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Aims: Sex‐specific differences in acute heart failure (AHF) are both relevant and underappreciated. Therefore, it is crucial to evaluate the risk/benefit ratio and the implementation of novel AHF therapies in women and men separately. Methods and results: We performed a pre‐defined sex‐specific analysis in AHF patients randomized to a strategy of early intensive and sustained vasodilatation versus usual care in an international, multicentre, open‐label, blinded endpoint trial. Inclusion criteria were AHF with increased plasma concentrations of natriuretic peptides, systolic blood pressure ≥100 mmHg, and plan for treatment in a general ward. Among 781 eligible patients, 288 (37%) were women. Women were older (median 83 vs. 76 years), had a lower body weight (median 64.5 vs. 77.6 kg) and lower estimated glomerular filtration rate (median 48 vs. 54 ml/min/1.73 m2). The primary endpoint, a composite of all‐cause mortality or rehospitalization for AHF at 180 days, showed a significant interaction of treatment strategy and sex (p for interaction = 0.03; hazard ratio adjusted for female sex 1.62, 95% confidence interval 1.05–2.50; p = 0.03). The combined endpoint occurred in 53 women (38%) in the intervention group and in 35 (24%) in the usual care group. The implementation of rapid up‐titration of renin–angiotensin–aldosterone system (RAAS) inhibitors was less successful in women versus men in the overall cohort and in patients with heart failure with reduced ejection fraction (median discharge % target dose in patients randomized to intervention: 50% in women vs. 75% in men). Conclusion: Rapid up‐titration of RAAS inhibitors was less successfully implemented in women possibly explaining their higher rate of all‐cause mortality and rehospitalization for AHF. Clinical Trial Registration: ClinicalTrials.gov, unique identifier NCT00512759. [ABSTRACT FROM AUTHOR]

Aims: Systemic inflammation may be central in the pathophysiology of acute heart failure (AHF). We aimed to assess the possible role of systemic inflammation in the pathophysiology, phenotyping, and risk stratification of patients with AHF. Methods and results: Using a novel Interleukin‐6 immunoassay with unprecedented sensitivity (limit of detection 0.01 ng/L), we quantified systemic inflammation in unselected patients presenting with acute dyspnoea to the emergency department in a multicentre study. One‐year mortality was the primary prognostic endpoint. Among 2042 patients, 1026 (50.2%) had an adjudicated diagnosis of AHF, 83.7% of whom had elevated interleukin‐6 concentrations (>4.45 ng/L). Interleukin‐6 was significantly higher in AHF patients compared to patients with other causes of dyspnoea (11.2 [6.1–26.5] ng/L vs. 9.0 [3.2–32.3] ng/L, p < 0.0005). Elevated interleukin‐6 concentrations were independently predicted by increasing N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity cardiac troponin T, as well as the clinical diagnosis of infection. Among the different AHF phenotypes, interleukin‐6 concentrations were highest in patients with cardiogenic shock (25.7 [14.0–164.2] ng/L) and lowest in patients with hypertensive AHF (9.3 [4.8–21.6] ng/L, p = 0.001). Inflammation as quantified by interleukin‐6 was a strong and independent predictor of 1‐year mortality both in all AHF patients, as well as those without clinically overt infection at presentation (adjusted hazard ratio [95% confidence interval] 1.45 [1.15–1.83] vs. 1.48 [1.09–2.00]). The addition of interleukin‐6 significantly improved the discrimination of the BIOSTAT‐CHF risk score. Conclusion: An unexpectedly high percentage of patients with AHF have subclinical systemic inflammation as quantified by interleukin‐6, which seems to contribute to AHF phenotype and to the risk of death. [ABSTRACT FROM AUTHOR]

Aims: Cardiac myosin‐binding protein C (cMyC) seems to be even more sensitive in the quantification of cardiomyocyte injury vs. high‐sensitivity cardiac troponin, and may therefore have diagnostic and prognostic utility. Methods and results: In a prospective multicentre diagnostic study, cMyC, high‐sensitivity cardiac troponin T (hs‐cTnT), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) plasma concentrations were measured in blinded fashion in patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists centrally adjudicated the final diagnosis. Diagnostic accuracy for acute heart failure (AHF) was quantified by the area under the receiver operating characteristic curve (AUC). All‐cause mortality within 360 days was the prognostic endpoint. Among 1083 patients eligible for diagnostic analysis, 51% had AHF. cMyC concentrations at presentation were higher among AHF patients vs. patients with other final diagnoses [72 (interquartile range, IQR 39–156) vs. 22 ng/L (IQR 12–42), P < 0.001)]. cMyC's AUC was high [0.81, 95% confidence interval (CI) 0.78–0.83], higher than hs‐cTnT's (0.79, 95% CI 0.76–0.82, P = 0.081) and lower than NT‐proBNP's (0.91, 95% CI 0.89–0.93, P < 0.001). Among 794 AHF patients eligible for prognostic analysis, 28% died within 360 days; cMyC plasma concentrations above the median indicated increased risk of death (hazard ratio 2.19, 95% CI 1.66–2.89; P < 0.001). cMyC's prognostic accuracy was comparable with NT‐proBNP's and hs‐cTnT's. cMyC did not independently predict all‐cause mortality when used in validated multivariable regression models. In novel multivariable regression models including medication, age, left ventricular ejection fraction, and discharge creatinine, cMyC remained an independent predictor of death and had no interactions with medical therapies at discharge. Conclusion: Cardiac myosin‐binding protein C may aid physicians in the rapid triage of patients with suspected AHF. [ABSTRACT FROM AUTHOR]

Aims: Acute kidney injury (AKI) during acute heart failure (AHF) is common and associated with increased morbidity and mortality. The underlying pathophysiological mechanism appears to have prognostic relevance; however, the differentiation of true, structural AKI from hemodynamic pseudo‐AKI remains a clinical challenge. Methods and results: The Basics in Acute Shortness of Breath Evaluation Study (NCT01831115) prospectively enrolled adult patients presenting with AHF to the emergency department. Mortality of patients was prospectively assessed. Haemoconcentration, transglomerular pressure gradient (n = 231) and tubular injury patterns (n = 253) were evaluated to investigate pathophysiological mechanisms underlying AKI timing (existing at presentation vs. developing during in‐hospital period). Of 1643 AHF patients, 755 patients (46%) experienced an episode of AKI; 310 patients (19%; 41% of AKI patients) presented with community‐acquired AKI (CA‐AKI), 445 patients (27%; 59% of AKI patients) developed in‐hospital AKI. CA‐AKI but not in‐hospital AKI was associated with higher mortality compared with no‐AKI (adjusted hazard ratio 1.32 [95%‐CI 1.01–1.74]; P = 0.04). Independent of AKI timing, haemoconcentration was associated with a lower two‐year mortality. Transglomerular pressure gradient at presentation was significantly lower in CA‐AKI compared to in‐hospital AKI and no‐AKI (P < 0.01). Urinary NGAL ratio concentrations were significantly higher in CA‐AKI compared to in‐hospital AKI (P < 0.01) or no‐AKI (P < 0.01). Conclusions: CA‐AKI but not in‐hospital AKI is associated with increased long‐term mortality and marked by decreased transglomerular pressure gradient and tubular injury, probably reflecting prolonged tubular ischemia due to reno‐venous congestion. Adequate decongestion, as assessed by haemoconcentration, is associated with lower long‐term mortality independent of AKI timing. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the diagnostic and prognostic utility of the QRS‐T angle, an electrocardiogram (ECG) marker quantifying depolarization–repolarization heterogeneity, in patients with suspected acute decompensated heart failure (ADHF). Methods and results: We prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of ADHF. The QRS‐T angle was automatically derived from a standard 12‐lead ECG recorded at presentation. The primary diagnostic endpoint was a final adjudicated diagnosis of ADHF. The primary prognostic endpoint was all‐cause mortality during 2 years of follow‐up. Among the 1915 patients enrolled, those with higher QRS‐T angles were older, were more commonly male, and had a higher rate of co‐morbidities such as arterial hypertension, coronary artery disease, or chronic kidney disease. ADHF was the final adjudicated diagnosis in 1140 (60%) patients. The QRS‐T angle in patients with ADHF was significantly larger than in patients with non‐cardiac causes of dyspnoea {median 110° [inter‐quartile range (IQR) 46–156°] vs. median 33° [IQR 15–57°], P < 0.001}. The diagnostic accuracy of the QRS‐T angle as quantified by the area under the receiver operating characteristic curve (AUC) was 0.75 [95% confidence interval (CI) 0.73–0.77, P < 0.001], which was inferior to N‐terminal pro‐B‐type natriuretic peptide (AUC 0.93, 95% CI 0.92–0.94, P < 0.001), but similar to that of high‐sensitivity troponin T (AUC 0.78, 95% CI 0.76–0.80, P = 0.09). The AUC of the QRS‐T angle for discrimination between ADHF and non‐cardiac dyspnoea remained similarly high in subgroups of patients known to be diagnostically challenging, including patients older than 75 years [0.71 (95% CI 0.67–0.74)], renal failure [0.79 (95% CI 0.71–0.87)], and atrial fibrillation at presentation [0.68 (95% CI 0.60–0.76)]. Mortality rates according to QRS‐T angle tertiles were 4%, 6%, and 10% after 30 days (P < 0.001) and 24%, 31%, and 43% after 2 years (P < 0.001). After adjustment for clinical, laboratory, and ECG parameters, the QRS‐T angle remained an independent predictor for 2 year mortality with a 4% increase in mortality for every 20° increase in QRS‐T angle (P = 0.02). Conclusions: The QRS‐T angle is a readily available and inexpensive marker that can assist in the discrimination between ADHF and non‐cardiac causes of acute dyspnoea and may aid in the risk stratification of these patients. [ABSTRACT FROM AUTHOR]

Background: The cardiac electrical biomarker (CEB) is a novel electrocardiographic (ECG) marker quantifying the dipolar activity of the heart with higher levels indicating myocardial injury.Methods: We prospectively enrolled 1097 patients presenting with suspected non-ST-elevation myocardial infarction (NSTEMI) to the emergency department (ED). Digital 12-lead ECGs were recorded at presentation and the CEB values were calculated in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 2 years of follow-up.Results: NSTEMI was the final diagnosis in 14% of patients. CEB levels were higher in patients with NSTEMI compared to other causes of chest pain (median 44 (IQR 21-98) vs. 30 (IQR 16-61), p < .001). A weak but significant correlation between levels of high-sensitivity cardiac troponin T (hs-cTnT) at admission to the ED and the CEB was found (r = .23, p < .001). The use of the CEB in addition to conventional ECG criteria improved the diagnostic accuracy for the diagnosis of NSTEMI as quantified by the area under the receiver operating characteristics curve from 0.66 to 0.71 (p < .001) and the sensitivity improved from 43% to 79% (p < .001).Conclusion: In conclusion, the CEB, an ECG marker of myocardial injury, significantly improves the accuracy and sensitivity of the ECG for the diagnosis of NSTEMI. [ABSTRACT FROM AUTHOR]

Aims: Treatment goals in acute heart failure (AHF) are poorly defined. We aimed to characterize further the impact of in-hospital haemoconcentration and worsening renal function (WRF) on short- and long-term mortality. Methods and results: Haematocrit, haemoglobin, total protein, serum creatinine, and albumin levels were measured serially in 1019 prospectively enrolled AHF patients. Haemoconcentration was defined as an increase in at least three of four of the haemoconcentration-defining parameters above admission values at any time during the hospitalization. Patients were divided into early (Day 1-4) and late haemoconcentration (>Day 4). Ninety-day mortality was the primary endpoint. Haemoconcentration occurred in 392 (38.5%) patients, with a similar incidence of the early (44.6%) and late (55.4%) phenotype. Signs of decongestion (reduction in BNP blood concentrations, P = 0.003; weight loss, P = 0.002) were significantly more pronounced in haemoconcentration patients. WRF was more common in haemoconcentration patients (P = 0.04). After adjustment for established risk factors for AHF mortality, including WRF and HF therapy at discharge, haemoconcentration was significantly associated with a reduction in 90-day mortality [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.37-0.95, P = 0.01]. The beneficial effect of haemoconcentration seemed to be exclusive for late haemoconcentration (late vs. early: adjusted HR 0.41, 95% CI 0.19-0.90, P = 0.03) and persisted in patients with or without WRF. Conclusions: Haemoconcentration represents an inexpensive and easily assessable pathophysiological signal of adequate decongestion in AHF and is associated with lower mortality. WRF in the setting of haemoconcentration does not appear to offset the benefits of haemoconcentration. [ABSTRACT FROM AUTHOR]

Background: The early detection of cardiac syncope is challenging. We aimed to evaluate the diagnostic value of 4 novel prohormones, quantifying different neurohumoral pathways, possibly involved in the pathophysiological features of cardiac syncope: midregional-pro-A-type natriuretic peptide (MRproANP), C-terminal proendothelin 1, copeptin, and midregional-proadrenomedullin., Methods and Results: We prospectively enrolled unselected patients presenting with syncope to the emergency department (ED) in a diagnostic multicenter study. ED probability of cardiac syncope was quantified by the treating ED physician using a visual analogue scale. Prohormones were measured in a blinded manner. Two independent cardiologists adjudicated the final diagnosis on the basis of all clinical information, including 1-year follow-up. Among 689 patients, cardiac syncope was the adjudicated final diagnosis in 125 (18%). Plasma concentrations of MRproANP, C-terminal proendothelin 1, copeptin, and midregional-proadrenomedullin were all significantly higher in patients with cardiac syncope compared with patients with other causes ( P <0.001). The diagnostic accuracies for cardiac syncope, as quantified by the area under the curve, were 0.80 (95% confidence interval [CI], 0.76-0.84), 0.69 (95% CI, 0.64-0.74), 0.58 (95% CI, 0.52-0.63), and 0.68 (95% CI, 0.63-0.73), respectively. In conjunction with the ED probability (0.86; 95% CI, 0.82-0.90), MRproANP, but not the other prohormone, improved the area under the curve to 0.90 (95% CI, 0.87-0.93), which was significantly higher than for the ED probability alone ( P =0.003). An algorithm to rule out cardiac syncope combining an MRproANP level of <77 pmol/L and an ED probability of <20% had a sensitivity and a negative predictive value of 99%., Conclusions: The use of MRproANP significantly improves the early detection of cardiac syncope among unselected patients presenting to the ED with syncope., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01548352., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)