Combining loop with thiazide diuretics in patients discharged home after a heart failure decompensation: Association with 30-day outcomes.

OBJECTIVE: To investigate the association of the addition of thiazide diuretic on top of loop diuretic and standard of care with short-term outcomes of patients discharged after surviving an acute heart failure (AHF) episode. METHODS: This is a secondary analysis of 14,403 patients from three independent cohorts representing the main departments involved in AHF treatment for whom treatment at discharge was recorded and included loop diuretics. Patients were divided according to whether treatment included or not thiazide diuretics. Short-term outcomes consisted of 30-day all-cause mortality, hospitalization (with a separate analysis for hospitalization due to AHF or to other causes) and the combination of death and hospitalization. The association between thiazide diuretics on short-term outcomes was explored by Cox regression and expressed as hazard ratios (HR) with 95 % confidence intervals, which were adjusted for 18 patient-related variables and 9 additional drugs (aside from loop and thiazide diuretics) prescribed at discharge. RESULTS: The median age was 81 (interquartile range=73-86) years, 53 % were women, and patients were mainly discharged from the cardiology (42 %), internal medicine or geriatric department (29 %) and emergency department (19 %). There were 1,367 patients (9.5 %) discharged with thiazide and loop diuretics, while the rest (13,036; 90.5 %) were discharged with only loop diuretics on top of the remaining standard of care treatments. The combination of thiazide and loop diuretics showed a neutral effect on all outcomes: death (adjusted HR 1.149, 0.850-1.552), hospitalization (0.898, 0.770-1.048; hospitalization due to AHF 0.799, 0.599-1.065; hospitalization due to other causes 1.136, 0.756-1.708) and combined event (0.934, 0.811-1.076). CONCLUSION: The combination of thiazide and loop diuretics was not associated with changes in risk of death, hospitalization or a combination of both.

Differential sex-related effect of left ventricular ejection fraction trajectory on the risk of mortality and heart failure readmission following hospitalization for acute heart failure: A longitudinal study.

AIMS: There is limited information on the sex-specific longitudinal changes of left ventricular ejection fraction (LVEF) after an acute heart failure (AHF) hospitalization. We aimed to investigate whether LVEF trajectories over time and their impact on mortality and AHF readmission rates differ between men and women. METHODS AND RESULTS: We conducted a retrospective sex-specific analysis of longitudinal LVEF measurements (n = 9581) in 3383 patients with an index hospitalization for AHF in a single tertiary-level hospital. Statistical techniques suited for longitudinal data analysis were used. The mean age of the sample was 73.8 ± 11.2 years, and 47.9% were women. The mean LVEF was 49.4 ± 15.3%. At a median follow-up of 2.58 years (interquartile range 0.77-5.62), we registered 2197 deaths (64.9%) and 2597 AHF readmissions in 1302 (38.5%) patients. The longitudinal analysis showed that women had consistently higher LVEF values throughout the follow-up with both trajectories characterized by an early peak-approximately at 1 year-followed by decreasing values in men but a plateau in women. Multivariate between-sex comparisons across LVEF categories revealed that women had lower rates of AHF readmissions when LVEF ≤40%. On the contrary, women displayed an excess risk of AHF readmissions when LVEF >60%. A trend in the same direction was found for cardiovascular and all-cause mortality. CONCLUSION: Sex was a significant factor in determining the follow-up trajectory of LVEF and predicting differences in outcomes after an AHF admission. The findings suggest that women have a higher risk of AHF readmissions at higher LVEF values, while men have a higher risk at lower LVEF values. For all-cause and cardiovascular mortality, the same direction of the association was inferred but they were not significant.

Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction-a substudy of the DAPA-VO2 study.

The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%-p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8-72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5-37.8), 67.4 ml/min/1.73 m2 (50.7-82.8), 1,285 pg/ml (898-2,305), 623.4 pg/ml (533.5-736.6), and 72.6 RU/ml (62.6-96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9-37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ-4.6, (-1.7 to -5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.

Evolocumab has no effects on heart failure with reduced ejection fraction injury biomarkers: The EVO-HF trial.

AIM: Patients with heart failure with reduced ejection fraction (HFrEF) have not been shown to benefit from statins. We hypothesized that, by limiting disease progression in stable HFrEF of ischaemic etiology, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab could reduce circulating troponin levels, a surrogate biomarker of myocyte injury and atherosclerosis progression. METHODS AND RESULTS: The EVO-HF multicentre prospective randomized trial compared evolocumab (420 mg/month administered subcutaneously) plus guideline-directed medical therapy (GDMT; n = 17) versus GDMT alone (n = 22) for 1 year in patients with stable coronary artery disease and left ventricular ejection fraction (LVEF) <40%, ischaemic aetiology, New York Heart Association class II, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥400 pg/ml, high-sensitivity troponin T (hs-TnT) >10 pg/ml, low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl. The primary endpoint was change in hs-TnT concentration. Secondary endpoints included NT-proBNP, interleukin-1 receptor-like 1 (ST2), high-sensitivity C-reactive protein (hs-CRP), LDL, low-density lipoprotein receptor (LDLR), high-density lipoprotein cholesterol (HDL-C), and PCSK9 levels at 1 year. Patients were mainly Caucasian (71.8%), male (79.5%), relatively young (mean age 68.1 ± 9.4 years), with a mean LVEF of 30.4 ± 6.5%, and managed with contemporary treatments. No significant changes in hs-TnT levels were observed in any group at 1 year. NT-proBNP and ST2 levels decreased in the GDMT plus evolocumab group (p = 0.045 and p = 0.008, respectively), without changes in hs-CRP, HDL-C, or LDLR. Total and LDL-C decreased in both groups, significantly higher in the intervention group (p = 0.003), and PCSK9 levels increased in the intervention group. CONCLUSIONS: This prospective randomized pilot trial, although with the limitation of the small sample size, does not support the benefit of evolocumab in reducing troponin levels in patients with elevated LDL-C levels, history of coronary artery disease, and stable HFrEF.

Clinical Predictors and Prognosis of Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) without ST-Segment Elevation in Older Adults.

A non-neglectable percentage of patients with non-ST elevation myocardial infarction (NSTEMI) show non-obstructive coronary arteries (MINOCA). Specific data in older patients are scarce. We aimed to identify the clinical predictors of MINOCA in older patients admitted for NSTEMI and to explore the long-term prognosis of MINOCA. This was a single-center, observational, consecutive cohort study of older (≥70 years) patients admitted for NSTEMI between 2010 and 2014 who underwent coronary angiography. Univariate and multivariate Cox regression were performed to analyze the association of variables with MINOCA and all-cause mortality and with major adverse cardiac events (MACE), defined as a combined endpoint of all-cause mortality and nonfatal myocardial infarction and a combined endpoint of cardiovascular mortality, nonfatal myocardial infarction, and unplanned revascularization. The registry included 324 patients (mean age 78.8 ± 5.4 years), of which 71 (21.9%) were diagnosed with MINOCA. Predictors of MINOCA were female sex, left bundle branch block, pacemaker rhythm, chest pain at rest, peak troponin level, previous MI, Killip ≥2, and ST segment depression. Regarding prognosis, patients with obstructive coronary arteries (stenosis ≥50%) and the subgroup of MINOCA patients with plaques <50% had a similar prognosis; while MINOCA patients with angiographically smooth coronary arteries had a reduced risk of MACE. We conclude that the following: (1) in elderly patients admitted for NSTEMI, certain universally available clinical, electrocardiographic, and analytical variables are associated with the diagnosis of MINOCA; (2) elderly patients with MINOCA have a better prognosis than those with obstructive coronary arteries; however, only those with angiographically smooth coronary arteries have a reduced risk of all-cause mortality and MACE.

Long-Term Prognostic Impact of Estimated Glomerular Filtration Rate on Admission in Patients Hospitalized for Acute Heart Failure.

INTRODUCTION: Although small-sample size studies have shown that basal alterations of estimated glomerular filtration rate (eGFR) are related to short- and mid-term higher mortality in acute heart failure (AHF), there is scarce information on the influence of an altered eGFR on long-term mortality and readmissions. Therefore, this multicenter study sought to investigate the relationship between eGFR on admission for AHF and both long-term mortality and readmissions in a large sample of patients. METHODS: We retrospectively evaluated 4,595 patients consecutively discharged after admission for AHF at three tertiary-care hospitals from January 1, 2008, to January 1, 2020. To investigate the effect of eGFR on admission with long-term morbimortality, we stratified the patients according to four eGFR categories: <30 mL·min-1·1.73 m-2 (G4 and G5 patients, n = 534), 30-44 mL·min-1·1.73 m-2 (G3b patients, n = 882), 45-59 mL·min-1·1.73 m-2 (G3a patients, n = 1,080), and ≥60 mL·min-1·1.73 m-2 (G1 and G2 patients, n = 2,099). eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation within the first 24 h following admission. RESULTS: At a median follow-up of 2.20 years, multivariate analyses revealed that compared to G1 and G2 patients, G4 and G5 patients exhibited a higher risk of all-cause (HR = 1.15, 95% CI: 01.02-1.30, p = 0.020) and cardiovascular (CV) (HR = 1.20, 95% CI: 1.04-1.39, p = 0.013) mortality. Similarly, multivariate analyses also showed that the lower the eGFR, the higher the risk of readmissions. In fact, compared to G1 and G2 patients, G4 and G5 patients displayed significantly increased incident rate ratios of total all-cause (28%), CV (26%), and HF-related (30%) readmissions. CONCLUSION: Data from this large study provide evidence that an eGFR below 30 mL·min-1·1.73 m-2 on admission could be an independent predictor for long-term mortality and readmissions in patients with AHF.

Frailty and Hospitalization Burden in Patients With Chronic Heart Failure.

Frailty is associated with increased mortality and hospitalizations in patients with heart failure (HF). However, there is little evidence regarding the burden of morbidity. In this study, we aimed to assess the association between frailty and recurrent all-cause HF hospitalizations in patients with stable chronic HF. This was an observational and prospective study that enrolled HF outpatients followed in a specialized HF unit of a single tertiary care center from 2017 to 2019. Frailty was assessed by Fried criteria. Robustness, prefrailty, and frailty were defined as 0, 1 to 2, and ≥3, respectively. The independent association between frailty status and recurrent hospitalizations was assessed through Famoye's bivariate Poisson regression model, and risk estimates were expressed as incidence rate ratios (IRR). A total of 277 patients were included. The mean age was 74 ± 10 years, 118 were women (42.6%), and 131 patients (47.3%) had left ventricular ejection fraction ≥50. According to Fried's score 61 patients (22%) were robust, 95 patients (34%) were prefrail, and 121 patients (44%) were frail. After a median follow-up of 2.21 (1.6 to 2.8) years, 52 patients (19%) died. We registered 348 all-cause hospitalizations in 144 patients (52%) and 178 HF hospitalizations in 108 patients (39%). Compared with robust patients, frailty was associated with a higher risk of all-cause and HF recurrent hospitalizations in multivariable analysis (IRR 2.01, 95% confidence interval 1.14 to 3.57, p = 0.017 and IRR 2.25, 95% confidence interval 1.16-4.36, p = 0.016, respectively). In conclusion, in patients with chronic HF, frailty identifies patients with an increased risk of total and recurrent all-cause and HF hospitalizations.

Hospitalization following an emergency-department visit for worsening heart failure: The role of left ventricular ejection fraction

Introduction and objectives:Patients with worsening heart failure (WHF) are frequently hospitalized. However, some of the patients with WHF are discharged from the emergency department without hospitalization. The factors influencing the decision of admission are heterogeneous and, in most cases, remain not well-defined. This study aimed to analyze whether left ventricular ejection fraction (LVEF) influences admission decisions following a visit to the emergency department for WHF.Patients and methods:This is a retrospective analysis of 3168 patients discharged from a hospitalization for acute heart failure in a single-center in Spain. During follow-up, visits to the emergency department for WHF, including those hospitalized (WHF-readmissions) and episodes of WHF directly discharged without hospitalization in 24h (WHF-DDWH), were recorded. The association between the LVEF categories (<50% and ≥50%) and recurrent WHF-DDWH was evaluated by negative binomial regression. Estimates of risk were expressed as incidence rate ratios (IRR).Results:The mean age (SD) of the study sample was 73.5 (11.2) years, and 1658 (52.3%) showed LVEF>50%. At a median (percentile 25% to percentile 75%) follow-up of 2.7 (1.0–5.8) years, 3341 episodes of WHF in 1439 patients were recorded. Of them, we registered 743 episodes of WHF-DDWH in 468 patients (22.2%). Compared to patients with LVEF<50%, those with LVEF≥50% exhibited an adjusted increased risk of recurrent WHF-DDWH (IRR: 1.36, CI 95%: 1.13–1.62, p=0.001).Conclusions:Following an acute heart failure admission, patients with LVEF≥50% showed an increased risk of same-day discharge for WHF. (AU)

Introducción y objetivos:Muchos de los pacientes que acuden a los servicios de urgencias (SU) por empeoramiento de la insuficiencia cardiaca (EIC) son hospitalizados, en cambio, otros son dados de alta desde el SU sin ingreso hospitalario (EIC-SUSIH). Los factores que definen esta condición son heterogéneos y no están bien establecidos. El objetivo de este estudio fue analizar si la fracción de eyección del ventrículo izquierdo (FEVI) influye en la decisión de ingresar a un paciente en el SU por EIC.Métodos:Análisis retrospectivo de 3.168 pacientes hospitalizados por insuficiencia cardiaca (IC) aguda en un solo centro en España. Durante el seguimiento, se registraron todas las visitas al SU por EIC y se catalogaron en dos grupos según fueron resueltas: hospitalizaciones y EIC-SUSIH. La asociación entre las categorías de FEVI (< 50%-≥ 50%) y las visitas recurrentes por EIC se analizaron mediante regresión binomial negativa.Resultados:La media de edad (desviación estándar) fue de 73,5 (1,2) años. Del total, 1.658 (52,3%) tenían FEVI > 50%. Tras una mediana de seguimiento (percentil 25%-percentil 75%) de 2,7 (1,0-5,8) años, se registraron 3.341 episodios de EIC en 1.439 pacientes y 743 casos de EIC-SUSIH en 468 pacientes (22,2%). Los pacientes con FEVI ≥ 50% mostraron un incremento del riesgo ajustado de presentar episodios recurrentes de EIC-SUSIH (Ratio de tasa incidencia (IRR): 1,36; IC 95%: 1,13-1,62; p = 0,001).Conclusiones:Tras un ingreso por IC aguda, los pacientes con FEVI ≥ 50% que acuden al SU por EIC, presentan un mayor riesgo de ser dados de alta sin ser ingresados. (AU)

Venous Leg Compression for Tissue Decongestion in Patients With Worsening Congestive Heart Failure.

Aims: Venous leg compression (VLC) with elastic bandages has been proposed as a potentially useful strategy for decreasing tissue congestion. We aimed to evaluate the effect of VLC on short-term changes on intravascular refill, assessed by inferior vena cava (IVC) diameter in patients with worsening heart failure (WHF) requiring parenteral furosemide. Additionally, we sought to evaluate whether early changes in IVC were related to short-term decongestion. Methods: This is a prospective study in which we included 20 consecutive ambulatory patients with WHF treated with subcutaneous furosemide and VLC for at least 72 h. The endpoints were (a) short-term changes in IVC, (b) the association between decongestion and 3-h IVC changes following VLC. Changes in continuous endpoints and their longitudinal trajectories were estimated with linear mixed regression models. All analyses were adjusted for multiple comparisons. Results: Following administration of subcutaneous furosemide and VLC, we found a significant increase in 3-h IVC diameter (ΔIVC = 1.6 mm, CI 95%: 0.7-2.5; p < 0.001), with a greater increase in those with baseline IVC≤21 mm (2.4 vs. 0.8 mm; p < 0.001). 3-h intravascular refill (increase in IVC≥2 mm) was associated with greater decongestion (natriuresis, weight, peripheral edemas, and dyspnea) in those with baseline IVC≤21 mm but not when IVC>21 mm (p < 0.05 for all comparisons). Conclusions: In this cohort of patients with congestive WHF treated with subcutaneous furosemide and VLC, we found a greater increase in short-term IVC in those with IVC ≤21 mm at baseline. In this subset of patients, a 3-h increase in IVC≥2 mm was associated with greater short-term decongestion.

Differences and Similarities between the Lung Transcriptomic Profiles of COVID-19, COPD, and IPF Patients: A Meta-Analysis Study of Pathophysiological Signaling Pathways.

Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease associated with high morbidity and mortality. Although many patients recover, long-term sequelae after infection have become increasingly recognized and concerning. Among other sequelae, the available data indicate that many patients who recover from COVID-19 could develop fibrotic abnormalities over time. To understand the basic pathophysiology underlying the development of long-term pulmonary fibrosis in COVID-19, as well as the higher mortality rates in patients with pre-existing lung diseases, we compared the transcriptomic fingerprints among patients with COVID-19, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD) using interactomic analysis. Patients who died of COVID-19 shared some of the molecular biological processes triggered in patients with IPF, such as those related to immune response, airway remodeling, and wound healing, which could explain the radiological images seen in some patients after discharge. However, other aspects of this transcriptomic profile did not resemble the profile associated with irreversible fibrotic processes in IPF. Our mathematical approach instead showed that the molecular processes that were altered in COVID-19 patients more closely resembled those observed in COPD. These data indicate that patients with COPD, who have overcome COVID-19, might experience a faster decline in lung function that will undoubtedly affect global health.

Profibrotic Role of Inducible Heat Shock Protein 90α Isoform in Systemic Sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease that affects skin and multiple internal organs. TGF-ß, a central trigger of cutaneous fibrosis, activates fibroblasts with the involvement of the stress-inducible chaperone heat shock protein 90 isoform α (Hsp90α). Available evidence supports overexpression and secretion of Hsp90α as a feature in profibrotic pathological conditions. The aim of this work is to investigate the expression and function of Hsp90α in experimental models of skin fibrosis such as human fibroblasts, C57BL/6 mice, and in human SSc. For this purpose, we generated a new experimental model based on doxorubicin administration with improved characteristics with respect to the bleomycin model. We visualized disease progression in vivo by fluorescence imaging. In this work, we obtained Hsp90α mRNA overexpression in human skin fibroblasts, in bleomycin- and doxorubicin-induced mouse fibrotic skin, and in lungs of bleomycin- and doxorubicin-treated mice. Hsp90α-deficient mice showed significantly decreased skin thickness compared with wild-type mice in both animal models. In SSc patients, serum Hsp90α levels were increased in patients with lung involvement and in patients with the diffuse form of SSc (dSSc) compared with patients with the limited form of SSc. The serum Hsp90α levels of patients dSSc were correlated with the Rodnan score and the forced vital capacity variable. These results provide new supportive evidence of the contribution of the Hsp90α isoform in the development of skin fibrosis. In SSc, these results indicated that higher serum levels were associated with dSSc and lung fibrosis.

Incidence, Treatment and Clinical Impact of Iron Deficiency in Chronic Heart Failure: A Longitudinal Analysis.

In patients with heart failure (HF), iron deficiency (ID) is a well-recognized therapeutic target; information about its incidence, patterns of iron repletion, and clinical impact is scarce. This single-centre longitudinal cohort study assessed the rates of ID testing and diagnosis in patients with stable HF, patterns of treatment with intravenous iron, and clinical impact of intravenous iron on HF rehospitalization risk. We included 711 consecutive outpatients (4400 visits) with stable chronic HF from 2014 to 2019 (median [interquartile range] visits per patient: 2 [2−7]. ID was defined as serum ferritin <100 µg/L, or 100−299 µg/L with transferrin saturation (TSAT) < 20%. During a median follow-up of 2.20 (1.11−3.78) years, ferritin and TSAT were measured at 2230 (50.7%) and 2183 visits (49.6%), respectively. ID was found at 846 (37.9%) visits, with ferritin and TSAT available (2230/4400), and intravenous iron was administered at 321/4400 (7.3%) visits; 233 (32.8%) patients received intravenous iron during follow-up. After multivariate analyses, iron repletion at any time during follow-up was associated with a lower risk of recurrent HF hospitalization (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.28−0.88; p = 0.016). Thus, ID was a frequent finding in patients with HF, and its repletion reduced the risk of recurrent HF hospitalizations.

Short-term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA-VO2 ): a randomized clinical trial.

AIMS: This study aimed to evaluate the effect of dapagliflozin on 1 and 3-month maximal functional capacity in patients with stable heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: In this multicentre, randomized, double-blind clinical trial, 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin (n = 45) or placebo (n = 45). The primary outcome was a change in peak oxygen consumption (peakVO2 ) at 1 and 3 months. Secondary endpoints were changes at 1 and 3 months in 6-min walk test (6MWT) distance, quality of life (Minnesota Living with Heart Failure Questionnaire [MLHFQ]), and echocardiographic parameters (diastolic function, left chamber volumes, and left ventricular ejection fraction). We used linear mixed regression analysis to compare endpoint changes. Estimates were adjusted for multiple comparisons. The mean age was 67.1 ± 10.7 years, 69 (76.7%) were men, 29 (32.2%) had type 2 diabetes, and 80 (88.9%) were in New York Heart Association class II. Baseline means of peakVO2 , 6MWT and MLHFQ were 13.2 ± 3.5 ml/kg/min, 363 ± 110 m, and 23.1 ± 16.2, respectively. The median (25th-75th percentile) of N-terminal pro-brain natriuretic peptide was 1221 pg/ml (889-2100). Most patients were on treatment with sacubitril/valsartan (88.9%), beta-blockers (91.1%), and mineralocorticoid receptor antagonists (74.4%). PeakVO2 significantly increased in patients on treatment with dapagliflozin (1 month: +Δ 1.09 ml/kg/min, 95% confidence interval [CI] 0.14-2.04; p = 0.021, and 3 months: +Δ 1.06 ml/kg/min, 95% CI 0.07-2.04; p = 0.032). Similar positive findings were found when evaluating changes from baseline. No significant differences were observed in secondary endpoints. CONCLUSIONS: Among patients with stable HFrEF, dapagliflozin resulted in a significant improvement in peakVO2 at 1 and 3 months. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04197635.

Evaluation of SARS-CoV-2 entry, inflammation and new therapeutics in human lung tissue cells.

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2.

Hospitalization following an emergency-department visit for worsening heart failure: The role of left ventricular ejection fraction.

INTRODUCTION AND OBJECTIVES: Patients with worsening heart failure (WHF) are frequently hospitalized. However, some of the patients with WHF are discharged from the emergency department without hospitalization. The factors influencing the decision of admission are heterogeneous and, in most cases, remain not well-defined. This study aimed to analyze whether left ventricular ejection fraction (LVEF) influences admission decisions following a visit to the emergency department for WHF. PATIENTS AND METHODS: This is a retrospective analysis of 3168 patients discharged from a hospitalization for acute heart failure in a single-center in Spain. During follow-up, visits to the emergency department for WHF, including those hospitalized (WHF-readmissions) and episodes of WHF directly discharged without hospitalization in 24h (WHF-DDWH), were recorded. The association between the LVEF categories (<50% and ≥50%) and recurrent WHF-DDWH was evaluated by negative binomial regression. Estimates of risk were expressed as incidence rate ratios (IRR). RESULTS: The mean age (SD) of the study sample was 73.5 (11.2) years, and 1658 (52.3%) showed LVEF>50%. At a median (percentile 25% to percentile 75%) follow-up of 2.7 (1.0-5.8) years, 3341 episodes of WHF in 1439 patients were recorded. Of them, we registered 743 episodes of WHF-DDWH in 468 patients (22.2%). Compared to patients with LVEF<50%, those with LVEF≥50% exhibited an adjusted increased risk of recurrent WHF-DDWH (IRR: 1.36, CI 95%: 1.13-1.62, p=0.001). CONCLUSIONS: Following an acute heart failure admission, patients with LVEF≥50% showed an increased risk of same-day discharge for WHF.

Efficacy and Safety of Subcutaneous Infusion of Non-formulated Furosemide in Patients with Worsening Heart Failure: a Real-World Study.

We aimed to evaluate the efficacy (short-term changes in surrogates of decongestion) and safety following the ambulatory administration of subcutaneous furosemide (SCF) in patients with WHF. Fifty-five ambulatory patients were treated with SCF administered by an elastomeric pump for at least 72 h. Surrogates of congestion were assessed at baseline, 72 h, and 30 days. Spot urinary sodium (uNa+) was assessed at baseline, 24-48-72 h, and 30 days. The median (IQI) of NT-proBNP and uNa+ at baseline was 5218 pg/mL (2856-10878) and 68±3 mmol/L, respectively. Following administration of SCF (median dose of 100 mg/daily), we found a sustained increase in uNa+ during the first 72 h of treatment compared to baseline, paralleled with evidence of decongestion at 72 h, and 30 days. No significant safety concerns were observed. SCF was an effective and safe diuretic strategy for outpatient congestion management. Non-formulated subcutaneous furosemide in patients with WHF. Efficacy and safety.

Comparación entre CA125 y NT-proBNP para valorar la congestión en insuficiencia cardíaca aguda / Comparison between CA125 and NT-proBNP for evaluating congestion in acute heart failure

Antecedentes: El antígeno carbohidrato 125 (CA125) y los péptidos natriuréticos tipo B son marcadores subrogados de congestión en pacientes con insuficiencia cardíaca aguda (ICA). El objetivo del estudio fue valorar la asociación entre CA125 y NT-proBNP y parámetros de congestión en pacientes con ICA.Métodos y resultadosEstudio observacional prospectivo multicéntrico, que incluyó a 191 pacientes hospitalizados por ICA. Se registró la presencia de derrame pleural, edema periférico y diámetro de vena cava inferior (VCI) durante las primeras 24-48 horas tras el ingreso y se evaluó su asociación independiente con las concentraciones de CA125 y la fracción amino-terminal del péptido natriurético tipo B (NT-proBNP). La edad media fue de 73,4 ± 12 años, 79 (41,4%) eran mujeres y 127 (66,5%) tenían fracción de eyección ventricular izquierda ≥ 50%. La mediana de CA125, NT-proBNP y diámetro VCI fue de 58 (22,7-129) U/mL, 3.985 (1.905-9.775) pg/mL y 21 (17-25) mm, respectivamente. El análisis multivariante mostró que el CA125 se asoció positiva e independientemente con presencia de edema periférico, derrame pleural y valores elevados de VCI. El NT-proBNP se relacionó con el derrame pleural y el diámetro de VCI, pero no con el edema. La adición del CA125 incrementó la capacidad discriminativa del modelo basal para identificar edema periférico y derrame pleural, no así el NT-proBNP. El predictor más importante para la dilatación de la VCI fue el CA125 (R2 = 48,3%).ConclusiónEn pacientes con ICA, los niveles séricos de CA125 se asocian de forma más significativa que los de NT-proBNP con el estado de congestión. (AU)

Background: Carbohydrate antigen 125 (CA125) and B-type natriuretic peptides are surrogate markers of congestion in patients with acute heart failure (AHF). The aim of the study was to assess the association between CA125 and NT-proBNP and congestion parameters in patients with AHF.Methods and resultsProspective multicentre observational study that included 191 patients hospitalised for AHF. We recorded the presence of pleural effusion, peripheral oedema and inferior vena cava (IVC) diameter during the first 24-48 hours after admission and evaluated their independent association with CA125 concentrations and the amino-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP). The mean age was 73.4 ± 12 years, 79 (41.4%) were women, and 127 (66.5%) had left ventricular ejection fraction ≥ 50%. The median of CA125, NT-proBNP and IVC diameter was 58 (22.7-129) U/mL, 3,985 (1,905-9,775) pg/mL and 21 (17-25) mm, respectively. Multivariate analysis showed that CA125 was positively and independently associated with the presence of peripheral oedema, pleural effusion and elevated IVC levels. NT-proBNP was associated with pleural effusion and IVC diameter but not with oedema. The addition of CA125 increased the discriminatory capacity of the baseline model to identify peripheral oedema and pleural effusion, but not NT-proBNP. The most important predictor of ICV dilation was CA125 (R2 = 48.3%).ConclusionIn patients with AHF, serum CA125 levels are associated more significantly than NT-proBNP with a state of congestion. (AU)

Bacterial metabolites trimethylamine N-oxide and butyrate as surrogates of small intestinal bacterial overgrowth in patients with a recent decompensated heart failure.

In patients with heart failure (HF), the exhaled concentrations of hydrogen after a breath test-a non-invasive assessment of small intestinal overgrowth- has been related to HF severity and higher risk of adverse outcomes. Indeed, two intestinal bacterial metabolites-blood Trimethylamine N-Oxide (TMAO) and butyrate-have been related to a worse prognosis in HF. However, the relationship between the exhaled concentrations of hydrogen after a breath test and these two metabolites remains unknown. Thus, in this post-hoc analysis, we sought to evaluate whether these two metabolites are associated with the exhaled concentrations of hydrogen after a breath test in patients with a recent admission for HF. We included 60 patients with a recent hospitalization for HF. Cumulative hydrogen over time was integrated into a single measurement by the area under the concentration curve (AUC-H2). A linear regression multivariable analysis was used to evaluate the associations. A 2-sided p-value < 0.05 was considered to be statistically significant. The median (p25-p75) amino-terminal pro-brain natriuretic peptide, AUC-H2, TMAO, and Butyrate were 4789 pg/ml (1956-11149), 1615 (700-2585), 0.68 (0.42-1.12), and 0.22 ± 13, respectively. After multivariate adjustment, TMAO and butyrate were significantly associated with AUC-H2 (p = 0.027 and p = 0.009, respectively). For TMAO, this association was positive and for butyrate, negative. Bacterial-origin metabolites TMAO and Butyrate were independently related to AUC-H2 in patients with a recent hospitalization for acute HF.