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Background and Aims To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. Methods A multi-centre, open-label, randomized, active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 hours). The primary endpoint was diuretic effect, assessed by change in weight (kg). Secondary endpoints included change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. Results 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 hours was 976 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 hours was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; p=0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) versus 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; p=0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. Conclusion In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. ClinicalTrials.gov Identifier NCT04860011

BACKGROUND: ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). METHODS: We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level. RESULTS: Overall, 3048 participants had baseline ET-1 measurements of: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28–4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53–2.50] for T3 and 1.36 [95% CI, 1.06–1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, –3.19 [95% CI, –3.66 to –2.72] mL/min/1.73 m 2 /y, T2, –2.08 [95% CI, –2.52 to –1.63] and T1 –2.35 [95% CI, –2.79 to –1.91]; P =0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25–0.01; P =0.029). CONCLUSIONS: Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.

Cardiac rhythm monitoring is performed to search for atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA). Prolonged cardiac rhythm monitoring increases AF detection but is challenging to implement in many healthcare settings and is not needed for all people after ischaemic stroke/TIA. We aimed to develop and validate a model that includes clinical, electrocardiogram (ECG), blood-based, and genetic biomarkers to identify people with a low probability of AF detection after ischaemic stroke or TIA. We will recruit 675 consenting participants who are aged over 18 years, who were admitted with ischaemic stroke or TIA in the 5 days prior, who are not known to have AF, and who would be suitable for anticoagulation if AF is found. We will collect baseline demographic and clinical data, a 12-lead ECG, and a venous blood sample for blood biomarkers (including midregional pro-atrial natriuretic peptide, MRproANP) and genetic data. We will perform up to 28 days of cardiac rhythm monitoring using an R-test or patch device to search for AF in all participants. The sample size of 675 participants is based on true sensitivity of 92.5%, null hypothesis sensitivity of 80%, 80% power, and 5% significance. The primary outcome is AF detection ≥30 s duration during 28 days of cardiac rhythm monitoring. Secondary outcomes are AF detection at 1-year, recurrent cardiovascular events, and mortality and will be identified by electronic linkage and telephone follow-up. The results will guide the development of a more personalized care pathway to search for AF after ischaemic stroke or TIA. This could help to reduce cardiac rhythm monitoring for people with a low probability of AF detection and allow more intensive cardiac monitoring to be focused on people who are more likely to have AF and benefit. Participants will be consented for their data to be used in future research studies, providing a rich resource for stroke and cardiovascular research communities. Cardiac rhythm monitoring is performed to search for atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA). Prolonged cardiac rhythm monitoring increases AF detection but is challenging to implement in many healthcare settings and is not needed for all people after ischaemic stroke/TIA. We aimed to develop and validate a model that includes clinical, electrocardiogram (ECG), blood-based, and genetic biomarkers to identify people with a low probability of AF detection after ischaemic stroke or TIA. We will recruit 675 consenting participants who are aged over 18 years, who were admitted with ischaemic stroke or TIA in the 5 days prior, who are not known to have AF, and who would be suitable for anticoagulation if AF is found. We will collect baseline demographic and clinical data, a 12-lead ECG, and a venous blood sample for blood biomarkers (including midregional pro-atrial natriuretic peptide, MRproANP) and genetic data. We will perform up to 28 days of cardiac rhythm monitoring using an R-test or patch device to search for AF in all participants. The sample size of 675 participants is based on true sensitivity of 92.5%, null hypothesis sensitivity of 80%, 80% power, and 5% significance. The primary outcome is AF detection ≥30 s duration during 28 days of cardiac rhythm monitoring. Secondary outcomes are AF detection at 1-year, recurrent cardiovascular events, and mortality and will be identified by electronic linkage and telephone follow-up. The results will guide the development of a more personalized care pathway to search for AF after ischaemic stroke or TIA. This could help to reduce cardiac rhythm monitoring for people with a low probability of AF detection and allow more intensive cardiac monitoring to be focused on people who are more likely to have AF and benefit. Participants will be consented for their data to be used in future research studies, providing a rich resource for stroke and cardiovascular research communities.

Up to 20% of patients in heart failure with reduced ejection fraction (HFrEF) trials are not taking diuretic agents at baseline, but little is known about them.The aim of this study was to examine outcomes in patients with HFrEF not taking diuretic medications and after diuretic medications are started.Patient characteristics and outcomes were compared between patients taking or not taking diuretic drugs at baseline in the ATMOSPHERE (Aliskiren Trial of Minimizing Outcomes for Patients With Heart Failure) and PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) trials combined. Patients starting diuretic medications were also compared with those remaining off diuretic drugs during follow-up. Symptoms (Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]), hospitalization for worsening heart failure (HF), mortality, and kidney function (estimated glomerular filtration rate slope) were examined.At baseline, the 3,079 of 15,415 patients (20%) not taking diuretic medications had a less severe HF profile, less neurohumoral activation, and better kidney function. They were less likely to experience the primary outcome (hospitalization for HF or cardiovascular death) than patients taking diuretic agents (adjusted HR: 0.77; 95% CI: 0.74-0.80; P 0.001) and death of any cause. Commencement of a diuretic drug was associated with higher subsequent risk for death (adjusted HR: 2.05; 95% CI: 1.99-2.11; P 0.001) and greater decreases in KCCQ-CSS and estimated glomerular filtration rate. The 5 strongest predictors of initiation of diuretic medications were higher N-terminal pro-B-type natriuretic peptide, higher body mass index, older age, history of diabetes, and worse KCCQ-CSS. In PARADIGM-HF, fewer patients who were treated with sacubitril/valsartan commenced diuretic agents (OR: 0.72; 95% CI: 0.58-0.88; P = 0.002).Patients with HFrEF not taking diuretic medications and those who remained off them had better outcomes than patients treated with diuretic agents or who commenced them.

AIMS: The aim of this study was to examine the association between patient-reported symptoms and the extent of pulmonary congestion in acute heart failure (AHF). METHODS AND RESULTS: In this prospective, observational study, patient-reported symptoms were assessed at baseline using the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) (range 0–100; 0 worst) in patients hospitalized for AHF. In a subset, patient-reported dyspnoea at rest and on exertion was examined (range 0–10; 10 worst) at baseline. In addition, 4-zone lung ultrasound (LUS) was performed at baseline at the time of echocardiography. B-lines were quantified offline, blinded to clinical findings, by a core laboratory. Chest X-ray (CXR) and physical examination findings were collected from the medical records. Among 322 patients (mean age 72, 60% men, mean left ventricular ejection fraction 39%) with AHF, the median KCCQ-TSS score was 33 (interquartile range 18–48). Worse KCCQ-TSS was associated with worse New York Heart Association class, dyspnoea at rest and on exertion, and peripheral oedema (p trend 0.25 for all). Similarly, KCCQ-TSS was not significantly associated with echocardiographic markers of left ventricular filling pressure, pulmonary pressure or with N-terminal pro-B-type natriuretic peptide level. CONCLUSIONS: Among patients hospitalized for AHF, at baseline, KCCQ-TSS was not associated with pulmonary congestion assessed by LUS, CXR, or physical examination. These findings suggest that the profound reduction in KCCQ-TSS in patients with AHF may not be solely explained by pulmonary congestion.

Background: Demographic differences in expected NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration are not well established. We aimed to establish reference ranges for NT-proBNP and explore the determinants of moderately elevated NT-proBNP under the universal definition of heart failure criteria. Methods: This is a cross-sectional study. NT-proBNP was measured in serum from 18 356 individuals without previous cardiovascular disease in the Generation Scotland Scottish Family Health Study. Age- and sex-stratified medians and 97.5th centiles were generated. Sex stratified risk factors for moderately elevated NT-proBNP (≥125 pg/mL) were investigated. Results: In males, median (97.5th centile) NT-proBNP concentration at age P sex interaction P sex interaction =0.007). Conclusions: An NT-proBNP ≥125 pg/mL is common in females without classical cardiovascular risk factors as well as older people. If NT-proBNP becomes widely used for screening in the general population, interpretation of NT-proBNP levels will require that age and sex-specific thresholds are used to identify patients with potential pathophysiology.

No abstract available.

Background Impaired health-related quality of life (HRQL) and pulmonary congestion are common and important findings among patients hospitalized for acute heart failure (AHF). There are few data describing the association between HQRL, symptoms and pulmonary congestion in AHF. Purpose This study investigates whether worse HRQL and symptoms is associated with more pulmonary congestion. Pulmonary congestion measured by lung ultrasound (LUS) in patients with AHF is a marker of worse prognosis at baseline and pre-discharge. Methods In this 2-site, prospective, observational study, four-zone LUS was performed at baseline (LUS1) and within 72h of hospital discharge (LUS2) in patients hospitalized for AHF. B-lines were quantified off-line, blinded to clinical findings and outcomes, by a core laboratory. Clinicians managing the patients were blinded to LUS findings. HRQL was assessed at baseline using the patient-reported Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS). Physician assessment of functional limitation at baseline was reported using the NYHA classification. In a subset of participants, patient-reported dyspnea at rest was also examined, at baseline and pre-discharge, using a numeric ranking scale (range 0–10; 10 worst). Dyspnea on exertion was also examined at baseline. Results Among 322 patients (mean age 72, 60% men, mean LVEF 39%) the median [interquartile range] KCCQ-TSS score was 33 [18–48]. Those with worse KCCQ-TSS scores, analyzed in tertiles, were younger, more likely to be obese and have diabetes mellitus and asthma/COPD, more likely to be on diuretics and report worse dyspnea at rest. At baseline, worse KCCQ-TSS was associated with worse NYHA class (Spearman's rho = −0.33, p Conclusion Among patients hospitalized for AHF, at baseline, worse KCCQ-TSS was associated with worse NYHA class, dyspnea at rest and dyspnea on exertion but was not significantly associated with pulmonary congestion assessed by LUS. A higher number of B-lines at baseline was associated with worse NYHA class. Patient-reported breathlessness and HQRL measures, although important, may not consistently reflect the degree of pulmonary congestion in patients with AHF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) (K23HL123533 to E.P.) and the British Heart Foundation (PG/13/17/30050 to R.T.C. and J.J.V.M.) Association of LUS1 B-lines & NYHA class

Aims:\ud We sought to examine sex differences in congestion in patients hospitalized for acute heart failure (AHF). Understanding congestive patterns in women and men with AHF may provide insights into sex differences in the presentation and prognosis of AHF patients.\ud \ud Methods and results:\ud In a prospective, two-site study in adults hospitalized for AHF, four-zone lung ultrasound (LUS) was performed at the time of echocardiography at baseline (LUS1) and, in a subset, pre-discharge (LUS2). B-lines on LUS and echocardiographic images were analysed offline, blinded to clinical information and outcomes. Among 349 patients with LUS1 data (median age 74, 59% male, and 87% White), women had higher left ventricular ejection fraction (mean 43% vs. 36%, P < 0.001), higher tricuspid annular plane systolic excursion (mean 17 vs. 15 mm, P = 0.021), and higher measures of filling pressures (median E/e′ 20 vs. 16, P < 0.001). B-line number on LUS1 (median 6 vs. 6, P = 0.69) and admission N-terminal pro-B-type natriuretic peptide levels (median 3932 vs. 3483 pg/mL, P = 0.77) were similar in women and men. In 121 patients with both LUS1 and LUS2 data, there was a similar and significant decrease in B-lines from baseline to discharge in both women and men. The risk of the composite 90 day outcome increased with higher B-line number on four-zone LUS2: unadjusted hazard ratio for each B-line tertile was 1.86 (95% confidence interval 1.08–3.20, P = 0.025) in women and 1.65 (95% confidence interval 1.03–2.64, P = 0.037) in men (interaction P = 0.72).\ud \ud Conclusions:\ud Among patients with AHF, echocardiographic markers differed between women and men at baseline, whereas B-line number on LUS did not. The dynamic changes in B-lines during a hospitalization for AHF were similar in women and men.

Introduction Acute heart failure (AHF) hospitalisation is typically lengthy, costly and associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM). Hopelessness independently predicted mortality in patients with risk factors of ischaemic heart disease. We hypothesize that patients randomised to OPM may be more hopeful and have better mental well-being, with better quality of life, patient and carer satisfaction. Methods We randomised patients with AHF, considered to need IV diuretic treatment for >2 days, to IPM or OPM. We recorded all-cause mortality (index-episode), and the number of full days alive and out-of-hospital (DAOH) within 60 days after randomisation. Quality of life (EQ5D-VAS), mental well-being [Short Warwick-Edinburgh Mental Wellbeing scale] and hope (Adult State Hope Scale) scores which have been validated as accurate in detecting fluctuations in hope were assessed up to 60 days follow-up. We calculated mean NHS cost savings and 95% central range (CR) from bootstrap analysis. Results Eleven patients were randomised to IPM and thirteen to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11 vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [log rank p=0.86]. (Figure 1). Patients randomised to IPM accrued a median of 47 [IQR 36, 51] vs 59 [41, 60] DAOH in OPM (p=0.13). 2 patients randomised to IPM (vs 6 OPM) were readmitted within 60 days [p=0.31]. Hope scores increased more with OPM within 30 days after randomisation but by 60 days, dropped to lower levels compared with the group allocated to IPM (not statistically significant). (Table 1). In-patients’ mental well-being score was higher at baseline but more out-patients had increased total well-being scores by the 60-day follow-up visit (p=0.04). (Table 2). 100% patients in both arms were satisfied according to the ‘NHS Family and Friends Test’ but interestingly 100% would choose OPM again whilst only 90% would choose Inpatient care again. Similarly, 100% carers were satisfied in the OPM arm whilst 60% only were satisfied if the patient was randomised to inpatient care. 100% carers would choose OPM again, vs 60% IPM carers.OPM was associated with mean cost savings of £2,658 (95% CR 460 - 4,857) per patient during the index episode. Conclusions Patients with acute HF randomised to OPM accrued more DAOH (albeit not statistically significant in this small pilot RCT). There was no increase in mortality but there was a higher risk of readmissions (not statistically significant). OPM was associated with improved mental well-being. But the initial increase in hope diminished within 60 days, possibly as a result of increased readmissions. The pilot RCT generated important hypotheses that need further testing in a large multicentre RCT. Conflict of Interest none

Background: Preliminary studies suggest that myocardial scar can be visualised by transthoracic echocardiography (TTE) using a low mechanical index (MI). Data describing the usefulness of scar imaging by TTE to predict myocardial viability are limited. Purpose: We investigated the association between myocardial scar, as imaged by low MI TTE, and viability as assessed by low-dose dobutamine stress echocardiography (DSE). Methods: We analysed 59 patients who had rest echocardiography including low MI (0.4-0.5) scans and DSEs, performed for myocardial viability between 29/04/2015 to 16/05/2018. Median age was 64 years (interquartile range 57-71), 55 (93%) were male. Left ventricular contrast opacification SonoVue (Braco) was used according to American Society of Echocardiography (ASE) standards (n = 39). Two experienced cardiologists blindly and independently performed 16-segment scar assessment at rest. Viability by DSE was used to represent the ‘gold standard’, from which sensitivity, specificity, negative and positive predictive values of viability assessed by scar at rest were calculated. Results: 42 (71%) of studies had evidence of scar at rest identified by low MI imaging. Presence of scar at rest has a sensitivity of 42%, specificity of 92%, positive and negative predictive values of 82 and 64%, respectively (Table 1). Specificity was higher in non-contrast compared to contrast images, at 97 and 90 %, respectively. The right coronary artery territory had a lower specificity compared to left anterior descending and circumflex territories. Conclusions: Presence of scar at rest has a low sensitivity but high specificity to predict non-viability on low-dose DSE. The presence of scar at rest TTE has the potential to reduce the need for low-dose DSE as these patients are unlikely to have viable myocardium in this region.

AIMS: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology. METHODS AND RESULTS: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P

Aims: \ud In patients at high risk of heart failure following myocardial infarction (MI) as a result of residual left ventricular systolic dysfunction (LVSD), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan may result in a greater attenuation of adverse left ventricular (LV) remodelling than renin angiotensin aldosterone system inhibition alone, due to increased levels of substrates for neprilysin with vasodilatory, anti‐hypertrophic, anti‐fibrotic, and sympatholytic effects.\ud \ud Methods: \ud We designed a randomized, double‐blinded, active‐comparator trial to examine the effect of sacubitril/valsartan to the current standard of care in reducing adverse LV remodelling in patients with asymptomatic LVSD following MI. Eligible patients were ≥3 months following MI, had an LV ejection fraction ≤40% as measured by echocardiography, were New York Heart Association functional classification I, tolerant of an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker at equivalent dose of ramipril 2.5 mg twice daily or greater, and taking a beta‐blocker unless contraindicated or intolerant. Patients were randomized to sacubitril/valsartan (target dose 97/103 mg twice daily) or valsartan (target dose 160 mg twice daily). The primary endpoint will be change in LV end‐systolic volume indexed for body surface area measured using cardiac magnetic resonance imaging over 52 weeks from randomization. Secondary endpoints include other magnetic resonance imaging‐based metrics of LV remodelling, biomarkers associated with LV remodelling and neurohumoral activation, and change in patient well‐being assessed using a patient global assessment questionnaire.\ud \ud Conclusions: \ud This trial will investigate the effect of neprilysin inhibition on LV remodelling and the neurohumoral actions of sacubitril/valsartan in patients with asymptomatic LVSD following MI.

Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF). However, their effects on cardiac structure and function in HFrEF are uncertain. Methods: We designed a multicenter, randomized, double-blind, placebo-controlled trial (the SUGAR-DM-HF trial [Studies of Empagliflozin and Its Cardiovascular, Renal and Metabolic Effects in Patients With Diabetes Mellitus, or Prediabetes, and Heart Failure]) to investigate the cardiac effects of empagliflozin in patients in New York Heart Association functional class II to IV with a left ventricular (LV) ejection fraction ≤40% and type 2 diabetes or prediabetes. Patients were randomly assigned 1:1 to empagliflozin 10 mg once daily or placebo, stratified by age ( Results: From April 2018 to August 2019, 105 patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LV ejection fraction 32.5% (9.8%), and 81 (77.1%) New York Heart Association II and 24 (22.9%) New York Heart Association III. Patients received standard treatment for HFrEF. In comparison with placebo, empagliflozin reduced LV end-systolic volume index by 6.0 (95% CI, –10.8 to –1.2) mL/m 2 ( P =0.015). There was no difference in LV global longitudinal strain. Empagliflozin reduced LV end-diastolic volume index by 8.2 (95% CI, –13.7 to –2.6) mL/m 2 ( P =0.0042) and reduced N-terminal pro-B-type natriuretic peptide by 28% (2%–47%), P =0.038. There were no between-group differences in other cardiovascular magnetic resonance measures, diuretic intensification, Kansas City Cardiomyopathy Questionnaire Total Symptom Score, 6-minute walk distance, or B-lines. Conclusions: The sodium-glucose cotransporter 2 inhibitor empagliflozin reduced LV volumes in patients with HFrEF and type 2 diabetes or prediabetes. Favorable reverse LV remodeling may be a mechanism by which sodium-glucose cotransporter 2 inhibitors reduce heart failure hospitalization and mortality in HFrEF. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03485092.

Introduction Burn injuries are associated with high morbidity and mortality. Burn care has improved significantly in the last few decades with emphasis on early surgical management, improvements in local wound care, and specialized critical care. While survival rates are improving, mortality remains high in certain patient populations, including those with larger burns. Burn injury induces a systemic hyperinflammatory response with detrimental side effects. Prior studies have offered early insights into the biochemical changes that occur after severe burn injury. The underlying cellular response is still largely unknown. The goal of this work is to characterize the blood transcriptome of severe burn injury and compare this response between patients who live or subsequently die of their injuries. Methods Burn patients presenting to a regional center between 2012–2017 were prospectively enrolled. Blood was collected on admission and at predetermined timepoints (Hours 2, 4, 8, 12, 24) over the first 24 hours. mRNA was isolated and a transcriptomic microarray was used to measure global transcript levels over time. To identify differentially regulated genes (FDR≤0.1) by injury severity, patients were grouped by burn size (TBSA >20%) and mortality. Microarray data was analyzed using bioinformatics software and pathway analysis. Descriptive statistics were generated with Mann-Whitney, Chi-Square, and Fisher’s exact test as appropriate. Results Sixty-eight patients were included in this analysis, most patients were male with a median age of 41 (IQR, 30.5–58.5) years, and TBSA of 20% (IQR, 11–34%). Thirty-five patients suffered %TBSA injury >20%, and this group experienced greater mortality (26% vs. 3%, p=0.008). There were no significant differences in age, race, or gender. Comparative analysis of genes from patients with < />20% TBSA revealed 1250, 444, 209, 20, 865, and 557 differentially regulated genes at hours 0, 2, 4, 8, 12 and 24 respectively. Pathway analysis reveals an initial upregulation in several immune/inflammatory pathways within the >20% TBSA groups between hours 0–2 followed by shutdown between hours 12–24. Immune pathways include Th17 activation pathway and natural killer cell signaling, inflammatory pathways include EIF2 signaling. These pathways remain upregulated in the group of patients with >20% TBSA who died. Conclusions Severe burn injury is associated with an early proinflammatory immune response followed by shutdown of these pathways. Burn patients who die show continued upregulation in the first 24 hours after injury in several proinflammatory pathways compared to those who live.

Aims: \ud Measurement of B‐type natriuretic peptide (BNP) or N‐terminal pro‐BNP is recommended as part of the diagnostic workup of patients with suspected heart failure (HF). We evaluated the diagnostic and prognostic utility of the novel urinary proteomic classifier HF1, compared with BNP, in HF. HF1 consists of 85 unique urinary peptide fragments thought, mainly, to reflect collagen turnover.\ud \ud Methods and results: \ud We performed urinary proteome analysis using capillary electrophoresis coupled with mass spectrometry in 829 participants. Of these, 622 had HF (504 had chronic HF and 118 acute HF) and 207 were controls (62 coronary heart disease patients without HF and 145 healthy controls). The area under the receiver operating characteristic (ROC) curve (AUC) using HF1 for the diagnosis of HF (cases vs. controls) was 0.94 (95% CI, 0.92–0.96). This compared with an AUC for BNP of 0.98 (95% CI, 0.97–0.99). Adding HF1 to BNP increased the AUC to 0.99 (0.98–0.99), P < 0.001, and led to a net reclassification improvement of 0.67 (95% CI, 0.54–0.77), P < 0.001. Among 433 HF patients followed up for a median of 989 days, we observed 186 deaths. HF1 had poorer predictive value to BNP for all‐cause mortality and did not add prognostic information when combined with BNP.\ud \ud Conclusions: \ud The urinary proteomic classifier HF1 performed as well, diagnostically, as BNP and provided incremental diagnostic information when added to BNP. HF1 had less prognostic utility than BNP.

Introduction Outpatient based management of heart failure is gaining popularity in the UK. Observation data and a small pilot randomised controlled trial suggested it is safe and clinically effective. However, the cost-effectiveness of this novel treatment approach is not known. Patient level costing is thought to be more accurate providing extra granularity when reviewing the cost of patient pathways. Methods We used the Trust’s patient level costing models from financial years 2018/19 and 2019/20 to calculate total treatment costs for the patients in the pilot prospective trial which randomised acute heart failure patients to receive inpatient vs outpatient based therapy. Patient level costing for inpatients would include hospital bed, nursing cost, consultant /ward doctor cost, non-pay costs (pharmacy including iv drugs, diagnostics e.g. pathology, radiology, ECG, echocardiography). Where patient level costs are unavailable, for example Community contacts, we have used a national average cost. Community centre visit - HRG code of N29AF 2018/19 National average cost £71 Home visit - HRG code of N29AF 2018/19 National average cost £71 GP visit - National average cost of £30 [1] All other costs used are from the Trust costing model. We also tested the feasibility of collecting quality of life data using EQ5D-5L and the visual analogue scale (VAS) where 100 means the ‘best health you can imagine’ and 0 is the worst. EQ-5D-5L 5 items each with a different domain: mobility, self-care, activities, pain and depression. Each is scored from 1-5 where 5 is the worst (severe limitation/unable to do). Value sets are used to transform the health profile into an index value that can be interpreted as a health utility; these range from -0.594 to 1.000 where a value below zero is taken to describe a health state whose quality is ‘worse than death’. Results 24 patients were randomised to 13 outpatients and 11 inpatients between July 2018 and June 2019: Inpatients received 5.8 ± 2.8 days of treatment, outpatients received 8.5 ± 5.2 (p=0.12). No patient was in CCU, HDU or ITU or received dialysis/haemofiltration. 1 patient randomised to inpatient care died during the index episode, but none died in the outpatient group. There was one extra AE Outpatients costed £31435 (£2418 on average). Therefore total average saving was £2663 per patient. Treatment groups varied little in their quality of life. EQ-5D-5L VAS scores are significantly higher for outpatient. [Figure 1] Indeed a linear mixed model confirms that treatment arm is significantly associated with higher VAS scores; an outpatient reports a VAS score 13 points higher on average than an inpatient, and there is evidence that the score increases slightly over time (0.18 points per day, equivalent to ≈ 11 points over the 60 day period) for all patients. [Table 1] This is not true of EQ-5D utility indices; estimates for treatment and time are non-significant (p=0.78 and p=0.88 respectively). Conclusion Outpatient based AHF management appears cost-effective. Total average saving was £2663 per patient. Treatment groups varied little in their quality of life. EQ-5D-5L VAS scores are significantly higher for outpatient. Conflict of Interest No conflict of interest

Introduction Worsening heart failure (HF) leading to hospital admission is common and associated with substantial morbidity and mortality. For many patients, the preferred place of care, including end-of-life care, is at home or in the community, but this is often thwarted by the need for intravenous (IV) diuretic therapy. Alternative models of ambulatory care exist but safety and efficacy should be compared to standard care in randomised controlled trials (RCT). Methods We randomised patients with pulmonary or peripheral oedema who no longer required supplementary oxygen and who were considered to need at least two more days of IV diuretic treatment. A left ventricular ejection fraction 100pg/mL within the previous two years were also required. Patients who were admitted to hospital as well as those seen in the emergency department or out-patient clinic could be enrolled. Patients were randomised to be admitted (conventional care) or for out-patient care (at home, in the community centre, or in a hospital ‘Furosemide lounge’. The primary safety outcome was all-cause mortality during the index episode and primary effectiveness outcome was the number of full days alive and out of hospital (which did not include day-care in the Furosemide lounge) within 30 days after randomisation. Statistical analysis was based on ‘intention to treat’. Results Of 24 patients enrolled, eleven were randomised to in-patient and thirteen to out-patient care. There was no statistically significant difference in all-cause mortality. Only one patient, who was randomised to inpatient care, died. Patients randomised to in-patient care accrued 16 [IQR 12.5 to 20.5] days alive out of hospital compared to 29 [IQR 20.5 to 29] days for those assigned to out-patient care (p=0.015). Two patients randomised to in-patient care required readmission within 30-days compared to five assigned to out-patient care. Using these data, we calculate that a trial using this primary endpoint would require 92 patients to show, compared to standard in-patient care, that outpatient care leads to at least two more days alive and out of hospital with 90% power. Conclusion In this feasibility RCT, out-patient intravenous diuretic treatment was associated with a favourable outcome compared to standard inpatient care which might also be a cost-effective and an approach to care preferred by many patients. Conflict of Interest No conflict of interest

Background: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. Methods: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial). Results: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73–0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62–0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82–1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43–0.65]; P Conclusions: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00853658, NCT01035255.

Background Estimated plasma volume (ePV) can be calculated from haematocrit and body weight, and has been shown to correlate with PV measured using 125Iodine labelled human serum albumin. Comparing a patient's ePV to ideal PV (iPV), an estimate of a patient's relative congestion, called PV status (PVS), is possible. Higher PVS is associated with increased mortality in patients with heart failure (HF), and has been proposed as a simple, cheap, and non-invasive way of assessing congestion. Purpose Whether PVS is associated with invasively measured markers of congestion is unknown. We calculated PVS in patients with HF who had right heart catheterisation (RHC), and assessed any correlation between PVS and invasive measures of congestion. Methods We calculated PVS in consecutive patients who had RHC performed as part of transplant assessment. iPV was calculated as: iPV = c × weight (kg) where c=39 in males and c=40 in females. ePV was calculated using subjects' haematocrit and weight as follows: ePV = (1 − haematocrit) × [a + (b × weight in kg)], where haematocrit is a fraction, a=1530 in males and a=864 in females, and b=41 in males and b=47.9 in females. PVS was calculated as: PVS = PVS = (ePV − iPV) /iPV × 100%. Correlation between PVS and invasive wedge pressure, mean right atrial (RA) pressure, and NTproBNP were made using Pearson correlation. Results PV indices and RHC data were available for 61 patients, 43 (71%) were male. Median age was 55 [IQR 48, 58] years. 20 (33%), 24 (39%), and 15 (25%) were NYHA association class II, III, and IV respectively. The median NTproBNP was 1390 [IQR 512, 3612] pg/ml and median ejection fraction was 29 [IQR 20, 35] %. The median PVS was −5.9% (IQR −12.5, −1.6]. Median wedge and mean-RA pressures were 14 [7, 21] and 4 [1, 8] mmHg, respectively. Correlation between mean RA pressure and PVS is shown in the figure. There was no correlation between PVS and mean RA pressure (r=0.12, p=0.34) or wedge pressure (r=0.01, p=0.92). There was a weak correlation between NTproBNP and PVS (r=0.31, p=0.01) Correlation mean RA pressure and PVS Conclusion PVS did not correlate with the invasive measures of congestion, mean RA and wedge pressure, but was weakly correlated with NTproBNP. Although there were limited number of patients in this study, we question the conclusion that PVS is a marker of congestion, and whether it can be used clinically for this purpose.

Background Mortality from acute myocardial infarction (AMI) has declined, increasing the pool of survivors at risk of later development of heart failure (HF). However, coronary reperfusion limits infarct size and secondary prevention therapy has improved. In light of these competing influences on risk of HF, we have examined long-term trends in incident HF hospitalisation (HFH) after AMI in a long-term, nationwide study with a single healthcare provider. Purpose To describe temporal trends in the risk of HFH following first AMI occurring in Scotland over a 26 year period. Methods All patients in Scotland discharged alive after a first AMI between 1990 and 2015 were followed until a first HFH or death until the end of 2016 (minimum follow-up 1 year, maximum 27 years). The cumulative incidence of HF was estimated at 1, 5 and 10 years following MI, accounting for the competing risk of death, with adjustment for comorbidities, age, sex and socioeconomic deprivation. In a sensitivity analysis, rates of HFH by AMI type (ST elevation MI [STEMI], non-STEMI and unknown ST type) were calculated for the period 2012 to 2015. Results A total of 184,826 people with no prior history of HF were discharged alive after a first AMI during the period of study. 23,414 (12.7%) had a first HFH during a median follow-up time of 6.8 years. Accounting for the competing risk of death, the cumulative incidence of first HFH, at 1 year, fell between 1990 and 2015 from 5.0% to 2.9%; the 5 year risk fell from 10.4% to 5.8%; 10 year risk from 14.8% to 9.0% (Figure). The adjusted risk of HFH at 1 year after discharge fell by 55% (95% CI 49–60%). The adjusted 5 year risk of HFH fell by 57% (95% CI 53–60%) and 10 year risk fell by 53% (95% CI 50–57%). The adjusted risk of death after first MI fell at 1 year (44%; 95% CI 39–48%), 5 years (37%; 34–39%) and 10 years (34%; 31–36%). The 10 year risk of HF following AMI was higher in older individuals ( Figure 1 Conclusion Despite an increasing pool of survivors of AMI at risk of HF, the incidence of HF hospitalisation following AMI in Scotland has consistently decreased since 1990. This is despite changes in the treatment and definition of AMI. These trends suggest that better treatment of MI and secondary prevention are having an impact on the risk of HF at a population level. Acknowledgement/Funding This study was funded by an NHS Greater Glasgow and Clyde endowment fund award (GN17CA406)

Aims: We investigated which patients with heart failure (HF) should receive specialist palliative care (SPC) by first creating a definition of need for SPC in patients hospitalised with HF using patient‐reported outcome measures (PROMs) and then testing this definition using the outcome of days alive and out of hospital (DAOH). We also evaluated which baseline variables predicted need for SPC and whether those with this need received SPC. Methods and results: PROMs assessing quality of life (QoL), symptoms, and mood were administered at baseline and every 4 months. SPC need was defined as persistently severe impairment of any PROM without improvement (or severe impairment immediately preceding death). We then tested whether need for SPC, so defined, was reflected in DAOH, a measure which combines length of stay, days of hospital re‐admission, and days lost due to death. Of 272 patients recruited, 74 (27%) met the definition of SPC needs. These patients lived one third fewer DAOH than those without SPC need (and less than a quarter of QoL‐adjusted DAOH). A Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score of

Background Heart failure (HF) is a major cause of morbidity and mortality worldwide. HF with preserved ejection fraction (HFpEF) now accounts for around half of the HF population. To date, no treatments for HFpEF have proven effect and outcomes have not improved in recent decades. The heterogeneity of the HFpEF population and the failure of randomised controlled trials (RCTs) to demonstrate effective therapies has led to attempts to identify sub-phenotypes of HFpEF which may respond to targeted therapies. Recent studies suggest that epicardial coronary artery disease (CAD) and coronary microvascular dysfunction (CMD) may play an important role in a substantial group of patients with HFpEF. A novel paradigm has been proposed suggesting that endothelium-dependent CMD may play a key role in the unifying pathophysiology of HFpEF. I performed a systematic review of the literature describing the prevalence of epicardial CAD and CMD in HFpEF populations. Most studies were retrospective observational and population-based studies with inconsistent definitions of HF, preserved left ventricular ejection fraction (LVEF) and CAD. Studies which documented CAD angiographically were almost exclusively performed in highly-selected convenience cohorts. Consequently, prevalence estimates of CAD in HFpEF varied considerably between studies. Similarly, studies assessing CMD in HFpEF reported inconsistent results due to variable definitions of CMD and methods of assessing coronary microvascular function. Therefore, the prevalence of epicardial CAD and CMD have not been prospectively and systematically studied in an unselected HFpEF population. Aims The main aims of this study were to determine the prevalence of obstructive epicardial CAD, CMD and previous myocardial infarction (MI) in an unselected cohort of patients hospitalised with HFpEF using reference standard invasive investigations. Methods This was a prospective, multicentre, observational study of patients hospitalised with HFpEF. All patients recruited had a confirmed diagnosis of HFpEF according to the 2016 European Society of Cardiology (ESC) HF guidelines. Participants underwent invasive coronary angiography with guidewire-based assessment of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), followed by vasoreactivity testing with intra-coronary acetylcholine. This allowed the comprehensive assessment of epicardial and microvascular structure and function to determine the prevalence of CAD, CMD and coronary endothelial dysfunction in the cohort. Adenosine perfusion cardiac magnetic resonance (CMR) imaging was also performed to assess the burden of myocardial infarction (MI), diffuse fibrosis and inducible ischaemia in the study population. Patients were followed up by electronic medical record linkage for a minimum of 12 months. Results Of 2285 near-consecutive patients hospitalised with suspected HF, 628 were confirmed to have a diagnosis of HFpEF, and 106 HFpEF patients met the inclusion criteria and agreed to participate in the study. A total of 83 participants underwent invasive coronary angiography or CMR. Seventy-five participants underwent invasive coronary angiography, 62 had guidewire-based coronary physiology testing, and 41 underwent vasoreactivity testing. Fifty-two participants underwent CMR and 44 had both invasive coronary angiography and CMR. Twenty-three patients did not proceed to the study investigations, predominantly due to a decline in health, functional status or renal function making proceeding with the study investigations inappropriate or unsafe. In this unselected hospitalised HFpEF cohort, the prevalence of obstructive epicardial CAD on invasive assessment was 51% (95% confidence interval [CI] 39-62%); half of patients with obstructive epicardial disease had no clinical history of CAD. On invasive coronary physiological testing, 41 patients (66% [95% CI 53-77%]) had endothelium-independent CMD, and 10 (24% [95% CI 13-40%]) had endothelium-dependent CMD. Overall, 91% of participants had evidence of macrovascular and/or microvascular CAD. Of those who underwent CMR, 27% (95% CI 16-41%) had evidence of previous MI and 32% (95% CI 19-48%) had inducible ischaemia. Over half of patients with CMR-proven MI had no history of clinically apparent MI. Over a median follow-up period of 18 months, study participants with obstructive epicardial CAD had significantly more hospitalisations (for any cause, a cardiovascular cause or HF) than those without obstructive CAD. There was no significant difference in outcomes between those with or without endothelium-independent or -dependent CMD. Conclusion Both epicardial CAD and CMD are common in the HFpEF population, and there is a high prevalence of clinically unrecognised obstructive epicardial CAD and previous MI. Patients with obstructive epicardial CAD had significantly more hospitalisations than those without obstructive disease. Treatments for epicardial CAD (e.g. coronary revascularisation) might improve quality of life and reduce hospitalisations in HFpEF patients with CAD. Although it has been hypothesised that CMD in HFpEF is the result of endothelial dysfunction, it appears to be predominantly due to endothelium-independent mechanisms. This may have important implications for future treatments directed at CMD in patients with HFpEF.

Patients with heart failure (HF), particularly those admitted to hospital, have a reduced life expectancy.1 When asked to consider their preferred place for end‐of‐life (EOL) care if recovery appears unlikely, many patients express a wish to spend their final days at home.2 Yet analysis of patients with HF in randomized controlled trials and in epidemiology studies suggests that most patients with HF die in hospital.3, 4 Whether there is a discrepancy between preferred and actual place of EOL care has not been evaluated in a prospective cohort of patients with HF. We aimed to address this question, and assess the acceptability to patients with HF (and their caregivers) of discussing EOL care.

Aims Pulmonary congestion is an important finding in patients with heart failure (HF) that can be quantified by lung ultrasound (LUS). We conducted a systematic review to describe dynamic changes in LUS findings of pulmonary congestion (B-lines) in HF and to examine the prognostic utility of B-lines in HF. Methods and results We searched online databases for studies conducted in patients with chronic or acute HF that used LUS to assess dynamic changes or the prognostic value of pulmonary congestion. We included studies in adult populations, published in English, and conducted in ≥25 patients. Of 1327 identified studies, 13 (25–290 patients) met the inclusion criteria: six reported on dynamic changes in LUS findings (438 patients) and seven on the prognostic value of B-lines in HF (953 patients). In acute HF, B-line number changed within as few as 3 h of HF treatment. In acute HF, ≥15 B-lines on 28-zone LUS at discharge identified patients at a more than five-fold risk for HF readmission or death. Similarly, in ambulatory patients with chronic HF, ≥3 B-lines on five- or eight-zone LUS marked those at a nearly four-fold risk for 6-month HF hospitalization or death. Conclusions Lung ultrasound findings change rapidly in response to HF therapy. This technique may represent a useful and non-invasive method to track dynamic changes in pulmonary congestion. Furthermore, residual congestion at the time of discharge in acute HF or in ambulatory patients with chronic HF may identify those at high risk for adverse events.

This study sought to assess the prevalence, changes in, and prognostic importance of B-lines, a pulmonary congestion measure by using a simplified lung ultrasonography (LUS) method in acute heart failure (AHF).Pulmonary congestion is an important finding in AHF, but conventional methods for its detection are insensitive.In a 2-site, prospective, observational study, 4-zone LUS was performed early during hospitalization for AHF (LUS1) and at discharge (LUS2). B-lines were quantified off-line, blinded to clinical findings and outcomes, by a core laboratory.Among 349 patients (median, 75 years of age; 59% men; mean ejection fraction 39%), the sum of B-lines in 4 zones ranged from 0 to 18 (LUS1). The risk of an adverse in-hospital event increased with rising number of B-lines on LUS1: the odds ratio for each B-line tertile was 1.82 (95% confidence interval [CI]: 1.14 to 2.88; p = 0.011). B-line count decreased from a median of 6 (LUS1) to 4 (LUS2; p 0.001) over 6 days (median). In 132 patients with LUS2 images, the risk of HF hospitalization or all-cause death was greater in patients with a higher number of B-lines at discharge. This relationship was stronger closer to discharge: unadjusted hazard ratio (HR) at 60 days was 3.30 (95% CI: 1.52 to 7.17; p = 0.002); 2.94 at 90 days (95% CI: 1.46 to 5.93; p = 0.003); and 2.01 at 180 days (95% CI: 1.11 to 3.64; p = 0.021). The association between number of B-lines and short- and long-term outcomes persisted after adjusting for important clinical variables, including N-terminal pro-B-type natriuretic peptide.Pulmonary congestion using a simplified 4-zone LUS method was common in patients with AHF and improved with therapy. A higher number of B-lines at baseline and discharge identified patients at increased risk for adverse events.

Introduction In patients at high risk of heart failure (HF) following myocardial infarction (MI) as a result of residual left ventricular systolic dysfunction (LVSD), the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan may result in a greater attenuation of adverse LV remodeling than renin angiotensin aldosterone system inhibition alone, due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. In a randomized, double-blinded, active-comparator trial, we examined the effect of sacubitril/valsartan compared with the angiotensin receptor blocker (ARB), valsartan, on LV remodeling in patients with asymptomatic LVSD following MI using the gold-standard method of LV assessment, cardiac magnetic resonance imaging (MRI). Hypothesis In patients with LVSD and no evidence of HF following an MI, treatment with sacubitril/valsartan will result in a greater reduction in the degree of adverse remodeling than valsartan. Methods Key inclusion criteria were: 1) ≥3 months following MI, 2) LV ejection fraction ≤40% as measured by echocardiography, 3) tolerance of an ACE inhibitor or ARB at equivalent dose of ramipril ≥2.5mg twice daily, 4) taking a beta-blocker unless contraindicated or intolerant. Key exclusion criteria were: 1) Symptomatic HF (NYHA ≥II), 2) eGFR 5.2mmol/L, 4) symptomatic hypotension and/or systolic blood pressure Results From 7/19/2018 to 6/28/2019, 93 patients were randomized and the final study visit took place on 6/19/2020. Results from this trial will be available for presentation at the HFSA meeting. Conclusions This trial will investigate the effect of neprilysin inhibition on LV remodeling and the neurohumoral actions of sacubitril/valsartan in patients with asymptomatic LVSD following MI.

The authors of the 2016 European Society of Cardiology (ESC) guidelines on the diagnosis and treatment of acute and chronic heart failure described a new term to categorise patients with a resting left ventricular ejection fraction (LVEF) in the range of 40 − 49%, so‐called heart failure with mid‐range ejection fraction (HFmrEF), formerly referred to as ‘grey‐area’ ejection fraction in the previous iteration of the guidelines.1, 2 This designation overlapped with the previously described heart failure with preserved ejection fraction (HFpEF), which had included patients with a LVEF > 40% in one clinical trial but, more generally, patients with a LVEF > 45%.3-6 Puzzlingly, the 2016 guideline authors continued to use the description HFpEF for patients with a LVEF ≥ 50%. This change in terminology has caused understandable confusion and should be replaced.

An 81-year-old woman with myeloma and a recent fractured femoral neck presented after a collapse. On arrival, she was tachycardic, hypotensive, and hypoxic. ECG showed incomplete right bundle branch block, prominent S waves in lead I, Q waves and T-wave inversion in lead III (FigureA, black arrows). Echocardiography, performed by a cardiologist in the emergency department (ED), revealed classic features of massive pulmonary thromboembolism, with right ventricle enlargement and regional impairment of the right ventricle free wall (McConnell’s sign) ( FigureB; Video E1, available online at http://www.annemergmed.com), 1 compression of the left ventricle, and a large serpentine thrombus in the right atrium, which extends into the right ventricle ( FigureB, white arrow; Video E1, available online at http://www.annemergmed.com).

Heart failure ( HF ) is common, affecting 1% to 2% of the general population,1–3with the prevalence rising to more than 10% in those aged more than 80 years.1,4 HF has a high morbidity and reduced life expectancy, with 5- and 10-year survival rates of 50% and 10% reported in epidemiologic studies.5,6 HF can broadly be divided into 2 groups: HF with reduced ejection fraction ( HF-REF ) and HF with preserved ejection fraction ( HF-PEF ). There is a suggestion that HF-PEF accounts for almost half of all patients with HF and that prognosis is equally poor between groups,7,8 although a recent meta-analysis of 41,972 patients showed HF-REF to have a worse prognosis.9 The main difference between these 2 groups is response to treatment. Where HF-REF has several evidence-based therapies proved to improve survival, no treatment has been shown to do so in HF-PEF. The HF-PEF phenotype also differs from HF-REF, with HF-PEF patients being older, more often women, obese, and with more comorbidities. HF-PEF diagnosis is challenging and essentially a diagnosis of exclusion, with comorbidities potentially making the diagnosis more difficult. This article describes the comorbidities commonly associated with HF-PEF, the potential influence of these comorbidities on morbidity and mortality, and the differential diagnosis.

Non-ischaemic cardiomyopathy (NICM) is a common cause of heart failure. If no cause is identified it is termed idiopathic dilated cardiomyopathy (IDCM). Guideline-recommended therapy can improve left ventricular systolic function (LVSF). Although criteria for defining myocardial recovery exist, its

Although peripartum cardiomyopathy (PPCM) is associated with mortality and morbidity, improvement in cardiac function – termed myocardial recovery – can occur. No study has systematically reviewed myocardial recovery in PPCM and its independent predictors. A systematic review was performed of

Examination of patients with reduced and preserved ejection fraction in the DIG (Digitalis Investigation Group) trials and the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) trials provides comparisons of outcomes in each of these types of heart failure. Comparison of the patients in these trials, along with the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function Trial), with patients of similar age, sex distribution, and comorbidity in trials of hypertension, diabetes mellitus, angina pectoris, and atrial fibrillation provides even more interesting insights into the relation between phenotype and rates of death and heart failure hospitalization. The poor clinical outcomes in patients with heart failure and preserved ejection fraction do not seem easily explained on the basis of age, sex, comorbidity, blood pressure, or left ventricular structural remodeling but do seem to be explained by the presence of the syndrome of heart failure. (J Am Coll Cardiol 2012;60:2349–56) © 2012 by the American College of Cardiology Foundation

Background— Premature treatment discontinuation and loss to follow-up (LTFU) with unknown outcomes leave uncertainty about the true efficacy and safety of a treatment and a lack of confidence in the results of any trial. We reviewed the extent of (and trends over time in) reporting LTFU and treatment discontinuation in large studies in chronic heart failure published since 1990. Methods and Results— Online databases were systematically reviewed to identify randomized controlled clinical trials (RCTs) in chronic heart failure with >400 participants and utilizing all-cause mortality as a component of the primary or secondary end point. Assessments were made of documentation of treatment discontinuation, LTFU, inclusion of and completeness of a Consolidated Standards Of Reporting Trials (CONSORT) diagram, and whether LTFU was differentiated from withdrawal of consent. Sixty-eight trials were identified, with >154 000 participants. Reasons for treatment discontinuation in pharmacotherapy trials were infrequently reported (35%), particularly in a CONSORT diagram (20%). Eighty-three percent of trials reported LTFU, although only 34% of these differentiated LTFU for vital status from withdrawal of consent. Use of a CONSORT diagram increased over time, although reporting of LTFU in the CONSORT diagram remained low overall at 35%. Conclusions— Participant flow through RCTs in chronic heart failure has not been uniformly reported, and the use of a complete CONSORT diagram has been low, although it seems to be improving. All study participants should be accounted for within a CONSORT diagram in any RCT to enable the practicing cardiologist to interpret how the results should influence his/her clinical practice.

Aims: Guidelines for the management of chronic heart failure (CHF) cite the results of randomized controlled trials (RCTs) to support treatment recommendations. The significance of an observed treatment-effect relies on the use of a boundary p-value, most commonly p

Calf muscles of five adolescents aged 12 to 15 years (three males, two females) with spastic diplegia were massaged for 14 minutes twice a week for 5 weeks in a controlled sequence, stretching the muscles transversely rather than longitudinally, without eliciting pain. Slow, passive test stretches were applied before and after massage. After massage, the range of movement was not consistently increased but, on average, greater force was needed to stretch the muscle than before massage. However, after massage the resting ankle angle sometimes changed so that the calf muscles were either shorter or longer. We suggest that these phenomena could be explained if massage resets sarcomere lengths which corrects for thixotropic effects (i.e. previous use modifies a muscle's mechanical behaviour). A redistribution on sarcomere lengths within muscles could also have reset proprioceptive feedback. The incidence of abnormal stretch reflexes during test stretches fell from 40 to 22%, comparing the first five sessions with the last five sessions. The amplitude of voluntary alternating ankle rotation increased in three participants. Motor skills were assessed with the Gross Motor Function Measure-66 (GMFM-66) 1 week before the test period, during the 5th week, and 12 weeks later. Our participants in Gross Motor Function Classification System (GMFCS) Levels I and II made sustained improvements in GMFM-66 scores (6.4% at 5 weeks falling to 5.5% at 17 weeks), one increase being significant. One participant in GMFCS Level III improved significantly only after massage of all leg muscles for 30 weeks.

This study examined the trends in the relative contributions of cardiovascular and noncardiovascular mortality to total mortality according to use of beta-blockers in clinical trials of patients with heart failure with reduced ejection fraction (HF-REF).With the increasingly widespread use of disease-modifying therapies, particularly beta-blockers, in HF-REF, the proportion of patients dying from cardiovascular causes is likely to be decreasing.In a systematic review, 2 investigators independently searched online databases to identify clinical trials including400 patients with chronic heart failure published between 1986 and 2014 and that adjudicated cause of death. Trials were divided into 3 groups on the basis of the proportion of patients treated with a beta-blocker (33% [low], 33% to 66% [medium], and66% [high]). Percentages of total deaths adjudicated as cardiovascular or noncardiovascular were calculated by weighted means and weighted standard deviations. Weighted Student t tests were used to compare results between groups.Sixty-six trials met the inclusion criteria with a total of 136,182 patients and 32,140 deaths. There was a sequential increase in the percentage of noncardiovascular deaths with increasing beta-blocker use from 11.4% of all deaths in trials with low beta-blocker use to 19.1% in those with high beta-blocker use (p0.001).In trials of patients with HF-REF, the proportion of deaths adjudicated as cardiovascular has decreased. Cardiovascular mortality, and not all-cause mortality, should be used as an endpoint for trials of new treatments for HF-REF.

A 44-year-old female presented with signs and symptoms of acute heart failure (HF) after a 4-week history of progressive breathlessness, orthopnea, and paroxysmal nocturnal dyspnea. Her only past medical history was of asthma (no previous hospital admissions). ECG demonstrated left ventricular hypertrophy (LVH), and chest x-ray film confirmed pulmonary infiltrates and bilateral pleural effusions. Initial blood tests showed a slightly elevated Troponin I at 0.66 μg/L, severely elevated B-type natriuretic peptide of 3273 pg/mL, and a markedly raised eosinophilia count of 3.58×109/L. Transthoracic echocardiography (TTE; Figure 1 and Movie I in the online-only Data Supplement) showed marked eccentric LVH with a 2-toned appearance of the left ventricle (LV), preserved ejection fraction (EF) at 61%, enlarged right ventricle, biatrial enlargement, and a restrictive LV filling pattern. Cardiac magnetic resonance (CMR; Avanto, 1.5T; Siemens, Erlangen, Germany) imaging with gadolinium contrast (Figure 2 and Movie II in the online-only Data Supplement) was performed to aid the diagnosis. Cine imaging using the steady-state free precession (SSFP) technique demonstrated severe LVH with preserved LV systolic function (EF 58.8%). Using a phase-sensitive inversion recovery technique 10 minutes after injection of gadolinium, there was marked subendocardial late …

Aims The primary aim of this study is to provide data to inform the design of a randomized controlled clinical trial (RCT) of a palliative care (PC) intervention in heart failure (HF). We will identify an appropriate study population with a high prevalence of PC needs defined using quantifiable measures. We will also identify which components a specific and targeted PC intervention in HF should include and attempt to define the most relevant trial outcomes. Methods An unselected, prospective, near‐consecutive, cohort of patients admitted to hospital with acute decompensated HF will be enrolled over a 2‐year period. All potential participants will be screened using B‐type natriuretic peptide and echocardiography, and all those enrolled will be extensively characterized in terms of their HF status, comorbidity, and PC needs. Quantitative assessment of PC needs will include evaluation of general and disease‐specific quality of life, mood, symptom burden, caregiver burden, and end of life care. Inpatient assessments will be performed and after discharge outpatient assessments will be carried out every 4 months for up to 2.5 years. Participants will be followed up for a minimum of 1 year for hospital admissions, and place and cause of death. Methods for identifying patients with HF with PC needs will be evaluated, and estimates of healthcare utilisation performed. Conclusion By assessing the prevalence of these needs, describing how these needs change over time, and evaluating how best PC needs can be identified, we will provide the foundation for designing an RCT of a PC intervention in HF.