Journal: Eur J Heart Fail

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Abstract

EFFECT OF PATIENT-CENTERED TRANSITIONAL CARE SERVICES ON PATIENT-REPORTED OUTCOMES: SEX SPECIFIC ANALYSIS OF THE PACT-HF RANDOMIZED CONTROLLED TRIAL.

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

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 23 Jul 2021; epub ahead of print
Blumer V, Gayowsky A, Xie F, Greene SJ, ... Zannad F, Van Spall HG
Eur J Heart Fail: 23 Jul 2021; epub ahead of print | PMID: 34302417
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Abstract

Treating Symptoms and Reversing Remodeling: Clinical and Echocardiographic 1-Year Outcomes with Percutaneous Mitral Valve Annuloplasty for Mild to Moderate Secondary Mitral Regurgitation.

Witte KK, Kaye DM, Lipiecki J, Siminiak T, ... Levy W, Starling RC
Aim
To determine the effects of percutaneous mitral annuloplasty on symptoms, walk distance and left ventricular (LV) structure and function in patients with mild or moderate secondary mitral regurgitation (SMR).
Methods and results
This was a pooled analysis of patients (n=68) who, despite guideline-directed medical therapy (GDMT) had symptomatic heart failure (HF) with mild (n=25) or moderate (n=43) SMR treated with percutaneous mitral annuloplasty as part of the TITAN, TITAN II, or REDUCE-FMR trials. Primary outcomes were changes in symptoms, 6 minute walk distance, and quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) after 1 year. Secondary analyses included changes in LV structure and function. At one year, NYHA status was maintained (48%) or improved (46%) in most patients, mean KCCQ scores increased from baseline by 10 units (95%CI 3 to17;p<0.01) and mean 6-minute walk test distance increased by 34 meters (95%CI 12 to 57;p<0.01). SMR grade improved in 25% of patients and was maintained in 58% of patients with changes in mean regurgitant volume of -7ml (95%CI -11 to -3;p<0.001), vena contracta -0.11 cm (95%CI -0.20 to -0.02;p<0.05), and EROA -0.03 cm2 (95%CI -0.06 to -0.01;p<0.05). There were non-significant improvements in LV ejection fraction and volumes. Survival over 1 year was 89% with no difference between mild (96%) and moderate (86%) SMR (log-rank p=0.22). Progression-free survival was 70% (82% in mild and 63% in moderate SMR (p=0.16)). Freedom from HF hospitalization was 73% (mild SMR 87% vs. moderate SMR 66%;p=0.07).
Conclusion
Among patients with symptomatic HF and mild or moderate SMR on GDMT, percutaneous mitral valve annuloplasty was associated with improvements in symptoms, SMR, a stabilization of LV structure and function, and high survival rates. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 18 Jul 2021; epub ahead of print
Witte KK, Kaye DM, Lipiecki J, Siminiak T, ... Levy W, Starling RC
Eur J Heart Fail: 18 Jul 2021; epub ahead of print | PMID: 34288287
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Abstract

The Ergoreflex: how the Skeletal Muscle Modulates Ventilation and Cardiovascular Function in Health and Disease.

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

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Eur J Heart Fail: 15 Jul 2021; epub ahead of print
Aimo A, Saccaro LF, Borrelli C, Fabiani I, ... Coats AJ, Giannoni A
Eur J Heart Fail: 15 Jul 2021; epub ahead of print | PMID: 34268843
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Abstract

Cardiac Output States in Patients with Severe Functional Tricuspid Regurgitation - Impact on Treatment Success and Prognosis.

Unterhuber M, Kresoja KP, Besler C, Rommel KP, ... Thiele H, Lurz P
Aims
To investigate whether there is evidence for distinct cardiac output (CO) based phenotypes in patients with chronic right heart failure associated with severe tricuspid regurgitation (TR) and to characterize their impact on TR treatment and outcome.
Methods and results
A total of 132 patients underwent isolated transcatheter tricuspid valve repair (TTVR) for functional TR at two centers. Patients were clustered according to k-means clustering into low (C-1: CI<1.7 l/min/m2 ), intermediate (C-2: CI=1.7-2.6 l/min/m2 ) and high CO (C-3: CI>2.6 l/min/m2 ) clusters. All-cause mortality and clinical characteristics during follow-up were compared among different CO-clusters. Mortality rates were highest for patients in a low - (24%) and high CO state (42%, log-rank p<0.001). High CO patients were characterized by larger vena cava inferior diameters (p=0.003), reduced liver function, higher incidence of ascites (p=0.006) and markedly reduced systemic vascular resistance (p<0.001) as compared to TTVR patients in other CO states. Despite comparable procedural success rates, the extent of changes in right atrial pressures (p=0.01) and right ventricular dimensions (p<0.001) per decrease in regurgitant volume following TTVR was less pronounced in high CO patients as compared to other CO states. Successful TTVR was associated with the smallest prognostic benefit among low- and high CO patients.
Conclusions
Patients with chronic right heart failure and severe TR display distinct CO states. The high CO state is characterized by advanced congestive hepatopathy, a substantial decrease in peripheral vascular tone, a lack of response of central venous pressures to TR reduction, and worse prognosis. These data are relevant to the pathophysiological understanding and management of this important clinical syndrome.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 15 Jul 2021; epub ahead of print
Unterhuber M, Kresoja KP, Besler C, Rommel KP, ... Thiele H, Lurz P
Eur J Heart Fail: 15 Jul 2021; epub ahead of print | PMID: 34272792
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Abstract

Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index.

Adamson C, Jhund PS, Docherty KF, Bělohlávek J, ... Sjöstrand M, McMurray JJ
Background
In heart failure with reduced ejection fraction (HFrEF), there is an \"obesity paradox\", where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a SGLT2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF).
Methods and results
BMI was examined using standard categories i.e. underweight (<18.5 kg/m2 ); normal weight (18.5-24.9 Kg/m2 ); overweight (25.0-29.9 Kg/m2 ); obesity class I (30.0-34.9 Kg/m2 ); class II (35.0-39.9 Kg/m2 ) and class III (≥40 Kg/m2 ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal-weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% CI) for the primary outcome with obesity category 1, the lowest risk group, as reference was: under-/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI e.g., HR for primary outcome: under-/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00); P for interaction=0.79. The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) Kg (p<0.001).
Conclusion
We confirmed an \"obesity survival paradox\" in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied.
Clinical trial registration
ClinicalTrials.gov number NCT03036124 (https://clinicaltrials.gov/ct2/show/NCT03036124).

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 15 Jul 2021; epub ahead of print
Adamson C, Jhund PS, Docherty KF, Bělohlávek J, ... Sjöstrand M, McMurray JJ
Eur J Heart Fail: 15 Jul 2021; epub ahead of print | PMID: 34272791
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Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 08 Jul 2021; epub ahead of print
Núñez J, de la Espriella R, Miñana G, Santas E, ... Lupón J, Bayés-Genís A
Eur J Heart Fail: 08 Jul 2021; epub ahead of print | PMID: 34241936
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Abstract

Proteomics to improve phenotyping in obese patients with heart failure with preserved ejection fraction.

Kresoja KP, Rommel KP, Wachter R, Henger S, ... Blüher M, Lurz P
Aims
Recent evidence points towards a distinct obese phenotype among patients with heart failure with preserved ejection fraction (HFpEF). We aimed to identify differentially expressed circulating biomarkers in obese HFpEF patients and link them to disease severity and outcomes.
Methods and results
From the LIFE-Heart study, 999 patients with HFpEF and 999 patients without heart failure (no-HF) were selected and 92 circulating serum biomarkers were measured using a proximity extension assay. Elevation of identified biomarkers was validated in 220 patients from the Aldo-DHF trial with diagnosed HFpEF. HFpEF patients were older and had more comorbidities including coronary artery disease and type 2 diabetes as compared to no-HF patients (P < 0.05 for all). After adjusting for covariates, adrenomedullin (ADM), galectin-9 (Gal-9), thrombospondin-2 (THBS-2), CD4, and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) were significantly higher in obese HFpEF patients [body mass index (BMI) ≥30 kg/m2 , n = 464] as compared to lean HFpEF (BMI <30 kg/m2 , n = 535) and obese no-HF patients (BMI ≥30 kg/m2 , n = 387) (P < 0.001 for both); these findings were verified in the Aldo-DHF validation cohort (P < 0.001). Except for CD4 these proteins were associated with increased estimates of left atrial pressure in a linear fashion. Importantly, ADM and CD4 were associated with increased mortality in obese HFpEF patients after adjusting for covariates.
Conclusion
Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS-2) and systemic inflammation (Gal-9, CD4) compared to obese non-HFpEF or lean HFpEF patients. These findings support the clinical definition of a distinct obese HFpEF phenotype and might merit further investigation.

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

Eur J Heart Fail: 06 Jul 2021; epub ahead of print
Kresoja KP, Rommel KP, Wachter R, Henger S, ... Blüher M, Lurz P
Eur J Heart Fail: 06 Jul 2021; epub ahead of print | PMID: 34231954
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Abstract

Stopping mineralocorticoid receptor antagonists after hyperkalaemia: trial emulation in data from routine care.

Trevisan M, Fu EL, Xu Y, Savarese G, ... Sjölander A, Carrero JJ
Aims
Whether to continue or stop mineralocorticoid receptor antagonists (MRA) after an episode of hyperkalaemia is a challenge in clinical practice. While stopping MRA may prevent recurrent hyperkalaemias, it deprives patients of their cardioprotection. We here assessed the association between stopping vs. continuing MRA therapy after hyperkalaemia and the subsequent risks of adverse health events.
Methods and results
Observational study from the Stockholm CREAtinine Measurements (SCREAM) project 2006-2018. We identified patients initiating MRA and surviving a first-detected episode of hyperkalaemia (plasma potassium >5.0 mmol/L). Using target trial emulation methods, we assessed the association between stopping vs. continuing MRA within 6 months after hyperkalaemia and subsequent outcomes. The primary outcome was the composite of hospital admission with heart failure, stroke, myocardial infarction, or death. The secondary outcome was occurrence of another hyperkalaemia event. Among 39 518 patients initiating MRA, we identified 7366 who developed hyperkalaemia. Median age was 76 years, 45% were women and 69% had a history of heart failure. Following hyperkalaemia, 2222 (30%) discontinued treatment. Compared with continuing MRA, stopping therapy was associated with a lower 2-year risk of recurrent hyperkalaemia [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.72-0.79], but a higher risk of the primary outcome (HR 1.10, 95% CI 1.06-1.14). Similar results were observed in patients with heart failure, after censoring when treatment decision was changed, and across pre-specified subgroups.
Conclusions
Stopping MRA after an episode of hyperkalaemia was associated with reduced risk for recurrent hyperkalaemia, but higher risk of death or cardiovascular events. Recurrent hyperkalaemia was common in either strategy.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Jun 2021; epub ahead of print
Trevisan M, Fu EL, Xu Y, Savarese G, ... Sjölander A, Carrero JJ
Eur J Heart Fail: 30 Jun 2021; epub ahead of print | PMID: 34196082
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Abstract

Post-discharge arrhythmic risk stratification of patients with acute myocarditis and life-threatening ventricular tachyarrhythmias.

Gentile P, Merlo M, Peretto G, Ammirati E, ... Frigerio M, Sinagra G
Background
The outcomes of patients presenting with acute myocarditis and life-threatening ventricular tachyarrhythmias (LT-VA) are unclear. The aim of this study was to assess incidence and predictors of recurrence of major arrhythmic events (MAEs) after hospital discharge in such patients.
Methods and results
We retrospectively analysed 156 patients (median age 44 years; 77% males) discharged with a diagnosis of acute myocarditis and LT-VA from 16 hospitals worldwide. Diagnosis of myocarditis was based on histology or on the combination of increased markers of cardiac injury and cardiac magnetic resonance (CMR) Lake Louise criteria. MAEs were defined as the relapse, after discharge, of sudden cardiac death (SCD) or ventricular fibrillation defibrillated successfully or sustained ventricular tachycardia (sVT) requiring implantable cardioverter-defibrillator therapy or synchronized external cardioversion. Median follow-up period was 23 months (first to third quartile [Q1-Q3] 7-60). Fifty-eight (37.2%) patients experienced MAEs after discharge, at a median time of 8 months (Q1-Q3 2.5-24.0 months; 60.3% of MAEs within the first year). At multivariable Cox analysis, variables independently associated to MAEs were presentation with sVT (hazard ratio [HR] 2.90, 95% confidence interval [CI] 1.38-6.11); late gadolinium enhancement (LGE) involving ≥2 myocardial segments (HR 4.51, 95% CI 2.39-8.53); and absence of positive short-tau inversion recovery (STIR) (HR 2.59, 95% CI 1.40-4.79) at first CMR.
Conclusions
Among patients discharged with the diagnosis of myocarditis and LT-VA, 37.2% had recurrences of MAEs during follow-up. Initial CMR pattern and sVT at presentation stratify the risk of arrhythmic recurrence.

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Eur J Heart Fail: 30 Jun 2021; epub ahead of print
Gentile P, Merlo M, Peretto G, Ammirati E, ... Frigerio M, Sinagra G
Eur J Heart Fail: 30 Jun 2021; epub ahead of print | PMID: 34196079
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Abstract

Cardiotoxicity associated with immune checkpoint inhibitors therapy: A meta-analysis.

Rubio-Infante N, Ramírez-Flores YA, Castillo EC, Lozano O, García-Rivas G, Torre-Amione G
Aims
The study aimed to estimate the cardiac immune-related adverse events (irAEs) incidence in immune checkpoint inhibitors (ICIs)-treated patients.
Methods and results
First, we performed an ICIs-pharmacovigilance analysis, finding 4.2% of cardiac disorders, including myocarditis, for anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapies. Patients treated with anti-PD-1 antibodies presented a greater number of cardiac adverse events (AEs) than treatment with anti-CTLA-4 (69.4% and 20%, respectively). Then, we analyzed the incidence and characteristics of cardiac irAEs in 1265 papers published prior to August 31, 2020. Of the 4751 patients studied, 1.3% presented cardiac irAEs, with myocarditis being the most frequent (50.8%); 15 patients died (24.6%) due to cardiac irAEs. Finally, we conducted a meta-analysis to determine cardiac irAEs in randomized clinical trials, identified through a systematic search from the clinicaltrials.gov database, finding an incidence of 3.1% for ICIs monotherapies, 5.8% for dual ICIs therapies, 3.7% (irAEs/AEs) for ICIs plus chemotherapy, and cardiac AEs were found in 2.5% of patients treated solely with chemotherapy.
Conclusions
Our study provides precise data for the incidence of cardiac irAEs among patients using ICIs, where despite its low incidence, the high rate of mortality is an important issue to consider. ICIs induce mainly myocarditis at the first doses, and dual therapies seem to provoke higher rate of cardiac irAEs than monotherapies or ICIs plus chemotherapy.

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Eur J Heart Fail: 30 Jun 2021; epub ahead of print
Rubio-Infante N, Ramírez-Flores YA, Castillo EC, Lozano O, García-Rivas G, Torre-Amione G
Eur J Heart Fail: 30 Jun 2021; epub ahead of print | PMID: 34196077
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Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1097-1105
Miller WL, Sorimachi H, Grill DE, Fischer K, Borlaug BA
Eur J Heart Fail: 29 Jun 2021; 23:1097-1105 | PMID: 33565251
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Abstract

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

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

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

Eur J Heart Fail: 29 Jun 2021; 23:1147-1155
Lang NN, Ahmad FA, Cleland JG, O'Connor CM, ... Felker GM, McMurray JJV
Eur J Heart Fail: 29 Jun 2021; 23:1147-1155 | PMID: 33620131
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Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1110-1119
Dauw J, Martens P, Tersalvi G, Schouteden J, ... Dupont M, Mullens W
Eur J Heart Fail: 29 Jun 2021; 23:1110-1119 | PMID: 33641220
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Abstract

Non-adherence to heart failure medications predicts clinical outcomes: assessment in a single spot urine sample by liquid chromatography-tandem mass spectrometry (results of a prospective multicentre study).

Gupta P, Voors AA, Patel P, Lane D, ... Squire IB, Ng LL
Aims
Liquid chromatography-mass spectrometry (LC-MS/MS) is an objective new technique to assess non-adherence to medications. We used this method to study the prevalence, predictors and outcomes of non-adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF).
Methods and results
This study included 1296 patients with HFrEF from BIOSTAT-CHF, a study that aimed to optimise guideline-recommended therapies. Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β-blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC-MS/MS. The relationship between medication non-adherence and the composite endpoint of all-cause death or heart failure hospitalisation, over a median follow-up of 21 months, was evaluated. Non-adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non-adherence was non-adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non-adherence to ACEi/ARBs and β-blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09-1.95, P = 0.008 and HR 1.48, 95% CI 1.12-1.96, P = 0.006, respectively). Non-adherence to β-blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67-3.68, P < 0.0005). Patients who were non-adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51-0.93, P = 0.014). Non-adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome.
Conclusion
Non-adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1182-1190
Gupta P, Voors AA, Patel P, Lane D, ... Squire IB, Ng LL
Eur J Heart Fail: 29 Jun 2021; 23:1182-1190 | PMID: 33759308
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Impact:
Abstract

Virtual optimization of guideline-directed medical therapy in hospitalized patients with heart failure with reduced ejection fraction: the IMPLEMENT-HF pilot study.

Bhatt AS, Varshney AS, Nekoui M, Moscone A, ... Adler DS, Vaduganathan M
Aims
Implementation of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains incomplete. Non-cardiovascular hospitalization may present opportunities for GDMT optimization. We assessed the efficacy and durability of a virtual, multidisciplinary \'GDMT Team\' on medical therapy prescription for HFrEF.
Methods and results
Consecutive hospitalizations in patients with HFrEF (ejection fraction ≤40%) were prospectively identified from 3 February to 1 March 2020 (usual care group) and 2 March to 28 August 2020 (intervention group). Patients with critical illness, de novo heart failure, and systolic blood pressure <90 mmHg in the preceeding 24 hs prior to enrollment were excluded. In the intervention group, a pharmacist-physician GDMT Team provided optimization suggestions to treating teams based on an evidence-based algorithm. The primary outcome was a GDMT optimization score, the sum of positive (+1 for new initiations or up-titrations) and negative therapeutic changes (-1 for discontinuations or down-titrations) at hospital discharge. Serious in-hospital safety events were assessed. Among 278 consecutive encounters with HFrEF, 118 met eligibility criteria; 29 (25%) received usual care and 89 (75%) received the GDMT Team intervention. Among usual care encounters, there were no changes in GDMT prescription during hospitalization. In the intervention group, β-blocker (72% to 88%; P = 0.01), angiotensin receptor-neprilysin inhibitor (6% to 17%; P = 0.03), mineralocorticoid receptor antagonist (16% to 29%; P = 0.05), and triple therapy (9% to 26%; P < 0.01) prescriptions increased during hospitalization. After adjustment for clinically relevant covariates, the GDMT Team was associated with an increase in GDMT optimization score (+0.58; 95% confidence interval +0.09 to +1.07; P = 0.02). There were no serious in-hospital adverse events.
Conclusions
Non-cardiovascular hospitalizations are a potentially safe and effective setting for GDMT optimization. A virtual GDMT Team was associated with improved heart failure therapeutic optimization. This implementation strategy warrants testing in a prospective randomized controlled trial.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1191-1201
Bhatt AS, Varshney AS, Nekoui M, Moscone A, ... Adler DS, Vaduganathan M
Eur J Heart Fail: 29 Jun 2021; 23:1191-1201 | PMID: 33768599
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Impact:
Abstract

Decongestion discriminates risk for one-year mortality in patients with improving renal function in acute heart failure.

Wettersten N, Horiuchi Y, van Veldhuisen DJ, Ix JH, ... Maisel A, Murray PT
Aims
Improving renal function (IRF) is paradoxically associated with worse outcomes in acute heart failure (AHF), but outcomes may differ based on response to decongestion. We explored if the relationship of IRF with mortality in hospitalized AHF patients differs based on successful decongestion.
Methods and results
We evaluated 760 AHF patients from AKINESIS for the relationship between IRF, change in B-type natriuretic peptide (BNP), and 1-year mortality. IRF was defined as a ≥20% increase in estimated glomerular filtration rate (eGFR) relative to admission. Adequate decongestion was defined as a ≥40% decrease in last measured BNP relative to admission. IRF occurred in 22% of patients who had a mean age of 69 years, 58% were men, 72% were white, and median admission eGFR was 49 mL/min/1.73 m2 . IRF patients had more severe heart failure reflected by lower admission eGFR, higher blood urea nitrogen, lower systolic blood pressure, lower sodium, and higher use of inotropes. IRF patients had higher 1-year mortality (25%) than non-IRF patients (15%) (P < 0.01). However, this relationship differed by BNP trajectory (P-interaction = 0.03). When stratified by BNP change, non-IRF patients and IRF patients with decreasing BNP had lower 1-year mortality than either non-IRF and IRF patients without decreasing BNP. However, in multivariate analysis, IRF was not associated with mortality [adjusted hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.7-1.5] while BNP was (adjusted HR 0.5, 95% CI 0.3-0.7). When IRF was evaluated as transiently occurring or persisting at discharge, again only BNP change was significantly associated with mortality.
Conclusion
Improving renal function is associated with mortality in AHF but not independent of other variables and congestion status. Achieving adequate decongestion, as reflected by lower BNP, in AHF is more strongly associated with mortality than IRF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1122-1130
Wettersten N, Horiuchi Y, van Veldhuisen DJ, Ix JH, ... Maisel A, Murray PT
Eur J Heart Fail: 29 Jun 2021; 23:1122-1130 | PMID: 33788989
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Impact:
Abstract

Cognitive impairment as a determinant of response to management plans after heart failure admission.

Huynh QL, Whitmore K, Negishi K, DePasquale CG, ... Stanton T, Marwick TH
Aims
Cognitive impairment (CI) is highly prevalent in heart failure (HF), and increases patients\' risks of readmission. This study sought to determine whether the presence and degree of CI could identify patients most likely to benefit from a HF disease management programme (DMP) to reduce readmissions.
Methods and results
A total of 1152 consecutive Australian patients admitted with HF (2014-2017) were prospectively followed up for 12 months. Of these, 324 patients who received DMP (1-month duration, including post-discharge home visits, medication reconciliation, exercise guidance and early clinical review) were matched (1:2 ratio) with 648 usual care patients. Cognitive function was assessed either on the day of or one day before discharge using the Montreal Cognitive Assessment (MoCA). Outcomes included readmission or death at 1, 3 and 12 months, and days at home within 12 months of discharge. Poorer cognitive function was associated with all adverse outcomes. Compared with usual care, DMP was associated with lower odds of 30-day [odds ratio (OR) 0.60, 95% confidence interval 0.40, 0.91] and 90-day (OR 0.53, 95% confidence interval 0.36, 0.77) readmission or death, and with 19 more days at home within 12 months, independent of HF therapy. The effect sizes of these associations were greater for patients with diminished cognition than those with normal cognition (interaction P = 0.036), and might have been more pronounced among those with mild CI compared with those with more severe CI (MoCA score 17-22; OR 0.42, 95% confidence interval 0.21, 0.87) at 30 days (OR 0.31, 95% confidence interval 0.16, 0.60 at 90 days). Patients with normal cognition had fewer events, irrespective of DMP.
Conclusions
Cognitive function may determine how HF patients respond to a DMP. Cognitive screening before implementation of a DMP may allow personalized plans for patients with different levels of cognitive function.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1205-1214
Huynh QL, Whitmore K, Negishi K, DePasquale CG, ... Stanton T, Marwick TH
Eur J Heart Fail: 29 Jun 2021; 23:1205-1214 | PMID: 33788985
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Impact:
Abstract

Splanchnic nerve modulation in heart failure: mechanistic overview, initial clinical experience, and safety considerations.

Fudim M, Ponikowski PP, Burkhoff D, Dunlap ME, ... Engelman ZJ, Shah SJ
Volume recruitment from the splanchnic compartment is an important physiological response to stressors such as physical activity and blood loss. In the setting of heart failure (HF), excess fluid redistribution from this compartment leads to increased cardiac filling pressures with limitation in exercise capacity. Recent evidence suggests that blocking neural activity of the greater splanchnic nerve (GSN) could have significant benefits in some patients with HF by reducing cardiac filling pressures and improving exercise capacity. However, to date the long-term safety of splanchnic nerve modulation (SNM) in the setting of HF is unknown. SNM is currently used in clinical practice to alleviate some forms of chronic abdominal pain. A systematic review of the series where permanent SNM was used as a treatment for chronic abdominal pain indicates that permanent SNM is well tolerated, with side-effects limited to transient diarrhoea or abdominal colic and transient hypotension. The pathophysiological role of the GSN in volume redistribution, the encouraging findings of acute and chronic pilot SNM studies and the safety profile from permanent SNM for pain provides a strong basis for continued efforts to study this therapeutic target in HF.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1076-1084
Fudim M, Ponikowski PP, Burkhoff D, Dunlap ME, ... Engelman ZJ, Shah SJ
Eur J Heart Fail: 29 Jun 2021; 23:1076-1084 | PMID: 33886137
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Impact:
Abstract

Surgical ablation of the right greater splanchnic nerve for the treatment of heart failure with preserved ejection fraction: first-in-human clinical trial.

Málek F, Gajewski P, Zymliński R, Janczak D, ... Engelman ZJ, Ponikowski PP
Aims
Inappropriate control of blood volume redistribution may be a mechanism responsible for exercise intolerance in heart failure with preserved ejection fraction (HFpEF). We propose to address this underlying pathophysiology with selective blockade of sympathetic signalling to the splanchnic circulation by surgical ablation of the right greater splanchnic nerve (GSN).
Methods and results
In a single-arm, prospective, two-centre trial, 10 patients with HFpEF (50% male, mean age 70 ± 3 years) all with New York Heart Association (NYHA) class III, left ventricular ejection fraction >40%, pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg with supine cycle ergometry, underwent ablation of the right GSN via thoracoscopic surgery. Patients were evaluated at baseline, 1, 3, 6 and 12 months after the procedure. The primary endpoint was a reduction in exercise PCWP at 3 months. There were no adverse events related to the blockade of the nerve during 12-month follow-up but three patients had significant peri-procedural adverse events related to the surgical procedure itself. At 3 months post-GSN ablation, patients demonstrated a reduction in 20 W exercise PCWP when compared to baseline [-4.5 mmHg (95% confidence interval, CI -14 to -2); P = 0.0059], which carried over to peak exercise [-5 mmHg (95% CI -11 to 0; P = 0.016). At 12 months, improvements were seen in NYHA class [3 (3) vs. 2 (1, 2); P = 0.0039] and quality of life assessed with the Minnesota Living with Heart Failure Questionnaire [60 (51, 71) vs. 22 (16, 27); P = 0.0039].
Conclusion
In this first-in-human study, GSN ablation in HFpEF proved to be feasible, with a suggestion of reduced cardiac filling pressure during exercise, improved quality of life and exercise capacity.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1134-1143
Málek F, Gajewski P, Zymliński R, Janczak D, ... Engelman ZJ, Ponikowski PP
Eur J Heart Fail: 29 Jun 2021; 23:1134-1143 | PMID: 33932262
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Impact:
Abstract

Long-term clinical experience with cardiac contractility modulation therapy delivered by the Optimizer Smart system.

Kuschyk J, Falk P, Demming T, Marx O, ... Rao I, Burkhoff D
Aims
We assessed long-term effects of cardiac contractility modulation delivered by the Optimizer Smart system on quality of life, left ventricular ejection fraction (LVEF), mortality and heart failure and cardiovascular hospitalizations.
Methods and results
CCM-REG is a prospective registry study including 503 patients from 51 European centres. Effects were evaluated in three terciles of LVEF (≤25%, 26-34% and ≥35%) and in patients with atrial fibrillation (AF) and normal sinus rhythm (NSR). Hospitalization rates were compared using a chi-square test. Changes in functional parameters of New York Heart Association (NYHA) class, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and LVEF were assessed with Wilcoxon signed-rank test, and event-free survival by Kaplan-Meier analysis. For the entire cohort and each subgroup, NYHA class and MLWHFQ improved at 6, 12, 18 and 24 months (P < 0.0001). At 24 months, NYHA class, MLWHFQ and LVEF showed an average improvement of 0.6 ± 0.7, 10 ± 21 and 5.6 ± 8.4%, respectively (all P < 0.001). LVEF improved in the entire cohort and in the LVEF ≤25% subgroup with AF and NSR. In the overall cohort, heart failure hospitalizations decreased from 0.74 [95% confidence interval (CI) 0.66-0.82] prior to enrolment to 0.25 (95% CI 0.21-0.28) events per patient-year during 2-year follow-up (P < 0.0001). Cardiovascular hospitalizations decreased from 1.04 (95% CI 0.95-1.13) events per patient-year prior to enrolment to 0.39 (95% CI 0.35-0.44) events per patient-year during 2-year follow-up (P < 0.0001). Similar reductions of hospitalization rates were observed in the LVEF, AF and NSR subgroups. Estimated survival was significantly better than predicted by MAGGIC at 1 and 3 years in the entire cohort and in the LVEF 26-34% and ≥35% subgroups.
Conclusions
Cardiac contractility modulation therapy improved functional status, quality of life, LVEF and, compared to patients\' prior history, reduced heart failure hospitalization rates. Survival at 1 and 3 years was significantly better than predicted by the MAGGIC risk score.

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

Eur J Heart Fail: 29 Jun 2021; 23:1160-1169
Kuschyk J, Falk P, Demming T, Marx O, ... Rao I, Burkhoff D
Eur J Heart Fail: 29 Jun 2021; 23:1160-1169 | PMID: 34002440
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Impact:
Abstract

Association between up-titration of medical therapy and total hospitalizations and mortality in patients with recent worsening heart failure across the ejection fraction spectrum.

Bistola V, Simitsis P, Parissis J, Ouwerkerk W, ... Voors AA, Filippatos G
Background
The role of neurohormonal inhibition in chronic heart failure (HF) is well established. There are limited data on the effect of up-titration of renin-angiotensin inhibitors (RASi) and beta-blockers (BBs) on clinical outcomes of patients with worsening HF across the left ventricular ejection fraction (LVEF) spectrum.
Methods and results
We analysed data from 2345 patients from BIOSTAT-CHF (80.9% LVEF <40%), who completed a 3-month up-titration period after recent worsening of HF. Patients were classified by achieved dose (% of recommended): ≥100%, 50-99%, 1-49%, and none. Recurrent event analysis using joint and shared frailty models was used to examine the association between RASi/BB dose and all-cause and HF hospitalizations. In the 21 months following up-titration, 512 patients died and 879 (37.5%) had ≥1 hospitalization. RASi up-titration was associated, incrementally, with reduced risk of all-cause hospitalization at all achieved dose levels compared to no treatment [hazard ratio (95% confidence interval): ≥100%: 0.60 (0.49-0.74), P < 0.001; 50-99%: 0.56 (0.46-0.68), P < 0.001; 1-49%: 0.71 (0.59-0.86), P < 0.001]. This association was consistent up to an LVEF of 49% (P < 0.001), and when considering only HF hospitalizations. Up-titration of BBs was associated with fewer all-cause hospitalizations only when LVEF was <40% (overall P < 0.001), but with more HF hospitalizations when LVEF was ≥50%. Up-titration of both RASi/BBs was associated with lower mortality in LVEF up to 49%.
Conclusion
After recent worsening of HF, up-titration of RASi and BBs was associated with a better prognosis in patients with LVEF ≤49%. Up-titration of BBs was associated with a greater risk of HF hospitalization when LVEF was ≥50%.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; 23:1170-1181
Bistola V, Simitsis P, Parissis J, Ouwerkerk W, ... Voors AA, Filippatos G
Eur J Heart Fail: 29 Jun 2021; 23:1170-1181 | PMID: 33998113
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Impact:
Abstract

Use of diuretics and outcomes in patients with type 2 diabetes: findings from the EMPA-REG OUTCOME trial.

Pellicori P, Fitchett D, Kosiborod MN, Ofstad AP, ... Testani JM, Cleland JGF
Aims
Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial.
Methods and results
The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes).
Conclusion
Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated.

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

Eur J Heart Fail: 29 Jun 2021; 23:1085-1093
Pellicori P, Fitchett D, Kosiborod MN, Ofstad AP, ... Testani JM, Cleland JGF
Eur J Heart Fail: 29 Jun 2021; 23:1085-1093 | PMID: 34031968
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Impact:
Abstract

Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial.

Solomon SD, de Boer RA, DeMets D, Hernandez AF, ... Petersson M, McMurray JJV
Aims
Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally developed as glucose-lowering agents, have been shown to reduce heart failure hospitalizations in patients with type 2 diabetes without established heart failure, and in patients with heart failure with and without diabetes. Their role in patients with heart failure with preserved and mildly reduced ejection fraction remains unknown.
Methods
Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) is an international, multicentre, parallel group, event-driven, randomized, double-blind trial in patients with chronic heart failure and left ventricular ejection fraction (LVEF) >40%, comparing the effect of dapagliflozin 10 mg once daily, vs. placebo, in addition to standard of care. Patients with or without diabetes, with signs and symptoms of heart failure, a LVEF >40%, elevation in natriuretic peptides and evidence of structural heart disease are eligible. The primary endpoint is time-to-first cardiovascular death or worsening heart failure event (heart failure hospitalization or urgent heart failure visit), and will be assessed in dual primary analyses - the full population and in those with LVEF <60%. The study is event-driven and will target 1117 primary events. A total of 6263 patients have been randomized.
Conclusions
DELIVER will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in patients with heart failure and preserved and mildly reduced ejection fraction.

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

Eur J Heart Fail: 29 Jun 2021; 23:1217-1225
Solomon SD, de Boer RA, DeMets D, Hernandez AF, ... Petersson M, McMurray JJV
Eur J Heart Fail: 29 Jun 2021; 23:1217-1225 | PMID: 34051124
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Impact:
Abstract

Vericiguat in patients with atrial fibrillation and heart failure with reduced ejection fraction: insights from the VICTORIA trial.

Ponikowski P, Alemayehu W, Oto A, Bahit MC, ... Armstrong PW, VICTORIA Study Group
Aims
We evaluated the relation between baseline and new-onset atrial fibrillation (AF) and outcomes, and assessed whether vericiguat modified the likelihood of new-onset AF in patients with worsening heart failure (HF) with reduced ejection fraction in VICTORIA.
Methods and results
Of 5050 patients randomized, 5010 with recorded AF status at baseline were analysed. Patients were classified into three groups: no known AF (n = 2661, 53%), history of AF alone (n = 992, 20%), and AF on randomization electrocardiogram (n = 1357, 27%). Compared with those with no AF, those with history of AF alone had a higher risk of cardiovascular death [adjusted hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.01-1.47] without excess myocardial infarction or stroke; neither type of AF was associated with a higher risk of the primary composite outcome (time to cardiovascular death or first HF hospitalization), HF hospitalizations, or all cause-death. The beneficial effect of vericiguat on the primary composite outcome and its components was evident irrespective of AF status at baseline. Over a median follow-up of 10.8 months, new-onset AF occurred in 6.1% of those with no AF and 18.3% with history of AF alone (P < 0.0001). These events were not influenced by vericiguat treatment (adjusted HR 0.93, 95% CI 0.75-1.16; P = 0.51), but were associated with an increase in the hazard of both primary and secondary outcomes.
Conclusions
Atrial fibrillation was present in nearly half of this high-risk population with worsening HF. A history of AF alone at baseline portends an increased risk of cardiovascular death. Neither type of AF affected the beneficial effect of vericiguat. Development of AF post-randomization was associated with an increase in both cardiovascular death and HF hospitalization which was not influenced by vericiguat.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Jun 2021; epub ahead of print
Ponikowski P, Alemayehu W, Oto A, Bahit MC, ... Armstrong PW, VICTORIA Study Group
Eur J Heart Fail: 29 Jun 2021; epub ahead of print | PMID: 34191395
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Impact:
Abstract

Ferric carboxymaltose for the treatment of iron deficiency in heart failure: a multinational cost-effectiveness analysis utilising AFFIRM-AHF.

McEwan P, Ponikowski P, Davis JA, Rosano G, ... Ramirez de Arellano A, Jankowska EA
Aims
Iron deficiency is common in patients with heart failure (HF). In AFFIRM-AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron-deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost-effectiveness of FCM compared with placebo in iron-deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM-AHF trial from Italian, UK, US and Swiss payer perspectives.
Methods and results
A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM-AHF trial. Health states were defined using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all-cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM-AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost-effective in Italy [incremental cost-effectiveness ratio (ICER) EUR 1269 per quality-adjusted life-year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43-0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost-effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology.
Conclusion
Ferric carboxymaltose is estimated to be a highly cost-effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems.

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

Eur J Heart Fail: 29 Jun 2021; epub ahead of print
McEwan P, Ponikowski P, Davis JA, Rosano G, ... Ramirez de Arellano A, Jankowska EA
Eur J Heart Fail: 29 Jun 2021; epub ahead of print | PMID: 34191394
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Impact:
Abstract

Cardiac, renal, and metabolic effects of sodium-glucose co-transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc task force on sodium-glucose co-transporter 2 inhibitors.

Herrington WG, Savarese G, Haynes R, Marx N, ... Baigent C, Cosentino F
In 2015, the first large-scale placebo-controlled trial designed to assess cardiovascular safety of glucose-lowering with sodium-glucose co-transporter 2 (SGLT2) inhibition in type 2 diabetes mellitus raised hypotheses that the class could favourably modify not only risk of atherosclerotic cardiovascular disease, but also hospitalization for heart failure, and the development or worsening of nephropathy. By the start of 2021, results from 10 large SGLT2 inhibitor placebo-controlled clinical outcome trials randomizing ∼71 000 individuals have confirmed that SGLT2 inhibitors can provide clinical benefits for each of these types of outcome in a range of different populations. The cardiovascular and renal benefits of SGLT2 inhibitors appear to be larger than their comparatively modest effect on glycaemic control or glycosuria alone would predict, with three trials recently reporting that clinical benefits extend to individuals without diabetes mellitus who are at risk due to established heart failure, or albuminuric chronic kidney disease. This European Society of Cardiology position paper summarizes reported results from these 10 large clinical outcome trials considering separately each of the different types of cardiorenal benefit, summarizes key molecular and pathophysiological mechanisms, and provides a synopsis of metabolic effects and safety. We also describe ongoing placebo-controlled trials among individuals with heart failure with preserved ejection fraction and among individuals with chronic kidney disease.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 28 Jun 2021; epub ahead of print
Herrington WG, Savarese G, Haynes R, Marx N, ... Baigent C, Cosentino F
Eur J Heart Fail: 28 Jun 2021; epub ahead of print | PMID: 34184823
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Impact:
Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 25 Jun 2021; epub ahead of print
Khan MS, Khan F, Fonarow GC, Sreenivasan J, ... Anker SD, Butler J
Eur J Heart Fail: 25 Jun 2021; epub ahead of print | PMID: 34173307
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Abstract

Baseline Characteristics of Patients in the PARALLAX Trial: Insights into Quality of Life and Exercise Capacity in Heart Failure with Preserved Ejection Fraction.

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

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 24 Jun 2021; epub ahead of print
Shah SJ, Cowie MR, Wachter R, Szecsödy P, ... Gong J, Pieske B
Eur J Heart Fail: 24 Jun 2021; epub ahead of print | PMID: 34170062
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Abstract

Impact of mitral regurgitation in patients with worsening heart failure: Insights from BIOSTAT-CHF.

Pagnesi M, Adamo M, Sama IE, Anker SD, ... Voors AA, Metra M
Background
Few data regarding the prevalence and prognostic impact of mitral regurgitation (MR) in patients with worsening chronic or new-onset acute heart failure (HF) are available. We investigated the role of MR in the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF).
Methods and results
We performed a retrospective post-hoc analysis including patients from both the index and validation BIOSTAT-CHF cohorts with data regarding MR status. The primary endpoint was a composite of all-cause death or HF hospitalization. Among 4023 patients included, 1653 patients (41.1%) had moderate-severe MR. Compared to others, patients with moderate-severe MR were more likely to have atrial fibrillation and chronic kidney disease and had larger left ventricular (LV) dimensions, lower left ventricular ejection fraction (LVEF), worse QoL, and higher plasma concentrations of NT-proBNP. A primary outcome event occurred in 697 patients with, compared to 836 patients without, moderate-severe MR (Kaplan-Meier 2-year estimate: 42.2% vs. 35.3%; hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.16-1.41; log-rank p < 0.0001). The association between MR and the primary endpoint remained significant after adjusting for baseline variables and the previously validated BIOSTAT-CHF risk score (adjusted HR, 1.11; 95% CI, 1.00-1.23; p = 0.041). Subgroup analyses showed a numerically larger impact of MR on primary endpoint in patients with lower LVEF, larger LV end-diastolic diameter, and higher plasma NT-proBNP.
Conclusions
Moderate-severe MR is common in patients with worsening chronic or new-onset acute HF and is strongly associated with outcome, independently of other features related to HF severity. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 22 Jun 2021; epub ahead of print
Pagnesi M, Adamo M, Sama IE, Anker SD, ... Voors AA, Metra M
Eur J Heart Fail: 22 Jun 2021; epub ahead of print | PMID: 34164895
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Abstract

Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials.

Schrage B, Beer BN, Savarese G, Dabboura S, ... Blankenberg S, Westermann D
Aims
Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCT). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials.
Methods and results
Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility.
Conclusion
The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials\' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 16 Jun 2021; epub ahead of print
Schrage B, Beer BN, Savarese G, Dabboura S, ... Blankenberg S, Westermann D
Eur J Heart Fail: 16 Jun 2021; epub ahead of print | PMID: 34145680
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Abstract

Aspirin and left ventricular assist devices: rationale and design for the international randomized, placebo-controlled, non-inferiority ARIES HM3 trial.

Mehra MR, Crandall DL, Gustafsson F, Jorde UP, ... Heatley G, Pagani FD
Aims
Over decades, left ventricular assist device (LVAD) technology has transitioned from less durable bulky pumps to smaller continuous-flow pumps which have substantially improved long-term outcomes and quality of life. Contemporary LVAD therapy is beleaguered by haemocompatibility-related adverse events including thrombosis, stroke and bleeding. A fully magnetically levitated pump, the HeartMate 3 (HM3, Abbott, USA) LVAD, has been shown to be superior to the older HeartMate II (HMII, Abbott, USA) pump by improving haemocompatibility. Experience with the HM3 LVAD suggests near elimination of de-novo pump thrombosis, a marked reduction in stroke rates, and only a modest decrease in bleeding complications. Since the advent of continuous-flow LVAD therapy, patients have been prescribed a combination of aspirin and anticoagulation therapy on the presumption that platelet activation and perturbations to the haemostatic axis determine their necessity. Observational studies in patients implanted with the HM3 LVAD who suffer bleeding have suggested a signal of reduced subsequent bleeding events with withdrawal of aspirin. The notion of whether antiplatelet therapy can be avoided in an effort to reduce bleeding complications has now been advanced.
Methods
To evaluate this hypothesis and its clinical benefits, the Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump (ARIES HM3) has been introduced as the first-ever international prospective, randomized, double-blind and placebo-controlled, non-inferiority trial in a patient population implanted with a LVAD.
Conclusion
This paper reviews the biological and clinical role of aspirin (100 mg) with LVADs and discusses the rationale and design of the ARIES HM3 trial.

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

Eur J Heart Fail: 16 Jun 2021; epub ahead of print
Mehra MR, Crandall DL, Gustafsson F, Jorde UP, ... Heatley G, Pagani FD
Eur J Heart Fail: 16 Jun 2021; epub ahead of print | PMID: 34142415
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Abstract

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

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

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

Eur J Heart Fail: 14 Jun 2021; epub ahead of print
Savarese G, Bodegard J, Norhammar A, Sartipy P, ... Vaduganathan M, Coats AJS
Eur J Heart Fail: 14 Jun 2021; epub ahead of print | PMID: 34132001
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Abstract

Influence of study discontinuation during the run-in period on the estimated efficacy of sacubitril/valsartan in the PARAGON-HF trial.

Suzuki K, Claggett B, Minamisawa M, Packer M, ... Solomon SD, Desai AS
Aims
The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result.
Methods and results
We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, non-completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74-1.00).
Conclusion
Patients with more advanced HF were at higher risk for non-completion of the run-in period in PARAGON-HF. Re-analysis of study outcomes accounting for the effect of run-in non-completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 10 Jun 2021; epub ahead of print
Suzuki K, Claggett B, Minamisawa M, Packer M, ... Solomon SD, Desai AS
Eur J Heart Fail: 10 Jun 2021; epub ahead of print | PMID: 34114720
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Impact:
Abstract

Impact of hospital transfer to hubs on outcomes of cardiogenic shock in the real world.

Lu DY, Adelsheimer A, Chan K, Yeo I, ... Cheung JW, Kim LK
Aims
Cardiogenic shock (CS) is associated with significant mortality, and there is a movement towards regional \'hub-and-spoke\' triage systems to coordinate care and resources. Limited data exist on outcomes of patients treated at CS transfer hubs.
Methods and results
Cardiogenic shock hospitalizations were obtained from the Nationwide Readmissions Database 2010-2014. Centres receiving any interhospital transfers with CS in a given year were classified as CS transfer \'hubs\'; those without transfers were classified as \'spokes.\' In-hospital mortality was compared among three cohorts: (A) direct admissions to spokes, (B) direct admissions to hubs, and (C) interhospital transfer to hubs. Among hospitals treating CS, 70.6% were classified as spokes and 29.4% as hubs. A total of 130 656 (31.7%) hospitalizations with CS were direct admission to spokes, 253 234 (61.4%) were direct admissions to hubs, and 28 777 (7.0%) were transfer to hubs. CS mortality was 47.8% at spoke hospitals and was lower at hub hospitals, both for directly admitted (39.3%, P < 0.01) and transferred (33.4%, P < 0.01) patients. Hospitalizations at hubs had higher procedural frequency (including coronary artery bypass graft, right heart catheterization, mechanical circulatory support), greater length of stay, and greater costs. On multivariable analysis, direct admission to CS hubs [odds ratio (OR) 0.86, 95% confidence interval (CI) 0.84-0.89, P < 0.01] and transfer to hubs (OR 0.72, 95% CI 0.69-0.76, P < 0.01) were both associated with lower mortality.
Conclusion
While acknowledging the limited ability of the Nationwide Readmissions Database to classify CS severity on presentation, treatment of CS at transfer hubs was associated with significantly lower mortality within this large real-world sample.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 10 Jun 2021; epub ahead of print
Lu DY, Adelsheimer A, Chan K, Yeo I, ... Cheung JW, Kim LK
Eur J Heart Fail: 10 Jun 2021; epub ahead of print | PMID: 34114302
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Abstract

Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy.

Palaskas NL, Segura A, Lelenwa L, Siddiqui BA, ... Maximilian Buja L, Iliescu C
Aims
Although immune checkpoint inhibitor (ICI) myocarditis carries a high reported mortality, increasing reports of smoldering myocarditis suggest a clinical spectrum of disease. Endomyocardial biopsy (EMB) remains the gold standard for diagnosis of ICI myocarditis, but different pathologic diagnostic criteria exist. The objective of this study was to classify the spectrum of ICI myocarditis and myocardial inflammation by pathology findings on EMB and correlate this with clinical outcomes.
Methods and results
All patients who had EMB at MD Anderson Cancer Center between January 2018 and August 2019 for suspected ICI myocarditis were retrospectively reviewed. A grading system (Grades 0-2) based on the degree of inflammatory infiltrate was developed by pathologists. Cardiovascular outcomes and treatment were compared between grades of pathology. We identified 28 patients who had EMB for suspected ICI myocarditis, of which 18 were positive for myocarditis/inflammation. There were four deaths (two in Grade 2 and two in Grade 1), but only one was attributable to myocarditis. Grade 2 patients had no myocarditis-associated deaths despite having the highest troponin T values (median 2063 pg/mL). Four patients with Grade 1 myocardial inflammation continued ICI without any immunomodulation, and all were alive without adverse cardiovascular events at follow-up.
Conclusion
We defined an EMB grading system for ICI myocarditis encompassing a spectrum of histologic findings of inflammatory infiltrates. A subset of low-grade myocardial inflammation patients were able to continue ICI without immunosuppressive therapy. Further studies are needed to identify low-risk patients who can be safely treated with ICI.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 10 Jun 2021; epub ahead of print
Palaskas NL, Segura A, Lelenwa L, Siddiqui BA, ... Maximilian Buja L, Iliescu C
Eur J Heart Fail: 10 Jun 2021; epub ahead of print | PMID: 34114291
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Abstract

Hypertensive disorders in women with peripartum cardiomyopathy: insights from the ESC Peripartum Cardiomyopathy Registry.

Jackson AM, Petrie MC, Frogoudaki A, Laroche C, ... van der Meer P, PPCM Investigators Group
Aims
Hypertensive disorders occur in women with peripartum cardiomyopathy (PPCM). How often hypertensive disorders co-exist, and to what extent they impact outcomes, is less clear. We describe differences in phenotype and outcomes in women with PPCM with and without hypertensive disorders during pregnancy.
Methods
The European Society of Cardiology PPCM Registry enrolled women with PPCM from 2012-2018. Three groups were examined: 1) women without hypertension (\'PPCM-noHTN\'); 2) women with hypertension but without pre-eclampsia (\'PPCM-HTN\'); 3) women with pre-eclampsia (\'PPCM-PE\'). Maternal (6-month) and neonatal outcomes were compared.
Results
Of 735 women included, 452 (61.5%) had PPCM-noHTN, 99 (13.5%) had PPCM-HTN and 184 (25.0%) had PPCM-PE. Compared to women with PPCM-noHTN, women with PPCM-PE had more severe symptoms (NYHA IV in 44.4% and 29.9%, p<0.001), more frequent signs of heart failure (pulmonary rales in 70.7% and 55.4%, p=0.002), higher baseline LVEF (32.7% and 30.7%, p=0.005) and smaller left ventricular end diastolic diameter (57.4mm [±6.7] and 59.8mm [±8.1], p<0.001). There were no differences in the frequencies of death from any cause, re-hospitalization for any cause, stroke, or thromboembolic events. Compared to women with PPCM-noHTN, women with PPCM-PE had a greater likelihood of left ventricular recovery (LVEF≥50%) (adjusted OR 2.08 95% CI 1.21-3.57) and an adverse neonatal outcome (composite of termination, miscarriage, low birth weight or neonatal death) (adjusted OR 2.84 95% CI 1.66-4.87).
Conclusion
Differences exist in phenotype, recovery of cardiac function and neonatal outcomes according to hypertensive status in women with PPCM.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 10 Jun 2021; epub ahead of print
Jackson AM, Petrie MC, Frogoudaki A, Laroche C, ... van der Meer P, PPCM Investigators Group
Eur J Heart Fail: 10 Jun 2021; epub ahead of print | PMID: 34114268
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Abstract

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

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

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

Eur J Heart Fail: 06 Jun 2021; epub ahead of print
Bhatt AS, Vaduganathan M, Claggett BL, Liu J, ... McMurray JJV, Solomon SD
Eur J Heart Fail: 06 Jun 2021; epub ahead of print | PMID: 34101308
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Impact:
Abstract

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

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

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:919-932
Sierpinski R, Josiak K, Suchocki T, Wojtas-Polc K, ... Ponikowski P, Jankowska EA
Eur J Heart Fail: 30 May 2021; 23:919-932 | PMID: 33111457
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Impact:
Abstract

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

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

© 2020 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:1026-1036
Zelniker TA, Morrow DA, Mosenzon O, Goodrich EL, ... Sabatine MS, Wiviott SD
Eur J Heart Fail: 30 May 2021; 23:1026-1036 | PMID: 33269486
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Impact:
Abstract

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

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

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

Eur J Heart Fail: 30 May 2021; 23:1012-1022
Becher PM, Schrage B, Ferrannini G, Benson L, ... Lund LH, Savarese G
Eur J Heart Fail: 30 May 2021; 23:1012-1022 | PMID: 33599357
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Impact:
Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:1002-1008
Bhatia K, Jain V, Gupta K, Bansal A, ... Damman K, Vaduganathan M
Eur J Heart Fail: 30 May 2021; 23:1002-1008 | PMID: 33609071
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Impact:
Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:954-963
Verbrugge FH, Reddy YNV, Sorimachi H, Omote K, Carter RE, Borlaug BA
Eur J Heart Fail: 30 May 2021; 23:954-963 | PMID: 33634544
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Impact:
Abstract

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

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

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

Eur J Heart Fail: 30 May 2021; 23:983-991
Woolley RJ, Ceelen D, Ouwerkerk W, Tromp J, ... Lam CS, Voors AA
Eur J Heart Fail: 30 May 2021; 23:983-991 | PMID: 33651430
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Impact:
Abstract

Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction.

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

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

Eur J Heart Fail: 30 May 2021; 23:882-894
Packer M, McMurray JJV
Eur J Heart Fail: 30 May 2021; 23:882-894 | PMID: 33704874
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Impact:
Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:995-999
Greenberg B, Adler E, Campagnari C, Yagil A
Eur J Heart Fail: 30 May 2021; 23:995-999 | PMID: 33724626
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Impact:
Abstract

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

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

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

Eur J Heart Fail: 30 May 2021; 23:947-953
Boorsma EM, Ter Maaten JM, Damman K, van Veldhuisen DJ, ... Santos K, Voors AA
Eur J Heart Fail: 30 May 2021; 23:947-953 | PMID: 33742751
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Impact:
Abstract

Identification of distinct phenotypic clusters in heart failure with preserved ejection fraction.

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

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

Eur J Heart Fail: 30 May 2021; 23:973-982
Uijl A, Savarese G, Vaartjes I, Dahlström U, ... Hoes AW, Koudstaal S
Eur J Heart Fail: 30 May 2021; 23:973-982 | PMID: 33779119
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Impact:
Abstract

Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): design and baseline characteristics.

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:1040-1048
Jering KS, Claggett B, Pfeffer MA, Granger C, ... Nicolau JC, Braunwald E
Eur J Heart Fail: 30 May 2021; 23:1040-1048 | PMID: 33847047
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Impact:
Abstract

Expert consensus on the monitoring of transthyretin amyloid cardiomyopathy.

Garcia-Pavia P, Bengel F, Brito D, Damy T, ... Sekijima Y, Elliott PM
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR-CM has stimulated increased awareness of the disease and patient identification. Stratification of patients with ATTR-CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best-practice guidance. In this report, experts with experience in treating amyloidosis and ATTR-CM developed consensus recommendations for monitoring the course of patients with ATTR-CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR-CM will help to elucidate, refine and define these and other measurements.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:895-905
Garcia-Pavia P, Bengel F, Brito D, Damy T, ... Sekijima Y, Elliott PM
Eur J Heart Fail: 30 May 2021; 23:895-905 | PMID: 33915002
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Impact:
Abstract

The combination of carboxy-terminal propeptide of procollagen type I blood levels and late gadolinium enhancement at cardiac magnetic resonance provides additional prognostic information in idiopathic dilated cardiomyopathy - A multilevel assessment of myocardial fibrosis in dilated cardiomyopathy.

Raafs AG, Verdonschot JAJ, Henkens MTHM, Adriaans BP, ... Heymans SRB, Hazebroek MR
Aims
To determine the prognostic value of multilevel assessment of fibrosis in dilated cardiomyopathy (DCM) patients.
Methods and results
We quantified fibrosis in 209 DCM patients at three levels: (i) non-invasive late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR); (ii) blood biomarkers [amino-terminal propeptide of procollagen type III (PIIINP) and carboxy-terminal propeptide of procollagen type I (PICP)], (iii) invasive endomyocardial biopsy (EMB) (collagen volume fraction, CVF). Both LGE and elevated blood PICP levels, but neither PIIINP nor CVF predicted a worse outcome defined as death, heart transplantation, heart failure hospitalization, or life-threatening arrhythmias, after adjusting for known clinical predictors [adjusted hazard ratios: LGE 3.54, 95% confidence interval (CI) 1.90-6.60; P < 0.001 and PICP 1.02, 95% CI 1.01-1.03; P = 0.001]. The combination of LGE and PICP provided the highest prognostic benefit in prediction (likelihood ratio test P = 0.007) and reclassification (net reclassification index: 0.28, P = 0.02; and integrated discrimination improvement index: 0.139, P = 0.01) when added to the clinical prediction model. Moreover, patients with a combination of LGE and elevated PICP (LGE+/PICP+) had the worst prognosis (log-rank P < 0.001). RNA-sequencing and gene enrichment analysis of EMB showed an increased expression of pro-fibrotic and pro-inflammatory pathways in patients with high levels of fibrosis (LGE+/PICP+) compared to patients with low levels of fibrosis (LGE-/PICP-). This would suggest the validity of myocardial fibrosis detection by LGE and PICP, as the subsequent generated fibrotic risk profiles are associated with distinct cardiac transcriptomic profiles.
Conclusion
The combination of myocardial fibrosis at CMR and circulating PICP levels provides additive prognostic value accompanied by a pro-fibrotic and pro-inflammatory transcriptomic profile in DCM patients with LGE and elevated PICP.

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

Eur J Heart Fail: 30 May 2021; 23:933-944
Raafs AG, Verdonschot JAJ, Henkens MTHM, Adriaans BP, ... Heymans SRB, Hazebroek MR
Eur J Heart Fail: 30 May 2021; 23:933-944 | PMID: 33928704
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Impact:
Abstract

Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology.

Rosano GMC, Moura B, Metra M, Böhm M, ... Seferovic PM, Coats AJS
Despite guideline recommendations and available evidence, implementation of treatment in heart failure (HF) is poor. The majority of patients are not prescribed drugs at target doses that have been proven to positively impact morbidity and mortality. Among others, tolerability issues related to low blood pressure, heart rate, impaired renal function or hyperkalaemia are responsible. Chronic kidney disease plays an important role as it affects up to 50% of patients with HF. Also, dynamic changes in estimated glomerular filtration rate may occur during the course of HF, resulting in inappropriate dose reduction or even discontinuation of decongestive or neurohormonal modulating therapy in clinical practice. As patients with HF are rarely naïve to pharmacologic therapies, the challenge is to adequately prioritize or select the most appropriate up-titration schedule according to patient profile. In this consensus document, we identified nine patient profiles that may be relevant for treatment implementation in HF patients with a reduced ejection fraction. These profiles take into account heart rate (<60 bpm or >70 bpm), the presence of atrial fibrillation, symptomatic low blood pressure, estimated glomerular filtration rate (<30 or >30 mL/min/1.73 m2 ) or hyperkalaemia. The pre-discharge patient, frequently still congestive, is also addressed. A personalized approach, adjusting guideline-directed medical therapy to patient profile, may allow to achieve a better and more comprehensive therapy for each individual patient than the more traditional, forced titration of each drug class before initiating treatment with the next.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 May 2021; 23:872-881
Rosano GMC, Moura B, Metra M, Böhm M, ... Seferovic PM, Coats AJS
Eur J Heart Fail: 30 May 2021; 23:872-881 | PMID: 33932268
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Impact:
Abstract

Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society Position statement on endomyocardial biopsy.

Seferović PM, Tsutsui H, McNamara DM, Ristić AD, ... Coats AJS, Starling RC
Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.

© 2021 Elsevier Inc. and Journal of Cardiac Failure. [Published by Elsevier Inc.] All rights reserved.

Eur J Heart Fail: 30 May 2021; 23:854-871
Seferović PM, Tsutsui H, McNamara DM, Ristić AD, ... Coats AJS, Starling RC
Eur J Heart Fail: 30 May 2021; 23:854-871 | PMID: 34010472
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Impact:
Abstract

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

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

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

Eur J Heart Fail: 29 May 2021; epub ahead of print
Packer M, Januzzi JL, Ferreira JP, Anker SD, ... Zannad F, EMPEROR-Reduced Trial Committees and Investigators
Eur J Heart Fail: 29 May 2021; epub ahead of print | PMID: 34053177
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Impact:
Abstract

Treatment patterns and clinical outcomes among patients <65 years with a worsening heart failure event.

Butler J, Yang M, Sawhney B, Chakladar S, Yang L, Djatche LM
Aims
Data regarding patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) following a worsening HF event (WHFE) are largely driven by findings from elderly patients. Younger patients are not well studied. The aim of this study was to evaluate treatment patterns and clinical outcomes in commercially insured chronic HFrEF patients <65 years old during 1-year periods before and after a WHFE.
Methods and results
A retrospective claims analysis was performed using the IBM® MarketScan® Commercial Database on HFrEF patients aged <65 years during the year before and after a WHFE, defined as HF hospitalization or outpatient intravenous diuretic use. Treatment patterns, rehospitalizations, health care resource utilization, and costs were assessed. A total of 4460 HFrEF patients with WHFE were included. Guideline-recommended HF therapy was initially underutilized, increased pre-WHFE, and peaked 0-3 months post-WHFE. The proportions of patients using dual and triple therapy were 31.5% and 9.8% pre-WHFE, 41.5% and 17.4% 0-3 months post-WHFE, and 34.6% and 13.9% 10-12 months post-WHFE, respectively. Within 30 and 90 days after a WHFE, 12% and 23% of patients had HF-related and 16% and 30% had all-cause rehospitalizations, respectively. HF-related and all-cause hospitalizations and outpatient visits peaked 0-3 months post-WHFE, whereas emergency department visits peaked 0-3 months pre-WHFE.
Conclusions
Use of HF medications increased pre-WHFE but decreased post-WHFE, despite recurrent hospitalizations. These findings suggest that age and insurance status may not totally explain the suboptimal treatment of HFrEF patients before and after a WHFE. Reasons for these trends need further study.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 May 2021; epub ahead of print
Butler J, Yang M, Sawhney B, Chakladar S, Yang L, Djatche LM
Eur J Heart Fail: 29 May 2021; epub ahead of print | PMID: 34053163
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Impact:
Abstract

Obesity, venous capacitance, and venous compliance in heart failure with preserved ejection fraction.

Sorimachi H, Burkhoff D, Verbrugge FH, Omote K, ... Sunagawa K, Borlaug BA
Aims
Circulating blood volume is functionally divided between the unstressed volume, which fills the vascular space, and stressed blood volume (SBV), which generates vascular wall tension and intravascular pressure. With decreases in venous capacitance, blood functionally shifts to the SBV, increasing central venous pressure and pulmonary venous pressures. Obesity is associated with both elevated venous pressure and heart failure with preserved ejection fraction (HFpEF). To explore the mechanisms underlying this association, we evaluated relationships between blood volume distribution, venous compliance, and body mass in patients with and without HFpEF.
Methods and results
Subjects with HFpEF (n = 62) and non-cardiac dyspnoea (NCD) (n = 79) underwent invasive haemodynamic exercise testing with echocardiography. SBV was estimated (eSBV) from measured haemodynamic variables fit to a comprehensive cardiovascular model. Compared to NCD, patients with HFpEF displayed a leftward-shifted central venous pressure-dimension relationship, indicating reduced venous compliance. eSBV was 81% higher at rest and 69% higher during exercise in HFpEF than NCD (both P < 0.0001), indicating reduced venous capacitance. Despite greater augmented eSBV with exercise, the increase in cardiac output was reduced in HFpEF, suggesting operation on the plateau of the Starling curve. Exercise eSBV was directly correlated with higher body mass index (r = 0.77, P < 0.0001) and inversely correlated with right ventricular-pulmonary arterial coupling (r = -0.57, all P < 0.0001).
Conclusions
Patients with HFpEF display reductions in systemic venous compliance and increased eSBV related to reduced venous capacitance, abnormalities in right ventricular-pulmonary artery interaction, and increased body fat. These data provide new evidence supporting an important role of venous dysfunction in obesity-related HFpEF and suggest that therapies that improve venous function may hold promise to improve clinical status in this cohort.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 May 2021; epub ahead of print
Sorimachi H, Burkhoff D, Verbrugge FH, Omote K, ... Sunagawa K, Borlaug BA
Eur J Heart Fail: 29 May 2021; epub ahead of print | PMID: 34053158
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Impact:
Abstract

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

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

© 2021 European Society of Cardiology.

Eur J Heart Fail: 28 May 2021; epub ahead of print
Ferreira JP, Konstam MA, McMurray JJV, Butler J, ... Packer M, Zannad F
Eur J Heart Fail: 28 May 2021; epub ahead of print | PMID: 34050594
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Abstract

Iron deficiency contributes to resistance to endogenous erythropoietin in anaemic heart failure patients.

Tkaczyszyn M, Comín-Colet J, Voors AA, van Veldhuisen DJ, ... van der Meer P, Jankowska EA
Aims
Abnormal endogenous erythropoietin (EPO) constitutes an important cause of anaemia in chronic diseases. We analysed the relationships between iron deficiency (ID) and the adequacy of endogenous EPO in anaemic heart failure (HF) patients, and the impact of abnormal EPO on 12-month mortality.
Methods and results
We investigated 435 anaemic HF patients (age: 74 ± 10 years; males: 60%; New York Heart Association class I or II: 39%; left ventricular ejection fraction: 43 ± 17%). Patients with EPO higher than expected for a given haemoglobin were considered EPO-resistant whereas those with EPO lower than expected - EPO-deficient. ID was defined as serum ferritin <100 µg/L or 100-299 µg/L with transferrin saturation <20%. EPO-resistant patients (22%) had more advanced HF whereas those with EPO deficiency (57%) were more frequently females and had worse renal function. Lower serum ferritin (indicating depleted body iron stores) was related to higher EPO observed/predicted ratio when adjusted for significant clinical confounders, including C-reactive protein. One year all-cause mortality was 28% in patients with EPO resistance compared to 17% in patients with EPO deficiency and 10% in patients with adequate EPO (log-rank test for the comparison EPO resistance vs. adequate EPO: P = 0.02). When adjusted for other prognosticators, there was still a trend towards increased 12-month mortality in patients with higher EPO level.
Conclusion
Anaemic HF patients with endogenous EPO deficiency vs. resistance have different clinical and laboratory characteristics. In such patients, ID contributes to EPO resistance independently of inflammation.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 28 May 2021; epub ahead of print
Tkaczyszyn M, Comín-Colet J, Voors AA, van Veldhuisen DJ, ... van der Meer P, Jankowska EA
Eur J Heart Fail: 28 May 2021; epub ahead of print | PMID: 34050579
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Impact:
Abstract

Prevalence and clinical outcomes of dystrophin-associated dilated cardiomyopathy without severe skeletal myopathy.

Restrepo-Cordoba MA, Wahbi K, Florian AR, Jiménez-Jáimez J, ... Garcia-Pavia P, European Genetic Cardiomyopathies Initiative Investigators (see online supplementary Appendix S1)
Aims
Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy.
Methods and results
At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up.
Conclusions
DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 27 May 2021; epub ahead of print
Restrepo-Cordoba MA, Wahbi K, Florian AR, Jiménez-Jáimez J, ... Garcia-Pavia P, European Genetic Cardiomyopathies Initiative Investigators (see online supplementary Appendix S1)
Eur J Heart Fail: 27 May 2021; epub ahead of print | PMID: 34050592
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Impact:
Abstract

Natural history and prognostic significance of iron deficiency and anaemia in ambulatory patients with chronic heart failure.

Graham FJ, Masini G, Pellicori P, Cleland JGF, ... Kazmi S, Clark AL
Aims
Iron deficiency (ID) and anaemia are common in heart failure; less is known about changes over time.
Methods and results
We investigated prevalence, incidence and resolution of ID and anaemia in 906 patients with chronic heart failure (median age 73 (65-79) years, 70% men, 51% with heart failure with reduced ejection fraction) 1 year apart. ID was defined as serum iron ≤13 µmol/L and anaemia as haemoglobin <13.0 g/dL for men or <12.0 g/dL for women. FAIR-HF criteria for ID were also considered. At baseline, 10% had anaemia without ID, 23% had ID without anaemia, 20% had both, and 47% had neither. Percentages changed little over 1 year, but 157 (30%) patients had new-onset ID, 104 (16%) new-onset anaemia, whilst ID resolved in 173 (44%) and anaemia in 63 (23%). Compared to those who remained iron replete (iron >13 µmol/L), mortality was higher in those with persistent or incident ID at 1 year [hazard ratio (HR) 1.81 (1.23-2.67), and HR 1.40 (0.91-2.14), respectively] in multivariable models (P = 0.02). Compared to persistent ID, resolution of ID was associated with a lower mortality [HR 0.61 (0.44-0.86); P = 0.004]. Changes in ID defined by FAIR-HF criteria were not similarly associated with mortality. Anaemia was associated with a poor outcome even if it resolved.
Conclusions
The prevalence and incidence of ID and anaemia are high in chronic heart failure but so is the rate of resolution. Persistent or incident ID, defined by a serum iron ≤13 µmol/L, is associated with higher mortality and resolution of ID with lower mortality.

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

Eur J Heart Fail: 27 May 2021; epub ahead of print
Graham FJ, Masini G, Pellicori P, Cleland JGF, ... Kazmi S, Clark AL
Eur J Heart Fail: 27 May 2021; epub ahead of print | PMID: 34050582
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Impact:
Abstract

Renal function and the effects of vericiguat in patients with worsening heart failure with reduced ejection fraction: insights from the VICTORIA (Vericiguat Global Study in Subjects with HFrEF) trial.

Voors AA, Mulder H, Reyes E, Cowie MR, ... Armstrong PW, VICTORIA Study Group
Aims
Vericiguat reduced the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization in patients with worsening HF with reduced ejection fraction (HFrEF) and a lower limit of baseline estimated glomerular filtration rate (eGFR) of 15 mL/min/1.73 m2 . We evaluated the relationship between the efficacy of vericiguat and baseline and subsequent changes in renal function.
Methods and results
In VICTORIA, core laboratory serum creatinine was measured at baseline (n = 4956) and weeks 16, 32, and 48. Worsening renal function (WRF), defined as an increase ≥0.3 mg/dL in creatinine from baseline to week 16, was assessed via a Cox model with respect to subsequent primary events. Mean age was 69 years, 24% were female, and mean baseline eGFR was 61 mL/min/1.73 m2 . During 48 weeks of treatment, the trajectories in eGFR and creatinine with vericiguat were similar to placebo (P = 0.50 and 0.18). The beneficial effects of vericiguat on the primary outcome were not influenced by baseline eGFR (interaction P = 0.48). WRF occurred in 15% of patients and was associated with worse outcomes (adjusted hazard ratio 1.28, 95% confidence interval 1.11-1.47; P < 0.001), but the beneficial effects of vericiguat on the primary outcome were similar in patients with or without WRF (interaction P = 0.76).
Conclusion
Renal function trajectories were similar between vericiguat- and placebo-treated patients and the beneficial effects of vericiguat on the primary outcome were consistent across the full range of eGFR and irrespective of WRF.

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

Eur J Heart Fail: 16 May 2021; epub ahead of print
Voors AA, Mulder H, Reyes E, Cowie MR, ... Armstrong PW, VICTORIA Study Group
Eur J Heart Fail: 16 May 2021; epub ahead of print | PMID: 33999486
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Impact:
Abstract

Association of preoperative infections, nasal Staphylococcus aureus colonization and gut microbiota with left ventricular assist device outcomes.

Yuzefpolskaya M, Lumish HS, Javaid A, Cagliostro B, ... Demmer RT, Colombo PC
Aims
Infections are common following left ventricular assist device (LVAD) implantation and predict adverse events. Infections are frequent prior to LVAD implantation although their impact on postoperative outcomes remains unknown. Gut and nasal microbial imbalance may predispose to mucosal colonization with pathogens. Herein, we investigated the predictive role of pre-LVAD infections, and explored the association of nasal Staphylococcus aureus (SA) colonization and gut microbiota, on postoperative outcomes.
Methods and results
Overall, 254 LVAD patients were retrospectively categorized based on pre-LVAD infection status: Group 1, bacterial/fungal bloodstream infection (BSI); Group 2, other bacterial/fungal; Group 3, viral; and Group 4, no infection. In a subset of patients, nasal SA colonization (n = 140) and pre-LVAD stool (n = 25) were analysed using 16S rRNA sequencing. A total of 75 (29%) patients had a pre-LVAD infection [Group 1: 22 (29%); Group 2: 41 (55%); Group 3: 12 (16%)]. Pre-LVAD BSIs were independent predictors of 1-year postoperative mortality and infections [Group 1 vs. 4: hazard ratio (HR) 2.70, P = 0.036 vs. HR 1.8, P = 0.046]. In an unadjusted analysis, pre-LVAD infections other than BSIs, INTERMACS profile ≤2, higher serum creatinine, lower serum albumin and nasal SA colonization were also significantly associated with postoperative infections. Patients with early post-LVAD infections exhibited decreased microbial diversity (P < 0.05).
Conclusions
Pre-LVAD infections are common. BSIs independently predict postoperative mortality and infections. Additional studies are needed to confirm our findings that pre-LVAD SA nasal colonization and gut microbial composition can help stratify patients\' risk for infectious complications after LVAD implantation.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 07 May 2021; epub ahead of print
Yuzefpolskaya M, Lumish HS, Javaid A, Cagliostro B, ... Demmer RT, Colombo PC
Eur J Heart Fail: 07 May 2021; epub ahead of print | PMID: 33964186
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Impact:
Abstract

Immunogenicity of the BNT162b2 mRNA vaccine in heart transplant recipients - a prospective cohort study.

Itzhaki Ben Zadok O, Shaul AA, Ben-Avraham B, Yaari V, ... Kornowski R, Ben-Gal T
Aims
To assess the short-term immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in a population of heart transplant (HTx) recipients. A prospective single-centre cohort study of HTx recipients who received a two-dose SARS-CoV-2 mRNA vaccine (BNT162b2, Pfizer-BioNTech).
Methods and results
Whole blood for anti-spike IgG (S-IgG) antibodies was drawn at days 21-26 and at days 35-40 after the first vaccine dose. Geometric mean titres (GMT) ≥50 AU/mL were interpreted positive. Included were 42 HTx recipients at a median age of 61 [interquartile range (IQR) 44-69] years. Median time from HTx to the first vaccine dose was 9.1 (IQR 2.6-14) years. Only 15% of HTx recipients demonstrated the presence of positive S-IgG antibody titres in response to the first vaccine dose [GMT 90 (IQR 54-229) AU/mL]. Overall, 49% of HTx recipients induced S-IgG antibodies in response to either the first or the full two-dose vaccine schedule [GMT 426 (IQR 106-884) AU/mL]. Older age [68 (IQR 59-70) years vs. 46 (IQR 34-63) years, P = 0.034] and anti-metabolite-based immunosuppression protocols (89% vs. 44%, P = 0.011) were associated with low immunogenicity. Importantly, 36% of HTx recipients who were non-responders to the first vaccine dose became S-IgG seropositive in response to the second vaccine dose. Approximately a half of HTx recipients did not generate S-IgG antibodies following SARS-CoV-2 two-dose vaccine.
Conclusions
The generally achieved protection from SARS-CoV-2 mRNA vaccination should be regarded with caution in the population of HTx recipients. The possible benefit of additive vaccine should be further studied.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 07 May 2021; epub ahead of print
Itzhaki Ben Zadok O, Shaul AA, Ben-Avraham B, Yaari V, ... Kornowski R, Ben-Gal T
Eur J Heart Fail: 07 May 2021; epub ahead of print | PMID: 33963635
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Impact:
Abstract

Primary results of long-term outcomes in the MOMENTUM 3 pivotal trial and continued access protocol study phase: a study of 2200 HeartMate 3 left ventricular assist device implants.

Mehra MR, Cleveland JC, Uriel N, Cowger JA, ... Goldstein DJ,  on behalf of the MOMENTUM 3 Investigators
Aim
The MOMENTUM 3 pivotal trial established superiority of the HeartMate 3 (HM3) left ventricular assist device (LVAD), a fully magnetically levitated centrifugal-flow pump, over the HeartMate II axial-flow pump. We now evaluate HM3 LVAD outcomes in a single-arm prospective continuous access protocol (CAP) post-pivotal trial study.
Methods and results
We enrolled 2200 HM3 implanted patients (515 pivotal trial and 1685 CAP patients) and compared outcomes including survival free of disabling stroke or reoperation to replace or remove a malfunctioning device (primary composite endpoint), overall survival and major adverse events at 2 years. The 2-year primary endpoint [76.7% vs. 74.8%; adjusted hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.71-1.08, P = 0.21] and overall survival (81.2% vs. 79.0%) were similar among CAP and pivotal cohorts despite sicker patients (more intra-aortic balloon pump use and INTERMACS profile 1) in CAP who were more often intended for destination therapy. Survival was similar between the CAP and pivotal trial in transplant ineligible patients (79.1% vs. 76.7%; adjusted HR 0.89, 95% CI 0.68-1.16, P = 0.38). In a pooled analysis, the 2-year primary endpoint was similar between INTERMACS profiles 1-2 (\'unstable\' advanced heart failure), profile 3 (\'stable\' on inotropic therapy), and profiles 4-7 (\'stable\' ambulatory advanced heart failure) (75.7% vs. 77.6% vs. 72.9%, respectively). The net burden of adverse events was lower in CAP (adjusted rate ratio 0.93, 95% CI 0.88-0.98, P = 0.006), with consequent decrease in hospitalization.
Conclusions
The primary results of accumulating HM3 LVAD experience suggest a lower adverse event burden and similar survival compared to the pivotal MOMENTUM 3 trial.

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

Eur J Heart Fail: 30 Apr 2021; epub ahead of print
Mehra MR, Cleveland JC, Uriel N, Cowger JA, ... Goldstein DJ,  on behalf of the MOMENTUM 3 Investigators
Eur J Heart Fail: 30 Apr 2021; epub ahead of print | PMID: 33932272
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Impact:
Abstract

The association between heart failure and incident cancer in women: an analysis of the Women\'s Health Initiative.

Leedy DJ, Reding KW, Vasbinder AL, Anderson GL, ... Qi L, Cheng RK
Aims
There is conflicting evidence whether heart failure (HF) is a risk factor for incident cancer. Despite population-based cohorts demonstrating this association, an analysis of the Physician\'s Health Study found no association in a cohort of mostly healthy males. We investigated the association of HF with incident cancer among a large cohort of post-menopausal women.
Methods and results
A prospective cohort study of 146 817 post-menopausal women age 50 to 79 years enrolled in the Women\'s Health Initiative from 1993-1998, and followed through 2015. The primary exposure was adjudicated incident HF diagnosis, including preserved and reduced ejection fraction in a sub-cohort. The primary outcome was adjudicated incident total and site-specific cancers. Hazard ratios were calculated using multivariable-adjusted Cox proportional hazard regression models. Over a median follow-up of 8.4 years, 3272 and 17 474 women developed HF and cancer, respectively. HF developed in 235 women prior to cancer. HF was associated with subsequent incident cancer [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.11-1.48]. Associations were observed for obesity-related cancers (HR 1.24, 95% CI 1.02-1.51), as well as lung and colorectal cancers (HR 1.58, 95% CI 1.09-2.30 and HR 1.52, 95% CI 1.02-2.27, respectively). HF with preserved ejection fraction (HR 1.34, 95% CI 1.06-1.67), but not HF reduced ejection fraction (HR 0.99, 95% CI 0.74-1.34), was associated with total cancer.
Conclusion
Heart failure was associated with an increase in cancer diagnoses in post-menopausal women. This association was strongest for lung cancer. Further research is needed to appreciate the underlying mechanisms responsible for this association.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 30 Apr 2021; epub ahead of print
Leedy DJ, Reding KW, Vasbinder AL, Anderson GL, ... Qi L, Cheng RK
Eur J Heart Fail: 30 Apr 2021; epub ahead of print | PMID: 33932263
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Impact:
Abstract

Heart failure with preserved ejection fraction according to the HFA-PEFF score in COVID-19 patients: clinical correlates and echocardiographic findings.

Hadzibegovic S, Lena A, Churchill TW, Ho JE, ... Tschöpe C, Anker MS
Aims
Viral-induced cardiac inflammation can induce heart failure with preserved ejection fraction (HFpEF)-like syndromes. COVID-19 can lead to myocardial damage and vascular injury. We hypothesised that COVID-19 patients frequently develop a HFpEF-like syndrome, and designed this study to explore this.
Methods and results
Cardiac function was assessed in 64 consecutive, hospitalized, and clinically stable COVID-19 patients from April-November 2020 with left ventricular ejection fraction (LVEF) ≥50% (age 56 ± 19 years, females: 31%, severe COVID-19 disease: 69%). To investigate likelihood of HFpEF presence, we used the HFA-PEFF score. A low (0-1 points), intermediate (2-4 points), and high (5-6 points) HFA-PEFF score was observed in 42%, 33%, and 25% of patients, respectively. In comparison, 64 subjects of similar age, sex, and comorbidity status without COVID-19 showed these scores in 30%, 66%, and 4%, respectively (between groups: P = 0.0002). High HFA-PEFF scores were more frequent in COVID-19 patients than controls (25% vs. 4%, P = 0.001). In COVID-19 patients, the HFA-PEFF score significantly correlated with age, estimated glomerular filtration rate, high-sensitivity troponin T (hsTnT), haemoglobin, QTc interval, LVEF, mitral E/A ratio, and H2 FPEF score (all P < 0.05). In multivariate, ordinal regression analyses, higher age and hsTnT were significant predictors of increased HFA-PEFF scores. Patients with myocardial injury (hsTnT ≥14 ng/L: 31%) vs. patients without myocardial injury, showed higher HFA-PEFF scores [median 5 (interquartile range 3-6) vs. 1 (0-3), P < 0.001] and more often showed left ventricular diastolic dysfunction (75% vs. 27%, P < 0.001).
Conclusion
Hospitalized COVID-19 patients frequently show high likelihood of presence of HFpEF that is associated with cardiac structural and functional alterations, and myocardial injury. Detailed cardiac assessments including echocardiographic determination of left ventricular diastolic function and biomarkers should become routine in the care of hospitalized COVID-19 patients.

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

Eur J Heart Fail: 30 Apr 2021; epub ahead of print
Hadzibegovic S, Lena A, Churchill TW, Ho JE, ... Tschöpe C, Anker MS
Eur J Heart Fail: 30 Apr 2021; epub ahead of print | PMID: 33932255
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Impact:
Abstract

Left atrial structure and function of the amyloidogenic V122I transthyretin variant in elderly African Americans.

Minamisawa M, Inciardi RM, Claggett B, Cuddy SAM, ... Chen LY, Solomon SD
Aims
African-American carriers of the transthyretin (TTR) valine-to-isoleucine substitution (V122I) are at increased risk of heart failure, yet many have relatively subtle abnormalities of left ventricular (LV) function. We sought to explore the influence of this mutation on left atrial (LA) structure and function in this population.
Methods and results
We assessed 1225 genotyped African-Americans (age range, 67-89 years) participating in the Atherosclerosis Risk in Communities study who underwent echocardiography and were in sinus rhythm at study Visit 5 (2011 to 2013). Six LA parameters [LA maximum/minimum volume index, ejection fraction, and LA reservoir, conduit, and contractile longitudinal strains (LS)] were compared between V122I TTR variant carriers (n = 46) and non-carriers (n = 1179). LA minimum volume index was significantly greater and LA contractile LS was worse in carriers than non-carriers (19.5 ± 10.6 mL/m2 vs. 16.3 ± 8.4 mL/m2 ; 15.0 ± 5.8% vs. 16.8 ± 5.7%, respectively, both P < 0.05). Carriers had a significantly higher number of LA abnormalities than non-carriers (1.8 ± 2.2 vs. 1.1 ± 1.6, P = 0.009). The number of subjects with at least four LA abnormalities was significantly increased among carriers compared with non-carriers (27% vs. 12%; odds ratio 2.43; 95% confidence interval 1.06-5.58 after adjusting for age, sex, body mass index, and LV wall thickness and global LS).
Conclusions
Left atrial enlargement and dysfunction were common in V122I TTR carriers with sinus rhythm than non-carriers, suggesting that abnormalities of LA function may represent early markers of subclinical disease in these individuals.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 29 Apr 2021; epub ahead of print
Minamisawa M, Inciardi RM, Claggett B, Cuddy SAM, ... Chen LY, Solomon SD
Eur J Heart Fail: 29 Apr 2021; epub ahead of print | PMID: 33928732
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Impact:

This program is still in alpha version.