Journal: Eur J Heart Fail

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Abstract

Urinary peptides in heart failure: a link to molecular pathophysiology.

He T, Mischak M, Clark AL, Campbell RT, ... Staessen JA, Latosinska A
Aims
Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology.
Methods and results
Analysable data from 5,608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (p<0.0001). No separation based on HF subtype was detectable.
Conclusions
HF, irrespective of ejection fraction subtype, was associated with differences in abundance of urinary peptides reflecting collagen turnover and inflammation. These peptides should be studied as tools in early detection, prognostication, and prediction of therapeutic response.

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Eur J Heart Fail: 20 Apr 2021; epub ahead of print
He T, Mischak M, Clark AL, Campbell RT, ... Staessen JA, Latosinska A
Eur J Heart Fail: 20 Apr 2021; epub ahead of print | PMID: 33881206
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Abstract

Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): Design and Baseline Characteristics.

Jering KS, Claggett B, Pfeffer MA, Granger C, ... Nicolau JC, Braunwald E
Aims
Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven ACE inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial.
Methods and results
PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7 days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or LVEF ≤ 40% and at least one additional factor augmenting risk of HF or death (age ≥70 years, eGFR <60ml/min/1.73m2 , diabetes, prior MI, atrial fibrillation, LVEF <30%, Killip class ≥III, STEMI without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints [cardiovascular (CV) death, HF hospitalization or outpatient development of HF]. Randomization of 5669 patients occurred 4.3 ± 1.8 days from presentation with index AMI. The mean age was 64 ± 12 years, 24% were women. The majority (76%) qualified with ST-segment elevation MI; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ± 9% and 58% were Killip class ≥2.
Conclusions
Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and CV death following AMI.

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Eur J Heart Fail: 11 Apr 2021; epub ahead of print
Jering KS, Claggett B, Pfeffer MA, Granger C, ... Nicolau JC, Braunwald E
Eur J Heart Fail: 11 Apr 2021; epub ahead of print | PMID: 33847047
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Abstract

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

© European Society of Cardiology 2021.

Eur J Heart Fail: 06 Apr 2021; epub ahead of print
Garcia-Pavia P, Rapezzi C, Adler Y, Arad M, ... Rigopoulos AG, Linhart A
Eur J Heart Fail: 06 Apr 2021; epub ahead of print | PMID: 33826207
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Abstract

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial.

Bolli R, Mitrani RD, Hare JM, Pepine CJ, ... Simari RD, Cardiovascular Cell Therapy Research Network (CCTRN)
Aims
CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy.
Methods and results
Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups.
Conclusions
This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 02 Apr 2021; epub ahead of print
Bolli R, Mitrani RD, Hare JM, Pepine CJ, ... Simari RD, Cardiovascular Cell Therapy Research Network (CCTRN)
Eur J Heart Fail: 02 Apr 2021; epub ahead of print | PMID: 33811444
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Abstract

Decongestion Discriminates Risk for One Year Mortality in Patients with Improving Renal Function in Acute Heart Failure.

Wettersten N, Horiuchi Y, van Veldhuisen DJ, Ix JH, ... Maisel A, Murray PT
Aims
Improving renal function (IRF) is paradoxically associated with worse outcomes in acute heart failure (AHF), but outcomes may differ based on response to decongestion. We explored if the relationship of IRF with mortality in hospitalized AHF patients differs based on successful decongestion.
Methods and results
We evaluated 760 AHF patients from AKINESIS for the relationship between IRF, change in B-type natriuretic peptide (BNP), and one-year mortality. IRF was defined as a ≥20% increase in estimated glomerular filtration rate (eGFR) relative to admission. Adequate decongestion was defined as a ≥40% decrease in last measured BNP relative to admission. IRF occurred in 22% of patients who had a mean age of 69 years, 58% men, 72% were white, and median admission eGFR was 49 ml/min/1.73m2 . IRF patients had more severe HF reflected by lower admission eGFR, higher BUN, lower systolic blood pressure, lower sodium, and higher use of inotropes. IRF patients had higher one-year mortality (25%) than non-IRF patients (15%) (p<0.01). However, this relationship differed by BNP trajectory (p-interaction = 0.03). When stratified by BNP change, non-IRF patients and IRF patients with decreasing BNP had lower one-year mortality than either non-IRF and IRF patients without decreasing BNP. However, in multivariate analysis, IRF was not associated with mortality (adjusted hazard ratio [HR]=1.0, 95% confidence interval [CI] 0.7-1.5) while BNP was (adjusted HR=0.5, 95% CI 0.3-0.7). When IRF was evaluated as transiently occurring or persisting at discharge, again only BNP change was significantly associated with mortality.
Conclusion
IRF is associated with mortality in AHF but not independent of other variables and congestion status. Achieving adequate decongestion, as reflected by lower BNP, in AHF is more strongly associated with mortality than improving kidney function.

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Eur J Heart Fail: 30 Mar 2021; epub ahead of print
Wettersten N, Horiuchi Y, van Veldhuisen DJ, Ix JH, ... Maisel A, Murray PT
Eur J Heart Fail: 30 Mar 2021; epub ahead of print | PMID: 33788989
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Abstract

Cognitive Impairment as a Determinant of Response to Management Plans After Heart Failure Admission.

Huynh QL, Whitmore K, Negishi K, DePasquale CG, ... Stanton T, Marwick TH
Aims
Cognitive impairment (CI) is highly prevalent in heart failure (HF), and increases patients\' risks of readmission. This study sought to determine whether the presence and degree of CI could identify patients most likely to benefit from a HF disease management program (DMP) to reduce readmissions.
Methods and results
1152 consecutive Australian patients admitted with HF (2014-17) were prospectively followed-up for 12 months. Of these, 324 patients who received DMP (1-month duration, including post-discharge home visits, medication reconciliation, exercise guidance and early clinical review) were matched (1:2 ratio) with 648 usual care patients. Cognitive function was assessed either on the day of or one day before discharge using the Montreal Cognitive Assessment (MoCA). Outcomes included readmission or death at 1-, 3- and 12-months, and days-at-home within 12 months, from discharge. Poorer cognitive function was associated with all adverse outcomes. Compared with usual care, DMP was associated with lower odds of 30-day (OR=0.60 [0.40, 0.91]) and 90-day (OR=0.53 [0.36, 0.77]) readmission or death, and with 19 more days-at-home within 12 months, independent of HF therapy. The effect sizes of these associations were greater for patients with diminished cognition than those with normal cognition (interaction p=0.036), and might have been more pronounced among those with mild CI compared with those with more severe CI (MoCA score 17-22, OR=0.42 [0.21, 0.87] at 30-day, OR=0.31 [0.16, 0.60] at 90-day). Patients with normal cognition had fewer events, irrespective of DMP.
Conclusions
Cognitive function may determine how HF patients respond to a DMP. Cognitive screening before implementation of a DMP may allow personalized plans for patients with different levels of cognitive function.

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Eur J Heart Fail: 30 Mar 2021; epub ahead of print
Huynh QL, Whitmore K, Negishi K, DePasquale CG, ... Stanton T, Marwick TH
Eur J Heart Fail: 30 Mar 2021; epub ahead of print | PMID: 33788985
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Abstract

Identification of Distinct Phenotypic Clusters in Heart Failure with Preserved Ejection Fraction.

Uijl A, Savarese G, Vaartjes I, Dahlström U, ... Hoes AW, Koudstaal S
Aims
We aimed to derive and validate clinically useful clusters of patients with heart failure with preserved ejection fraction (HFpEF; left ventricular ejection fraction ≥50%).
Methods and results
We derived a cluster model from 6909 HFpEF patients from the Swedish Heart Failure Registry (SwedeHF) and externally validated this in 2153 patients from the Chronic Heart Failure ESC-guideline based Cardiology Practice Quality project (CHECK-HF) registry. In SwedeHF, the median age was 80 [interquartile range 72-86] years, 52% of patients were female and most frequent comorbidities were hypertension (82%), atrial fibrillation (68%), and ischaemic heart disease (48%). Latent class analysis identified five distinct clusters: Cluster 1 (10% of patients) were young patients with a low comorbidity burden and the highest proportion implantable devices, cluster 2 (30%) patients had atrial fibrillation, hypertension without diabetes, cluster 3 (25%) patients were the oldest with many cardiovascular comorbidities and hypertension, cluster 4 (15%) patients had obesity, diabetes and hypertension, and cluster 5 (20%) patients were older with ischaemic heart disease, hypertension and renal failure and were most frequently prescribed diuretics. The clusters were reproduced in the CHECK-HF cohort. Patients in cluster 1 had the best prognosis, while patients in cluster 3 and 5 had the worst age- and sex adjusted prognosis.
Conclusions
Five distinct clusters of HFpEF patients were identified that differed in clinical characteristics, HF drug therapy and prognosis. These results confirm the heterogeneity of HFpEF and form a basis for tailoring trial design to individualised drug therapy in HFpEF patients. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 28 Mar 2021; epub ahead of print
Uijl A, Savarese G, Vaartjes I, Dahlström U, ... Hoes AW, Koudstaal S
Eur J Heart Fail: 28 Mar 2021; epub ahead of print | PMID: 33779119
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Abstract

Virtual Optimization of Guideline-Directed Medical Therapy in Hospitalized Patients with Heart Failure with Reduced Ejection Fraction: the IMPLEMENT-HF Pilot Study.

Bhatt AS, Varshney AS, Nekoui M, Moscone A, ... Adler DS, Vaduganathan M
Aims
HFrEF GDMT implementation remains incomplete. Non-cardiovascular hospitalization may present opportunities for GDMT optimization. We assessed the efficacy and durability of a virtual, multidisciplinary \"GDMT Team\" on medical therapy prescription for HFrEF.
Methods and results
Consecutive hospitalizations in patients with HFrEF≤40% were prospectively identified from February 3 to March 1, 2020 (usual care group) and March 2 to August 28, 2020 (intervention group). Patients with critical illness, de-novo HF, and SBP<90mmHg were excluded. In the intervention group, a pharmacist-physician GDMT Team provided optimization suggestions to treating teams based on an evidence-based algorithm. The primary outcome was a GDMT optimization score, the net of positive (+1 for new initiations or up-titrations) & negative therapeutic changes (-1 for discontinuations or down-titrations) at hospital discharge. Serious in-hospital safety events were assessed. Among 278 consecutive encounters with HFrEF, 118 met eligibility criteria; 29 (25%) received usual care and 89 (75%) received the GDMT Team intervention. Among usual care encounters, there were no changes in GDMT prescription during hospitalization. In the intervention group, β-blocker (72% to 88%; P=0.01), ARNI (6% to 17%; P=0.03), MRA (16% to 29%; P=0.05), and triple therapy (9% to 26%; P<0.01) prescriptions increased during hospitalization. After adjustment, the GDMT Team was associated with an increase in GDMT optimization score (+0.58; 95% CI: +0.09 to +1.07; P=0.02). There were no serious in-hospital adverse events.
Conclusions
Non-cardiovascular hospitalizations are a potentially safe and effective setting for GDMT optimization. A virtual GDMT Team was associated with improved HF therapeutic optimization. This implementation strategy warrants testing in a prospective randomized controlled trial. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 25 Mar 2021; epub ahead of print
Bhatt AS, Varshney AS, Nekoui M, Moscone A, ... Adler DS, Vaduganathan M
Eur J Heart Fail: 25 Mar 2021; epub ahead of print | PMID: 33768599
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Abstract

Change in Ejection Fraction and Long-Term Mortality in Adults Referred for Echocardiography.

Strange G, Playford D, Scalia GM, Celermajer DS, ... Stewart S, NEDA Investigators
Aims
We investigated long-term mortality associated with changes in left ventricular ejection fraction (LVEF) in a large, real-world patient cohort.
Methods and results
117 275 adults (46% women, 63 ± 16 years) had LVEF quantified by the same method ≥6 months apart. This included 17 343 cases (48% women, 66 ± 15 years) being initially investigated for heart failure (HF). During 3.3 (IQR 1.7 to 6.0) years from first-to-last echocardiogram, median change in LVEF was -1 (IQR -8 to +5) units from a baseline of 62% (IQR 54% to 69%). During subsequent 7.6 (IQR 4.3 to 10.1) years follow-up, 11 397 (9.7%) and 34 101 (29.1%) cases died from cardiovascular disease and all-causes, respectively. Actual 5-year, all-cause mortality increased from 12% to 29% among those with the smallest to the largest decrease in LVEF (from <5 units to >50 units); the adjusted risk of cardiovascular-related mortality increased 2- to 8-fold beyond a > 10-unit decline in LVEF (versus minimal change; p < 0.001 all comparisons). Among those initially investigated for HF (32% with initial LVEF <50%), the adjusted hazard ratio for cardiovascular-related mortality ranged from 0.35 (95% CI 0.28-0.49) to 4.21 (95% CI 3.30-5.22) for a > 30-unit increase to >30-unit decline in LVEF (versus minimal change; p < 0.001 for both comparisons). A distinctive, bi-directional plateau of improved versus worsening mortality was evident around a final LVEF of 50% to 55%.
Conclusions
These data, derived from a large, heterogeneous cohort of adults being followed-up with echocardiography, suggest that modest LVEF changes (particularly around an LVEF of 50% to 55%) may be of clinical significance. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 24 Mar 2021; epub ahead of print
Strange G, Playford D, Scalia GM, Celermajer DS, ... Stewart S, NEDA Investigators
Eur J Heart Fail: 24 Mar 2021; epub ahead of print | PMID: 33768605
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Abstract

Center procedural volume and adverse in-hospital outcomes for patients undergoing percutaneous transvenous edge-to-edge mitral valve repair using MitraClip® technique in Germany.

Keller K, Hobohm L, Schmidtmann I, Münzel T, Baldus S, von Bardeleben RS
Aims
The number of transcatheter mitral valve repairs increased substantially during last years. A better understanding of the relationship between hospital volume of transcatheter transvenous mitral valve repairs using MitraClip® (TMVr) and patient outcomes may provide information for future policy decisions to improve patients´ management.
Methods and results
We analysed patients\' characteristics and in-hospital outcomes for all TMVr using MitraClip® performed in Germany 2011-2017. Hospitals were stratified regarding center volumes and patients were compared for baseline characteristics and adverse in-hospital events. Overall, 24,709 in-patients were treated during the observation period. Patients treated in centers with ≤10 procedures annually developed more often pulmonary embolism (OR 2.22 [95%CI 1.19-4.13], P=0.012) compared to those treated in centers with >10 procedures annually, whereas no association of center volume (≤10 or >10) was found with in-hospital mortality (P=0.728). Although patients treated in centers with TMVr volume >25 annually had higher numbers of comorbidities compared to those in centers ≤25 procedures, in-hospital mortality did not differ (3.6% vs. 3.5%, P=0.485). Similarly, when center volumes were stratified for ≤50 vs. >50 procedural volumes, these were not associated with in-hospital mortality (P=0.792). A decreasing number of mitral valve surgical interventions after MitraClip® was observed over time particularly in high-volume centers.
Conclusion
Annual numbers of MitraClip® implantations increased from 2011 to 2017 in Germany, whereas in-hospital mortality remained stable. Although patients treated by high-volume centers had a more unfavorable risk-profile, in-hospital mortality is comparable.

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Eur J Heart Fail: 22 Mar 2021; epub ahead of print
Keller K, Hobohm L, Schmidtmann I, Münzel T, Baldus S, von Bardeleben RS
Eur J Heart Fail: 22 Mar 2021; epub ahead of print | PMID: 33759319
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Abstract

Italian Society of Interventional Cardiology (GIse) registry Of Transcatheter treatment of mitral valve regurgitaTiOn (GIOTTO): impact of valve disease aetiology and residual mitral regurgitation after MitraClip implantation.

Bedogni F, Popolo Rubbio A, Grasso C, Adamo M, ... Testa L, Tamburino C
Aims
The Italian Society of Interventional Cardiology (GIse) registry Of Transcatheter treatment of mitral valve regurgitaTiOn (GIOTTO) was conceived in order to assess the safety and efficacy of MitraClip therapy in Italy. The aim of this study was to assess procedural and mid-term outcomes, and clinical and echocardiographic predictors of mid-term mortality after MitraClip therapy, stratifying the results according to the diagnosis of functional and degenerative mitral regurgitation (FMR vs. DMR).
Methods and results
Between January 2016 and March 2020, 1659 patients were prospectively included in the GIOTTO registry (FMR 59.4% vs. DMR 40.6%). Acute Mitral Valve Academic Research Consortium (MVARC) technical success was achieved in 97.2% of patients, without differences between FMR and DMR and with sustained results at 30 days. In the study population, all-cause mortality was 4.0%, 17.5% and 34.6% at 30 days, 1 year and 2 years, respectively. Cardiovascular death was the most frequent cause of mortality. Overall hospitalization rates were 6.3%, 23.4% and 31.7% at 30 days, 1 year and 2 years, respectively. The most frequent cause of hospitalization was heart failure, particularly in the first 30 days. FMR and MVARC structural and functional failure were strongly associated with 1-year mortality. Residual mitral regurgitation 1+ (rMR) was independently related to a reduced risk of 1-year mortality (hazard ratio 0.62; P = 0.005). Coherently, at 2-year follow up, FMR was associated with worse outcomes than DMR, and Kaplan-Meier all-cause mortality was related to rMR.
Conclusions
Functional mitral regurgitation aetiology affects 1-year mortality after MitraClip implantation, and differences in mortality and hospitalization rates between FMR and DMR can be observed within 2 years. Optimal rMR 1+ was correlated to a more favourable mid-term outcome, particularly in FMR.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 19 Mar 2021; epub ahead of print
Bedogni F, Popolo Rubbio A, Grasso C, Adamo M, ... Testa L, Tamburino C
Eur J Heart Fail: 19 Mar 2021; epub ahead of print | PMID: 33742754
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Abstract

Dipeptidyl peptidase 3, a marker of the antagonist pathway of the renin-angiotensin-aldosterone system in patients with heart failure.

Boorsma EM, Ter Maaten JM, Damman K, van Veldhuisen DJ, ... Santos K, Voors AA
Aims
Recently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1-7) [Ang (1-7)]. Ang (1-7) is part of the angiotensin-converting enzyme-Ang (1-7)-Mas pathway which is considered to antagonize the renin-angiotensin-aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.
Methods and results
Dipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3-LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3-227.7) vs. 120.7 IU/mL (IQR 34.74-338.9), P < 0.001, for Q1-3 vs. Q4] and aldosterone [88 (IQR 44-179) vs. 116 IU/mL (IQR 46-241), P < 0.001, for Q1-3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log-alanine aminotransferase, log-total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor-23 and N-terminal pro-B-type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.
Conclusions
In patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.

© 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: 19 Mar 2021; epub ahead of print
Boorsma EM, Ter Maaten JM, Damman K, van Veldhuisen DJ, ... Santos K, Voors AA
Eur J Heart Fail: 19 Mar 2021; epub ahead of print | PMID: 33742751
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Abstract

A machine learning risk score predicts mortality across the spectrum of left ventricular ejection fraction.

Greenberg B, Adler E, Campagnari C, Yagil A
Aims
Heart failure (HF) guideline recommendations categorize patients according to left ventricular ejection (LVEF). Mortality risk, however, varies considerably within each category and the likelihood of death in an individual patient is often uncertain. Accurate assessment of mortality risk is an important component in the decision-making process for many therapies. In this report, we assess the accuracy of MARKER-HF, a recently described machine learning-based risk score, in predicting mortality of patients in the three guideline-defined HF categories and its ability to distinguish risk of death for patients within each category.
Methods and results
MARKER-HF was used to calculate mortality risk in a hospital-based cohort of 4064 patients categorized into groups with reduced, mid-range, or preserved LVEF. MARKER-HF was substantially more accurate than LVEF in predicting mortality and was highly accurate in all three HF categories, with c-statistics ranging between 0.83 to 0.89. Moreover, MARKER-HF accurately discriminated between patients at high, intermediate and low levels of mortality risk within each of the three categories of HF used by guidelines.
Conclusions
MARKER-HF accurately predicts mortality in patients within the three categories of HF used in guidelines for management recommendations and it discriminates between magnitude of risk of patients in each category. MARKER-HF mortality risk prediction should be helpful to providers in making recommendations regarding the advisability of therapies designed to mitigate this risk, particularly when they are costly or associated with adverse events, and for patients and their families in making future plans.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 15 Mar 2021; epub ahead of print
Greenberg B, Adler E, Campagnari C, Yagil A
Eur J Heart Fail: 15 Mar 2021; epub ahead of print | PMID: 33724626
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Abstract

Quality of life in men and women with heart failure: association with outcome, and comparison of the Kansas City Cardiomyopathy Questionnaire and the EuroQol 5 dimensions questionnaire.

Ravera A, Santema BT, Sama IE, Meyer S, ... Metra M, Voors AA
Aims
We sought to analyse quality of life (QoL) measures derived from two questionnaires widely used in clinical trials, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5 dimensions (EQ-5D), and to compare their prognostic value in men and women with heart failure and reduced ejection fraction (HFrEF).
Methods and results
From the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) we compared KCCQ and EQ-5D at baseline and after nine months in 1276 men and 373 women with new-onset or worsening symptoms of HFrEF, who were sub-optimally treated and in whom there was an anticipated up-titration of guidelines-derived medical therapies. Women had significantly worse baseline QoL (median) as compared with men, both when assessed with KCCQ overall score (KCCQ-OS, 44 vs 53, p<0.001) and EQ-5D utility score (0.62 vs 0.73, p<0.001). QoL improved equally in women and men at follow-up. All summary measures of QoL were independently associated with all-cause mortality, with KCCQ-OS showing the most remarkable association with mortality up to one year compared to the EQ-5D scores (C-statistic 0.650 for KCCQ-OS vs 0.633 and 0.599 for EQ-5D US and EQ-5D VAS respectively). QoL was associated with all outcomes analysed, both in men and in women (all p for interaction with sex >0.2).
Conclusion
Amongst patients with HFrEF, women reported significantly worse QoL than men. QoL was independently associated with subsequent outcome, similarly in men and in women. The KCCQ in general, and KCCQ-OS in particular, showed the strongest independent association with outcome.

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Eur J Heart Fail: 15 Mar 2021; epub ahead of print
Ravera A, Santema BT, Sama IE, Meyer S, ... Metra M, Voors AA
Eur J Heart Fail: 15 Mar 2021; epub ahead of print | PMID: 33728762
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Impact:
Abstract

Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction.

Packer M, McMurray JJV
Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. However, the conventional approach to the implementation is based on a historically-driven sequence that is not strongly evidence-based, typically requires ≥6 months, and frequently lead to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2-4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease-of-use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over uptitration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated 3-step approach, which consists of the simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by the initiation of sacubitril/valsartan, and 1-2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be reordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence-based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.

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Eur J Heart Fail: 10 Mar 2021; epub ahead of print
Packer M, McMurray JJV
Eur J Heart Fail: 10 Mar 2021; epub ahead of print | PMID: 33704874
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Abstract

Determinants and consequences of heart rate and stroke volume response to exercise in patients with heart failure and preserved ejection fraction.

Wolsk E, Kaye DM, Komtebedde J, Shah SJ, ... Møller JE, Gustafsson F
Aims
A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO - heart rate and stroke volume - and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses.
Methods and results
Data from two prospective trials of HFpEF (n = 108) and a study of healthy participants (n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39-56% of patients with HFpEF and 3-56% of healthy participants depending on the definition used, but some (n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m2 , healthy participants: +24 ± 12 mL/m2 , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF.
Conclusion
The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 07 Mar 2021; epub ahead of print
Wolsk E, Kaye DM, Komtebedde J, Shah SJ, ... Møller JE, Gustafsson F
Eur J Heart Fail: 07 Mar 2021; epub ahead of print | PMID: 33686716
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Abstract

Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction.

Woolley RJ, Ceelen D, Ouwerkerk W, Tromp J, ... Lam CS, Voors AA
Aims
The lack of effective therapies for patients with heart failure with preserved ejection fraction (HFpEF) is often ascribed to the heterogeneity of patients with HFpEF. We aimed to identify distinct pathophysiologic clusters of HFpEF based on circulating biomarkers.
Methods and results
We performed an unsupervised cluster analysis using 363 biomarkers from 429 patients with HFpEF. Relative differences in expression profiles of the biomarkers between clusters were assessed and used for pathway over-representation analyses. We identified four distinct patient subgroups based on their biomarker profiles: cluster 1 with the highest prevalence of diabetes mellitus and renal disease; cluster 2 with oldest age and frequent age-related comorbidities; cluster 3 with youngest age, largest body size, least symptoms and lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels; and cluster 4 with highest prevalence of ischaemic aetiology, smoking and chronic lung disease, most symptoms, as well as highest NT-proBNP and troponin levels. Over a median follow-up of 21 months, the occurrence of death or heart failure hospitalization was highest in clusters 1 and 4 (62.1% and 62.8%, respectively) and lowest in cluster 3 (25.6%). Pathway over-representation analyses revealed that the biomarker profile of patients in cluster 1 was associated with activation of inflammatory pathways while the biomarker profile of patients in cluster 4 was specifically associated with pathways implicated in cell proliferation regulation and cell survival.
Conclusion
Unsupervised cluster analysis based on biomarker profiles identified mutually exclusive subgroups of patients with HFpEF with distinct biomarker profiles, clinical characteristics and outcomes, suggesting different underlying pathophysiological pathways.

© 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: 01 Mar 2021; epub ahead of print
Woolley RJ, Ceelen D, Ouwerkerk W, Tromp J, ... Lam CS, Voors AA
Eur J Heart Fail: 01 Mar 2021; epub ahead of print | PMID: 33651430
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Abstract

Diuretic response and effects of diuretic omission in ambulatory heart failure patients on chronic low-dose loop diuretic therapy.

Dauw J, Martens P, Tersalvi G, Schouteden J, ... Dupont M, Mullens W
Aims
To study loop diuretic response and effect of loop diuretic omission in ambulatory heart failure (HF) patients on chronic low-dose loop diuretics.
Methods and results
Urine collections were performed on two consecutive days in 40 ambulatory HF patients with 40-80 mg furosemide (day 1 with loop diuretic; day 2 without loop diuretic). Three phases were collected each day: (i) first 6 h; (ii) rest of the day; and (iii) night. On the day of loop diuretic intake, the total natriuresis was 125.9 (86.9-155.0) mmol/24 h and urine output was 1650 (1380-2025) mL/24 h. There was a clear loop diuretic response with a natriuresis of 9.4 (6.7-15.9) mmol/h and a urine output of 117 (83-167) mL/h during the first 6 h, followed by a significant drop in natriuresis and urine output during the rest of the day [2.6 (1.8-4.8) mmol/h and 55 (33-71) mL/h] and night [2.2 (1.6-3.5) mmol/h and 44 (34-73) mL/h]. On day 2, after loop diuretic omission, the natriuresis and urine output remained similarly low the entire day, resulting in a 50% reduction in natriuresis [55.1 (33.5-77.7) mmol/24 h; P < 0.001] and a 31% reduction in urine output [1035 (875-1425) mL/24 h; P < 0.001] compared with the day of loop diuretic intake.
Conclusion
Patients with HF on chronic loop diuretic treatment still have a clear diuretic response phase, while loop diuretic omission leads to a significant drop in natriuresis and urine output, arguing against routine cessation of low-dose loop diuretics.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 27 Feb 2021; epub ahead of print
Dauw J, Martens P, Tersalvi G, Schouteden J, ... Dupont M, Mullens W
Eur J Heart Fail: 27 Feb 2021; epub ahead of print | PMID: 33641220
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Abstract

The Heart Failure Association Atlas: Heart Failure Epidemiology and Management Statistics 2019.

Seferović PM, Vardas P, Jankowska EA, Maggioni AP, ... Coats AJS, National Heart Failure Societies of the ESC member countries (see Appendix)
Aims
The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) developed the HFA Atlas to provide a contemporary description of heart failure (HF) epidemiology, resources, reimbursement of guideline-directed medical therapy (GDMT) and activities of the National Heart Failure Societies (NHFS) in ESC member countries.
Methods and results
The HFA Atlas survey was conducted in 2018-2019 in 42 ESC countries. The quality and completeness of source data varied across countries. The median incidence of HF was 3.20 [interquartile range (IQR) 2.66-4.17] cases per 1000 person-years, ranging from ≤2 in Italy and Denmark to >6 in Germany. The median HF prevalence was 17.20 (IQR 14.30-21) cases per 1000 people, ranging from ≤12 in Greece and Spain to >30 in Lithuania and Germany. The median number of HF hospitalizations was 2671 (IQR 1771-4317) per million people annually, ranging from <1000 in Latvia and North Macedonia to >6000 in Romania, Germany and Norway. The median length of hospital stay for an admission with HF was 8.50 (IQR 7.38-10) days. Diagnostic and management resources for HF varied, with high-income ESC member countries having substantially more resources compared with middle-income countries. The median number of hospitals with dedicated HF centres was 1.16 (IQR 0.51-2.97) per million people, ranging from <0.10 in Russian Federation and Ukraine to >7 in Norway and Italy. Nearly all countries reported full or partial reimbursement of standard GDMT, except ivabradine and sacubitril/valsartan. Almost all countries reported having NHFS or working groups and nearly half had HF patient organizations.
Conclusions
The first report from the HFA Atlas has shown considerable heterogeneity in HF disease burden, the resources available for its management and data quality across ESC member countries. The findings emphasize the need for a systematic approach to the capture of HF statistics so that inequalities and improvements in care may be quantified and addressed.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 25 Feb 2021; epub ahead of print
Seferović PM, Vardas P, Jankowska EA, Maggioni AP, ... Coats AJS, National Heart Failure Societies of the ESC member countries (see Appendix)
Eur J Heart Fail: 25 Feb 2021; epub ahead of print | PMID: 33634931
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Abstract

Diagnostic scores predict morbidity and mortality in patients hospitalized for heart failure with preserved ejection fraction.

Verbrugge FH, Reddy YNV, Sorimachi H, Omote K, Carter RE, Borlaug BA
Aims
To investigate the prognostic value of diagnostic scores for heart failure (HF) with preserved ejection fraction (HFpEF).
Methods and results
Consecutive patients with HFpEF admitted for unequivocal decompensated HF treated with intravenous loop diuretics were evaluated (n = 443; mean age 78 ± 12 years; 60% women). The HFA-PEFF and H2 FPEF scores were calculated for all patients with echocardiography data available within 1 year and the population was stratified according to HFA-PEFF scores 2-4 (n = 79), 5 (n = 93), or 6 (n = 271) and H2 FPEF score probabilities <90% (n = 80), 90-95% (n = 61), and 96-100% (n = 293). HF readmission rates (95% confidence intervals) increased from 28.9 (22.7-35.0) per 100 patient-years in HFA-PEFF 2-4 to 46.0 (38.5-53.5) in HFA-PEFF 5 and 45.0 (40.1-49.8) in HFA-PEFF 6. Similarly, HF readmission rates increased with increasing H2 FPEF probability: <0.90 [31.8 (25.3-38.2) per 100 patient-years], 0.90-0.95 [41.5 (32.9-50.1)], and 0.96-1.00 [45.9 (41.2-50.6]. Median survival was 65 months (36-89 months) in HFA-PEFF score 2-4, 45 months (26-59 months) in HFA-PEFF score 5, and 28 months (22-42 months) in HFA-PEFF score 6 (P < 0.001), while the hazard ratio (95% confidence interval) for all-cause mortality was 1.16 (1.02-1.32) per 0.10 increase in H2 FPEF probability.
Conclusions
Among patients hospitalized with HFpEF, higher HFpEF probability according to diagnostic scores is associated with increased risk of subsequent HF readmissions and all-cause mortality.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 25 Feb 2021; epub ahead of print
Verbrugge FH, Reddy YNV, Sorimachi H, Omote K, Carter RE, Borlaug BA
Eur J Heart Fail: 25 Feb 2021; epub ahead of print | PMID: 33634544
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Abstract

Pharmacotherapy for heart failure with reduced ejection fraction and health-related quality of life: a systematic review and meta-analysis.

Turgeon RD, Barry AR, Hawkins NM, Ellis UM
Aims
The aim of this study was to synthesize the evidence on the effect of heart failure with reduced ejection fraction (HFrEF) pharmacotherapy on health-related quality of life (HRQoL).
Methods and results
We searched MEDLINE, Embase, CENTRAL, CINAHL, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform in June 2020. Randomized placebo-controlled trials evaluating contemporary HFrEF pharmacotherapy and reporting HRQoL as an outcome were included. Two reviewers independently assessed studies for eligibility, extracted data, and assessed risk of bias and GRADE certainty of evidence. The primary outcome was HRQoL at last available follow-up analysed using a random-effects model. We included 37 studies from 5770 identified articles. Risk of bias was low in 10 trials and high/unclear in 27 trials. High certainty evidence from meta-analyses demonstrated improved HRQoL over placebo with sodium-glucose co-transporter 2 (SGLT2) inhibitors [standardized mean difference (SMD) 0.16, 95% confidence interval (CI) 0.08-0.23] and intravenous iron (SMD 0.52, 95% CI 0.04-1.00). Furthermore, high certainty evidence from ≥1 landmark trial further supported improved HRQoL with angiotensin receptor blockers (ARBs) (SMD 0.09, 95% CI 0.02-0.17), ivabradine (SMD 0.14, 95% CI 0.04-0.23), hydralazine-nitrate (SMD 0.24, 95% CI 0.04-0.44) vs. placebo, and for angiotensin receptor-neprilysin inhibitor (ARNI) compared with an angiotensin-converting enzyme (ACE) inhibitor (SMD 0.09, 95% CI 0.02-0.17). Findings were inconclusive for ACE inhibitors, beta-blockers, digoxin, and oral iron based on low-to-moderate certainty evidence.
Conclusion
ARBs, ARNIs, SGLT2 inhibitors, ivabradine, hydralazine-nitrate, and intravenous iron improved HRQoL in patients with HFrEF. These findings can be incorporated into discussions with patients to enable shared decision-making.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 24 Feb 2021; epub ahead of print
Turgeon RD, Barry AR, Hawkins NM, Ellis UM
Eur J Heart Fail: 24 Feb 2021; epub ahead of print | PMID: 33634543
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Abstract

Haemodynamic effects of the nitroxyl donor cimlanod (BMS-986231) in chronic heart failure: a randomized trial.

Lang NN, Ahmad FA, Cleland JG, O\'Connor CM, ... Felker GM, McMurray JJV
Aims
Nitroxyl provokes vasodilatation and inotropic and lusitropic effects in animals via post-translational modification of thiols. We aimed to compare effects of the nitroxyl donor cimlanod (BMS-986231) with those of nitroglycerin (NTG) or placebo on cardiac function in patients with chronic heart failure with reduced ejection fraction (HFrEF).
Methods and results
In a randomized, multicentre, double-blind, crossover trial, 45 patients with stable HFrEF were given a 5 h intravenous infusion of cimlanod, NTG, or placebo on separate days. Echocardiograms were done at the start and end of each infusion period and read in a core laboratory. The primary endpoint was stroke volume index derived from the left ventricular outflow tract at the end of each infusion period. Stroke volume index with placebo was 30 ± 7 mL/m2 and was lower with cimlanod (29 ± 9 mL/m2 ; P = 0.03) and NTG (28 ± 8 mL/m2 ; P = 0.02). Transmitral E-wave Doppler velocity on cimlanod or NTG was lower than on placebo and, consequently, E/e\' (P = 0.006) and E/A ratio (P = 0.003) were also lower. NTG had similar effects to cimlanod on these measurements. Blood pressure reduction was similar with cimlanod and NTG and greater than with placebo.
Conclusion
In patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar. The effects of cimlanod may be explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. Ongoing trials of cimlanod will further define its potential role in the treatment of heart failure.

© 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: 22 Feb 2021; epub ahead of print
Lang NN, Ahmad FA, Cleland JG, O'Connor CM, ... Felker GM, McMurray JJV
Eur J Heart Fail: 22 Feb 2021; epub ahead of print | PMID: 33620131
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Abstract

Effect of dapagliflozin on anaemia in DAPA-HF.

Docherty KF, Curtain JP, Anand IS, Bengtsson O, ... McMurray JJV, DAPA-HF Investigators and Committees
Aim
Anaemia is common in heart failure and associated with worse outcomes. We examined the effect of dapagliflozin on correction of anaemia in patients with heart failure (HF) and reduced ejection fraction in DAPA-HF. We also analysed the effect of dapagliflozin on outcomes, according to anaemia status at baseline.
Methods and results
Anaemia was defined at baseline as a haematocrit <39% in men and <36% in women. Resolution of anaemia was defined as two consecutive haematocrit measurements above these thresholds at any time during follow-up. The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized in DAPA-HF, 4691 had a haematocrit available at baseline, of which 1032 were anaemic (22.0%). The rate of the primary outcome was higher in patients with anaemia (16.1 per 100 person-years) compared with those without (12.9 per 100 person-years). Anaemia was corrected in 62.2% of patients in the dapagliflozin group, compared with 41.1% of patients in the placebo group. The effect of dapagliflozin on the primary outcome was consistent in anaemic compared with non-anaemic patients [hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.52-0.88 vs. HR 0.76, 95% CI 0.65-0.89; interaction P = 0.44]. Similar findings were observed for cardiovascular death, HF hospitalization, and all-cause mortality. Patients with resolution of anaemia had better outcomes than those in which anaemia persisted.
Conclusion
Patients with anaemia had worse outcomes in DAPA-HF. Dapagliflozin corrected anaemia more often than placebo and improved outcomes, irrespective of anaemia status at baseline.

© 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: 21 Feb 2021; epub ahead of print
Docherty KF, Curtain JP, Anand IS, Bengtsson O, ... McMurray JJV, DAPA-HF Investigators and Committees
Eur J Heart Fail: 21 Feb 2021; epub ahead of print | PMID: 33615642
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Abstract

Sodium-glucose co-transporter 2 inhibition in patients hospitalized for acute decompensated heart failure: rationale for and design of the EMPULSE trial.

Tromp J, Ponikowski P, Salsali A, Angermann CE, ... Teerlink JR, Voors AA
Aims
Treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction. There is limited experience with the in-hospital initiation of SGLT2 inhibitors in patients with acute HF (AHF) with or without diabetes. EMPULSE is designed to assess the clinical benefit and safety of the SGLT2 inhibitor empagliflozin compared with placebo in patients hospitalized with AHF.
Methods
EMPULSE is a randomized, double-blind, parallel-group, placebo-controlled multinational trial comparing the in-hospital initiation of empagliflozin (10 mg once daily) with placebo. Approximately 500 patients admitted for AHF with dyspnoea, signs of fluid overload, and elevated natriuretic peptides will be randomized 1:1 stratified to HF status (de-novo and decompensated chronic HF) to either empagliflozin or placebo at approximately 165 sites across North America, Europe and Asia. Patients will be enrolled regardless of ejection fraction and diabetes status and will be randomized during hospitalization and after stabilization (between 24 h and 5 days after admission), with treatment continued up to 90 days after initiation. The primary outcome is clinical benefit at 90 days, consisting of a composite of all-cause death, HF events, and ≥5 point change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), assessed using a \'win-ratio\' approach. Secondary outcomes include assessments of safety, change in KCCQ-TSS from baseline to 90 days and change in natriuretic peptides from baseline to 30 days.
Conclusion
The EMPULSE trial will evaluate the clinical benefit and safety of empagliflozin in patients hospitalized for AHF.

© 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: 19 Feb 2021; epub ahead of print
Tromp J, Ponikowski P, Salsali A, Angermann CE, ... Teerlink JR, Voors AA
Eur J Heart Fail: 19 Feb 2021; epub ahead of print | PMID: 33609072
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Abstract

Prevention of heart failure events with sodium-glucose co-transporter 2 inhibitors across a spectrum of cardio-renal-metabolic risk.

Bhatia K, Jain V, Gupta K, Bansal A, ... Damman K, Vaduganathan M
Aims
Trials have tested the safety and efficacy of sodium-glucose co-transporter 2 inhibitors (SGLT2i) across various disease states. We performed a meta-analysis of randomized controlled trials (RCTs) to estimate the relative and absolute effects of SGLT2i in the prevention of heart failure (HF) events across different risk groups.
Methods and results
We conducted a systematic review and meta-analysis of large, placebo-controlled RCTs with >1000 participants evaluating HF hospitalization and the composite of cardiovascular (CV) death or HF hospitalization. Due to varying durations of therapeutic exposure and follow-up, absolute risk reductions and number needed to treat were calculated based on incidence rates (per 100 patient-years). Across 71 553 patients enrolled in 10 late-phase RCTs, SGLT2i reduced the risk of HF hospitalization by 31% [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.64-0.74; I2  = 0%] and the composite outcome of CV death or HF hospitalization by 24% (HR 0.76, 95% CI 0.72-0.80; I2  = 1.4%) compared with placebo. The number of patient-years of treatment exposure needed to prevent one CV death or HF hospitalization ranged from 19-26 (established HF) to 72-125 (chronic kidney disease) to 96-400 (high-risk type 2 diabetes). In mixed-effects meta-regression analyses, the benefits of SGLT2i on HF hospitalizations or the composite outcome (CV death or HF hospitalization) were not influenced by age, sex, or change in intermediate markers (glycated haemoglobin, systolic blood pressure, and body weight) (all P ≥ 0.10).
Conclusion
Despite wide variation in baseline risks and disease states evaluated, SGLT2i demonstrated comparable relative risk reductions in preventing HF events. Patients at highest baseline risk derived the greatest absolute benefits in preventing HF events. These composite estimates may help guide targeted implementation of SGLT2i for the prevention of HF events in type 2 diabetes and chronic kidney disease and in the treatment of HF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 19 Feb 2021; epub ahead of print
Bhatia K, Jain V, Gupta K, Bansal A, ... Damman K, Vaduganathan M
Eur J Heart Fail: 19 Feb 2021; epub ahead of print | PMID: 33609071
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Abstract

Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.

Sliwa K, van der Meer P, Petrie MC, Frogoudaki A, ... Seferovic PM, Bauersachs J
This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects.

© 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: 19 Feb 2021; epub ahead of print
Sliwa K, van der Meer P, Petrie MC, Frogoudaki A, ... Seferovic PM, Bauersachs J
Eur J Heart Fail: 19 Feb 2021; epub ahead of print | PMID: 33609068
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Impact:
Abstract

Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial.

Ferreira JP, Claggett BL, Liu J, Desai AS, ... Solomon SD, McMurray JJV
Aims
The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan.
Methods and results
The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up.
Conclusions
Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.

© 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: 19 Feb 2021; epub ahead of print
Ferreira JP, Claggett BL, Liu J, Desai AS, ... Solomon SD, McMurray JJV
Eur J Heart Fail: 19 Feb 2021; epub ahead of print | PMID: 33609066
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Abstract

Universal definition and classification of heart failure: A report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by Canadian Heart Failure Society, Heart Failure Association of India, the Cardiac Society of Australia and New Zealand, and the Chinese Heart Failure Association.

Bozkurt B, Coats AJS, Tsutsui H, Abdelhamid CM, ... Zhang J, Zieroth S
In this document, we propose a universal definition of heart failure (HF) as a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion. We also propose revised stages of HF as: At-risk for HF (Stage A), Pre-heart failure (Stage B), Symptomatic HF (Stage C) and Advanced HF (Stage D). Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). These include HF with reduced ejection fraction (HFrEF): symptomatic HF with LVEF ≤40%; HF with mildly reduced ejection fraction (HFmrEF): symptomatic HF with LVEF 41-49%; HF with preserved ejection fraction (HFpEF): symptomatic HF with LVEF ≥50%; and HF with improved ejection fraction (HFimpEF): symptomatic HF with a baseline LVEF ≤40%, a ≥10 point increase from baseline LVEF, and a second measurement of LVEF > 40%.

© 2021 European Society of Cardiology and Elsevier, Inc.

Eur J Heart Fail: 18 Feb 2021; epub ahead of print
Bozkurt B, Coats AJS, Tsutsui H, Abdelhamid CM, ... Zhang J, Zieroth S
Eur J Heart Fail: 18 Feb 2021; epub ahead of print | PMID: 33605000
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Impact:
Abstract

Use of sodium-glucose co-transporter 2 inhibitors in patients with heart failure and type 2 diabetes mellitus: data from the Swedish Heart Failure Registry.

Becher PM, Schrage B, Ferrannini G, Benson L, ... Lund LH, Savarese G
Aims
Use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in real-world heart failure (HF) is poorly characterised. In contemporary patients with HF and type 2 diabetes mellitus (T2DM) we assessed over time SGLT2i use, clinical characteristics and outcomes associated with SGLT2i use.
Methods and results
Type 2 diabetes patients enrolled in the Swedish HF Registry between 2016-2018 were considered. We performed multivariable logistic regression models to assess the independent predictors of SGLT2i use and Cox regression models in a 1:3 propensity score-matched cohort and relevant subgroups to investigate the association between SGLT2i use and outcomes. Of 6805 eligible HF patients with T2DM, 376 (5.5%) received SGLT2i, whose use increased over time with 12% of patients on treatment at the end of 2018. Independent predictors of SGLT2i use were younger age, HF specialty care, ischaemic heart disease, preserved kidney function, and absence of anaemia. Over a median follow-up of 256 days, SGLT2i use was associated with a 30% lower risk of cardiovascular (CV) death/first HF hospitalisation (hazard ratio 0.70, 95% confidence interval 0.52-0.95), which was consistent regardless of ejection fraction, background metformin treatment and kidney function. SGLT2i use was also associated with a lower risk of all-cause and CV death, HF and CV hospitalisation, and CV death/myocardial infarction/stroke.
Conclusion
In a contemporary HF cohort with T2DM, SGLT2i use increased over time, was more common with specialist care, younger age, ischaemic heart disease, and preserved renal function, and was associated with lower mortality and morbidity.

© 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 Feb 2021; epub ahead of print
Becher PM, Schrage B, Ferrannini G, Benson L, ... Lund LH, Savarese G
Eur J Heart Fail: 17 Feb 2021; epub ahead of print | PMID: 33599357
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Impact:
Abstract

Efficacy and safety of dapagliflozin according to aetiology in heart failure with reduced ejection fraction: insights from the DAPA-HF trial.

Butt JH, Nicolau JC, Verma S, Docherty KF, ... McMurray JJV, Køber L
Aims
We examined the efficacy and safety of dapagliflozin, compared with placebo, according to aetiology in patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).
Methods and results
Aetiology was investigator-reported and categorized as ischaemic or non-ischaemic. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. A total of 4744 patients were randomized in DAPA-HF, of whom 2674 (56.4%) patients had an ischaemic aetiology. Participants with an ischaemic aetiology had a higher risk of cardiovascular mortality [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.13-1.63], but lower risk of HF hospitalization (HR 0.83, 95% CI 0.70-0.98) than non-ischaemic patients. Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in both patients with ischaemic and non-ischaemic aetiology (HR 0.77, 95% CI 0.65-0.92, and HR 0.71, 95% CI 0.58-0.87, respectively; P for interaction = 0.55). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement of Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) of ≥5 points (P for interaction = 0.32) and decreased the proportion with a deterioration in KCCQ-TSS of ≥5 points (P for interaction = 0.76), irrespective of aetiology. Study drug discontinuation and serious adverse events were similar according to treatment groups, irrespective of aetiology.
Conclusions
Dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, similarly in patients with ischaemic and non-ischaemic aetiology. In addition, dapagliflozin was safe and well-tolerated, irrespective of aetiology.

© 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: 15 Feb 2021; epub ahead of print
Butt JH, Nicolau JC, Verma S, Docherty KF, ... McMurray JJV, Køber L
Eur J Heart Fail: 15 Feb 2021; epub ahead of print | PMID: 33594755
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Impact:
Abstract

The significance of left ventricular ejection time in heart failure with reduced ejection fraction.

Alhakak AS, Teerlink JR, Lindenfeld J, Böhm M, Rosano GMC, Biering-Sørensen T
Left ventricular ejection time (LVET) is defined as the time interval from aortic valve opening to aortic valve closure, and is the phase of systole during which the left ventricle ejects blood into the aorta. LVET has been used for several decades to assess left ventricular function and contractility. However, there is a recent interest in LVET as a measure of therapeutic action for novel drugs in patients with heart failure with reduced ejection fraction (HFrEF), since LVET is shortened in these patients. This review provides an overview of the available information on LVET including methods of measuring LVET, mechanistic understanding of LVET, association of LVET with outcomes, mechanisms behind shortened LVET in HFrEF and the potential implications of drugs that affect and normalize LVET.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 14 Feb 2021; epub ahead of print
Alhakak AS, Teerlink JR, Lindenfeld J, Böhm M, Rosano GMC, Biering-Sørensen T
Eur J Heart Fail: 14 Feb 2021; epub ahead of print | PMID: 33590579
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Impact:
Abstract

Contributions of cardiac dysfunction and volume status to central haemodynamics in chronic heart failure.

Miller WL, Sorimachi H, Grill DE, Fischer K, Borlaug BA
Aims
Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF.
Methods and results
Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator-dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume (\'euvolaemia\') (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e\' velocity, r = -0.44), and left atrial strain (r = -0.47). In multivariable regression TBV, left ventricular e\', and left atrial strain were independently associated with PCWP (all P < 0.05).
Conclusions
While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 08 Feb 2021; epub ahead of print
Miller WL, Sorimachi H, Grill DE, Fischer K, Borlaug BA
Eur J Heart Fail: 08 Feb 2021; epub ahead of print | PMID: 33565251
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Impact:
Abstract

Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.

Rohde LE, Vaduganathan M, Claggett BL, Polanczyk CA, ... McMurray JJV, Solomon SD
Aims
Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment.
Methods and results
We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (Pinteraction  < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05).
Conclusions
Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 08 Feb 2021; epub ahead of print
Rohde LE, Vaduganathan M, Claggett BL, Polanczyk CA, ... McMurray JJV, Solomon SD
Eur J Heart Fail: 08 Feb 2021; epub ahead of print | PMID: 33565237
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Impact:
Abstract

A prospective STudy using invAsive haemodynamic measurements foLLowing catheter ablation for AF and early HFpEF: STALL AF-HFpEF.

Sugumar H, Nanayakkara S, Vizi D, Wright L, ... Kaye DM, Ling LH
Aims
The impact of atrial fibrillation (AF) ablation in early heart failure with preserved ejection fraction (HFpEF) is unknown. Our aim was to determine the impact of AF ablation on symptoms and exercise haemodynamic parameters of early HFpEF.
Methods and results
Symptomatic AF patients referred for index AF ablation with ejection fraction ≥50% underwent baseline quality of life questionnaires, echocardiography, cardiac magnetic resonance imaging, exercise right heart catheterisation (exRHC), and brain natriuretic peptide (BNP) testing. HFpEF was defined by resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or peak exercise PCWP ≥25 mmHg. Patients with HFpEF were offered AF ablation and follow-up exRHC ≥6 months post-ablation. Of 54 patients undergoing baseline evaluation, 35 (65%) had HFpEF identified by exRHC. HFpEF patients were older (64 ± 10 vs. 54 ± 13 years, P < 0.01), and more frequently female (54% vs. 16%, P < 0.01), hypertensive (63% vs. 16%, P < 0.001), and suffering persistent AF (66% vs. 11%, P < 0.001), compared to those without HFpEF. Twenty HFpEF patients underwent AF ablation and follow-up exRHC 12 ± 6 months post-ablation. Nine (45%) patients no longer fulfilled exRHC criteria for HFpEF at follow-up. Patients remaining arrhythmia free (n = 9, 45%) showed significant improvements in peak exercise PCWP (29 ± 4 to 23 ± 2 mmHg, P < 0.01) and Minnesota Living with Heart Failure (MLHF) score (55 ± 30 to 22 ± 30, P < 0.01) while the remainder did not (PCWP 31 ± 5 to 30.0 ± 4 mmHg, P = NS; MLHF score 55 ± 23 to 25 ± 20, P = NS).
Conclusion
Heart failure with preserved ejection fraction frequently coexists in patients with symptomatic AF and preserved ejection fraction. Restoration and maintenance of sinus rhythm in patients with comorbid AF and HFpEF improves haemodynamic parameters, BNP and symptoms associated with HFpEF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 08 Feb 2021; epub ahead of print
Sugumar H, Nanayakkara S, Vizi D, Wright L, ... Kaye DM, Ling LH
Eur J Heart Fail: 08 Feb 2021; epub ahead of print | PMID: 33565197
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Impact:
Abstract

One-year results of the first-in-man study investigating the Atrial Flow Regulator for left atrial shunting in symptomatic heart failure patients: the PRELIEVE study.

Paitazoglou C, Bergmann MW, Özdemir R, Pfister R, ... Mahfoud F, AFR-PRELIEVE Investigators
Aims
Attenuating exercise-induced elevated left atrial pressure with an atrial shunt device is under clinical investigation for treatment of symptomatic heart failure (HF).
Methods and results
PRELIEVE was a prospective, non-randomised, multicentre, first-in-man study in symptomatic HF patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction and pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg during exercise. Here, we provide follow-up data up to 1 year after implantation of the Atrial Flow Regulator (AFR) device. The AFR was successfully implanted in 53 patients (HFrEF n = 24 and HFpEF n = 29). Two patients were not enrolled due to an unsuccessful transseptal puncture. There was one device embolisation into the left atrium, which required surgical removal. One patient experienced a serious procedure-related adverse event (post-procedural bleeding and syncope). All patients with sufficient echocardiography readout confirmed device patency with left-right shunt both at 3 (n = 47/51, 92%) and 12 (n = 45/49, 92%) months. At 3 months, rest PCWP decreased by 5 (-12, 0) mmHg (P = 0.0003, median Q1, Q3). No patient developed a stroke, worsening of right heart function or significant increase of pulmonary artery pressure. Six (6/53, 11%) patients were hospitalised for worsening of HF and three (3/53, 6%) patients died. We observed improvements in New York Heart Association functional class, 6-min walking distance and quality of life (Kansas City Cardiomyopathy Questionnaire) in certain patients.
Conclusions
Implantation of the AFR device in HF patients was feasible. No shunt occlusion, stroke or new right HF was observed during the 1-year follow-up, with clinical improvements in certain patients.

© 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 Feb 2021; epub ahead of print
Paitazoglou C, Bergmann MW, Özdemir R, Pfister R, ... Mahfoud F, AFR-PRELIEVE Investigators
Eur J Heart Fail: 07 Feb 2021; epub ahead of print | PMID: 33555114
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Impact:
Abstract

Prognostic value of cardiopulmonary exercise testing in cardiac amyloidosis.

Nicol M, Deney A, Lairez O, Vergaro G, ... Arnulf B, Logeart D
Aims
In amyloid patients, cardiac involvement dramatically worsens functional capacity and prognosis. We sought to study how the cardiopulmonary exercise test (CPET) could help in functional assessment and risk stratification of patients with cardiac amyloidosis (CA).
Methods and results
We carried out a multicentre study including patients with light chain (AL) or transthyretin (TTR) CA. All patients underwent exhaustive examination including CPET and follow-up. The primary prognostic endpoint was the occurrence of death or heart failure hospitalization. Overall, 150 patients were included (91 AL and 59 TTR CA). Median age, systolic blood pressure, N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin T were 70 (64-78) years, 121 [interquartile range (IQR) 109-139] mmHg, 2806 (IQR 1218-4638) ng/L and 64 (IQR 33-120) ng/L, respectively. New York Heart Association classes were I-II in 64%. Median peak oxygen consumption (VO2 ) and circulatory power were low at 13.0 (10.0-16.9) mL/kg/min and 1730 (1318-2614) mmHg/mL/min, respectively. The minute ventilation/carbon dioxide production slope was increased to 37 (IQR 33-45). A total of 77 patients (51%) had chronotropic insufficiency. After a median follow-up of 20 months, there were 37 deaths and 44 heart failure hospitalizations. At multivariate Cox analysis, peak VO2  ≤13 mL/kg/min [hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.6-4.8], circulatory power ≤1730 mmHg/mL/min (HR 2.4, 95% CI 1.2-4.6) and NT-proBNP ≥1800 ng/L (HR 2.2, 95% CI 1.1-4.3) were found to be associated with the primary outcome. No events occurred in patients with both peak VO2  >13 mL/kg/min and NT-proBNP <1800 ng/L, while the association of VO2  ≤13 mL/kg/min with NT-proBNP ≥1800 ng/L identified a very high-risk subgroup.
Conclusion
In CA, CPET is helpful in assessing functional capacity, circulatory and chronotropic responses as well as the prognosis of patients along with cardiac biomarkers.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Jan 2021; 23:231-239
Nicol M, Deney A, Lairez O, Vergaro G, ... Arnulf B, Logeart D
Eur J Heart Fail: 30 Jan 2021; 23:231-239 | PMID: 33006180
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Impact:
Abstract

Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial.

Giannoni A, Borrelli C, Mirizzi G, Richerson GB, Emdin M, Passino C
Aims
Increased chemosensitivity to carbon dioxide (CO2 ) is an important trigger of central apnoeas (CA) in heart failure (HF), with negative impact on outcome. We hypothesized that buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing in animals, can decrease CO2 chemosensitivity and CA in HF.
Methods and results
The BREATH study was a randomized, double-blind, placebo-controlled, crossover study (EudraCT-code 2015-005383-42). Outpatients with systolic HF (left ventricular ejection fraction <50%) and moderate-severe CA [nocturnal apnoea-hypopnoea index (AHI) ≥15 events/h] were randomly assigned to either oral buspirone (15 mg thrice daily) or placebo for 1 week, with a crossover design (1 week of wash-out). The primary effectiveness endpoint was a decrease in CO2 chemosensitivity >0.5 L/min/mmHg. The primary safety endpoint was freedom from serious adverse events. Sixteen patients (age 71.3 ± 5.8 years, all males, left ventricular ejection fraction 29.8 ± 7.8%) were enrolled. In the intention-to-treat analysis, more patients treated with buspirone (8/16, 50%) had a CO2 chemosensitivity reduction >0.5 L/min/mmHg from baseline than those treated with placebo (1/16, 6.7%) (difference between groups 43%, 95% confidence interval 14-73%, P = 0.016). Buspirone compared to baseline led to a 41% reduction in CO2 chemosensitivity (P = 0.001) and to a reduction in the AHI, central apnoea index and oxygen desaturation index of 42%, 79%, 77% at nighttime and 50%, 78%, 86% at daytime (all P < 0.01); no difference was observed after placebo administration (all P > 0.05). No patient reported buspirone-related serious adverse events.
Conclusions
Buspirone reduces CO2 chemosensitivity and improves CA and oxygen saturation across the 24 h in patients with HF.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Jan 2021; 23:312-320
Giannoni A, Borrelli C, Mirizzi G, Richerson GB, Emdin M, Passino C
Eur J Heart Fail: 30 Jan 2021; 23:312-320 | PMID: 32441857
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Impact:
Abstract

Viral presence-guided immunomodulation in lymphocytic myocarditis: an update.

Sinagra G, Porcari A, Gentile P, Artico J, ... Bussani R, Merlo M
Latest statements from European and American societies recommend to rule out viral presence in endomyocardial biopsy (EMB) via polymerase chain reaction (PCR) analysis before starting immunosuppression or immunomodulation in acute lymphocytic myocarditis presenting with life-threatening scenarios. However, recommendations in myocarditis are mostly based on heterogeneous studies enrolling patients with inflammatory cardiomyopathies and established heart failure rather than acute myocarditis. Thus, definitive evidence of a survival benefit from immunomodulation guided by viral presence is currently lacking. Finally, distinguishing innocent bystanders from causative agents among EMB-detected viruses remain challenging and a major goal to achieve in the near future. Therefore, considerable divergence remains between official recommendations and clinical practice, including the possibility of starting immunosuppressive therapy empirically, without knowing viral PCR results. This review systematically discusses the unsolved issues of immunomodulation guided by viral presence in acute lymphocytic myocarditis, namely (i) virus epidemiology and prognosis, (ii) variability of viral presence rates, (iii) the role of potential viral bystander findings, and (iv) the main results of immunosuppression controlled trials in lymphocytic myocarditis. Furthermore, a practical approach for the critical use of viral presence analysis in guiding immunomodulation is provided, highlighting its importance before starting immunosuppression or immunomodulation. Future, multicentre studies are needed to address specific scenarios such as fulminant lymphocytic myocarditis and a virus-tailored management as for parvovirus B19.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Jan 2021; 23:211-216
Sinagra G, Porcari A, Gentile P, Artico J, ... Bussani R, Merlo M
Eur J Heart Fail: 30 Jan 2021; 23:211-216 | PMID: 32683758
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Impact:
Abstract

Unveiling outcomes in coexisting severe aortic stenosis and transthyretin cardiac amyloidosis.

Rosenblum H, Masri A, Narotsky DL, Goldsmith J, ... Maurer MS, Castaño A
Aims
Advances in diagnostic imaging have increased the recognition of coexisting transthyretin cardiac amyloidosis (ATTR-CA) and severe aortic stenosis (AS), with a reported prevalence between 8-16%. In this prospective study, we aimed to evaluate the implications of ATTR-CA on outcomes after transcatheter aortic valve replacement (TAVR).
Methods and results
At two academic centres, we screened patients with severe AS undergoing TAVR for ATTR-CA. Using Kaplan-Meier analysis, we compared survival free from death and a combined endpoint of death and first heart failure hospitalization between patients with and without ATTR-CA. Cox proportional-hazards models were used to determine the association of ATTR-CA with these endpoints. The rate of heart failure hospitalization was compared amongst those with and without ATTR-CA. Overall, 204 patients (83 years, 65% male, Society of Thoracic Surgeons score 6.6%, 72% New York Heart Association class III/IV) were included, 27 (13%) with ATTR-CA. Over a median follow-up of 2.04 years, there was no difference in mortality (log rank, P = 0.99) or the combined endpoint (log rank, P = 0.79) between patients with and without ATTR-CA. In Cox proportional-hazards models, the presence of ATTR-CA was not associated with death. However, patients with ATTR-CA had increased rates of heart failure hospitalization at 1 year (0.372 vs. 0.114 events/person-year, P < 0.004) and 3 years (0.199 vs. 0.111 events/person-year, P = 0.087) following TAVR.
Conclusion
In moderate-risk patients with severe AS undergoing TAVR, there was a 13% prevalence of ATTR-CA, which did not affect mortality. The observed increase in heart failure hospitalization following TAVR in those with ATTR-CA suggests the consequences of the underlying infiltrative myopathy.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Jan 2021; 23:250-258
Rosenblum H, Masri A, Narotsky DL, Goldsmith J, ... Maurer MS, Castaño A
Eur J Heart Fail: 30 Jan 2021; 23:250-258 | PMID: 32729170
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Impact:
Abstract

Left ventricular systolic ejection time is an independent predictor of all-cause mortality in heart failure with reduced ejection fraction.

Alhakak AS, Sengeløv M, Jørgensen PG, Bruun NE, ... Gislason G, Biering-Sørensen T
Aims
Colour tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to obtain cardiac time intervals including isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and systolic ejection time (SET). The myocardial performance index (MPI) is defined as [(IVCT + IVRT)/SET]. Whether cardiac time intervals obtained by the TDI M-mode method can be used to predict outcome in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown.
Methods and results
A total of 997 patients with HFrEF (mean age 67 ± 11 years, 74% male) underwent an echocardiographic examination including TDI. During a median follow-up of 3.4 years (interquartile range 1.9-4.8 years), 165 (17%) patients died. The risk of mortality increased by 9% per 10 ms decrease in SET [per 10 ms decrease: hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06-1.13; P < 0.001]. The association remained significant even after multivariable adjustment for clinical and echocardiographic parameters (per 10 ms decrease: HR 1.06, 95% CI 1.01-1.11; P = 0.030). The MPI was a significant predictor in an unadjusted model (per 0.1 increase: HR 3.06, 95% CI 1.16-8.06; P = 0.023). However, the association did not remain significant after multivariable adjustment. No significant associations between IVCT or IVRT and mortality were found in unadjusted nor adjusted models. Additionally, SET provided incremental prognostic information with regard to predicting mortality when added to established clinical predictors of mortality in patients with HFrEF.
Conclusion
In patients with HFrEF, SET provides independent and incremental prognostic information regarding all-cause mortality.

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 Jan 2021; 23:240-249
Alhakak AS, Sengeløv M, Jørgensen PG, Bruun NE, ... Gislason G, Biering-Sørensen T
Eur J Heart Fail: 30 Jan 2021; 23:240-249 | PMID: 33034122
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Impact:
Abstract

Mechanical circulatory support does not reduce advanced myocardial fibrosis in patients with end-stage heart failure.

Kassner A, Oezpeker C, Gummert J, Zittermann A, ... Morshuis M, Milting H
Aims
Mechanical unloading by ventricular assist devices (VADs) has become increasingly important for the therapy of end-stage heart failure during the last decade. However, VAD support was claimed to be associated with partial reverse remodelling. Unfortunately, the literature describes the contradictory effects of VAD systems on cardiac fibrosis, a hallmark of cardiac remodelling. To clarify these inconsistent results, the effects on cardiac fibrosis before and after mechanical unloading in 125 patients were examined.
Methods and results
Left ventricular myocardial tissue from ischaemic or non-ischaemic cardiomyopathy patients undergoing VAD implantation and subsequent cardiac transplantation and non-failing hearts of the control group were analysed for 4-hydroxyproline (4OH-P) content as a marker for collagen protein. In addition, collagen cross-linking and mRNAs of collagens I and III and transforming growth factor beta-1 were measured. 4OH-P content was significantly increased in failing hearts compared with the control group and increased (P < 0.05) after mechanical unloading (nmol/mg tissue, mean ± standard deviation: 16.74 ± 9.68 vs. 7.75 ± 2.39 and 18.57 ± 9.19). However, plotting of the 4OH-P ratios (post/pre-VAD) against the collagen content pre-VAD could be fitted by non-linear regression. Collagen cross-linking correlated strongly with the total collagen content in pre- and post-VAD myocardium (r2  = 0.73 and 0.71, respectively). In contrast to the total collagen content, all three mRNAs of fibrotic genes were significantly down-regulated during VAD support when compared to pre-VAD.
Conclusions
This investigation of a comparably large patient cohort revealed that cardiac fibrosis was strongly increased in heart failure and increased even after mechanical unloading. The mRNAs of collagens I and III are independently regulated from the collagen protein.

© 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 Jan 2021; 23:324-334
Kassner A, Oezpeker C, Gummert J, Zittermann A, ... Morshuis M, Milting H
Eur J Heart Fail: 30 Jan 2021; 23:324-334 | PMID: 33038287
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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): 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: 30 Jan 2021; 23:277-285
Damy T, Garcia-Pavia P, Hanna M, Judge DP, ... Sultan MB, Witteles R
Eur J Heart Fail: 30 Jan 2021; 23:277-285 | PMID: 33070419
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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: 30 Jan 2021; 23:264-274
Bézard M, Kharoubi M, Galat A, Poullot E, ... Oghina S, Damy T
Eur J Heart Fail: 30 Jan 2021; 23:264-274 | PMID: 33094885
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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/m2 ; 95% confidence interval (CI) 1.3-9.5] and cell mass (4.2 g/m2 ; 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/m2 ; 95% CI 3.6-8.9; P = 0.0001), cell mass (4.0 g/m2 ; 95% CI 1.8-6.2; P = 0.0007) and matrix mass (1.7 g/m2 ; 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/m2 , 95% CI 1.5-8.8, P = 0.007; cell mass: 3.7 g/m2 , 95% CI 0.3-7.0, P = 0.03; matrix mass: 1.7 g/m2 , 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/m2 ; 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: 30 Jan 2021; 23:293-301
Halliday BP, Owen R, Gregson J, S Vassiliou V, ... Pennell DJ, Prasad SK
Eur J Heart Fail: 30 Jan 2021; 23:293-301 | PMID: 33225554
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Abstract

Intravenous immunoglobulin therapy in adult patients with idiopathic chronic cardiomyopathy and cardiac parvovirus B19 persistence: a prospective, double-blind, randomized, placebo-controlled clinical trial.

Hazebroek MR, Henkens MTHM, Raafs AG, Verdonschot JAJ, ... van Empel VPM, Heymans SRB
Aims
Previous uncontrolled studies suggested 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.
Methods and results
Fifty patients (39 men; mean age 54 ± 11 years) with idiopathic chronic (>6 months) DCM on optimal medical therapy, left ventricular ejection fraction (LVEF) <45%, and endomyocardial biopsy (EMB) B19V load of >200 copies/µg DNA were blindly randomized to either IVIg (n = 26, 2 g/kg over 4 days) or placebo (n = 24). The primary outcome was change in LVEF at 6 months after randomization. Secondary outcomes were change in functional capacity assessed by 6-min walk test (6MWT), quality of life [Minnesota Living with Heart Failure Questionnaire (MLHFQ)], left ventricular end-diastolic volume (LVEDV), and EMB B19V load at 6 months after randomization. LVEF significantly improved in both IVIg and placebo groups (absolute mean increase 5 ± 9%, P = 0.011 and 6 ± 10%, P = 0.008, respectively), without a significant difference between groups (P = 0.609). Additionally, change in 6MWT [median (interquartile range) 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 mL/m2 vs. placebo -29 ± 40 mL/m2 ; P = 0.334) did not significantly differ between groups. Moreover, despite increased circulating B19V antibodies upon IVIg administration, reduction in cardiac B19V did not significantly differ between groups.
Conclusion
Intravenous immunoglobulin 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.
Clinical trial registration
ClinicalTrials.gov ID NCT00892112.

© 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 Jan 2021; 23:302-309
Hazebroek MR, Henkens MTHM, Raafs AG, Verdonschot JAJ, ... van Empel VPM, Heymans SRB
Eur J Heart Fail: 30 Jan 2021; 23:302-309 | PMID: 33347677
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Abstract

Use of biomarkers to diagnose and manage cardiac amyloidosis.

Castiglione V, Franzini M, Aimo A, Carecci A, ... Emdin M, Vergaro G
Amyloidoses are characterized by the tissue accumulation of misfolded proteins into insoluble fibrils. The two most common types of systemic amyloidosis result from the deposition of immunoglobulin light chains (AL) and wild-type or variant transthyretin (ATTRwt/ATTRv). Cardiac involvement is the main determinant of outcome in both AL and ATTR, and cardiac amyloidosis (CA) is increasingly recognized as a cause of heart failure. In CA, circulating biomarkers are important diagnostic tools, allow to refine risk stratification at baseline and during follow-up, help to tailor the therapeutic strategy and monitor the response to treatment. Among amyloid precursors, free light chains are established biomarkers in AL amyloidosis, while the plasma transthyretin assay is currently being investigated as a tool for supporting the diagnosis of ATTRv amyloidosis, predicting outcome and monitor response to novel tetramer stabilizers or small interfering RNA drugs in ATTR CA. Natriuretic peptides (NPs) and troponins are consistently elevated in patients with AL and ATTR CA. Plasma NPs, troponins and free light chains hold prognostic significance in AL amyloidosis, and are evaluated for therapy decision-making and follow-up, while the value of NPs and troponins in ATTR is less well established. Biomarkers can be usefully integrated with clinical and imaging variables at all levels of the clinical algorithm of systemic amyloidosis, from screening to diagnosis and prognosis, and treatment tailoring.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Jan 2021; 23:217-230
Castiglione V, Franzini M, Aimo A, Carecci A, ... Emdin M, Vergaro G
Eur J Heart Fail: 30 Jan 2021; 23:217-230 | PMID: 33527656
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This program is still in alpha version.