BACKGROUND Elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (tBil) may reflect congestion and liver dysfunction in acute heart failure (AHF), while lower ALT also associates with sarcopenia. OBJECTIVES The purpose of this study was to assess ALT, AST, and tBil levels in AHF patients during high-intensity care (HIC) vs usual care (UC) follow-up. METHODS ALT, AST, and tBil were measured 1 to 2 days predischarge in 1,062 AHF patients, and again after 90 days of either HIC or UC according to the STRONG-HF (Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP testinG, of Heart Failure therapies) protocol. The primary endpoint was 180-day all-cause death or HF hospitalization. RESULTS Median (Q1-Q3) baseline ALT, AST, and tBil were 21(15-32) U/L, 23 (17-32) U/L, and 14(10-21) umol/L, respectively. Patients with lower ALT had lower body mass index. Patients with lower ALT, but not tBil or AST, were more likely to have edema, elevated jugular venous pressure, and orthopnea, and use more diuretics prerandomization. A nonsignificant inverse association between ALT and the primary outcome (HR: 0.82 [95% CI: 0.66-1.01] per log-unit, P 1/4 0.06) was observed. Greater reductions of ALT, AST, and tBil to 90 days were associated with greater improvement of edema, rales, NYHA functional class, and N-terminal pro-B-type natriuretic peptide. After 90 days, the HIC group had a greater reduction in AST and tBil than the UC group, while nonsignificant for ALT. The treatment effect of HIC over UC on the primary outcome was consistent across the baseline ALT, AST, and tBil range (all P interaction >0.10), but patients with lower ALT experienced greater health status improvement from HIC. CONCLUSIONS Lower ALT was associated with lower body mass index and more congestion in AHF, supporting previous studies suggesting ALT as a sarcopenia marker. The beneficial effect of HIC on health status was greater in low baseline ALT patients. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies [STRONG-HF]; NCT03412201)

We read with great interest the article authored by Kalter-Leibovici et al. Initial treatment in acute heart failure (AHF) is crucial in shaping short-term outcomes. Administered in the prehospital phase or emergency department (ED), early interventions—such as timing and dose of intravenous diuretics or vasodilators—may impact stabilization and decongestion. However, most predictive models, including the one discussed here, often omit these parameters, potentially missing an opportunity to refine risk stratification and anticipate complications. Beyond the ED, in-hospital treatment remains critical. The STRONG-HF trial demonstrated that intensifying medical therapy during hospitalization improves post-discharge outcomes, yet readmission rates remain high. This raises questions about the endpoint itself—whether it fully captures the benefits of optimized early care—or whether it reflects the inherent complexity of AHF as a progressive disease. Most ED-based studies focus on short- to mid-term readmissions (30–90 days), overlooking longer-term trajectories. Additionally, biomarkers such as NT-proBNP and renal function indicators, alongside advanced risk stratification tools, could enhance therapy guidance and discharge decisions. Yet, they remain underutilized in predictive models. Incorporating these parameters in future analyses may provide more actionable insights and improve long-term care strategies for AHF patients.

We examined current evidence regarding the effects of anti-inflammatory therapies in patients with acute heart failure (AHF) on the risk of cardiovascular outcomes, inflammatory markers, natriuretic peptides, and renal function. Despite growing evidence that inflammation plays a pivotal role in both the development and progression of heart failure, including AHF, only a few trials have been conducted to date in patients with AHF. A systematic literature search of PubMed, Medline, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted in November 2024 to identify randomized controlled trials (RCTs) evaluating anti-inflammatory therapies in adult patients with AHF. Meta-analyses were conducted to estimate effects on clinical outcomes (death, HF readmission, or worsening HF) and inflammatory and other markers. Five RCTs were identified that enrolled a total of 289 patients to an anti-inflammatory intervention and 273 to a control. Prednisone was examined in two RCTs, anakinra in two, and colchicine in one. Three of the five trials required elevated C-reactive protein (CRP) level for entry. Anti-inflammatory therapy was associated with a reduced risk of the composite outcome (hazard ratio 0.55 [95

During the past century, the characteristics of patients with heart failure (HF) and acute HF (AHF) have shifted from patients with severe pump failure due to rheumatic, hypertensive and ischemic heart disease to older and more obese patients with multiple severe comorbidities. The pathophysiology of AHF has shifted, in parallel, from that of advanced, end-stage pump failure caused by severe left ventricular dysfunction to age, obesity and comorbidity-related cardiovascular dysfunction combined with neurohormonal and inflammatory dysregulation or “inflammaging.” With the advent of neurohormonal blockers leading to improved outcomes of patients with chronic HF, the focus of AHF therapy has also changed from care directed at early symptom improvement to therapies directed toward longer-term improvements in quality of life and outcomes. Studies conducted in the past 5 years suggest that the beneficial effects seen with the 4 pillars of guideline-directed medical therapy for HF, mostly comprising neurohormonal blockade, can be extended to AHF when these therapies are initiated and rapidly uptitrated during admission and after discharge. A recent pilot study, CORTAHF (Effect of Short-Term Prednisone Therapy on CRP Change in Emergency Department Patients With Acute Heart Failure and Elevated Inflammatory Markers), has suggested that these benefits can be extended by treating patients with AHF and markers of inflammatory activation with anti-inflammatory therapies. Future studies should further examine whether combined anti-inflammatory therapy and neurohormonal blockade can lead to the reversal of disrupted underlying pathophysiology and remission in patients with AHF.

BACKGROUND:Previous studies have shown important but sometimes heterogeneous differences between women and men with heart failure (HF). OBJECTIVES:This study aims to investigate sex differences in the phenotype and journey of men and women in a large contemporary acute heart failure (AHF) cohort. METHODS:The authors analyzed 6,545 AHF patients (40% women) enrolled in RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF). RESULTS:Women were older (78 vs 72 years; P < 0.001) and had higher ejection fraction (45% vs 35%; P < 0.001). During hospitalization, women received lower diuretic doses (furosemide equivalent through day 5: 200 vs 240 mg intravenous; P < 0.001) and achieved lower weight loss (relative; P = 0.026), with slightly lower diuretic response (-0.33 vs -0.36 kg/40 mg furosemide at day 5; P = 0.011) and similar sign and symptom improvement by day 5 compared with men (all adjusted P > 0.05). More women experienced worsening renal function by day 5 (WRF; adjusted HR: 1.24 [95% CI: 1.06-1.46]; P = 0.009). Women experiencing WRF had increased risk of 180-day cardiovascular death and rehospitalizations for HF or renal failure (RF) and of rehospitalizations for HF/RF compared with men and women without WRF (adjusted P for interaction: P < 0.001). Incidence of other outcomes was similar in women and men (all P > 0.20). CONCLUSIONS:During an AHF hospitalization, women received lower doses of loop diuretic agents and achieved less weight loss with slightly lower diuretic response compared with men, despite similar symptom relief and postdischarge outcomes. Early incident WRF was more frequent in women and was associated with worse 180-day outcomes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778).

AIMS:Residual congestion (RC) is common at discharge after acute decompensated heart failure (ADHF) and is associated with early mortality and rehospitalization. The prognostic value of distinct RC phenotypes (i.e. intravascular and tissue congestion) remains unclear. This analysis investigated RC phenotypes and their outcomes. METHODS AND RESULTS:Patients with congestion at admission from two large ADHF trials, PROTECT (rolofylline; index) and RELAX-AHF-2 (serelaxin; replication), were classified based on clinical signs at day 7/discharge as intravascular (jugular venous pressure) or tissue (pulmonary rales/peripheral oedema) congestion, each alone, combined or neither. Cox regression assessed 180-day mortality after adjusting for risk factors. Overall, 1557 patients with predominantly combined (i.e. tissue and intravascular) congestion at admission were included, with a median age of 72 years. By day 7 or discharge, 580 (37%) patients had RC. In these patients, intravascular congestion (n = 260; 45%) was most common, followed by combined (n = 185; 32%) and tissue (n = 135; 23%) congestion. During hospitalization, patients with solely intravascular RC had greater diuretic responses, shorter hospital stays and received lower doses of intravenous loop diuretics than those with tissue or combined congestion (all p < 0.05). Residual intravascular and tissue congestion were independently associated with increased 180-day mortality (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.15-2.49, and HR 2.07, 95% CI 1.25-3.41, respectively) compared to decongested patients. In the RELAX-AHF-2 substudy (n = 476), similar findings were observed. CONCLUSIONS:Patients with intravascular RC had better diuretic responses and shorter hospital stays than those with tissue/combined RC, but worse outcomes than decongested patients. This study highlights the importance of RC assessment to identify at-risk patients. Future studies should evaluate phenotype-guided treatments.

BACKGROUND:Aortic stenosis leads to increased afterload, which may be detrimental in a failing left ventricle and has been associated with an increased risk of hospitalizations due to heart failure and mortality in chronic heart failure. The prevalence and impact of aortic stenosis in acute heart failure are less well described. This post hoc analysis aimed to evaluate the prevalence and prognostic impact of aortic stenosis in a large cohort of patients hospitalized due to acute heart failure. METHODS AND RESULTS:All patients from the Relaxin in Acute Heart Failure 2 (RELAX-AHF-2) trial with data available on aortic stenosis severity were included in the present analysis (n = 6241). Patients with severe aortic stenosis were ineligible for RELAX-AHF-2. Baseline characteristics, in-hospital outcomes and 180-day clinical outcomes were compared between patients with and without aortic stenosis. Mild or moderate aortic stenosis was present in 454 (7.3%) patients. Patients with aortic stenosis were older, more commonly female, had more comorbidities, and had higher left ventricular ejection fractions compared to patients without aortic stenosis. Mild or moderate aortic stenosis was associated with a higher risk of cardiovascular mortality or readmission for heart or renal failure (unadjusted hazard ratio (HR) 1.32, 95% CI 1.11-1.57). This association was maintained when adjusting for age and sex, but not after comprehensive multivariable adjustment (adjusted HR 1.04, 95% CI 0.82-1.32). CONCLUSION:The presence of mild or moderate aortic stenosis reflects an increased risk profile in patients with acute heart failure, but it is not an independent predictor of poor clinical outcomes.

Aims The optimal dose of diuretics and nitrates for acute heart failure treatment remains uncertain. This study aimed to assess the association between intravenous nitrates and loop diuretics doses within the initial 4 h of emergency department presentation and the number of days alive and out of hospital (NDAOH) through 30 days. Methods This was an ancillary study of the ELISABETH stepped-wedge cluster randomized trial that included 502 acute heart failure patients 75 years or older in 15 French emergency departments. The primary endpoint was the NDAOH at 30 days. The total dose of intravenous nitrates and loop diuretics administered in the initial 4 h were each categorized into three classes: 'no nitrate', '> 0-16', and '> 16 mg' for nitrates and '< 60', '60', and '> 60 mg' for diuretics. Secondary endpoints included 30-day mortality, 30-day hospital readmission, and hospital length of stay in patients alive at 30 days. Generalized linear mixed models were used to examine associations with the endpoints. Results Of 502 patients, the median age was 87 years, with 59% women. The median administered dose within the initial 4 h was 16 mg (5.0; 40.0) for nitrates and 40 mg (40.0; 80.0) for diuretics. The median NDAOH at 30 days was 19 (0.0-24.0). The adjusted ratios of the NDAOH were 0.88 [95% confidence interval (CI): 0.63-1.23] and 0.76 (95% CI: 0.58-1.00) for patients that received 60 and > 60 mg, respectively, compared with patients that received 40 mg or less of diuretics. Compared with patients who did not receive nitrates, the adjusted ratios of the NDAOH were 1.17 (95% CI: 0.82-1.67) and 1.45 (95% CI: 0.90-2.33) for patients who received 1-16 and > 16 mg, respectively. There was no significant association with any of the secondary endpoints. Conclusion In this ancillary analysis, there was no significant association between different doses of diuretics and nitrates with the NDAOH at 30 days. Point estimates and CIs may suggest that the optimal doses are less than 60 mg of diuretics, and more than 16 mg of nitrates in the first 4 h.

Abstract Aims Acute heart failure (AHF) impacts millions globally, with outcomes varying based on socio‐economic status (SES). Methods SES measured by annual household income, years of education and medical insurance coverage. Each patient's income and education level relative to the median or mean, respectively, in the country was calculated, and categorized into tertiles (0, 1 or 2 from lowest to highest). SES scores (0–5) were computed as the sum of these levels plus insurance coverage (0 = no or 1 = yes). Patients' baseline characteristics, outcomes (HF readmission, death and their composite) and the effect of high‐intensity care (HIC) vs. usual care (UC) were examined by SES scores 0–2, 3 and 4–5. Results Lower SES patients, who were younger, predominantly female, Black and non‐European, had fewer comorbidities such as atrial fibrillation, diabetes and ischaemic heart disease and exhibited milder HF, indicated by a lower NYHA class, lower creatinine and higher cholesterol before discharge. Despite having milder HF and less comorbidities, after adjusting for baseline characteristics, patients with higher SES had numerically better outcomes, though differences were not statistically significant. 180‐day hazard ratios (HRs) for HF readmission or death were 0.75 (95% CI 0.48–1.16) for SES scores of 3 and 0.85 (95% CI 0.58–1.23) for scores of 4–5, compared to 0–2. Higher SES patients had numerically better treatment effect from HIC, with HRs of 0.69 for SES 0–2, 0.72 for SES 3 and 0.50 for SES 4–5. Conclusions In this post hoc analysis of the STRONG‐HF study, lower SES was associated with milder acute HF but similar 180‐day outcomes. Higher SES patients benefitted more from HIC.

Increased variability in systolic blood pressure, expressed as the coefficient of variation (BPCoV), is associated with poor cardiovascular outcomes. Variability could be due to episodic non-adherence to medical recommendations in some patients. Reports of targeted attempts to mitigate such variation are lacking. A behavioral intervention targeted at patients with initially high BPCoV may decrease variability. In this single-site, single arm prospective proof-of-concept trial, an electronic health record review identified patients with excessive variability (BPCov>10%). Enrolled patients received a blood pressure monitor and a remotely delivered behavioral intervention for 3 months. The primary outcome was mean blood pressure variability before versus after the intervention. Of 551 initially screened patients, 107 (19.4%) met the BPCoV criteria, and 25 consented (6 females and 19 males, mean age 64.24 years). Average BPCoV for the 6 months pre-enrollment was 12.96 (SD=2.11) compared to 7.02 (SD=3.54) during intervention (p<0.001). Other variability metrics also improved. Sensitivity analyses (different timeframes, using measurements obtained in the clinic vs. home monitor) all showed significant improvement. This proof-of-concept trial suggests that patients with high systolic blood pressure variability can successfully engage in a remotely delivered behavioral intervention, and that such an intervention can reduce such variability. Trial Registration: NCT05814562, ClinicalTrials.gov.

Infective endocarditis (IE) complicated by septic or cardiogenic shock is linked to a marked increase in morbidity and mortality rates. This systematic review and meta-analysis sought to evaluate clinical outcomes, identify prognostic factors, and assess the effects of valve surgical intervention in patients with infective endocarditis complicated by shock. Systematic searches were performed in PubMed, Cochrane Library, and Google Scholar databases, following PRISMA and MOOSE guidelines. Included were observational studies published from January 2015 to May 2025 that reported on adult patients with infective endocarditis complicated by septic or cardiogenic shock. A random-effects model was utilized for data synthesis (restricted maximum likelihood with Hartung–Knapp adjustment), and meta-regression was conducted to assess sources of heterogeneity. Seven observational studies were included (n = 183–255,838). In-hospital mortality among patients with shock was 62.3

Abstract Aims Patients hospitalized with acute heart failure (AHF) treated with a 7 day prednisone course in the CORTAHF pilot trial had a greater improvement in health‐related quality of life (QoL) at Day 7 in both the overall population and in patients with baseline interleukin 6 > 13 pg/mL. This post‐hoc analysis examines the specific QoL domains and the relationship between clinical signs of congestion and QoL. Methods In the CORTAHF pilot trial, patients with AHF and high‐sensitivity C‐reactive protein (hsCRP) > 20 mg/L were randomized 1:1 to once‐daily oral 40 mg prednisone for 7 days plus usual care or usual care alone. Patients completed the EQ‐5D‐5L, including the EQ‐VAS, at baseline and Days 7 and 31. We estimated baseline‐adjusted treatment effects on each of the five QoL dimensions and evaluated the interaction between baseline EQ‐VAS and treatment effect on hsCRP change at Day 7 (the primary endpoint). The correlation between changes in signs of congestion and EQ‐VAS were evaluated. Results Among 100 randomized patients, the improvement in QoL at Day 7 was driven by significant effects on the EQ‐5D‐5L mobility [win odds 1.48, 95% confidence interval (CI) 1.05–2.12] and usual activities (win odds 1.50, 95% CI 1.05–2.20) domains. The treatment effect on 7 day hsCRP change was independent of baseline EQ‐VAS (interaction P = 0.13). Decongestion and EQ‐VAS improvement were correlated (r = −0.528, P < 0.0001). Conclusions In patients with AHF and high hsCRP levels, 7 day burst steroid therapy improved QoL mostly by affecting the mobility and usual activities domains. QoL improvement was correlated with decongestion and may therefore not be a direct effect of steroid therapy, but mediated through improvement in HF symptoms and signs. Inflammatory activation was reduced by prednisone irrespective of baseline EQ‐VAS.

Aims The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. Methods and results We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0-3 h), the load phase (3-6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6-9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (-0.50 [-12.7, 7.4] kg at 2 months, and -0.75 [-15.9, 7.5] kg at 3 months; both p < 0.0001). Conclusions The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors.

AIMS:Serelaxin is recombinant human relaxin-2, a hormone responsible for haemodynamic adaptations and organ protection in pregnancy. In the RELAX-AHF trial, serelaxin demonstrated reductions in cardiac, renal and hepatic damage. In RELAX-AHF-2, organ damage-related biomarkers were assessed in a biomarker substudy. METHODS AND RESULTS:Patients enrolled within 16 h of presentation for heart failure hospitalization were randomized to 48-h infusions of either serelaxin (30 μg/kg/day) or placebo, and plasma samples were obtained at baseline, 2, 5, and 14 days in patients participating in the biomarker substudy. Of the 6545 patients analysed in RELAX-AHF-2, 1020 (15.6%) patients (mean age 72 ± 12 years; 61% male) were enrolled in the biomarker substudy. Compared to placebo, serelaxin decreased percentage change from baseline in troponin T through day 14 (serelaxin +0.2% vs. placebo +40.3%; p = 0.042), as well as creatinine (-0.8% vs. +5.8%; p = 0.002), cystatin C (+3.8% vs. +8.3%; p = 0.016), and uric acid (+0.8% vs. +7.2%; p = 0.0014) at day 2. The decrease of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to day 2 was greater in serelaxin-treated patients (-39.8% vs. -27.6%; p = 0.002). Early changes in NT-proBNP and troponin, but not creatinine, cystatin C and uric acid, were associated with 180-day mortality. In this substudy population, serelaxin did not reduce 180-day cardiovascular death (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.49-1.25; p = 0.30), but significantly reduced worsening heart failure through day 5 (HR 0.55; 95% CI 0.33-0.93; p = 0.027). CONCLUSION:In this substudy, serelaxin decreased plasma concentrations of cardiac, renal and hepatic injury markers. Changes of most of these markers were associated with cardiovascular mortality. In this pre-specified biomarker subgroup, serelaxin did not reduce 180-day cardiovascular mortality but significantly reduced worsening heart failure through day 5.