BACKGROUND: Self-reported health-related quality of life is an established prognostic tool in stable outpatients. However, its prognostic relevance in patients presenting with an acute onset of symptoms such as acute dyspnoea is largely unknown. METHODS: This major unmet clinical need was addressed in a secondary analysis of a prospective study, enrolling patients presenting with acute dyspnoea to the emergency departments of two university hospitals in Switzerland. Self-reported health-related quality of life was obtained at presentation with the use of the generic EQ-5D tool and directly compared to the objective risk prediction marker N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary endpoint was all-cause mortality within 90 and 720 days. Cox proportional hazard regressions were performed with age, sex, history of heart failure, systolic blood pressure, haemoglobin, estimated glomerular filtration rate and NT-proBNP as predictors. Prognostic accuracies were calculated with the use of area under the receiver operating characteristics curve (AUC). RESULTS: Among 1144 eligible patients (median age 74 years, 42% women, 52% acute heart failure), 7% died within 90 days and 28% within 720 days after presentation to the emergency department. The EQ-5D index was strongly associated with mortality. In adjusted Cox regression analyses, the hazard ratios of the EQ-5D index for 90- and 720-day mortality were 7.8 (95% confidence interval [CI] 3.4–17.9) and 5.0 (95% CI 3.3–7.6), respectively. Prognostic accuracies of the EQ-5D index for 90- and 720-day mortality were 0.68 and 0.65, and comparable to the prognostic accuracy of NT-proBNP (both AUCs: 0.69, p-value for comparison 0.915 and 0.121). CONCLUSIONS: Self-reported health-related quality of life assessed by the generic EQ-5D tool provides moderate-to-high prognostic accuracy in patients presenting with acute dyspnoea to the emergency department and may aid physicians in risk stratification. Trial registration: https://clinicaltrials.gov NCT01831115.

AIMS:Among cancer patients presenting with acute dyspnoea, the prevalence of acute heart failure (AHF), resource use and diagnostic accuracy of natriuretic peptides remain unknown. This study aimed to address these knowledge gaps. METHODS AND RESULTS:Patients presenting with acute dyspnoea to the emergency department (ED) were prospectively enrolled in a multicentre diagnostic study. AHF was centrally adjudicated by two independent cardiologists based on current guidelines. B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) concentrations were measured at ED presentation. Cancer status, resource use, and long-term outcomes were prospectively assessed. Among 2153 patients, 473 (22.0%) had an active or past cancer. AHF was the most common final diagnosis in both cancer and non-cancer patients (44.4% vs. 51.0%, p = 0.01). Among the alternative diagnoses, pneumonia and cancer-related dyspnoea were more frequent in patients with cancer, while anxiety disorder/hyperventilation was frequent in patients without cancer. Hospitalization rate and length of hospital stay were both higher in cancer patients (p < 0.01). Among AHF-related signs, rales and pleural effusion showed a significant interaction with cancer status and had lower diagnostic accuracy in cancer patients. The area under the curve (AUC) of NT-proBNP was lower in cancer than in non-cancer patients (0.89 vs. 0.93, p = 0.01), while that of BNP was similar (0.93 vs. 0.95, p = ns). This difference was mainly due to active cancers. CONCLUSIONS:Acute heart failure was the most common diagnosis in cancer patients presenting with acute dyspnoea. Rales, pleural effusion, and NT-proBNP had lower diagnostic accuracy versus patients without cancer, while that of BNP remained robust.

The possible clinical utility of Bone Morphogenetic Protein 10 (BMP10), a novel atrial-specific biomarker, is incompletely understood. We aimed to test the hypothesis that BMP10 has high diagnostic and prognostic accuracy in patients presenting with acute dyspnea. In a multicenter diagnostic study, BMP10, high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were determined in patients presenting with acute dyspnea to the emergency department. The final diagnosis was centrally adjudicated by two independent cardiologists blinded to BMP10. Diagnostic accuracy for acute heart failure (AHF) was quantified using the area under the receiver operating characteristic curve (AUC). 720-day all-cause mortality and the composite of all-cause mortality or AHF rehospitalization were prognostic endpoints. Among 933 consecutive patients, 54

Aims We hypothesized that the current gold standard for risk stratification of patients with acute heart failure (AHF), the Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF (MEESSI-AHF) risk score, can be further improved by adding systemic inflammation as quantified by C-reactive protein (CRP). Methods and results In a prospective multicentre diagnostic study (BASEL V), AHF was centrally adjudicated by two independent cardiologists. The MEESSI-AHF risk score was calculated using an established reduced and recalibrated model containing 12 independent risk factors. Model extension was performed by refitting and adding CRP in the logistic regression model with 30-day mortality as binary outcome. Discrimination, calibration and clinical usefulness were used to assess the performance of the extended Multiple Estimation of risk based on the Emergency department Spanish Score In patients (MEESSI) model. Validation was performed in an independent, retrospective and single-centre AHF cohort. Among 1208 AHF patients with complete data allowing calculation of the recalibrated MEESSI and the extended MEESSI models, the prognostic accuracy for 30-day mortality of the extended MEESSI model (c-statistic 0.83, 95% confidence interval [CI] 0.79-0.87) was significantly higher compared to the recalibrated model (c-statistic 0.79, 95% CI 0.75-0.83, p = 0.013). The extended model allowed to stratify a higher percentage of patients into the lowest risk group compared to the recalibrated model (33.1% vs. 20.3%). Demonstrating a calibration plot's slope of 1.00 (95% CI 0.81-1.19) and an intercept of 0.0 (95% CI -0.22 to 0.22), the extended MEESSI model achieved excellent and improved calibration. Results were confirmed in the independent validation cohort (n = 575). Conclusions Quantifying inflammation using CRP concentration provided incremental value in AHF risk stratification using the established MEESSI model.

Background: The characterization of the different pathophysiological mechanisms involved in normotensive versus hypertensive acute heart failure (AHF) might help to develop individualized treatments. Methods: The extent of hemodynamic cardiac stress and cardiomyocyte injury was quantified by measuring the B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT) concentrations in 1152 patients presenting with centrally adjudicated AHF to the emergency department (ED) (derivation cohort). AHF was classified as normotensive with a systolic blood pressure (SBP) of 90–140 mmHg and hypertensive with SBP > 140 mmHg at presentation to the ED. Findings were externally validated in an independent AHF cohort (n = 324). Results: In the derivation cohort, with a median age of 79 years, 43% being women, 667 (58%) patients had normotensive and 485 (42%) patients hypertensive AHF. Hemodynamic cardiac stress, as quantified by the BNP and NT-proBNP, was significantly higher in normotensive as compared to hypertensive AHF [1105 (611–1956) versus 827 (448–1419) pg/mL, and 5890 (2959–12,162) versus 4068 (1986–8118) pg/mL, both p < 0.001, respectively]. Similarly, the extent of cardiomyocyte injury, as quantified by hs-cTnT, was significantly higher in normotensive AHF as compared to hypertensive AHF [41 (24–71) versus 33 (19–59) ng/L, p < 0.001]. A total of 313 (28%) patients died during 360 days of follow-up. All-cause mortality was higher in patients with normotensive AHF vs. patients with hypertensive AHF (hazard ratio 1.66, 95%CI 1.31–2.10; p < 0.001). Normotensive patients with a high BNP, NT-proBNP, or hs-cTnT had the highest mortality. The findings were confirmed in the validation cohort. Conclusion: Biomarker profiling revealed a higher extent of hemodynamic stress and cardiomyocyte injury in patients with normotensive versus hypertensive AHF.

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 m(2)). 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.

European Journal of Heart FailureVolume 25, Issue 4 p. 597-598 LETTER TO THE EDITOR Reply to ‘Interleukin-6 in acute heart failure: it does work, but how much?’ Eleni Michou, Eleni Michou orcid.org/0000-0002-1372-1451 Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, Basel, SwitzerlandSearch for more papers by this authorDesiree Wussler, Desiree Wussler Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, Basel, Switzerland Department of Internal Medicine, University Hospital Basel, Basel, SwitzerlandSearch for more papers by this authorChristian Mueller, Corresponding Author Christian Mueller [email protected] Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, Basel, Switzerland Corresponding author. Email: [email protected]Search for more papers by this author Eleni Michou, Eleni Michou orcid.org/0000-0002-1372-1451 Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, Basel, SwitzerlandSearch for more papers by this authorDesiree Wussler, Desiree Wussler Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, Basel, Switzerland Department of Internal Medicine, University Hospital Basel, Basel, SwitzerlandSearch for more papers by this authorChristian Mueller, Corresponding Author Christian Mueller [email protected] Cardiovascular Research Institute Basel (CRIB) and Department of Cardiology, University Hospital Basel, Basel, Switzerland Corresponding author. Email: [email protected]Search for more papers by this author First published: 15 February 2023 https://doi.org/10.1002/ejhf.2802Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Michou E, Wussler D, Belkin M, Simmen C, Strebel I, Nowak A, et al. Quantifying inflammation using interleukin-6 for improved phenotyping and risk stratification in acute heart failure. Eur J Heart Fail. 2023. https://doi.org/10.1002/ejhf.2767 2Kozhuharov N, Goudev A, Flores D, Maeder MT, Walter J, Shrestha S, et al.; GALACTIC Investigators. Effect of a strategy of comprehensive vasodilation vs usual care on mortality and heart failure rehospitalization among patients with acute heart failure: the GALACTIC randomized clinical trial. JAMA. 2019; 322: 2292–302. 3Zannad F, Stein K, Garcia AA, Anker SD, Armstrong PW, Calvo G, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail. 2013; 15: 1082–94. 4Wussler D, Du Fay De Lavallaz J, Mueller C. Five-year risk of stroke after TIA or minor ischemic stroke. N Engl J Med. 2018; 379: 1580. 5Mueller C, Laule-Kilian K, Christ A, Brunner-La Rocca HP, Perruchoud AP. Inflammation and long-term mortality in acute congestive heart failure. Am Heart J. 2006; 151: 845–50. 6Ridker PM. From CRP to IL-6 to IL-1: moving upstream to identify novel targets for atheroprotection. Circ Res. 2016; 118: 145–56. Volume25, Issue4April 2023Pages 597-598 ReferencesRelatedInformation

AimsObese patients have lower natriuretic peptide concentrations. We hypothesized that adjusting the concentration of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) for obesity could further increase its clinical utility in the early diagnosis of acute heart failure (AHF).Methods and resultsThis hypothesis was tested in a prospective diagnostic study enrolling unselected patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient information including cardiac imaging. NT‐proBNP plasma concentrations were applied: first, using currently recommended cut‐offs; second, using cut‐offs lowered by 33% with body mass index (BMI) of 30–34.9 kg/m2 and by 50% with BMI ≥ 35 kg/m2. Among 2038 patients, 509 (25%) were obese, of which 271 (53%) had AHF. The diagnostic accuracy of NT‐proBNP as quantified by the area under the receiver‐operating characteristic curve was lower in obese versus non‐obese patients (0.890 vs. 0.938). For rapid AHF rule‐out in obese patients, the currently recommended cut‐off of 300 pg/ml achieved a sensitivity of 96.7% (95% confidence interval [CI] 93.8–98.2%), ruling out 29% of patients and missing 9 AHF patients. For rapid AHF rule‐in, the age‐dependent cut‐off concentrations (age <50 years: 450 pg/ml; age 50–75 years: 900 pg/ml; age >75 years: 1800 pg/ml) achieved a specificity of 84.9% (95% CI 79.8–88.9%). Proportionally lowering the currently recommended cut‐offs by BMI increased sensitivity to 98.2% (95% CI 95.8–99.2%), missing 5 AHF patients; reduced the proportion of AHF patients remaining in the ‘gray zone’ (48% vs. 26%; p = 0.002), achieving a specificity of 76.5% (95% CI 70.7–81.4%).ConclusionsAdjusting NT‐proBNP concentrations for obesity seems to further increase its clinical utility in the early diagnosis of AHF.

Background: Current guidelines recommend interpreting concentrations of NPs (natriuretic peptides) irrespective of the time of presentation to the emergency department. We hypothesized that diurnal variations in NP concentration may affect their diagnostic accuracy for acute heart failure. Methods: In a secondary analysis of a multicenter diagnostic study enrolling patients presenting with acute dyspnea to the emergency department and using central adjudication of the final diagnosis by 2 independent cardiologists, the diagnostic accuracy for acute heart failure of BNP (B-type NP), NT-proBNP (N-terminal pro-B-type NP), and MR-proANP (midregional pro-atrial NP) was compared among 1577 daytime presenters versus 908 evening/nighttime presenters. In a validation study, the presence of a diurnal rhythm in BNP and NT-proBNP concentrations was examined by hourly measurements in 44 stable individuals. Results: Among patients adjudicated to have acute heart failure, BNP, NT-proBNP, and MR-proANP concentrations were comparable among daytime versus evening/nighttime presenters (all P=nonsignificant). Contrastingly, among patients adjudicated to have other causes of dyspnea, evening/nighttime presenters had lower BNP (median, 44 [18–110] versus 74 [27–168] ng/L; P<0.01) and NT-proBNP (median, 212 [72–581] versus 297 [102–902] ng/L; P<0.01) concentrations versus daytime presenters. This resulted in higher diagnostic accuracy as quantified by the area under the curve of BNP and NT-proBNP among evening/nighttime presenters (0.97 [95% CI, 0.95–0.98] and 0.95 [95% CI, 0.93–0.96] versus 0.94 [95% CI, 0.92–0.95] and 0.91 [95% CI, 0.90–0.93]) among daytime presenters (both P<0.01). These differences were not observed for MR-proANP. Diurnal variation of BNP and NT-proBNP with lower evening/nighttime concentration was confirmed in 44 stable individuals (P<0.01). Conclusions: BNP and NT-proBNP, but not MR-proANP, exhibit a diurnal rhythm that results in even higher diagnostic accuracy among evening/nighttime presenters versus daytime presenters. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01831115, NCT02091427, and NCT02210897.

Dear Editor, Acute heart failure (AHF) is the most common diagnosis in the emergency department (ED) leading to hospitalization [1, 2]. Although tachyarrhythmia is the most common trigger of AHF, the optimal treatment for reducing the heart rate in AHF triggered by tachyarrhythmia is largely unknown. Particular controversy exists regarding the efficacy and safety of digoxin in AHF triggered by tachyarrhythmia [3]. As the negative chronotropic effect of digoxin is mainly thought to be due to increasing vagal tone, few have questioned the possible effectiveness of digoxin in AHF, a situation characterized by substantially increased sympathetic tone [4]. On the other hand, among all currently available negative chronotropic agents, digoxin is the only one with positive inotropic effects, and it is inexpensive and widely available, rendering digoxin a very attractive option. Therefore, the aim of this study was to evaluate the short-term efficacy and safety of digoxin loading in consecutive patients presenting with AHF triggered by tachyarrhythmia. This was a single-center, retrospective cohort study including patients from January 2012 until December 2018 admitted to the University Hospital Basel, with AHF triggered by tachyarrhythmia (atrial fibrillation/atrial flutter). For this analysis, patients were eligible if they were naïve to digoxin (or digitoxin) and received at least 0.75 mg i.v. or per os (the minimal expected effective dose) digoxin for heart rate control in either the ED, the general medical ward, or the intensive care unit (ICU) [5]. Medical data of interest, including vital signs, laboratory values, medications prior to and after digoxin use, and predefined adverse events (AEs) possibly related to digoxin were obtained from the detailed medical chart (Online Supplement). Beta blocker was converted to metoprolol-equivalent dose for calculation [6]. The study was approved by the ethics committee (reference number: 2019-00956) for all the patients that had not refused the general informed consent for the use of routinely collected data. The primary efficacy outcome was heart rate reduction at 24 h and 48 h after 0.75 mg or more of digoxin was given. The primary safety outcomes were AEs possibly related to digoxin, transfer to the ICU, and those observed compared to predicted 30-day mortality. MEESSI score was calculated to compare observed and predicted mortality [7]. Secondary endpoints included change in systolic and diastolic blood pressure at 24 h and 48 h. Among 210 patients recruited between January 2012 and December 2018, the mean age was 79 years, 61% were women, and most had mild-to-moderate renal dysfunction (Table S1). Twenty-three percent of patients had received intravenous beta blockers in the ED prior to receiving digoxin. No patient received additional intravenous beta blocker within 48 h of digoxin (Table S2). One hundred and fifty-seven patients (75%) remained in atrial fibrillation 48 h after receiving at least 0.75 mg of digoxin. Ninety-one patients (43%) were discharged with the maintenance dose of digoxin. One hundred and twenty-two patients (58%) received at least 0.75 mg digoxin within 24 h of admission, while 26% received it within 48 h and the rest of the patients received it after 48 h of admission. Among these patients, heart rate was significantly reduced from 141 ± 22 beats per minute (bpm) at presentation to 101 ± 23 bpm at 24 h and 98 ± 22 bpm at 48h (both p < 0.001). Systolic blood pressure increased significantly after 24 h and 48 h (p < 0.001) with a consistent response irrespective of sex or renal function (Fig. 1, Tables S3 and S4). One patient (0.5%) experienced relevant nausea possibly related to digoxin (Table S5). Predicted and observed 30-day mortality (10.9% [95% confidence Interval (CI): 9.4–12.5] and 9.0% [95% CI 5.9–13.7], respectively) were comparable. These findings extend and corroborate observations from two propensity score-matched studies regarding long-term outcomes in patients hospitalized for AHF and atrial fibrillation in the United States. Digoxin initiation was associated with a lower risk of AHF readmission and not with mortality [8, 9]. These findings also seem to support the safety of an unadjusted loading dose in elderly patients with mild-to-moderate renal dysfunction, although this was not formally tested. Some limitations warrant consideration when interpreting the findings of this study. First, this was a single-center study. Second, this was an uncontrolled study and co-administration of other negative chronotropic drugs after digoxin loading could have confounded the effect of digoxin. Therefore, it is important to highlight that no relevant changes in the doses of the beta blocker occurred and less than 10% of patients received additional doses of amiodarone within the 48 h study period. In conclusion, digoxin was very effective in reducing the heart rate among patients with AHF triggered by tachyarrhythmia with a favorable safety profile. It offers physicians a widely available and inexpensive treatment option for these patients. We are indebted to all the patients and colleagues who made this study possible. Open access funding provided by Universitat Basel. The study was supported by research grants from the University Hospital Basel, the University of Basel, the Swiss National Science Foundation, the Swiss Heart Foundation, the Kommission für Technologie und Innovation (KTI), Abbott, Beckman Coulter, Ortho Clinical Diagnostics, Quidel, Roche, Siemens, and Singulex. Christian Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the University of Basel, the University Hospital Basel, Abbott, Beckman Coulter, Idorsia, Ortho Clinical Diagnostics, Quidel, Roche, Siemens, Singulex, and Sphingotec as well as speaker honoraria/consulting honoraria from Acon, Amgen, Astra Zeneca, Boehringer Ingelheim, BMS, Idorsia, Novartis, Osler, Roche, and Sanofi outside of the submitted work. Danielle M. Gualandro received research grants from FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brazil) and consulting honoraria from Roche, outside the submitted work. Pedro Lopez-Ayala has received research support from the Swiss Heart Foundation (FF20079). Tobias Breidthardt received speaker or advisory fees from AstraZeneca, Daiichi-Sankyo, Roche, and Vifor. These payments were made directly to the University Hospital Basel and no personal payments were received. Christian Puelacher reports research funding from Roche Diagnostics, the University of Basel, and the University Hospital Basel, outside of the submitted work. All other authors declare that they have no conflict of interest with this study. The authors designed the study, gathered and analyzed the data, vouch for the data and analysis, wrote the letter, and decided to publish. Christian Mueller, Pedro Lopez-Ayala, Fatima Aliyeva, Androniki Papachristou, and Samyut Shrestha had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and approved the letter. The letter and its contents have not been published previously and are not being considered for publications elsewhere in whole or in part in any language, including publicly accessible websites or e-print servers. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

AimsCardiac 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 resultsIn 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.ConclusionCardiac myosin‐binding protein C may aid physicians in the rapid triage of patients with suspected AHF.

Abstract Aims Readmission and mortality are the most common and often combined endpoints in acute heart failure (AHF) trials, but an association between these two outcomes is poorly investigated. The aim of this study was to determine whether unplanned readmission is associated with a greater subsequent risk of death in patients with acute dyspnoea due to cardiac and non‐cardiac causes. Methods and results Derivation cohort (1371 patients from the LEDA study) and validation cohort (1986 patients from the BASEL V study) included acute dyspnoea patients admitted to the emergency department. Cox regression analysis was used to determine the association of 6 month readmission and the risk of 1 year all‐cause mortality in AHF and non‐AHF patients and those readmitted due to cardiovascular and non‐cardiovascular causes. In the derivation cohort, 666 (49%) of patients were readmitted at 6 months and 282 (21%) died within 1 year. Six month readmission was associated with an increased 1 year mortality risk in both the derivation cohort [adjusted hazard ratio (aHR) 3.0 (95% confidence interval, CI 2.2–4.0), P < 0.001] and the validation cohort (aHR 1.8, 95% CI 1.4–2.2, P < 0.001). The significant association was similarly observed in AHF (aHR 3.2, 95% CI 2.1–4.9, P < 0.001) and other causes of acute dyspnoea (aHR 2.9, 95% CI 1.9–4.5, P < 0.001), and it did not depend on the aetiology [aHR 2.2, 95% CI 1.6–3.1 for cardiovascular readmissions; aHR 4.1, 95% CI 2.9–5.7 for non‐cardiovascular readmissions (P < 0.001 for both)] or timing of readmission. Conclusion​s Our study demonstrated a long‐lasting detrimental association between readmission and death in AHF and non‐AHF patients with acute dyspnoea. These patients should be considered ‘vulnerable patients’ that require personalized follow‐up for an extended period.

Acute dyspnoea is a very common symptom in the acute cardiac care setting. In contrast to current beliefs, acute dyspnoea, as the leading symptom in the emergency department, is associated with about twice the mortality risk, compared to acute chest pain. Rapid and accurate identification of the cause of dyspnoea is critical to the initiation of specific and effective treatment. In most patients, a rapid and accurate diagnosis in the emergency department can be achieved by a combination of vital signs, including pulse oximetry, detailed patient history, physical examination, blood tests (including natriuretic peptides—BNP, NT-proBNP, or MR-proANP), venous blood gases, and C-reactive protein in all patients, and D-dimers in selected patients, electrocardiograms, and chest X-ray. It is key to remember that the prevalence of acute heart failure in unselected patients with acute dyspnoea is about 50%. Therefore, a high awareness for the presence of acute heart failure is mandatory. Acute heart failure, pneumonia, obstructive pulmonary diseases (chronic obstructive pulmonary disease and asthma), pulmonary embolism, and anxiety disorders represent more than 90% of all cases with acute dyspnoea in the emergency department. In about 10–15%, two acute causes (e.g. acute heart failure and pneumonia) may be present and require combined treatment. Transthoracic echocardiography should be immediately performed in all patients with acute dyspnoea and shock, and in those patients in whom the diagnosis remains uncertain, even after initial work-up.

Background Quantifying the activity of the adrenomedullin system might help to monitor and guide treatment in acute heart failure (AHF) patients. The aims were to (1) identify AHF patients with marked benefit or harm from specific treatments at hospital discharge and (2) predict mortality by quantifying the adrenomedullin system activity. Methods This was a prospective multicentre study. AHF diagnosis and phenotype were centrally adjudicated by two independent cardiologists among patients presenting to the emergency department with acute dyspnoea. Adrenomedullin system activity was quantified using the biologically active component, bioactive adrenomedullin (bio-ADM), and a prohormone fragment, midregional proadrenomedullin (MR-proADM). Bio-ADM and MR-proADM concentrations were measured in a blinded fashion at presentation and at discharge. Interaction with specific treatments at discharge and the utility of these biomarkers on predicting outcomes during 365-day follow-up were assessed. Results Among 1886 patients with adjudicated AHF, 514 patients (27.3%) died during 365-day follow-up. After adjusting for age, creatinine, and treatment at discharge, patients with bio-ADM plasma concentrations above the median (> 44.6 pg/mL) derived disproportional benefit if treated with diuretics (interaction p values < 0.001). These findings were confirmed when quantifying adrenomedullin system activity using MR-proADM ( n = 764) (interaction p values < 0.001). Patients with bio-ADM plasma concentrations above the median were at increased risk of death (hazard ratio 1.87, 95% CI 1.57–2.24; p < 0.001). For predicting 365-day all-cause mortality, both biomarkers performed well, with MR-proADM presenting an even higher predictive accuracy compared to bio-ADM ( p < 0.001). Conclusions Quantifying the adrenomedullin’s system activity may help to personalise post-discharge diuretic treatment and enable accurate risk-prediction in AHF.

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.

AIMS:Whereas up to about half of patients with heart failure with reduced ejection fraction (HFrEF) report no or only mild symptoms and are considered as clinically stable, the progressive nature of HFrEF, often silent, renders clinical stability a misleading situation, especially if disease progression is unrecognized. We highlight the challenges in the definition of clinical stability and mild symptomatic status in HFrEF, outline clinical characteristics and available diagnostic tools, and discuss evidence and gaps in the current guidelines for the management of these patients. METHODS AND RESULTS:This is a state-of-the-art review that focuses on clinical, diagnostic, and therapeutic aspects in mildly symptomatic HFrEF patients; summarizes the challenges; and proposes directions for future research in this group of patients. The New York Heart Association classification has been widely used as a measure of prognosis in HFrEF, but it lacks objectivity and reproducibility in terms of symptoms assessment. The definition of clinical stability as described in current guidelines is vague and may often lead to underdiagnosis of disease progression in patients who appear to be 'stable' but in fact are at an increased risk of clinical worsening, hospitalization, or death. Although an increasing number of clinical trials proved that the efficacy of HFrEF therapies was unrelated to the symptomatic status of patients and led to their implementation early in the course of the disease, clinical inertia in terms of under-prescription or underdosing of guideline-recommended medications in mildly symptomatic HFrEF patients is still a challenging issue to deal with. CONCLUSIONS:Mildly symptomatic status in a patient with HFrEF is very frequent; it should not be ignored and should not be regarded as an index of disease stability. The application of risk scores designed to predict mortality and mode of death should be engaged among mildly symptomatic patients, not only to identify the most suitable HF candidates for cardioverter defibrillator implantation, but also to identify patients who might benefit from early intensification of medical treatment before the implementation of more interventional approaches.

Acute heart failure (AHF) is a complex and heterogeneous syndrome not only associated with a concerning rise in incidence, but also with still unacceptably high rates of mortality and morbidity. As this dismal outcome is at least in part due to a mismatch between the severity of AHF and the intensity of its management, both in-hospital and immediately after discharge, early and accurate risk prediction could contribute to more effective, risk-adjusted management. Biomarkers are noninvasive and highly reproducible quantitative tools that have improved the understanding of AHF pathophysiology. They can help guide the intensity of AHF management. In addition, using a statistical model to estimate risk from a combination of several predictor variables such as vital signs or demographics has gained more and more attention over recent years. In this context, the aim of a statistical model, which gives a so-called risk score, is to help clinicians to make more standardised decisions. This review highlights recent advances and remaining uncertainties regarding risk stratification in AHF by characterising and comparing the potential of biomarkers and risk scores.