Journal: Eur J Heart Fail

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Abstract

Short-term Effects of Dapagliflozin on Maximal Functional Capacity in Heart Failure with Reduced Ejection Fraction (DAPA-VO ): A Randomized Clinical Trial.

Palau P, Amiguet M, Domínguez E, Sastre C, ... Núñez J, DAPA-VO2 Investigators
Aims
This study aimed to evaluate the effect of dapagliflozin on 1 and 3-month maximal functional capacity in patients with stable heart failure with reduced ejection fraction (HFrEF).
Methods and results
In this multicenter, randomized, double-blinded clinical trial, 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin (n=45) or placebo (n=45) (http://clinicaltrials.gov identifier: NCT04197635). The primary outcome was a change in peak oxygen consumption (peakVO2 ) at 1 and 3-month. Secondary endpoints were changes at 1 and 3-month in the distance walked in 6 minutes (6MWT), quality of life (Minnesota Living with Heart Failure Questionnaire -MLHFQ-), and echocardiographic parameters (diastolic function, left chambers volumes, and left ventricular ejection fraction). We used linear mixed regression analysis to compare endpoints changes. Estimates were adjusted for multiple comparisons. The mean age was 67.1 ± 10.7 years, 63 (76.7%) were men, 29 (32.2%) had type-2 diabetes, and 80 (89.9%) were on NYHA II. The baseline means of peakVO2 , 6MWT and MLHFQ were 13.2±3.5 mL/kg/min, 363±110 meters, and 23.1±16.2, respectively. The median (p25%-p75%) of N-terminal pro-brain natriuretic peptide was 1221 pg/ml (889-2100). Most patients were on treatment with sacubitril/valsartan (88.9%), beta-blockers (91.1%), and aldosterone receptor antagonists (74.4%). PeakVO2 significantly increased in patients on treatment with dapagliflozin (1-month: +Δ 1.09 mL/kg/min, CI 95%=0.14-2.04; p=0.021 and 3-month: +Δ 1.06 mL/kg/min, CI 95%=0.07-2.04; p=0.032). Similar positive findings were found when evaluating changes from baseline. We did not find significant differences in secondary endpoints.
Conclusions
Among patients with stable HFrEF, dapagliflozin resulted in a significant improvement in peakVO2 at 1 and 3-month.

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Eur J Heart Fail: 23 May 2022; epub ahead of print
Palau P, Amiguet M, Domínguez E, Sastre C, ... Núñez J, DAPA-VO2 Investigators
Eur J Heart Fail: 23 May 2022; epub ahead of print | PMID: 35604416
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Abstract

Outcomes with Empagliflozin in Heart Failure with Preserved Ejection Fraction Using DELIVER-like Endpoint Definitions.

Anker SD, Siddiqi TJ, Filippatos G, Zannad F, ... Packer M, Butler J
Aims
To report data from EMPEROR-Preserved according to prespecified endpoints of DELIVER.
Methods and results
To assess the impact of DELIVER-like definition on EMPEROR-Preserved outcomes, the following differences were reconciled: 1) primary outcome in DELIVER added urgent HF visits to cardiovascular death or HF hospitalizations; 2) EMPEROR-Preserved trial did not require documentation of physical findings or laboratory tests for confirming a HF hospitalization and it included events of 12-24 hours if intensification of treatment was not only oral diuretics; 3) DELIVER excluded undetermined causes of deaths from primary endpoint; 4) The composite renal endpoint in DELIVER included a sustained reduction of ≥50% eGFR and incorporated renal death; and 5): DELIVER will assess outcomes in the total population and in EF <60% separately. Using the endpoint definitions from DELIVER, the primary outcome overall occurred in 13.1% in the empagliflozin and 16.8% in the placebo group (HR 0.76 [0.67, 0.87]; P<0.001). The relative risk reduction (RRR) changed from 21% to 24% when urgent HF visits were added, and undetermined death was eliminated. Compared to overall population RRR of 24%, it was 28% in patients with EF <60%. Death from cardiovascular causes excluding undetermined causes occurred in 6.2% in the empagliflozin and in 7.1% in the placebo group (HR 0.88 [0.73, 1.07]). The RRR for the renal endpoint (changed from 22% in the overall population (HR 0.78; 95% CI, 0.54 to 1.13) to 40% when patients with EF <60% were assessed (P=0.037).
Conclusion
Findings from the EMPEROR-Preserved were modestly altered when analyzed using cardiovascular trial endpoint definitions of the DELIVER trial. For the composite renal endpoint, the effect of empagliflozin became statistically significant in patients with LVEF <60% using the DELIVER definition.

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Eur J Heart Fail: 23 May 2022; epub ahead of print
Anker SD, Siddiqi TJ, Filippatos G, Zannad F, ... Packer M, Butler J
Eur J Heart Fail: 23 May 2022; epub ahead of print | PMID: 35604680
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Abstract

Prognostic impact of the updated 2018 HFA-ESC definition of advanced heart failure: Results from the HELP-HF Registry.

Pagnesi M, Lombardi CM, Chiarito M, Stolfo D, ... Pini D, Metra M
Background
The Heart Failure Association of the European Society of Cardiology (HFA-ESC) proposed a definition of advanced heart failure (HF) which has not been validated, yet. We assessed its prognostic impact in a consecutive series of patients with high-risk HF.
Methods and results
The HELP-HF registry enrolled consecutive patients with HF and at least one high-risk \"I NEED HELP\" marker, evaluated at four Italian centres between January 1st , 2020, and November 30th , 2021. Patients meeting the HFA-ESC advanced HF definition were compared to patients not meeting this definition. The primary endpoint was the composite of all-cause mortality or first HF hospitalization. Out of 4,753 patients with HF screened, 1,149 (24.3%) patients with at least one high-risk \"I NEED HELP\" marker were included (mean age 75.1 ± 11.5 years, 67.3% males, median LVEF 35% [IQR 25-50%]). Among them, 193 (16.8%) patients met the HFA-ESC advanced HF definition. As compared to others, these patients were younger, had lower LVEF, higher natriuretic peptides and a worse clinical profile. The 1-year rate of the primary endpoint was 69.3% in patients with advanced HF according to the HFA-ESC definition versus 41.8% in the others (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.82-2.74, p<0.001). The prognostic impact of the HFA-ESC advanced HF definition was confirmed after multivariable adjustment for relevant covariates (adjusted HR 1.98, 95% CI 1.57-2.50, p<0.001).
Conclusions
The HFA-ESC advanced HF definition had a strong prognostic impact in a contemporary, real-world, multicentre high-risk cohort of patients with HF. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 23 May 2022; epub ahead of print
Pagnesi M, Lombardi CM, Chiarito M, Stolfo D, ... Pini D, Metra M
Eur J Heart Fail: 23 May 2022; epub ahead of print | PMID: 35603658
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Abstract

Endovascular Ablation of the Right Greater Splanchnic Nerve in Heart Failure with Preserved Ejection Fraction: Early Results of the REBALANCE-HF Trial Roll-in Cohort.

Fudim M, Fail PS, Litwin SE, Shaburishvili T, ... Burkhoff D, Shah SJ
Background
In heart failure with preserved ejection fraction (HFpEF), excessive redistribution of blood volume into the central circulation leads to elevations of intracardiac pressures with exercise limitations. Splanchnic ablation for volume management (SAVM) has been proposed as a therapeutic intervention.
Aims
Here we present preliminary safety and efficacy data from the initial roll-in cohort of the REBALANCE-HF trial.
Methods
The open-label (roll-in) arm of REBALANCE-HF will enroll up to 30 patients, followed by the randomized, sham-controlled portion of the trial (up to 80 additional patients). Patients with HF, LVEF ≥50%, and invasive peak exercise PCWP ≥25 mmHg underwent SAVM. Baseline and follow-up assessments included resting and exercise PCWP, NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6-minute walk test, and NTproBNP. Efficacy and safety were assessed at 1 and 3 months.
Results
Here we report on the first 18 patients with HFpEF have been enrolled into the roll-in, open-label arm of the study across 9 centers; 14 (78%) female; 16 (89%) NYHA class III; and median (IQR) age 75.2 (68.4-81) years, LVEF 61.0 (56.0-63.2)%, and average (SD) 20W exercise PCWP 36.4 (±8.6) mmHg. All 18 patients were successfully treated. Three non-serious moderate device/procedure-related adverse events were reported. At 1-month, the mean PCWP at 20W exercise decreased from 36.4 (±8.6) to 28.9 (±7.8) mmHg (p<0.01), NYHA class improved by at least 1 class in 33% of patients (p=0.02) and KCCQ score improved by 22.1 points (95% CI 9.4-34.2) (p<0.01).
Conclusion
The preliminary open-label results from the multi-center REBALANCE-HF roll-in cohort support the safety and efficacy of SAVM in HFpEF. The findings require confirmation in the ongoing randomized, sham-controlled portion of the trial. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 22 May 2022; epub ahead of print
Fudim M, Fail PS, Litwin SE, Shaburishvili T, ... Burkhoff D, Shah SJ
Eur J Heart Fail: 22 May 2022; epub ahead of print | PMID: 35598154
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Abstract

Left atrial disease and left atrial reverse remodeling across different stages of heart failure development and progression: a new target for prevention and treatment.

Inciardi RM, Bonelli A, Biering-Sorensen T, Cameli M, ... Solomon SD, Metra M
The left atrium is a dynamic chamber with peculiar characteristics. Stressors and disease mechanisms may deeply modify its structure and function, leading to left atrial remodeling and disease. Left atrial disease is a predictor of poor outcomes. It may be a consequence of left ventricular systolic and diastolic dysfunction and neurohormonal and inflammatory activation and/or actively contribute to the progression and clinical course of heart failure through multiple mechanisms such as left ventricular filling and development of atrial fibrillation and subsequent embolic events. There is growing evidence that therapy may improve left atrial function and reverse left atrial remodeling. Whether this translates into changes in patient\'s prognosis is still unknown. In this review we report current data about changes in left atrial size and function across different stages of development and progression of heart failure. At each stage, drug therapies, life-style interventions and procedures have been associated to improvement in left atrial structure and function, namely a reduction in left atrial volume and/or an improvement in left atrial strain, a process that can be defined as left atrial reverse remodeling and, in some cases, this has been associated with improvement in clinical outcomes. Further evidence is still needed mainly with respect of the possible role of left atrial reverse remodeling as an independent mechanism affecting the patient\'s clinical course and as regards better standardization of clinically meaningful changes in left atrial measurements. Summarizing current evidence, this review may be the basis for further studies. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 22 May 2022; epub ahead of print
Inciardi RM, Bonelli A, Biering-Sorensen T, Cameli M, ... Solomon SD, Metra M
Eur J Heart Fail: 22 May 2022; epub ahead of print | PMID: 35598167
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Abstract

Sex and Central Obesity in Heart Failure with Preserved Ejection Fraction.

Sorimachi H, Omote K, Omar M, Popovic D, ... Jensen MD, Borlaug BA
Aims
Obesity is a risk factor for heart failure with preserved ejection fraction (HFpEF), particularly in women, but the mechanisms remain unclear. The present study aimed to investigate the impact of central adiposity in patients with HFpEF and explore potential sex differences.
Methods and results
124 women and 105 men with HFpEF underwent invasive hemodynamic exercise testing and rest echocardiography. Central obesity was defined as a waist circumference (WC) ≥88 cm for women and ≥102 cm for men. Exercise-normalized pulmonary capillary wedge (PCWP) responses were evaluated by the ratio of PCWP to workload (PCWP/Watts) and after normalizing to body weight (PCWL). The prevalence of central obesity (77%) exceeded that of general obesity (62%) defined by body mass index (BMI≥30kg/m2 ). Compared to patients without central adiposity, patients with HFpEF and central obesity displayed greater prevalence of diabetes and dyslipidemia, higher right and left heart filling pressures and pulmonary artery pressures during exertion, and more severely reduced aerobic capacity. Associations between WC and fasting glucose, low density lipoprotein (LDL)-cholesterol, peak workload, and pulmonary artery pressures were observed in women but not in men with HFpEF. Although increased WC was associated with elevated PCWP in both sexes, the association with PCWP/Watts was observed in women but not in men. The strength of correlation between PCWP/Watts and WC was more robust in women with HFpEF as compared to men (Meng\'s test p=0.0008), and a significant sex interaction was observed in the relationship between PCWL and WC (p for interaction=0.02).
Conclusions
Central obesity is even more common than general obesity in HFpEF, and there appear to be important sexual dimorphisms in its relationships with metabolic abnormalities and hemodynamic perturbations, with greater impact in women. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 22 May 2022; epub ahead of print
Sorimachi H, Omote K, Omar M, Popovic D, ... Jensen MD, Borlaug BA
Eur J Heart Fail: 22 May 2022; epub ahead of print | PMID: 35599453
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Abstract

Distinct pathophysiological pathways in women and men with heart failure.

Ravera A, Santema BT, de Boer RA, Anker SD, ... Voors AA, Sama IE
Aims
Clinical differences between women and men have been described in heart failure (HF). However, less is known about the underlying pathophysiological mechanisms. In this study, we compared multiple circulating biomarkers to gain better insights into differential HF pathophysiology between women and men.
Methods and results
In 537 women and 1485 men with HF, we compared differential expression of a panel of 363 biomarkers. Then, we performed a pathway over-representation analysis to identify differential biological pathways in women and men. Findings were validated in an independent HF cohort (575 women, 1123 men). In both cohorts, women were older and had higher ejection fraction (LVEF). In the index and validation cohorts respectively, we found 14/363 and 12/363 biomarkers that were relatively up-regulated in women, while 21/363 and 14/363 were up-regulated in men. In both cohorts, the strongest up-regulated biomarkers in women were leptin and fatty acid binding protein-4, compared to matrix metalloproteinase-3 in men. Similar findings were replicated in a subset of patients from both cohorts matched by age and LVEF. Pathway over-representation analysis revealed increased activity of pathways associated with lipid metabolism in women, and neuroinflammatory response in men (all p < 0.0001).
Conclusion
In two independent cohorts of HF patients, biomarkers associated with lipid metabolic pathways were observed in women, while biomarkers associated with neuro-inflammatory response were more active in men. Differences in inflammatory and metabolic pathways may contribute to sex differences in clinical phenotype observed in HF, and provide useful insights towards development of tailored HF therapies. This article is protected by copyright. All rights reserved.

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Eur J Heart Fail: 21 May 2022; epub ahead of print
Ravera A, Santema BT, de Boer RA, Anker SD, ... Voors AA, Sama IE
Eur J Heart Fail: 21 May 2022; epub ahead of print | PMID: 35596674
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Abstract

Effects of sildenafil on symptoms and exercise capacity for heart failure with reduced ejection fraction and pulmonary hypertension (The SilHF study): A randomised placebo-controlled multicentre trial.

Cooper TJ, Cleland JG, Guazzi M, Pellicori P, ... Steine K, Dickstein K
Background
Pulmonary hypertension (PHT) may complicate heart failure with reduced ejection fraction (HFrEF) and is associated with a substantial symptom burden and poor prognosis. Sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, might have beneficial effects on pulmonary haemodynamics, cardiac function and exercise capacity in HFrEF and PHT.
Aims
To determine the safety, tolerability, and efficacy of sildenafil in patients with HFrEF and indirect evidence of PHT.
Methods and results
The Sildenafil in Heart Failure (SilHF) trial was an investigator-led, randomised, multinational trial in which patients with HFrEF and a pulmonary artery systolic pressure (PASP) ≥40 mmHg by echocardiography were randomly assigned in a 2:1 ratio to receive sildenafil (up to 40 mg three times/day) or placebo. The co-primary endpoints were improvement in patient global assessment by visual analogue scale and in the 6-minute walk test at 24 weeks. The planned sample size was 210 participants but, due to problems with supplying sildenafil/placebo and recruitment, only 69 patients (11 women, median age 68 (IQR 62, 74) years, median left ventricular ejection fraction 29% (IQR 24, 35), median PASP 45 (IQR 42,55) mmHg) were included. Compared to placebo, sildenafil did not improve symptoms, quality of life, PASP or walk test distance. Sildenafil was generally well tolerated, but those assigned to sildenafil had numerically more serious adverse events (33% vs. 21%).
Conclusion
Compared to placebo, sildenafil did not improve symptoms, quality of life or exercise capacity in patients with HFrEF and PHT.

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Eur J Heart Fail: 21 May 2022; epub ahead of print
Cooper TJ, Cleland JG, Guazzi M, Pellicori P, ... Steine K, Dickstein K
Eur J Heart Fail: 21 May 2022; epub ahead of print | PMID: 35596935
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Abstract

Multi-Variable Biomarker Approach in Identifying Incident Heart Failure in Chronic Kidney Disease Results from the Chronic Renal Insufficiency Cohort (CRIC) Study.

Janus SE, Hajjari J, Chami T, Mously H, ... Rahman M, Al-Kindi SG
Aims
Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality in the ever-growing population of patients with chronic kidney disease (CKD). There is a need to enhance early prediction to initiate treatment in CKD. We sought to study the feasibility of a multi-variable biomarker approach to predict incident HF risk in CKD.
Methods
We examined 3182 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) without prevalent HF and who underwent serum/plasma assays for 11 blood biomarkers at baseline visit (BNP, CXCL12, fibrinogen, fractalkine, high sensitivity CRP, myeloperoxidase, high sensitivity troponin, fibroblast growth factor 23-(FGF23), NGAL (Neutrophil gelatinase-associated lipocalin), Fetuin A, Aldosterone). The population was randomly divided into derivation (n=1629) and validation (n=1553) cohorts. Biomarkers that were associated with HF after adjustment for established HF risk factors were combined into an overall biomarker score (number of biomarkers above the Youden\'s index cut-off value). Cox regression was used to explore the predictive role of a biomarker panel to predict incident HF.
Results
A total of 411 patients developed incident HF at a median follow-up of 7 years. In the derivation cohort, 4 biomarkers were associated with HF (BNP, FGF23, fibrinogen, hsTNT). In a model combining all 4 biomarkers, BNP (HR 2.96 (2.14-4.09)), FGF23 (HR 1.74 (1.30-2.32)), fibrinogen (HR 2.40 (1.74-3.3)), and hsTNT (HR 2.89 (2.06-4.04)) were associated with incident HF. The incidence of HF increased with the biomarker score, to a similar degree in both derivation and validation cohorts: from 2.0% in score of 0 to 46.6% in score of 4 in the derivation cohort to 2.4% in score of 0 to 43.5% in score of 4 in the validation cohort. A model incorporating biomarkers in addition to clinical factors reclassified risk in 601 (19%) participants [352 (11%) participants to higher risk and 249 (8%) to lower risk] compared with clinical risk model alone (net reclassification improvement of 0.16).
Conclusion
A basic panel of 4 blood biomarkers (BNP, FGF23, fibrinogen, and HsTNT) can be used as a standalone score to predict incident HF in patients with CKD allowing early identification of patients at high-risk for HF. Addition of biomarker score to clinical risk model modestly reclassifies HF risk and slightly improves discrimination.

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Eur J Heart Fail: 19 May 2022; epub ahead of print
Janus SE, Hajjari J, Chami T, Mously H, ... Rahman M, Al-Kindi SG
Eur J Heart Fail: 19 May 2022; epub ahead of print | PMID: 35587997
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Abstract

Head-to-head comparison between recommendations by the ESC and ACC/AHA/HFSA Heart Failure Guidelines.

Bayés-Genís A, Aimo A, Metra M, Anker S, ... Rosano G, Coats AJ
Recommendations represent the core messages of Guidelines, and are particularly important when the body of scientific evidence is rapidly growing, as in the case of heart failure (HF). The main messages from two latest major HF Guidelines, endorsed by the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA), are partially overlapping, starting from the four pillars of treatment for HF with reduced ejection fraction. Some notable differences exist, in part related to the timing of recent publications (most notably, the Universal Definition of Heart Failure paper and the EMPEROR-Preserved trial), and in part reflecting differing views of the natural history of HF (with a clear differentiation between stages A and B HF in the ACC/AHA/HFSA Guidelines). Different approaches are proposed to specific issues such as risk stratification and implantable cardioverter defibrillator use for primary prevention in HFrEF patients with non-ischaemic aetiology. The ACC/AHA/HFSA Guidelines put a greater emphasis on some issues that are particularly relevant to the US setting, such as the cost-effectiveness of therapies and the impact of health disparities on HF care. A comparison between Guideline recommendations may give readers a deeper understanding of the ESC and ACC/AHA/HFSA Guidelines, and help them apply sensible approaches to their own practice, wherever that may be in the world. A comparison may possibly also help further harmonization of recommendations between future Guidelines, by identifying why some areas have led to conflicting recommendation, even when ostensibly reviewing the same published evidence.

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Eur J Heart Fail: 17 May 2022; epub ahead of print
Bayés-Genís A, Aimo A, Metra M, Anker S, ... Rosano G, Coats AJ
Eur J Heart Fail: 17 May 2022; epub ahead of print | PMID: 35579428
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Abstract

Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for TAVI Results of the IIISAS randomised trial.

Kvaslerud AB, Bardan S, Andresen K, Kløve SF, ... Gullestad L, Broch K
Aims
The aim of this trial was to evaluate whether intravenous iron could provide benefit beyond transcatheter aortic valve implantation (TAVI) in iron deficient patients with severe aortic stenosis.
Methods and results
In this randomised, placebo-controlled, double-blinded, single-centre trial, we enrolled patients with severe aortic stenosis and iron deficiency (defined as ferritin < 100 μg/L, or 100-299 μg/L with a transferrin saturation < 20 %) who were evaluated for TAVI. Patients were randomly assigned (1:1) to receive i.v. ferric derisomaltose or placebo approximately three months before TAVI. The primary endpoint was the between-group, baseline-adjusted six-minute walk distance measured three months after TAVI. Secondary outcomes included quality of life, iron stores, handgrip strength, NYHA class, and safety. Between January 2020 and September 2021, we randomised 74 patients to ferric derisomaltose and 75 patients to placebo. The modified intention-to-treat population comprised the 104 patients who completed the six-minute walk test at baseline and three months after successful TAVI. Iron stores were restored in 76 % of the patients allocated to iron and 13 % of the patients allocated to placebo (p < 0.001). There was no difference in the baseline-adjusted six-minute walk distance between the two treatment arms (p = 0.82). The number of serious adverse events, quality of life, handgrip strength, and NYHA class did not differ between the treatment arms.
Conclusion
Treatment with intravenous iron did not provide clinical benefit beyond TAVI in iron deficient patients with severe aortic stenosis.

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Eur J Heart Fail: 17 May 2022; epub ahead of print
Kvaslerud AB, Bardan S, Andresen K, Kløve SF, ... Gullestad L, Broch K
Eur J Heart Fail: 17 May 2022; epub ahead of print | PMID: 35579454
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Abstract

Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure.

Nath M, Romaine SP, Koekemoer A, Hamby S, ... Timmons JA, Samani NJ
Aims
Chronic Heart Failure (CHF) is a systemic syndrome with a poor prognosis and a need for novel therapies. We investigated whether whole-blood transcriptomic profiling can provide new mechanistic insights into cardiovascular (CV) mortality in CHF.
Methods and results
Transcriptome profiles were generated at baseline from 944 CHF patients from the BIOSTAT-CHF Study - of whom 626 survived and 318 died from a CV cause during a follow-up of 21 months. Multivariable analysis, including adjustment for cell count, identified 1,153 genes (6.5%) that were differentially expressed between those that survived or died and strongly related to a validated clinical risk score for adverse prognosis. The differentially expressed genes mainly belonged to 5 non-redundant pathways: Adaptive immune response, proteasome-mediated ubiquitin-dependent protein catabolic process, T-cell co-stimulation, positive regulation of T-cell proliferation and erythrocyte development. These five pathways were selectively related (RV coefficients >0.20) with seven circulating protein biomarkers of CV mortality (FGF23, sST2, adrenomedullin, hepcidin, pentraxin-3, WFDC2 and IL-6) revealing an intricate relationship between immune and iron homeostasis. The pattern of survival-associated gene expression matched with 29 perturbagen-induced transcriptome signatures in the iLINCS drug-repurposing database, identifying drugs, approved for other clinical indications, that were able to reverse in vitro the molecular changes associated with adverse prognosis in CHF.
Conclusion
Systematic modeling of the whole blood protein-coding transcriptome defined molecular pathways that provide a link between clinical risk factors and adverse cardiovascular prognosis in CHF, identifying both established and new potential therapeutic targets.

© 2022 European Society of Cardiology.

Eur J Heart Fail: 15 May 2022; epub ahead of print
Nath M, Romaine SP, Koekemoer A, Hamby S, ... Timmons JA, Samani NJ
Eur J Heart Fail: 15 May 2022; epub ahead of print | PMID: 35570197
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Abstract

Factors associated with health-related quality of life in heart failure in 23,000 patients from 40 countries: Results of the G-CHF Research Program.

Johansson I, Balasubramanian K, Bangdiwala S, Mielniczuk L, ... Yusuf S, GCHF investigators
Aims
To examine clinical and social correlates of health-related quality of life (HRQL), in patients with heart failure (HF) from high- (HIC), upper middle- (UMIC), lower middle-(LMIC) and low-income (LIC) countries.
Methods and results
Between 2017 and 2020, we enrolled 23,292 patients with HF (32% inpatients, 61% men) from 40 countries in the Global Congestive Heart Failure Study. We recorded HRQL at baseline using Kansas City Cardiomyopathy Questionnaire (KCCQ)-12. In a cross-sectional analysis, we compared age- and sex-adjusted mean KCCQ-12 summary scores (SS: 0-100, higher=better) between patients from different country income levels. We used multivariable linear regression examining correlations (estimated coefficients) of KCCQ-12-SS with sociodemographic-, comorbidity-, treatment- and symptom-covariates. The adjusted model (37 covariates) was informed by univariable findings, clinical importance and backward selection. Mean age was 63 years and 40% were in NYHA class III-IV. Average HRQL was 55±0.5. It was 62.5 (95% CI 62.0-63.1) in HIC, 56.8 (56.1-57.4) in UMIC, 48.6 (48.0-49.3) in LMIC, and 38.5 (37.3-39.7) in LICs (p<0.0001). Strong correlates (estimated coefficient [95% CI]) of KCCQ-12-SS were NYHA class III vs class I/II (-12.1 [-12.8 to -11.4] and class IV vs. class I/II (-16.5 [-17.7 to -15.3]), effort dyspnea (-9.5[-10.2 to -8.8]) and living in LIC vs. HIC (-5.8[-7.1 to -4.4]). Symptoms explained most of the KCCQ-12-SS variability (partial R2 =0.32 of total adjusted R2 =0.51), followed by sociodemographic factors (R2 =0.12). Results were consistent in populations across income levels.
Conclusion
The most important correlates of HRQL in HF patients relate to HF symptom severity, irrespective of country-income level.

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Eur J Heart Fail: 15 May 2022; epub ahead of print
Johansson I, Balasubramanian K, Bangdiwala S, Mielniczuk L, ... Yusuf S, GCHF investigators
Eur J Heart Fail: 15 May 2022; epub ahead of print | PMID: 35570198
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Abstract

Changes in Cardiac Biomarkers in Association with Alterations in Cardiac Structure and Function, and Health Status in HFrEF: The EVALUATE-HF Trial.

Myhre PL, Claggett BL, Shah AM, Prescott MF, ... Solomon SD, Desai AS
Aims
N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T (cTnT) and soluble ST2 (sST2) provide complementary prognostic information in HF with reduced ejection fraction (HFrEF). We aimed to assess the association between changes in these markers with changes in cardiac structure, function and health status.
Methods and results
Patients in the EVALUATE-HF trial (N=464) were randomized to sacubitril/valsartan or enalapril for 12 weeks, followed by 12-week open-label sacubitril/valsartan. Cardiac biomarkers, echocardiography, and Kansas City Cardiomyopathy Questionnaires (KCCQ) were completed at baseline, and after 12 and 24 weeks. A total of 410 patients (88%) had serial biomarker measurements available (mean age 67±9 years, 75% male and 75% white). After 24 weeks of treatment NT-proBNP, sST2 and cTnT decreased by median (Q1,Q3) -31% (-55%,+6%), -6% (-19%,+8%) and -3% (-13%,+8%), respectively (all P<0.001). Decreases in NT-proBNP were associated with reductions in cardiac volumes and improvements in systolic and diastolic function and health status. Decreases in cTnT were associated with reductions in LV mass, but not with changes in LV function or KCCQ. Decreases in sST2 were consistently associated with improvements in health status, but not with measures of cardiac structure or function. There were no effect modification from treatment on the associations investigated (P-for-interaction>0.05).
Conclusion
In HFrEF, serial changes in NT-proBNP correlate with changes in several key measures of cardiac structure and health status. cTnT changes correlate with changes in LV mass and sST2 with changes in health status. These data highlight possible complementary pathophysiologic implications of changes NT-proBNP, cTnT and sST2.

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Eur J Heart Fail: 12 May 2022; epub ahead of print
Myhre PL, Claggett BL, Shah AM, Prescott MF, ... Solomon SD, Desai AS
Eur J Heart Fail: 12 May 2022; epub ahead of print | PMID: 35560696
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Impact:
Abstract

Characteristics, management, and outcomes of patients with left-sided infective endocarditis complicated by heart failure: A substudy of the ESC-EORP EURO-ENDO (European infective endocarditis) registry.

Bohbot Y, Habib G, Laroche C, Stöhr E, ... Tribouilloy C, EORP EURO-ENDO Registry Investigators Group
Aims
To evaluate the current management and survival of patients with left-sided infective endocarditis (IE) complicated by congestive heart failure (CHF) in the ESC-EORP European Endocarditis (EURO-ENDO) registry.
Methods and results
Among the 3116 patients enrolled in this prospective registry, 2449 (mean age:60 years, 69% male) with left-sided (native or prosthetic) IE were included in this study. Patients with CHF (n=698, 28.5%) were older, with more comorbidity and more severe valvular damage (mitro-aortic involvement, vegetations>10mm and severe regurgitation/new prosthesis dehiscence) than those without CHF (all p≤0.019). Patients with CHF experienced higher 30-day and one-year mortality than those without (20.5% vs. 9.0% and 36.1% vs. 19.3%, respectively) and CHF remained strongly associated with 30-day(OR95%CI=2.37[1.73-3.24];p<0.001) and one-year mortality(HR95%CI=1.69[1.40-2.05];p<0.001) after adjustment for established outcome predictors, including early surgery, or after propensity matching for age, sex, and comorbidity(n=618[88.5%] for each group, both p<0.001). Early surgery, performed on 49% of these patients with IE complicated by CHF, remained associated with a substantial reduction in 30-day mortality following multivariable analysis, after adjustment for age, sex, Charlson index, cerebrovascular accident, staphylococcus aureus IE, Streptococcal IE, uncontrolled infection, vegetation size>10mm, severe valvular regurgitation and/or new prosthetic dehiscence, perivalvular complication, and prosthetic IE(OR95%CI=0.22[0.12-0.38];p<0.001) and in one-year mortality(HR95%CI=0.29[0.20-0.41];p<0.001).
Conclusion
CHF is common in left-sided IE and is associated with older age, greater comorbidity, more advanced lesions, and markedly higher 30-day and one-year mortality. Early surgery is strongly associated with lower mortality but is performed on only approximately half of patients with CHF, mainly because of a surgical risk considered prohibitive.

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Eur J Heart Fail: 04 May 2022; epub ahead of print
Bohbot Y, Habib G, Laroche C, Stöhr E, ... Tribouilloy C, EORP EURO-ENDO Registry Investigators Group
Eur J Heart Fail: 04 May 2022; epub ahead of print | PMID: 35508915
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Impact:
Abstract

Redefining the epidemiology of cardiac amyloidosis. A systematic review and meta-analysis of screening studies.

Aimo A, Merlo M, Porcari A, Georgiopoulos G, ... Emdin M, Rapezzi C
Background
An algorithm for non-invasive diagnosis of amyloid transthyretin cardiac amyloidosis (ATTR-CA) and novel disease-modifying therapies have prompted an active search of CA.
Methods
We performed a systematic search for screening studies on CA, focusing on the prevalence, sex and age distribution in different clinical settings.
Results
The prevalence of CA in different settings was as follows: bone scintigraphy for non-cardiac reasons (n=5 studies), 1% (95% confidence interval [CI] 0-1%); heart failure (HF) with preserved ejection fraction (n=6), 12% (95% CI 6-20%); HF with reduced or mildly reduced ejection fraction (n=2), 10% (95% CI 6-15%); conduction disorders warranting pacemaker implantation (n=1), 2% (95% 0-4%); surgery for carpal tunnel syndrome (CTS; n=3), 7% (95% CI 5-10%); hypertrophic cardiomyopathy phenotype (n=2), 7% (95% CI 5-9%); severe aortic stenosis (n=7), 8% (95% CI 5-13%); autopsy series of \"unselected\" elderly individuals (n=4), 21% (95% CI 7-39%). The average age of CA patients in the different settings ranged from 74 to 90 years, and the percentage of men from 50% to 100%. Many patients had ATTR-CA, but the average percentage of patients with amyloid light-chain (AL) CA was up to 18%.
Conclusions
Searching for CA in specific settings allows to identify a relatively high number of cases, who may be eligible for treatment if the diagnosis is unequivocal. ATTR-CA accounts for many cases of CA across the different settings, but AL-CA is not infrequent. Median age at diagnosis falls in the eighth or ninth decades, and many patients diagnosed with CA are women.

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Eur J Heart Fail: 04 May 2022; epub ahead of print
Aimo A, Merlo M, Porcari A, Georgiopoulos G, ... Emdin M, Rapezzi C
Eur J Heart Fail: 04 May 2022; epub ahead of print | PMID: 35509173
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Impact:
Abstract

Improving Clinical Trial Efficiency Using a Machine Learning Based Risk Score to Enrich Study Populations.

Jering KS, Campagnari C, Claggett B, Adler E, ... Yagil A, Greenberg B
Aims
Prognostic enrichment strategies can make trials more efficient, although potentially at the cost of diminishing external validity. Whether using a risk score to identify a population at increased mortality risk could improve trial efficiency is uncertain. We aimed to assess whether Machine learning Assessment of RisK and EaRly mortality in Heart Failure (MARKER-HF), a previously validated risk score, could improve clinical trial efficiency.
Methods and results
Mortality rates and association of MARKER-HF with all-cause death by one year was evaluated in four community-based heart failure (HF) and five HF clinical trial cohorts. Sample size required to assess effects of an investigational therapy on mortality was calculated assuming varying underlying MARKER-HF risk and proposed treatment effect profiles. Patients from community-based HF cohorts (n=11,297) had higher observed mortality and MARKER-HF scores than did clinical trial patients (n=13,165) with HF with either reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). MARKER-HF score was strongly associated with risk of one-year mortality both in the community (HR 1.48 [95% CI: 1.44-1.52]) and clinical trial cohorts with HFrEF (HR 1.41 [95% CI: 1.30-1.54]), and HFpEF (HR 1.74 [95% CI: 1.53-1.98]), per 0.1 increase in MARKER-HF. Using MARKER-HF to identify patients for a hypothetical clinical trial assessing mortality reduction with an intervention, enabled a reduction in sample size required to show benefit.
Conclusion
Using a reliable predictor of mortality such as MARKER-HF to enrich clinical trial populations provides a potential strategy to improve efficiency by requiring a smaller sample size to demonstrate a clinical benefit.

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Eur J Heart Fail: 04 May 2022; epub ahead of print
Jering KS, Campagnari C, Claggett B, Adler E, ... Yagil A, Greenberg B
Eur J Heart Fail: 04 May 2022; epub ahead of print | PMID: 35508918
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Impact:
Abstract

Improved survival of left ventricular assist device carriers in Europe according to implantation eras - results from the PCHF-VAD registry.

Jakus N, Brugts JJ, Claggett B, Timmermans P, ... Cikes M, PCHF-VAD registry
Background:
and aim
Temporal changes in patient selection and major technological developments in have occurred in the field of LVADs, yet analyses depicting this trend are lacking for Europe. We describe the advances of European LVAD programmes from the PCHF-VAD registry across device implantation eras.
Methods
Of 583 patients from 13 European centres in the registry, 556 patients (mean age 53 ± 12 years, 82% male) were eligible for this analysis. Patients were divided to eras (E) by date of LVAD implantation: E1 from December 2006 to and including December 2012 (6 years), E2 from January 2013 to January 2020 (7 years).
Results
Patients implanted more recently were older with more comorbidities, but less acutely ill. Receiving an LVAD in E2 was associated with improved 1-year survival in adjusted analysis (HR 0.58 [0.35-0.98] p = 0.043). LVAD implantation in E2 was associated with a significantly lower chance of heart transplantation (adjusted HR 0.40 [0.23-0.67], p = 0.001), and lower risk of LVAD-related infections (adjusted HR 0.64, [0.43-0.95], p = 0.027), both in unadjusted and adjusted analyses. The adjusted risk of haemocompatibility-related events decreased (HR 0.60 [0.39-0.91], p = 0.016), while the heart failure-related events increased in E2 (HR 1.67 [1.02-2.75], p = 0.043).
Conclusion
In an analysis depicting the evolving landscape of cf-LVAD carriers in Europe over 13 years, a trend towards better survival is seen in the recent years, despite older recipients with more comorbidities, potentially attributable to increasing expertise of LVAD centres, improved patient selection and pump technology. However, a smaller chance of undergoing heart transplantation was noted in the second era, underscoring the relevance of improved outcomes on LVAD support.

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Eur J Heart Fail: 04 May 2022; epub ahead of print
Jakus N, Brugts JJ, Claggett B, Timmermans P, ... Cikes M, PCHF-VAD registry
Eur J Heart Fail: 04 May 2022; epub ahead of print | PMID: 35508920
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Impact:
Abstract

Incidence and Risk Factors for Pacemaker Implantation in Light Chain and Transthyretin Cardiac Amyloidosis.

Porcari A, Rossi M, Cappelli F, Canepa M, ... Sinagra G, Merlo M
Aims
The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. We sought to characterise the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light chain (AL) and transthyretin (ATTR) CA.
Methods and results
Consecutive patients with AL and ATTR-CA diagnosed at participating Centres (2017-2020) were included. Clinical data recorded within ±1 month from diagnosis were collected from electronic medical records. The primary study outcome was the need for clinically-indicated PM implantation. Patients with PM (n = 41) and/or permanent defibrillator in situ (n = 13) at CA diagnosis were excluded. The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were males, median age 76 years. During a median follow-up of 33 months (interquartile range 21-46), 36 (8.9%) patients experienced the primary outcome: 10 AL-CA, 2 variant ATTR-CA and 24 wild-type ATTR-CA (p = 0.08 at time-to-event analysis). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p = 0.002), PR interval (HR 1.013, p = 0.002) and QRS >120 ms (HR 4.7, p = 0.001) on baseline ECG were independently associated with PM implantation. The absence of these 3 factors had a negative predictive value of 92% with an area under the curve of 91.8% at 6 months.
Conclusion
In a large cohort of AL and ATTR-CA patients, 8.9% implanted a PM in the 3 years following diagnosis. History of atrial fibrillation, PR >200 ms and QRS >120 ms predicted future PM implantation.

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Eur J Heart Fail: 04 May 2022; epub ahead of print
Porcari A, Rossi M, Cappelli F, Canepa M, ... Sinagra G, Merlo M
Eur J Heart Fail: 04 May 2022; epub ahead of print | PMID: 35509181
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Impact:
Abstract

Predictors of primary prevention implantable cardioverter defibrillator use in heart failure with reduced ejection fraction: Impact of the predicted risk of sudden cardiac death and all-cause mortality.

Schrage B, Lund LH, Benson L, Dahlström U, ... Levy WC, Savarese G
Aims
Use of implantable cardioverter-defibrillators (ICD) for primary prevention of sudden cardiac death (SCD) in heart failure with reduced ejection fraction (HFrEF) is limited. We aimed to investigate barriers to ICD use in HFrEF while considering the predicted risk of mortality and SCD.
Method and results
Patients from the SwedeHF registered in 2011-2018 and with an indication for primary prevention ICD were analyzed. The Seattle Proportional Risk and Seattle HF Models were used to predict the proportional SCD and all-cause mortality risk, respectively. A multivariable logistic regression model was fitted to identify independent predictors of ICD use/non-use; Cox regression models to evaluate the interaction between predicted SCD/mortality risk and ICD use for mortality. Of 13,475 patients, only 15.5% had an ICD. Those with higher predicted proportional SCD risk (>45%) had an ~80% higher likelihood to have an ICD. Other predictors of non-use were follow-up in primary vs. specialty care, higher comorbidity burden and lower socioeconomic status. ICD use was associated with lower mortality only in patients with higher predicted SCD and lower mortality risk (34% and 37% relative risk reduction for 3-year all-cause and cardiovascular mortality). In this subgroup of patients underuse of ICD was 81.8%.
Conclusion
In a contemporary registry, only 15.5% patients with an indication for primary prevention ICD had the device. While a high predicted proportional SCD risk was appropriately linked to ICD use, the lack of specialized follow-up, higher comorbidity burden, and lower socioeconomic status were major unjustified impediments to implementation. Our findings suggest areas for improving ICD use for primary prevention of SCD in clinical practice. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 03 May 2022; epub ahead of print
Schrage B, Lund LH, Benson L, Dahlström U, ... Levy WC, Savarese G
Eur J Heart Fail: 03 May 2022; epub ahead of print | PMID: 35502681
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Impact:
Abstract

The Effect of Cardiac Resynchronization without a Defibrillator on Morbidity and Mortality: An Individual-Patient-Data Meta-Analysis of COMPANION and CARE-HF.

Cleland JGF, Bristow MR, Freemantle N, Olshansky B, ... Daubert JC, deMets D
Background
Cardiac resynchronization therapy (CRT) reduces morbidity and mortality for patients with heart failure, reduced left ventricular ejection fraction, QRS duration >130 ms and in sinus rhythm.
Objectives
To identify patient-characteristics that predict the effect, specifically, of CRT-pacemakers (CRT-P) on all-cause mortality or the composite of hospitalisation for heart failure or all-cause mortality.
Methods
An individual patient-data meta-analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization - Heart Failure (CARE-HF) trials. Only patients assigned to CRT-P or control (n = 1738) were included in order to avoid confounding from concomitant defibrillator therapy. The influence of baseline characteristics on treatment effects was investigated.
Results
Median age was 67 (59-73) years, most patients were men (70%), 68% had a QRS duration of 150-199 ms and 80% had left bundle branch block (LBBB). Patients assigned to CRT-P had lower rates for all-cause mortality (HR 0.68 (95% CI 0.56 to 0.81; p < 0.0001) and the composite outcome (HR 0.67 (95% CI 0.58 to 0.78; p < 0.0001). No pre-specified characteristic, including sex, aetiology of ventricular dysfunction, QRS duration (within the studied range) or morphology or PR interval significantly influenced the effect of CRT-P on all-cause mortality or the composite outcome. However, CRT-P had a greater effect on the composite outcome for patients with lower body surface area (BSA) and those prescribed beta-blockers.
Conclusions
CRT-P reduces morbidity and mortality in appropriately selected patients with heart failure. Benefits may be greater in smaller patients and in those receiving beta-blockers. Neither QRS duration nor morphology independently predicted the benefit of CRT-P.

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Eur J Heart Fail: 01 May 2022; epub ahead of print
Cleland JGF, Bristow MR, Freemantle N, Olshansky B, ... Daubert JC, deMets D
Eur J Heart Fail: 01 May 2022; epub ahead of print | PMID: 35490339
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Impact:
Abstract

Cardiac Remodelling Part 2: Clinical, Imaging and Laboratory Findings A review from the Biomarkers Working Group of the Heart Failure Association of the ESC.

Aimo A, Vergaro G, González A, Barison A, ... Emdin M, Bayes-Genis A
In patients with heart failure (HF), the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Biomarker Study Group of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with HFrEF because most studies on cardiac remodelling focused on this setting.

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Eur J Heart Fail: 30 Apr 2022; epub ahead of print
Aimo A, Vergaro G, González A, Barison A, ... Emdin M, Bayes-Genis A
Eur J Heart Fail: 30 Apr 2022; epub ahead of print | PMID: 35488811
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Impact:
Abstract

Pathological Findings of Clinically Suspected Myocarditis Temporally Associated with COVID-19 Vaccination.

Yamamoto M, Tajiri K, Ayuzawa S, Ieda M
Reports on the pathological findings of patients with myocarditis after coronavirus disease 2019 (COVID-19) vaccination are limited. We present a case series of four patients with clinically suspected myocarditis temporally associated with COVID-19 vaccination who underwent endomyocardial biopsy with no evidence of viral genomes in tissue specimens. Two patients had fulminant myocarditis with marked inflammatory cell infiltration comprised mostly of CD8+ T-cells and macrophages, and the other two had suspected myocarditis based on the biochemical evidence of myocardial injury and ST changes on an electrocardiogram. However, they did not meet the histological criteria of myocarditis. Immunosuppressive therapy effectively reduced myocardial damage, and all four patients had improved clinical courses. Temporal association does not prove causation, and it cannot be excluded that the two biopsy-proven cases reported are simply a random association of a naturally occurring virus-negative immune-mediated lymphocytic myocarditis occurring after the vaccination.

© 2022 European Society of Cardiology.

Eur J Heart Fail: 30 Apr 2022; epub ahead of print
Yamamoto M, Tajiri K, Ayuzawa S, Ieda M
Eur J Heart Fail: 30 Apr 2022; epub ahead of print | PMID: 35488842
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Impact:
Abstract

Combination of late gadolinium enhancement and genotype improves prediction of prognosis in non-ischemic dilated cardiomyopathy.

Mirelis JG, Escobar-Lopez L, Ochoa JP, Espinosa MÁ, ... Dominguez F, García-Pavía P
Aims
Genotype and left ventricular (LV) scar on cardiac magnetic resonance (CMR) are increasingly recognized as risk markers for adverse outcomes in non-ischemic dilated cardiomyopathy (DCM). We investigated the combined influence of genotype and late gadolinium enhancement (LGE) in assessing prognosis in a large cohort of patients with DCM.
Methods and results
Outcomes of 600 patients with DCM (53.3±14.1 years, 66% males) who underwent clinical CMR and genetic testing were retrospectively analyzed. The primary endpoints were end-stage heart failure (ESHF) and malignant ventricular arrhythmias (MVA). During a median follow-up of 2.7 years (interquartile range 1.3-4.9), 24 (4.00%) and 48 (8.00%) patients had ESHF and MVA, respectively. In total, 242 (40.3%) patients had pathogenic/likely pathogenic variants (positive genotype) and 151 (25.2%) had LGE. In survival analysis, positive LGE was associated with MVA and ESHF (both, p<0.001) while positive genotype was associated with ESHF (p=0.034) but not with MVA (p=0.102). Classification of patients according to genotype (G+/G-) and LGE presence (L+/L-) revealed progressively increasing events across L-/G-, L-/G+, L+/G- and L+/G+ groups and resulted in optimized MVA and ESHF prediction (p<0.001 and p=0.001, respectively). Hazard ratios for MVA and ESHF in patients with either L+ or G+ compared with those with L-/G- were 4.71 (95% confidence interval: 2.11-10.50, p<0.001) and 7.92 (95% confidence interval: 1.86-33.78, p<0.001), respectively.
Conclusion
Classification of patients with DCM according to genotype and LGE improves MVA and ESHF prediction. Scar assessment with CMR and genotyping should be considered to select patients for primary prevention ICD placement.

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Eur J Heart Fail: 29 Apr 2022; epub ahead of print
Mirelis JG, Escobar-Lopez L, Ochoa JP, Espinosa MÁ, ... Dominguez F, García-Pavía P
Eur J Heart Fail: 29 Apr 2022; epub ahead of print | PMID: 35485241
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Impact:
Abstract

Epicardial Adipose Tissue related to Left Atrial and Ventricular Function in Heart Failure with Preserved (HFpEF) versus Reduced and Mildly Reduced Ejection Fraction (HFrEF/HFmrEF).

Jin X, Hung CL, Tay WT, Soon D, ... Voors AA, Lam CSP
Background
Different associations between epicardial adipose tissue (EAT) and cardiac function have been suggested in patients with heart failure with preserved (HFpEF) versus reduced and mildly reduced ejection fraction (HFrEF/HFmrEF). However, few studies have directly compared the association between EAT and left atrial (LA) and ventricular (LV) function in patients with HFpEF and HFrEF/HFmrEF.
Methods
We studied EAT thickness using transthoracic echocardiography in a multicenter cohort of 149 community-dwelling controls without HF, 99 patients with HFpEF, and 366 patients with HFrEF/HFmrEF. EAT thickness was averaged from parasternal long-axis and short-axis views, respectively, and off-line speckle tracking analysis was performed to quantify LA and LV function. Data were validated in an independent cohort of 626 controls, 243 patients with HFpEF, and 180 patients with HFrEF/HFmrEF. For LV function, LV global longitudinal strain (GLS) was measured in both derivation and validation cohorts. For the LA function, LAGLS at reservoir, contractile and conduit phase were measured in the derivation cohort, and only LAGLS at reservoir phase was measured in the validation cohort.
Results
In the derivation cohort, EAT thickness was lower in HFrEF/HFmrEF (7.3±2.5mm) compared to HFpEF (8.3±2.6mm, p<0.05) and controls (7.9±1.8mm, p<0.05). Greater EAT thickness was associated with better LV and contractile LA function in HFrEF/HFmrEF, but not in HFpEF (p for interaction < 0.05). These findings were confirmed in the validation cohort, where EAT thickness was lower in HFrEF/HFmrEF (6.7±1.4mm) compared to HFpEF (9.6±2.8mm; p<0.05) and controls (7.7±2.3mm; p<0.05). Greater EAT thickness was associated with better LV and reservoir LA function in patients with HFrEF/HFmrEF but worse LV and reservoir LA function in patients with HFpEF (p for interaction <0.05). Thickened EAT (EAT thickness >10mm) was associated with LA dysfunction (LAGLS at reservoir phase<23%) in HFpEF, but not in HFrEF/HFmrEF.
Conclusion
EAT thickness is greater in patient with HFpEF than HFrEF/HFmrEF. Increased EAT thickness is associated with worse LA and LV function in HFpEF but the opposite in HFrEF/HFmrEF. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 27 Apr 2022; epub ahead of print
Jin X, Hung CL, Tay WT, Soon D, ... Voors AA, Lam CSP
Eur J Heart Fail: 27 Apr 2022; epub ahead of print | PMID: 35475591
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Impact:
Abstract

Transient versus persistent improved ejection fraction in non-ischemic dilated cardiomyopathy.

Manca P, Stolfo D, Merlo M, Gregorio C, ... Savarese G, Sinagra G
Aims
The recent definition of heart failure with improved ejection fraction (HFimpEF) outlined the importance of the longitudinal assessment of left ventricular ejection fraction (LVEF). However, long-term progression and outcomes of this subgroup are poorly explored. We sought to assess the LVEF trajectories and the correlations with outcome in non-ischemic dilated cardiomyopathy (NICM) with improved ejection fraction (impEF).
Methods and results
Consecutive NICM patients with baseline LVEF ≤40% enrolled in the Trieste Heart Muscle Disease Registry with ≥1 LVEF assessment after baseline were included. ImpEF was defined as a baseline LVEF ≤40%, and second evaluation showing both a ≥10% point increase from baseline LVEF and LVEF>40%. Transient impEF was defined by the documentation of recurrent LVEF ≤40% during follow-up. The primary endpoint was a composite of all-cause death, heart transplantation and left ventricular assist device (D/HT/LVAD). Among 800 patients, 460 (57%) had impEF (median time to improvement 13 months). Transient impEF was observed in 189 patients (41% of the overall impEF group) and was associated with higher risk of D/HT/LVAD compared with persistent impEF at multivariable analysis (HR 2.54; 95%CI 1.60-4.04). The association of declining LVEF with the risk of D/HT/LVAD was non-linear, with a steep increase up to 8% points reduction, then remaining stable.
Conclusions
In NICM, we observed a 57% rate of impEF. However, recurrent decline in LVEF was observed in ≈40% of impEF patients and it was associated with an increased risk of D/HT/LVAD.

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Eur J Heart Fail: 22 Apr 2022; epub ahead of print
Manca P, Stolfo D, Merlo M, Gregorio C, ... Savarese G, Sinagra G
Eur J Heart Fail: 22 Apr 2022; epub ahead of print | PMID: 35460146
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Impact:
Abstract

Quality of life assessed six months after hospitalisation for acute heart failure: An analysis from REPORT-HF (International Registry to assess mEdical Practice with lOngitudinal obseRvation for Treatment of Heart Failure).

McNaughton CD, McConnachie A, Cleland JG, Spertus JA, ... Ghadanfar M, Collins SP
Aims
Recovery of well-being after hospitalisation for acute heart failure (AHF) is a measure of the success of interventions and the quality of care but has rarely been quantified. Accordingly, we measured health status after discharge in an international registry (REPORT-HF) of AHF.
Methods and results
The analysis included 4,606 patients with AHF who survived to hospital discharge, had known vital status at six months, and were enrolled in the United States of America, Russian Federation, or Western Europe, where the Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered. Median age was 69 years (quartiles 59-78), 40% were women, and 34% had a left ventricular ejection fraction (LVEF) <40%, and 12% patients died by six months. Of 2,475 patients with a follow-up KCCQ, 28% were \"alive and well\" (KCCQ>75), while 43% had poor health status (KCCQ ≤50). Being \"alive and well\" was associated with new-onset AHF, LVEF <40%, younger age, higher baseline KCCQ, country, and race. Associations were similar for increasing health status, with the exception of country and addition of comorbidities.
Conclusion
In this international global registry, health status recovery after AHF hospitalisation was highly variable. Those with the best health status at 6 months were younger, had new-onset HF, and higher baseline KCCQ; nearly one-third of survivors were \"alive and well\". Investigating reasons for changes in KCCQ after hospitalisation might identify new therapeutic targets to improve patient-centred outcomes.

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Eur J Heart Fail: 16 Apr 2022; epub ahead of print
McNaughton CD, McConnachie A, Cleland JG, Spertus JA, ... Ghadanfar M, Collins SP
Eur J Heart Fail: 16 Apr 2022; epub ahead of print | PMID: 35429091
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Impact:
Abstract

Unmasking the Prevalence of Amyloid Cardiomyopathy in the Real World: Results from Phase 2 of AC-TIVE Study, an Italian Nationwide Survey.

Merlo M, Pagura L, Porcari A, Cameli M, ... Rapezzi C, Sinagra G
Aim
To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions.
Methods and results
This is an Italian prospective multicentric study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥ 55 years old with an \"AC suggestive\" echocardiogram (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (#NCT04738266). 381 patients with an \"AC suggestive\" echocardiogram were identified among a cohort of 5315 screened subjects. 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% CI: 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥ 2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy > 70%.
Conclusion
In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved LVEF, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 13 Apr 2022; epub ahead of print
Merlo M, Pagura L, Porcari A, Cameli M, ... Rapezzi C, Sinagra G
Eur J Heart Fail: 13 Apr 2022; epub ahead of print | PMID: 35417089
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Impact:
Abstract

Practical outpatient management of worsening chronic heart failure.

Girerd N, Mewton N, Tartière JM, Guijarro D, ... Rossignol P, Roubille F
Management of worsening heart failure (WHF) has traditionally been hospital-based, but with the rising burden of HF, the pressure on health care systems exerted by this disease necessitates a different strategy than long (and costly) hospital stays. A strategy for outpatient intravenous (IV) diuretic treatment of WHF has been developed in certain American centers in the past 10 years, whereas European centers have been mostly favoring \"classic\" in-hospital management of WHF. Embracing novel, outpatient approaches for treating WHF could substantially reduce the burden on healthcare systems while improving patient\'s satisfaction and quality of life. The present article is intended to provide essential knowledge and practical guidelines aimed at helping clinicians implement these new ambulatory approaches using day hospital and/or at-home hospitalization. The topics addressed by our group of HF experts include the pathophysiological background of diuretic therapy, the most suitable profile of WHF that may be managed in an ambulatory setting, the pharmacological protocols that can be used, as well as a detailed description of healthcare structures that can be proposed to deliver these ambulatory care interventions. The practical aspects of day hospital and Hospital-at-Home (HaH) IV diuretics administration are specifically emphasized. The algorithm provided along with the practical IV diuretics protocols should assist HF clinicians in implementing this new approach in their local clinical setting.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 13 Apr 2022; epub ahead of print
Girerd N, Mewton N, Tartière JM, Guijarro D, ... Rossignol P, Roubille F
Eur J Heart Fail: 13 Apr 2022; epub ahead of print | PMID: 35417093
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Impact:
Abstract

Predictors of relapse, death or heart transplantation in myocarditis before the introduction of immunosuppression: negative prognostic impact of female gender, fulminant onset, lower ejection fraction and serum autoantibodies.

Baritussio A, Schiavo A, Basso C, Giordani AS, ... Marcolongo R, Caforio ALP
Aims
Outcome predictors in myocarditis are not well defined; we aimed at identifying predictors of death, heart transplantation (HTx) and relapse before the introduction of immunosuppression.
Methods and results
From 1992 to 2012 we consecutively included 466 patients (68% male, 37±17 years, single centre recruitment, median follow-up 50 months), 216 with clinically suspected and 250 with biopsy (Bx)-proven myocarditis. Serum anti heart (AHA) and antiintercalated disk (AIDA) auto-antibodies were measured by indirect immunofluorescence. We performed univariable and multivariable analysis of clinical and diagnostic features at diagnosis. Survival free from death or HTx at 10 years was 83% in the whole group and was lower in Bx- proven vs. clinically suspected myocarditis (76% vs 94% respectively, p<0.001). Female gender (hazard ratio (HR) 2.7, 95% Confidence Intervals (CI) 1.1-6.5), fulminant presentation (HR 13.77, CI 9.7-261.73), high-titre organ-specific AHA (HR 4.2, CI 1.2-14.7) and anti-nuclear antibodies (ANA) (HR 5.2, CI 2.1-12.8) were independent predictors of death or HTx; higher echocardiographic left ventricular ejection fraction (LVEF) at diagnosis was protective, with a 0.93 times risk reduction for each 1% LVEF increase (CI 0.89-0.96). History of myocarditis at diagnosis (HR 8.5, CI 3.5-20.7) was independent predictor of myocarditis relapse at follow-up; older age was protective (HR 0.95, CI 0.91-0.99). Predictors of death, HTx and relapse did not differ in Bx-proven vs. clinically suspected myocarditis.
Conclusions
Young age and a previous myocarditis were independent relapse predictors; female gender, fulminant onset, lower LVEF at presentation and high-titre organ-specific AHA and ANA were independent predictors of death and HTx, suggesting that autoimmune features predict worse prognosis.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 04 Apr 2022; epub ahead of print
Baritussio A, Schiavo A, Basso C, Giordani AS, ... Marcolongo R, Caforio ALP
Eur J Heart Fail: 04 Apr 2022; epub ahead of print | PMID: 35377503
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Impact:
Abstract

Comparing and contrasting risk factors for heart failure in patients with and without history of myocardial infarction: data from HOMAGE and the UK Biobank.

Rastogi T, Ho FK, Rossignol P, Merkling T, ... Zannad F, Girerd N
Aims
Myocardial infarction (MI) is among the commonest attributable risk factors for heart failure (HF). We compared clinical characteristics associated with the progression to HF in patients with or without a history of MI in the HOMAGE cohort and validated our results in UK Biobank.
Methods and results
During a follow-up of 5.2 (3.5-5.9) years, 177 (2.4%) patients with prior MI and 370 (1.92%) patients without prior MI experienced HF onset in the HOMAGE cohort (n = 26 478, history of MI: n = 7241). Older age, male sex and higher heart rate were significant risk factors of HF onset in patients with and without prior MI. Lower renal function was more strongly associated with HF onset in patients with prior MI. Higher body mass index (BMI), systolic blood pressure and blood glucose were significantly associated with HF onset only in patients without prior MI (all p for interactions <0.05). In the UK Biobank (n = 500 001, history of MI: n = 4555), higher BMI, glycated haemoglobin, diabetes and hypertension had a stronger association with HF onset in participants without prior MI compared to participants with MI (all p for interactions <0.05).
Conclusion
The importance of clinical risk factors associated with HF onset is dependent on whether the patient has had a prior MI. Diabetes and hypertension are associated with new-onset HF only in the absence of MI history. Patients may benefit from targeted risk management based on MI history.

© 2022 European Society of Cardiology.

Eur J Heart Fail: 01 Apr 2022; epub ahead of print
Rastogi T, Ho FK, Rossignol P, Merkling T, ... Zannad F, Girerd N
Eur J Heart Fail: 01 Apr 2022; epub ahead of print | PMID: 35365899
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Impact:
Abstract

Characteristics and outcomes of patients screened for transcatheter mitral valve implantation: 1-year results from the CHOICE-MI registry.

Ben Ali W, Ludwig S, Duncan A, Weimann J, ... Modine T, CHOICE-MI Investigators
Aims
Transcatheter mitral valve implantation (TMVI) represents a novel treatment option for patients with mitral regurgitation (MR) unsuitable for established therapies. The CHOICE-MI registry aimed to investigate outcomes of patients undergoing screening for TMVI.
Methods and results
From May 2014 to March 2021, patients with MR considered suboptimal candidates for transcatheter edge-to-edge repair (TEER) and at high risk for mitral valve surgery underwent TMVI screening at 26 centres. Characteristics and outcomes were investigated for patients undergoing TMVI and for TMVI-ineligible patients referred to bailout-TEER, high-risk surgery or medical therapy (MT). The primary composite endpoint was all-cause mortality or heart failure hospitalization after 1 year. Among 746 patients included (78.5 years, interquartile range [IQR] 72.0-83.0, EuroSCORE II 4.7% [IQR 2.7-9.7]), 229 patients (30.7%) underwent TMVI with 10 different dedicated devices. At 1 year, residual MR ≤1+ was present in 95.2% and the primary endpoint occurred in 39.2% of patients treated with TMVI. In TMVI-ineligible patients (n = 517, 69.3%), rates of residual MR ≤1+ were 37.2%, 100.0% and 2.4% after bailout-TEER, high-risk surgery and MT, respectively. The primary endpoint at 1 year occurred in 28.8% of patients referred to bailout-TEER, in 42.9% of patients undergoing high-risk surgery and in 47.9% of patients remaining on MT.
Conclusion
This registry included the largest number of patients treated with TMVI to date. TMVI with 10 dedicated devices resulted in predictable MR elimination and sustained functional improvement at 1 year. In TMVI-ineligible patients, bailout-TEER and high-risk surgery represented reasonable alternatives, while MT was associated with poor clinical and functional outcomes.

© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 25 Mar 2022; epub ahead of print
Ben Ali W, Ludwig S, Duncan A, Weimann J, ... Modine T, CHOICE-MI Investigators
Eur J Heart Fail: 25 Mar 2022; epub ahead of print | PMID: 35338542
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Impact:
Abstract

Responder analysis for improvement in six-minute walk test with ferric carboxymaltose in patients with heart failure with reduced ejection fraction and iron deficiency.

Anker SD, Ponikowski P, Khan MS, Friede T, ... Filippatos GS, Butler J
Aim
Improving functional capacity is a key goal in heart failure (HF). This pooled analysis of FAIR-HF and CONFIRM-HF assessed the likelihood of improvement or deterioration in 6-min walk test (6MWT) among iron-deficient patients with chronic HF with reduced ejection fraction (HFrEF) receiving ferric carboxymaltose (FCM).
Methods and results
Data for 760 patients (FCM: 454; placebo: 306) were analysed. The proportions of patients receiving FCM or placebo who had ≥20, ≥30, and ≥ 40 m improvements or ≥ 10 m deterioration in 6MWT at 12 and 24 weeks were assessed. Patients receiving FCM experienced a mean (standard deviation) 31.1 (62.3) m improvement in 6MWT vs 0.1 (77.1) m improvement for placebo at week 12 (difference in mean changes 26.8 [16.6;37.0]). At week 12, the odds [95% CI] of 6MWT improvements of ≥20 m (odds ratio: 2.16 [1.57-2.96]; p < 0.0001), ≥30 m (2.00 [1.44-2.78]; p < 0.0001), and ≥ 40 m (2.29 [1.60-3.27]; p < 0.0001) were greater with FCM vs placebo, while the odds of a deterioration ≥10 m were reduced with FCM vs placebo (0.55 [0.38-0.80]; p = 0.0019). Among patients who experienced 6MWT improvements of ≥20, ≥30, or ≥ 40 m with FCM at week 12, more than 80% sustained this improvement at week 24.
Conclusion
FCM resulted in a significantly higher likelihood of improvement and a reduced likelihood of deterioration in 6MWT vs placebo among iron-deficient patients with HF. Of the patients experiencing clinically significant improvements at week 12, the majority sustained this improvement at week 24. These results are supportive of FCM to improve exercise capacity in HF. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 25 Mar 2022; epub ahead of print
Anker SD, Ponikowski P, Khan MS, Friede T, ... Filippatos GS, Butler J
Eur J Heart Fail: 25 Mar 2022; epub ahead of print | PMID: 35334136
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Impact:
Abstract

Cardiac Remodelling Part 1: From Cells and Tissues to Circulating Biomarkers.

González A, Richards AM, de Boer RA, Thum T, ... Coats AJ, Bayes-Genis A
Cardiac remodelling refers to changes in left ventricular (LV) structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leukocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g., proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and many biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of review paper on biomarkers of cardiac remodelling. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 25 Mar 2022; epub ahead of print
González A, Richards AM, de Boer RA, Thum T, ... Coats AJ, Bayes-Genis A
Eur J Heart Fail: 25 Mar 2022; epub ahead of print | PMID: 35334137
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Impact:
Abstract

The effect of intravenous ferric carboxymaltose on right ventricular function - insights from the IRON-CRT trial.

Martens P, Dupont M, Dauw J, Nijst P, ... Tang WHW, Mullens W
Aims
Ferric carboxymaltose (FCM) improves left ventricular function in heart failure with reduced ejection fraction (HFrEF). Yet, the effect of FCM on right ventricular (RV) function remains insufficiently elucidated.
Methods and results
This is a pre-defined analysis of the IRON-CRT trial in which symptomatic HFrEF patients with iron deficiency and reduced left ventricular ejection fraction (LVEF) despite optimal medical therapy and cardiac resynchronization therapy (CRT) underwent 1:1 randomization to FCM or placebo in a double-blind fashion. RV function was measured as the change from baseline to 3-month follow-up in RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE) and pulsed Doppler peak velocity at the RV lateral annulus (RV S\'), systolic pulmonary artery pressure (SPAP) and its coupling to the right ventricle (TAPSE/SPAP ratio). The RV contractile reserve was measured as the change in TAPSE during incremental pacing at 70, 90 and 110 bpm. A total of 75 patients underwent randomization and received FCM (n = 37) or placebo (n = 38). At baseline 72.5% had RV dysfunction and 70% had RV dilatation. At 3-month follow-up, patients receiving FCM had a significant improvement in RV FAC (+4.1% [+1.4% - +6.9%] vs. -2.2% [-4.9% - +0.6%] in the placebo group, p = 0.002) and TAPSE (+0.98 mm [+0.28 mm - +1.62 mm] vs. -0.19 mm [-0.85 mm - +0.48 mm] in the placebo group, p = 0.020), but not RV S\'. Patients receiving FCM had a numerically lower SPAP (p = 0.073) and significant improvement in TAPSE/SPAP ratio (+0.097 [+0.048 - +0.146] vs. +0.002 [-0.046 - +0.051] in the placebo group, p = 0.008). At baseline both groups had diminished RV contractile reserve during incremental pacing, which was attenuated at 3-month follow-up in the FCM group (p = 0.004). Patients manifesting more RV function improvement were more likely to exhibit higher degrees of LVEF improvement (p < 0.05 for all).
Conclusions
Treatment with FCM in HFrEF patients results in an improvement in RV function and structure and improves the RV contractile reserve.

© 2022 European Society of Cardiology.

Eur J Heart Fail: 18 Mar 2022; epub ahead of print
Martens P, Dupont M, Dauw J, Nijst P, ... Tang WHW, Mullens W
Eur J Heart Fail: 18 Mar 2022; epub ahead of print | PMID: 35303390
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Impact:
Abstract

Impact of the COVID-19 pandemic on prescription of sacubitril/valsartan in Italy.

Rosano GMC, Celant S, Olimpieri PP, Colatrella A, ... Colivicchi F, Russo P
Aims
The present study sought to examine the effect of the COVID-19 pandemic and lockdown measures on the prescription of sacubitril/valsartan in patients with heart failure (HF) in Italy.
Methods and results
Data from Italian Medicines Agency (AIFA) monitoring registries were analysed. The sacubitril/valsartan monitoring registry is based on 6-month prescriptions. A monthly aggregation on new activations throughout the observational period was computed. From March to December 2020, the initiation of new HF patients on sacubitril/valsartan decreased by nearly 40% with prescriptions dropping to values similar to 2018 when the registry was still operated off-line. A slight increase in prescriptions was observed after the lockdown measures were lifted, but prescriptions remained constantly below the pre-lockdown period.
Conclusion
A marked and worrisome decline during the COVID-19 pandemic in the activation of a life-saving treatment such as sacubitril/valsartan was observed. This decline was clearly linked to the lockdown measures instated to counteract the COVID-19 pandemic. Upcoming studies should analyse the occurrence of new cases of HF as well as the severity of patients admitted to hospitals and their mortality compared to pre-pandemic levels.

© 2022 European Society of Cardiology.

Eur J Heart Fail: 18 Mar 2022; epub ahead of print
Rosano GMC, Celant S, Olimpieri PP, Colatrella A, ... Colivicchi F, Russo P
Eur J Heart Fail: 18 Mar 2022; epub ahead of print | PMID: 35303393
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Impact:
Abstract

Dronedarone for the Treatment of Atrial Fibrillation with Concomitant Heart Failure with Preserved and Mildly Reduced Ejection Fraction: Post-Hoc Analysis of the ATHENA Trial.

Vaduganathan M, Piccini JP, Camm AJ, Crijns HJGM, ... Wieloch M, Hohnloser SH
Aims
Limited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure with preserved and mildly reduced ejection fraction. (HFpEF and HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF.
Methods and results
ATHENA was an international, multicenter trial that randomized 4,628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with 1) symptomatic HFpEF and HFmrEF (defined as LVEF>40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), 2) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF≤40%), and 3) those without HF. We assessed effects of dronedarone vs placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or LV dysfunction, and 3,672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73±9 years, 37% were women, and had a mean LVEF of 57±9%. Over 21±5 months mean follow-up, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69-0.84) without heterogeneity based on HF status (Pinteraction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (Pinteraction =0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favored dronedarone vs. placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant.
Conclusions
Dronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 14 Mar 2022; epub ahead of print
Vaduganathan M, Piccini JP, Camm AJ, Crijns HJGM, ... Wieloch M, Hohnloser SH
Eur J Heart Fail: 14 Mar 2022; epub ahead of print | PMID: 35293087
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Impact:
Abstract

The Association of Improvement in Left Ventricular Ejection Fraction with Outcomes in Patients with Heart Failure with Reduced Ejection Fraction: Data from CHAMP-HF.

DeVore AD, Hellkamp AS, Thomas L, Albert NM, ... Hernandez AF, Fonarow GC
Aims
We assessed for an association between improvements in left ventricular ejection fraction (LVEF) and future outcomes, including health status, in routine clinical practice.
Methods and results
CHAMP-HF was a registry of outpatients with heart failure (HF) and LVEF <40%. Enrolled participants completed the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at regular intervals and were followed as part of routine care. We assessed for associations between improvements in LVEF (>10%) over time and concurrent changes in KCCQ-12, as well as the subsequent risk of poor outcomes. We included 2092 participants in the study. They had the following characteristics: median age 67 years (25th , 75th percentile 58, 75), 29% female, median duration of HF 2.7 years (0.6, 6.8), and median baseline LVEF 30% (23, 35). Of the study participants, 689 (34%) had a >10% absolute improvement in LVEF. Participants with an LVEF improvement also had an improvement in KCCQ-12 overall summary score compared with participants without an LVEF improvement (+7.6 vs +3.5, adjusted effect estimate +4.1 [95% CI 2.3 to 5.7]). Similarly, subsequent all-cause death or HF hospitalization occurred in 12% in the LVEF improvement group vs 25% in the group without an LVEF improvement (adjusted HR 0.50, 95% CI 0.41 to 0.61).
Conclusion
In a large cohort of outpatients with chronic HF, improvements in LVEF were associated with improved health status and a reduced risk for future clinical events. These data underscore the importance of improvement in LVEF as a treatment target for medical interventions for patients with chronic HF.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 14 Mar 2022; epub ahead of print
DeVore AD, Hellkamp AS, Thomas L, Albert NM, ... Hernandez AF, Fonarow GC
Eur J Heart Fail: 14 Mar 2022; epub ahead of print | PMID: 35293088
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Impact:
Abstract

Heart Failure Quality of Care and In-Hospital Outcomes During the COVID-19 Pandemic Findings from the Get With The Guidelines-Heart Failure Registry.

Keshvani N, Mehta A, Alger HM, Rutan C, ... Fonarow GC, Pandey A
Aims
Assess heart failure (HF) in-hospital quality of care and outcomes before and during the COVID-19 pandemic.
Methods & results
Patients hospitalized for HF with ejection fraction (EF) <40% in American Heart Association Get With The Guidelines©-HF registry during pandemic (3/1/2020 - 4/1/2021) and pre-pandemic (2/1/2019 - 2/29/2020) periods were included. Adherence to HF process of care measures, in-hospital mortality, and length of stay (LOS) were compared in pre-pandemic vs. pandemic periods and patients with vs. without COVID-19. 42,004 pre-pandemic and 37,027 pandemic period patients (median age 68, 33% women, 58% White) were included without observed differences across clinical characteristics, comorbidities, vital signs, or EF. Utilization of guideline-directed medical therapy at discharge was comparable across both periods, with rates of ICD placement or prescription lower during the pandemic (vs. pre-pandemic period). In-hospital mortality (3.0% vs 2.5%, p<0.001) and LOS (mean 5.7 vs. 5.4 days, p<0.001) were higher during the pandemic vs pre-pandemic. The highest in-hospital mortality during the pandemic was observed among patients hospitalized in the Northeast region (3.4%). Among patients concurrently diagnosed with COVID-19 (N=549; 1.5%), adherence to ICD placement or prescription, prescription of aldosterone antagonist or ACE/ARB/ARNi at discharge were lower, and in-hospital mortality (8.2% vs. 3.0%, p<0.001) and length of stay (mean 7.7 days vs. 5.7 days, p<0.001) were higher than those without COVID-19.
Conclusion
Among GWTG-HF participating hospitals, patients hospitalized for HFrEF during the pandemic received similar care quality but experienced higher in-hospital mortality than the pre-pandemic period. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 13 Mar 2022; epub ahead of print
Keshvani N, Mehta A, Alger HM, Rutan C, ... Fonarow GC, Pandey A
Eur J Heart Fail: 13 Mar 2022; epub ahead of print | PMID: 35289038
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Impact:
Abstract

Health Status Improvement with Ferric Carboxymaltose in Heart Failure with Reduced Ejection Fraction and Iron Deficiency.

Butler J, Khan MS, Friede T, Jankowska EA, ... Anker SD, Ponikowski P
Aim
Intravenous ferric carboxymaltose (FCM) has been shown to improve overall quality of life in iron-deficient heart failure with reduced ejection fraction (HFrEF) patients at a trial population level. This FAIR-HF and CONFIRM-HF pooled analysis explored the likelihood of individual improvement or deterioration in Kansas City Cardiomyopathy Questionnaire (KCCQ) domains with FCM vs placebo and evaluated the stability of this response over time.
Methods
Changes vs baseline in KCCQ overall summary score (OSS), clinical summary score (CSS) and total symptom score (TSS) were assessed at weeks 12 and 24 in FCM and placebo groups . Mean between-group differences were estimated and individual responder analyses and analyses of response stability were performed.
Results
Overall, 760 (FCM: 454) patients were studied. At week 12, the mean improvement in KCCQ OSS was 10.6 points with FCM vs 4.8 points with placebo (least-square mean difference [95% confidence interval (CI)]: 4.36 [2.14;6.59] points). A higher proportion of patients on FCM vs placebo experienced a KCCQ OSS improvement of ≥5 (58.3% vs 43.5%; odds ratio [95% CI]: 1.81 [1.30;2.51]), ≥10 (42.4% vs 29.3%; 1.73 [1.23;2.43]) or ≥15 (32.1% vs 22.6%; 1.46 [1.02;2.11]) points. Differences were similar at week 24 and for CSS and TSS domains. Of FCM patients with a ≥5-, ≥10- or ≥15-point improvement in KCCQ OSS at week 12, >75% sustained this improvement at week 24.
Conclusion
Treatment of iron-deficient HFrEF patients with intravenous FCM conveyed clinically relevant improvements in health status at an individual-patient level; benefits were sustained over time in most patients. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 12 Mar 2022; epub ahead of print
Butler J, Khan MS, Friede T, Jankowska EA, ... Anker SD, Ponikowski P
Eur J Heart Fail: 12 Mar 2022; epub ahead of print | PMID: 35279929
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Impact:
Abstract

Use of evidence-based therapy in heart failure with reduced ejection fraction across age strata.

Stolfo D, Lund LH, Becher PM, Orsini N, ... Sinagra G, Savarese G
Aims
In older patients guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF; EF<40%) is not contraindicated, but adherence to guidelines is limited. We investigated the implementation of GDMT in HFrEF across different age strata in a large nationwide cohort.
Methods and results
Patients with HFrEF and HF duration ≥3 months registered in the Swedish HF Registry between 2000-2018 were analyzed according to age. Multivariable logistic and multinomial regressions were fitted to investigate factors associated with underuse/underdosing. Of 27,430 patients, 31% were <70, 34% 70-79 and 35% ≥80 years old. Use of treatments progressively decreased with increasing age. Use of renin-angiotensin-system/angiotensin receptor neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists was, respectively, 80%, 88% and 35% in age ≥80 years; 90%, 93% and 47% in age 70-79 years; and 95%, 95% and 54% in age <70 years. Among patients with an indication, use of implantable cardioverter defibrillator and cardiac resynchronization therapy (CRT) was, respectively, 7% and 23% in age ≥80; 22% and 42% in age 70-79; and 29% and 50% in age <70 years. Older patients were less likely treated with target doses of or combinations of HF medications. Except for CRT, after extensive adjustments, age was inversely associated with the likelihood of GDMT use and target dose achievement.
Conclusion
In HFrEF, gaps persist in the use of medications and devices. In disagreement with current recommendations, older patients remain undertreated. Improving strategies and a more individualized approach for implementing use of GDMT in HFrEF are required, in particular in older patients. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 11 Mar 2022; epub ahead of print
Stolfo D, Lund LH, Becher PM, Orsini N, ... Sinagra G, Savarese G
Eur J Heart Fail: 11 Mar 2022; epub ahead of print | PMID: 35278267
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Impact:
Abstract

Genetic and phenotypic profiling of supranormal ejection fraction reveals decreased survival and underdiagnosed heart failure.

Forrest IS, Rocheleau G, Bafna S, Argulian E, ... Natarajan P, Do R
Aims
Individuals with supranormal left ventricular ejection fraction (snLVEF; LVEF>70%) have increased mortality. However, the genetic and phenotypic profile of snLVEF remains unknown. This study aimed to determine the relationship of both snLVEF genetic risk and phenotype with survival and underdiagnosed heart failure (HF).
Methods and results
A snLVEF genetic risk score (GRS) was applied and cases of snLVEF were identified in 486,754 individuals across two population-based cohorts (BioMe Biobank and UK Biobank). The snLVEF GRS and phenotype were evaluated for association with survival, as well as HF diagnosis, markers, symptoms, and medications. Of 486,754 participants, the median age was 58 years, 20,069 (4.1%) died, and 10,043 (2.1%) had diagnosed HF. Both snLVEF GRS (hazard ratio [HR]=1.1 for top 10% versus bottom 10% GRS; P=0.002) and phenotype (HR=1.4; P=0.003) were associated with increased all-cause mortality. Both snLVEF GRS and phenotype were associated with reduced HF diagnosis (odds ratio [OR]=0.97 and OR=0.63, respectively; both P<0.002). However, the snLVEF GRS and phenotype were both associated with elevated brain natriuretic peptide (BNP) levels (146 and 185 pg/mL increase, respectively; P<0.001), including 268 out of 455 (59%) individuals with snLVEF phenotype who had BNP >100 pg/mL. Among 476,711 participants without HF diagnoses, snLVEF GRS and phenotype were associated with increased HF symptoms (e.g. exertional dyspnea OR=1.4 and OR=1.3; P<0.003) and HF medications (e.g. loop diuretic OR=1.2 and OR=1.03; P<0.02). Associations were consistent in hypertensive individuals without cardiac comorbidities.
Conclusions
Genetic predisposition to and presence of snLVEF are associated with decreased survival and underdiagnosed HF. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 11 Mar 2022; epub ahead of print
Forrest IS, Rocheleau G, Bafna S, Argulian E, ... Natarajan P, Do R
Eur J Heart Fail: 11 Mar 2022; epub ahead of print | PMID: 35278270
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Abstract

Defining Changes in Physical Limitation from the Patient Perspective: Insights from the VITALITY-HFpEF Randomized Trial.

Butler J, Spertus JA, Bamber L, Khan MS, ... Armstrong PW, VITALITY-HFpEF Study Group
Background
Clinically important thresholds in patient-reported outcomes measures like the Kansas City Cardiomyopathy Questionnaire (KCCQ) have not been defined for patients with heart failure and preserved ejection fraction (HFpEF). The aim of this study was to estimate meaningful thresholds for improvement or worsening in the KCCQ-Physical Limitation Score (PLS) in patients with HFpEF.
Methods
In this pre-specified analysis from VITALITY-HFpEF, anchor- and distribution-based approaches were used to estimate thresholds for improvement or worsening in the KCCQ-PLS using Patient Global Impression of Change (PGIC) as an anchor. The KCCQ-PLS contains 6 elements, with each increment in response resulting in a change of 4.17 points when converted to a 0-100 scale. The mean change in KCCQ-PLS from baseline to week 12 was calculated for each PGIC group to estimate a meaningful within-patient change.
Results
Of 789 patients enrolled, 698 had complete KCCQ-PLS and PGIC data at week 12. The mean (±SD) changes in KCCQ-PLS corresponding to PGIC changes of \"a little better,\" \"better,\" and \"much better\" were 5.7±18.6, 11.6±19.3, and 18.4±25.3 points, respectively. The scores of patients who responded \"a little better\" (n=177) overlapped substantially with those who reported \"no change\" (n=193; mean change 2.8±18.9). The mean change in KCCQ-PLS for patients responding \"a little worse\" (n=32) was -2.6±18.0 points. The threshold for meaningful within-patient change in KCCQ-PLS based on distribution-based analyses was 12.3 points. Using area-under-curve (AUC) analyses of KCCQ-PLS, the sensitivity and specificity of a 4.17-point change were 0.61 and 0.57, for an 8.33-point change they were 0.49 and 0.64, and for a 12.5-point change were 0.44 and 0.72 for being at least a little better on the PGIC (AUC=0.54).
Conclusion
In the VITALITY-HFpEF trial, a change in KCCQ-PLS of ≥8.33 points (corresponding to an improvement in ≥2 response categories of KCCQ-PLS) may represent the minimal clinically important difference for improvement and a change of ≤ -4.17 points (corresponding to a worsening in ≥1 response category of KCCQ-PLS) may suggest deterioration in patients with HFpEF.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 09 Mar 2022; epub ahead of print
Butler J, Spertus JA, Bamber L, Khan MS, ... Armstrong PW, VITALITY-HFpEF Study Group
Eur J Heart Fail: 09 Mar 2022; epub ahead of print | PMID: 35274420
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Abstract

Association Between Dosing And Combination Use Of Medications And Outcomes In Heart Failure With Reduced Ejection Fraction: Data From The Swedish Heart Failure Registry.

D\'Amario D, Rodolico D, Rosano GM, Dahlström U, ... Lund LH, Savarese G
Aims
To assess the association between combination, dose and use of current guideline-recommended target doses (TD) of Renin-Angiotensin System inhibitors (RASi), Angiotensin Receptor Neprilysin inhibitors (ARNi) and β-blockers, and outcomes in a large and unselected contemporary cohort of patients with heart failure and reduced ejection fraction (HFrEF).
Methods and results
17 809 out-patients registered in the Swedish HF Registry (SwedeHF) from May 2000 to December 2018, with EF <40% and duration of HF ≥90 days were selected. Primary outcome was a composite of time to cardiovascular (CV) death and first HF hospitalization. Compared with no use of RASi or ARNi, the adjusted HR (95% CI) was 0.83 (0.76 to 0.91) with <50% of TD, 0.78 (0.71 to 0.86) with 50%-99%, and 0.73 (0.67 to 0.80) with ≥100% of TD. Compared with no use of β-blockers, the adjusted HR (95% CI) was 0.86 (0.76 to 0.91), 0.81 (0.74 to 0.89) and 0.74 (0.68 to 0.82) with <50%, 50%-99% and ≥100% of TD, respectively. Patients receiving both an ACEi/ARB/ARNi and a β-blocker at 50%-99% of TD had a lower adjusted risk of the primary outcome compared with patients only receiving one drug, i.e. ACEi/ARB/ARNi or β-blocker, even if this was at ≥100% of TD.
Conclusion
HFrEF patients using higher doses of RASi or ARNi and β-blockers had lower risk of CV death or HF hospitalization. Use of two drug classes at 50%-99% of TD dose was associated with lower risk than one drug class at 100% of TD.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 07 Mar 2022; epub ahead of print
D'Amario D, Rodolico D, Rosano GM, Dahlström U, ... Lund LH, Savarese G
Eur J Heart Fail: 07 Mar 2022; epub ahead of print | PMID: 35257446
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Abstract

Renal effects of guideline-directed medical therapies in heart failure: a consensus document from the Heart Failure Association of the European Society of Cardiology.

Mullens W, Martens P, Testani JM, Tang WHW, ... Coats A, Damman K
Novel pharmacologic treatment options reduce mortality and morbidity in a cost-effective manner in patients with heart failure (HF). Undisputedly, the effective implementation of these agents is an essential element of good clinical practice, which is endorsed by the European Society of Cardiology (ESC) guidelines on acute and chronic HF. Yet, physicians struggle to implement these therapies as they have to balance the true and/or perceived risks versus their substantial benefits in clinical practice. Any worsening of biomarkers of renal function is often perceived as being disadvantageous and is in clinical practice one of the most common reasons for ineffective drug implementation. However, even in this context, they clearly reduce mortality and morbidity in HF with reduced ejection fraction (HFrEF) patients, even in patients with poor renal function. Furthermore these agents are also beneficial in HF with mildly reduced ejection fraction (HFmrEF) and sodium-glucose cotransporter 2 (SGLT2) inhibitors more recently demonstrated a beneficial effect in HF with preserved ejection fraction (HFpEF). The emerge of several new classes (angiotensin receptor-neprilysin inhibitor [ARNI], SGLT2 inhibitors, vericiguat, omecamtiv mecarbil) and the recommendation by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF of early initiation and titration of quadruple disease-modifying therapies (ARNI/angiotensin-converting enzyme inhibitor + beta-blocker + mineralocorticoid receptor antagonist and SGLT2 inhibitor) in HFrEF increases the likelihood of treatment-induced changes in renal function. This may be (incorrectly) perceived as deleterious, resulting in inertia of starting and uptitrating these lifesaving therapies. Therefore, the objective of this consensus document is to provide advice of the effect HF drugs on renal function.

© 2022 European Society of Cardiology.

Eur J Heart Fail: 03 Mar 2022; epub ahead of print
Mullens W, Martens P, Testani JM, Tang WHW, ... Coats A, Damman K
Eur J Heart Fail: 03 Mar 2022; epub ahead of print | PMID: 35239201
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Abstract

Finerenone in patients with CKD and T2D with and without heart failure: A prespecified subgroup analysis of the FIDELIO-DKD trial.

Filippatos G, Pitt B, Agarwal R, Farmakis D, ... Anker SD, FIDELIO-DKD Investigators
Aims
This prespecified analysis of the FIDELIO-DKD trial compared the effects of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) by history of heart failure (HF).
Methods
Patients with T2D and CKD (urine albumin-to-creatinine ratio ≥ 30-5000 mg/g and estimated glomerular filtration rate (eGFR) ≥25-<75 mL/min/1.73 m2 ), without symptomatic HF with reduced ejection fraction (New York Heart Association II-IV) and treated with optimized renin-angiotensin system blockade were randomized to finerenone or placebo. The composite cardiovascular (CV) outcome (CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for HF) and composite kidney outcome (kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death) were analysed by investigator-reported medical history of HF.
Results
Of 5674 patients, 436 (7.7%) had a history of HF. Over a median follow-up of 2.6 years, the effect of finerenone compared with placebo on the composite CV outcome was consistent in patients with and without a history of HF (hazard ratio [HR] 0.73 [95% confidence interval (CI) 0.50-1.06] and 0.90 [95% CI 0.77-1.04], respectively; interaction P = 0.33). The effect of finerenone on the composite kidney outcome did not differ by history of HF (HR 0.79 [95% CI 0.52-1.20] and 0.83 [95% CI 0.73-0.94], respectively; interaction P = 0.83).
Conclusion
In FIDELIO-DKD, finerenone improved cardiorenal outcome in patients with CKD and T2D irrespective of baseline HF history. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 02 Mar 2022; epub ahead of print
Filippatos G, Pitt B, Agarwal R, Farmakis D, ... Anker SD, FIDELIO-DKD Investigators
Eur J Heart Fail: 02 Mar 2022; epub ahead of print | PMID: 35239204
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Abstract

Vericiguat in Patients with Coronary Artery Disease and Heart Failure with Reduced Ejection Fraction.

Saldarriaga C, Atar D, Stebbins A, Lewis BS, ... Armstrong PW, VICTORIA Study Group
Aims
Coronary artery disease (CAD) portends worse outcomes in heart failure (HF). We aimed to characterize patients with CAD and worsening HF with reduced ejection fraction (HFrEF) and evaluate post hoc whether vericiguat\'s treatment effect varied according to CAD.
Methods and results
Cox proportional hazards were generated for the primary endpoint of cardiovascular death or HF hospitalization (CVD/HFH). CAD was defined as previous myocardial infarction, percutaneous coronary intervention, or coronary artery bypass grafting. Of 5048 patients in VICTORIA with available data on CAD status, 2704 had CAD and were older, were more frequently male, diabetic, and had a lower glomerular filtration rate than those without CAD (all p <0.0001). Use of implantable cardioverter defibrillators and cardiac resynchronization therapy (CRT) was higher in patients with versus without CAD (33.5 vs. 21.1%; p <0.0001 and 16.3 vs. 12.8%; p = 0.0006). The primary endpoint of CVD/HFH was higher in those with versus without CAD (40.6 vs. 30.1/100 patient-years; adjusted hazard ratio [HR] 1.23; p <0.001) as was all-cause mortality (17.9% vs. 12.7%; adjusted HR 1.32; p <0.001). The primary outcome of CVD/HFH associated with vericiguat in patients with or without CAD was 38.8 vs. 27.6 per 100 patient-years and for placebo was 42.6 vs. 32.7 per 100 patient-years (interaction p = 0.78).
Conclusion
In this post hoc study, CAD was associated with more CVD and HFH in patients with HFrEF and worsening HF. Vericiguat was beneficial and safe regardless of concomitant CAD. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 02 Mar 2022; epub ahead of print
Saldarriaga C, Atar D, Stebbins A, Lewis BS, ... Armstrong PW, VICTORIA Study Group
Eur J Heart Fail: 02 Mar 2022; epub ahead of print | PMID: 35239245
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Abstract

Durability of benefit after transcatheter tricuspid valve intervention: Insights from actigraphy.

Stocker TJ, Cohen DJ, Arnold SV, Sommer S, ... Nabauer M, Hausleiter J
Aims
Tricuspid regurgitation (TR) is associated with high mortality, morbidity and reduced physical capacity. This study was designed to examine the long-term impact of transcatheter tricuspid valve intervention (TTVI) on physical activity by using the method of actigraphy.
Methods and results
In this study, we prospectively included 128 heart failure patients with severe TR (median age 79 years, 48% female) who were scheduled for TTVI. Patients were equipped with activity tracking-devices for one week before TTVI, and again at 1-6 months and one year after TTVI. We compared continuous physical activity (CPA), defined as the mean number of steps/day with New York Heart-association class, quality of life assessments, and six-minute-walk distance (all p<.01). TTVI reduced TR to grade ≤2+ in 94% of patients. Median (IQR) CPA at baseline was 3108 steps/day (IQR 1350-4959), which increased by 31.4% to 3958 steps/day (IQR 1823-5657) at 1-6 months and 4080 steps/day (IQR 2293-6514) at 1 year after TTVI (p<.001 for both comparisons). The impact of TTVI was significantly higher in advanced heart failure patients with low baseline activity (baseline-CPA <1350 steps/day; one-year CPA increase: +121.3%; p<.001), when compared to moderate activity patients (baseline-CPA 1350-4959 steps/day; one-year CPA increase: +27.5%; p<.01) or high activity patients (baseline-CPA >4959 steps/day; one-year CPA change: +2.6%; p=.39).
Conclusion
One-week actigraphy demonstrates durable improvement of physical activity after TTVI. Fragile chronic heart failure patients with very low baseline activity, as determined by actigraphy in this study, significantly benefit from transcatheter intervention and should not be excluded from TTVI. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 02 Mar 2022; epub ahead of print
Stocker TJ, Cohen DJ, Arnold SV, Sommer S, ... Nabauer M, Hausleiter J
Eur J Heart Fail: 02 Mar 2022; epub ahead of print | PMID: 35239253
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Abstract

The Response to Cardiac Resynchronization Therapy in LMNA cardiomyopathy.

Sidhu K, Castrini AI, Parikh V, Reza N, ... Haugaa K, Lakdawala NK
Aims
Cardiac implantable electronic device (CIED) therapy is fundamental to the management of LMNA-cardiomyopathy due to the high frequency of atrioventricular block and ventricular tachyarrhythmias. We aim to define the role of cardiac resynchronization therapy (CRT) in impacting heart failure in LMNA-cardiomyopathy.
Methods and results
From 9 referral centers, LMNA-cardiomyopathy patients who underwent CRT with available pre- and post- echocardiograms were identified retrospectively. Factors associated with CRT response were identified [defined as improvement in left ventricular ejection fraction (LVEF) ≥5% 6-months post-implant] and the associated impact on the primary outcome of death, implantation of a left ventricular assist device or cardiac transplantation was assessed. We identified 105 patients (51±10 years) undergoing CRT, including 70 (67%) who underwent CRT as a CIED upgrade. The mean change in LVEF ~6 months post CRT was +4±9%. A CRT response occurred in 40 (38%) patients and was associated with lower baseline LVEF or a high percentage of right ventricular pacing prior to CRT in patients with pre-existing CIED. In patients with an ESC Class I guideline indication for CRT, response rates were 61%. A CRT response was evident at thresholds of LVEF ≤45% or percent pacing ≥50%. There was a 1.3 year estimated median difference in event-free survival in those who responded to CRT (p=0.04).
Conclusion
Systolic function improves in patients with LMNA-cardiomyopathy who undergo CRT, especially with strong guideline indications for implantation. Post CRT improvements in LVEF are associated with survival benefits in this population with otherwise limited options.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 28 Feb 2022; epub ahead of print
Sidhu K, Castrini AI, Parikh V, Reza N, ... Haugaa K, Lakdawala NK
Eur J Heart Fail: 28 Feb 2022; epub ahead of print | PMID: 35229420
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Abstract

Cardiac energetics in patients with chronic heart failure and iron deficiency: an in-vivo  P magnetic resonance spectroscopy study.

Papalia F, Jouhra F, Amin-Youssef G, Shah AM, Charles-Edwards G, Okonko DO
Aims
Iron deficiency (ID) is prevalent and adverse in chronic heart failure (CHF) but few human studies have explored the myocardial mechanism(s) that potentially underlie this adversity. Because mitochondrial oxidative phosphorylation (OXPHOS) provides over 90% of the hearts adenosine triphosphate (ATP), and iron is critical for OXPHOS, we hypothesized that patients with CHF and ID would harbour greater cardiac energetic impairments than patients without ID.
Methods and results
Phosphorus magnetic resonance spectroscopy was used to quantify the phosphocreatine (PCr) to ATP (PCr/ATP) ratio, an index of in-vivo cardiac energetics, in CHF patients and healthy volunteers. Cardiac structure and function was assessed from magnetic resonance short stack cines. Patients with (n = 27) and without (n = 12) ID, and healthy volunteers (n = 11), were similar with respect to age and gender. The PCr/ATP ratio was lower in patients with ID (1.03 [0.83-1.38]) compared to those without ID (1.72 [1.51-2.26], p < 0.01) and healthy volunteers (1.39 [1.10-3.68], p < 0.05). This was despite no difference in cardiac structure and function between patients with and without ID, and despite adjustment for the presence of anaemia, haemoglobin levels, cardiac rhythm, or New York Heart Association (NYHA) class. In the total CHF cohort, the PCr/ATP ratio correlated with ferritin levels (rho = 0.4, p < 0.01), and was higher in NYHA class I than class II or III patients (p = 0.02).
Conclusion
Iron deficiency is associated with greater cardiac energetic impairment in patients with CHF irrespective of anaemia and cardiac structure and function. Suppression of cardiac mitochondrial function might therefore be a mechanism via which ID worsens human CHF.

© 2022 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 2022; epub ahead of print
Papalia F, Jouhra F, Amin-Youssef G, Shah AM, Charles-Edwards G, Okonko DO
Eur J Heart Fail: 22 Feb 2022; epub ahead of print | PMID: 35199406
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Abstract

Eligibility for pharmacological therapies in heart failure with reduced ejection fraction: implications of the new Chronic Kidney Disease Epidemiology Collaboration creatinine equation for estimating glomerular filtration rate.

Butt JH, Adamson C, Docherty KF, Vaduganathan M, ... Jhund PS, McMurray JJV
Aims
The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimating glomerular filtration rate (eGFR), based on serum creatinine, that does not incorporate race may reclassify individuals, irrespective of race, from one eGFR category to another, with implications for eligibility for treatments in patients with heart failure and reduced ejection fraction (HFrEF).
Methods and results
A total of 43 138 ambulatory patients with HFrEF from 12 clinical trials were included (mean age 64.3 years; 9580 [22.2%] women). Mean eGFR was 67 (standard deviation [SD] 21) ml/min/1.73 m2 and 70 (SD 21) ml/min/1.73 m2 using the original and new CKD-EPI equations, respectively (mean difference 3.20 ml/min/1.73 m2 , 95% confidence interval [CI] 3.17-3.23, p < 0.001). Of the 935 patients with chronic kidney disease (CKD) stages 4 or 5, identified using the original equation, 309 (33.0%) were reclassified to CKD stages 1-3 (eGFR ≥30 mL/min/1.73 m2 ) with the new equation. However, the opposite was observed among the 2521 Black patients (5.8%) included, with a reduction in mean eGFR from 75 to 68 ml/min/1.73 m2 using the original and new equations, respectively (mean difference 6.94 ml/min/1.73 m2 , [95% CI 6.82-7.06], p < 0.001). The number of Black patients with an eGFR <30 ml/min/1.73 m2 increased from 49 (1.9%) using the original equation to 71 (2.8%) with the new equation.
Conclusions
The new CKD-EPI creatinine equation reclassified CKD stage in a large proportion of patients with HFrEF enrolled in clinical trials. As eGFR is an essential determinant of eligibility for several key pharmacological therapies in HFrEF, this reclassification could result in a substantial change in the proportion of patients considered eligible for such therapies and reduce the proportion of eligible Black patients.

© 2022 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 2022; epub ahead of print
Butt JH, Adamson C, Docherty KF, Vaduganathan M, ... Jhund PS, McMurray JJV
Eur J Heart Fail: 22 Feb 2022; epub ahead of print | PMID: 35199418
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Abstract

Influence of ejection fraction on biomarker expression and response to spironolactone in people at risk of heart failure: findings from the HOMAGE trial.

Ferreira JP, Verdonschot JAJ, Girerd N, Bozec E, ... Cleland JG, Zannad F
Aims
Left ventricular ejection fraction (LVEF) can provide haemodynamic information and may influence the response to spironolactone and other heart failure (HF) therapies. We aimed to study patient characteristics and circulating protein associations with LVEF, and whether LVEF influenced the response to spironolactone.
Methods and results
HOMAGE enrolled patients aged >60 years at high risk of developing HF with a LVEF ≥45%. Overall, 527 patients were randomized to either spironolactone or standard of care for ≈9 months, and 276 circulating proteins were measured using Olink® technology. A total of 364 patients had available LVEF determined by the Simpson\'s biplane method. The respective LVEF tertiles were: tertile 1: <60% (n = 122), tertile 2: 60%-65% (n = 121), and tertile 3: >65% (n = 121). Patients with a LVEF >65% had smaller left ventricular chamber size and volumes, and lower natriuretic peptide levels. Compared to patients with a LVEF <60%, those with LVEF >65% had higher levels of circulating c-c motif chemokine ligand-23 and interleukin-8, and lower levels of tissue plasminogen activator, brain natriuretic peptide (BNP), S100 calcium binding protein A12, and collagen type I alpha 1 chain (COL1A1). Spironolactone significantly reduced the circulating levels of BNP and COL1A1 without significant treatment-by-LVEF heterogeneity: BNP change β = -0.36 log2 and COL1A1 change β = -0.16 log2 (p < 0.0001 for both; interaction p > 0.1 for both). Spironolactone increased LVEF from baseline to month 9 by 1.1% (p = 0.007).
Conclusion
Patients with higher LVEF had higher circulating levels of chemokines and inflammatory markers and lower levels of stretch, injury, and fibrosis markers. Spironolactone reduced the circulating levels of natriuretic peptides and type 1 collagen, and increased LVEF.

© 2022 European Society of Cardiology.

Eur J Heart Fail: 22 Feb 2022; epub ahead of print
Ferreira JP, Verdonschot JAJ, Girerd N, Bozec E, ... Cleland JG, Zannad F
Eur J Heart Fail: 22 Feb 2022; epub ahead of print | PMID: 35199421
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Impact:

This program is still in alpha version.