Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Renal function and natriuresis-guided diuretic therapy - a pre-specified analysis from the PUSH-AHF trial.

AIM: In a randomized controlled trial, we recently showed that a natriuresis-guided diuretic approach improved natriuresis and diuresis in patients with acute heart failure (HF). In this pre-specified analysis, we investigated the association between (worsening) renal function, outcomes and the effect of intensive natriuresis-guided loop diuretic therapy as compared with standard of care. METHODS AND RESULTS: The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) trial randomized patients to natriuresis-guided diuretic therapy or standard of care. Serum creatinine and estimated glomerular filtration rate (eGFR) were assessed at fixed timepoints, and worsening renal function (WRF) was assessed at 72 h. The primary outcome was the interaction between randomized treatment allocation, baseline eGFR and the dual primary outcome of PUSH-AHF: total natriuresis at 24 h and time to all-cause mortality or HF rehospitalization at 180 days. In 309 patients, median baseline eGFR was 53 (35-73) ml/min/1.73 m2, and 58% had eGFR <60 ml/min/1.73 m2. Baseline eGFR did not significantly modify the treatment effect of natriuresis-guided diuretic therapy on natriuresis at 24 h (p for interaction = 0.730). However, baseline eGFR significantly modified the effect on all-cause mortality and HF rehospitalization (p for interaction = 0.017): the risk of this second primary outcome was lower in patients with lower eGFR who were randomized to the natriuresis-guided group. In the natriuresis-guided arm, eGFR decreased more (-11.0 vs. -6.91 ml/min/1.73 m2; p = 0.002) during the first 3 days, but this effect was attenuated at discharge (-10.3 vs. -8.69 ml/min/1.73 m2; p = 0.38). WRF was more frequently observed in patients randomized to natriuresis-guided treatment, but was not associated with worse clinical outcomes. CONCLUSIONS: Natriuresis-guided diuretic treatment improved diuresis and natriuresis irrespective of baseline eGFR and occurrence of WRF, was effective even in patients with low eGFR, and the observed effect on eGFR was transient and not associated with worse clinical outcomes.

Artificial intelligence-assisted automated heart failure detection and classification from electronic health records.

AIMS: Electronic health records (EHR) linked to Digital Imaging and Communications in Medicine (DICOM), biological specimens, and deep learning (DL) algorithms could potentially improve patient care through automated case detection and surveillance. We hypothesized that by applying keyword searches to routinely stored EHR, in conjunction with AI-powered automated reading of DICOM echocardiography images and analysing biomarkers from routinely stored plasma samples, we were able to identify heart failure (HF) patients. METHODS AND RESULTS: We used EHR data between 1993 and 2021 from Tayside and Fife (~20% of the Scottish population). We implemented a keyword search strategy complemented by filtering based on International Classification of Diseases (ICD) codes and prescription data to EHR data set. We then applied DL for the automated interpretation of echocardiographic DICOM images. These methods were then integrated with the analysis of routinely stored plasma samples to identify and categorize patients into HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), and controls without HF. The final diagnosis was verified through a manual review of medical records, measured natriuretic peptides in stored blood samples, and by comparing clinical outcomes among groups. In our study, we selected the patient cohort through an algorithmic workflow. This process started with 60 850 EHR data and resulted in a final cohort of 578 patients, divided into 186 controls, 236 with HFpEF, and 156 with HFrEF, after excluding individuals with mismatched data or significant valvular heart disease. The analysis of baseline characteristics revealed that compared with controls, patients with HFrEF and HFpEF were generally older, had higher BMI, and showed a greater prevalence of co-morbidities such as diabetes, COPD, and CKD. Echocardiographic analysis, enhanced by DL, provided high coverage, and detailed insights into cardiac function, showing significant differences in parameters such as left ventricular diameter, ejection fraction, and myocardial strain among the groups. Clinical outcomes highlighted a higher risk of hospitalization and mortality for HF patients compared with controls, with particularly elevated risk ratios for both HFrEF and HFpEF groups. The concordance between the algorithmic selection of patients and manual validation demonstrated high accuracy, supporting the effectiveness of our approach in identifying and classifying HF subtypes, which could significantly impact future HF diagnosis and management strategies. CONCLUSIONS: Our study highlights the feasibility of combining keyword searches in EHR, DL automated echocardiographic interpretation, and biobank resources to identify HF subtypes.

Titration of Medications after Acute Heart Failure is Safe, Tolerated, and Effective Regardless of Risk.

BACKGROUND: Guideline-directed medical therapy decisions may be less affected by single patient variables such as blood pressure or kidney function and more by overall risk profile. In STRONG-HF, high intensity care (HIC) in the form of rapid uptitration of heart failure (HF) guideline-directed medical therapy (GDMT) was effective overall, but the safety, tolerability and efficacy of HIC across the spectrum of HF severity is unknown. Evaluating this with a simple risk-based framework offers an alternative and more clinically translatable approach than traditional subgroup analyses. OBJECTIVES: To assess safety, tolerability, and efficacy of HIC according to the simple, powerful, and clinically translatable Meta-Analysis Global Group in Chronic (MAGGIC) HF risk score. METHODS: In STRONG-HF, 1078 patients with acute HF were randomized to HIC (uptitration of treatments to 100% of recommended doses within 2 weeks of discharge and 4 scheduled outpatient visits over the 2 months after discharge) versus usual care (UC). The primary endpoint was the composite of all-cause death or first HF rehospitalization at Day 180. Baseline HF risk profile was determined by the previously validated MAGGIC risk score. Treatment effect was stratified according to MAGGIC risk score both as a categorical and continuous variable. RESULTS: Among 1062 patients (98.5%) with complete data for whom a MAGGIC score could be calculated at baseline, GDMT use at baseline was similar across MAGGIC tertiles. Overall GDMT prescriptions achieved for individual medication classes were higher in the HIC versus UC group and did not differ by MAGGIC risk score tertiles (interaction non-significant). The incidence of all-cause death or HF readmission at Day 180 was, respectively, 16.3%, 18.9%, and 23.2% for MAGGIC risk score tertiles 1-3. The HIC arm was at lower risk of all-cause death or HF readmission at Day 180 (HR 0.66, 95% CI 0.50-0.86) and this finding was robust across MAGGIC risk score modeled as a categorical (HR 0.51, 0.62, 0.68 in tertile 1, 2, and 3, respectively, (interaction non-significant) for all comparisons) and continuous (p-interaction=NS) variable. The rate of adverse events was higher in the HIC group, but this observation did not differ based on MAGGIC risk score tertile (interaction non-significant). CONCLUSIONS: HIC led to better use of GDMT and lower HF-related morbidity and mortality compared to UC regardless of underlying HF risk profile.

Finerenone in patients with heart failure with mildly reduced or preserved ejection fraction: Rationale and design of the FINEARTS-HF trial.

AIM: Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non-steroidal MRA finerenone. The FINEARTS-HF trial is designed to evaluate the long-term efficacy and safety of the selective non-steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. METHODS: FINEARTS-HF is a global, multicentre, event-driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II-IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml (or B-type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT-proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. CONCLUSIONS: The FINEARTS-HF trial will determine the efficacy and safety of the non-steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04435626 and EudraCT 2020-000306-29.

Characteristics, treatment, and outcomes of early vs. late enrollees of the STRONG-HF trial.

BACKGROUND: The STRONG-HF trial showed that high-intensity care (HIC) consisting of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up reduced all-cause death or heart failure (HF) readmission at 180 days compared to usual care (UC). We hypothesized that significant differences in patient characteristics, management, and outcomes over the enrolment period may exist. METHODS: Two groups of the 1,078 patients enrolled in STRONG-HF were created according to the order of enrolment within center. The early group consisted of the first 10 patients enrolled at each center (N = 342) and the late group consisted of the following patients (N = 736). RESULTS: Late enrollees were younger, had more frequently reduced ejection fraction, slightly lower NT-proBNP and creatinine levels compared with early enrollees. The primary outcome occurred less frequently in early compared to late enrollees (15% vs. 21%, aHR 0.65, 95% CI 0.42-0.99, P = .044). No treatment-by-enrolment interaction was seen in respect to the average percentage of optimal dose of GDMT after randomization, which was consistently higher in early and late patients randomized to HIC compared to UC. The higher use of renin-angiotensin-inhibitors in the HIC arm was more pronounced in the late enrollees both after randomization (interaction-P = .013) and at 90 days (interaction-P < .001). No interaction was observed for safety events. Patients randomized late to UC displayed a trend toward more severe outcomes (26% vs. 16%, P = .10), but the efficacy of HIC showed no interaction with the enrolment group (aHR 0.77, 95% CI 0.35-1.67 in early and 0.58, 95% CI 0.40-0.83 in late enrollees, adjusted interaction-P = .51) with similar outcomes in the HIC arm in late and early enrollees (16% vs. 13%, P = .73). CONCLUSIONS: Late enrollees have different clinical characteristics and higher event rates compared to early enrollees. GDMT implementation in the HIC arm robustly achieved similar doses with consistent efficacy in early and late enrollees, mitigating the higher risk of adverse outcome in late enrollees. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03412201.

Achieved dose and treatment discontinuation of candesartan in men and women with chronic heart failure: data from CHARM.

AIMS: Angiotensin receptor blockers have been shown to reduce heart failure hospitalization and cardiovascular mortality in men and women with heart failure with reduced ejection fraction (HFrEF). It is unknown whether there are differences between men and women in achieved dose and treatment discontinuation due to adverse events of candesartan. METHODS AND RESULTS: We conducted a post hoc analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. A total of 3172 men and 1106 women with HFrEF [left ventricular ejection fraction (LVEF) ≤ 40%] in New York Heart Association class II-IV were randomized to candesartan or placebo. Every 2 weeks, patients were up-titrated from 4 or 8, to16, to 32 mg once daily, unless a higher dose was contraindicated or not tolerated. Women were older (66 vs. 64 years), had a higher LVEF (29.9% vs. 28.6%), and had more hypertension (54% vs. 47%) than men. The mean achieved dose of candesartan was 21.5 ± 12.6 mg in men and 20.7 ± 12.9 mg in women (P = 0.19). In both the candesartan and placebo groups, cardiovascular death and heart failure hospitalizations were higher in men and women who achieved lower dose levels. Event rates for achieved dose levels of 0, 4 or 8, 16, and 32 mg candesartan were 20.8, 17.2, 14.0, and 10.1 per 100 person-years in men, respectively, and 23.6, 13.7, 14.0, and 9.1 per 100 person-years in women, respectively. In each of the achieved dose levels, there was no sex difference in the proportion of patients with an event, neither in the candesartan group nor in the placebo group (P-value for all > 0.05). There was no significant interaction between sex and treatment-related discontinuation for hypotension (P = 0.520), an increase in creatinine (P = 0.102), and hyperkalaemia (P = 0.905). CONCLUSIONS: In a randomized clinical trial in patients with HFrEF, men and women achieved similar doses of candesartan. Primary event rates and treatment-related discontinuation due to adverse events were also similar between men and women.

Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction - Results from the EMPULSE trial.

AIM: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium-glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41-49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41-49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. CONCLUSION: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF.

Bioactive adrenomedullin as a marker of congestion and disease progression in patients with a systemic right ventricle.

BACKGROUND: Adults with a systemic right ventricle (sRV) are at a high risk for heart failure (HF) hospitalisation and mortality. Bioactive adrenomedullin (bio-ADM) has been proposed as a marker of congestion and prognosis in patients with cardiovascular disease. We aimed to evaluate the association between bio-ADM and mortality and HF events in sRV patients. METHODS: Plasma bio-ADM was measured by a novel immunoassay in plasma of 85 sRV patients. A composite endpoint of all-cause mortality and HF events was used as outcome. HF events were defined as onset or progression of HF signs or symptoms requiring hospitalisation, initiation or intensification of therapy. Multivariable Cox regression analyses were performed to evaluate the association between bio-ADM and outcome. RESULTS: The mean age of the patients was 37 ±â€¯9 years and 65% were male. Patients with higher plasma bio-ADM concentrations were more often treated with diuretics (p = 0.007), possibly because of signs and/or symptoms of congestion. During a median follow-up of 10.2 years, 33.7% of the patients reached the endpoint. After adjustment for age and N-terminal pro B-type natriuretic peptide (NT-pro BNP), higher bio-ADM levels were associated with a higher risk of the composite endpoint (hazard ratio: 2.09 [95%-confidence interval: 1.15-3.78]). Bio-ADM improved risk prediction when added to NT-proBNP and age (C-statistic improved from 0.748 to 0.776 [p = 0.03]). CONCLUSIONS: Bio-ADM can be considered as a marker of congestion and independent predictor of death and HF events in adult patients with a sRV. Moreover, in terms of risk prediction, it has added value to NT-proBNP.

Incidence and predictors of heart failure with reduced and preserved ejection fraction after ST-elevation myocardial infarction in the contemporary era of early percutaneous coronary intervention.

AIMS: The development and incidence of de-novo heart failure after ST-elevation myocardial infarction (STEMI) in the contemporary era of rapid reperfusion are largely unknown. We aimed to establish the incidence of post-STEMI heart failure, stratified by left ventricular ejection fraction (LVEF) and to find predictors for its occurrence. Furthermore, we investigated the course of left ventricular systolic and diastolic function after STEMI. METHODS AND RESULTS: A total of 1172 all-comer STEMI patients from the CardioLines Biobank were included. Patients were predominantly male (74.5%) and 64 ± 12 years of age. During a median follow-up of 3.7 years (2.0, 5.5) we found a total incidence of post-STEMI heart failure of 10.9%, of which 52.1% heart failure with reduced ejection fraction (HFrEF), 29.4% heart failure with mildly reduced ejection fraction and 18.5% heart failure with preserved ejection fraction (HFpEF). Independent predictors for the development of HFrEF were male sex (ß = 0.97, p = 0.009), lung crepitations (ß = 1.09, p = 0.001), potassium level (mmol/L, ß = 0.43, p = 0.012), neutrophil count (109/L, ß = 0.09, p = 0.001) and a reduced LVEF (ß = 1.91, p < 0.001) at baseline. Independent predictors for the development of HFpEF were female sex (ß = 0.99, p = 0.029), pre-existing kidney failure (ß = 1.95, p = 0.003) and greater left atrial volume index (ß = 0.04, p = 0.033) at baseline. Follow-up echocardiography (median follow-up 20 months) showed an improvement in LVEF (p < 0.001), whereas changes in diastolic function parameters showed both improvement and deterioration. CONCLUSION: In the current era of early STEMI reperfusion, still one in 10 patients develops heart failure, with approximately half of the patients with a reduced and half with a mildly reduced or normal LVEF. Predictors for the development of HFrEF were different from HFpEF.

Prediction of new-onset heart failure in patients with type 2 diabetes derived from ALTITUDE and CANVAS.

AIM: To create and validate a prediction model to identify patients with type 2 diabetes (T2D) at high risk of new-onset heart failure (HF), including those treated with a sodium-glucose cotransporter-2 (SGLT2) inhibitor. METHODS: A prediction model was developed from the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), a trial in T2D patients with albuminuria or cardiovascular disease. We included 5081 patients with baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) measurement and no history of HF. The model was developed using Cox regression and validated externally in the placebo arm of the Canagliflozin Cardiovascular Assessment Study (CANVAS), which included 996 participants with T2D and established cardiovascular disease or high cardiovascular risk, and in patients treated with canagliflozin. RESULTS: ALTITUDE participants (mean age 64 ± 9.8 years) had a median serum NT-proBNP level of 157 (25th-75th percentile 70-359) pg/mL. Higher NT-proBNP level, troponin T (TnT) level and body mass index (BMI) emerged as significant and independent predictors of new-onset HF in both cohorts. The model further contained urinary albumin-to-creatinine ratio, glycated haemoglobin, age, haematocrit, and use of calcium channel blockers. A prediction model including these variables had a C-statistic of 0.828 (95% confidence interval [CI] 0.801-0.855) in ALTITUDE and 0.800 (95% CI 0.720-0.880) in CANVAS. The C-statistic of this model increased to 0.847 (95% CI 0.792-0.902) in patients after 1 year of canagliflozin treatment. CONCLUSION: In patients with T2D, higher NT-proBNP level, TnT level and BMI are independent and externally validated predictors of new-onset HF, including patients using an SGLT2 inhibitor. This newly developed model may identify patients at high risk of new-onset HF, contributing to early recognition and possibly prevention.

Impact of Rapid Up-Titration of Guideline-Directed Medical Therapies on Quality of Life: Insights From the STRONG-HF Trial.

BACKGROUND: This analysis provides details on baseline and changes in quality of life (QoL) and its components as measured by EQ-5D-5L questionnaire, as well as association with objective outcomes, applying high-intensity heart failure (HF) care in patients with acute HF. METHODS: In STRONG-HF trial (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) patients with acute HF were randomized just before discharge to either usual care or a high-intensity care strategy of guideline-directed medical therapy up-titration. Patients ranked their state of health on the EQ-5D visual analog scale score ranging from 0 (the worst imaginable health) to 100 (the best imaginable health) at baseline and at 90 days follow-up. RESULTS: In 1072 patients with acute HF with available assessment of QoL (539/533 patients assigned high-intensity care/usual care) the mean baseline EQ-visual analog scale score was 59.2 (SD, 15.1) with no difference between the treatment groups. Patients with lower baseline EQ-visual analog scale (meaning worse QoL) were more likely to be women, self-reported Black and non-European (P<0.001). The strongest independent predictors of a greater improvement in QoL were younger age (P<0.001), no HF hospitalization in the previous year (P<0.001), lower NYHA class before hospital admission (P<0.001) and high-intensity care treatment (mean difference, 4.2 [95% CI, 2.5-5.8]; P<0.001). No statistically significant heterogeneity in the benefits of high-intensity care was seen across patient subgroups of different ages, with left ventricular ejection fraction above or below 40%, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and systolic blood pressure above or below the median value. The treatment effect on the primary end point did not vary significantly across baseline EQ-visual analog scale (Pinteraction=0.87). CONCLUSIONS: Early up-titration of guideline-directed medical therapy significantly improves all dimensions of QoL in patients with HF and improves prognosis regardless of baseline self-assessed health status. The likelihood of achieving optimal doses of HF medications does not depend on baseline QoL. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03412201.

Epicardial adipose tissue and pericardial constraint in heart failure with preserved ejection fraction.

AIMS: Obesity and epicardial adiposity play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), and both are associated with increased filling pressures and reduced exercise capacity. The haemodynamic basis for these observations remains inaccurately defined. We hypothesize that an abundance of epicardial adipose tissue (EAT) within the pericardial sac is associated with haemodynamic signs of pericardial constraint. METHODS AND RESULTS: HFpEF patients who underwent invasive heart catheterization with simultaneous echocardiography were included. Right atrial pressure (RAP), right ventricular end-diastolic pressure, and pulmonary capillary wedge pressure (PCWP) were invasively measured. The presence of a square root sign on the right ventricular pressure waveform and the RAP/PCWP ratio (surrogate parameters for pericardial constraint) were investigated. EAT thickness alongside the right ventricle was measured on echocardiography. Sixty-four patients were studied, with a mean age of 73 ± 10 years, 64% women, and a mean body mass index (BMI) of 28.6 ± 5.4 kg/m2 . In total, 47 patients (73%) had a square root sign. The presence of a square root sign was associated with higher BMI (29.3 vs. 26.7 kg/m2 , P = 0.02), higher EAT (4.0 vs. 3.4 mm, P = 0.03), and higher RAP (9 vs. 6 mmHg, P = 0.04). Women had more EAT than men (4.1 vs. 3.5 mm, P = 0.04), despite a comparable BMI. Women with a square root sign had significantly higher EAT (4.3 vs. 3.3 mm, P = 0.02), a higher mean RAP (9 vs. 5 mmHg, P = 0.02), and a higher RAP/PCWP ratio (0.52 vs. 0.26, P = 0.002). In men, such associations were not seen, although there was no significant interaction between men and women (P > 0.05 for all analyses). CONCLUSIONS: Obesity and epicardial adiposity are associated with haemodynamic signs of pericardial constraint in patients with HFpEF. The pathophysiological and therapeutic implications of this finding need further study.

Blood pressure and intensive treatment up-titration after acute heart failure hospitalization: Insights from the STRONG-HF trial.

AIMS: A high-intensity care (HIC) strategy with rapid guideline-directed medical therapy (GDMT) up-titration and close follow-up visits improved outcomes, compared to usual care (UC), in patients recently hospitalized for acute heart failure (AHF). Hypotension is a major limitation to GDMT implementation. We aimed to assess the impact of baseline systolic blood pressure (SBP) on the effects of HIC versus UC and the role of early SBP changes in STRONG-HF. METHODS AND RESULTS: A total of 1075 patients hospitalized for AHF with SBP ≥100 mmHg were included in STRONG-HF. For the purpose of this post-hoc analysis, patients were stratified by tertiles of baseline SBP (<118, 118-128, and ≥129 mmHg) and, in the HIC arm, by tertiles of changes in SBP from the values measured before discharge to those measured at 1 week after discharge (≥2 mmHg increase, ≤7 mmHg decrease to <2 mmHg increase, and ≥8 mmHg decrease). The primary endpoint was 180-day heart failure rehospitalization or death. The effect of HIC versus UC on the primary endpoint was independent of baseline SBP evaluated as tertiles (pinteraction = 0.77) or as a continuous variable (pinteraction = 0.91). In the HIC arm, patients with increased, stable and decreased SBP at 1 week reached 83.5%, 76.2% and 75.3% of target doses of GDMT at day 90. The risk of the primary endpoint was not significantly different between patients with different SBP changes at 1 week (adjusted p = 0.46). CONCLUSIONS: In STRONG-HF, the benefits of HIC versus UC were independent of baseline SBP. Rapid GDMT up-titration was performed also in patients with an early SBP drop, resulting in similar 180-day outcome as compared to patients with stable or increased SBP.

Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the VICTORIA trial.

AIMS: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. METHODS AND RESULTS: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years). CONCLUSIONS: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.

Sex-related similarities and differences in responses to heart failure therapies.

Although sex-related differences in the epidemiology, risk factors, clinical characteristics and outcomes of heart failure are well known, investigations in the past decade have shed light on an often overlooked aspect of heart failure: the influence of sex on treatment response. Sex-related differences in anatomy, physiology, pharmacokinetics, pharmacodynamics and psychosocial factors might influence the response to pharmacological agents, device therapy and cardiac rehabilitation in patients with heart failure. In this Review, we discuss the similarities between men and women in their response to heart failure therapies, as well as the sex-related differences in treatment benefits, dose-response relationships, and tolerability and safety of guideline-directed medical therapy, device therapy and cardiac rehabilitation. We provide insights into the unique challenges faced by men and women with heart failure, highlight potential avenues for tailored therapeutic approaches and call for sex-specific evaluation of treatment efficacy and safety in future research.

Recurrent Hospitalizations and Response to Vericiguat in Heart Failure and Reduced Ejection Fraction.

BACKGROUND: In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction. OBJECTIVES: This study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization. METHODS: The treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro-B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported. RESULTS: There were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro-B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo. CONCLUSIONS: Additional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

Distinguishing heart failure with reduced ejection fraction from heart failure with preserved ejection fraction: A phenomics approach.

AIM: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. METHODS AND RESULTS: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age- and sex-matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi-block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross-referenced with small-molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60-71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)-8 and IL-6 were possible targets related to lower EF and worsening renal function. CONCLUSION: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF.

Biomarker and transcriptomics profiles of serum selenium concentrations in patients with heart failure are associated with immunoregulatory processes.

BACKGROUND: Low selenium concentrations are associated with worse outcomes in heart failure (HF). However, the underlying pathophysiologic mechanisms remain incompletely understood. Therefore, we aimed to contrast serum selenium concentrations to blood biomarker and transcriptomic profiles in patients with HF. METHODS: Circulating biomarkers, whole blood transcriptomics and serum selenium measurements in a cohort of 2328 patients with HF were utilized. Penalized linear regression and gene expression analysis were used to assess biomarker and transcriptomics profiles, respectively. As a proof-of-principle, potential causal effects of selenium on excreted cytokines concentrations were investigated using human peripheral blood mononuclear cells (PBMCs). RESULTS: Mean selenium levels were 60.6 µg/L in Q1 and 122.0 µg/L in Q4. From 356 biomarkers and 20 clinical features, the penalized linear regression model yielded 44 variables with <5 % marginal false discovery rate as predictors of serum selenium. Biomarkers associated positively with selenium concentrations included: epidermal growth factor receptor (EGFR), IFN-gamma-R1, CD4, GDF15, and IL10. Biomarkers associated negatively with selenium concentrations included: PCSK9, TNFSF13, FGF21 and PAI. Additionally, 148 RNA transcripts were found differentially expressed between high and low selenium status (Padj.<0.05; log-fold-change<|0.25|). Enrichment analyses of the selected biomarkers and RNA transcripts identified similar enriched processes, including regulation processes of leukocyte differentiation and activation, as well as cytokines production. The mRNA expression of two selenoproteins (MSRB1 and GPX4) were strongly correlated with serum selenium, while GPX4, SELENOK, and SELENOS were associated with prognosis. In the in-vitro setting, PBMCs supplemented with selenium showed significantly lower abundance of several (pro-)inflammatory cytokines. CONCLUSION: These data suggest that immunoregulation is an important mechanism through which selenium might have beneficial roles in HF. The beneficial effects of higher serum selenium concentrations are likely because of global immunomodulatory effects on the abundance of cytokines. MSRB1 and GPX4 are potential modulators of and should be pursued in future research.