Effect of Flu Vaccination on Severity and Outcome of Heart Failure Decompensations.

OBJECTIVE: To investigate the relationship of seasonal flu vaccination with the severity of decompensation and long-term outcomes of patients with heart failure (HF). METHODS: We analyzed 6147 consecutively enrolled patients with decompensated HF who presented to 33 Spanish emergency departments (EDs) during January and February of 2018 and 2019, grouped according to seasonal flu vaccination status. The severity of HF decompensation was assessed by the Multiple Estimation of Risk Based on the Emergency Department Spanish Score in Patients With Acute Heart Failure (MEESSI-AHF) + MEESSI scale, need of hospitalization and in-hospital all-cause mortality. The long-term outcomes analyzed were 90-day postdischarge adverse events and 90-day all-cause death. Associations between vaccination, HF decompensation severity and long-term outcomes were explored by unadjusted and adjusted logistic and Cox regressions by using 14 covariables that could act as potential confounders. RESULTS: Overall median (IQR) age was 84 (IQR = 77-89) years, and 56% were women. Vaccinated patients (n = 1139; 19%) were older, had more comorbidities and had worse baseline status, as assessed by New York Heart Association class and Barthel index, than did unvaccinated patients (n = 5008; 81%). Infection triggering decompensation was more common in vaccinated patients (50% vs 41%; P < 0.001). In vaccinated and unvaccinated patients, high or very-high risk decompensation was seen in 21.9% and 21.1%; hospitalization occurred in 72.5% and 73.7%; in-hospital mortality was 7.4% and 7.0%; 90-day postdischarge adverse events were 57.4% and 53.2%; and the 90-day mortality rate was 15.8% and 16.6%, respectively, with no significant differences between cohorts. After adjusting, vaccinated decompensated patients with HF had decreased odds for hospitalization (OR = 0.823, 95%CI = 0.709-0.955). CONCLUSION: In patients with HF, seasonal flu vaccination is associated with less severe decompensations.

Influence of Meteorological Temperature and Pressure on the Severity of Heart Failure Decompensations.

OBJECTIVE: To investigate the relationship between ambient temperature and atmospheric pressure (AP) and the severity of heart failure (HF) decompensations. METHODS: We analysed patients coming from the Epidemioloy Acute Heart Failure Emergency (EAHFE) Registry, a multicentre prospective cohort study enrolling patients diagnosed with decompensated HF in 26 emergency departments (EDs) of 16 Spanish cities. We recorded patient and demographic data and maximum temperature (Tmax) and AP (APmax) the day before ED consultation. Associations between temperature and AP and severity endpoints were explored by logistic regression. We used restricted cubic splines to model continuous non-linear associations of temperature and AP with each endpoint. RESULTS: We analysed 16,545 patients. Daily Tmax and APmax (anomaly) of the day before patient ED arrival ranged from 0.8 to 41.6° and from - 61.7 to 69.9 hPa, respectively. A total of 12,352 patients (75.2%) were hospitalised, with in-hospital mortality in 1171 (7.1%). The probability of hospitalisation by HF decompensation showed a U-shaped curve versus Tmax and an increasing trend versus APmax. Regarding temperature, hospitalisation significantly increased from 20 °C (reference) upwards (25 °C: OR = 1.12, 95% CI = 1.04-1.21; 40 °C: 1.65, 1.13-2.40) and below 5.4 °C (5 °C: 1.21, 1.01-1.46). Concerning the mean AP of the city (anomaly = 0 hPa), hospitalisation increased when APmax (anomaly) was above + 7.0 hPa (atmospheric anticyclone; + 10 hPa: 1.14, 1.05-1.24; + 30 hPa: 2.02. 1.35-3.03). The lowest probability of mortality also corresponded to cold-mild temperatures and low AP, with a significant increased risk only found for Tmax above 24.3 °C (25 °C: 1.13, 1.01-1.27; 40 °C: 2.05, 1.15-3.64) and APmax (anomaly) above + 3.4 hPa (+ 10 hPa: 1.21, 1.07-1.36; + 30 hPa: 1.73, 1.06-2.81). Sensitivity analysis confirmed the main analysis results. CONCLUSION: Temperature and AP are independently associated with the severity of HF decompensations, with possible different effects on the need for hospitalisation and in-hospital mortality.

Is myocardial fibrosis appropriately assessed by calibrated and 2D strain derived integrated backscatter?

AIMS: Increased collagen content of the myocardium modifies tissue reflectivity and integrated backscatter (IBS) indexes are suggested as markers of myocardial fibrosis (MF). We sought to assess the correlation between calibrated (c) IBS and bidimensional (2D) strain derived IBS with left ventricular (LV) MF in patients with severe aortic stenosis (AS). METHODS AND RESULTS: We made a prospective observational cohort study including 157 patients with severe AS referred for surgical aortic valve replacement (AVR), with complete preoperative transthoracic echocardiography, cardiac magnetic resonance (CMR) and endomyocardial biopsy (EMB) obtained from the anterior basal septum at the time of surgery. Two groups of 30 patients were specifically evaluated, with and without late gadolinium enhancement (LGE) at CMR. IBS was obtained at QRS peak from both parasternal long axis (PLAX) and apical-three-chamber (AP3C) views and measured in decibels (dB). Whole-cardiac cycle IBS at basal anterior septum was obtained from 2D longitudinal strain. Correlation analysis of reflectivity indexes was performed with global and segmental (anterior basal septum) values of native T1 and extracellular volume (ECV), and EMB collagen volume fraction (CVF) (Masson´s Trichrome). IBS values were compared in both group of patients (LGE + vs. LGE -). 60 patients (74 [36-74] years, 45% male) with high gradient (mean gradient: 63 ± 20mmHg), normal flow (45 ± 10mL/m2) AS and preserved left ventricular ejection fraction (60 ± 9%) were included. Basal septum cIBS was - 17.45 (-31.2-10.95) and - 9.17 ± 9.45dB from PLAX and A3C views, respectively. No significant correlations were found between IBS and both non-invasive CMR tissue characterization and CVF: median MF of 9.7(2.1-79.9)%. Acoustic indexes were not significantly different according to the presence of pre-operative LGE. CONCLUSION: In this group of patients with classical severe AS, IBS reflectivity indexes are of no added value to discriminate the presence of MF.

Effects of MIdazolam versus MOrphine in acute cardiogenic pulmonary edema and chronic obstructive pulmonary disease: An analysis of MIMO trial.

AIMS: Chronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure. The MIMO trial showed that patients with acute cardiogenic pulmonary edema (ACPE) treated with midazolam had fewer serious adverse events than those treated with morphine. In this post hoc analysis, we examined whether the presence/ absence of COPD modifies the reduced risk of midazolam over morphine. METHODS: Patients >18 years old clinically diagnosed with ACPE and with dyspnea and anxiety were randomized (1:1) at emergency department arrival to receive either intravenous midazolam or morphine. In this post hoc analysis, we calculated the relative risk (RR) of serious adverse events in patients with and without COPD. Calculating the CochranMantel-Haenszel interaction test, we evaluated if COPD modified the reduced risk of serious adverse events in the midazolam arm compared to morphine. RESULTS: Overall, 25 (22.5%) of the 111 patients randomized had a history of COPD. Patients with COPD were more commonly men with a history of previous episodes of heart failure, than participants without COPD. In the COPD group, the RR for the incidence of serious adverse events in the midazolam versus morphine arm was 0.36 (95%CI, 0.1-1.46). In the group without COPD, the RR was 0.44 (95%CI, 0.22-0.91). The presence of COPD did not modify the reduced risk of serious adverse events in the midazolam arm compared to morphine (p for interaction =0.79). CONCLUSIONS: The reduced risk of serious adverse events in the midazolam group compared with morphine is similar in patients with and without COPD.

Hyperkalemia in acute heart failure: Short term outcomes from the EAHFE registry.

OBJECTIVE: Both hyperkalemia (HK) and Acute Heart Failure (AHF) are associated with increased short-term mortality, and the management of either may exacerbate the other. As the relationship between HK and AHF is poorly described, our purpose was to determine the relationship between HK and short-term outcomes in Emergency Department (ED) AHF. METHODS: The EAHFE Registry enrolls all ED AHF patients from 45 Spanish ED and records in-hospital and post-discharge outcomes. Our primary outcome was all-cause in-hospital death, with secondary outcomes of prolonged hospitalization (>7 days) and 7-day post-discharge adverse events (ED revisit, hospitalization, or death). Associations between serum potassium (sK) and outcomes were explored using logistic regression by restricted cubic spline (RCS) curves, with sK =4.0 mEq/L as the reference, adjusting by age, sex, comorbidities, patient baseline status and chronic treatments. Interaction analyses were performed for the primary outcome. RESULTS: Of 13,606 ED AHF patients, the median (IQR) age was 83 (76-88) years, 54% were women, and the median (IQR) sK was 4.5 mEq/L (4.3-4.9) with a range of 4.0-9.9 mEq/L. In-hospital mortality was 7.7%, with prolonged hospitalization in 35.9%, and a 7-day post-discharge adverse event rate of 8.7%. Adjusted in-hospital mortality increased steadily from sK ≥4.8 (OR = 1.35, 95% CI = 1.01-1.80) to sK = 9.9 (8.41, 3.60-19.6). Non-diabetics with elevated sK had higher odds of death, while chronic treatment with mineralocorticoid-receptor antagonists exhibited a mixed effect. Neither prolonged hospitalization nor post-discharge adverse events was associated with sK. CONCLUSION: In ED AHF, initial sK >4.8 mEq/L was independently associated with in-hospital mortality, suggesting that this cohort may benefit from aggressive HK treatment.

Impact of the MEESSI-AHF tool to guide disposition decision-making in patients with acute heart failure in the emergency department: a before-and-after study.

OBJECTIVES: To determine the impact of risk stratification using the MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with acute heart failure) scale to guide disposition decision-making on the outcomes of ED patients with acute heart failure (AHF), and assess the adherence of emergency physicians to risk stratification recommendations. METHODS: This was a prospective quasi-experimental study (before/after design) conducted in eight Spanish EDs which consecutively enrolled adult patients with AHF. In the pre-implementation stage, the admit/discharge decision was performed entirely based on emergency physician judgement. During the post-implementation phase, emergency physicians were advised to 'discharge' patients classified by the MEESSI-AHF scale as low risk and 'admit' patients classified as increased risk. Nonetheless, the final decision was left to treating emergency physicians. The primary outcome was 30-day all-cause mortality. Secondary outcomes were days alive and out of hospital, in-hospital mortality and 30-day post-discharge combined adverse event (ED revisit, hospitalisation or death). RESULTS: The pre-implementation and post-implementation cohorts included 1589 and 1575 patients, respectively (median age 85 years, 56% females) with similar characteristics, and 30-day all-cause mortality was 9.4% and 9.7%, respectively (post-implementation HR=1.03, 95% CI=0.82 to 1.29). There were no differences in secondary outcomes or in the percentage of patients entirely managed in the ED without hospitalisation (direct discharge from the ED, 23.5% vs 24.4%, OR=1.05, 95% CI=0.89 to 1.24). Adjusted models did not change these results. Emergency physicians followed the MEESSI-AHF-based recommendation on patient disposition in 70.9% of cases (recommendation over-ruling: 29.1%). Physicians were more likely to over-rule the recommendation when 'discharge' was recommended (56.4%; main reason: need for hospitalisation for a second diagnosis) than when 'admit' was recommended (12.8%; main reason: no appreciation of severity of AHF decompensation by emergency physician), with an OR for over-ruling the 'discharge' compared with the 'admit' recommendation of 8.78 (95% CI=6.84 to 11.3). CONCLUSIONS: Implementing the MEESSI-AHF risk stratification tool in the ED to guide disposition decision-making did not improve patient outcomes.

Prevalence, Related Factors and Association of Left Bundle Branch Block With Prognosis in Patients With Acute Heart Failure: a Simultaneous Analysis in 3 Independent Cohorts.

OBJECTIVES: To determine the prevalence, characteristics and association with prognosis of left bundle branch block (LBBB) in 3 different cohorts of patients with acute heart failure (AHF). METHODS AND RESULTS: We retrospectively analyzed 12,950 patients with AHF who were included in the EAHFE (Epidemiology Acute Heart Failure Emergency), RICA (National Heart Failure Registry of the Spanish Internal Medicine Society), and BASEL-V (Basics in Acute Shortness of Breath Evaluation of Switzerland) registries. We independently analyzed the relationship between baseline and clinical characteristics and the presence of LBBB and the potential association of LBBB with 1-year all-cause mortality and a 90-day postdischarge combined endpoint (Emergency Department reconsultation, hospitalization or death). The prevalence of LBBB was 13.5% (95% confidence interval: 12.9%-14.0%). In all registries, patients with LBBB more commonly had coronary artery disease and previous episodes of AHF, were taking chronic spironolactone treatment, had lower left ventricular ejection fraction and systolic blood pressure values and higher NT-proBNP levels. There were no differences in risk for patients with LBBB in any cohort, with adjusted hazard ratios (95% confidence interval) for 1-year mortality in EAHFE/RICA/BASEL-V cohorts of 1.02 (0.89-1.17), 1.15 (0.95-1.38) and 1.32 (0.94-1.86), respectively, and for 90-day postdischarge combined endpoint of 1.00 (0.88-1.14), 1.14 (0.92-1.40) and 1.26 (0.84-1.89). These results were consistent in sensitivity analyses. CONCLUSIONS: Less than 20% of patients with AHF present LBBB, which is consistently associated with cardiovascular comorbidities, reduced left ventricular ejection fraction and more severe decompensations. Nonetheless, after taking these factors into account, LBBB in patients with AHF is not associated with worse outcomes.

Pulmonary embolism in patients with COVID-19: incidence, risk factors, clinical characteristics, and outcome.

AIMS: We investigated the incidence, risk factors, clinical characteristics, and outcomes of pulmonary embolism (PE) in patients with COVID-19 attending emergency departments (EDs), before hospitalization. METHODS AND RESULTS: We retrospectively reviewed all COVID-19 patients diagnosed with PE in 62 Spanish EDs (20% of Spanish EDs, case group) during the first COVID-19 outbreak. COVID-19 patients without PE and non-COVID-19 patients with PE were included as control groups. Adjusted comparisons for baseline characteristics, acute episode characteristics, and outcomes were made between cases and randomly selected controls (1:1 ratio). We identified 368 PE in 74 814 patients with COVID-19 attending EDs (4.92‰). The standardized incidence of PE in the COVID-19 population resulted in 310 per 100 000 person-years, significantly higher than that observed in the non-COVID-19 population [35 per 100 000 person-years; odds ratio (OR) 8.95 for PE in the COVID-19 population, 95% confidence interval (CI) 8.51-9.41]. Several characteristics in COVID-19 patients were independently associated with PE, the strongest being D-dimer >1000 ng/mL, and chest pain (direct association) and chronic heart failure (inverse association). COVID-19 patients with PE differed from non-COVID-19 patients with PE in 16 characteristics, most directly related to COVID-19 infection; remarkably, D-dimer >1000 ng/mL, leg swelling/pain, and PE risk factors were significantly less present. PE in COVID-19 patients affected smaller pulmonary arteries than in non-COVID-19 patients, although right ventricular dysfunction was similar in both groups. In-hospital mortality in cases (16.0%) was similar to COVID-19 patients without PE (16.6%; OR 0.96, 95% CI 0.65-1.42; and 11.4% in a subgroup of COVID-19 patients with PE ruled out by scanner, OR 1.48, 95% CI 0.97-2.27), but higher than in non-COVID-19 patients with PE (6.5%; OR 2.74, 95% CI 1.66-4.51). Adjustment for differences in baseline and acute episode characteristics and sensitivity analysis reported very similar associations. CONCLUSIONS: PE in COVID-19 patients at ED presentation is unusual (about 0.5%), but incidence is approximately ninefold higher than in the general (non-COVID-19) population. Moreover, risk factors and leg symptoms are less frequent, D-dimer increase is lower and emboli involve smaller pulmonary arteries. While PE probably does not increase the mortality of COVID-19 patients, mortality is higher in COVID-19 than in non-COVID-19 patients with PE.

High-sensitivity cardiac troponin T 30 days all-come mortality in patients with acute heart failure. A Propensity Score-Matching Analysis Based on the EAHFE Registry. TROPICA4 Study.

BACKGROUND: Acute heart failure (AHF) patients with high troponin levels have a worse prognosis. High-sensitive troponin T (hs-TnT) has been used as a tool to stratify prognosis in many scales but always as a qualitative and not as a quantitative variable. OBJECTIVES: The main objective of this study was to determine the best hs-TnT cut-off for prediction of 30-day all-cause mortality. METHODS: The EAHFE registry, a prospective follow-up cohort of patients with AHF, was analysed. We performed a propensity score analysis of the optimal hs-TnT cut-off point previously determined by receiver operating characteristic (ROC) curve analysis. RESULTS: Of the 13 791 patients in the EAHFE cohort, we analysed 3190 patients in whom hs-TnT determination was available. The area under the ROC curve for 30-day all-cause mortality was 0.70 (CI95% 0.68 to 0.71; P < .001), establishing an optimal cut-off of hs-TnT of 35 ng/L. The sensitivity and specificity of this cut-off were 76.2 and 55.5%, respectively, with a negative predictive value (NPV) of 95.3%. A propensity score was made with 34 variables showing differences based on the cut-off of 35 ng/L for hs-TnT. In the analysis of the population obtained with the propensity score, patients with hs-TnT > 35 ng/L showed a greater 30-day all-cause mortality, with a HR of 2.95 (CI95% 1.83-4.75; P < .001). External validation reported similar results. CONCLUSIONS: An hs-TnT value of 35 ng/L is an adequate cut-off to evaluate the prediction of 30-day all-cause mortality with a NPV of 95.3%.

Effect of Barthel Index on the Risk of Thirty-Day Mortality in Patients With Acute Heart Failure Attending the Emergency Department: A Cohort Study of Nine Thousand Ninety-Eight Patients From the Epidemiology of Acute Heart Failure in Emergency Departments Registry.

STUDY OBJECTIVE: We assess the value of the Barthel Index (BI) in predicting 30-day mortality risk among patients with acute heart failure who are attending the emergency department (ED). METHODS: We selected 9,098 acute heart failure patients from the Acute Heart Failure in Emergency Departments registry who had BI score available both at baseline and the ED visit. Patients' data were collected from 41 Spanish hospitals during four 1- to 2-month periods between 2009 and 2016. Unadjusted and adjusted logistic regression models were used to assess the association between 30-day mortality and BI score. c Statistics were used to estimate their prognostic value. RESULTS: The mean baseline BI score was 79.4 (SD 24.6) and the mean ED BI score was 65.3 (SD 29.1). Acute functional decline (≥5-point decrease between baseline BI and ED BI score) was observed in 5,771 patients (53.4%). Within 30 days of the ED visit, 905 patients (9.9%) died. There was a steep inverse gradient in 30-day mortality risk for baseline BI and ED BI score. For instance, compared with BI score=100, a BI score of 50 to 55 doubled the mortality risk both at baseline and the ED visit. At the ED visit, a BI score of 0 to 5 carried a 5-fold increase in risk after adjustment for other risk predictors. In comparison with baseline BI score, ED BI score consistently provided greater discrimination. Neither baseline BI score nor the change in BI score from baseline to the ED visit added further prognostic value to the ED BI score. CONCLUSION: Functional status assessed by the BI score at the ED visit is a strong predictor of 30-day mortality in acute heart failure patients, with higher predictive value than baseline BI score and acute functional decline. Routine recording of BI score at the ED visit may help in decisionmaking and health care planning.

Analysis of How Emergency Physicians' Decisions to Hospitalize or Discharge Patients With Acute Heart Failure Match the Clinical Risk Categories of the MEESSI-AHF Scale.

STUDY OBJECTIVE: The Multiple Estimation of Risk Based on the Emergency Department Spanish Score in Patients With Acute Heart Failure (MEESSI-AHF) is a validated clinical decision tool that characterizes risk of mortality in emergency department (ED) acute heart failure patients. The objective of this study is to compare the distribution of risk categories between hospitalized and discharged ED patients with acute heart failure. METHODS: We included consecutive acute heart failure patients from 34 Spanish EDs. Patients were retrospectively classified according to MEESSI-AHF risk categories. We calculated the odds of hospitalization (versus direct discharge from the ED) across MEESSI-AHF risk categories. Next, we assessed the following 30-day postdischarge outcomes: ED revisit, hospitalization, death, and their combination. We used Cox hazards models to determine the adjusted association between ED disposition decision and the outcomes among patients who were stratified into low- and increased-risk categories. RESULTS: We included 7,930 patients (80.5 years [SD 10.1 years]; women 54.7%; hospitalized 75.3%). Compared with that for low-risk MEESSI-AHF patients, odds ratios for hospitalization of patients in intermediate-, high-, and very-high-risk categories were 1.83 (95% confidence interval [CI] 1.64 to 2.05), 3.05 (95% CI 2.48 to 3.76), and 3.98 (95% CI 3.13 to 5.05), respectively. However, almost half (47.6%) of all discharged patients were categorized as being at increased risk by MEESSI-AHF, and 19.0% of all the increased-risk patients were discharged from the ED. Among the low-risk MEESSI-AHF patients, the 30-day postdischarge mortality did not differ by ED disposition (hazard ratio [HR] for discharged patients with respect to hospitalized ones 0.65; 95% CI 0.70 to 1.11), nor did it differ in the increased-risk group (HR 0.88; 95% CI 0.63 to 1.23). The discharged low-risk MEESSI-AHF patients had higher risks of 30-day ED revisit and hospitalization (HR 1.86, 95% CI 1.57 to 2.20; and HR 1.92, 95% CI 1.54 to 2.40, respectively) compared with the admitted patients, as did the discharged patients in the increased-risk group (HR 1.62, 95% CI 1.39 to 1.89; and HR 1.40, 95% CI 1.16 to 1.68, respectively), with similar results for the combined endpoint. CONCLUSION: The disposition decisions made in current clinical practice for ED acute heart failure patients calibrate with MEESSI-AHF risk categories, but nearly half of the patients currently discharged from the ED fall into increased-risk MEESSI-AHF categories.

Morphine Use in the Treatment of Acute Cardiogenic Pulmonary Edema and Its Effects on Patient Outcome: A Systematic Review.

PURPOSE OF REVIEW: To analyze whether the use of morphine, as initial treatment in acute cardiogenic pulmonary edema (ACPE), has an impact in clinical outcomes and mortality. A systematic review of the literature was performed, including all the studies comparing clinical outcomes in patients with ACPE who were treated or not with morphine. RECENT FINDINGS: Seven studies were selected, none of which were a randomized trial focused on answering the aim of this systematic review. The studies consisted of clinical trial secondary analysis assessing non-invasive ventilation in ACPE, one open non-randomized trial, two propensity score evaluations from large registries, and three clinical case reviews. Most of the studies showed unfavorable results with the use of morphine in terms of adverse events and mortality, and many of them were statistically significant. Finally, the ongoing MIdazolam versus MOrphine in acute cardiogenic pulmonary edema (MIMO) trial was specifically designed to compare the results of morphine use versus midazolam. The potential hemodynamic and sedative benefit of the use of morphine for vasodilatation and dyspnea amelioration may be opposed by an increase in mortality, ICU admission, and adverse events. Until there is a randomized clinical trial, the use of morphine for ACPE should be limited.

The subset of patients with acute heart failure able to secrete relaxin-2 at pregnancy concentrations could have a longer survival: a pilot study.

OBJECTIVE: To investigate how many patients with acute heart failure (AHF) hypersecrete relaxin-2 concentrations similar to those of pregnant women and determine their long-term outcome. METHODS: In consecutive AHF patients relaxin-2 was quantified by ELISA sandwich method. Patients were divided into pregnancy-like group (PLG, relaxin-2 ≥ 500 pg/mL) and control group (CG, relaxin-2 < 500 pg/mL). The primary outcome was all-cause death during follow-up. Secondary endpoints were prolonged hospitalisation (>10 days), combined endpoint (death, rehospitalisation, ED revisit) 30 days after discharge, and 30-day, one-year and three-year death rates. RESULTS: We included 814 patients [81 (SD = 9) years; 53.0% women] followed during 1.9 (SD 2.8) years; 517 (63.5%) died. Twenty patients (2.5%) formed the PLG (median relaxin-2 = 1459 pg/mL; IQR = 1722) and 794 the CG (median = 26; IQR = 44). There was no interaction with variables included on adjustment (age, sex, ischaemic cardiomyopathy, NT-proBNP, glycaemia, and sodium). PLG patients did not have better short-term secondary endpoints, but did show a significantly lower three-year mortality [ORadjusted = 0.17 (0.05-0.5), p = 0.003]. CONCLUSIONS: The small proportion of AHF patients achieving relaxin-2 concentrations similar to those observed in pregnancy may survive longer.

Predicting 30-Day Mortality for Patients With Acute Heart Failure in the Emergency Department: A Cohort Study.

Background: Physicians in the emergency department (ED) need additional tools to stratify patients with acute heart failure (AHF) according to risk. Objective: To predict mortality using data that are readily available at ED admission. Design: Prospective cohort study. Setting: 34 Spanish EDs. Participants: The derivation cohort included 4867 consecutive ED patients admitted during 2009 to 2011. The validation cohort comprised 3229 patients admitted in 2014. Measurements: 88 candidate risk factors and 30-day mortality. Results: Thirteen independent risk factors were identified in the derivation cohort and were combined into an overall score, the MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score. This score predicted 30-day mortality with excellent discrimination (c-statistic, 0.836) and calibration (Hosmer-Lemeshow P = 0.99) and provided a steep gradient in 30-day mortality across risk groups (<2% for patients in the 2 lowest risk quintiles and 45% in the highest risk decile). These characteristics were confirmed in the validation cohort (c-statistic, 0.828). Multiple sensitivity analyses did not find important amounts of confounding or bias. Limitations: The study was confined to a single country. Participating EDs were not selected randomly. Many patients had missing data. Measurement of some risk factors was subjective. Conclusion: This tool has excellent discrimination and calibration and was validated in a different cohort from the one that was used to develop it. Physicians can consider using this tool to inform clinical decisions as further studies are done to determine whether the tool enhances physician decision making and improves patient outcomes. Primary Funding Source: Instituto de Salud Carlos III, Spanish Ministry of Health; Fundació La Marató de TV3; and Catalonia Govern.

Exploring Binding Mechanisms in Nuclear Hormone Receptors by Monte Carlo and X-ray-derived Motions.

In this study, we performed an extensive exploration of the ligand entry mechanism for members of the steroid nuclear hormone receptor family (androgen receptor, estrogen receptor α, glucocorticoid receptor, mineralocorticoid receptor, and progesterone receptor) and their endogenous ligands. The exploration revealed a shared entry path through the helix 3, 7, and 11 regions. Examination of the x-ray structures of the receptor-ligand complexes further showed two distinct folds of the helix 6-7 region, classified as "open" and "closed", which could potentially affect ligand binding. To improve sampling of the helix 6-7 loop, we incorporated motion modes based on principal component analysis of existing crystal structures of the receptors and applied them to the protein-ligand sampling. A detailed comparison with the anisotropic network model (an elastic network model) highlights the importance of flexibility in the entrance region. While the binding (interaction) energy of individual simulations can be used to score different ligands, extensive sampling further allows us to predict absolute binding free energies and analyze reaction kinetics using Markov state models and Perron-cluster cluster analysis, respectively. The predicted relative binding free energies for three ligands binding to the progesterone receptor are in very good agreement with experimental results and the Perron-cluster cluster analysis highlighted the importance of a peripheral binding site. Our analysis revealed that the flexibility of the helix 3, 7, and 11 regions represents the most important factor for ligand binding. Furthermore, the hydrophobicity of the ligand influences the transition between the peripheral and the active binding site.

The GALA study: relationship between galectin-3 serum levels and short- and long-term outcomes of patients with acute heart failure.

OBJECTIVE: We tested the hypothesis that early measurement of galectin-3 at the emergency department (ED) during an episode of acute heart failure (AHF) allows predicting short- and long-term outcomes. METHODS: We performed an exploratory study including 115 patients consecutively diagnosed with AHF in a single ED. Clinical and analytical variables were recorded. The primary endpoint was 30-day all-cause mortality, and secondary endpoints were 30-day composite outcome (death, rehospitalization or ED reconsultation, whichever first) and 1-year mortality. RESULTS: Seven patients (6.1%) died within 30 days and 43 (37.4%) within 1 year. The 30-day composite endpoint was observed in 21.1% of patients. Galectin-3 was correlated with NT-proBNP and the glomerular filtration rate but not with age and s-cTnI. Measured at time of ED arrival, galectin-3 showed good discriminatory capacity for 30-day mortality (AUC ROC: 0.732; 95% CI 0.512-0.953; p = 0.041) but not for 1-year mortality (0.521; 0.408-0.633; p = 0.722). Patients with galectin-3 concentrations >42 µg/L had an OR = 7.67(95%CI = 1.57-37.53; p = 0.012) for 30-day mortality. Conversely, NT-proBNP only showed predictive capacity for 1-year mortality (0.642; 0.537-0.748; p = 0.014). Patients with NT-proBNP concentrations >5400 ng/L had an OR = 4.34 (95%CI = 1.93-9.77; p < 0.001) for 1-year mortality. These increased short- (galectin-3) and long-term (NT-proBNP) risks remained significant after adjustment for age or renal function. s-cTnI failed in both short- and long term death prediction. No biomarker predicted the short-term composite endpoint. CONCLUSION: These results suggest that galectin-3 could help to monitor the risk of short-term mortality in unselected patients with AHF attended in the ED.

An all-atom, active site exploration of antiviral drugs that target Flaviviridae polymerases.

Natural 2'-modified nucleosides are the most widely used antiviral therapy. In their triphosphorylated form, also known as nucleotide analogues, they target the active site of viral polymerases. Viral polymerases have an overall right-handed structure that includes the palm, fingers and thumb domains. These domains are further subdivided into structurally conserved motifs A-G, common to all viral polymerases. The structural motifs encapsulate the allosteric/initiation (N1) and orthosteric/catalytic (N2) nucleotide-binding sites. The current study investigated how nucleotide analogues explore the N2 site of viral polymerases from three genera of the family Flaviviridae using a stochastic, biophysical, Metropolis Monte Carlo-based software. The biophysical simulations showed a statistical distinction in nucleotide-binding energy and exploration between phylogenetically related viral polymerases. This distinction is clearly demonstrated by the respective analogue contacts made with conserved viral polymerase residues, the heterogeneous dynamics of structural motifs, and the orientation of the nucleotide analogues within the N2 site. Being able to simulate what occurs within viral-polymerase-binding sites can prove useful in rational drug designs against viruses.

Endothelial dysfunction evaluated by peripheral arterial tonometry is related with peak TnI values in patients with ST elevation myocardial infarction treated with primary angioplasty.

PURPOSE: The role of endothelial-dependent function in patients with acute ST elevation myocardial infarction (STEMI) is not clear. Endothelial dysfunction may contribute to the pathophysiological processes occurring after STEMI and influence the extension of myocardial necrosis. Endothelial-dependent dysfunction evaluated by peripheral arterial tonometry (PAT) has already showed to be correlated with microvascular coronary endothelial dysfunction. Our purpose was to evaluate the impact of endothelial dysfunction on peak Troponin I (TnI) values, as a surrogate for the extension of myocardial infarction, in patients with STEMI treated with primary angioplasty (P-PCI). METHODS: 58 patients with STEMI treated with P-PCI (mean age 59.0 ± 14.0 years, 46 males) were included. Endothelial function was assessed by reactive hyperaemia index (RHI) determined by PAT. Patients were divided in two groups according to the previously reported RHI threshold for high risk (1.67). The extension of myocardial necrosis was evaluated by peak TnI levels. RESULTS: RHI median value was 1.78 (IQR0.74);25 patients had endothelial dysfunction (RHI b 1.67). The two groups had no significant differences in age, gender, main risk factors and pain-to-balloon time. Patients with an RHI b 1.67 had significant larger infarcts: TnI 73.5 ng/mL (IQR 114.42 ng/mL) versus TnI 33.2 ng/mL (IQR 65.2 ng/mL); p = 0.028. On multivariate analysis, the presence of an RHI b 1.67 kept significant impact on TnI peak values (p=0.02). CONCLUSIONS: The presence of endothelial-dependent dysfunction, assessed by PAT, is related with higher peak TnI values in STEMI patients treated with P-PCI. These results strength the possibility that endothelial-dependent dysfunction may be a marker of poor prognosis and eventually a therapeutic target in patients with STEMI.

The Index of Microcirculatory Resistance as a Predictor of Echocardiographic Left Ventricular Performance Recovery in Patients With ST-Elevation Acute Myocardial Infarction Undergoing Successful Primary Angioplasty.

BACKGROUND: This study aims to evaluate the relationship between IMR (Index of Microcirculatory Resistance) and the echocardiographic evolution of left ventricular (LV) systolic and diastolic performance after ST-elevation acute myocardial infarction (STEMI), undergoing primary angioplasty (P-PCI). METHODS: IMR was evaluated immediately after P-PCI. Echocardiograms were performed within the first 24 hours (Echo1) and at 3 months (Echo2): LV volumes, ejection fraction (LVEF), wall motion score index (WMSI), E/é ratio, global longitudinal strain (GLS), and left atrial volume were measured. RESULTS: Forty STEMI patients were divided in 2 groups according to median IMR: Group 1 (IMR < 26), with less microvascular dysfunction, and Group 2 (IMR > = 26), with more microvascular dysfunction. In Echo1 GLS was significantly better in Group 1 (-14.9 vs. -12.9 in Group 2, P = 0.005). However, there were no significant differences between the two groups in LV systolic volume, LVEF and WMS. Between Echo1 and Echo2, there were significant improvements in LVEF (0.48 ± 0.06 vs. 0.55 ± 0.06, P < 0.0001), GLS (-14.9 ± 1.3 vs. -17.3 ± 7.6, P = 0.001), and E/é ratio (9.3 ± 3.4 vs. 8.2 ± 2.0, P = 0.037) in Group 1, but not in Group 2: LVEF (0.49 ± 0.06 vs. 0.50 ± 0.05, P = 0.47), GLS (-12.9 ± 2.4 vs. -14.4 ± 3.2, P = 0.052), and E/é ratio (8.8 ± 2.4 vs. 10.0 ± 4.7, P = 0.18). WMSI improved significantly more in Group 1 (reduction of -17.1% vs. -6.8% in Group 2, P = 0.015). CONCLUSION: Lower IMR was associated with better myocardial GLS acutely after STEMI, and with a significantly higher recovery of the LVEF, WMSI, E/E' ratio and GLS, suggesting that IMR is an early marker of cardiac recovery, after acute myocardial infarction.