There is a large spectrum of acute decompensated heart failure presentations resulting from the interaction between an acute precipitant and the patient’s underlying cardiac and non-cardiac conditions. A robust classification scheme at admission is crucial for appropriate triage and targeted treatment of high-risk populations. Such a scheme should incorporate timely actionable items to generate immediate management decisions, including characteristics that suggest life-threatening clinical presentations, the factors that could be favourably modified by in-hospital interventions, such as correctable aetiologies and congestion/hypoperfusion status, and in-hospital trajectories determined by patient responses to inpatient treatment. In-hospital trajectories determine the intensity of escalation therapies and timing for initiation/up-titration of guideline-directed medical treatment. In the long term, some patients experience a progressive downsloping course culminating in advanced heart failure, while others maintain a relatively stable remitting-relapsing trajectory. For future clinical trials, a comprehensive classification scheme integrating in-hospital and long-term trajectories could profoundly affect study design by ensuring interventions are tested in more homogeneous patient populations and facilitating nuanced patient stratification.

Acute heart failure (AHF) is a systemic condition characterised by multiorgan involvement that varies from subclinical to overt organ failure. The liver is particularly vulnerable due to its dual blood supply and sensitivity to haemodynamic and inflammatory disturbances. Abnormal liver function tests are highly prevalent in patients with AHF, reflecting major mechanisms: passive hepatic venous congestion from elevated central venous pressure, hepatocellular ischaemia from low cardiac output, systemic inflammation and poor metabolic status associated with cachexia. In patients with AHF, liver function tests at admission, during hospitalisation and at discharge are independently associated with rehospitalisation, cardiovascular and all-cause mortality. Persistent abnormalities after hospitalisation often reflect incomplete decongestion or irreversible structural liver changes. Therapeutic strategies focus on decongestion, optimisation of cardiac output and medication adjustments to avoid hepatotoxicity. Despite significant advances in understanding cardio-hepatic interactions, major gaps remain, including the lack of standardised definitions, limited mechanistic studies and the underrepresentation of patients with heart failure with preserved ejection fraction in contemporary research. Future research should explore targeted therapies to improve cardiohepatic interactions and patient outcomes.

BACKGROUND AND AIMS:The frequency and prognostic significance of abnormalities in serum magnesium concentrations have not been described in a contemporary heart failure (HF) population. The authors evaluated the prognostic significance of magnesium concentrations in patients with HF with reduced ejection fraction (HFrEF) enrolled in GALACTIC-HF trial. METHODS:GALACTIC-HF was a randomized, double-blind, multicentre, event-driven trial that investigated the efficacy and safety of omecamtiv mecarbil compared with placebo in HF patients with left ventricular ejection fraction ≤ 35%. The primary outcome was the composite of a first worsening HF event or cardiovascular death. RESULTS:A total of 6147 outpatients had baseline serum magnesium data. Of these, 1082 (17.6%) had magnesium concentrations below .75 mmol/L, 4410 (71.7%) had concentrations within the normal range, and 655 (10.7%) had concentrations above .95 mmol/L. The incidence rate (per 100 person-years) for the primary composite outcome was highest in patients with hypermagnesaemia (34.9, 95% confidence interval 31.2-39.0), while rates were similar between those with hypomagnesaemia (21.5, 19.4-23.8), and normal magnesium (20.9, 19.9-22.0). Similar trends were observed for the components of the primary outcome and all-cause death. The incidence rate of sudden death and ventricular tachyarrhythmia did not differ among the three magnesium groups, but the risk of death from worsening HF was highest in patients with hypermagnesaemia. CONCLUSIONS:In GALACTIC-HF, 10.7% of outpatients with HFrEF had hypermagnesaemia, which was associated with a higher risk of the primary outcome compared with normal magnesium concentrations. Abnormal magnesium levels were not associated with a higher risk of sudden death or ventricular tachyarrhythmias. These findings do not support routine correction of hypomagnesaemia.

ABSTRACT Introduction and Methods Cancer therapy–related cardiac dysfunction (CTRCD) is a well established and potentially life‐threatening complication of contemporary oncologic treatment. Although comprehensive cardio‐oncology guidelines have been developed, their integration into routine hematology and oncology practice remains inconsistent. This consensus statement, developed by a multidisciplinary panel of cardio‐oncology experts, aims to provide practical, case‐based guidance to help oncology providers recognize, assess, and manage CTRCD across a spectrum of malignancies and cardiovascular presentations. Clinical Scenarios and Discussion We present representative clinical scenarios that illustrate real‐world challenges in cardio‐oncology and apply evidence‐based recommendations from current guidelines, including those from the European Society of Cardiology (ESC) and the International Cardio‐Oncology Society (ICOS)—to support informed decision‐making. Key areas of focus include baseline cardiovascular risk stratification prior to initiating potentially cardiotoxic therapies, with an emphasis on biomarker and imaging surveillance strategies tailored to individual risk profiles. Also, this document outlines the application of guideline‐directed medical therapy (GDMT) for cancer patients with heart failure. Conclusion By offering a structured, user‐friendly framework, this document seeks to bridge the implementation gap between oncology and cardiology disciplines. Our goal is to equip oncology providers with accessible tools that facilitate early recognition, consistent surveillance, and timely referral, thereby preserving cancer treatment intensity while minimizing cardiovascular morbidity.

This clinical consensus statement revisits the role of left ventricular ejection fraction (LVEF) as a measurement of cardiac function, a prognostic marker and a major criterion to classify patients with heart failure, and gives new advice for clinical practice. Heart failure is traditionally classified on the basis of LVEF thresholds and this has major implications for treatment recommendations. However, the reproducibility of LVEF measurement is poor and its prognostic and diagnostic value lessens when it is above 45%, with no relationship with the severity of either cardiac dysfunction or outcomes at higher values. These limitations dictate the need for a more comprehensive approach to classify and assess heart failure focusing more on the trajectory of LVEF rather than to its absolute value. Furthermore, the assessment of LVEF is not required for the initiation of treatments like sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists and diuretics in patients with suspected de novo heart failure and elevated N-terminal pro-B-type natriuretic peptide levels. Future research utilizing advanced imaging techniques and biomarkers which can better characterize myocardial structure, metabolism and performance may facilitate the identification of alternative therapeutic targets and better ways to monitor heart failure therapies across the entire spectrum of LVEF.

Background There is limited published information on outcome adjudication in heart failure (HF) trials, particularly in heart failure with preserved ejection fraction (HFpEF). Objectives The study sought to compare investigator reports with clinical events committee (CEC) adjudication and assess the impact of the SCTI (Standardized Data Collection for Cardiovascular Trials) criteria. Methods In the EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction) trial, we compared investigator reports with CEC for concordance, treatment effect on primary composite outcome events and components (first event primary heart failure hospitalization [HHF] or cardiovascular [CV] mortality), prognosis after first HHF, total HHF, and trial duration with and without SCTI criteria. Results The CEC confirmed 67.4% investigator-reported events for the primary outcome (CV mortality 82.7%, HHF 66.3%). The HR for treatment effect did not differ between adjudication methods for the primary outcome: investigator reports (HR: 0.77; 95% CI: 0.69-0.87), CEC (HR: 0.79; 95% CI: 0.69-0.90), its components, or total HHFs. The prognosis after the first HHF for all-cause mortality and CV mortality also did not differ between investigator reports and the CEC, nor did investigator reports and HHFs with a different CEC cause. SCTI criteria were present in 92% of CEC HHFs with a similar treatment effect to non-SCTI criteria. The investigator-reported primary events reached the protocol target number 6 months earlier than the CEC (7 months with full SCTI criteria). Conclusions Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation in HFpEF. The use of granular (SCTI) criteria did not improve trial performance. Our data suggest that a broader definition of an HHF event could be particularly beneficial in HFpEF clinical trials. (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction; NCT03057951).

BACKGROUND:Patients with heart failure with reduced ejection fraction (HFrEF) have a heightened stroke risk. However, stroke as an endpoint in heart failure trials remains under-reported. OBJECTIVES:The authors sought to define the incidence, characteristics, predictors, modifier treatments, and prognostic impact of stroke in patients with HFrEF who were enrolled in randomized controlled trials (RCTs). METHODS:The authors systematically reviewed MEDLINE for RCTs of pharmacologic and nonpharmacologic treatments in HFrEF. The annualized stroke incidence was the primary outcome. Subgroup analyses and meta-regressions were performed to determine the baseline modulating characteristics and to assess the association of stroke with other clinical outcomes. RESULTS:Of 7,104 records, 188 RCTs fulfilled inclusion criteria for the systematic review. Of these, 158 studies (84.0%) did not report stroke outcomes and were excluded from the meta-analysis, leading to a final cohort of 30 studies, with 61 arms and 75,327 patients. Stroke incidence was 1.1% (95% CI: 0.9%-1.3%; I2: 74%) with high heterogeneity across trials. Higher NYHA functional class (P < 0.001), lower systolic blood pressure (P < 0.001), diuretic use (P = 0.001), and diabetes (P < 0.001) were associated with stroke. No association of renin-angiotensin-aldosterone inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and transcatheter mitral valve replacement with stroke was observed. Stroke was associated with higher risk of all-cause and cardiovascular mortality, heart failure hospitalization and acute coronary syndromes (P < 0.001 for all). CONCLUSIONS:Stroke was reported in a vast minority of HFrEF RCTs with heterogeneous definitions and no reference to underlying mechanisms. Despite under-reporting, stroke incidence is non-negligible. Stroke is associated with HFrEF-specific characteristics and outcomes, whereas it is not impacted by current HFrEF treatments. There is a need for dedicated research into preventive strategies and effective treatments to address this debilitating and deadly comorbidity. (Stroke Events in Heart Failure With Reduced Ejection Fraction-A Systematic Review and Meta-Analysis of Pharmacologic Randomized Trial; CRD42023418422).

Perturbations in kidney function are frequently encountered in heart failure (HF) across its spectrum in both chronic and acute settings with distinct implications for patient management and prognosis. Lack of consensus on the threshold for clinically meaningful changes in kidney function has led to heterogeneity in the clinical characteristics and background therapies of individuals enrolled in clinical trials, and in multiple aspects of trial design. A meaningful and collaborative interaction among the disciplines of cardiology and nephrology, clinical trialists, industry sponsors, and regulatory agencies is vital to the development of standardized definitions of changes in kidney function across HF settings. To achieve this critically important objective, the Heart Failure Collaboratory assembled experts in HF and nephrology, including key stakeholders in the U.S. Food and Drug Administration and industry, with the goal of developing initial recommendations for improved standardization of design and conduct of clinical trials in HF. Recommendations included how and when to measure baseline and changes in kidney function, discouraging the use of the term “acute kidney injury,” and the consideration of urinary markers in the assessment of kidney function.

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.

Background: Lactate dehydrogenase (LDH) is a cytoplasmic enzyme found in most cells that catalyses the forward and backwards conversion of pyruvate to lactate. Tissue LDH concentrations are hundreds of times higher than those in plasma, and cellular damage results in elevated circulating concentrations of LDH. Consequently, increased LDH levels are a non-specific measure of cellular injury in critically ill patients, and are a poor prognostic finding in these individuals. However, whether LDH levels are also prognostically important in heart failure (HF) is unknown. Hypothesis: LDH concentration is associated with fatal and non-fatal outcomes in patients with HF and reduced ejection fraction (HFrEF). Methods: GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a randomized, double-blind, multicenter, event-driven trial that evaluated the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil (OM) versus placebo in 8,232 patients with HFrEF. The primary outcome was a time-to-first-event analysis of a composite of worsening HF (hospitalization or urgent visit) or cardiovascular death. We assessed associations between baseline LDH and clinical outcomes. Results: In GALACTIC-HF, baseline LDH data were available for 8,179 patients, including 6,138 outpatients. Among outpatients, patients with higher LDH were more frequently female and had worse HF status. They were also more likely to have an ischemic etiology and elevated serum creatinine, liver enzymes, creatine kinase, NT-proBNP, and troponin I. Compared to patients in the lowest LDH quartile Q1 (LDH 155[144-163](U/L)), the hazard ratios (HR) (95% CI) for the primary outcome were Q2 (LDH 183[177-188]): 1.15 (1.02–1.31), Q3 (LDH 207[201-215]): 1.39 (1.23–1.58), and Q4 (LDH 253[236-280]): 1.84 (1.62–2.08), respectively. Even after adjustment for the aforementioned biomarkers and other prognostic variables, elevated LDH remained independently associated with higher HR: Q2 (1.14, 1.00-1.31); Q3 (1.29, 1.13-1.47); and Q4 (1.51, 1.32-1.73). Similar trends were seen for the components of the primary outcome and all-cause mortality ( Figure ). The treatment effect of OM compared with placebo on clinical outcomes was not modified by LDH subgroups. Conclusions: In GALACTIC-HF, higher LDH levels were independently associated with increased risk of fatal and non-fatal outcomes in patients with HFrEF.

Background Older age is associated with a high prevalence of comorbidities and worse cardiovascular (CV) outcomes in patients with heart failure (HF) with reduced ejection fraction. Omecamtiv mecarbil, a selective cardiac myosin activator, exerts minimal effects on blood pressure and heart rate and has limited extracardiac activity, and thus it may be well-tolerated in older individuals. The safety profile and clinical benefits of omecamtiv mecarbil across the age spectrum remain uncertain. Objectives This study aims to assess CV outcomes, treatment response, and tolerability to omecamtiv mecarbil according to age in patients enrolled in the GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) trial. Methods GALACTIC-HF was a randomized, global, double-blind clinical trial testing omecamtiv mecarbil vs placebo in patients with symptomatic HF with reduced ejection fraction. Key eligibility criteria included an age between 18-85 years, elevated natriuretic peptides, and a left ventricular ejection fraction (LVEF) ≤35%. We examined the treatment effect of omecamtiv mecarbil vs placebo for the primary endpoint of CV death or first HF event (hospitalization or urgent visit for HF) in both the overall population and the severe HF subgroup (LVEF ≤30%, NYHA functional class III/IV, HF hospitalization within 6 months), as well as safety outcomes according to prespecified age groups (<65 or ≥65 years). Results A total of 8,232 patients (age 64.5 ± 11.4 years, 54.5% ≥65 years, 21% female) were included. The rate of the primary outcome was 21.4 per 100 patient years (py) in those <65 years of age and 28.8 per 100 py in those ≥65 years of age. The treatment effect of omecamtiv mecarbil for the primary outcome (HR: 0.92 [95% CI: 0.86-0.99]; P = 0.03) was consistent in age groups (Pinteraction = 0.76) and irrespective of age as a continuous variable (Pinteraction = 0.19, after adjusting for treatment interactions with known modifiers of the effects of omecamtiv mecarbil: LVEF and baseline atrial fibrillation status). In patients with severe HF, omecamtiv mecarbil significantly reduced the risk of the primary outcome in both patients <65 years of age (HR: 0.77 [95% CI: 0.64-0.92]) and those ≥65 years of age (HR: 0.83 [95% CI: 0.71-0.97]; Pinteraction = 0.47). The safety profile of omecamtiv mecarbil was consistent irrespective of age (Pinteraction > 0.05 for all). Conclusions In GALACTIC-HF, older individuals were well-represented and faced higher risks of CV events. Treatment with omecamtiv mecarbil was safe irrespective of age and reduced the risk of CV death or first HF event across the age spectrum, especially in those with severe HF. (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure [GALACTIC-HF]; NCT02929329.)

Background: Although it is known that increased urinary protein excretion is predictive of both end-stage kidney disease and cardiovascular (CV) outcomes, laboratory quantification of urinary albumin is rarely carried out in CV practice. However, dipstick urine testing is often performed in primary and secondary care, although the results may not be routinely inspected or acted upon. Given the renewed emphasis on CV-metabolic-kidney overlap in medicine, we have examined the prognostic value of semiquantitative urine dipstick protein (DP) assessments in patients with heart failure and reduced ejection fraction (HFrEF). Hypothesis: DP predicts clinical outcomes and enables risk stratification in HFrEF. Methods: GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a randomized, double-blind, multicenter, event-driven trial that evaluated the efficacy and safety of the cardiac myosin activator omecamtiv mecarbil (OM) versus placebo in 8,232 patients with HFrEF. The primary outcome was a time-to-first-event analysis of a composite of worsening HF (hospitalization or urgent visit) or CV death. We assessed associations between baseline DP and clinical outcomes. Results: Baseline DP data were available for 7,790 patients, of whom 5,910 (75.9%) had a negative test or trace proteinuria, 995 (12.8%) had 1+, and 885 (11.4%) had ≥2+ proteinuria. Patients with DP ≥2+ were younger, more often were in NYHA class III/IV and had diabetes, had higher systolic blood pressure, and lower eGFR (Figure). Mean LVEF was 27% across all DP groups. The rate of the primary outcome (per 100 person-years) increased significantly with increasing DP: negative/trace (21.8, 95% confidential interval [CI] 20.8–22.7); 1+ (34.8, 31.8–38.0); and ≥2+ (38.1, 34.7–41.9). Similar trends were seen for the components of the primary outcome and all cause mortality (Figure). Although individual hazard ratios were partially attenuated after adjustment for recognized prognostic variables, including NT-proBNP and eGFR, higher DP remained significantly associated with worse outcomes. The treatment effect of OM compared with placebo on clinical outcomes was not modified by DP category. Conclusions: DP is a simple inexpensive test with prognostic value in HFrEF.

Steroidal mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, have demonstrated substantial benefits in randomized controlled trials for patients with heart failure with reduced ejection fraction. However, their effectiveness in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction remains uncertain, and the implementation of this class has remained low, in part due to its side effects and tolerability profile. Emerging therapies that target the mineralocorticoid receptor and/or the production of aldosterone may offer alternative strategies to treat the aldosterone-mineralocorticoid receptor axis. For instance, the nonsteroidal MRA finerenone has shown efficacy in reducing cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease, as well as decreasing the combined endpoint of cardiovascular death and heart failure hospitalizations in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction populations. Large-scale, direct comparative outcome studies are currently lacking that compare steroidal MRAs vs emerging therapies. This review critically assesses the structural and mechanistic distinctions between nonsteroidal and nonsteroidal MRAs as well as mineralocorticoid receptor modulators and aldosterone synthase inhibitors; summarizes available evidence across heart failure, diabetes, and chronic kidney disease populations; and highlights ongoing and forthcoming research aimed at addressing key unanswered questions in this rapidly evolving therapeutic field.

AIMS:Empagliflozin improves outcomes in acute heart failure (AHF). Patients with AHF and low blood pressure (BP) have poor prognosis. Whether empagliflozin is effective and safe in patients with AHF and low BP is currently unknown. The aim of this study was to assess the efficacy and safety of empagliflozin (vs. placebo) in patients with low BP - either systolic BP (SBP) <110 mmHg or diastolic BP (DBP) <70 mmHg - at randomization. METHODS AND RESULTS:EMPULSE included 530 patients with AHF followed for 90 days. The primary outcome was a hierarchical composite of all-cause mortality, HF events, and Kansas City Cardiomyopathy Questionnaire total symptom score changes at 90 days tested using the win ratio (WR). Patients were required to have SBP ≥100 mmHg for randomization. A total of 131 (25%) patients had SBP <110 mmHg and 190 (36%) DBP <70 mmHg. In placebo, low BP was associated with more clinical and adverse events. Compared to placebo, BP changes with empagliflozin were of small magnitude (-2 to 2 mmHg), not reaching statistical significance. Patients presenting with low BP increased their BP, on average, throughout the 90-day follow-up, regardless of treatment group. Empagliflozin (vs. placebo) improved clinical outcomes regardless of BP at randomization, potentially with a larger magnitude of effect in patients presenting with low DBP at randomization: primary outcome WR = 1.48, 95% confidence interval (CI) 1.15-1.90, p = 0.0025; WR = 1.23, 95% CI 0.94-1.60 in DBP ≥70 mmHg and WR = 2.11, 95% CI 1.46-3.04 in DBP < 70 mmHg (interaction p = 0.02). CONCLUSIONS:Patients admitted for AHF with low BP had a higher risk of clinical events. Empagliflozin did not lower BP more than placebo and was effective and safe irrespective of BP. Empagliflozin should be considered for the treatment of AHF patients even when presenting with low BP.

Atrial fibrillation (AF) and heart failure (HF) are common cardiovascular conditions that frequently coexist. Among patients with HF, more than one-half also have AF. Both are associated with significant morbidity and mortality. Moreover, the prevalence of each is increasing globally, and this trend is expected to continue owing to an aging population and increased life expectancy. Diagnosis of AF in a patient with HF is associated with greater symptom burden, more frequent hospitalizations, and a worse prognosis. Guideline-directed medical therapy (GDMT) for HF can affect the incidence of AF. Once present, AF can influence the efficacy of some components of GDMT for HF. In this review, we discuss the effect of GDMT for HF across the spectrum of ejection fraction on prevention of AF as well as the benefit of GDMT in patients with vs without AF.