were examined using linear regression models, and with incident HF using Cox regression models. We selected biomarkers significantly associated with incident HF, and evaluated whether BMI modified these associations.
Results
Among 8202 individuals, 41% were overweight (BMI 25-30kg/m ), and 16% were obese (BMI≥30kg/m ). Mean age of the cohort was 49 years (range 28-75), and 50% were women. All biomarkers except renin were associated with BMI: inverse associations were observed with NT-proBNP, MR-proANP, CT-pro-ET-1 and aldosterone whereas positive associations were observed with the remaining biomarkers (P ≤0.001). During 11.3±3.1 years follow-up, 357 HF events were recorded. Only NT-proBNP, MR-proANP and cTnT remained associated with incident HF (P<0.001), and a significant biomarker*BMI interaction was not observed (P >0.1). Combined NT-proBNP and cTnT measurements modestly improved performance metrics of the clinical HF model in overweight (ΔC-statistic=0.024; LHRχ =38; P<0.001) and in obese (ΔC-statistic=0.020; LHRχ =32; P<0.001) individuals.
Conclusions
Plasma concentrations of several cardiovascular biomarkers are influenced by obesity. Only NT-proBNP, MR-proANP and cTnT were associated with incident HF, and BMI did not modify these associations. A combination of NT-proBNP and cTnT improves HF risk prediction in overweight and in obese individuals. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 13 Jan 2021; epub ahead of print
Suthahar N, Meems LMG, Groothof D, Bakker SJL, ... van Veldhuisen DJ, de Boer RA
Eur J Heart Fail: 13 Jan 2021; epub ahead of print | PMID: 33443299
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Temporal trends in mortality and readmission after acute heart failure: A systematic review and meta-regression in the past four decades.

Kimmoun A, Takagi K, Gall E, Ishihara S, ... Javanainen T, Bastian K
Aims
Acute heart failure (AHF) is frequent and life-threatening disease. However, innovative AHF therapies have remained limited, and care is based on experts opinion. Temporal trends and benefits of long-term oral cardiovascular medications on AHF outcomes remain uncertain.
Methods and results
This study is registered with PROSPERO (CRD42018099885). A systematic review ranging from 1980 to 2017, searched AHF studies with more than 100 patients that reported death and/or readmission. Primary outcomes were temporal trends, assessed by meta-regression, for 30-day or one-year all-cause death and/or readmission rates. Secondary outcomes were temporal trends of oral cardiovascular therapies and their influence on primary outcomes. Among the 45143 studies screened, 285 were included, representing 15 million AHFs. In the past decades, though mortality and readmission remain high, there was a decline in 30-day all-cause death (OR for a 10-year increment: 0.74 (0.61-0.91); p=0.004) that persisted at one year (OR 0.86 (0.77- 0.96); p=0.007), while 30-day and one-year all-cause readmission rate remained roughly unchanged. Trends of primary outcomes were linear and did not differ among continents. Decline in one-year all-cause death rate correlated with high proportions of oral or beta-blockers, especially when combined with oral renin-angiotensin-aldosterone system inhibitors, but not with diuretics while trends in readmission remained unchanged with these therapies.
Conclusions
Though AHF outcomes remain poor, the present study revealed global favorable trends of survival after AHF episodes probably associated with greater use of oral neurohormonal antagonists. The present study urges to implement the combination of oral renin-angiotensin-aldosterone system inhibitors and beta-blockers in patients at risk of AHF. This article is protected by copyright. All rights reserved.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 13 Jan 2021; epub ahead of print
Kimmoun A, Takagi K, Gall E, Ishihara S, ... Javanainen T, Bastian K
Eur J Heart Fail: 13 Jan 2021; epub ahead of print | PMID: 33443295
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Circulating cardiovascular microRNAs in critically ill COVID-19 patients Short title: microRNA signatures in COVID-19.

Garg A, Seeliger B, Derda AA, Xiao K, ... Bär C, Thum T
Aims
Corona virus disease 2019 (COVID-19) is a still growing pandemic, causing many deaths and socio-economic damage. Elevated expression of the SARS-CoV-2 entry receptor ACE2 on cardiac cells of patients with heart diseases may be related to cardiovascular burden. We have thus analysed cardiovascular and inflammatory microRNAs (miRs), sensitive markers of cardiovascular damage, in critically ill, ventilated patients with COVID-19 or Influenza associated acute respiratory distress syndrome (Influenza-ARDS) admitted to intensive care unit (ICU) and healthy controls.
Methods and results
Circulating miRs (miR-21, miR-126, miR-155, miR-208a and miR-499) were analyzed in a discovery cohort consisting of patients with mechanically-ventilated COVID-19 (n = 18) and healthy controls (n = 15). A validation study was performed in an independent cohort of mechanically-ventilated COVID-19 patients (n = 20), Influenza-ARDS patients (n = 13) and healthy controls (n = 32). In both cohorts RNA was isolated from serum and cardiovascular disease/inflammatory-relevant miR concentrations were measured by miR-specific TaqMan PCR analyses. In both the discovery and the validation cohort, serum concentration of miR-21, miR-155, miR-208a and miR-499 were significantly increased in COVID-19 patients compared to healthy controls. Calculating the area under the curve (AUC) using ROC-analysis miR-155, miR-208a and miR-499 showed a clear distinction between COVID-19 and Influenza-ARDS patients.
Conclusion
In this exploratory study, inflammation and cardiac myocyte-specific miRs were upregulated in critically ill COVID-19 patients. Importantly, miR profiles were able to differentiate between severely ill, mechanically-ventilated Influenza-ARDS and COVID-19 patients, indicating a rather specific response and cardiac involvement of COVID-19.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 08 Jan 2021; epub ahead of print
Garg A, Seeliger B, Derda AA, Xiao K, ... Bär C, Thum T
Eur J Heart Fail: 08 Jan 2021; epub ahead of print | PMID: 33421274
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiac Myosin-Binding Protein C in the Diagnosis and Risk Stratification of Acute Heart Failure.

Kozhuharov N, Wussler D, Kaier T, Strebel I, ... Marber M,
Aims
Cardiac myosin-binding protein C (cMyC) seems to be even more sensitive in the quantification of cardiomyocyte injury versus high-sensitivity cardiac troponin (hs-cTn), and may therefore have diagnostic and prognostic utility.
Methods and results
In a prospective multicentre diagnostic study, cMyC, hs-cTnT, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations were measured in blinded fashion in patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists centrally adjudicated the final diagnosis. Diagnostic accuracy for acute heart failure (AHF) was quantified by the area under the receiver-operating characteristics curve (AUC). All-cause mortality within 360 days was the prognostic endpoint. Among 1083 patients eligible for diagnostic analysis, 51% had AHF. cMyC concentrations at presentation were higher among AHF patients versus patients with other final diagnoses (72 (IQR 39-156) versus 22 ng/L (IQR 12-42), p < 0.001)). cMyC\'s AUC was high (0.81, 95%CI 0.78-0.83), higher than hs-cTnT\'s (0.79, 95%CI 0.76-0.82, p = 0.081) and lower than NT-proBNP\'s (0.91, 95%CI 0.89-0.93, p < 0.001). Among 794 AHF patients eligible for prognostic analysis, 28% died within 360 days; cMyC plasma concentrations above the median indicated increased risk of death (hazard ratio 2.19, 95%CI 1.66-2.89; p < 0.001). cMyC\'s prognostic accuracy was comparable with NT-proBNP\'s and hs-cTnT\'s. cMyC did not independently predict all-cause mortality when used in validated multivariable regression models. In novel multivariable regression models including medication, age, left ventricular ejection fraction, and discharge creatinine, cMyC remained an independent predictor of death and had no interactions with medical therapies at discharge.
Conclusion
cMyC may aid physicians in the rapid triage of patients with suspected AHF.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 08 Jan 2021; epub ahead of print
Kozhuharov N, Wussler D, Kaier T, Strebel I, ... Marber M,
Eur J Heart Fail: 08 Jan 2021; epub ahead of print | PMID: 33421273
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Peripheral and Pulmonary Effects of Inorganic-Nitrite during Exercise in Heart Failure with Preserved Ejection Fraction.

Reddy YNV, Stewart GM, Obokata M, Koepp KE, Borlaug BA
Aims
To determine whether inorganic nitrite improves peripheral and pulmonary O transport during exercise in heart failure with preserved ejection fraction(HFpEF).
Methods and results
Data from two invasive, randomized, double-blind, placebo-controlled trials with matched workload exercise of inhaled and intravenous sodium nitrite were pooled for this analysis(n=51). Directly measured O consumption(VO ), and blood gas data were used to evaluate the effect of nitrite on skeletal muscle O conductance(Dm), VO kinetics, alveolar capillary membrane O conductance(D ), and O utilization during submaximal exercise. As compared to placebo, treatment with nitrite resulted in an improvement in Dm (+4.9±6.5 vs -0.9±4.3 ml/mmHg*min, p=0.0008) as well as VO kinetics measured by mean response time (-5.0±6.9 vs -0.6±6.0 sec, p=0.03), with preserved O utilization despite increased convective O delivery through cardiac output (+0.4±0.7 vs -0.3±0.9 L/min, p=0.02). Nitrite improved D (+2.5 ± 6.3 vs -2.0 ± 9.0 ml/mmHg*min, p=0.05) with exercise, which was associated with lower pulmonary capillary pressures (r=-0.34, p=0.02), and reduced pulmonary dead space ventilation fraction (-0.01 ± 0.05 vs +0.02 ± 0.05, p=0.02).
Conclusion
Sodium nitrite enhances skeletal muscle O conductance during exercise as well as pulmonary O diffusion, optimizing O kinetics in tandem with increased convective O delivery through cardiac output augmentation. The favorable combined pulmonary, cardiac and peripheral effects of nitrite may improve exercise tolerance in people with HFpEF and requires further investigation.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 08 Jan 2021; epub ahead of print
Reddy YNV, Stewart GM, Obokata M, Koepp KE, Borlaug BA
Eur J Heart Fail: 08 Jan 2021; epub ahead of print | PMID: 33421267
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oral Sucrosomial iron improves exercise capacity and quality of life in heart failure with reduced ejection fraction and iron deficiency: A non-randomized, open-label, proof-of-concept study.

Karavidas A, Troganis E, Lazaros G, Balta D, ... Parissis J, Farmakis D
Background
Oral sucrosomial iron (SI) combines enhanced bioavailability and tolerance compared to conventional oral iron along with similar efficacy compared to intravenous iron in several conditions associated with iron deficiency (ID).
Methods and results
In this non-randomized, open-label study, we sought to evaluate prospectively the effects of SI on clinical parameters, exercise capacity and quality of life in 25 heart failure patients with reduced ejection fraction (HFrEF) and ID, treated with SI 28 mg daily for 3 months, in comparison to 25 matched HFrEF controls. All patients were on optimal stable HF therapy. Patients were followed for 6 months for death or worsening HF episodes. There were no differences in baseline characteristics between groups. At 3 months, SI was associated with significant increase in haemoglobin, serum iron and serum ferritin levels (all p ≤ 0.001) along with a significant improvement in 6-min walked distance (6MWD) and Kansas City Cardiomyopathy Questionnaire (all p < 0.01), even after adjustment for baseline parameters; these differences persisted at 6 months. Over the study period, there were no deaths, while 10 patients (20%) in total (4 in SI group and 6 in control group), experienced worsening HF (OR = 0.51, 95%CI, 0.41-6.79, p = 0.482). Drug-associated diarrhoea was reported by one patient in SI group and led to drug discontinuation; no other adverse events were reported.
Conclusions
In this proof-of-concept study, SI was well tolerated and improved exercise capacity and quality of life in HFrEF patients with ID. Randomized studies are required to further investigate the effects of this therapy.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 08 Jan 2021; epub ahead of print
Karavidas A, Troganis E, Lazaros G, Balta D, ... Parissis J, Farmakis D
Eur J Heart Fail: 08 Jan 2021; epub ahead of print | PMID: 33421230
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effects of dapagliflozin in heart failure with reduced ejection fraction, and COPD: An analysis of DAPA-HF.

Dewan P, Docherty KF, Bengtsson O, de Boer RA, ... Jhund PS, McMurray JJ
Aims
Chronic obstructive pulmonary disease (COPD) is an important comorbidity in HFrEF, associated with worse outcomes and often suboptimal treatment because of under-prescription of beta-blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. To examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).
Methods & results
We examined whether the effects of dapagliflozin in DAPA-HF were modified by COPD status. The primary outcome was the composite of an episode of worsening heart failure (HF) event or cardiovascular (CV) death. 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline NT-proBNP, and less likely to be treated with a beta-blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without 18.9 (95% CI 16.0-22.2) versus 13.0 (12.1-14.0) per 100 person-years; hazard ratio (HR) for COPD versus no COPD 1.44 (1.21-1.72), P<0.001. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with (HR 0.67 [95%CI 0.48-0.93]) and without COPD (0.76 [0.65-0.87]); interaction p-value 0.47.
Conclusions
In DAPA-HF, one-in-eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all prespecified outcomes was consistent in patients with and without COPD.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 22 Dec 2020; epub ahead of print
Dewan P, Docherty KF, Bengtsson O, de Boer RA, ... Jhund PS, McMurray JJ
Eur J Heart Fail: 22 Dec 2020; epub ahead of print | PMID: 33368858
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Intravenous Immunoglobulin Therapy in Adult Patients with Chronic Idiopathic Cardiomyopathy and Cardiac Parvovirus B19 persistence.

Hazebroek MR, Henkens MTHM, Raafs AG, Verdonschot JAJ, ... van Empel VPM, Heymans SRB
Aim
Previous uncontrolled studies indicated a possible benefit of intravenous immunoglobulin (IVIg) in parvovirus B19 (B19V)-related dilated cardiomyopathy (DCM). This randomized, double-blind, placebo-controlled single-centre trial investigated the benefits of IVIg beyond conventional therapy in idiopathic chronic DCM patients with B19V persistence (NCT00892112).
Methods and results
Fifty patients (39 men; mean(±SD) age 54±11years) with chronic (>6 months) idiopathic DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200copies/μgDNA were blindly randomized to either IVIg (n=26, 2g/kg over four days) or placebo (n=24). The primary outcome was change in LVEF at six months after randomization. Secondary outcomes were change in functional capacity assessed by 6-minute walking test (6mwt), quality of life (Minnesota Living with Heart Failure Questionnaire (MLHFQ), left ventricular end-diastolic volume (LVEDV), and EMB B19V load at six months after randomization. LVEF significantly improved in both IVIg and placebo group (absolute mean (±SD) increase 5±9%, P=0.011 and 6±10%, P=0.008, respectively), without a significant difference between both groups (P=0.609). Additionally, change in 6mwt (median [IQR] IVIg 36[13;82] vs placebo 32[5;80]m, P=0.573), MLHFQ (IVIg 0[-7;5] vs placebo -2[-6;6], P=0.904) and LVEDV (IVIg -16±49 vs placebo -29±40ml/m , P=0.334) did not significantly differ between both groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups.
Conclusion
IVIg therapy does not significantly improve cardiac systolic function or functional capacity beyond standard medical therapy in patients with idiopathic chronic DCM and cardiac B19V persistence.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 20 Dec 2020; epub ahead of print
Hazebroek MR, Henkens MTHM, Raafs AG, Verdonschot JAJ, ... van Empel VPM, Heymans SRB
Eur J Heart Fail: 20 Dec 2020; epub ahead of print | PMID: 33347677
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Is Acute heart failure a distinctive disorder? An analysis from BIOSTAT-CHF.

Davison BA, Senger S, Sama IE, Koch GG, ... Voors AA, Cotter G
Aims
This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients.
Methods and results
The BIOSTAT-CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort. Patients with acute HF had substantially higher morbidity and mortality (6 months mortality was 12..3% for acute HF and 4..7% for worsening HF in chronic outpatients). Multivariable models predicting 180-day mortality and 180-day HF re-admission differed substantially between acute HF and worsening HF in chronic outpatients. CA-125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C-index of 0..71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C-index of 0..913 in the index cohort and 0..901 in the validation cohort.
Conclusion
The study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 18 Dec 2020; epub ahead of print
Davison BA, Senger S, Sama IE, Koch GG, ... Voors AA, Cotter G
Eur J Heart Fail: 18 Dec 2020; epub ahead of print | PMID: 33340221
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

OUTSTEP-HF: Randomised controlled trial comparing short-term effects of sacubitril/valsartan versus enalapril on daily physical activity in patients with chronic heart failure with reduced ejection fraction.

Piepoli MF, Hussain RI, Comin-Colet J, Dosantos R, ... Jaarsma T, Edelmann F
Aims
OUTSTEP-HF compared the effect of sacubitril/valsartan versus enalapril on six-minute walk test (6MWT) distance, non-sedentary daytime physical activity and heart failure (HF) symptoms in patients with HF with reduced ejection fraction (HFrEF).
Methods and results
Ambulatory patients (N=621) with stable symptomatic HFrEF were randomised 1:1 to sacubitril/valsartan (N=310) or enalapril (N=311). Changes in physical activity and mean daily non-sedentary daytime activity from baseline to Week 12 were measured using 6MWT and a wrist-worn accelerometer device, respectively. After 12 weeks, 6MWT improved by 35.09 m with sacubitril/valsartan (97.5% CI: 27.85, 42.32) and by 26.11 m with enalapril (97.5% CI: 18.78, 33.43); however, there was no significant difference between groups (LSM treatment difference: 8.98 m [97.5% CI: -1.31, 19.27]; p=0.0503). Mean daily non-sedentary daytime activity decreased by 27 minutes with sacubitril/valsartan and by 21 minutes with enalapril (LSM treatment difference: -6 minutes [97.5% CI: -25.7, 13.4], p=0.4769) after 12 weeks. 6MWT improved by ≥30 m in 51% of patients in sacubitril/valsartan group versus 44% of patients treated with enalapril (OR [95% CI]: 1.251 [0.895, 1.748]). At Week 4, non-sedentary daytime activity increased by ≥10% in 58% of patients treated with sacubitril/valsartan versus 64% with enalapril; 58% treated with sacubitril/valsartan reported improved HF symptoms as assessed by patient global assessment versus 43% with enalapril. However, these differences did not persist at Week 12.
Conclusion
After 12 weeks of treatment, there was no significant benefit of sacubitril/valsartan on either 6MWT or in daytime physical activity measured by actigraphy compared with enalapril. (ClinicalTrials.gov number, NCT02900378).

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 12 Dec 2020; epub ahead of print
Piepoli MF, Hussain RI, Comin-Colet J, Dosantos R, ... Jaarsma T, Edelmann F
Eur J Heart Fail: 12 Dec 2020; epub ahead of print | PMID: 33314487
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium-glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58.

Zelniker TA, Morrow DA, Mosenzon O, Goodrich EL, ... Sabatine MS, Wiviott SD
Aims
Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels.
Methods and results
This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CV death/HHF regardless of baseline NT-proBNP (P-interaction 0.72) or hsTnT quartiles (P-interaction 0.93). Given their higher baseline risk, patients with NT-proBNP and/or hsTnT levels above the median derived larger absolute risk reductions with dapagliflozin (NT-proBNP 1.9% vs. 0%, P-interaction 0.010; hsTnT 1.8% vs. 0.1%, P-interaction 0.026).
Conclusion
Patients with type 2 diabetes mellitus and higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the relative risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in patients with higher baseline biomarker levels.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 01 Dec 2020; epub ahead of print
Zelniker TA, Morrow DA, Mosenzon O, Goodrich EL, ... Sabatine MS, Wiviott SD
Eur J Heart Fail: 01 Dec 2020; epub ahead of print | PMID: 33269486
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Design of a prospective patient-level pooled analysis of two parallel trials of empagliflozin in patients with established heart failure.

Packer M, Butler J, Filippatos G, Zannad F, ... Anker SD,
Aim
The EMPEROR-Reduced trial demonstrated that empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with a reduced ejection fraction, and the EMPEROR-Preserved trial is currently evaluating the effect of the drug on the same endpoint in patients with an ejection fraction >40%. However, neither the trial was designed to have adequate statistical power to evaluate the effects of empagliflozin and dapagliflozin on major adverse renal outcomes or on mortality. Herein we describe the design of a prospective individual patient-level pooled analysis of two large-scale trials with empagliflozin (EMPEROR-Reduced and EMPEROR-Preserved) in patients with heart failure across the spectrum of ejection fraction.
Methods
The trials were carried out in parallel using the same administrative structure and committees, randomization procedure, schedule of study visits and adjudication criteria and similar groups of investigators and case report forms. The two component trials specified the same primary and key secondary endpoints and used an identical hierarchical testing procedure, which included a pooled analysis of the two trials as a key component of the hierarchy. Consequently, the pooled analysis has been prospectively assigned a false positive error rate, which is conditional on one or both trials first achieving success on their primary and one or both key secondary endpoints. The pooled analysis has its own statistical plan with its own endpoints, and this plan was finalized before either trial had begun recruitment of patients into either study. The primary endpoint of the pooled analysis is a composite of serious adverse renal outcomes, defined by chronic dialysis, renal transplantation and a profound or sustained decrease in glomerular filtration rate. All-cause and cardiovascular mortality are specified as secondary endpoints.
Conclusion
The planned pooled analysis has an unusually high degree of statistical rigour that will allow it to address important questions that cannot be fully addressed by the individual trials.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 29 Nov 2020; epub ahead of print
Packer M, Butler J, Filippatos G, Zannad F, ... Anker SD,
Eur J Heart Fail: 29 Nov 2020; epub ahead of print | PMID: 33251659
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Baseline Characteristics of Patients with Heart Failure with Preserved Ejection Fraction in the EMPEROR-Preserved Trial.

Anker SD, Butler J, Filippatos G, Khan MS, ... Packer M,
Background
EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares it with patients enrolled in prior HFpEF trials.
Methods
EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients (left ventricular ejection fraction [LVEF] >40%) with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of HF hospitalization.
Results
Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72±9 years, 45% were women. Almost all patients had New York Heart Association (NYHA) Class II or III symptoms (99.6%), and 23% had prior HF hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54±9%) was slightly lower while the median NT-proBNP (974 [499-1731] pg/mL) was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin converting enzyme inhibitors/angiotensin receptor blockers/ARNi\'s (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists.
Conclusion
When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of co-morbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 28 Nov 2020; epub ahead of print
Anker SD, Butler J, Filippatos G, Khan MS, ... Packer M,
Eur J Heart Fail: 28 Nov 2020; epub ahead of print | PMID: 33251670
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure.

Boorsma EM, Beusekamp JC, Ter Maaten JM, Figarska SM, ... Damman K, Voors AA
Aims
Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF.
Methods and results
This study was a pre-defined sub-study of a double-blind, randomized, placebo-controlled, multicentre study (EMPA-RESPONSE-AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38-89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P < 0.001), without affecting plasma glucose concentration, while fractional sodium and chloride excretion and urinary osmolality remained unchanged (P >0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 ± 8 vs. 2 ± 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (-10 ± 12 vs. -2 ± 12 mL/min/1.73 m ; P = 0.009), which recovered within 30 days.
Conclusion
In patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 28 Nov 2020; epub ahead of print
Boorsma EM, Beusekamp JC, Ter Maaten JM, Figarska SM, ... Damman K, Voors AA
Eur J Heart Fail: 28 Nov 2020; epub ahead of print | PMID: 33251643
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Advanced cancer is also a heart failure syndrome - an hypothesis.

Anker MS, Sanz AP, Zamorano JL, Mehra MR, ... Coats AJS, Anker SD

We present the hypothesis that advanced stage cancer is also a heart failure syndrome. It can develop independently of or in addition to cardiotoxic effects of anti-cancer therapies. This includes an increased risk of ventricular arrhythmias. We suggest the pathophysiologic link for these developments includes generalized muscle wasting (i.e. sarcopenia) due to tissue homeostasis changes leading to cardiac wasting associated cardiomyopathy. Cardiac wasting with thinning of the ventricular wall increases ventricular wall stress, even in the absence of ventricular dilation. In addition, arrhythmias may be facilitated by cellular wasting processes affecting structure and function of electrical cells and conduction pathways. We submit that in some patients with advanced cancer (but not terminal cancer), heart failure therapy or defibrillators may be relevant treatment options. The key points in selecting patients for such therapies may be the predicted life expectancy, quality of life at intervention time, symptomatic burden, and consequences for further anti-cancer therapies. The cause of death in advanced cancer is difficult to ascertain and consensus on event definitions in cancer is not established yet. Clinical investigations on this are called for. Broader ethical considerations must be taken into account when aiming to target cardiovascular problems in cancer patients. We suggest that focused attention to evaluating cardiac wasting and arrhythmias in cancer will herald a further evolution in the rapidly expanding field of cardio-oncology. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 27 Nov 2020; epub ahead of print
Anker MS, Sanz AP, Zamorano JL, Mehra MR, ... Coats AJS, Anker SD
Eur J Heart Fail: 27 Nov 2020; epub ahead of print | PMID: 33247608
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association between renin-angiotensin-aldosterone system inhibitor use and COVID-19 hospitalization and death: a 1.4 million patient nationwide registry analysis.

Savarese G, Benson L, Sundström J, Lund LH
Aims
Renin-angiotensin-aldosterone system inhibitors (RAASi) improve outcomes in cardiorenal disease but concerns have been raised over increased risk of incident hospitalization and death from coronavirus disease 2019 (COVID-19). We investigated the association between use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs) or mineralocorticoid receptor antagonists (MRAs) and COVID-19 hospitalization/death in a large nationwide population.
Methods and results
Patients with hypertension, heart failure, diabetes, kidney disease, or ischaemic heart disease registered in the Swedish National Patient Registry until 1 February 2020 were included and followed until 31 May 2020. COVID-19 cases were defined based on hospitalization/death for COVID-19. Multivariable logistic and Cox regressions were fitted to investigate the association between ACEi/ARB and MRA and risk of hospitalization/death for COVID-19 in the overall population, and of all-cause mortality in COVID-19 cases. We performed consistency analysis to quantify the impact of potential unmeasured confounding. Of 1 387 746 patients (60% receiving ACEi/ARB and 5.8% MRA), 7146 (0.51%) had incident hospitalization/death from COVID-19. After adjustment for 45 variables, ACEi/ARB use was associated with a reduced risk of hospitalization/death for COVID-19 (odds ratio 0.86, 95% confidence interval 0.81-0.91) in the overall population, and with reduced mortality in COVID-19 cases (hazard ratio 0.89, 95% confidence interval 0.82-0.96). MRA use was not associated with risk of any outcome. Consistency analysis showed that unmeasured confounding would need to be large for there to be harmful signals associated with RAASi use.
Conclusions
In a 1.4 million nationwide cohort, use of RAASi was not associated with increased risk of hospitalization for or death from COVID-19.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 21 Nov 2020; epub ahead of print
Savarese G, Benson L, Sundström J, Lund LH
Eur J Heart Fail: 21 Nov 2020; epub ahead of print | PMID: 33222412
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ventricular tachycardia, premature ventricular contractions, and mortality in unselected patients with lung, colon, or pancreatic cancer: a prospective study.

Anker MS, von Haehling S, Coats AJ, Riess H, ... Landmesser U, Anker SD
Aims
Many cancer patients die due to cardiovascular disease and sudden death, but data on ventricular arrhythmia prevalence and prognostic importance are not known.
Methods and results
Between 2005 and 2010, we prospectively enrolled 120 unselected patients with lung, colon, or pancreatic cancer due to one of three diagnoses: colorectal (n=33), pancreatic (n=54), or non-small cell lung cancer (n=33). All were free of manifest cardiovascular disease. They were compared to 43 healthy controls similar in age and sex distribution. Each participant underwent 24-hour electrocardiogram recording and cancer patients were followed for up to 12.5 years for survival (median 21 months). 96 cancer patients (80%) died during follow-up (5-year survival: 27% [95%CI 19-35%]). Non-sustained ventricular tachycardia (NSVT) was more frequent in cancer patients vs. controls (8% vs. 0%, p=0.021). The number of premature ventricular contractions (PVCs) over 24 hours was not increased in cancer patients vs. controls (median 4 vs. 9, p=0.2). In multivariable analysis, NSVT (HR 2.44, p=0.047) and PVCs (per 100, HR 1.021, p=0.047) were both significant predictors of mortality, independent of other univariable mortality predictors including tumour stage, cancer type, potassium concentration, prior surgery, prior cardiotoxic chemotherapy, and haemoglobin. In patients with colorectal and pancreatic cancer, ≥50 PVCs/24 hours predicted mortality (HR 2.30, p=0.0024), and was identified in 18% and 26% of patients, respectively.
Conclusions
Non-sustained ventricular tachycardia is more frequent in unselected patients with colorectal, pancreatic, and non-small cell lung cancer and together with PVCs predict long-term mortality. This raises the prospect of cardiovascular mortality being a target for future treatment interventions in selected cancers.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 21 Nov 2020; epub ahead of print
Anker MS, von Haehling S, Coats AJ, Riess H, ... Landmesser U, Anker SD
Eur J Heart Fail: 21 Nov 2020; epub ahead of print | PMID: 33222388
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Myocardial remodelling after withdrawing therapy for heart failure in patients with recovered dilated cardiomyopathy: insights from TRED-HF.

Halliday BP, Owen R, Gregson J, S Vassiliou V, ... Pennell DJ, Prasad SK
Aims
To characterize adverse ventricular remodelling after withdrawing therapy in recovered dilated cardiomyopathy (DCM).
Methods and results
TRED-HF was a randomized controlled trial with a follow-on single-arm cross-over phase that examined the safety and feasibility of therapy withdrawal in patients with recovered DCM over 6 months. The primary endpoint was relapse of heart failure defined by (i) a reduction in left ventricular (LV) ejection fraction >10% and to <50%, (ii) >10% increase in LV end-diastolic volume and to above the normal range, (iii) a twofold rise in N-terminal pro-B-type natriuretic peptide and to >400 ng/L, or (iv) evidence of heart failure. LV mass, LV and right ventricular (RV) global longitudinal strain (GLS) and extracellular volume were measured using cardiovascular magnetic resonance at baseline and follow-up (6 months or relapse) for 48 patients. LV cell and extracellular matrix masses were derived. The effect of withdrawing therapy, stratified by relapse and genotype, was investigated in the randomized and follow-on phases. In the randomized comparison, withdrawing therapy led to an increase in mean LV mass [5.4 g/m ; 95% confidence interval (CI) 1.3-9.5] and cell mass (4.2 g/m ; 95% CI 0.5-8.0) and a reduction in LV (3.5; 95% CI 1.6-5.5) and RV (2.4; 95% CI 0.1-4.7) GLS. In a non-randomized comparison of all patients (n = 47) who had therapy withdrawn in either phase, there was an increase in LV mass (6.2 g/m ; 95% CI 3.6-8.9; P = 0.0001), cell mass (4.0 g/m ; 95% CI 1.8-6.2; P = 0.0007) and matrix mass (1.7 g/m ; 95% CI 0.7-2.6; P = 0.001) and a reduction in LV GLS (2.7; 95% CI 1.5-4.0; P = 0.0001). Amongst those who had therapy withdrawn and did not relapse, similar changes were observed (n = 28; LV mass: 5.1 g/m , 95% CI 1.5-8.8, P = 0.007; cell mass: 3.7 g/m , 95% CI 0.3-7.0, P = 0.03; matrix mass: 1.7 g/m , 95% CI 0.4-3.0, P = 0.02; LV GLS: 1.7, 95% CI 0.1-3.2, P = 0.04). Patients with TTN variants (n = 10) who had therapy withdrawn had a greater increase in LV matrix mass (mean effect of TTN: 2.6 g/m ; 95% CI 0.4-4.8; P = 0.02).
Conclusion
In TRED-HF, withdrawing therapy caused rapid remodelling, with early tissue and functional changes, even amongst patients who did not relapse.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 21 Nov 2020; epub ahead of print
Halliday BP, Owen R, Gregson J, S Vassiliou V, ... Pennell DJ, Prasad SK
Eur J Heart Fail: 21 Nov 2020; epub ahead of print | PMID: 33225554
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Haemodynamic characteristics of COVID-19 patients with acute respiratory distress syndrome requiring mechanical ventilation. An invasive assessment using right heart catheterization.

Caravita S, Baratto C, Di Marco F, Calabrese A, ... Parati G, Senni M
Aims
Interstitial pneumonia due to coronavirus disease 2019 (COVID-19) is often complicated by severe respiratory failure. In addition to reduced lung compliance and ventilation/perfusion mismatch, a blunted hypoxic pulmonary vasoconstriction has been hypothesized, that could explain part of the peculiar pathophysiology of the COVID-19 cardiorespiratory syndrome. However, no invasive haemodynamic characterization of COVID-19 patients has been reported so far.
Methods and results
Twenty-one mechanically-ventilated COVID-19 patients underwent right heart catheterization. Their data were compared both with those obtained from non-mechanically ventilated paired control subjects matched for age, sex and body mass index, and with pooled data of 1937 patients with \'typical\' acute respiratory distress syndrome (ARDS) from a systematic literature review. Cardiac index was higher in COVID-19 patients than in controls [3.8 (2.7-4.5) vs. 2.4 (2.1-2.8) L/min/m , P < 0.001], but slightly lower than in ARDS patients (P = 0.024). Intrapulmonary shunt and lung compliance were inversely related in COVID-19 patients (r = -0.57, P = 0.011) and did not differ from ARDS patients. Despite this, pulmonary vascular resistance of COVID-19 patients was normal, similar to that of control subjects [1.6 (1.1-2.5) vs. 1.6 (0.9-2.0) WU, P = 0.343], and lower than reported in ARDS patients (P < 0.01). Pulmonary hypertension was present in 76% of COVID-19 patients and in 19% of control subjects (P < 0.001), and it was always post-capillary. Pulmonary artery wedge pressure was higher in COVID-19 than in ARDS patients, and inversely related to lung compliance (r = -0.46, P = 0.038).
Conclusions
The haemodynamic profile of COVID-19 patients needing mechanical ventilation is characterized by combined cardiopulmonary alterations. Low pulmonary vascular resistance, coherent with a blunted hypoxic vasoconstriction, is associated with high cardiac output and post-capillary pulmonary hypertension, that could eventually contribute to lung stiffness and promote a vicious circle between the lung and the heart.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 15 Nov 2020; epub ahead of print
Caravita S, Baratto C, Di Marco F, Calabrese A, ... Parati G, Senni M
Eur J Heart Fail: 15 Nov 2020; epub ahead of print | PMID: 33200458
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Renal profiling based on estimated glomerular filtration rate and spot urine sodium identifies high-risk acute heart failure patients.

Biegus J, Zymliński R, Testani J, Marciniak D, ... Banasiak W, Ponikowski P
Aims
In acute heart failure (AHF), assessment of renal function comprises estimation of glomerular filtration rate (eGFR), which does not provide any information about renal sodium/water handling. We describe the interactions between urinary sodium concentration and eGFR to better characterize AHF patients.
Methods and results
In 219 patients with AHF, spot urine sodium (UNa ) and eGFR were assessed on admission, day 1 and day 2 of hospitalization. We found no correlation between UNa and eGFR (calculated on each consecutive day, as an average of all three values, and as changes from baseline; all P > 0.05). The population was subsequently divided into four profiles based on eGFR (preserved vs. impaired; cutoff of 60 mL/min/1.73 m ) and UNa (sodium excreter vs. non-excreter; cutoff of 60 mmol/L). At day 1, there were 70 (31.9%) patients classified as preserved eGFR/sodium excreter, 37 (16.8%) as impaired eGFR/sodium non-excreter, 72 (32.9%) as impaired eGFR/sodium excreter, and 40 (18%) as preserved eGFR/sodium non-excreter. Both sodium non-excreter profiles were associated with an increased risk of in-hospital heart failure worsening [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.3-6.4], inotrope use (OR 2.6, 95% CI 1.1-6.7) and rehospitalization due to AHF (OR 3.2, 95% CI 1.6-6.2; all P < 0.05). The preserved eGFR/sodium non-excreter profile was associated with highest 1-year mortality (52.5%) and remained an independent prognosticator after adjustment for other prognosticators (hazard ratio 2.9, 95% CI 1.7-5.2; P < 0.0005).
Conclusions
In AHF, values of spot UNa and eGFR are not interrelated. Concomitant assessment of eGFR and spot UNa may be useful for better clinical and therapeutic profiling of patients.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 13 Nov 2020; epub ahead of print
Biegus J, Zymliński R, Testani J, Marciniak D, ... Banasiak W, Ponikowski P
Eur J Heart Fail: 13 Nov 2020; epub ahead of print | PMID: 33190378
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study.

Tomasoni D, Inciardi RM, Lombardi CM, Tedino C, ... Senni M, Metra M
Aims
To assess the prognostic value of a history of heart failure (HF) in patients with coronavirus disease 2019 (COVID-19).
Methods and results
We enrolled 692 consecutive patients admitted for COVID-19 in 13 Italian cardiology centres between 1 March and 9 April 2020. Mean age was 67.4 ± 13.2 years, 69.5% of patients were males, 90 (13.0%) had a history of HF, median hospitalization length was 14 days (interquartile range 9-24). In-hospital death occurred in 37 of 90 patients (41.1%) with HF history vs. 126 of those with no HF history (20.9%). The increased risk of death associated with HF history remained significant after adjustment for clinical variables related to COVID-19 and HF severity, including comorbidities, oxygen saturation, lymphocyte count and plasma troponin [adjusted hazard ratio (HR) for death: 2.25; 95% confidence interval (CI) 1.26-4.02; P = 0.006 at multivariable Cox regression model including 404 patients]. Patients with a history of HF also had more in-hospital complications including acute HF (33.3% vs. 5.1%, P < 0.001), acute renal failure (28.1% vs. 12.9%, P < 0.001), multiorgan failure (15.9% vs. 5.8%, P = 0.004) and sepsis (18.4% vs. 8.9%, P = 0.006). Other independent predictors of outcome were age, sex, oxygen saturation and oxygen partial pressure at arterial gas analysis/fraction of inspired oxygen ratio (PaO /FiO ). In-hospital treatment with corticosteroids and heparin had beneficial effects (adjusted HR for death: 0.46; 95% CI 0.29-0.74; P = 0.001; n = 404 for corticosteroids, and adjusted HR 0.41; 95% CI 0.25-0.67; P < 0.001; n = 364 for heparin).
Conclusions
Hospitalized patients with COVID-19 and a history of HF have an extremely poor outcome with higher mortality and in-hospital complications. HF history is an independent predictor of increased in-hospital mortality.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 11 Nov 2020; epub ahead of print
Tomasoni D, Inciardi RM, Lombardi CM, Tedino C, ... Senni M, Metra M
Eur J Heart Fail: 11 Nov 2020; epub ahead of print | PMID: 33179839
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ejection fraction and mortality: a nationwide register-based cohort study of 499 153 women and men.

Stewart S, Playford D, Scalia GM, Currie P, ... Strange G,
Aims
We investigated the sex-based risk of mortality across the spectrum of left ventricular ejection fraction (LVEF) in a large cohort of patients in Australia.
Methods and results
Quantified levels of LVEF from 237 046 women (48.1%) and 256 109 men undergoing first-time, routine echocardiography (2000-2019) were linked to 119 232 deaths (median 5.6 years of follow-up). Overall, 17.6% of men vs. 8.3% of women had an LVEF <50%. An LVEF <40% was associated with the highest crude cardiovascular-related and all-cause mortality at 5 years (∼20-30% and ∼ 40-50%, respectively). Thereafter, actual cardiovascular-related and all-cause mortality at 5 years in both sexes steeply improved to a nadir LVEF of 65.0-69.9% (reference group). Below this LVEF level, the adjusted hazard ratio (HR) for cardiovascular-related mortality for a LVEF of 55.0-59.9% was 1.36 [95% confidence interval (CI) 1.16-1.59; P < 0.001] in women and 1.21 (95% CI 1.05-1.39; P = 0.008) in men. In women, an LVEF of 60.0-64.9% was also associated with a HR 1.33 (95% CI 1.16-1.52; P < 0.001) for cardiovascular-related mortality. These associations were most striking in women and men aged <65 years and were replicated in those with suspected heart failure (32 403 cases aged 65.2 ± 16.1 years, 57.0% women). For pre-existing heart failure (33 738 cases aged 67.6 ± 16.9 years, 46.5% women), the specific threshold of increased mortality was at and below 50.0-54.9%.
Conclusions
Among patients investigated for suspected or established cardiovascular disease, we found clinically relevant sex-based differences in the distribution and mortality associated with an LVEF <65.0-69.9%. Specifically, they suggest a greater risk of mortality at higher LVEF levels among women.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 03 Nov 2020; epub ahead of print
Stewart S, Playford D, Scalia GM, Currie P, ... Strange G,
Eur J Heart Fail: 03 Nov 2020; epub ahead of print | PMID: 33150657
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Optimized Implementation of cardiac resynchronization therapy - a call for action for referral and optimization of care.

Mullens W, Auricchio A, Martens P, Witte K, ... Ruschitzka F, Leclercq C

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure hospitalization rates and reduces all-cause mortality. Nevertheless, up to two-thirds of eligible patients are not referred for CRT. Furthermore, post implantation follow-up is often fragmented and suboptimal, hampering the potential maximal treatment effect. This joint position statement from three ESC Associations, HFA, EHRA and EACVI focuses on optimized implementation of CRT. We offer theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on four actionable domains; (I) overcoming CRT under-utilization, (II) better understanding of pre-implant characteristics, (III) abandoning the term \'non-response\' and replacing this by the concept of disease modification, and (IV) implementing a dedicated post-implant CRT care pathway.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 01 Nov 2020; epub ahead of print
Mullens W, Auricchio A, Martens P, Witte K, ... Ruschitzka F, Leclercq C
Eur J Heart Fail: 01 Nov 2020; epub ahead of print | PMID: 33136300
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

In-hospital care in acute heart failure during the COVID-19 pandemic: insights from the German-wide Helios hospital network.

König S, Hohenstein S, Meier-Hellmann A, Kuhlen R, ... Bollmann A,
Aims
The coronavirus disease 2019 (COVID-19) pandemic has led to changes in health care utilization for different acute cardiovascular diseases. Whether hospitalization rates and in-hospital mortality were affected by the pandemic in patients with acute symptomatic heart failure (HF) was investigated in this study.
Methods and results
Administrative data provided by 67 German Helios hospitals were examined for patients with a main discharge diagnosis of HF using ICD codes. Urgent hospital admissions per day were compared for a study period (13 March-21 May 2020) with control intervals in 2020 (1 January-12 March) and 2019 (13 March-21 May), resulting in a total of 13 484 patients excluding all patients with laboratory-proven COVID-19 infection. Incidence rate ratios (IRR) were calculated using Poisson regression. Generalized linear mixed models were used for univariable and multivariable analysis to identify predictors of in-hospital mortality. The number of admissions per day was lower in the study period compared to the same year [IRR 0.69, 95% confidence interval (CI) 0.67-0.73, P < 0.01] and the previous year control group (IRR 0.73, 95% CI 0.70-0.76, P < 0.01). Age was similar throughout the intervals, but case severity increased in terms of distribution within New York Heart Association (NYHA) classes and comorbidities. Within the study period, 30-day rates for urgent hospital readmissions were higher compared to the same year but not the previous year control group. In-hospital mortality was 7.3% in the study period, 6.1% in the same year (P = 0.03) and 6.0% in the previous year control group (P = 0.02). In multivariable analysis, age, NYHA class and other predictors of fatal outcome were identified but hospitalization during the study period was not independently associated with mortality.
Conclusion
Our data showed a significant reduction of urgent hospital admissions for HF with increased case severity and concomitant in-hospital mortality during the COVID-19 pandemic in Germany. Identifying causes of reduced inpatient treatment rates is essential for the understanding and valuation with regard to future optimal management of patients with HF.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 01 Nov 2020; epub ahead of print
König S, Hohenstein S, Meier-Hellmann A, Kuhlen R, ... Bollmann A,
Eur J Heart Fail: 01 Nov 2020; epub ahead of print | PMID: 33135851
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

European Society of Cardiology Working Group on Adult Congenital Heart Disease and Study Group for Adult Congenital Heart Care in Central and South Eastern European Countries consensus paper: current status, provision gaps and investment required.

Brida M, Šimkova I, Jovović L, Prokšelj K, ... Roos-Hesselink JW, Diller GP
Aims
To examine the current status of care and needs of adult congenital heart disease (ACHD) services in the Central and South Eastern European (CESEE) region.
Methods and results
We obtained data regarding the national ACHD status for 19 CESEE countries from their ACHD representative based on an extensive survey for 2017 and/or 2018. Thirteen countries reported at least one tertiary ACHD centre with a median year of centre establishment in 2007 (interquartile range 2002-2013). ACHD centres reported a median of 2114 patients under active follow-up with an annual cardiac catheter and surgical intervention volume of 49 and 40, respectively. The majority (90%) of catheter or surgical interventions were funded by government reimbursement schemes. However, all 19 countries had financial caps on a hospital level, leading to patient waiting lists and restrictions in the number of procedures that can be performed. The median number of ACHD specialists per country was 3. The majority of centres (75%) did not have ACHD specialist nurses. The six countries with no dedicated ACHD centres had lower Gross Domestic Product per capita compared to the remainder (P = 0.005).
Conclusion
The majority of countries in CESEE now have established ACHD services with adequate infrastructure and a patient workload comparable to the rest of Europe, but important gaps still exist. ACHD care is challenged or compromised by limited financial resources, insufficient staffing levels, and reimbursement caps on essential procedures compared to Western Europe. Active advocacy and increased resources are required to address the inequalities of care across the continent.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 01 Nov 2020; epub ahead of print
Brida M, Šimkova I, Jovović L, Prokšelj K, ... Roos-Hesselink JW, Diller GP
Eur J Heart Fail: 01 Nov 2020; epub ahead of print | PMID: 33135840
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: a position statement from the Cardio-Oncology Study Group of the Heart Failure Association and the Cardio-Oncology Council of the European Society of Cardiology.

Pudil R, Mueller C, Čelutkienė J, Henriksen PA, ... de Boer RA, Lyon AR

Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients. The Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the Cardio-Oncology Council of the ESC have evaluated the current evidence for the role of cardiovascular biomarkers in cancer patients before, during and after cardiotoxic cancer therapies. The characteristics of the main two biomarkers troponin and natriuretic peptides are discussed, the link to the mechanisms of cardiovascular toxicity, and the evidence for their clinical use in surveillance during and after anthracycline chemotherapy, trastuzumab and HER2-targeted therapies, vascular endothelial growth factor inhibitors, proteasome inhibitors, immune checkpoint inhibitors, cyclophosphamide and radiotherapy. Novel surveillance clinical pathways integrating cardiac biomarkers for cancer patients receiving anthracycline chemotherapy or trastuzumab biomarkers are presented and future direction in cardio-oncology biomarker research is discussed.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:1966-1983
Pudil R, Mueller C, Čelutkienė J, Henriksen PA, ... de Boer RA, Lyon AR
Eur J Heart Fail: 30 Oct 2020; 22:1966-1983 | PMID: 33006257
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The role of cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach.

Hoes MF, Tromp J, Ouwerkerk W, Bomer N, ... Voors AA, van der Meer P
Aims
Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF.
Methods and results
Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT-CHF index study. Results were validated in 1700 HF patients from the BIOSTAT-CHF validation cohort. The primary combined outcome was all-cause mortality and/or HF hospitalizations. Human pluripotent stem cell-derived cardiomyocytes were subjected to hypoxic, pro-inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin-6 and N-terminal pro-B-type natriuretic peptide (P < 0.001 for all). Cathepsin D levels were independently associated with the primary combined outcome [hazard ratio (HR) per standard deviation (SD): 1.12; 95% confidence interval (CI) 1.02-1.23], which was validated in an independent cohort (HR per SD: 1.23, 95% CI 1.09-1.40). In vitro experiments demonstrated that human stem cell-derived cardiomyocytes released cathepsin D and troponin T in response to mechanical stretch. ShRNA-mediated silencing of cathepsin D resulted in increased necrosis, abrogated autophagy, increased stress-induced metabolism, and increased release of troponin T from human stem cell-derived cardiomyocytes under stress.
Conclusions
Circulating cathepsin D levels are associated with HF severity and poorer outcome, and reduced levels of cathepsin D may have detrimental effects with therapeutic potential in HF.

© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2102-2111
Hoes MF, Tromp J, Ouwerkerk W, Bomer N, ... Voors AA, van der Meer P
Eur J Heart Fail: 30 Oct 2020; 22:2102-2111 | PMID: 31797504
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Circulating levels and prognostic value of soluble ST2 in heart failure are less influenced by age than N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T.

Aimo A, Januzzi JL, Vergaro G, Richards AM, ... Passino C, Emdin M
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.

Eur J Heart Fail: 30 Oct 2020; 22:2078-2088
Aimo A, Januzzi JL, Vergaro G, Richards AM, ... Passino C, Emdin M
Eur J Heart Fail: 30 Oct 2020; 22:2078-2088 | PMID: 31919929
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiac iron concentration in relation to systemic iron status and disease severity in non-ischaemic heart failure with reduced ejection fraction.

Hirsch VG, Tongers J, Bode J, Berliner D, ... Wollert KC, Kempf T
Aims
Low cardiac iron levels promote heart failure in experimental models. While cardiac iron concentration (CI) is decreased in patients with advanced heart failure with reduced ejection fraction (HFrEF), CI has never been measured in non-advanced HFrEF. We measured CI in left ventricular (LV) endomyocardial biopsies (EMB) from patients with non-advanced HFrEF and explored CI association with systemic iron status and disease severity.
Methods and results
We enrolled 80 consecutive patients with non-ischaemic HFrEF with New York Heart Association class II or III symptoms and a median (interquartile range) LV ejection fraction of 25 (18-33)%. CI was 304 (262-373) μg/g dry tissue. CI was not related to immunohistological findings or the presence of cardiotropic viral genomes in EMBs and was not related to biomarkers of systemic iron status or anaemia. Patients with CI in the lowest quartile (CI ) had lower body mass indices and more often presented with heart failure histories longer than 6 months than patients in the upper three quartiles (CI ). CI patients had higher serum N-terminal pro-B-type natriuretic peptide levels than CI patients [3566 (1513-6412) vs. 1542 (526-2811) ng/L; P = 0.005]. CI patients also had greater LV end-diastolic (P = 0.001) and end-systolic diameter indices (P = 0.003) and higher LV end-diastolic pressures (P = 0.046) than CI patients.
Conclusion
Low CI is associated with greater disease severity in patients with non-advanced non-ischaemic HFrEF. CI is unrelated to systemic iron homeostasis. The prognostic and therapeutic implications of CI measurements in EMBs should be further explored.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2038-2046
Hirsch VG, Tongers J, Bode J, Berliner D, ... Wollert KC, Kempf T
Eur J Heart Fail: 30 Oct 2020; 22:2038-2046 | PMID: 32155309
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The prevalence and importance of frailty in heart failure with reduced ejection fraction - an analysis of PARADIGM-HF and ATMOSPHERE.

Dewan P, Jackson A, Jhund PS, Shen L, ... Zile MR, McMurray JJV
Aims
Frailty, characterized by loss of homeostatic reserves and increased vulnerability to physiological decompensation, results from an aggregation of insults across multiple organ systems. Frailty can be quantified by counting the number of \'health deficits\' across a range of domains. We assessed the frequency of, and outcomes related to, frailty in patients with heart failure and reduced ejection fraction (HFrEF).
Methods and results
Using a cumulative deficits approach, we constructed a 42-item frailty index (FI) and applied it to identify frail patients enrolled in two HFrEF trials (PARADIGM-HF and ATMOSPHERE). In keeping with previous studies, patients with FI ≤0.210 were classified as non-frail and those with higher scores were divided into two categories using score increments of 0.100. Clinical outcomes were examined, adjusting for prognostic variables. Among 13 625 participants, mean (± standard deviation) FI was 0.250 (0.10) and 8383 patients (63%) were frail (FI >0.210). The frailest patients were older and had more symptoms and signs of heart failure. Women were frailer than men. All outcomes were worse in the frailest, with high rates of all-cause death or all-cause hospitalization: 40.7 (39.1-42.4) vs. 22.1 (21.2-23.0) per 100 person-years in the non-frail; adjusted hazard ratio 1.63 (1.53-1.75) (P < 0.001). The rate of all-cause hospitalizations, taking account of recurrences, was 61.5 (59.8-63.1) vs. 31.2 (30.3-32.2) per 100 person-years (incidence rate ratio 1.76; 1.62-1.90; P < 0.001).
Conclusion
Frailty is highly prevalent in HFrEF and associated with greater deterioration in quality of life and higher risk of hospitalization and death. Strategies to prevent and treat frailty are needed in HFrEF.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2123-2133
Dewan P, Jackson A, Jhund PS, Shen L, ... Zile MR, McMurray JJV
Eur J Heart Fail: 30 Oct 2020; 22:2123-2133 | PMID: 32353205
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society.

Lyon AR, Dent S, Stanway S, Earl H, ... Plummer C, Lenihan D

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:1945-1960
Lyon AR, Dent S, Stanway S, Earl H, ... Plummer C, Lenihan D
Eur J Heart Fail: 30 Oct 2020; 22:1945-1960 | PMID: 32463967
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Depression and heart failure: the lonely comorbidity.

Sbolli M, Fiuzat M, Cani D, O\'Connor CM

Depression is a frequent and debilitating comorbidity that affects heart failure (HF) patients. Up to 30% of HF patients suffer from depression and even more have depressive symptoms. Moreover, depression carries a risk for HF, especially in high-risk groups, and is significantly associated with worse quality of life and clinical outcomes. The pathophysiology of depression and HF is poorly understood, but both diseases share several mechanisms and risk factors, including dysregulation of platelet reactivity, inflammation, neuroendocrine function, arrhythmias, high-risk behaviours, and social factors. Current HF guidelines advise to screen HF patients for depression and several screening questionnaires are available. Ultimately, the diagnosis of depression is based on DSM-5 criteria. Depression treatment consists of non-pharmacological and pharmacological therapies. Non-pharmacological therapies, such as exercise training and cognitive-behavioural therapy, have been shown to have beneficial effects on depressive symptoms. Selective serotonin reuptake inhibitors, the mainstay of antidepressant therapy, appear to be safe in HF but have not shown superiority over placebo in HF in short- and long-term randomized clinical trials. New therapies to treat depression are under investigation and may offer the opportunity to improve depression management in HF, including N-methyl-D-aspartate receptor antagonists, repetitive transcranial magnetic stimulation and omega-3 supplementation. New technologies may offer several advantages for the screening and diagnosis of depression but they remain to be tested in future research. In this review, we examine the intersection of depression and HF, summarize the epidemiology and pathophysiology, and discuss new opportunities to diagnose and treat HF patients with depression.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2007-2017
Sbolli M, Fiuzat M, Cani D, O'Connor CM
Eur J Heart Fail: 30 Oct 2020; 22:2007-2017 | PMID: 32468714
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prevalence and prognostic impact of the coexistence of multiple frailty domains in elderly patients with heart failure: the FRAGILE-HF cohort study.

Matsue Y, Kamiya K, Saito H, Saito K, ... Momomura SI, Kagiyama N
Aims
To describe the prevalence, overlap, and prognostic implications of physical and social frailties and cognitive dysfunction in hospitalized elderly patients with heart failure.
Methods and results
The FRAGILE-HF study was a prospective multicentre cohort study enrolling consecutive hospitalized patients with heart failure aged ≥65 years. The study objectives were to examine the prevalence, overlap, and prognostic implications of the coexistence of multiple frailty domains. Physical frailty, social frailty, and cognitive dysfunction were evaluated by the Fried phenotype model, Makizako\'s 5 items, and Mini-Cog, respectively. The primary study outcome was the combined endpoint of heart failure rehospitalization and all-cause death within 1 year. Among 1180 enrolled hospitalized patients (median age, 81 years; 57.4% male), physical frailty, social frailty, and cognitive dysfunction were identified in 56.1%, 66.4%, and 37.1% of the patients, respectively. The number of identified frailty domains was 0, 1, 2, and 3 in 13.5%, 31.4%, 36.9%, and 18.2% of the patients, respectively. During follow-up, the combined endpoint occurred in 383 patients. Adjusted hazard ratios for 1, 2, and 3 domains, with 0 domains as the reference, were 1.38 [95% confidence interval (CI) 0.89-2.13; P = 0.15], 1.60 (95% CI 1.04-2.46; P = 0.034), and 2.04 (95% CI 1.28-3.24; P = 0.003), respectively. Incorporating the number of frailty domains into the pre-existing risk model yielded a 22.0% (95% CI 0.087-0.352; P = 0.001) net reclassification improvement for the primary outcome.
Conclusions
The coexistence of multiple frailty domains is prevalent in hospitalized elderly patients with heart failure. Holistic assessment of multi-domain frailty provides additive value to known prognostic factors.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2112-2119
Matsue Y, Kamiya K, Saito H, Saito K, ... Momomura SI, Kagiyama N
Eur J Heart Fail: 30 Oct 2020; 22:2112-2119 | PMID: 32500539
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

F-FDG PET/CT brain glucose metabolism as a marker of different types of depression comorbidity in chronic heart failure patients with impaired systolic function.

Lyra V, Parissis J, Kallergi M, Rizos E, ... Kremastinos D, Chatziioannou S
Aims
Depression is an important issue in heart failure (HF). The study investigated whole-brain and regional brain glucose metabolism in HF patients and its association with depression comorbidity.
Methods and results
Twenty-nine hospitalized patients with symptomatic systolic HF (left ventricular ejection fraction <40%), New York Heart Association (NYHA) class II-IV and mean age of 55.5 ± 12.0 years, had psychometric questionnaires before discharge and anF-FDG PET/CT brain scan after discharge. Semi-automated image analysis was performed on all cases and 30 matched controls. The metabolic parameter mean standardized uptake value (SUV ) was calculated for the whole brain and three brain regions implicated in depression pathogenesis. A standardized SUV was also estimated by dividing regional brain SUV with whole-brain SUV . Cases had lower average whole-brain SUV (3.90 ± 1.49 vs. 5.10 ± 1.35, P = 0.001) and average regional brain SUV (4.57 ± 2.31 vs. 9.96 ± 3.58, P < 0.001) compared to controls. Whole-brain SUV had a significant correlation with patient age, NYHA class, diabetes, creatinine levels, depression, and cognitive impairment. Regional brain SUV was correlated with whole-brain SUV and depression. The standardized SUV , in particular, was found to be a robust index that could differentiate HF patients with \'epiphenomenal\' (>0.93) or \'real\' (≤0.93) depression.
Conclusion
Heart failure patients with more severe disease showed whole-brain and regional brain hypometabolism inF-FDG PET/CT. Depressed HF patients (Beck Depression Inventory score >13) exhibited different metabolic patterns that could be used to differentiate between \'epiphenomenal\' and \'real\' depression. Namely, presence of whole-brain hypometabolism suggested \'epiphenomenal\' depression, whereas absence suggested \'real\' depression. Presence of significant relative regional brain hypometabolism enhanced the likelihood of \'real\' depression diagnosis.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2138-2146
Lyra V, Parissis J, Kallergi M, Rizos E, ... Kremastinos D, Chatziioannou S
Eur J Heart Fail: 30 Oct 2020; 22:2138-2146 | PMID: 32530569
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association between glycated haemoglobin levels and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the TECOS randomized clinical trial.

McAlister FA, Zheng Y, Westerhout CM, Buse JB, ... Holman RR,
Aims
Whether glycaemic control is associated with cardiovascular outcomes in patients with type 2 diabetes (T2D) is unclear. Consequently, we assessed the relationship between glycated haemoglobin (HbA ) and cardiovascular outcomes in a placebo-controlled randomized trial which demonstrated no cardiovascular effect of sitagliptin in patients with T2D and atherosclerotic vascular disease.
Methods and results
Secondary analysis of 14 656 TECOS participants with time to event analyses using multivariable Cox proportional hazard models. During a median 3.0 (interquartile range 2.3-3.8) year follow-up, 456 (3.1% of 14 656) patients had first hospitalization for heart failure (HF), 1084 (11.5%) died, 1406 (9.6%) died or were hospitalized for HF, and 1689 (11.5%) had a non-HF cardiovascular event (cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, or hospitalization for unstable angina). Associations between baseline or time-varying HbA and cardiovascular outcomes were U-shaped, with the lowest risk when HbA was around 7%. Each one-unit increase in the time-varying HbA above 7% was associated with an adjusted hazard ratio (HR) of 1.21 [95% confidence interval (CI) 1.11-1.33] for first HF hospitalization, 1.11 (1.03-1.21) for all-cause death, 1.18 (1.09-1.26) for death or HF hospitalization, and 1.10 (1.02-1.17) for non-HF cardiovascular events. Each one-unit decrease in the time-varying HbA below 7% was associated with an adjusted HR of 1.35 (95% CI 1.12-1.64) for first HF hospitalization, 1.37 (1.16-1.61) for death, 1.42 (1.23-1.64) for death or HF hospitalization, and 1.22 (1.06-1.41) for non-HF cardiovascular events.
Conclusion
Glycated haemogobin exhibits a U-shaped association with cardiovascular outcomes in patients with T2D and atherosclerotic vascular disease, with nadir around 7%.
Clinical trial registration
ClinicalTrials.gov Identifier: NCT00790205.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2026-2034
McAlister FA, Zheng Y, Westerhout CM, Buse JB, ... Holman RR,
Eur J Heart Fail: 30 Oct 2020; 22:2026-2034 | PMID: 32621557
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.

McEwan P, Darlington O, McMurray JJV, Jhund PS, ... Bergenheim K, Qin L
Aim
To estimate the cost-effectiveness of dapagliflozin added to standard therapy, vs. standard therapy only, in patients with heart failure (HF) with reduced ejection fraction (HFrEF), from the perspective of UK, German, and Spanish payers.
Methods and results
A lifetime Markov model was built to estimate outcomes in patients with HFrEF. Health states were defined by Kansas City Cardiomyopathy Questionnaire total symptom score, type 2 diabetes and worsening HF events. The incidence of worsening HF and all-cause mortality was estimated using negative binomial regression models and parametric survival analysis, respectively. Direct healthcare costs (2019 British pounds/Euro) and patient-reported outcomes (EQ-5D) were sourced from the existing literature and the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF), respectively; the median duration of follow-up in DAPA-HF was 18.2 months (range: 0-27.8). Future costs and effects were discounted at 3.0% for the Spanish and German analyses and 3.5% for the UK analysis. In the UK setting, treatment with dapagliflozin was estimated to increase life-years and quality-adjusted life-years (QALYs) from 5.62 to 6.20 (+0.58) and 4.13 to 4.61 (+0.48), respectively, and reduce lifetime hospitalizations for HF (925 and 820 events per 1000 patients for placebo and dapagliflozin, respectively). Similar results were obtained for Germany and Spain. The incremental cost-effectiveness ratios were £5822, €5379 and €9406/QALY in the UK, Germany and Spain, respectively. In probabilistic sensitivity analyses, more than 90% of simulations were cost-effective at a willingness-to-pay threshold of £20 000/QALY in UK and €20 000/QALY in Germany and Spain.
Conclusion
Dapagliflozin is likely to be a cost-effective treatment for HFrEF in the UK, German and Spanish healthcare systems.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2147-2156
McEwan P, Darlington O, McMurray JJV, Jhund PS, ... Bergenheim K, Qin L
Eur J Heart Fail: 30 Oct 2020; 22:2147-2156 | PMID: 32749733
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Serum potassium in the PARADIGM-HF trial.

Ferreira JP, Mogensen UM, Jhund PS, Desai AS, ... Solomon SD, McMurray JJV
Aims
The associations between potassium level and outcomes, the effect of sacubitril-valsartan on potassium level, and whether potassium level modified the effect of sacubitril-valsartan in patients with heart failure and a reduced ejection fraction were studied in PARADIGM-HF. Several outcomes, including cardiovascular death, sudden death, pump failure death, non-cardiovascular death and heart failure hospitalization, were examined.
Methods and results
A total of 8399 patients were randomized to either enalapril or sacubitril-valsartan. Potassium level at randomization and follow-up was examined as a continuous and categorical variable (≤3.5, 3.6-4.0, 4.1-4.9, 5.0-5.4 and ≥5.5 mmol/L) in various statistical models. Hyperkalaemia was defined as K  ≥5.5 mmol/L and hypokalaemia as K  ≤3.5 mmol/L. Compared with potassium 4.1-4.9 mmol/L, both hypokalaemia [hazard ratio (HR) 2.40, 95% confidence interval (CI) 1.84-3.14] and hyperkalaemia (HR 1.42, 95% CI 1.10-1.83) were associated with a higher risk for cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non-cardiovascular death and heart failure hospitalization. Sacubitril-valsartan had no effect on potassium overall. The benefit of sacubitril-valsartan over enalapril was consistent across the range of baseline potassium levels.
Conclusions
Although both higher and lower potassium levels were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk for death.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2056-2064
Ferreira JP, Mogensen UM, Jhund PS, Desai AS, ... Solomon SD, McMurray JJV
Eur J Heart Fail: 30 Oct 2020; 22:2056-2064 | PMID: 32809261
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A combined bioinformatics, experimental and clinical approach to identify novel cardiac-specific heart failure biomarkers: is Dickkopf-3 (DKK3) a possible candidate?

Piek A, Suthahar N, Voors AA, de Boer RA, Silljé HHW
Aims
Cardiac specificity provides an advantage in correlating heart failure (HF) biomarker plasma levels with indices of cardiac function and remodelling, as shown for natriuretic peptides. Using bioinformatics, we explored the cardiac specificity of secreted proteins and investigated in more detail the relationship of Dickkopf-3 (DKK3) gene expression and DKK3 plasma concentrations with cardiac function and remodelling in (pre)clinical studies.
Methods and results
The cardiac specificity of secreted proteins was determined using RNAseq data for a large panel of organs and tissues. This showed that natriuretic peptides (NPPA and NPPB) are highly cardiac-specific (>99%), whereas other HF biomarkers, including galectin-3 (Gal-3, LGALS3) and growth differentiation factor-15 (GDF-15), lack cardiac specificity (<4%). DKK3 was cardiac-enriched (44%), warranting further investigation. In three different HF mouse models, cardiac Dkk3 expression was altered, but DKK3 plasma concentrations were not. In humans, DKK3 plasma concentrations were higher in HF patients (n = 2090) in comparison with age- and sex-matched controls without HF (n = 240) (46.4 ng/mL vs. 36.3 ng/mL; P < 0.001). Multivariate regression analysis revealed that DKK3 was strongly associated with HF risk factors and comorbidities, including age, kidney function and atrial fibrillation. After correction for existing prediction models, DKK3 did not independently predict HF outcome [all-cause mortality/HF hospitalization, hazard ratio 1.13 (0.79-1.61) per DKK3 doubling; P = 0.503].
Conclusions
Of actively secreted HF biomarkers, only natriuretic peptides showed high cardiac specificity. Despite a cardiac specificity of 44%, secreted DKK3 had limited additional diagnostic and prognostic value.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2065-2074
Piek A, Suthahar N, Voors AA, de Boer RA, Silljé HHW
Eur J Heart Fail: 30 Oct 2020; 22:2065-2074 | PMID: 32809235
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Serum uric acid, influence of sacubitril-valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF.

Selvaraj S, Claggett BL, Pfeffer MA, Desai AS, ... McMurray JJV, Solomon SD
Aims
This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies.
Methods and results
We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA.
Conclusions
Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2093-2101
Selvaraj S, Claggett BL, Pfeffer MA, Desai AS, ... McMurray JJV, Solomon SD
Eur J Heart Fail: 30 Oct 2020; 22:2093-2101 | PMID: 32840930
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan.

Ibrahim NE, Piña IL, Camacho A, Bapat D, ... Januzzi JL,
Aims
We sought to determine sex-based differences in biomarkers, self-reported health status, and magnitude of longitudinal changes in measures of reverse cardiac remodelling among patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%) treated with sacubitril/valsartan (S/V).
Methods and results
This was a subgroup analysis of patients initiated on S/V in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE-HF) study. There were 226 (28.5%) women in the study. Though women had lower baseline N-terminal pro B-type natriuretic peptide (NT-proBNP), they had more rapid early reduction in the biomarker after initiation of S/V. Compared to men, women had lower average baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 Total Symptom score (67.6 vs. 71.9; P = 0.003) but showed greater linear improvement (7.4 vs. 5.5 points; P < 0.001) and faster pace of KCCQ change (P < 0.001) over the course of the trial. Women and men demonstrated similar degrees of reverse left ventricular remodelling following S/V initiation; however, women did so earlier than men with more consistent changes. These results remained unchanged with adjustment for relevant covariates. Reduction in NT-proBNP was associated with reverse cardiac remodelling in both women and men. Treatment with S/V was well tolerated in all.
Conclusions
In women with HFrEF, treatment with S/V was associated with significant NT-proBNP reduction, health status improvement and reverse cardiac remodelling.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2018-2025
Ibrahim NE, Piña IL, Camacho A, Bapat D, ... Januzzi JL,
Eur J Heart Fail: 30 Oct 2020; 22:2018-2025 | PMID: 32946164
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials.

Teerlink JR, Diaz R, Felker GM, McMurray JJV, ... Kurtz CE,
Aims
The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials.
Methods and results
Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594).
Conclusions
GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:2160-2171
Teerlink JR, Diaz R, Felker GM, McMurray JJV, ... Kurtz CE,
Eur J Heart Fail: 30 Oct 2020; 22:2160-2171 | PMID: 32985088
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Heart Failure Association of the European Society of Cardiology update on sodium-glucose co-transporter 2 inhibitors in heart failure.

Seferović PM, Fragasso G, Petrie M, Mullens W, ... Coats AJS, Rosano GMC

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given: • Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin are recommended for the prevention of HF hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or at high cardiovascular risk. • Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalization and cardiovascular death in symptomatic patients with HF and reduced ejection fraction already receiving guideline-directed medical therapy regardless of the presence of type 2 diabetes mellitus.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Oct 2020; 22:1984-1986
Seferović PM, Fragasso G, Petrie M, Mullens W, ... Coats AJS, Rosano GMC
Eur J Heart Fail: 30 Oct 2020; 22:1984-1986 | PMID: 33068051
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ultrasound imaging of congestion in heart failure: examinations beyond the heart.

Pellicori P, Platz E, Dauw J, Ter Maaten JM, ... Gargani L, Girerd N

Congestion, related to pressure and/or fluid overload, plays a central role in the pathophysiology, presentation and prognosis of heart failure and is an important therapeutic target. While symptoms and physical signs of fluid overload are required to make a clinical diagnosis of heart failure, they lack both sensitivity and specificity, which might lead to diagnostic delay and uncertainty. Over the last decades, new ultrasound methods for the detection of elevated intracardiac pressures and/or fluid overload have been developed that are more sensitive and specific, thereby enabling earlier and more accurate diagnosis and facilitating treatment strategies. Accordingly, we considered that a state-of-the-art review of ultrasound methods for the detection and quantification of congestion was timely, including imaging of the heart, lungs (B-lines), kidneys (intrarenal venous flow), and venous system (inferior vena cava and internal jugular vein diameter).

© 2020 European Society of Cardiology.

Eur J Heart Fail: 28 Oct 2020; epub ahead of print
Pellicori P, Platz E, Dauw J, Ter Maaten JM, ... Gargani L, Girerd N
Eur J Heart Fail: 28 Oct 2020; epub ahead of print | PMID: 33118672
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Trial characteristics associated with under-enrolment of females in randomized controlled trials of heart failure with reduced ejection fraction: a systematic review.

Whitelaw S, Sullivan K, Eliya Y, Alruwayeh M, ... Mamas MA, Van Spall HGC
Aims
To evaluate temporal trends in the enrolment of females in randomized controlled trials (RCTs) of heart failure with reduced ejection fraction (HFrEF) published in high-impact journals, and assess RCT characteristics associated with under-enrolment.
Methods and results
We searched MEDLINE, EMBASE and CINAHL for studies published from January 2000 to May 2019 in journals with impact factor ≥10. We included RCTs that recruited adults with HFrEF. We used a 20% threshold below the sex distribution of HFrEF to define under-enrolment. We used multivariable logistic regression to assess trial characteristics independently associated with under-enrolment. We included 317 RCTs. Among the 183 097 participants, mean (standard deviation) age was 63.0 (7.0) years and 25.5% were female. Females were under-enrolled in 71.6% [95% confidence interval (CI) 66.6-76.6%] of the RCTs; enrolment did not increase significantly between 2000-2019. Sex-related eligibility criteria [odds ratio (OR) 2.05, 95% CI 1.01-4.16; P = 0.046]; recruitment in ambulatory settings (OR 2.56, 95% CI 1.37-4.81; P = 0.003); trial coordination in North America (OR 4.44, 95% CI 1.09-18.07; P = 0.037), Europe (OR 6.79, 95% CI 1.63-27.39; P = 0.018) and Asia (OR 9.33, 95% CI 1.40-12.40; P = 0.033); drug (OR 1.76, 95% CI 1.96-7.36; P < 0.001) and device/surgical interventions (OR 1.69, 95% CI 1.16-9.43; P = 0.002); and men in first and last authorship position (OR 1.32, 95% CI 1.12-3.54; P = 0.047) were associated with under-enrolment of females.
Conclusions
Females were under-enrolled relative to disease distribution in a majority of high-impact HFrEF RCTs, with no change in temporal trends between 2000 and 2019. Trial characteristics and gender of trial leaders were associated with under-enrolment.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 28 Oct 2020; epub ahead of print
Whitelaw S, Sullivan K, Eliya Y, Alruwayeh M, ... Mamas MA, Van Spall HGC
Eur J Heart Fail: 28 Oct 2020; epub ahead of print | PMID: 33118664
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Measuring physical activity with activity monitors in patients with heart failure: from literature to practice. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology.

Klompstra L, Kyriakou M, Lambrinou E, Piepoli MF, ... Volterrani M, Jaarsma T

The aims of this paper were to provide an overview of available activity monitors used in research in patients with heart failure and to identify the key criteria in the selection of the most appropriate activity monitor for collecting, reporting, and analysing physical activity in heart failure research. This study was conducted in three parts. First, the literature was systematically reviewed to identify physical activity concepts and activity monitors used in heart failure research. Second, an additional scoping literature search for validation of these activity monitors was conducted. Third, the most appropriate criteria in the selection of activity monitors were identified. Nine activity monitors were evaluated in terms of size, weight, placement, costs, data storage, water resistance, outcomes and validation, and cut-off points for physical activity intensity levels were discussed. The choice of a monitor should depend on the research aims, study population and design regarding physical activity. If the aim is to motivate patients to be active or set goals, a less rigorously tested tool can be considered. On the other hand, if the aim is to measure physical activity and its changes over time or following treatment adjustment, it is important to choose a valid activity monitor with a storage and battery longevity of at least one week. The device should provide raw data and valid cut-off points should be chosen for analysing physical activity intensity levels. Other considerations in choosing an activity monitor should include data storage location and ownership and the upfront costs of the device.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 26 Oct 2020; epub ahead of print
Klompstra L, Kyriakou M, Lambrinou E, Piepoli MF, ... Volterrani M, Jaarsma T
Eur J Heart Fail: 26 Oct 2020; epub ahead of print | PMID: 33111464
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

High soluble transferrin receptor in patients with heart failure: a measure of iron deficiency and a strong predictor of mortality.

Sierpinski R, Josiak K, Suchocki T, Wojtas-Polc K, ... Ponikowski P, Jankowska EA
Aims
Iron deficiency (ID) is frequent in heart failure (HF), linked with exercise intolerance and poor prognosis. Intravenous iron repletion improves clinical status in HF patients with left ventricular ejection fraction (LVEF) ≤45%. However, uncertainty exists about the accuracy of serum biomarkers in diagnosing ID. The aims of this study were (i) to identify the iron biomarker with the greatest accuracy for the diagnosis of ID in bone marrow in patients with ischaemic HF, and (ii) to establish the prevalence of ID using this biomarker and its prognostic value in HF patients.
Methods and results
Bone marrow was stained for iron in 30 patients with ischaemic HF with LVEF ≤45% and 10 healthy controls, and ID was diagnosed for 0-1 grades (Gale scale). A total of 791 patients with HF with LVEF ≤45% were prospectively followed up for 3 years. Serum ferritin, transferrin saturation, soluble transferrin receptor (sTfR) were assessed as iron biomarkers. Most patients with HF (n = 25, 83%) had ID in bone marrow, but none of the controls (P < 0.001). Serum sTfR had the best accuracy in predicting ID in bone marrow (area under the curve 0.920, 95% confidence interval 0.761-0.987, for cut-off 1.25 mg/L sensitivity 84%, specificity 100%). Serum sTfR was ≥1.25 mg/L in 47% of HF patients, in 56% and 46% of anaemics and non-anaemics, respectively (P < 0.05). The reclassification methods revealed that serum sTfR significantly added the prognostic value to the baseline prognostic model, and to the greater extent than plasma N-terminal pro B-type natriuretic peptide. Based on internal derivation and validation procedures, serum sTfR ≥1.41 mg/L was the optimal threshold for predicting 3-year mortality, independent of other established variables.
Conclusions
High serum sTfR accurately reflects depleted iron stores in bone marrow in patients with HF, and identifies those with a high 3-year mortality.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 26 Oct 2020; epub ahead of print
Sierpinski R, Josiak K, Suchocki T, Wojtas-Polc K, ... Ponikowski P, Jankowska EA
Eur J Heart Fail: 26 Oct 2020; epub ahead of print | PMID: 33111457
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A current and future outlook on upcoming technologies in remote monitoring of patients with heart failure.

Bekfani T, Fudim M, Cleland JGF, Jorbenadze A, ... Sievert H, Anker SD

Heart failure is a major health and economic challenge in both developing and developed countries. Despite advances in pharmacological and device therapies for patients with a reduced left ventricular ejection fraction (LVEF) and heart failure, their quality of life and exercise capacity are often persistently impaired, morbidity and mortality remain high and the health economic and societal costs are considerable. For patients with heart failure and preserved LVEF, diuretic management has an essential role for controlling congestion and symptoms, even if no intervention has convincingly shown to reduce morbidity or mortality. Remote monitoring might improve care delivery and clinical outcomes for patients regardless of LVEF. A great variety of innovative remote monitoring technologies and algorithms are being introduced, including patient self-managed testing, wearable devices, technologies either integrated into established clinically indicated therapeutic devices, such as pacemakers and defibrillators, or as stand-alone are in development providing the promise of further improvements in service delivery and clinical outcomes. In this article, we will discuss unmet needs in the management of patients with heart failure, how remote monitoring might contribute to future solutions, and provide an overview of current and novel remote monitoring technologies.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 26 Oct 2020; epub ahead of print
Bekfani T, Fudim M, Cleland JGF, Jorbenadze A, ... Sievert H, Anker SD
Eur J Heart Fail: 26 Oct 2020; epub ahead of print | PMID: 33111389
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Frequency, trends and institutional variation in 30-day all-cause mortality and unplanned readmissions following hospitalisation for heart failure in Australia and New Zealand.

Labrosciano C, Horton D, Air T, Tavella R, ... Hariharaputhiran S, Ranasinghe I
Aims
National 30-day mortality and readmission rates after heart failure (HF) hospitalisations are a focus of US policy intervention and yet have rarely been assessed in other comparable countries. We examined the frequency, trends and institutional variation in 30-day mortality and unplanned readmission rates after HF hospitalisations in Australia and New Zealand.
Methods and results
We included patients >18 years hospitalised with HF at all public and most private hospitals from 2010-15. The primary outcomes were the frequencies of 30-day mortality and unplanned readmissions, and the institutional risk-standardised mortality rate (RSMR) and readmission rate (RSRR) evaluated using separate cohorts. The mortality cohort included 153 592 patients (mean age 78.9 ± 11.8 years, 51.5% male) with 16 442 (10.7%) deaths within 30 days. The readmission cohort included 148 704 patients (mean age 78.6 ± 11.9 years, 51.7% male) with 33 158 (22.3%) unplanned readmission within 30 days. In 392 hospitals with at least 25 HF hospitalisations, the median RSMR was 10.7% (range 6.1-17.3%) with 59 hospitals significantly different from the national average. Similarly, in 391 hospitals with at least 25 HF hospitalisations, the median RSRR was 22.3% (range 17.7-27.1%) with 24 hospitals significantly different from the average. From 2010-15, the adjusted 30-day mortality [odds ratio (OR) 0.991/month, 95% confidence interval (CI) 0.990-0.992, P < 0.01] and unplanned readmission (OR 0.998/month, 95% CI 0.998-0.999, P < 0.01) rates declined.
Conclusion
Within 30 days of a HF hospitalisation, one in 10 patients died and almost a quarter of those surviving experienced an unplanned readmission. The risk of these outcomes varied widely among hospitals suggesting disparities in HF care quality. Nevertheless, a substantial decline in 30-day mortality and a modest decline in readmissions occurred over the study period.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 22 Oct 2020; epub ahead of print
Labrosciano C, Horton D, Air T, Tavella R, ... Hariharaputhiran S, Ranasinghe I
Eur J Heart Fail: 22 Oct 2020; epub ahead of print | PMID: 33094886
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Natural history and impact of treatment with tafamidis on major cardiovascular outcome-free survival time in a cohort of patients with transthyretin amyloidosis.

Bézard M, Kharoubi M, Galat A, Poullot E, ... Oghina S, Damy T
Aims
Hereditary (ATTRv) and wild-type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR-ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTR-ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)-free survival time without cardiac decompensation, heart transplant, or death.
Methods and results
From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR-ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (n = 98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N-terminal pro-B-type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132).
Conclusion
In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR-ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real-life population.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 22 Oct 2020; epub ahead of print
Bézard M, Kharoubi M, Galat A, Poullot E, ... Oghina S, Damy T
Eur J Heart Fail: 22 Oct 2020; epub ahead of print | PMID: 33094885
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

de Boer RA, Hulot JS, Tocchetti CG, Aboumsallem JP, ... Lyon AR, Backs J

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 21 Oct 2020; epub ahead of print
de Boer RA, Hulot JS, Tocchetti CG, Aboumsallem JP, ... Lyon AR, Backs J
Eur J Heart Fail: 21 Oct 2020; epub ahead of print | PMID: 33094495
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study.

Damy T, Garcia-Pavia P, Hanna M, Judge DP, ... Sultan MB, Witteles R
Aims
Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.
Methods and results
In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval (CI): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo.
Conclusion
Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80 mg as the optimal dose.
Clinical trial registration
ClinicalTrials.gov NCT01994889; NCT02791230.

© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 17 Oct 2020; epub ahead of print
Damy T, Garcia-Pavia P, Hanna M, Judge DP, ... Sultan MB, Witteles R
Eur J Heart Fail: 17 Oct 2020; epub ahead of print | PMID: 33070419
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.