Journal: Eur J Heart Fail

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Abstract

Rationale and Design of the Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) randomized trial.

Amat-Santos IJ, Sánchez-Luna JP, Abu-Assi E, Melendo Viu M, ... Raposeiras-Roubín S, Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) investigators
Aims
Despite aortic stenosis (AS) relief, patients undergoing transcatheter aortic valve implantation (TAVI) are at increased risk of developing heart failure (HF) within first months of intervention. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have been shown to reduce the risk of HF hospitalization in individuals with diabetes mellitus (DM), reduced left ventricular ejection fraction (LVEF) and chronic kidney disease (CKD). However, the effect of SGLT-2 inhibitors on outcomes after TAVI is unknown. The Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) trial is designed to assess the clinical benefit and safety of the SGLT-2 inhibitor dapagliflozin in patients undergoing TAVI.
Methods
DapaTAVI is an independent pragmatic, controlled, prospective, randomized, open-label blinded end-point, multi-center trial conducted in Spain, evaluating the effect of dapagliflozin 10 mg/day on the risk of death and worsening HF in patients with severe AS undergoing a TAVI. Candidate patients should have prior history of HF admission plus ≥1 of the following criteria: 1) DM, 2) LVEF ≤40%, or 3) estimated glomerular filtrate rate between 25 and 75 mL/min/1.73 m2. A total of 1020 patients will be randomized (1:1) to dapagliflozin versus no dapagliflozin. Key secondary outcomes include: (i) Incidence rate of individual components of the primary outcome; (ii) Cardiovascular mortality; (iii) The composite of HF hospitalization or CV death; (iv) Total number of recurrent HF hospitalizations.
Conclusion
DapaTAVI will determine the efficacy and safety of dapagliflozin in a broad spectrum of frail patients after AS relief by TAVI. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 23 Oct 2021; epub ahead of print
Amat-Santos IJ, Sánchez-Luna JP, Abu-Assi E, Melendo Viu M, ... Raposeiras-Roubín S, Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) investigators
Eur J Heart Fail: 23 Oct 2021; epub ahead of print | PMID: 34693613
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Abstract

Death of a child and the risk of heart failure: a population-based cohort study from Denmark and Sweden.

Wei D, Li J, Janszky I, Chen H, ... Ljung R, László KD
Aims
We aimed to investigate whether the death of a child, one of the most severe stressors, is associated with the risk of heart failure (HF).
Methods and results
We conducted a population-based cohort study involving parents of live-born children recorded in the Danish and Swedish Medical Birth Registers during 1973-2016 and 1973-2014, respectively (n=6,717,349). We retrieved information on child death, HF diagnosis and sociodemographic characteristics of the parents from several nationwide registries. We performed Poisson regression models to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for HF in relation to bereavement. A total of 129,829 (1.9%) parents lost at least one child during the follow-up. Bereaved parents had a 35% higher risk of HF than the non-bereaved [IRR (95% CI): 1.35 (1.29-1.41), P<0.001]. The increased HF risk was observed not only when the child died due to cardiovascular or other natural causes, but also when the loss was due to unnatural causes. The association tended to be U-shaped when we categorized the exposed parents by the number of remaining live children at loss or by the age of the deceased child.
Conclusion
We found that the death of a child was associated with an increased risk of HF. The finding that not only cardiovascular and other natural deaths, but also unnatural deaths were associated with HF suggests that stress-related mechanisms may contribute to the development of HF. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 23 Oct 2021; epub ahead of print
Wei D, Li J, Janszky I, Chen H, ... Ljung R, László KD
Eur J Heart Fail: 23 Oct 2021; epub ahead of print | PMID: 34693593
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Abstract

Pathophysiology of Takotsubo Syndrome - a joint scientific statement from the Heart Failure Association Takotsubo Syndrome Study Group and Myocardial Function Working Group of the European Society of Cardiology - Part 2: vascular pathophysiology, gender and sex hormones, genetics, chronic cardiovascular problems and clinical implications.

Omerovic E, Citro R, Bossone E, Redfors B, ... Heymans S, Lyon AR
While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused the catecholamines and sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 15 Oct 2021; epub ahead of print
Omerovic E, Citro R, Bossone E, Redfors B, ... Heymans S, Lyon AR
Eur J Heart Fail: 15 Oct 2021; epub ahead of print | PMID: 34655287
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Abstract

The prevalence and clinical associations of ultrasound measures of congestion in patients at risk of developing heart failure.

Cuthbert JJ, Pellicori P, Flockton R, Kallvikbacka-Bennett A, ... Cleland JGF, Clark AL
Aims
Congestion is a cardinal feature of untreated heart failure (HF) and might be detected by ultrasound (US) before overt clinical signs appear.
Methods and results
We investigated the prevalence and clinical associations of subclinical congestion in 238 patients with at least one clinical risk factor for HF (diabetes, ischaemic heart disease, or hypertension) using three US variables: (i) inferior vena cava (IVC) diameter; (ii) jugular vein distensibility (JVD) ratio (the ratio of the jugular vein diameter during the Valsalva manoeuvre to that at rest); (iii) the number of B-lines from a 28-point lung US. US congestion was defined as IVC diameter > 2.0 cm, JVD ratio < 4.0 or B-lines count > 14. The prevalence of subclinical congestion (defined as at least one positive US marker of congestion) was 30% (13% by IVC diameter, 9% by JVD ratio and 13% by B-line quantification). Compared to patients with no congestion on US, those with at least one marker had larger left atria and higher plasma concentrations of natriuretic peptides. Patients with raised plasma N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide had a lower JVD ratio (7.69 vs. 8.80; P = 0.05) and more often had at least one lung B-line (74% vs. 63%; P = 0.05). However, plasma natriuretic peptide concentrations were more closely related to left atrial volume than other US measures of congestion.
Conclusions
Subclinical evidence of congestion by US is common in patients with clinical risk factors for HF. Whether these measurements provide additional value for predicting the development of HF and its prevention deserves consideration.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 09 Oct 2021; epub ahead of print
Cuthbert JJ, Pellicori P, Flockton R, Kallvikbacka-Bennett A, ... Cleland JGF, Clark AL
Eur J Heart Fail: 09 Oct 2021; epub ahead of print | PMID: 34632680
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Abstract

Plasma Biomarkers Associated with Adverse Outcomes in Patients with Calcific Aortic Stenosis.

Vidula MK, Orlenko A, Zhao L, Salvador L, ... Gordon D, Chirinos JA
Aims
Enhanced risk stratification of patients with aortic stenosis (AS) is necessary to identify patients at high risk for adverse outcomes, and may allow for better management of patient subgroups at high risk of myocardial damage. The objective of this study was to identify plasma biomarkers and multimarker profiles associated with adverse outcomes in AS.
Methods and results
We studied 708 patients with calcific AS and measured 49 biomarkers using a Luminex platform. We studied the correlation between biomarkers and the risk of 1) death and 2) death or heart failure hospitalization (DHFA). We also utilized machine-learning (ML) methods (a tree-based pipeline optimizer platform) to develop multimarker models associated with the risk of death and DHFA. In this cohort with median follow-up of 2.8 years, multiple biomarkers were significantly predictive of death in analyses adjusted for clinical confounders, including TNF-α (hazard ratio (HR) 1.28, p < 0.0001), TNFRI (TNFRSF1A; HR 1.38, p < 0.0001), fibroblast growth factor (FGF)-23 (HR 1.22, p < 0.0001), NT-proBNP (HR 1.58, p < 0.0001), MMP-7 (HR 1.24, p = 0.0002), syndecan-1 (HR 1.27, p = 0.0002), ST2 (IL1RL1; HR 1.22, p = 0.0002), IL-8 (CXCL8; HR 1.22, p = 0.0005), pentraxin (PTX)-3 (HR 1.17, p = 0.001), NGAL (LCN2; HR 1.18, p < 0.0001), osteoprotegerin (OPG) (TNFRSF11B; HR 1.26, p = 0.0002), and endostatin (COL18A1; HR 1.28, p = 0.0012). Several biomarkers were also significantly predictive of DHFA in adjusted analyses including FGF-23 (HR 1.36, p < 0.0001), TNF-α (HR 1.26, p < 0.0001), TNFRI (HR 1.34, p < 0.0001), angiopoietin-2 (HR 1.26, p < 0.0001), syndecan-1 (HR 1.23, p = 0.0006), ST2 (HR 1.27, p < 0.0001), IL-8 (HR 1.18, p = 0.0009), PTX-3 (HR 1.18, p = 0.0002), OPG (HR 1.20, p = 0.0013), and NT-proBNP (HR 1.63, p < 0.0001). ML-multimarker models were strongly associated with adverse outcomes (mean 1-year probability of death of 0%, 2%, and 60%; mean 1-year probability of DHFA of 0%, 4%, 97%; p < 0.0001). In these models, IL-6 (a biomarker of inflammation) and FGF-23 (a biomarker of calcification) emerged as the biomarkers of highest importance.
Conclusion
Plasma biomarkers are strongly associated with the risk of adverse outcomes in patients with AS. Biomarkers of inflammation and calcification were most strongly related to prognosis. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 09 Oct 2021; epub ahead of print
Vidula MK, Orlenko A, Zhao L, Salvador L, ... Gordon D, Chirinos JA
Eur J Heart Fail: 09 Oct 2021; epub ahead of print | PMID: 34632675
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Abstract

Feasibility and efficacy of transcatheter interatrial shunt devices for chronic heart failure: A systematic review and meta-analysis.

Lauder L, Pereira TV, Degenhardt MC, Ewen S, ... da Costa BR, Mahfoud F
Aims
To assess the feasibility and efficacy of interatrial shunt devices (IASD) for the treatment of chronic heart failure (CHF).
Methods
MEDLINE and the Cochrane Central Register of Controlled Trials from inception until April 2021 were searched for prospective studies investigating dedicated transcatheter IASD for the treatment of CHF. Standardised mean differences were calculated for the within-group changes before and after implantation of the IASD. The predefined primary outcome was change in six-minute walking distance (6MWD) from baseline to 12 months. Other outcomes were change in NYHA class, health-related quality of life (HRQoL), echocardiographic and hemodynamic data, device performance and safety. Subgroup analyses were crude univariable meta-regression analyses.
Results
Six studies (five single-arm open-label studies, one sham-controlled trial) were included. In these, 226 patients underwent IASD implantation using four different devices. From baseline to 12 months, 6MWD increased by 28.1 m (95% CI: 10.9 to 45.3) with no evidence for a difference between devices (p for interaction = 0.66) and patients with left-ventricular ejection fraction (LVEF) >40% or ≤ 40% (p for interaction = 0.21). At 12 months, HRQoL improved by 17.7 points (95% CI: 10.8 to 24.6) and pulmonary capillary wedge pressure (PCWP) decreased by 2.0 mmHg (95% CI: -3.6 to -0.4), respectively. There were no changes in LVEF or NT-proBNP during follow-up. Shunt patency ranged from 50% for the first-generation v-Wave to 100% for the Corvia IASD II and the second-generation v-Wave system. The summary risk of serious adverse device-related effects was 8% (95% CI: 1 to 20) at 12 months.
Conclusion
IASD implantation in CHF is feasible and associates with improved submaximal exercise capacity (measured by 6MWD) and HRQoL, and reductions in PCWP. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 09 Oct 2021; epub ahead of print
Lauder L, Pereira TV, Degenhardt MC, Ewen S, ... da Costa BR, Mahfoud F
Eur J Heart Fail: 09 Oct 2021; epub ahead of print | PMID: 34628706
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Abstract

Early and short-term intensive management after discharge for patients hospitalized with acute heart failure, a randomized study (ECAD-HF).

Logeart D, Berthelot E, Bihry N, Eschalier R, ... Vicaut E, Isnard R
Aims
Hospitalization for acute heart failure (HF) is followed by a vulnerable time with increased risk of readmission or death, thus requiring particular attention after discharge. In this study we examined the impact of intensive, early follow-up among patients at high readmission risk at discharge after treatment for acute HF.
Methods and results
Hospitalized acute HF patients were included with at least one of the following: previous acute HF < 6 months, systolic blood pressure ≤ 110 mmHg, creatininemia ≥180 μmol/L, or BNP ≥350 pg/mL or NTproBNP ≥2200 pg/mL. Patients were randomized to either optimized care and education with serial consultations with HF specialist and dietician during the first 2-3 weeks, or to standard post-discharge care according to guidelines. Primary end-point was all-cause death or first unplanned hospitalization during 6-month follow-up. Among 482 randomized patients (median age 77 and median left ventricular ejection fraction 35%), 224 were hospitalized or died. In the intensive group, loop diuretics (46%), betablockers (49%), ACE-inhibitors or angiotensin receptors blockers (39%) and mineralocorticoid receptor antagonists (47%) were titrated. No difference was observed between the two groups for primary end-point (HR 0.97; 95CI 0.74-1.26), nor for mortality at 6 or 12 months or unplanned HF rehospitalization. Additionally, no difference between the two groups according to age, previous HF and left ventricular ejection fraction was found.
Conclusion
In high-risk HF, we found intensive follow-up early post-discharge did not improve outcomes. This vulnerable post-discharge time requires further studies to clarify useful transitional care services. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 08 Oct 2021; epub ahead of print
Logeart D, Berthelot E, Bihry N, Eschalier R, ... Vicaut E, Isnard R
Eur J Heart Fail: 08 Oct 2021; epub ahead of print | PMID: 34628697
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Abstract

COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.

Rosano G, Jankowska EA, Ray R, Metra M, ... Volterrani M, Coats AJS
Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 05 Oct 2021; epub ahead of print
Rosano G, Jankowska EA, Ray R, Metra M, ... Volterrani M, Coats AJS
Eur J Heart Fail: 05 Oct 2021; epub ahead of print | PMID: 34612556
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Abstract

Effects of an outpatient intervention comprising nurse-led non-invasive assessments, telemedicine support and remote cardiologists\' decisions in patients with heart failure (AMULET Study): a randomised controlled trial.

Krzesiński P, Jankowska EA, Siebert J, Galas A, ... Ponikowski P, Gielerak G
Aim
Prevention of heart failure (HF) hospitalisations and deaths constitutes a major therapeutic aim in patients with HF. The role of telemedicine in this context remains equivocal. We investigated whether an outpatient telecare based on nurse-led non-invasive assessments supporting remote therapeutic decisions (AMULET telecare) could improve clinical outcomes in patients after an episode of acute HF during the12-month follow-up.
Methods and results
In this prospective randomised controlled trial, patients with HF and left ventricular ejection fraction (LVEF) ≤49%, after an episode of acute HF within recent 6 months, were randomly assigned to receive either an outpatient telecare based on nurse-led non-invasive assessments (n = 300) (AMULET model) or standard care (n = 305). The primary outcome, being a composite of unplanned HF hospitalisation or cardiovascular death, occurred in 51 (17.1%) patients in the telecare group and 73 (23.9%) patients in the standard care group up to 12 months after randomization (HR: 0.69, 95% CI: 0.48-0.99, p = 0.044). The implementation of AMULET telecare, as compared to the standard care, reduced the risk of first unplanned HF hospitalisation (HR: 0.62; 95% CI: 0.42-0.91, p = 0.015) as well as the risk of total unplanned HF hospitalisations (HR: 0.64, 95% CI: 0.41-0.99, p = 0.044).There was no difference in cardiovascular mortality between the study groups (HR: 1.03, 95% CI: 0.54-1.67, p = 0.930).
Conclusion
AMULET telecare as compared to standard care significantly reduced the risk of HF hospitalisation or cardiovascular death during the 12-month follow-up among patients with HF and LVEF≤49% after an episode of acute HF (ClinicalTrials.gov: NCT03476590).

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Eur J Heart Fail: 05 Oct 2021; epub ahead of print
Krzesiński P, Jankowska EA, Siebert J, Galas A, ... Ponikowski P, Gielerak G
Eur J Heart Fail: 05 Oct 2021; epub ahead of print | PMID: 34617373
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Abstract

A randomized clinical trial on the short-term effects of 12-week sacubitril/valsartan vs. enalapril on peak oxygen consumption in patients with heart failure with reduced ejection fraction: results from the ACTIVITY-HF study.

Halle M, Schöbel C, Winzer EB, Bernhardt P, ... Sieder C, Lecker LSM
Aims
ACTIVITY-HF was a randomized, double-blind, active-controlled study, which assessed the short-term effect of sacubitril/valsartan compared with the active comparator enalapril on improving maximal exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF).
Methods and results
A total of 201 ambulatory patients with HFrEF (left ventricular ejection fraction ≤ 40%, New York Heart Association class III) across 34 centres in Germany were randomized (1:1) to receive sacubitril/valsartan 97/103 mg bid (n = 103) or enalapril 10 mg bid (n = 98). The primary endpoint of the study was the change from baseline in peak oxygen consumption (VO2 ; adjusted to body weight) after 12 weeks, and the key secondary endpoint was change from baseline in peak VO2 after 6 weeks. The study population was predominantly male (81.1%) with a mean age of 66.9 years and a body mass index of 29.4 kg/m2 . Change in peak VO2 from baseline to Week 12 was similar between sacubitril/valsartan and enalapril groups [least squares mean difference: 0.32 mL/min/kg; 95% confidence interval (CI) -0.21, 0.85; P = 0.2327]. Similarly, no significant differences were observed between the two treatment groups in minute ventilation to carbon dioxide production slope, exercise capacity at first ventilatory threshold or Borg scale at either Week 6 or Week 12. Change in heart rate at first ventilatory threshold was lower in the sacubitril/valsartan group compared with the enalapril group at Week 12 (mean -3.75 bpm; 95% CI -7.03, -0.48; P = 0.0248). The safety of sacubitril/valsartan was comparable to enalapril.
Conclusion
In patients with HFrEF, short-term treatment with sacubitril/valsartan for 12 weeks did not result in significant benefits on peak VO2 when compared with enalapril.

© 2021 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 Sep 2021; epub ahead of print
Halle M, Schöbel C, Winzer EB, Bernhardt P, ... Sieder C, Lecker LSM
Eur J Heart Fail: 29 Sep 2021; epub ahead of print | PMID: 34591356
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Abstract

Head-to-head comparison of contemporary heart failure risk scores.

Codina P, Lupón J, Borrellas A, Spitaleri G, ... McMurray J, Bayes-Genis A
Aims
Several heart failure (HF) web-based risk scores are currently used in clinical practice. Currently, we lack head-to-head comparison of the accuracy of risk scores. This study aimed to assess correlation and mortality prediction performance of Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC-HF) risk score, which includes clinical variables + medications; Seattle Heart Failure Model (SHFM), which includes clinical variables + treatments + analytes; PARADIGM Risk of Events and Death in the Contemporary Treatment of Heart Failure (PREDICT-HF) and Barcelona Bio-Heart Failure (BCN-Bio-HF) risk calculator, which also include biomarkers, like N-terminal pro B-type natriuretic peptide (NT-proBNP).
Methods and results
A total of 1166 consecutive patients with HF from different aetiologies that had NT-proBNP measurement at first visit were included. Discrimination for all-cause mortality was compared by Harrell\'s C-statistic from 1 to 5 years, when possible. Calibration was assessed by calibration plots and Hosmer-Lemeshow test and global performance by Nagelkerke\'s R2 . Correlation between scores was assessed by Spearman rank test. Correlation between the scores was relatively poor (rho value from 0.66 to 0.79). Discrimination analyses showed better results for 1-year mortality than for longer follow-up (SHFM 0.817, MAGGIC-HF 0.801, PREDICT-HF 0.799, BCN-Bio-HF 0.830). MAGGIC-HF showed the best calibration, BCN-Bio-HF overestimated risk while SHFM and PREDICT-HF underestimated it. BCN-Bio-HF provided the best discrimination and overall performance at every time-point.
Conclusions
None of the contemporary risk scores examined showed a clear superiority over the rest. BCN-Bio-HF calculator provided the best discrimination and overall performance with overestimation of risk. MAGGIC-HF showed the best calibration, and SHFM and PREDICT-HF tended to underestimate risk. Regular updating and recalibration of online web calculators seems necessary to improve their accuracy as HF management evolves at unprecedented pace.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 23 Sep 2021; epub ahead of print
Codina P, Lupón J, Borrellas A, Spitaleri G, ... McMurray J, Bayes-Genis A
Eur J Heart Fail: 23 Sep 2021; epub ahead of print | PMID: 34558158
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Abstract

Effects of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction patients with chronic obstructive pulmonary disease in EMPHASIS-HF and RALES.

Yeoh SE, Dewan P, Serenelli M, Ferreira JP, ... Jhund PS, McMurray JJV
Aims
Heart failure with reduced ejection fraction (HFrEF) and chronic obstructive pulmonary disease (COPD) individually cause significant morbidity and mortality. Their coexistence is associated with even worse outcomes, partly due to suboptimal heart failure therapy, especially underutilisation of beta-blockers. Our aim was to investigate outcomes in HFrEF patients with and without COPD, and the effects of mineralocorticoid receptor antagonists (MRAs) on outcomes.
Methods and results
We studied the effect of MRA therapy in a post-hoc pooled analysis of 4397 HFrEF patients in the RALES and EMPHASIS-HF trials. The primary endpoint was the composite of heart failure hospitalisation or cardiovascular death. A total of 625 (14.2%) of the 4397 patients had COPD. Patients with COPD were older, more often male, and smokers, but less frequently treated with a beta-blocker. In patients with COPD, event rates (per 100 person-years) for the primary endpoint and for all-cause mortality were 25.2 (95% confidence interval 22.1-28.7) and 17.2 (14.9-19.9), respectively, compared with 19.9 (18.8-21.1) and 12.8 (12.0-13.7) in participants without COPD. The risks of all-cause hospitalisation and sudden death were also higher in patients with COPD. The benefit of MRA, compared with placebo, was consistent in patients with or without COPD for all outcomes, e.g. hazard ratio for the primary outcome 0.66 (0.50-0.85) for COPD and 0.65 (0.58-0.73) for no COPD (interaction p = 0.93). MRA-induced hyperkalaemia was less frequent in patients with COPD.
Conclusions
In RALES and EMPHASIS-HF, one-in-seven patients with HFrEF had coexisting COPD. HFrEF patients with COPD had worse outcomes than those without. The benefits of MRAs were consistent, regardless of COPD status.

© 2021 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 Sep 2021; epub ahead of print
Yeoh SE, Dewan P, Serenelli M, Ferreira JP, ... Jhund PS, McMurray JJV
Eur J Heart Fail: 17 Sep 2021; epub ahead of print | PMID: 34536265
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Abstract

Recovery of Cardiac Function Following COVID-19 - ECHOVID-19: A Prospective Longitudinal Cohort Study.

Lassen MCH, Skaarup KG, Lind JN, Alhakak AS, ... Schou M, Biering-Sørensen T
Aims
The degree of cardiovascular sequelae following COVID-19 remains unknown. The aim of this study was to investigate whether cardiac function recovers following COVID-19.
Methods and results
A consecutive sample of patients hospitalized with COVID-19 were prospectively included in this longitudinal study. All patients underwent an echocardiographic examination during hospitalization and two months later. All participants were successfully matched 1:1 with COVID-19-free controls on age and sex. A total of 91 patients were included in this study (mean age 63±12 and 59% males). A median of 77 [72,92] days passed between the two examinations. Right ventricular (RV) function improved following resolution of COVID-19: tricuspid annular plane systolic excursion (TAPSE): (2.28cm±0.40 vs 2.11cm±0.38, P<0.001) and longitudinal strain of the right ventricle (RVLS) (25.3%±5.5 vs 19.9%±5.8, P<0001). In contrast, left ventricular (LV) systolic function assessed by global longitudinal strain (GLS) did not significantly improve (17.4±2.9 vs 17.6%±3.3, P=0.6). NT-proBNP decreased between the two examinations (177.6 (80.3,408,0) vs 1.7 (5.7,24.0), P<0.001). None of the participants had elevated troponins at follow-up compared to 18 (27.7%) during hospitalization. Recovered COVID-19 patients had significantly lower GLS (17.4%±2.9 vs 18.8%±2.9, P=0.001 & adjusted P=0.004), TAPSE (2.28cm±0.40 vs 2.67cm±0.44, P<0.001 & adjusted P<0.001), and RVLS (25.3%±5.5 vs 26.6%±5.8, P=0.50 & adjusted P<0.001) compared to matched controls.
Conclusion
Acute COVID-19 affected negatively RV function and cardiac biomarkers but recovered following resolution of COVID-19. In contrast, the observed reduced LV function during acute COVID-19 did not improve post-COVID-19. Compared to the matched controls, both LV and RV function remained impaired.

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Eur J Heart Fail: 11 Sep 2021; epub ahead of print
Lassen MCH, Skaarup KG, Lind JN, Alhakak AS, ... Schou M, Biering-Sørensen T
Eur J Heart Fail: 11 Sep 2021; epub ahead of print | PMID: 34514713
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Abstract

Heart failure with preserved ejection fraction after left-sided valve surgery: prevalent and relevant.

Kammerlander AA, Nitsche C, Donà C, Koschutnik M, ... Hengstenberg C, Mascherbauer J
Aims
To investigate the epidemiological and prognostic relationship between heart failure with preserved ejection fraction (HFpEF) and left-sided valve surgery using all-cause mortality as a primary endpoint.
Methods and results
We studied a total of 973 patients, of whom 673 had undergone left-sided valve surgery (time from surgery to enrolment 50 ± 30 months after valve surgery) and 300 patients with HFpEF without prior surgery served as control group. Among patients after surgery, 67.4% fulfilled all criteria of HFpEF according to current guideline recommendations, 20.6% had no heart failure (HF), and 12.0% had HF with mid-range or reduced ejection fraction (HFmrEF/HFrEF). During 83 ± 39 months of follow-up, a total of 335 (34.4%) patients died. Compared to surgical patients with no subsequent HF, patients with HFpEF and HFmrEF/HFrEF after surgery showed significantly higher all-cause mortality rates [hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.25-2.57, P = 0.001; and HR 1.86, 95% CI 1.16-2.98, P = 0.010, respectively]. This increased mortality rate was similar to the control HFpEF group without surgery (HR 2.05, 95% CI 1.38-3.02, P < 0.001). Results remained consistent after adjustment for clinical and imaging risk factors and when using the established HFA-PEFF risk score for HFpEF diagnosis. Notably, only 12.5% of HFpEF patients after surgery were diagnosed with HF despite regular follow-up visits by board-certified cardiologists. In contrast, 92.1% of HFmrEF/HFrEF patients after surgery were diagnosed correctly.
Conclusions
Heart failure with preserved ejection fraction following left-sided valve surgery is highly prevalent, associated with unfavourable outcomes, but rarely recognized.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 09 Sep 2021; epub ahead of print
Kammerlander AA, Nitsche C, Donà C, Koschutnik M, ... Hengstenberg C, Mascherbauer J
Eur J Heart Fail: 09 Sep 2021; epub ahead of print | PMID: 34506046
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Impact:
Abstract

Sympathetic vasoconstrictor activity before and after left ventricular assist device implantation in patients with end-stage heart failure.

Heusser K, Wittkoepper J, Bara C, Haverich A, ... Jordan J, Tank J
Aims
Sympathetic overactivity, which predicts poor outcome in patients with heart failure, normalizes following cardiac transplantation. We tested the hypothesis that haemodynamic improvement following left ventricular assist device (LVAD) implantation is also associated with reductions in centrally generated sympathetic activity.
Methods and results
In eight patients with heart failure (two women, six men, age 44-66 years), we continuously recorded electrocardiogram, beat-to-beat finger blood pressure, respiration, and muscle sympathetic nerve activity (MSNA) before and after implantation of the continuous-flow LVAD devices HeartWare HVAD (n = 4) and HeartMate II (n = 2), and the non-continuous-flow device HeartMate 3 (n = 2). LVAD implantation increased cardiac output by 1.29 ± 0.88 L/min (P = 0.060) and mean arterial pressure by 16.2 ± 7.9 mmHg (P < 0.001), while reducing pulse pressure by 25.3 ± 9.8 mmHg (P < 0.001). LVAD implantation did not change MSNA burst frequency (-1.3 ± 7.5 bursts/min, P = 0.636), total activity (+0.62 ± 1.83 au, P = 0.369), or normalized activity (+0.63 ± 4.23, P = 0.685). MSNA burst incidence was decreased (-7.8 ± 9.3 bursts/100 heart beats, P = 0.049). However, cardiac ectopy altered MSNA bursting patterns that could be mistaken for sympatholysis.
Conclusion
Implantation of current design LVAD does not consistently normalize sympathetic activity in patients with end-stage heart failure despite haemodynamic improvement.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 07 Sep 2021; epub ahead of print
Heusser K, Wittkoepper J, Bara C, Haverich A, ... Jordan J, Tank J
Eur J Heart Fail: 07 Sep 2021; epub ahead of print | PMID: 34496114
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Impact:
Abstract

Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC).

Meijers WC, Bayes-Genis A, Mebazaa A, Bauersachs J, ... Mueller C, de Boer RA
New biomarkers are being evaluated for their ability to advance the management of patients with heart failure. Despite a large pool of interesting candidate biomarkers, besides natriuretic peptides virtually none have succeeded in being applied into the clinical setting. In this review, we examine the most promising emerging candidates for clinical assessment and management of patients with heart failure. We discuss high-sensitivity cardiac troponins (Tn), procalcitonin, novel kidney markers, soluble suppression of tumorigenicity 2 (sST2), galectin-3, growth differentiation factor-15 (GDF-15), cluster of differentiation 146 (CD146), neprilysin, adrenomedullin (ADM), and also discuss proteomics and genetic-based risk scores. We focused on guidance and assistance with daily clinical care decision-making. For each biomarker, analytical considerations are discussed, as well as performance regarding diagnosis and prognosis. Furthermore, we discuss potential implementation in clinical algorithms and in ongoing clinical trials.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 07 Sep 2021; epub ahead of print
Meijers WC, Bayes-Genis A, Mebazaa A, Bauersachs J, ... Mueller C, de Boer RA
Eur J Heart Fail: 07 Sep 2021; epub ahead of print | PMID: 34498368
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Impact:
Abstract

Integration of imaging and circulating biomarkers in heart failure: a consensus document by the Biomarkers and Imaging Study Groups of the Heart Failure Association of the European Society of Cardiology.

Moura B, Aimo A, Al-Mohammad A, Flammer A, ... Emdin M, Richards AM
Circulating biomarkers and imaging techniques provide independent and complementary information to guide management of heart failure (HF). This consensus document by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) presents current evidence-based indications relevant to integration of imaging techniques and biomarkers in HF. The document first focuses on application of circulating biomarkers together with imaging findings, in the broad domains of screening, diagnosis, risk stratification, guidance of treatment and monitoring, and then discusses specific challenging settings. In each section we crystallize clinically relevant recommendations and identify directions for future research. The target readership of this document includes cardiologists, internal medicine specialists and other clinicians dealing with HF patients.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 04 Sep 2021; epub ahead of print
Moura B, Aimo A, Al-Mohammad A, Flammer A, ... Emdin M, Richards AM
Eur J Heart Fail: 04 Sep 2021; epub ahead of print | PMID: 34482622
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Impact:
Abstract

Phenotyping heart failure patients for iron deficiency and use of intravenous iron therapy: data from the Swedish Heart Failure Registry.

Becher PM, Schrage B, Benson L, Fudim M, ... Lund LH, Savarese G
Aims
Iron deficiency (ID) is associated with poor prognosis regardless of anaemia. Intravenous iron improves quality of life and outcomes in patients with ID and heart failure (HF) with reduced ejection fraction (HFrEF). In the Swedish HF registry, we assessed (i) frequency and predictors of ID testing; (ii) prevalence and outcomes of ID with/without anaemia; (iii) use of ferric carboxymaltose (FCM) and its predictors in patients with ID.
Methods and results
We used multivariable logistic regressions to assess patient characteristics independently associated with ID testing/FCM use, and Cox regressions to assess risk of outcomes associated with ID. Of 21 496 patients with HF and any ejection fraction enrolled in 2017-2018, ID testing was performed in 27%. Of these, 49% had ID and more specifically 36% had ID-/anaemia-, 15% ID-/anaemia+, 29% ID+/anaemia-, and 20% ID+/anaemia+ (48%, 39%, 13%, 30% and 18% in HFrEF, respectively). Risk of recurrent all-cause hospitalizations was higher in patients with ID regardless of anaemia. Of 1959 patients with ID, 19% received FCM (24% in HFrEF). Important independent predictors of ID testing and FCM use were anaemia, higher New York Heart Association class, having HFrEF, and referral to HF specialty care.
Conclusion
In this nationwide HF registry, ID testing occurred in only about a quarter of the patients. Among tested patients, ID was present in one half, but only one in five patients received FCM indicating low adherence to current guidelines on screening and treatment.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 02 Sep 2021; epub ahead of print
Becher PM, Schrage B, Benson L, Fudim M, ... Lund LH, Savarese G
Eur J Heart Fail: 02 Sep 2021; epub ahead of print | PMID: 34476878
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Impact:
Abstract

Dosing of losartan in men versus women with heart failure with reduced ejection fraction: the HEAAL trial.

Ferreira JP, Konstam MA, McMurray JJV, Butler J, ... Packer M, Zannad F
Aims
In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit.
Methods and results
The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66 years and 30% of patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high- vs. low-dose losartan for the composite outcome of all-cause death or all-cause hospitalization: 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women; interaction P = 0.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III/IV, and estimated glomerular filtration rate <60 mL/min. Patients with these features had a poorer response to high-dose losartan. Subgroup analyses supported no benefit from high-dose losartan in patients with poorer kidney function and severe heart failure symptoms.
Conclusions
Compared with men, women might need lower doses of losartan to achieve similar treatment benefit. However, beyond sex, other factors (e.g. kidney function, age, and symptoms) may influence the response to high-dose losartan, suggesting that sex-based subgroup findings may be biased by other confounders.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Aug 2021; 23:1477-1484
Ferreira JP, Konstam MA, McMurray JJV, Butler J, ... Packer M, Zannad F
Eur J Heart Fail: 30 Aug 2021; 23:1477-1484 | PMID: 34050594
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Impact:
Abstract

Concentration-dependent clinical and prognostic importance of high-sensitivity cardiac troponin T in heart failure and a reduced ejection fraction and the influence of empagliflozin: the EMPEROR-Reduced trial.

Packer M, Januzzi JL, Ferreira JP, Anker SD, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Aims
Circulating troponin is an important measure of risk in patients with heart failure, but it has not been used to determine if disease severity influences the responses to drug treatments in randomized controlled trials.
Methods and results
In the EMPEROR-Reduced trial, patients with class II-IV heart failure and a reduced ejection fraction were randomly assigned to placebo or empagliflozin 10 mg daily and followed for the occurrence of serious heart failure and renal events. High-sensitivity cardiac troponin T (hs-cTnT) was measured in 3636 patients (>97%) at baseline, and patients were divided into four groups based on the degree of troponin elevation. With increasing concentrations of hs-cTnT, patients were progressively more likely to have diabetes and atrial fibrillation, to have New York Heart Association class III-IV symptoms and been hospitalized for heart failure within the prior year, and to have elevated levels of natriuretic peptides and worse renal function (P-trend < 0.0001 for all comparisons), but importantly, the troponin groups did not differ with respect to ejection fraction. A linear relationship was observed between the logarithm of hs-cTnT and the combined risk of cardiovascular death or hospitalization for heart failure (P = 0.0015). When treated with placebo, patients with the highest levels of hs-cTnT had risks of cardiovascular death and hospitalization for heart failure that were 3-5 fold greater than those with values in the normal range. Patients with higher levels of hs-cTnT were also more likely to experience worsening of renal function and serious adverse renal events and showed the least improvement in health status (as measured by the Kansas City Cardiomyopathy Questionnaire). When compared with placebo, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, regardless of the baseline level of hs-cTnT, whether the effects of treatment were analysed as hazard ratios or absolute risk reductions.
Conclusions
Elevations in hs-cTnT reflect the clinical severity, stability and prognosis of patients with heart failure and a reduced ejection fraction, with biomarkers, comorbidities, clinical course and risks that are proportional to the magnitude of hs-cTnT elevation. Empagliflozin exerted favourable effects on heart failure and renal outcomes, regardless of the baseline concentration of hs-cTnT.

© 2021 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 Aug 2021; 23:1529-1538
Packer M, Januzzi JL, Ferreira JP, Anker SD, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Eur J Heart Fail: 30 Aug 2021; 23:1529-1538 | PMID: 34053177
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Impact:
Abstract

Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial.

Bhatt AS, Vaduganathan M, Claggett BL, Liu J, ... McMurray JJV, Solomon SD
Aims
Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β-blocker and mineralocorticoid receptor antagonist (MRA) use and dosing in a large randomized clinical trial.
Methods and results
Patients with full data on medication use were included. We examined β-blocker and MRA use in patients randomized to sacubitril/valsartan vs. enalapril through 12-month follow-up. New initiations and discontinuations of β-blocker and MRA were compared between treatment groups. Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β-blocker and MRA at any dose was 87% and 56%, respectively. Mean doses of β-blocker and MRA were similar between treatment groups at baseline and at 6-month and 12-month follow-up. New initiations through 12-month follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β-blockers [37 (9.0%) vs. 42 (10.2%), P = 0.56] and MRA [127 (7.6%) vs. 143 (9.2%), P = 0.10]. Among patients on MRA therapy at baseline, there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12 months [125 (6.2%) vs. 187 (9.0%), P = 0.001]. Discontinuations of β-blockers were not significantly different between groups in follow-up (2.2% vs. 2.6%, P = 0.26).
Conclusions
Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose down-titration of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.

© 2021 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 Aug 2021; 23:1518-1524
Bhatt AS, Vaduganathan M, Claggett BL, Liu J, ... McMurray JJV, Solomon SD
Eur J Heart Fail: 30 Aug 2021; 23:1518-1524 | PMID: 34101308
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Impact:
Abstract

Dietary interventions and nutritional supplements for heart failure: a systematic appraisal and evidence map.

Khan MS, Khan F, Fonarow GC, Sreenivasan J, ... Anker SD, Butler J
Aims
To appraise meta-analytically determined effect of dietary interventions and nutritional supplements on heart failure (HF)-related outcomes, and create an evidence map to visualize the findings and certainty of evidence.
Methods and results
Online databases were systematically searched for meta-analyses of randomized controlled trials (RCTs) evaluating the effect of dietary interventions and nutritional supplements on HF outcomes and incidence. These were then updated if new RCTs were available. Estimates were pooled using a random-effects model and reported as risk ratios (RRs) or mean differences with 95% confidence intervals. We identified 14 relevant meta-analyses, to which 21 new RCTs were added. The total evidence base reviewed included 122 RCTs (n = 176 097 participants) assessing 14 interventions. We found that coenzyme Q10 was associated with lower all-cause mortality [RR 0.69 (0.50-0.96); I2  = 0%; low certainty of evidence] in HF patients. Incident HF risk was reduced with Mediterranean diet [RR 0.45 (0.26-0.79); I2  = 0%; low certainty of evidence]. Vitamin E supplementation was associated with a small but significant increase in the risk of HF hospitalization [RR 1.21 (1.04-1.40); I2 = 0%; moderate certainty of evidence]. There was moderate certainty of evidence that thiamine, vitamin D, iron, and L-carnitine supplementation had a beneficial effect on left ventricular ejection fraction.
Conclusion
Coenzyme Q10 may reduce all-cause mortality in HF patients, while a Mediterranean diet may reduce the risk of incident HF; however, the low certainty of evidence warrants the need for further RCTs to confirm a definite clinical role. RCT data were lacking for several common interventions including intermittent fasting, caffeine, DASH diet, and ketogenic diet. More research is needed to fill the knowledge gap.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Aug 2021; 23:1468-1476
Khan MS, Khan F, Fonarow GC, Sreenivasan J, ... Anker SD, Butler J
Eur J Heart Fail: 30 Aug 2021; 23:1468-1476 | PMID: 34173307
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Impact:
Abstract

Baseline characteristics of patients in the PARALLAX trial: insights into quality of life and exercise capacity in heart failure with preserved ejection fraction.

Shah SJ, Cowie MR, Wachter R, Szecsödy P, ... Gong J, Pieske B
Aims
We sought to describe the baseline characteristics of PARALLAX [a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure (HF) with mildly reduced and preserved ejection fraction (HFpEF)]; compare PARALLAX to recent HFpEF trials; and examine the clinical characteristics associated with quality of life (QOL) and 6-min walk test distance (6MWD).
Methods and results
A total of 2566 patients with HF and left ventricular ejection fraction (LVEF) >40% were randomized, of whom 96% had an LVEF ≥45%. Multivariable linear regression was used to determine characteristics associated with Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and 6MWD. Mean age was 73 ± 8 years, 51% were female, and comorbidities were common. Of the QOL measures tested in PARALLAX, the Short Form Health Survey-36 physical functioning score was most closely correlated with 6MWD (R = 0.41, P < 0.001), and outperformed the KCCQ physical limitation score (R = 0.33) and KCCQ-CSS (R = 0.31) on multivariable analyses. Female sex, higher body mass index, history of coronary artery disease, lower LVEF, and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with worse (lower) KCCQ-CSS; older age, female sex, higher body mass index, diabetes, coronary artery disease, chronic obstructive pulmonary disease, prior HF hospitalization, lower LVEF, and higher NT-proBNP were associated with shorter 6MWD (P < 0.05 for all associations).
Conclusions
PARALLAX is the largest HFpEF study to date to examine 6MWD together with QOL. The KCCQ-CSS and 6MWD were modestly correlated, and several factors were associated with worse values of both. These results provide insight into the association between QOL and exercise capacity in HFpEF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Aug 2021; 23:1541-1551
Shah SJ, Cowie MR, Wachter R, Szecsödy P, ... Gong J, Pieske B
Eur J Heart Fail: 30 Aug 2021; 23:1541-1551 | PMID: 34170062
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Impact:
Abstract

Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden).

Savarese G, Bodegard J, Norhammar A, Sartipy P, ... Vaduganathan M, Coats AJS
Aims
Use and dosing of guideline-directed medical therapy (GDMT) in patients with heart failure (HF) have been shown to be suboptimal. Among new users of GDMT in HF, we followed the real-life patterns of dose titration and discontinuation of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers, mineralocorticoid receptor antagonists (MRA) and angiotensin receptor-neprilysin inhibitors (ARNI).
Methods and results
New users were identified in health care databases in Sweden, UK and US between 2016-2019. Inclusion criterion was a recent HF hospitalization (HHF) triggering the initiation of GDMT. Patients were grouped by GDMT, i.e. ACEi, ARB, beta-blocker, MRA and ARNI, and stratified by initial dose. Follow-up was 12 months, until death or study end. Outcomes were dose titration within each drug class, discontinuation and first HHF or death. Dose/discontinuation follow-up was assessed daily based on the coverage length of a filled prescription and reported on day 365. New users of ACEi (n = 8426), ARB (n = 2303), beta-blockers (n = 10 476), MRA (n = 17 421), and ARNI (n = 29 546) were identified. Over 12 months, target dose achievement was 15%, 10%, 12%, 30%, and discontinuation was 55%, 33%, 24% and 27% for ACEi, ARB, beta-blockers and ARNI, respectively. MRA was rarely titrated and discontinuation rates were high (40%). Event rates for HHF or death ranged from 40.0-86.9 per 100 patient-years across the treatment groups.
Conclusion
Despite high risk of clinical events following HHF, new initiation of GDMT was followed by consistent patterns of low up-titration and early GDMT discontinuation in three countries with different health care and economies. Our data highlight the urgent need for moving away from long sequential approach when initiating HF treatment and for improving just-in-time decision support for patients and health care providers.

© 2021 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 Aug 2021; 23:1499-1511
Savarese G, Bodegard J, Norhammar A, Sartipy P, ... Vaduganathan M, Coats AJS
Eur J Heart Fail: 30 Aug 2021; 23:1499-1511 | PMID: 34132001
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Impact:
Abstract

Antigen carbohydrate 125 as a biomarker in heart failure: a narrative review.

Núñez J, de la Espriella R, Miñana G, Santas E, ... Lupón J, Bayés-Genís A
Congestion explains many of the signs and symptoms of acute heart failure (AHF) and disease progression. However, accurate quantification of congestion is challenging in daily practice. Antigen carbohydrate 125 (CA125) or mucin 16 (MUC16), a large glycoprotein synthesized by mesothelial cells, has emerged as a reliable proxy of congestion and inflammation in patients with heart failure (HF). In AHF syndromes, CA125 is strongly associated with right-sided HF parameters and a higher risk of adverse clinical events beyond standard prognostic factors, including natriuretic peptides. Furthermore, CA125 has the potential for both monitoring and guide HF treatment following a decompensated HF event. The wide availability of CA125 in most clinical laboratories, together with its standardized measurement and reduced cost, makes this marker attractive for routine use in decompensated HF. Further research is required to understand better its biological role and its promising utility as a tool to guide decongestive therapy in HF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Aug 2021; 23:1445-1457
Núñez J, de la Espriella R, Miñana G, Santas E, ... Lupón J, Bayés-Genís A
Eur J Heart Fail: 30 Aug 2021; 23:1445-1457 | PMID: 34241936
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Impact:
Abstract

The ergoreflex: how the skeletal muscle modulates ventilation and cardiovascular function in health and disease.

Aimo A, Saccaro LF, Borrelli C, Fabiani I, ... Coats AJS, Giannoni A
The control of ventilation and cardiovascular function during physical activity is partially regulated by the ergoreflex, a cardiorespiratory reflex activated by physical activity. Two components of the ergoreflex have been identified: the mechanoreflex, which is activated early by muscle contraction and tendon stretch, and the metaboreflex, which responds to the accumulation of metabolites in the exercising muscles. Patients with heart failure (HF) often develop a skeletal myopathy with varying degrees of severity, from a subclinical disease to cardiac cachexia. HF-related myopathy has been associated with increased ergoreflex sensitivity, which is believed to contribute to dyspnoea on effort, fatigue and sympatho-vagal imbalance, which are hallmarks of HF. Ergoreflex sensitivity increases significantly also in patients with neuromuscular disorders. Exercise training is a valuable therapeutic option for both HF and neuromuscular disorders to blunt ergoreflex sensitivity, restore the sympatho-vagal balance, and increase tolerance to physical exercise. A deeper knowledge of the mechanisms mediating ergoreflex sensitivity might enable a drug or device modulation of this reflex when patients cannot exercise because of advanced skeletal myopathy.

© 2021 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 Aug 2021; 23:1458-1467
Aimo A, Saccaro LF, Borrelli C, Fabiani I, ... Coats AJS, Giannoni A
Eur J Heart Fail: 30 Aug 2021; 23:1458-1467 | PMID: 34268843
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Impact:
Abstract

Effect of patient-centered transitional care services on patient-reported outcomes in heart failure: sex-specific analysis of the PACT-HF randomized controlled trial.

Blumer V, Gayowsky A, Xie F, Greene SJ, ... Zannad F, Van Spall HGC
Aims
We assessed the effect of transitional care on patient-reported outcomes (PROs) in women and men hospitalized for heart failure.
Methods and results
In this sex-specific analysis of a stepped wedge cluster randomized trial in Canada, the effect of a patient-centered transitional care model was tested on pre-specified PROs of discharge preparedness (B-PREPARED score, range 0-22), quality of transition [Care Transitions Measure-3 (CTM-3) score, range 0-100], and health-related quality of life (HRQOL) (EQ-5D-5L, range 0-1). Among 986 patients (47.4% women), B-PREPARED at 6 weeks was greater with the intervention than usual care [mean difference (MD) 4.01 (95% confidence interval-CI 2.90-5.12); P < 0.001], with no sex differences (P sex-interaction = 0.24). CTM-3 at 6 weeks was greater with the intervention than usual care [MD 10.52 (95% CI 6.00-15.04); P < 0.001], with no sex differences (P sex-interaction = 0.69). EQ-5D-5L was greater with intervention than usual care at discharge [MD 0.17 (95% CI 0.12-0.22); P < 0.001], 6 weeks [MD 0.06 (95% CI 0.01-0.12); P = 0.02], and 6 months [MD 0.05 (95% CI -0.01 to 0.12); P = 0.09], although the 6-month difference was not statistically significant. At discharge, women reported lower EQ-5D-5L but experienced significantly greater treatment benefit than men (P sex-interaction = 0.02). Treatment effect on EQ-5D-5L was numerically greater in women than men at 6 weeks and 6 months, but there were no significant sex differences (P sex-interaction 0.18 and 0.19, respectively).
Conclusion
A patient-centered transitional care model improved discharge preparedness, transition quality, and HRQOL in the weeks following heart failure hospitalization, with effects largely consistent in women and men. However, women reported lower HRQOL and experienced greater treatment benefit in this endpoint than men at hospital discharge.
Clinical trial registration
ClinicalTrials.gov NCT02112227.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Aug 2021; 23:1488-1498
Blumer V, Gayowsky A, Xie F, Greene SJ, ... Zannad F, Van Spall HGC
Eur J Heart Fail: 30 Aug 2021; 23:1488-1498 | PMID: 34302417
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Impact:
Abstract

Impact of epicardial adipose tissue on cardiovascular haemodynamics, metabolic profile, and prognosis in heart failure.

Pugliese NR, Paneni F, Mazzola M, De Biase N, ... Ruschitzka F, Masi S
Aims
We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary-echocardiography exercise stress.
Methods and results
We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C-reactive protein in HFrEF, while having a direct association with troponin T and C-reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO2 ) and peripheral extraction (AVO2 diff), regardless of body mass index. EAT was inversely correlated with peak VO2 and AVO2 diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow-up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54-0.91).
Conclusion
In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 22 Aug 2021; epub ahead of print
Pugliese NR, Paneni F, Mazzola M, De Biase N, ... Ruschitzka F, Masi S
Eur J Heart Fail: 22 Aug 2021; epub ahead of print | PMID: 34427016
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Abstract

Association of COVID-19 with impaired endothelial glycocalyx, vascular function and myocardial deformation 4 months after infection.

Lambadiari V, Mitrakou A, Kountouri A, Thymis J, ... Dimopoulos MA, Ikonomidis I
Aims
SARS-CoV-2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers 4 months after COVID-19 infection.
Methods and results
In a case-control prospective study, we included 70 patients 4 months after COVID-19 infection, 70 age- and sex-matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow-mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV), (v) global left and right ventricular longitudinal strain (GLS), and (vi) malondialdehyde (MDA), an oxidative stress marker, thrombomodulin and von Willebrand factor as endothelial biomarkers. COVID-19 patients had similar CFR and FMD as hypertensives (2.48 ± 0.41 vs. 2.58 ± 0.88, P = 0.562, and 5.86 ± 2.82% vs. 5.80 ± 2.07%, P = 0.872, respectively) but lower values than controls (3.42 ± 0.65, P = 0.0135, and 9.06 ± 2.11%, P = 0.002, respectively). Compared to controls, both COVID-19 and hypertensives had greater PBR5-25 (2.07 ± 0.15 µm and 2.07 ± 0.26 µm, P = 0.8 vs. 1.89 ± 0.17 µm, P = 0.001), higher PWV (carotid-femoral PWV 12.09 ± 2.50 vs. 11.92 ± 2.94, P = 0.7 vs. 10.04 ± 1.80 m/s, P = 0.036) and impaired left and right ventricular GLS (-19.50 ± 2.56% vs. -19.23 ± 2.67%, P = 0.864 vs. -21.98 ± 1.51%, P = 0.020 and -16.99 ± 3.17% vs. -18.63 ± 3.20%, P = 0.002 vs. -20.51 ± 2.28%, P < 0.001). MDA and thrombomodulin were higher in COVID-19 patients than both hypertensives and controls (10.67 ± 0.32 vs 1.76 ± 0.03, P = 0.003 vs. 1.01 ± 0.05 nmol/L, P = 0.001 and 3716.63 ± 188.36 vs. 3114.46 ± 179.18 pg/mL, P = 0.017 vs. 2590.02 ± 156.51 pg/mL, P < 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress and endothelial dysfunction markers.
Conclusions
SARS-CoV-2 may cause endothelial and vascular dysfunction linked to impaired cardiac performance 4 months after infection.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 19 Aug 2021; epub ahead of print
Lambadiari V, Mitrakou A, Kountouri A, Thymis J, ... Dimopoulos MA, Ikonomidis I
Eur J Heart Fail: 19 Aug 2021; epub ahead of print | PMID: 34415085
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Abstract

Guidance on the management of left ventricular assist device (LVAD) supported patients for the non-LVAD specialist healthcare provider: executive summary.

Ben Gal T, Ben Avraham B, Milicic D, Crespo-Leiro MG, ... Jaarsma T, Gustafsson F
The accepted use of left ventricular assist device (LVAD) technology as a good alternative for the treatment of patients with advanced heart failure together with the improved survival of patients on the device and the scarcity of donor hearts has significantly increased the population of LVAD supported patients. Device-related, and patient-device interaction complications impose a significant burden on the medical system exceeding the capacity of LVAD implanting centres. The probability of an LVAD supported patient presenting with medical emergency to a local ambulance team, emergency department medical team and internal or surgical wards in a non-LVAD implanting centre is increasing. The purpose of this paper is to supply the immediate tools needed by the non-LVAD specialized physician - ambulance clinicians, emergency ward physicians, general cardiologists, and internists - to comply with the medical needs of this fast-growing population of LVAD supported patients. The different issues discussed will follow the patient\'s pathway from the ambulance to the emergency department, and from the emergency department to the internal or surgical wards and eventually back to the general practitioner.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 17 Aug 2021; epub ahead of print
Ben Gal T, Ben Avraham B, Milicic D, Crespo-Leiro MG, ... Jaarsma T, Gustafsson F
Eur J Heart Fail: 17 Aug 2021; epub ahead of print | PMID: 34409711
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Abstract

Two-year outcomes from the MitrAl ValvE RepaIr Clinical (MAVERIC) trial: a novel percutaneous treatment of functional mitral regurgitation.

Patterson T, Gregson J, Erglis A, Joseph J, ... Horrigan M, Redwood SR
Aims
We report the 2-year outcomes of the MitrAl ValvE RepaIr Clinical (MAVERIC) trial. Functional mitral regurgitation (FMR) is associated with poor outcomes for which there remains an unmet clinical need. ARTO is a transcatheter annular reduction device for the treatment of FMR and an emerging alternative for patients at high surgical risk. The MAVERIC trial was designed to evaluate the safety and performance of the ARTO system in FMR and heart failure (HF).
Methods and results
MAVERIC is an international multicentre, prospective, single arm study enrolling patients with FMR grade ≥ 2, New York Heart Association (NYHA) class ≥II symptoms despite maximal medical therapy. Patients were excluded if they had significant structural mitral valve abnormality or life expectancy <1 year. The primary outcome measures were a composite safety outcome and efficacy defined as mitral regurgitation (MR) reduction 30 days post-procedure. Secondary outcome measures included safety, change in MR grade, NYHA class and hospitalization for HF at 2 years. Forty-five patients were enrolled. The composite safety outcome was met (2/45 adverse events at 30 days) and no device-related deaths occurred at 2-year follow-up. A sustained reduction in MR [grade < 2: 21/31 (68%) vs. 31/31(0%); P < 0.0001], left ventricular end-diastolic volume index (90.0 ± 30 vs. 106 ± 26 mL/m2 ; P = 0.004) and anteroposterior diameter (35.5 ± 4.7 vs. 41.4 ± 4.6 mm; P < 0.0001) was seen at 2 years compared to baseline. Progressive symptomatic improvement [NYHA class ≤II: 27/34 (80%) vs. 12/34 (36%); P < 0.0001] and a reduction in HF hospitalizations (19.8% 2 years post vs. 52.3% 2 years prior; P < 0.001) were seen at 2 years compared to baseline.
Conclusions
The ARTO system is a safe and effective treatment for FMR with reductions in left ventricular end-diastolic volumes sustained to 2 years.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 05 Aug 2021; epub ahead of print
Patterson T, Gregson J, Erglis A, Joseph J, ... Horrigan M, Redwood SR
Eur J Heart Fail: 05 Aug 2021; epub ahead of print | PMID: 34363280
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Abstract

Layer-specific global longitudinal strain and the risk of heart failure and cardiovascular mortality in the general population: the Copenhagen City Heart Study.

Skaarup KG, Lassen MCH, Johansen ND, Sengeløv M, ... Møgelvang R, Biering-Sørensen T
Aims
Layer-specific global longitudinal strain (GLS) has been demonstrated to predict outcome in various patient cohorts. However, little is known regarding the prognostic value of layer-specific GLS in the general population and whether different layers entail differential prognostic information. The aim of the present study was to investigate the prognostic value of whole wall (GLSWW ), endomyocardial (GLSEndo ), and epimyocardial (GLSEpi ) GLS in the general population.
Methods and results
A total of 4013 citizens were included in the present study. All 4013 had two-dimensional speckle tracking echocardiography performed and analysed. Outcome was a composite endpoint of incident heart failure and/or cardiovascular death. Mean age was 56 years and 57% were female. During a median follow-up time of 3.5 years, 133 participants (3.3%) reached the composite outcome. Sex modified the relationship between all GLS parameters and outcome. In sex-stratified analysis, no GLS parameter remained significant predictors of outcome in females. In contrast, GLSWW [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.02-1.31, per 1% decrease] and GLSEpi (HR 1.19, 95% CI 1.04-1.38, per 1% decrease) remained as significant predictors of outcome in males after multivariable adjustment (including demographic, clinical, biochemistry, and echocardiographic parameters). Lastly, only in males did GLS parameters provide incremental prognostic information to general population risk models.
Conclusions
In the general population, sex modifies the prognostic value of GLS resulting in GLSEpi being the only layer-specific prognosticator in males, while no GLS parameter provides independent prognostic information in females.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 28 Jul 2021; epub ahead of print
Skaarup KG, Lassen MCH, Johansen ND, Sengeløv M, ... Møgelvang R, Biering-Sørensen T
Eur J Heart Fail: 28 Jul 2021; epub ahead of print | PMID: 34327782
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Abstract

Impact on clinical outcomes of right ventricular response to percutaneous correction of secondary mitral regurgitation.

Caiffa T, De Luca A, Biagini E, Lupi L, ... Stolfo D, Sinagra G
Aims
In patients with heart failure and reduced ejection fraction (HFrEF) and secondary mitral regurgitation (SMR), impaired right ventricular function (RVF) may negatively influence the prognosis. Percutaneous mitral valve repair (pMVR) can promote the recovery of RVF. We sought to characterize the response of the right ventricle to pMVR in HFrEF with SMR and to assess the association between improved RVF after pMVR and outcomes.
Methods and results
Overall, 221 patients with HFrEF and SMR ≥3+ successfully treated with pMVR in four tertiary care centres for heart failure were included. Improved RVF was defined as Δ right ventricular fractional area change (ΔRVFAC) ≥5% at early follow-up (median time 4 months). The primary endpoint was a composite of death/heart transplantation (D/HT). Mean age was 69 ± 11 years, mean left ventricular ejection fraction was 31 ± 8% and mean RVFAC was 34 ± 9%. ΔRVFAC ≥5% occurred in 88 patients (40%) and was independent of the measures of left ventricular reverse remodelling. During a median follow-up of 29 months (interquartile range 12-46), 81 patients (37%) reached the primary endpoint. After adjustment for other significant covariates, ΔRVFAC ≥5% was significantly associated with lower risk of D/HT (hazard ratio 0.52, 95% confidence interval 0.29-0.94, P = 0.030). In the secondary outcome analysis exploring the risk of heart failure hospitalizations, ΔRVFAC ≥5% confirmed the prognostic association with the endpoint.
Conclusions
In patients with HFrEF and SMR, about 40% of patients improved RVF after pMVR. RVF improvement was associated with better long-term survival free from HT and lower risk of heart failure hospitalization.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 27 Jul 2021; epub ahead of print
Caiffa T, De Luca A, Biagini E, Lupi L, ... Stolfo D, Sinagra G
Eur J Heart Fail: 27 Jul 2021; epub ahead of print | PMID: 34318980
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Impact:

This program is still in alpha version.