Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Carbohydrate antigen 125 on epicardial fat and its association with local inflammation and fibrosis-related markers.

BACKGROUND: Carbohydrate antigen 125 (CA125) is a proteolytic fragment of MUC-16 that is increased in heart failure (HF) and associated with inflammation, fluid overload, and worse adverse events. Our main objective was to study the expression of CA125 on epicardium and its association with inflammation, adipogenesis, and fibrosis. METHODS: Epicardial fat biopsies and blood were obtained from 151 non-selected patients undergoing open heart surgery. Immunohistochemistry, ELISA, or real-time PCR were used for analyzing protein or mRNA expression levels of CA125 and markers of inflammatory cells, fibroblasts, and adipocytes. Epithelial or stromal cells from epicardium were isolated and cultured to identify CA125 and its association with the adipogenesis and fibrosis pathways, respectively. RESULTS: The median age was 71 (63-74) years, 106 patients (70%) were male, and 62 (41%) had an established diagnosis of HF before surgery. The slice of epicardial fat biopsy determined a positive and colorimetric staining on the epithelial layer after incubating with the CA125 M11 antibody, providing the first description of CA125 expression in the human epicardium. Epicardial CA125 showed a strong and positive correlation with markers of inflammation and fibrosis in the epicardial fat tissue while exhibiting a negative correlation with markers of the adipogenesis pathway. This relationship remained significant after adjusting for potential confounders such as a prior HF diagnosis and plasma CA125 levels. CONCLUSION: Epicardial cells express CA125, which is positively associated with inflammatory and fibroblast markers in epicardial adipose tissue. These results suggest that CA125 may be biologically involved in HF progression (transition from adipogenesis to fibrosis).

Non-invasive heart failure monitoring: leveraging smart scales and digital biomarkers to improve heart failure outcomes.

Heart failure (HF) is a significant global concern, impacting patient morbidity, mortality, and healthcare costs. Guideline-directed medical therapy and various preventive measures have proven effective in improving clinical outcomes and reducing HF hospitalizations. Recent data indicates that remote HF monitoring facilitates early detection of HF decompensation by observing upstream events and parameters before clinical signs and symptoms manifest. Moreover, these innovative devices have been shown to decrease unnecessary HF hospitalizations and, in some cases, provide predictive insights before an actual HF incident. In this review, we aim to explore the data regarding smart scales and digital biomarkers and summarize both FDA-approved devices and emerging technologies by assessing their clinical utility, mechanism of HF decompensation detection, and ongoing trials. Furthermore, we also discuss the future trend of integrating these devices into routine clinical practice to improve patient clinical outcomes.

Lower heart rate in patients with acute heart failure: the role of left ventricular ejection fraction.

BACKGROUND: The clinical impact of heart rate (HR) in heart failure with preserved ejection fraction (HFpEF) is a matter of debate. Among those with HFpEF, chronotropic incompetence (CI) has emerged as a pathophysiological mechanism linked to the severity of the disease. In this study, we sought to evaluate whether admission heart rate in acute heart failure differs along left ventricular ejection fraction (LVEF). METHODS: We included retrospectively 3,712 consecutive patients admitted for acute heart failure (AHF) in the Cardiology department of a third level center. HR values were assessed at presentation. LVEF was assessed by transthoracic echocardiogram during the index admission and stratified into four categories: reduced ejection fraction (≤40%), mildly reduced ejection fraction (41-49%), preserved ejection fraction (50-64%) and supranormal ejection fraction (≥65%). The association between HR and LVEF was assessed by multivariate linear and multinomial regression analyses. RESULTS: The mean age of the sample was 73,9 ± 11.3 years, 1,734 (47,4%) were women, and 1,214 (33,2%), 570 (15,6%), 1,229 (33,6%) and 648 (17,7%) patients showed LVEF ≤40%, 41-49%, 50-64%, and ≥65% respectively. The median HR at admission was 95 (IQR 78-120) beats per minute and 1,653 were on atrial fibrillation (45.2%). There was an inverse relationship between HR at admission and LVEF. Lower HR was significantly associated with a higher LVEF in the whole sample (p < 0,001). This inverse relationship was found in sinus rhythm but not in patients with atrial fibrillation. CONCLUSION: HR at admission for AHF is a predictor of LVEF but only in patients with sinus rhythm.

Combinational Diuretics in Heart Failure.

PURPOSE OF REVIEW: Diuretics are the cornerstone therapy for acute heart failure (HF) and congestion. Patients chronically exposed to loop diuretics may develop diuretic resistance as a consequence of nephron remodelling, and the combination of diuretics will be necessary to improve diuretic response and achieve decongestion. This review integrates data from recent research and offers a practical approach to current pharmacologic therapies to manage congestion in HF with a focus on combinational therapy. RECENT FINDINGS: Until recently, combined diuretic treatment was based on observational studies and expert opinion. Recent evidence from clinical trials has shown that combined diuretic treatment can be started earlier without escalating the doses of loop diuretics with an adequate safety profile. Diuretic combination is a promising strategy for overcoming diuretic resistance in HF. Further studies aiming to get more insights into the pathophysiology of diuretic resistance and large clinical trials confirming the safety and efficacy over standard diuretics regimens are warranted.

Sodium-glucose Co-transporter 2 Inhibitors in Acute Heart Failure: A Review of the Available Evidence and Practical Guidance on Clinical Use.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors were initially conceived as glucose-lowering agents. However, striking renal and cardiovascular benefits were observed in type 2 diabetes trials. This led to evaluate it in dedicated studies in chronic heart failure (HF) and chronic kidney disease, which also showed remarkable clinical results. Given this findings, and taking into account the multiple mechanisms of action, the use of SGLT2 inhibitors in acute heart failure seemed promising. Sotagliflozin was the first SGLT2 inhibitor to reduce heart failure hospitalizations within the acute setting in the SOLOIST-WHF trial. Only type 2 diabetes patients were included, with a preserved and reduced ejection fraction. In slightly less than half of the cohort, this medication was started when the diuretic therapy was transitioned from intravenous to oral, during the hospital admission. In the rest of the patients, sotagliflozin was started early after discharge. Empagliflozin proved to be safe, well-tolerated, increased diuresis, and reduced a combined clinical endpoint (worsening HF, rehospitalization for HF, or death at 60 days) when administered within the first 24 hours of an acute heart failure hospitalization in the EMPA-RESPONSE-AHF trial. More recently, empagliflozin showed a reduction in a composite primary endpoint of death, heart failure events, and quality of life compared to placebo in the EMPULSE trial. Empagliflozin was started after the initial stabilization phase, but while patients were still admitted and receiving intravenous loop diuretics. Less than half of the patients were diabetic and two-thirds had a left ventricular ejection fraction below 40%. Dapagliflozin is currently being tested in the DAPA ACT HF-TIMI 68 trial, which plans to enroll 2400 patients admitted with acute heart failure and reduced ejection fraction. We envision SGLT2 inhibitors as a useful tool in acute heart failure syndrome given the additive diuretic effect, and minimal impact on blood pressure, kidney function, and electrolytes. Its dosage schedule is simple and can help initiation and tolerance of other medical therapy. However, there is an increased risk of genital infections and euglycaemic ketoacidosis. Notwithstanding, once critically ill and fasting patients are excluded, early administration of SGLT2 inhibitors is safe. This review summarizes the development of SGLT2 inhibitors and the available evidence supporting their use during an acute heart failure admission. We also propose a practical guideline for in-hospital initiation and monitoring.

Effect of SGLT2 inhibitors on anemia and their possible clinical implications.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. Since the first studies with these drugs, an initial increase in hemoglobin/hematocrit levels was observed, which was attributed to an increase in hemoconcentration associated with its diuretic effect, although it was early appearent that these drugs increased erythropoietin levels and erythropoiesis, and improved iron metabolism. Mediation studies found that the increase in hemoglobin was strongly associated with the cardiorenal benefits of these drugs. In this review, we discuss the mechanisms for improving erythropoiesis and the implication of the increase in hemoglobin on the cardiorenal prognostic benefit of these drugs.

Kidney Replacement Therapies and Ultrafiltration in Cardiorenal Syndrome.

BACKGROUND: Some patients with cardiorenal syndrome 1 and congestion exhibit resistance to diuretics. This scenario complicates management and is associated with a worse prognosis. In some cases, rescue treatment may be considered by starting kidney replacement therapies or ultrafiltration. This decision is complex and necessitates a profound understanding of these techniques and the pathophysiology of this syndrome. These modalities are classified into continuous, intermittent, and ultrafiltration therapies, each with its own advantages and disadvantages that are pertinent in selecting the optimal treatment. SUMMARY: In patients with diuretic-resistant cardiorenal syndrome, extracorporeal ultrafiltration and kidney replacement therapies have the potential to relieve congestion, restore the neurohormonal system, and improve quality of life. KEY MESSAGES: (i) In cardiorenal syndrome, the resistance to diuretics is common. (ii) Extracorporeal ultrafiltration and renal replacement therapies are rescue options that may improve the management of these patients. (iii) Better understanding of these modalities will help the development of new devices which are friendlier, safer, and more affordable for patients in these clinical settings.

Unraveling the Mechanisms Behind Exercise Intolerance and Recovery in Long COVID.

BACKGROUND: Patients suffering from long COVID may exhibit autonomic dysregulation. However, the association between autonomic dysregulation and exercise intolerance and the impact of therapeutic interventions on its modulation remains unclear. This study investigated the relationship between heart rate recovery at the first minute (HRR1), a proxy for autonomic imbalance, and exercise intolerance in patients with long COVID. Additionally, the study aimed to assess the effects of a 12-week home-based inspiratory muscle training program on autonomic modulation in this patient population. METHODS: This study is a post hoc subanalysis of a randomized trial in which 26 patients with long COVID were randomly assigned to receive either a 12-week inspiratory muscle training program or usual care alone (NCT05279430). The data were analyzed using Pearson's correlation and linear mixed regression analysis. RESULTS: The mean age was 50.4 ± 12.2 years, and 11 (42.3%) were women. Baseline HRR1 was significantly correlated with maximal functional capacity (peakVO2) (r = 0.402, P = .041). Patients with lower baseline HRR1 (≤22 bpm) exhibited higher resting heart rates and lower peakVO2. Inspiratory muscle training led to a more substantial increase in peakVO2 in patients with lower HRR1 at baseline (P = .019). Additionally, a significant improvement in HRR1 was observed in the IMT group compared to the usual care group after 12-week (Δ +9.39, 95% CI = 2.4-16.4, P = .010). CONCLUSION: Lower baseline HRR1 is associated with exercise intolerance in long COVID patients and may serve as a valuable criterion for identifying individuals likely to benefit more from a home-based inspiratory muscle training program.

Histopathology of congestive nephropathy: a case description and literature review.

Congestive nephropathy is an underappreciated manifestation of cardiorenal syndrome and is characterized by a potentially reversible kidney dysfunction caused by a reduced renal venous outflow secondary to right-sided heart failure or intra-abdominal hypertension. To date, the histological diagnostic criteria for congestive nephropathy have not been defined. We herein report a case of acute renal dysfunction following cardiac allograft failure and present a review of the relevant literature to elucidate the current understanding of the disease. Our case demonstrated that congestion-driven nephropathy may be histopathologically characterized by markedly dilated veins and peritubular capillaries, focally accentuated low-grade acute tubular damage, small areas of interstitial fibrosis, and tubular atrophy on a background of normal glomeruli and predominantly normal tubular cell differentiation.

Improvement in left atrial strain following ferric carboxymaltose in heart failure: an analysis of the Myocardial-IRON trial.

AIMS: Iron deficiency (ID) is associated with an impaired cardiac function and remodelling in heart failure (HF). Treatment with ferric carboxymaltose (FCM) has been showed recently to improve biventricular systolic function and ventricular strain parameters in patients with HF with reduced ejection fraction and ID, but there is no evidence on the benefit of FCM on the left atrium (LA). In this study, we aimed to evaluate the effect of FCM on LA longitudinal strain (LA-LS). METHODS AND RESULTS: This is a post hoc subanalysis of a double-blind, placebo-controlled, randomized clinical trial that enrolled 53 ambulatory patients with HF, left ventricular ejection fraction (LVEF) < 50%, and ID [Myocardial-IRON trial (NCT03398681)], treated with FCM or placebo. Cardiac magnetic resonance-featured tracking (CMR-FT) strain changes were evaluated before and 7 and 30 days after randomization using linear mixed regression analysis. The median age of the sample was 68 years (interquartile range: 64-76), and 20 (69%) were men. Mean ± standard deviation of LVEF was 39 ± 11%, and most (97%) were in stable New York Heart Association class II. At baseline, mean LA-LS was -8.9 ± 3.5%. At 30 days, and compared with placebo, LA-LS significantly improved in those allocated to FCM treatment arm (LA-LS = -12.0 ± 0.5 and -8.5 ± 0.6, respectively; - ∆ 3.55%, P < 0.001). CONCLUSIONS: In patients with stable HF, LVEF < 50%, and ID, treatment with FCM was associated with short-term improvements in LA-LS assessed by CMR-FT. Future works should assess the potential benefit of iron repletion on LA function.

Exercise training response according to baseline ferrokinetics in heart failure with preserved ejection fraction: A substudy of the TRAINING-HF trial.

BACKGROUND: Iron deficiency (ID) is associated with impaired functional capacity in patients with heart failure (HF), even in those with preserved ejection fraction (HFpEF). This study aimed to evaluate the effect of baseline ferrokinetics on peak oxygen consumption (peakVO2) improvement after a 12-week physical therapy programme in patients with stable HFpEF. METHODS: This study is a post-hoc sub-analysis of a randomized clinical trial in which 59 stable patients with HFpEF were randomized to receive a 12-week programme of inspiratory muscle training (IMT), functional electrical stimulation (FES), IMT + FES or usual care (UC) to evaluate change in peakVO2 (NCT02638961). Serum ferritin and transferrin saturation (TSAT) determinations were assessed at baseline. ID was defined as ferritin <100 ng/mL and/or TSAT <20% if ferritin was within 100-299 ng/mL. We used a linear mixed regression model to analyse between-treatment changes in peakVO2 across ferrokinetics status at 12 and 24 weeks. RESULTS: The mean age was 74 ± 9 years, and 36 (61%) had ID. The mean of peakVO2 was 9.9 ± 2.5 mL/kg/min. The median of ferritin and transferrin saturation (TSAT) was 91 (50-181) ng/mL and 23% (16-30), respectively. A total of 52 patients completed the trial (13 patients per arm). Compared with those patients on UC, patients allocated to any of the active arms showed less improvement in peak VO2 when they showed ID (P-value for interaction <0.001), lower values of ferritin (P-value for interaction <0.001), or TSAT (P-value for interaction <0.001). CONCLUSIONS: Ferrokinetics status plays an essential role in modifying the aerobic capacity response to physical therapies in patients with HFpEF. Further studies are required to confirm these findings.

In-hospital versus after-discharge complete revascularization in patients with ST segment elevation myocardial infarction and multivessel disease. REVIVA-ST trial.

INTRODUCTION: Complete revascularization (CR) in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), is associated with a reduction in major adverse cardiovascular events (MACE). However, there is uncertainty about whether nonculprit-lesion revascularization should be performed, during index hospitalization or delayed, especially regarding health care resources utilization. In this study, we aimed to evaluate the impact of in-hospital nonculprit-lesion revascularization vs. delayed (after discharge) revascularization on the length of index hospitalization. METHODS: In this single-center study, we randomly assigned patients with STEMI and MVD who underwent successful culprit-lesion PCI to a strategy of either CR during in-hospital admission or a delayed CR after discharge. The first primary endpoint was the length of hospital stay. The second endpoint was the composite of cardiovascular death, myocardial infarction or ischemia-driven revascularization at 12 months (MACE). RESULTS: From January 2018 to December 2022, we enrolled 258 patients (131 allocated to CR during in-hospital admission and 127 to an after-discharge CR). We found a significant reduction in the length of hospital stay in those assigned to after-discharge CR strategy [4 days (3-5) versus 7 days (5-9); p = 0.001]. At 12-month of follow-up, no differences were found in the occurrence of MACE, 7 (5.34%) patients in in-hospital CR and 4 (3.15%) in after-discharge CR strategy; (hazard ratio, 0.59; 95% confidence interval, 0.17 to 2.02; p = 0.397). CONCLUSIONS: In STEMI patients with MVD, an after-discharge CR strategy reduces the length of index hospitalization without an increased risk of MACE after 12 months of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04743154.

Biomarkers of lung congestion and injury in acute heart failure.

Acute heart failure (AHF) classification and management are primarily based on lung congestion and/or hypoperfusion. The quantification of the vascular and tissue lung damage is not standard practice though biomarkers of lung injury may play a relevant role in this context. Haemodynamic stress promotes alveolar and vascular derangement with loss of functional units, impaired lung capillary permeability and fluid swelling. This culminates in a remodelling process with activation of inflammatory and cytokines pathways. Four families of lung surfactant proteins (i.e., SP-A, SP-B, SP-C, and SP-D), essential for the membrane biology and integrity are released by alveolar type II pneumocites. With deregulation of fluid handling and gas exchange pathways, SPs become sensitive markers of lung injury. We report the pathobiology of lung damage; the pathophysiological and clinical implications of alveolar SPs along with the newest evidence for some classical HF biomarkers that have also shown to reflect a vascular and/or a tissue lung-related activity.

Effect of paced heart rate on quality of life and natriuretic peptides for stage B or C heart failure with preserved ejection fraction: A secondary analysis of the myPACE trial.

AIM: Emerging evidence suggests a beneficial effect of higher heart rates in some patients with heart failure with preserved ejection fraction (HFpEF). This study aimed to evaluate the impact of higher backup pacing rates in HFpEF patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony across left ventricular (LV) volumes and LV ejection fraction (LVEF). METHODS AND RESULTS: This is a post-hoc analysis of the myPACE clinical trial that evaluated the effects of personalized accelerated pacing setting (myPACE) versus standard of care on changes in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, N-terminal pro-brain natriuretic peptide (NT-proBNP), pacemaker-detected activity levels, and atrial fibrillation (AF) burden in patients with HFpEF with preexisting pacemakers. Between-treatment comparisons were performed using linear regression models adjusting for the baseline value of the exposure (ANCOVA design). This study included 93 patients with pre-trial transthoracic echocardiograms available (usual care n = 49; myPACE n = 44). NT-proBNP levels and MLHFQ scores improved in a higher magnitude in the myPACE group at lower indexed LV end-diastolic volumes (iLVEDV) (NT-proBNP-iLVEDV interaction p = 0.006; MLHFQ-iLVEDV interaction p = 0.068). In addition, personalized accelerated pacing led to improved changes in activity levels and NT-proBNP, especially at higher LVEF (activity levels-LVEF interaction p = 0.009; NT-proBNP-LVEF interaction p = 0.058). No evidence of heterogeneity was found across LV volumes or LVEF for pacemaker-detected AF burden. CONCLUSIONS: In the post-hoc analysis of the myPACE trial, we observed that the benefits of a personalized accelerated backup pacing on MLHFQ score, NT-proBNP, and pacemaker-detected activity levels appear to be more pronounced in patients with smaller iLVEDV and higher LVEF.

Urinary Cell Cycle Arrest Biomarkers and Diuretic Efficiency in Acute Heart Failure.

INTRODUCTION: This study aimed to evaluate the association between the NephroCheck® test AKIRisk® score, diuretic efficiency (DE), and the odds of worsening kidney function (WKF) within the first 72 h of admission in patients hospitalized for acute heart failure (AHF). METHODS: The study prospectively enrolled 125 patients admitted with AHF. NephroCheck® test was obtained within the first 24 h of admission. DE was defined as net fluid urine output per 40 mg of furosemide equivalents. RESULTS: The median AKIRisk® score was 0.11 (IQR 0.06-0.34), and 38 (30.4%) patients had an AKIRisk® score >0.3. The median cumulative DE at 72 h was 1,963 mL (IQR 1317-3,239 mL). At 72 h, a total of 10 (8%) patients developed an absolute increase in sCr ≥0.5 mg/dL (WKF). In a multivariable setting, there was an inverse association between the AKIRisk® score and DE within the first 72 h. In fact, the highest the AKIRisk® score (centered at 0.3), the higher the likelihood of poor DE (below the median) and WKF at 72 h (odds ratio [OR] 2.04; 95%; CI: 1.02-4.07; p = 0.043, and OR 3.31, 95% CI: 1.30-8.43; p = 0.012, respectively). CONCLUSION: In patients with AHF, a higher NephroCheck® AKIRisk® score is associated with poorer DE and a higher risk of WKF at 72 h. Further research is needed to confirm the role of urinary cell cycle arrest biomarkers in the AHF scenario.

Practical Approaches to the Management of Cardiorenal Disease beyond Congestion.

BACKGROUND: The coexistence of heart and kidney diseases, also called cardiorenal syndrome, is very common, leads to increased morbidity and mortality, and poses diagnostic and therapeutic difficulties. There is a risk-treatment paradox, such that patients with the highest risk are treated with lesser disease-modifying medical therapies. SUMMARY: In this document, different scientific societies propose a practical approach to address and optimize cardiorenal therapies and related comorbidities systematically in chronic cardiorenal disease beyond congestion. Cardiorenal programs have emerged as novel models that may assist in delivering coordinated and holistic management for these patients. KEY MESSAGES: (1) Cardiorenal disease is a ubiquitous entity in clinical practice and is associated with numerous barriers that limit medical treatment. (2) The present article focuses on the practical approaches to managing chronic cardiorenal disease beyond congestion to overcome some of these barriers and improve the treatment of this high-risk population.

Association between N-terminal pro-brain natriuretic peptide and maximal functional capacity in heart failure with preserved ejection fraction: The modifying role of obesity.

This study investigates the association between maximal functional capacity (peakVO2) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in 133 ambulatory patients with heart failure with preserved ejection fraction (HFpEF), focusing on patients with obesity. Across all participants, NT-proBNP inversely correlated with peakVO2. However, this association varied based on obesity status. In patients without obesity, there was an inverse relationship between NT-proBNP and peakVO2, while no significant correlation was observed in patients with obesity. These findings suggest that in stable ambulatory HFpEF, NT-proBNP did not predict peakVO2 in patients with obesity.

Trajectory of Urine Albumin-Creatinine Ratio in Patients with Acute Heart Failure.

INTRODUCTION: Albuminuria is prevalent in patients with chronic heart failure and is a risk factor for disease progression. However, its clinical meaning in acute heart failure remains elusive. This study analyzed the trajectory of urine albumin to creatinine ratio (UACR) between admission and discharge and its association with decongestion. METHODS: In this prospective observational study, 63 patients were enrolled. UACR, B-type natriuretic peptide (BNP), and clinical congestion score (CCS) were obtained at admission and discharge. We used linear mixed regression analysis to compare changes in the natural logarithm of UACR (logUACR) and its association with changes in markers of decongestion. Estimates were reported as least squares mean with their respective 95% CIs. RESULTS: The median age of the study population was 87 years, 68.5% were women, and 69.8% had a left ventricular ejection fraction >50%. LogUACR at discharge significantly decreased in the overall population compared to admission (Δ -0.47, 95% CI: -0.78 to -0.15, p value = 0.003). The magnitude of UACR drop at discharge was associated with changes in surrogate markers of decongestion. Patients who showed a greater reduction in BNP at discharge exhibited a greater reduction in UACR (p = 0.016). The same trend was also found with clinical decongestion, as assessed by changes in CCS, however, without achieving statistical significance (p = 0.171). UACR change at discharge was not associated with changes in serum creatinine (p value = 0.923). CONCLUSION: In elderly patients with AHF and volume overload, the level of UACR significantly decreased upon discharge compared to admission. This reduction in UACR was closely linked to decreases in BNP.