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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 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

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.

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.

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)