Journal: Eur J Heart Fail

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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 TAVR.
Methods and results
At two academic centers, 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 (HF) 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 HF hospitalization was compared amongst those with and without ATTR-CA. 204 patients (83 yrs, 65% male, STS 6.6%, 72% NYHA class III/IV) were included, 27 (13%) with ATTR-CA. Over 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 HF 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 HF hospitalization following TAVR in those with ATTR-CA suggests the consequences of the underlying infiltrative myopathy.

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Eur J Heart Fail: 29 Jul 2020; epub ahead of print
Rosenblum H, Masri A, Narotsky DL, Goldsmith J, ... Maurer MS, Castaño A
Eur J Heart Fail: 29 Jul 2020; epub ahead of print | PMID: 32729170
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Abstract

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

McEwan P, Darlington O, McMurray JJV, Jhund PS, ... Bergenheim K, Qin L
Aim
To estimate the cost-effectiveness of dapagliflozin added to standard therapy, versus standard therapy only, in patients with heart failure (HF) with reduced ejection fraction, from the perspective of UK, German, and Spanish payers.
Methods and results
A lifetime Markov model was built to estimate outcomes in patients with HFrEF. Health states were defined by Kansas City Cardiomyopathy Total Symptom Score, type 2 diabetes and worsening HF events. The incidence of worsening HF and all-cause mortality was estimated using negative binomial regression models and parametric survival analysis, respectively. Direct healthcare costs (2019 British pounds/Euro) and patient-reported outcomes (EQ-5D) were sourced from the existing literature and the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF), respectively; the median duration of follow-up in DAPA-HF was 18.2 months (range: 0-27.8). Future costs and effects were discounted at 3.0% for the Spanish and German analyses and 3.5% for the UK analysis. In the UK setting, treatment with dapagliflozin was estimated to increase life-years and quality-adjusted life-years (QALYs) from 5.62 to 6.20 (+0.58) and 4.13 to 4.61 (+0.48), respectively, and reduce lifetime hospitalisations for HF (925 and 820 events per 1,000 patients for placebo and dapagliflozin, respectively). Similar results were obtained for Germany and Spain. The incremental cost-effectiveness ratios were £5,822, €5,379 and €9,406/QALY in the UK, Germany and Spain, respectively. In probabilistic sensitivity analyses, more than 90% of simulations were cost-effective at a willingness-to-pay threshold of £20,000/QALY in UK and €20,000/QALY in Germany and Spain.
Conclusion
Dapagliflozin is likely to be a cost-effective treatment for HFrEF in the UK, German and Spanish healthcare systems. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 03 Aug 2020; epub ahead of print
McEwan P, Darlington O, McMurray JJV, Jhund PS, ... Bergenheim K, Qin L
Eur J Heart Fail: 03 Aug 2020; epub ahead of print | PMID: 32749733
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Abstract

Transcatheter Tricuspid Valve Repair in the Setting of Heart Failure with Preserved or Reduced Left Ventricular Ejection Fraction.

Kresoja KP, Lauten A, Orban M, Rommel KP, ... Hausleiter J, Lurz P
Aims
Severe tricuspid regurgitation (TR) impairs prognosis in patients with left-sided heart failure (HF) with preserved (≥50%, HFpEF) and reduced ejection fraction (<50%, HFrEF). Transcatheter tricuspid valve leaflet edge-to-edge repair (TTVR) potentially improves prognosis among patients with severe TR. We sought to assess the impact of left-sided HF types on outcomes of TTVR.
Methods and results
In this retrospective study 71 HFpEF and 40 HFrEF patients, defined according to the European Society of Cardiology criteria, with isolated TR treated by TTVR, in two tertiary care centres, between 2016 and 2019 were analysed. The primary outcome was a composite outcome of all-cause mortality, HF hospitalization at 12 months (median follow-up 238[IQR175-365]days). Additionally, a propensity score matching with a conservatively treated cohort of 914 patients with severe TR was performed. Procedural success did not differ between HFpEF (mean age 75.9 ± 9.3 years) or HFrEF (mean age 74.7 ± 9.1 years) patients (86% vs. 78%,p = 0.299). The primary endpoint occurred more frequently in patients with HFrEF as compared to HFpEF (50 vs. 30%,p = 0.016). Procedural success was associated with a reduced occurrence of the primary endpoint among patients with HFpEF (p < 0.001) but not HFrEF (p = 0.813), while both groups showed improvement in New York Heart Association functional class (both p < 0.001). After matching for age, EuroSCORE II, presence of an RV-lead and systolic pulmonary artery pressure, successful TTVR was associated with lower mortality as compared to conservative therapy in HFpEF patients (p = 0.020), but not in HFrEF patients (p = 0.274).
Conclusion
TTVR might be a therapeutic option in patients with severe TR and HFpEF compared to conservative therapy. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 01 Aug 2020; epub ahead of print
Kresoja KP, Lauten A, Orban M, Rommel KP, ... Hausleiter J, Lurz P
Eur J Heart Fail: 01 Aug 2020; epub ahead of print | PMID: 32741057
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Abstract

Prevalence and incidence of intraventricular conduction delays and outcomes in patients with heart failure and reduced ejection fraction: Insights from PARADIGM-HF and ATMOSPHERE.

Kristensen SL, Castagno D, Shen L, Jhund P, ... McMurray JJ,
Aims
The importance of intraventricular conduction delay (IVCD), incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) is not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials.
Methods and results
Risk of the primary composite outcome of cardiovascular death or HF hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11,861 patients without an intracardiac device. At baseline, 1,789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) RBBB, 454 (3.8%) non-specific IVCD, 2588 (21.8%) \"mildly abnormal\" QRS (110-129 milliseconds [ms]) and 6506 (54.9%) QRS <110 ms. During a median follow-up of 2.5 years, the risk of the primary composite endpoint was higher among those with a wide QRS, irrespective of morphology: hazard ratios (95% CI) LBBB 1.36 (1.23, 1.50), RBBB 1.54 (1.31, 1.79), nonspecific IVCD 1.65 (1.40, 1.94) and QRS 110-129 ms 1.35 (95% CI 1.23, 1.47), compared with QRS duration <110 ms. A total of 1,234 (15.6%) patients developed new-onset QRS-widening ≥130 ms (6.1 per 100 py). Incident LBBB occurred in 495 (6.3%) patients (2.4 per 100 py) and was associated with a higher risk of the primary composite outcome; HR 1.42 (1.12, 1.82).
Conclusion
In patients with HFrEF, a wide QRS was associated with worse clinical outcomes irrespective of morphology. The annual incidence of new-onset LBBB was around 2.5%, and associated with a higher risk of adverse outcomes, highlighting the importance of repeat ECG review.

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Eur J Heart Fail: 27 Jul 2020; epub ahead of print
Kristensen SL, Castagno D, Shen L, Jhund P, ... McMurray JJ,
Eur J Heart Fail: 27 Jul 2020; epub ahead of print | PMID: 32720404
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Abstract

Serum Potassium in the PARADIGM-HF trial.

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

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Eur J Heart Fail: 17 Aug 2020; epub ahead of print
Ferreira JP, Mogensen UM, Jhund PS, Desai AS, ... Solomon SD, McMurray JJV
Eur J Heart Fail: 17 Aug 2020; epub ahead of print | PMID: 32809261
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Abstract

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

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

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Eur J Heart Fail: 17 Aug 2020; epub ahead of print
Piek A, Suthahar N, Voors AA, de Boer RA, Silljé HHW
Eur J Heart Fail: 17 Aug 2020; epub ahead of print | PMID: 32809235
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Abstract

Temporal trends in decompensated heart failure and outcomes during COVID-19: A multisite report from heart failure referral centres in London.

Cannata A, Bromage DI, Rind IA, Gregorio C, ... Shah AM, McDonagh TA
Aims
Admission rates for acute decompensated heart failure declined during COVID-19. However, the impact of this reduction on hospital mortality is unknown. We describe temporal trends in the presentation of patients with acute heart failure (HF) and their in-hospital outcomes from two referral centres in London during the COVID-19 pandemic.
Methods and results
A total of 1372 patients hospitalized for HF in two referral centres in South London between 7 January and 14 June 2020, were included in the study and compared to the same time period in 2019. The primary outcome was all-cause in-hospital mortality. HF hospitalizations were significantly reduced during the COVID-19 pandemic, compared to 2019 (p<0.001). Specifically, we observed a temporary reduction in hospitalizations during the COVID-19 peak, followed by a return to 2019 levels. Patients admitted during the COVID-19 pandemic had similar demographic characteristics compared to the same period in 2019. However, in-hospital mortality was significantly higher in 2020 compared to 2019 (p=0.015). Hospitalization in 2020 was independently associated with worse in-hospital mortality (hazard ratio [HR] 2.23, 95% Confidence Interval [CI] 1.34 - 3.72; p=0.002).
Conclusion
During the COVID-19 pandemic there was a reduction in HF hospitalizations and higher in-hospital mortality. Hospitalisation for HF in 2020 is independently associated with more adverse outcomes. Further studies are required to investigate the predictors of these adverse outcomes to help inform potential changes to the management of HF patients while some constraints to usual care remain. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 17 Aug 2020; epub ahead of print
Cannata A, Bromage DI, Rind IA, Gregorio C, ... Shah AM, McDonagh TA
Eur J Heart Fail: 17 Aug 2020; epub ahead of print | PMID: 32809274
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Abstract

Survival following concomitant aortic valve procedure during left ventricular assist device surgery: an ISHLT Mechanically Assisted Circulatory Support (IMACS) Registry.

Veenis JF, Yalcin YC, Brugts JJ, Constantinescu AA, ... Bogers AJJC, Caliskan K
Aims
The aim of this study was to compare early- and late-term survival and causes of death between patients with and without a concomitant aortic valve (AoV) procedure during continuous-flow left ventricular assist device (LVAD) surgery.
Methods and results
All adult primary continuous-flow LVAD patients from the International Society of Heart and Lung Transplantation (ISHLT) Mechanically Assisted Circulatory Support (IMACS) registry (n=15,267) were included in this analysis and stratified into patients with concomitant AoV procedure (being AoV replacement or AoV repair) and without AoV procedure. The primary outcome was early (≤90 days) survival post-LVAD surgery. Secondary outcomes were late survival, survival of patients alive 90 days post-LVAD surgery (conditional survival) and its determinants. Patients who underwent concomitant AoV replacement (n=457) had a significantly reduced late survival compared with patients with AoV repair (n=328) or without an AoV procedure (n=14,482) (56% versus 61%, 62%, respectively p=0.001). After adjustment for other significant predictors, concomitant AoV replacement remained an independent predictor for early (HR 1.226 [1.037-1.449]) and late mortality (HR 1.477 [1.154-1.890]). However, patients undergoing AoV replacement or repair, in whom the presence of moderate-to-severe AoR was diagnosed prior to LVAD implantation, had survival similar to patients not undergoing aortic valve interventions.
Conclusion
Concomitant AoV surgery in patients undergoing LVAD implantation is an independent predictor of mortality. Additional research is needed to determine the best AoV surgical strategy at the time of LVAD surgery. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 17 Aug 2020; epub ahead of print
Veenis JF, Yalcin YC, Brugts JJ, Constantinescu AA, ... Bogers AJJC, Caliskan K
Eur J Heart Fail: 17 Aug 2020; epub ahead of print | PMID: 32809227
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Abstract

Heart Failure In Covid-19 Patients: Prevalence, Incidence And Prognostic Implications.

Rey JR, Caro-Codón J, Rosillo SO, Iniesta ÁM, ... López-Sendón JL, Merino JL
Aims
Data regarding impact of COVID-19 in chronic heart failure (CHF) patients and its potential to trigger acute heart failure (AHF) is lacking. The aim of this work was to study characteristics, cardiovascular outcomes and mortality in patients with confirmed COVID-19 infection and prior diagnosis of HF. Also, to identify predictors and prognostic implications for AHF decompensations during hospital admission and to determine whether there was a correlation between withdrawal of HF guideline-directed medical therapy (GDMT) and worse outcomes during hospitalization.
Methods and results
A total of 3080 consecutive patients with confirmed COVID-19 infection and at least 30-day follow-up were analyzed. Patients with previous history of CHF (152, 4.9%), were more prone to develop AHF (11.2% vs 2.1%; p<0.001) and had higher levels of NT-proBNP. Also, previous CHF group had higher mortality rates (48.7% vs 19.0%; p<0.001). In contrast, 77 patients (2.5%) were diagnosed of AHF and the vast majority (77.9%) developed in patients without history of HF. Arrhythmias during hospital admission and CHF were main predictors of AHF. Patients developing AHF had significantly higher mortality (46.8% vs 19.7%; p<0.001). Finally, withdrawal of beta-blockers, mineralocorticoid antagonists and ACE/ARB inhibitors was associated with a significant increase of in-hospital mortality.
Conclusions
Patients with COVID-19 have a significant incidence of AHF, entity that carries within a very high mortality. Moreover, patients with history of CHF are prone to develop acute decompensation after COVID-19 diagnosis. Withdrawal of GDMT was associated with higher mortality.

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Eur J Heart Fail: 23 Aug 2020; epub ahead of print
Rey JR, Caro-Codón J, Rosillo SO, Iniesta ÁM, ... López-Sendón JL, Merino JL
Eur J Heart Fail: 23 Aug 2020; epub ahead of print | PMID: 32833283
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Abstract

Serum Uric Acid, Influence of Sacubitril/Valsartan, and Cardiovascular Outcomes in Heart Failure with Preserved Ejection Fraction: PARAGON-HF.

Selvaraj S, Claggett BL, Pfeffer MA, Desai AS, ... McMurray JJV, Solomon SD
Aims
To determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure with preserved ejection fraction (HFpEF), and whether sacubitril/valsartan reduces SUA and SUA-related therapies.
Methods and results
We analyzed 4795 participants from PARAGON-HF. We related baseline hyperuricemia (using assay definitions) to the primary outcome (CV death and total HF hospitalization). Between baseline and 4 months, we assessed the association between changes in SUA and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and other cardiac biomarkers. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. Average age was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricemia was associated with increased risk for the primary outcome (rate ratio 1.61, 95%CI 1.37, 1.90). The treatment effect of sacubitril/valsartan for the primary endpoint was not significantly modified by hyperuricemia (p-interaction = 0.14). Sacubitril/valsartan reduced SUA -0.38 mg/dL (95%CI: -0.45, -0.31) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 vs. -0.32 mg/dL) (p-interaction = 0.031). Sacubitril/valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (p < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity Troponin T (p < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA.
Conclusions
SUA independently predicted adverse outcomes in HFpEF. Sacubitril/valsartan reduced SUA and related therapy initiation compared to valsartan. Reducing SUA was associated with improved outcomes.

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Eur J Heart Fail: 24 Aug 2020; epub ahead of print
Selvaraj S, Claggett BL, Pfeffer MA, Desai AS, ... McMurray JJV, Solomon SD
Eur J Heart Fail: 24 Aug 2020; epub ahead of print | PMID: 32840930
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Abstract

Integration of a palliative approach into heart failure care: a European Society of Cardiology Heart Failure Association position paper.

Hill L, Geller TP, Baruah R, Beattie JM, ... Strömberg A, Jaarsma T

The Heart Failure Association of the European Society of Cardiology has published a previous position paper and various guidelines over the past decade recognizing the value of palliative care for those affected by this burdensome condition. Integrating palliative care into evidence-based heart failure management remains challenging for many professionals, as it includes the identification of palliative care needs, symptom control, adjustment of drug and device therapy, advance care planning, family and informal caregiver support, and trying to ensure a \"good death\". This new position paper aims to provide day-to-day practical clinical guidance on these topics, supporting the coordinated provision of palliation strategies as goals of care fluctuate along the heart failure disease trajectory. The specific components of palliative care for symptom alleviation, spiritual and psychosocial support, and the appropriate modification of guideline-directed treatment protocols, including drug deprescription and device deactivation, are described for the chronic, crisis and terminal phases of heart failure. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 05 Sep 2020; epub ahead of print
Hill L, Geller TP, Baruah R, Beattie JM, ... Strömberg A, Jaarsma T
Eur J Heart Fail: 05 Sep 2020; epub ahead of print | PMID: 32892431
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Abstract

National Trends in Heart Failure Mortality in Men and Women, United Kingdom, 2000-2017.

Taylor CJ, Ordóñez-Mena JM, Jones NR, Roalfe AK, ... Marshall T, Hobbs FR
Aims
To understand gender differences in the prognosis of women and men with heart failure, we compared mortality, cause of death and survival trends over time.
Methods and results
We analysed UK primary care data for 26 725 women and 29 234 men over age 45 years with a new diagnosis of heart failure between 1st January 2000 and 31st December 2017 using the Clinical Practice Research Datalink, inpatient Hospital Episode Statistics and the Office for National Statistics death registry. Age-specific overall survival and cause-specific mortality rates were calculated by gender and year. During the study period 15 084 women and 15 822 men with heart failure died. Women were on average five years older at diagnosis (79.6 vs 74.8 years). Median survival was lower in women compared to men (3.99 vs 4.47 years), but women had a 14% age-adjusted lower risk of all-cause mortality (HR 0.86, 95%CI: 0.84-0.88). HF was equally likely to be cause of death in women and men (HR 1.03, 95%CI: 0.96-1.12). There were modest improvements in survival for both genders, but these were greater in men. The reduction in mortality risk in women was greatest for those diagnosed in the community (HR 0.83, 95%CI: 0.80-0.85).
Conclusions
Women are diagnosed with heart failure older than men but have a better age-adjusted prognosis. Survival gains were less in women over the last two decades. Addressing gender differences in heart failure diagnostic and treatment pathways should be a clinical and research priority. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 05 Sep 2020; epub ahead of print
Taylor CJ, Ordóñez-Mena JM, Jones NR, Roalfe AK, ... Marshall T, Hobbs FR
Eur J Heart Fail: 05 Sep 2020; epub ahead of print | PMID: 32892471
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Abstract

Plasma D-dimer concentrations predicting stroke risk and rivaroxaban benefit in patients with heart failure and sinus rhythm: an analysis from the COMMANDER-HF trial.

Ferreira JP, Lam CSP, Anker SD, Mehra MR, ... Greenberg B, Zannad F
Background
D-dimer is a marker of fibrin degradation that reflects intra-vascular coagulation. Therefore, plasma concentrations of D-dimer might predict thromboembolic risk and rivaroxaban treatment effect.
Aims
To investigate the association between D-dimer levels and the risk of stroke and other thrombotic, bleeding and fatal events, and whether D-dimer concentrations could predict rivaroxaban 2.5mg/bd (vs. placebo) effect in patients enrolled in the COMMANDER-HF trial who were in sinus rhythm, had HFrEF and coronary artery disease.
Methods
Survival models with treatment-by-plasma D-dimer interaction. Baseline measurement of D-dimer was available in 4,107 (82%) of 5,022 patients enrolled. Median (percentile ) follow-up was 21 (12.9-32.8) months.
Results
The median (percentile ) plasma concentration of D-dimer was 360 (215-665)ng/mL. The D-dimer tertiles were: 1) ≤255; 2) 256-515; 3) >515ng/mL. Patients within the tertile-3 were older, and had lower BMI, blood pressure, hemoglobin, eGFR, and LVEF. Higher plasma D-dimer concentrations were independently associated with higher rates of death, stroke, and venous thromboembolism. For example, the all-cause death adjusted HR (95%CI) of tertile-3 vs. tertile-1 was 1.77 (1.48-2.11), p<0.001. The effect of rivaroxaban was similar in each tertile of D-dimer for all outcomes except stroke. Patients within the tertile-3 had the greatest absolute and relative stroke reduction (HR [95%CI] tertile-1=1.16 [0.49-2.74], tertile-2=1.45 [0.77-2.73], and tertile-3=0.36 [0.18-0.70]; interaction =0.008). The number-needed-to-treat to prevent one stroke in tertile-3 was 36.
Conclusion
In COMMANDER-HF, rivaroxaban reduced the risk of stroke but the benefit may be confined to patients with D-dimer concentrations above 515ng/mL. Prospective trials are warranted to confirm these findings.

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Eur J Heart Fail: 20 Sep 2020; epub ahead of print
Ferreira JP, Lam CSP, Anker SD, Mehra MR, ... Greenberg B, Zannad F
Eur J Heart Fail: 20 Sep 2020; epub ahead of print | PMID: 32959502
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Abstract

Cardiac output improvement by pecavaptan: A novel dual-acting vasopressin V1a/V2 receptor antagonist in experimental heart failure.

Mondritzki T, Mai TA, Vogel J, Pook E, ... Truebel H, Kolkhof P
Aims
Arginine vasopressin (AVP) mediates deleterious effects via vascular V1a and renal V2 receptors in heart failure (HF). Despite positive short-term decongestive effects in phase II HF studies, selective V2 receptor antagonism has shown no long-term mortality benefit, potentially related to unopposed V1a receptor activation. We compared the novel dual V1a/V2 receptor antagonist pecavaptan with the selective V2 receptor antagonist tolvaptan in preclinical HF models.
Methods and results
In vitro IC50 determination in recombinant cell lines revealed similar receptor selectivity profiles (V2:V1a) of tolvaptan and pecavaptan for human and dog AVP receptors, respectively. Two canine models were used to compare haemodynamic and aquaretic effects: (a) anaesthetised dogs with tachypacing-induced HF, and (b) conscious telemetric dogs with a non-invasive cardiac output (CO) monitor. Tolvaptan and pecavaptan exhibited no differences in urinary output. In HF dogs, pecavaptan counteracted the AVP-induced increase in afterload and decrease in CO (pecavaptan: 1.83 l/min ± 0.31; vs. tolvaptan: 1.46 ± 0.07 l/min, P < 0.05). In conscious telemetric animals, pecavaptan led to a significant increase in CO (+0.26 l/min ± 0.17, P = 0.0086 vs. placebo), in cardiac index (+0.58 l/min/m ± 0.39, P = 0.009 vs. placebo) and a significant decrease in total peripheral resistance (-5348.6 dyn x s/cm ± 3601.3, P < 0.0001 vs. placebo), whereas tolvaptan was without any significant effect.
Conclusions
Simultaneous blockade of vascular V1a and renal V2 receptors efficiently induces aquaresis and counteracts AVP-mediated haemodynamic aggravation in HF models. Dual V1a/V2 antagonism may lead to improved outcomes in HF.

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Eur J Heart Fail: 17 Sep 2020; epub ahead of print
Mondritzki T, Mai TA, Vogel J, Pook E, ... Truebel H, Kolkhof P
Eur J Heart Fail: 17 Sep 2020; epub ahead of print | PMID: 32946151
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Abstract

Self-care of heart failure patients: practical management recommendations from the Heart Failure Association of the European Society of Cardiology.

Jaarsma T, Hill L, Bayes-Genis A, Brunner La Rocca HP, ... Seferovic P, Strömberg A

Self-care is essential in the long-term management of chronic heart failure. Heart failure guidelines stress the importance of patient education on treatment adherence, lifestyle changes, symptom monitoring and adequate response to possible deterioration. Self-care is related to medical and person-centered outcomes in patients with heart failure such as better quality of life as well as lower mortality and readmission rates. Although guidelines give general direction for self-care advice, health care professionals working with patients with heart failure need more specific recommendations. The aim of the management recommendations in this paper is to provide practical advice for health professionals delivering care to patients with heart failure. Recommendations for nutrition, physical activity, medication adherence, psychological status, sleep, leisure and travel, smoking, immunization and preventing infections, symptom monitoring, and symptom management are consistent with information from guidelines, expert consensus documents, recent evidence and expert opinion.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 17 Sep 2020; epub ahead of print
Jaarsma T, Hill L, Bayes-Genis A, Brunner La Rocca HP, ... Seferovic P, Strömberg A
Eur J Heart Fail: 17 Sep 2020; epub ahead of print | PMID: 32945600
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Abstract

Association of Left Ventricular Ejection Fraction with Worsening Renal Function in Patients with Acute Heart Failure: Insights from the RELAX-AHF-2 Study.

Feng S, Janwanishstaporn S, Teerlink J, Metra M, ... Voors AA, Greenberg B
Background
Whether risk of worsening renal function (WRF) during acute heart failure (AHF) hospitalization or the association between in-hospital WRF and post-discharge outcomes vary according to left ventricular ejection fraction (LVEF) are uncertain. We assessed incidence of WRF, factors related to its development and impact of WRF on post-discharge outcomes across the spectrum of LVEF in patients enrolled in RELAX-AHF-2.
Methods and results
6112 patients who had LVEF measured on admission and renal function determined prospectively during hospitalization were included. WRF, defined as rise in serum creatinine ≥0.3mg/dl from baseline through day 5, occurred in 1722 patients (28.2%). Incidence increased progressively from lowest to highest LVEF quartile (p<0.001). After baseline adjustment, WRF risk in Q4 (LVEF>50%) remained significantly greater than in Q1 (LVEF <29%; HR 1.2, 95% CI 1.00-1.43; P=0.05). Age and co-morbidity burden including chronic kidney disease increased as LVEF increased. Neither admission hemodynamic abnormalities, extent of diuresis during hospitalization nor residual congestion explained the increased incidence of WRF in patients with higher LVEF. Serelaxin treatment and diuretic responsiveness were associated with reduced risk of WRF in all LVEF quartiles. WRF in patients in the upper three LVEF quartiles increased risk of post-discharge events.
Conclusions
WRF incidence during AHF hospitalization increases progressively with LVEF. Greater susceptibility of patients with higher LVEF to WRF appears more related to their advanced age and worse underlying kidney function rather than hemodynamic or treatment effects. WRF is associated with increased risk of post-discharge events except in patients in the lowest LVEF quartile. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 21 Sep 2020; epub ahead of print
Feng S, Janwanishstaporn S, Teerlink J, Metra M, ... Voors AA, Greenberg B
Eur J Heart Fail: 21 Sep 2020; epub ahead of print | PMID: 32964537
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Abstract

Coronary Microvascular Dysfunction is Associated with Exertional Haemodynamic Abnormalities in Patients with HFpEF.

Ahmad A, Corban MT, Toya T, Verbrugge FH, ... Borlaug BA, Lerman A
Aims
This study uniquely explored the relationship between coronary microvascular function and exercise haemodyanmics using concurrent invasive testing.
Methods and results
Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive CAD and normal LVEF (>50%) underwent haemodyanmic exercise assessment and concurrent coronary reactivity testing. HFpEF was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg at rest and/or ≥25 mmHg at peak exercise. Endothelium-independent CMD was defined as a coronary flow reserve (CFR) ≤2.5, while endothelium-dependent CMD was defined as ≤50% increase in coronary blood flow (CBF) in response to intracoronary acetylcholine infusions. Patients with HFpEF (n=22) had significantly lower CFR (2.5±0.6 vs. 3.2±0.7;P=0.0003) and median %CBF increase in response to intracoronary acetylcholine (1[-35; 34] vs. 64[-4; 133];P=0.002) compared to patients without HFpEF (n=29). PAWP was significantly higher in patients with endothelium-independent CMD compared to controls during both rest and exercise. This significant elevation was only present during exercise in patients with endothelium-dependent CMD compared to controls. CFR had significant inverse correlations with PAWP at rest (r=-0.31; P=0.03) and peak exercise (r=-0.47, P=0.001). CFR also had positive correlations with maximal exercise capacity [in Watts/Kg] (r=0.33, P=0.02).
Conclusions
Coronary microvascular function is inversely associated with filling pressures, particularly during exercise. Both types of CMD are associated with higher filling pressures at peak exercise. These findings underscore the potential mechanism and therapeutic target for CMD and HFpEF.

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Eur J Heart Fail: 18 Sep 2020; epub ahead of print
Ahmad A, Corban MT, Toya T, Verbrugge FH, ... Borlaug BA, Lerman A
Eur J Heart Fail: 18 Sep 2020; epub ahead of print | PMID: 32949186
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Abstract

Omecamtiv Mecarbil in Chronic Heart Failure with Reduced Ejection Fraction, GALACTIC-HF: Baseline Characteristics and Comparison with Contemporary Clinical Trials.

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

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 26 Sep 2020; epub ahead of print
Teerlink JR, Diaz R, Felker GM, McMurray JJV, ... Kurtz CE,
Eur J Heart Fail: 26 Sep 2020; epub ahead of print | PMID: 32985088
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Abstract

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

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

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

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Eur J Heart Fail: 01 Oct 2020; epub ahead of print
Pudil R, Mueller C, Čelutkienė J, Henriksen PA, ... de Boer RA, Lyon AR
Eur J Heart Fail: 01 Oct 2020; epub ahead of print | PMID: 33006257
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Abstract

Prognostic value of cardio-pulmonary exercise testing in cardiac amyloidosis.

Nicol M, Deney A, Lairez O, Vergaro G, ... Arnulf B, Logeart D
Background
In amyloid patients, cardiac involvement dramatically worsens functional capacity and prognosis.
Purpose
We sought to study how the cardio-pulmonary exercise test (CPET) could help in functional assessment and risk stratification of patients with cardiac amyloidosis (CA).
Methods
We carried out a multicenter 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 (HF) hospitalization.
Results
We included 150 patients: 91 AL and 59 TTR CA. Median age, systolic blood pressure, NT-proBNP and cardiac troponin T were 70 [64-78] years old, 121 [IQR 109-139] mmHg, 2809 [IQR 1218-4638] ng/L and 64 [IQR 33-120] ng/L respectively. NYHA classes were I- II in 64%. Median peak VO and circulatory power were low at 13.0 mL/kg/min [10.0-16.9] and 1729 mmHg.mL min [1318-2614] respectively. The VE/VCO slope was increased to 37 [IQR 33-45]. Seventy-seven patients (51%) had chronotropic insufficiency. After a median follow-up of 20 months, there were 37 deaths and 44 HF hospitalizations. Multivariate Cox analysis shows that peak VO  ≤ 13 mL/kg/min (HR 2.7; CI95% 1.6-4.8), circulatory power ≤ 1800 mmHg.mL.min (HR 2.4; CI95% 1.2-4.6) and NT-proBNP ≥1800 ng/L (HR 2.2; CI95% 1.1-4.3) were associated with the primary outcome. There was no event in patients with both peak VO2 > 13 mL/kg/min and NTproBNP <1800 ng/L, while the association of VO2 ≤ 13 mL/kg/min and NTproBNP ≥1800 ng/L identified a very high-risk subgroup.
Conclusion
In CA, CPET helps to assess functional capacity, circulatory and chronotropic responses and helps to assess the prognosis of patients along with cardiac biomarkers.

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Eur J Heart Fail: 01 Oct 2020; epub ahead of print
Nicol M, Deney A, Lairez O, Vergaro G, ... Arnulf B, Logeart D
Eur J Heart Fail: 01 Oct 2020; epub ahead of print | PMID: 33006180
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Abstract

Standardized Definitions for Evaluation of Heart Failure Therapies: Scientific Expert Panel from the Heart Failure Collaboratory and Academic Research Consortium (HF-ARC).

Abraham WT, Psotka MA, Fiuzat M, Filippatos G, ... Anker SD, O\'Connor CM

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation. CONDENSED ABSTRACT: The Heart Failure Collaboratory and Academic Research Consortium multi-stakeholder partnership convened to establish expert consensus definitions and key concepts for heart failure clinical trials including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. With uniform definitions, heart failure interventions can be better standardized, evaluated, and compared between trials and patient populations, and the quality of generated evidence may be strengthened.

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Eur J Heart Fail: 04 Oct 2020; epub ahead of print
Abraham WT, Psotka MA, Fiuzat M, Filippatos G, ... Anker SD, O'Connor CM
Eur J Heart Fail: 04 Oct 2020; epub ahead of print | PMID: 33017862
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Abstract

ACE inhibitor/angiotensin II receptor blocker treatment and hemodynamic factors are associated with increased cardiac mRNA expression of ACE2 in patients with cardiovascular disease.

Lebek S, Tafelmeier M, Messmann R, Provaznik Z, ... Arzt M, Wagner S
Aims
The coronavirus disease 2019 (Covid-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either ACE inhibitors or angiotensin 1-receptor blockers (ACEi/ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic.
Methods and results
We have measured ACE2 mRNA expression using real-time qPCR in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB versus 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent from potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression.
Conclusion
Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery heart disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, hemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 04 Oct 2020; epub ahead of print
Lebek S, Tafelmeier M, Messmann R, Provaznik Z, ... Arzt M, Wagner S
Eur J Heart Fail: 04 Oct 2020; epub ahead of print | PMID: 33017071
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Abstract

Left Ventricular Systolic Ejection Time is an Independent Predictor of All-Cause Mortality in Heart Failure with Reduced Ejection Fraction.

Saed Alhakak A, Sengeløv M, Jørgensen PG, Bruun NE, ... Gislason G, Biering-Sørensen T
Background
Color Tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to obtain the cardiac time intervals including the 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 10ms decrease in SET (per 10 ms decrease: HR 1.09; 95% CI (1.06-1.13), p <0.001). The association remained significant even after multivariable adjustment for clinical and echocardiographic parameters (per 10ms 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 the IVCT or IVRT and mortality were found in unadjusted nor adjusted models. Additionally, the 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, the SET provides independent and incremental prognostic information regarding all-cause mortality.

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Eur J Heart Fail: 08 Oct 2020; epub ahead of print
Saed Alhakak A, Sengeløv M, Jørgensen PG, Bruun NE, ... Gislason G, Biering-Sørensen T
Eur J Heart Fail: 08 Oct 2020; epub ahead of print | PMID: 33034122
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Abstract

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

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

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

Eur J Heart Fail: 17 Sep 2020; epub ahead of print
Ibrahim NE, Piña IL, Camacho A, Bapat D, ... Januzzi JL,
Eur J Heart Fail: 17 Sep 2020; epub ahead of print | PMID: 32946164
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Abstract

The Cancer Patient and Cardiology.

Zamorano JL, Gottfridsson C, Asteggiano R, Atar D, ... Suter TM, Minotti G

Advances in cancer treatment have improved clinical outcomes, leading to an increasing population of cancer survivors. Yet, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach including expertise from oncology, cardiology, and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and management, and long-term follow-up strategies for patients at risk of cancer therapy-related cardiotoxicities. Research is highly needed to better define strategies for early identification, follow-up, and management. While the academic cardio-oncology community may be the best vehicle to foster awareness and research in this field, additional stakeholders (industry, government agencies, and patient organizations) have to be involved to facilitate cross-disciplinary interactions and help in the design and funding of cardio-oncology trials. The overarching goal of cardio-oncology is to assist clinicians in providing optimal care for patients with cancer and for cancer survivors, to provide insight into future areas of research and to search for collaborations with industry, funding bodies, and patient advocates. However, many unmet needs remain. This document is the product of brainstorming presentations and active discussions held at the Cardiovascular Round Table (CRT) workshop organised in January 2020 by the European Society of Cardiology (ESC). This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 17 Aug 2020; epub ahead of print
Zamorano JL, Gottfridsson C, Asteggiano R, Atar D, ... Suter TM, Minotti G
Eur J Heart Fail: 17 Aug 2020; epub ahead of print | PMID: 32809231
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Abstract

Cachexia, muscle wasting, and frailty in cardiovascular disease.

Bielecka-Dabrowa A, Ebner N, Dos Santos MR, Ishida J, Hasenfuss G, von Haehling S

The last several years have seen increasing interest in understanding cachexia, muscle wasting, and physical frailty across the broad spectrum of patients with cardiovascular illnesses. This interest originally started in the field of heart failure, but has recently been extended to other areas such as atrial fibrillation, coronary artery disease, peripheral artery disease as well as to patients after cardiac surgery or transcatheter aortic valve implantation. Tissue wasting and frailty are prevalent among many of the affected patients. The ageing process itself and concomitant cardiovascular illness decrease lean mass while fat mass is relatively preserved, making elderly patients particularly prone to develop wasting syndromes and frailty. The aim of this review is to provide an overview of the available knowledge of body wasting and physical frailty in patients with cardiovascular illness, particularly focussing on patients with heart failure in whom most of the available data has been gathered. In addition, mechanisms of wasting and possible therapeutic targets are discussed.

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Eur J Heart Fail: 18 Sep 2020; epub ahead of print
Bielecka-Dabrowa A, Ebner N, Dos Santos MR, Ishida J, Hasenfuss G, von Haehling S
Eur J Heart Fail: 18 Sep 2020; epub ahead of print | PMID: 32949422
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Abstract

Heart Failure Association of the European Society of Cardiology Update on Sodium Glucose Co-transporter-2 Inhibitors in Heart Failure (an update on the Sodium-glucose co-transporter 2 inhibitors in heart failure: beyond glycaemic control. The position paper of the Heart Failure Association of the European Society of Cardiology).

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

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given: Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin have consistently demonstrated to be effective for the prevention of HF hospitalisation in patients with T2DM and established CV disease or at high CV risk. The specifically listed agents are recommended. Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalisation and CV death in symptomatic patients with HF and reduced ejection fraction, already receiving guideline directed medical therapy, regardless of the presence of T2DM.

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Eur J Heart Fail: 16 Oct 2020; epub ahead of print
Seferović PM, Fragasso G, Petrie M, Mullens W, ... Coats AJS, Rosano GMC
Eur J Heart Fail: 16 Oct 2020; epub ahead of print | PMID: 33068051
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Abstract

Telemonitoring in patients with chronic heart failure and moderate depressed symptoms - results of the Telemedical Interventional Monitoring in Heart Failure (TIM-HF) study.

Koehler J, Stengel A, Hofmann T, Wegscheider K, ... Koehler F, Laufs U
Background
Depression is a frequent comorbidity in patients with chronic heart failure (CHF). Telemonitoring has emerged as a novel option in CHF care. However, patients with depression were excluded in most telemedicine studies.
Aims
This prespecified subgroup-analysis of the Telemedical Interventional Monitoring in Heart Failure (TIM-HF) trial investigates the effect on depressive symptoms over a period of 12 months.
Methods
The TIM-HF study randomly assigned 710 patients with CHF to either usual care (UC) or a telemedical intervention (TM) using non-invasive devices for daily monitoring electrocardiogram, blood pressure and body weight. Depression was evaluated by the Patient Health Questionnaire (PHQ-9) with scores ≥10 defining clinically relevant depressive symptoms. Mixed model repeated measures were performed to calculate changes in PHQ-9 score. Quality of life (Qol) was measured by the Short Form-36 (SF-36).
Results
At baseline, 156 patients had a PHQ-9 score ≥10 points (TM: 79, UC: 77) with a mean of 13.2 points indicating moderate depressiveness. Patients randomized to telemedicine showed an improvement of their PHQ-9 scores, whereas UC patients remained constant (p=0.004). Qol parameters were improved in the TM group compared to UC. Adjustment was performed for follow-up, NYHA class, medication, age, current living status, number of hospitalizations within last 12 months and serum creatinine. In the study population without depression the PHQ-9 score was similar at baseline and follow-up.
Conclusion
Telemedical care improved depressive symptoms and had a positive influence on quality of life in patients with CHF and moderate depression.

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Eur J Heart Fail: 14 Oct 2020; epub ahead of print
Koehler J, Stengel A, Hofmann T, Wegscheider K, ... Koehler F, Laufs U
Eur J Heart Fail: 14 Oct 2020; epub ahead of print | PMID: 33063412
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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 80mg, 20mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80mg or 20mg; 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 80mg (P =0.0030) and 20mg (P=0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80mg (Cox hazards model [95% CI]: 0.690 [0.487-0.979], P=0.0378) and 20mg (0.715 [0.450-1.137], P=0.1564). The mean (SE) change in NT-proBNP from baseline to Month 30 was -1170.51 (587.31), P=0.0468 with tafamidis 80mg vs. 20mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80mg vs 20mg (0.700 [0.501-0.979], P=0.0374). Incidence of adverse events in both tafamidis doses were comparable to placebo.
Conclusion
Tafamidis, both 80mg and 20mg, 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 80mg as the optimal dose. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

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

Frequency, Trends and Institutional Variation in 30-Day All-Cause Mortality and Unplanned Readmissions Following Hospitalisation for Heart Failure in Australia and New Zealand.

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

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Eur J Heart Fail: 22 Oct 2020; epub ahead of print
Labrosciano C, Horton D, Air T, Tavella R, ... Hariharaputhiran S, Ranasinghe I
Eur J Heart Fail: 22 Oct 2020; epub ahead of print | PMID: 33094886
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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 senile (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 is used in France to treat patients with ATTRv with neuropathy (alone or with cardiomyopathy). Recently, the Phase III ATTRACT 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 ATTRACT trial and to assess the impact of tafamidis on major cardiovascular outcome-free (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. 467 (72%) patients matched the inclusion criteria of the ATTRACT study. 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, Nt-proBNP 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 ATTRACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcome in a real-life population.

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Eur J Heart Fail: 22 Oct 2020; epub ahead of print
Bézard M, Kharoubi M, Galat A, Poullot E, ... Oghina S, Damy T
Eur J Heart Fail: 22 Oct 2020; epub ahead of print | PMID: 33094885
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Abstract

Common Mechanistic Pathways in Cancer and Heart Failure.

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

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation, and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Further, genetic predisposition and clonal hematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Also, altered angiogenesis is a common hallmark for failing hearts and tumors and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the 2 pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. Also, preclinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including all ages, and men and women, with proper adjudication of both cancer and CV end points, are essential to accurately study these two pathologies at the same time.

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Eur J Heart Fail: 21 Oct 2020; epub ahead of print
de Boer RA, Hulot JS, Gabriele Tocchetti C, Aboumsallem JP, ... Lyon AR, Backs J
Eur J Heart Fail: 21 Oct 2020; epub ahead of print | PMID: 33094495
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This program is still in alpha version.