<div><h4>Effect of phosphodiesterase-5 inhibition on SystEmic Right VEntricular size and function - a multi-center, double-blind, randomized, placebo-controlled trial - SERVE.</h4><i>Greutmann M, Tobler D, Engel R, Heg D, ... Schwerzmann M, SERVE Investigators</i><br /><b>Background:</b><br/>and aims</b><br />In adults with congenital heart disease and systemic right ventricles, progressive right ventricular systolic dysfunction is common and is associated with adverse outcomes. Our aim was to assess the impact of the phosphodiesterase-5-inhibitor tadalafil on right ventricular systolic function.<br /><b>Methods and results</b><br />This was a double-blind, randomized, placebo-controlled, multi-center superiority trial (NCT03049540) involving 100 adults with systemic right ventricles (33 women, mean age: 40.7 years, SD 10.7), comparing tadalafil 20mg once daily versus placebo (1:1-ratio). Primary endpoint was the change in right ventricular endsystolic volume after three years of therapy. Secondary endpoints were changes in right ventricular ejection fraction, exercise capacity and NT-proBNP-concentration. Primary endpoint assessment by intention to treat analysis at three years of follow up was possible in 83 patients (42 patients in the tadalafil group and 41 patients in the placebo group). No significant changes over time in right ventricular endsystolic volumes were observed in the tadalafil and the placebo-group, and no significant differences between treatment groups (3.4ml, 95% CI, -4.3 to 11.0, p=0.39). No significant changes over time were observed for the pre-specified secondary endpoints for the entire study population, without differences between the tadalafil and the placebo-group.<br /><b>Conlcusions</b><br />In this trial in adults with systemic right ventricles, right ventricular systolic function, exercise capacity and neuro-hormonal activation remained stable over a three-year follow-up period. No significant treatment effect of tadalafil was observed. Further research is needed to find effective treatment for improvement of ventricular function in adults with systemic right ventricles. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 01 Jun 2023; epub ahead of print</small></div>

<div><h4>Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure in elderly patients: a sub-analysis of the STRONG-HF randomized clinical trial.</h4><i>Arrigo M, Biegus J, Asakage A, Mebazaa A, ... Cotter G, Cohen-Solal A</i><br /><b>Aims</b><br />STRONG-HF examined a high-intensity care (HIC) strategy of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up after acute heart failure (AHF) admission. We assess the role of age on efficacy and safety of HIC.<br /><b>Methods and results</b><br />Hospitalised AHF patients, not treated with optimal GDMT were randomized to HIC or usual care. The primary endpoint of 180-day death or HF-readmission occurred equally in older (>65 years, n=493, 74±5 years) and younger patients (53±11 years, adjusted hazard ratio [aHR] 1.02, 95% confidence interval [CI] 0.73-1.43, p=0.89). Older patients received slightly lower GDMT to day 21, but same doses at day 90 and 180. The effect of HIC on the primary endpoint was numerically higher in younger (aHR 0.51, 95% CI 0.32-0.82) than older patients (aHR 0.73, 95% CI 0.46-1.15, adjusted interaction-p=0.30), partially related to COVID-19 deaths. After exclusion of COVID-19 deaths, the effect of HIC was similar in younger (aHR 0.51, 95% CI 0.32-0.82) and older patients (aHR 0.63, 95% CI 0.32-1.02), adjusted interaction-p=0.56, with no treatment-by-age interaction (interaction-p=0.57). HIC induced larger improvements in quality of life to day 90 in younger (EQ-VAS adjusted-mean-difference 5.51, 95% CI 3.20-7.82) than in older patients (1.77, 95% CI -0.75-4.29, interaction-p=0.032). HIC was associated with similar rates of adverse events in older and younger patients.<br /><b>Conclusion</b><br />HIC after AHF was safe and resulted in a significant reduction of all-cause death or HF-readmission at 180 days across the study age spectrum. Older patients have smaller benefits in terms of quality of life. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 29 May 2023; epub ahead of print</small></div>

<div><h4>Comparison of Pulmonary Congestion severity using AI-assisted scoring vs. clinical experts: A Secondary Analysis of BLUSHED-AHF.</h4><i>Goldsmith AJ, Jin M, Lucassen R, Duggan NM, ... Pang P, Russell FM</i><br /><b>Background</b><br />Acute decompensated heart failure (ADHF) is the leading cause of cardiovascular hospitalizations in the United States. Detecting B-lines through lung ultrasound (LUS) can enhance clinicians\' prognostic and diagnostic capabilities. Artificial Intelligence/Machine Learning (AI/ML)-based automated guidance systems may allow novice users to apply LUS to clinical care.<br /><b>Aim</b><br />We investigated whether an AI/ML automated LUS congestion score correlates with expert\'s interpretations of B-line quantification from an external patient dataset.<br /><b>Methods</b><br />This was a secondary analysis from the BLUSHED-AHF study which investigated the effect of LUS-guided therapy on patients with ADHF. In BLUSHED-AHF, LUS was performed and B-lines were quantified by ultrasound operators. Two experts then separately quantified the number of B-lines per ultrasound video clip recorded. Here, an AI/ML-based lung congestion score (LCS) was calculated for all LUS clips from BLUSHED-AHF. Spearman correlation was computed between LCS and counts from each of the original three raters.<br /><b>Results</b><br />A total of 3,858 LUS clips were analyzed on 130 patients. The LCS demonstrated good agreement with the two experts\' B-line quantification score (r=0.894, 0.882). Both experts\' B-line quantification scores had significantly better agreement with the LCS than they did with the ultrasound operator\'s score (p<0.005, p<0.001).<br /><b>Conclusion</b><br />AI/ML-based LCS correlated with expert-level B-line quantification. Future studies are needed to determine whether automated tools may assist novice users in LUS interpretation. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 23 May 2023; epub ahead of print</small></div>

<div><h4>Renal and Blood Pressure Effects of Dapagliflozin in Recently Hospitalized Patients with Heart Failure with Mildly Reduced or Preserved Ejection Fraction: Insights from the DELIVER Trial.</h4><i>Chatur S, Cunningham JW, Vaduganathan M, Mc Causland FR, ... McMurray JJV, Solomon SD</i><br /><b>Background</b><br />Patients recently hospitalized for heart failure (HF) often have unstable hemodynamics and experience worsening renal failure, and are at elevated risk for recurrent HF events. In DELIVER, dapagliflozin reduced HF events or cardiovascular death including among patients who were hospitalized or recently hospitalized.<br /><b>Methods</b><br />We examined the effects of dapagliflozin vs. placebo on eGFR slope (acute and chronic), 1 month change in systolic blood pressure (SBP), and the occurrence of serious hypovolemic or renal adverse events in patients with and without HF hospitalization within 30 days of randomization.<br /><b>Results</b><br />The 654 (90 randomized during hospitalization, 147 1-7 days post-discharge and 417 8-30 days post-discharge) recently hospitalized patients had lower baseline eGFR compared with those without recent HF hospitalization median[IQR] of 55 [43,71] vs 60 [47,75] ml/min/1.73m<sup>2</sup> ). Dapagliflozin consistently reduced the risk of all-cause (P<sub>interaction</sub> =0.20), cardiac-related (P<sub>interaction</sub> =0.75), and HF-specific (P<sub>interaction</sub> =0.90) hospitalizations, irrespective of recent HF hospitalization. In those recently hospitalized, acute placebo-corrected eGFR reductions with dapagliflozin were modest and similar to patients without recent hospitalization (-2.0 [-4.1,+0.1] vs. -3.4 [-3.9,-2.9] ml/min/1.73m<sup>2</sup> , P<sub>interaction</sub> =0.12). Dapagliflozin\'s effect to slow chronic eGFR decline was similar regardless of recent hospitalization (P<sub>interaction</sub> =0.57). Dapagliflozin had a minimal effect on 1-month SBP and to a similar degree in patients with and without recent hospitalization (-1.3 vs.-1.8 mmHg, P<sub>interaction</sub> =0.64). There was no treatment-related excess in renal or hypovolemic serious AE, irrespective of recent HF hospitalization.<br /><b>Conclusion</b><br />In patients recently hospitalized with HF, initiation of dapagliflozin had minimal effects on BP and did not increase renal or hypovolemic serious AEs, yet afforded long-term cardiovascular and kidney protective effects. These data suggest that the benefit to risk ratio favours initiation of dapagliflozin among stabilized patients hospitalized or recently hospitalized for HF. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 22 May 2023; epub ahead of print</small></div>

<div><h4>Coronary revascularization for heart failure with coronary artery disease: a systematic review and meta-analysis of randomized trials.</h4><i>Iaconelli A, Pellicori P, Dolce P, Busti M, ... Crea F, Cleland JG</i><br /><b>Background:</b><br/>and aims</b><br />Coronary artery disease (CAD) is a common cause of heart failure (HF). Whether coronary revascularisation improves outcomes in patients with HF receiving guideline-recommended pharmacological therapy (GRPT) remains uncertain; therefore, we conducted a systematic review and meta-analysis of relevant randomized controlled trials (RCTs).<br /><b>Methods</b><br />We searched in public databases for RCTs published between 1<sup>st</sup> January 2001 and 22<sup>nd</sup> November 2022, investigating the effects of coronary revascularisation on morbidity and mortality in patients with chronic HF due to CAD. All-cause mortality was the primary outcome.<br /><b>Results</b><br />We included five RCTs that enrolled, altogether, 2,842 patients (most aged <65 years; 85% men; 67% with left ventricular ejection fraction ≤35%). Overall, compared to medical therapy alone, coronary revascularisation was associated with a lower risk of all-cause mortality (HR 0.88 [95% CI, 0.79-0.99]; p=0.0278) and cardiovascular mortality (HR 0.80 [95% CI, 0.70-0.93]; p=0.0024) but not the composite of hospitalisation for HF or all-cause mortality (HR 0.87 [95% CI, 0.74-1.01]; p=0.0728). There were insufficient data to show whether the effect of CABG or PCI were similar or differed.<br /><b>Conclusions</b><br />For patients with chronic HF and CAD enrolled in RCTs, the effect of coronary revascularization on all-cause mortality was statistically significant but neither substantial (HR 0.88) nor robust (upper 95% CI close to 1.0). RCTs were not blinded, which may bias reporting of the cause-specific reasons for hospitalization and mortality. Further trials are required to determine which patients with HF and CAD obtain a substantial benefit from coronary revascularization by either CABG or PCI. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 22 May 2023; epub ahead of print</small></div>

<div><h4>Prevalence, Characteristics and Prognostic Impact of Aortic Valve Disease in Patients with Heart Failure and Reduced, Mildly Reduced, and Preserved Ejection Fraction: An Analysis of the ESC Heart Failure Long-Term Registry.</h4><i>Shahim B, Shahim A, Adamo M, Chioncel O, ... Metra M, Lund LH</i><br /><b>Aims</b><br />To assess the prevalence, clinical characteristics, and outcomes of patients with heart failure (HF) with or without moderate to severe aortic valve disease (AVD) (stenosis, AS; regurgitation, AR; mixed MAVD).<br /><b>Methods and results</b><br />Data from the prospective ESC HFA EORP HF Long-Term Registry including both chronic and acute HF were analyzed. Of 15 216 patients with HF (62.5% reduced EF, HFrEF; 14.0% mildly reduced, HFmrEF; 23.5% preserved, HFpEF), 706 patients (4.6%) had AR, 648 (4.3%) AS and 234 (1.5%) MAVD. The prevalence of AS, AR and MAVD was 6%, 8% and 3% in HFpEF, 6%, 3% and 2% in HFmrEF and 4%, 3% and 1% in HFrEF. The strongest associations were observed for age and HFpEF with AS, and for left ventricular end-diastolic diameter (LVEDD) with AR. AS (adjusted HR 1.43, 95% CI 1.23-1.67), and MAVD (1.37, 95% CI 1.07-1.75) but not AR (1.13, 95% CI 0.96-1.33) were independently associated with the 12-month composite outcome of CV death and HF hospitalization. The associations between AS and the composite outcome were observed regardless of EF category.<br /><b>Conclusions</b><br />In the ESC HFA EORP HF Long-Term Registry, one in ten patients with HF had AVD, with AS and MAVD being especially common in HFpEF and AR being similarly distributed across all EF categories. AS and MAVD, but not AR, were independently associated with increased risk of in-hospital mortality and 12-month composite outcome, regardless of EF category. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 21 May 2023; epub ahead of print</small></div>

<div><h4>Impact of Dapagliflozin on cardiac remodeling in patients with chronic heart failure: DAPA-MODA study.</h4><i>Pascual-Figal DA, Zamorano JL, Domingo M, Morillas H, ... Juanatey JRG, Comins MA</i><br /><b>Rationale</b><br />Dapagliflozin improves the prognosis of patients with heart failure (HF), regardless left ventricular ejection fraction (LVEF). However, its effect on cardiac remodeling parameters, specifically left atrial (LA) remodeling, is not well established.<br /><b>Methods</b><br />DAPA-MODA trial (NCT04707352) is a multicenter, single-arm, open-label, prospective and interventional study that aimed to evaluate the effect of dapagliflozin on cardiac remodeling parameters over six months.. Patients with stable chronic heart failure receiving optimized guideline-directed therapy, except for any SGLT2i, were included. Echocardiography was performed at baseline, 30 and 180 days, and analyzed by a central core-lab in a blinded manner to both patient and time. The primary end-point was the change of maximal LA volume index (LAVI).<br /><b>Results</b><br />A total of 162 patients (64.2% men, 70.5±10.6 years, 52% LVEF>40%) were included in the study. At baseline, LA dilatation was observed (LAVI 49.1±24.4 ml/m2) and LA parameters were similar between LVEF-based phenotypes (≤40% vs. >40%). LAVI showed a significant reduction at 180 days (-6.6% (CI95% -11.1, -1.8, p=0.008), primarily due to a decrease in reservoir volume (-13.8%, p=0.007). LV geometry improved with significant reductions in LV mass index (-13.9%, p<0.001), end-diastolic volume (-8.0%, p<0.001) and end-systolic volume (-11.9%, p<0.001) at 180 days. NT-proBNP showed a significant reduction at 180 days (-18.2% [CI95% -27.1, -8.2], p<0.001), without changes in filling doppler measures.<br /><b>Conclusion</b><br />Dapagliflozin administration in stable out-setting patients with chronic HF and optimized therapy results in global reverse remodeling of cardiac structure, including reductions in LA volumes and improvement in LV geometry and NT-proBNP concentrations. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 21 May 2023; epub ahead of print</small></div>

<div><h4>Electronic nudges to increase influenza vaccination uptake among patients with heart failure: a prespecified analysis of the NUDGE-FLU trial.</h4><i>Johansen ND, Vaduganathan M, Bhatt AS, Lee SG, ... Krause TG, Biering-Sørensen T</i><br /><b>Aims</b><br />Seasonal influenza vaccination is strongly recommended in patients with heart failure (HF). The NUDGE-FLU trial recently found two electronic behavioural nudging letter strategies - a letter highlighting potential cardiovascular benefits of vaccination and a repeated letter at day 14 - effective in increasing influenza vaccination in Denmark. The aims of this prespecified analysis was to further examine vaccination patterns and effects of these behavioural nudges in patients with HF including potential off-target effects on guideline-directed medical therapy (GDMT) use.<br /><b>Methods and results</b><br />The nationwide NUDGE-FLU trial randomized 964 870 Danish citizens ≥65 years to usual care or 9 different electronic nudging letter strategies. Letters were delivered through the official Danish electronic letter system. The primary endpoint was the receipt of an influenza vaccine; additional outcomes for this analysis included GDMT use. In this analysis, we also assessed influenza vaccination rates in the overall Danish HF population including those <65 years (n = 65 075). During the 2022-2023 season, influenza vaccination uptake was 71.6% in the overall Danish HF population but this varied considerably with only 44.6% uptake in those <65 years. A total of 33 109 NUDGE-FLU participants had HF at baseline. Vaccination uptake was higher among those on higher levels of baseline GDMT (≥3 classes: 85.3% vs. ≤2 classes: 81.9%; p < 0.001). HF status did not modify the effects of the two overall successful nudging strategies on influenza vaccination uptake (cardiovascular gain-framed letter: p<sub>interaction</sub>  = 0.37; repeated letter: p<sub>interaction</sub>  = 0.55). No effect modification was observed across GDMT use levels for the repeated letter (p<sub>interaction</sub>  = 0.88), whereas a trend towards attenuated effect among those on low levels of GDMT was observed for the cardiovascular gain-framed letter (p<sub>interaction</sub>  = 0.07). The letters had no impact on longitudinal GDMT use.<br /><b>Conclusions</b><br />Approximately 1 in 4 patients with HF did not receive influenza vaccination with a pronounced implementation gap in those <65 years where less than half were vaccinated. HF status did not modify the effectiveness of cardiovascular gain-framed and repeated electronic nudging letters in increasing influenza vaccination rates. No unintended negative effects on longitudinal GDMT use were observed.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 21 May 2023; epub ahead of print</small></div>

<div><h4>Effect of Dapagliflozin on Health Status and Quality-of-Life Across the Spectrum of Ejection Fraction: Participant-Level Pooled Analysis from the DAPA-HF & DELIVER Trials.</h4><i>Bhatt AS, Kosiborod MN, Vaduganathan M, Claggett BL, ... McMurray JJV, Solomon SD</i><br /><b>Introduction</b><br />Patients with heart failure experience a high burden of symptoms, physical limitations, and poor quality-of-life. Dapagliflozin improves heart failure hospitalization and cardiovascular death in patients with reduced, mildly reduced, and preserved ejection fractions. We examined the effects of dapagliflozin on health status, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), across the full spectrum of left ventricular ejection fraction (LVEF).<br /><b>Methods</b><br />Participant-level data were pooled from the DAPA-HF and DELIVER trials. Both trials were randomized, global, double-blind, placebo-controlled trials of patients with symptomatic HF and elevated natriuretic peptides. DAPA-HF and DELIVER included patients with LVEF≤40% and LVEF>40%, respectively. KCCQ was evaluated at randomization and at 8-months post randomization; the effect of dapagliflozin vs. placebo on KCCQ total symptom score (TSS) was a prespecified secondary outcome in both trials. Interaction testing was performed to assess potential heterogeneity in the effects of dapagliflozin vs. placebo on KCCQ TSS, Clinical Summary Score (CSS), Overall Summary Score (OSS), and Physical Limitations Score (PLS), by continuous LVEF using restricted cubic splines. Responder analyses examining the proportion of patients with meaningful deterioration (≥5 point decline) and meaningful improvements (≥5 point increase) in KCCQ-TSS was assessed across LVEF categories.<br /><b>Results</b><br />Of 11 007 patients randomized, 10 238 (93%) had full data on KCCQ-TSS at randomization. Benefits of dapagliflozin vs. placebo on KCCQ-TSS, -CSS, -OSS, -PLS, at 8 months were consistent across the full range of LVEF (P for interactions = 0.19, 0.10, 0.12, 0.10 respectively). In responder analyses, fewer dapagliflozin- vs. placebo-treated patients had clinically meaningful deteriorations in KCCQ-TSS (Overall: 21% vs. 23%; LVEF≤40%: 21% vs. 29%; LVEF 41%-60%: 21% vs. 26%; LVEF>60%: 22% vs. 27%). A greater proportion of patients randomized to dapagliflozin experienced meaningful improvements in KCCQ-TSS (Overall: 50% vs. 45%; LVEF≤40%: 48% vs. 41%; LVEF 41%-60%: 51% vs. 49%; LVEF>60%: 53% vs. 45%). The effects of dapagliflozin vs. placebo on clinically meaningful deteriorations and improvements in health status by KCCQ-TSS were consistent across the full spectrum of LVEF assessed continuously (p for interaction: 0.20 and 0.64, respectively). Across the LVEF spectrum, the number-needed-to-treat to affect ≥5 point improvement in health status assessed by KCCQ-TSS was 20. Health status declines preceeding a HF hospitalization by approximately 10 points on average were observed in both trials, evident up to 3 months prior to the event.<br /><b>Conclusions</b><br />In participant-level pooled analyses of DAPA-HF and DELIVER, dapagliflozin improved all key domains of health status across the full range of LVEF. Clinically meaningful improvements in health status were also observed consistently across the full range of LVEF, including in those with LVEF above 60%. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 21 May 2023; epub ahead of print</small></div>

<div><h4>Patient profiles in heart failure with reduced ejection fraction: prevalence, characteristics, treatments and outcomes in a real-world heart failure population.</h4><i>Musella F, Rosano GMC, Hage C, Benson L, ... Lund LH, Savarese G</i><br /><b>Background</b><br />The Heart Failure Association of the European Society of Cardiology has recently proposed to optimize guidelines-directed medical treatments according to patient\'s profiles. Aim of this analysis was to investigate prevalence/characteristics/treatments/outcomes for individual profiles.<br /><b>Methods and results</b><br />Patients with heart failure with reduced ejection fraction (HFrEF) enrolled in the Swedish Heart Failure Registry (SwedeHF) between 2013-2021 were considered. Among 108 profiles generated by combining different strata of renal function (by estimated glomerular filtration rate, eGFR), systolic blood pressure (sBP), heart rate, atrial fibrillation (AF) status and presence of hyperkalaemia, 93 were identified in our cohort. Event rates for a composite of cardiovascular (CV) mortality or first HF hospitalization were calculated for each profile. The 9 most frequent profiles accounting for 70.5% of the population had eGFR 30-60 or ≥60 mL/min/1.73m<sup>2</sup> , sBP 90-140mmHg and no hyperkalaemia. Heart rate and AF were evenly distributed. The highest risk of CV mortality/first HF hospitalization was observed in those with concomitant eGFR 30-60 mL/min/1.73m<sup>2</sup> and AF. We also identified 9 profiles with the highest event rates, representing only 5% of the study population, characterized by no hyperkalaemia, even distribution among the sBP strata, predominance of eGFR <30mL/min/1.73m<sup>2</sup> and AF. The 3 profiles with eGFR 30-60mL/min/1.73m<sup>2</sup> also showed sBP <90mmHg.<br /><b>Conclusions</b><br />In a real-world cohort most patients fit in a few easily identifiable profiles; the 9 profiles at highest risk of mortality/morbidity accounted for only 5% of the population. Our data might contribute to identifying profile-tailored approaches to guide drugs´ implementation and follow-ups. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 21 May 2023; epub ahead of print</small></div>

<div><h4>Effects of Dapagliflozin on Heart Failure Hospitalizations According to Severity of Inpatient Course: Insights from DELIVER and DAPA-HF.</h4><i>Chatur S, Kondo T, Claggett BL, Docherty K, ... Solomon SD, Vaduganathan M</i><br /><b>Aims</b><br />Dapagliflozin resulted in significant and sustained reductions in first and recurrent HF hospitalizations among patients with HF across the spectrum of ejection fraction. How treatment with dapagliflozin differentially impacts hospitalization for HF of varying complexity is not well studied.<br /><b>Methods and results</b><br />In the DELIVER and DAPA-HF trials, we examined the effects of dapagliflozin on adjudicated HF hospitalizations of varying complexity and hospital length of stay (LOS). HF hospitalizations requiring ICU stay, IV vasoactive therapies, invasive/non-invasive ventilation, mechanical fluid removal or MCS were categorized as complicated. The balance were classified as uncomplicated. Of the total 1209 HF hospitalizations reported in DELIVER, 71% (854) were uncomplicated and 29% (355) were complicated. Of the total 799 HF hospitalizations reported in DAPA-HF, 57% (453) were uncomplicated and 43% (346) were complicated. Relative to patients experiencing a first uncomplicated HF hospitalization, those with complicated HF hospitalizations had a significantly higher in-hospital mortality both in DELIVER (16.8% vs. 2.3%, p < 0.001) and DAPA-HF (15.1% vs. 3.8%, p < 0.001). Dapagliflozin similarly reduced total \'uncomplicated\' (DELIVER: RR 0.67, 95% CI: 0.55-0.82 and DAPA-HF: RR 0.69, 95% CI: 0.54-0.87) and \'complicated\' HF hospitalizations (DELIVER: 0.82, 95% CI: 0.63-1.06 and DAPA-HF: 0.75, 95% CI: 0.58-0.97). Dapagliflozin consistently reduced hospitalizations irrespective of their LOS: <5 days (DELIVER: RR 0.76; 95% CI: 0.58-0.99 and DAPA-HF: 0.58; 95%: 0.42-0.80) or ≥5 days (DELIVER: RR 0.71; 95% CI: 0.58-0.86 and DAPA-HF: 0.77; 95% CI: 0.62-0.94).<br /><b>Conclusion</b><br />A substantial proportion of hospitalizations (~30%-40%) among patients with HF irrespective of ejection fraction required intensification of treatment beyond standard intravenous diuretics. Such patients experienced significantly higher in-hospital mortality. Treatment with dapagliflozin consistently reduced HF hospitalizations regardless of severity of inpatient treatment course or LOS. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 21 May 2023; epub ahead of print</small></div>

<div><h4>Prevalence, Characteristics and Cardiovascular and Non-cardiovascular Outcomes in Patients with Heart Failure with Supra-normal Ejection Fraction; Insight from the JROADHF Study.</h4><i>Horiuchi Y, Asami M, Ide T, Yahagi K, ... Tsutsui H, Tanabe K</i><br /><b>Aims</b><br />We aimed to investigate the characteristics and prognosis of patients with heart failure with supra-normal ejection fraction (HFsnEF) compared to HF with normal EF (HFnEF).<br /><b>Methods and results</b><br />Among 11,573 patients enrolled in the nationwide registry of hospitalized patients with HF in Japan, 1,943 patients (16.8%) were classified as HFsnEF (left ventricular EF [LVEF] > 65%), 3,277 (28.3%) as HFnEF (50% ≤ LVEF ≤ 65%), 2,024 (17.5%) as HF with mildly reduced EF (40% ≤ EF < 50%) and 4,329 (37.4%) as HF with reduced EF (LVEF < 40%). Patients with HFsnEF were older, more likely to be women, had lower natriuretic peptide values, and had smaller left ventricles than those with HFnEF. The primary endpoint, the composite of cardiovascular death or HF readmission, did not differ between HFsnEF (802/1943, 41.3%) and HFnEF (1413/3277, 43.1%) during a median follow-up period of 870 days (hazard ratio [HR] 0.96 [0.88-1.05], p = 0.346). The incidence of secondary outcomes, including all-cause, cardiovascular, and non-cardiovascular deaths and HF readmission, did not differ between HFsnEF and HFnEF. In the multivariable Cox regression analysis, HFsnEF compared to HFnEF was associated with a lower adjusted HR for HF readmission but not with the primary and other secondary endpoints. HFsnEF was associated with a higher HR for the composite endpoint and all-cause death in women, and a higher HR for all-cause death in patients with renal dysfunction.<br /><b>Conclusions</b><br />HFsnEF is a common and distinctive phenotype, and has different characteristics and prognoses from HFnEF. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 May 2023; epub ahead of print</small></div>

<div><h4>Incremental prognostic value of biomarkers in PARADIGM-HF.</h4><i>McDowell K, Campbell R, Simpson J, Cunningham JW, ... Packer M, McMurray JJV</i><br /><b>Background</b><br />It is uncertain how much candidate biomarkers improve risk prediction when added to comprehensive models including routinely collected clinical and laboratory variables in heart failure.<br /><b>Methods</b><br />Aldosterone, cystatin C, high sensitivity-troponin T (hs-TnT), galectin-3, growth differentiation factor-15 (GDF-15), kidney injury molecule-1 (KIM-1), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), soluble suppression of tumorigenicity-2 (ST2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and urinary albumin to creatinine ratio (UACR) were measured in 1559 of PARADIGM-HF participants.We tested whether these biomarkers, individually or collectively, improved the performance of the PREDICT-HF prognostic model, which includes clinical, routine laboratory, and natriuretic peptide data, for the primary endpoint and cardiovascular and all-cause mortality.<br /><b>Results</b><br />The mean age of participants was 67.3 ± 9.9 years, 1254 (80.4%) were men and 1103 (71%) were NYHA class II. During a mean follow-up of 30.7 months, 300 patients experienced the primary outcome and 197 died. Added individually, only 4 biomarkers were independently associated with all outcomes: hs-TnT, GDF-15, cystatin C and TIMP-1. When all biomarkers were added simultaneously to the PREDICT-HF models, only hs-TnT remained an independent predictor of all three endpoints. GDF-15 also remained predictive of the primary endpoint; TIMP-1 was the only other predictor of both cardiovascular and all-cause mortality. Individually or in combination, these biomarkers did not lead to statistically significant improvements in discrimination or reclassification.<br /><b>Conclusions</b><br />None of the biomarkers studied individually or collectively led to a meaningful improvement in the prediction of outcomes over what is provided by clinical, routine laboratory, and natriuretic peptide variables. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 May 2023; epub ahead of print</small></div>

<div><h4>Clinical characteristics of HFrEF patients with rare pathogenic variants in DCM-associated genes: a subgroup analysis of the PARADIGM-HF trial.</h4><i>Barat A, Chen CW, Patel-Murray N, McMurray JJV, ... Yates D, Gimpelewicz C</i><br /><b>Aims</b><br />To evaluate the prevalence of pathogenic variants in genes associated with dilated cardiomyopathy (DCM) in a clinical trial population with heart failure and reduced ejection fraction (HFrEF) and describe the baseline characteristics by variant carrier status.<br /><b>Methods and results</b><br />This was a post hoc analysis of the Phase 3 PARADIGM-HF trial. Forty-four genes, divided into three tiers, based on definitive, moderate or limited evidence of association with DCM, were assessed for rare predicted loss-of-function (pLoF) variants, which were prioritised using ClinVar annotations, measures of gene transcriptional output and evolutionary constraint, and pLoF confidence predictions. Prevalence was reported for pLoF variant carriers based on DCM-associated gene tiers. Clinical features were compared between carriers and non-carriers. Of the 1412 HFrEF participants with whole-exome sequence data, 68 (4.8%) had at least one pLoF variant in the 8 tier-1 genes (definitive/strong association with DCM), with Titin being most commonly affected. The prevalence increased to 7.5% when considering all 44 genes. Among patients with idiopathic aetiology, 10.0% (23/229) had tier-1 variants only and 12.6% (29/229) had tier-1, -2 or -3 variants. Compared to non-carriers, tier-1 carriers were younger (4 years; adjusted p-value [p<sub>adj</sub> ]=4×10<sup>-3</sup> ), leaner (27.8 kg/m<sup>2</sup> vs. 29.4 kg/m<sup>2</sup> ; p<sub>adj</sub> =3.2x10<sup>-3</sup> ), had lower EF (27.3% vs. 29.8%; p<sub>adj</sub> =5.8x10<sup>-3</sup> ), and less likely to have ischaemic aetiology (37.3% vs 67.4%; p<sub>adj</sub> =4×10<sup>-4</sup> ).<br /><b>Conclusion</b><br />Deleterious pLoF variants in genes with definitive/strong association to DCM were identified in ~5% of HFrEF patients from a PARADIGM-HF trial subset, who were younger, had lower EF and were less likely to have had an ischaemic aetiology. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 May 2023; epub ahead of print</small></div>

<div><h4>Sex-specific analysis of the rapid up-titration of guideline-directed medical therapies after a hospitalisation for acute heart failure: insights from the STRONG-HF trial.</h4><i>Čerlinskaitė-Bajorė K, Lam CSP, Sliwa K, Adamo M, ... Cotter G, Čelutkienė J</i><br /><b>Aims</b><br />The aim of this study was to evaluate efficacy and safety of rapid up-titration of guideline directed medical therapies in men and women hospitalized for acute heart failure (AHF).<br /><b>Methods and results</b><br />In STRONG-HF AHF patients were randomised just prior to discharge to either usual care (UC) or a high-intensity care (HIC) strategy of guideline-directed medical therapies (GDMT) up-titration. In these analyses, we compare the implementation, efficacy, and safety of the HIC strategy between men and women. In the randomised AHF population, 416/1078 (39%) were women. By day 90, a higher proportion of both sexes in the HIC group had been up-titrated to full doses of GDMT compared to UC. Overall, there were no differences in the primary endpoint between the sexes. The primary endpoint, 180-day HF readmission or death, occurred in 15.8% HIC women vs 23.5% women in the UC group (adjusted HR 0.67 [95% CI 0.40-1.13]) and in 14.9% HIC men vs 23.5% UC men (adjusted HR 0.57 [95% CI 0.38-0.88]), adjusted interaction p = 0.65. There was no significant treatment-by-sex interaction in quality-of-life improvement or in adverse events, including serious or fatal adverse events.<br /><b>Conclusion</b><br />The results of the current analyses suggest that a rapid up-titration of GDMT immediately after an AHF hospitalisation can and should be implemented similarly in men and women, as it results in reduction of 180-day all-cause death or HF readmission, quality-of-life improvement in both men and women with a similar safety profile.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 May 2023; epub ahead of print</small></div>

<div><h4>Iron deficiency in heart failure: screening, prevalence, incidence and outcome Data from the Swedish Heart Failure registry and the Stockholm CREAtinine Measurements collaborative project.</h4><i>Lindberg F, Lund LH, Benson L, Linde C, ... Carrero JJ, Savarese G</i><br /><b>Aims</b><br />Iron deficiency (ID) is common in heart failure (HF) and linked with poor prognosis regardless of anemia. We assessed temporal trends in ID testing, ID prevalence, ID incidence, iron need, and outcomes associated with ID in HF across the ejection fraction (EF) spectrum.<br /><b>Methods and results</b><br />From the Swedish HF registry, we enrolled 15 197 patients from Region Stockholm with available EF and collected laboratory tests from routine practice. Iron screening improved since 2016 but remained <25% as of 2018. In 1486 patients with iron biomarkers at baseline, the prevalence of ID was 55% (HF with reduced EF 54%; mildly reduced EF 51%; preserved EF 61%). Iron need was ≥1500 mg in 72% of patients. ID was independently associated with higher risk for repeated HF hospitalizations (incidence rate ratio [IRR] 1.62, 95% confidence interval [CI] 1.13-2.31) and with cardiovascular (CV) death or repeated HF hospitalizations (IRR 1.63, 95% CI 1.15-2.30) regardless of EF (p-interaction 0.21 and 0.26, respectively), but not with all-cause death, CV death, or first HF hospitalization. Among 96 patients without ID at baseline and with follow-up iron biomarkers, 21% developed ID within 6 months.<br /><b>Conclusions</b><br />ID screening improved over time but is still limitedly implemented, despite being highly prevalent and incident, and independently associated with CV death or repeated HF hospitalizations regardless of EF. Most patients with ID had an iron need necessitating either repeated administrations of intravenous iron or a preparation permitting >1000 mg doses. These data highlight the need for improved screening for ID in HF. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 28 Apr 2023; epub ahead of print</small></div>

<div><h4>Hyponatraemia and changes in natraemia during hospitalization for acute heart failure and associations with in-hospital and long-term outcomes - from the ESC HFA EORP Heart Failure Long-Term Registry.</h4><i>Kapłon-Cieślicka A, Benson L, Chioncel O, Crespo-Leiro MG, ... Heart Failure Association (HFA) of the European Society of Cardiology (ESC) and the ESC Heart Failure Long-Term Registry Investigators, Gale CP</i><br /><b>Aims</b><br />To comprehensively assess hyponatraemia in acute heart failure (AHF) regarding prevalence, associations, hospital course, and post-discharge outcomes.<br /><b>Methods and results</b><br />Of 8,298 patients in the ESC-HF Long-Term Registry hospitalized for AHF with any ejection fraction, 20% presented with hyponatraemia (serum sodium <135 mmol/L). Independent predictors included lower systolic blood pressure, estimated glomerular filtration rate (eGFR) and haemoglobin, along with diabetes, hepatic disease, use of thiazide diuretics, mineralocorticoid receptor antagonists, digoxin, higher doses of loop diuretics, and non-use of angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers and beta-blockers. In-hospital death occurred in 3.3%. The prevalence of hyponatraemia and in-hospital mortality with different combinations were: 9% hyponatraemia both at admission and discharge (hyponatraemia Yes/Yes, in-hospital mortality 6.9%), 11% Yes/No (in-hospital mortality 4.9%), 8% No/Yes (in-hospital mortality 4.7%), and 72% No/No (in-hospital mortality 2.4%). Correction of hyponatraemia was associated with improvement in eGFR. In-hospital development of hyponatraemia was associated with greater diuretic use and worsening eGFR but also more effective decongestion. Among hospital survivors, 12-month mortality was 19% and adjusted hazard ratios were for hyponatraemia Yes/Yes 1.60 (1.35-1.89), Yes/No 1.35 (1.14-1.59), and No/Yes 1.18 (0.96-1.45). For death or HF hospitalization they were 1.38 (1.21-1.58), 1.17 (1.02-1.33), and 1.09 (0.93-1.27), respectively.<br /><b>Conclusion</b><br />Among patients with AHF, 20% had hyponatraemia at admission, which was associated with more advanced HF and normalized in half of patients during hospitalization. Admission hyponatraemia (possibly dilutional), especially if it did not resolve, was associated with worse in-hospital and post-discharge outcomes. Hyponatraemia developing during hospitalization (possibly depletional) was associated with lower risk. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 27 Apr 2023; epub ahead of print</small></div>

<div><h4>Natriuretic Peptides: Role in the Diagnosis and Management of Heart Failure: A Scientific Statement From the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America and Japanese Heart Failure Society.</h4><i>Tsutsui H, Albert NM, Coats AJS, Anker SD, ... Yamamoto K, Yoshimura M</i><br /><AbstractText>Natriuretic peptides, brain (B-type) natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up-to-date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptides-guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions.</AbstractText><br /><br />© 2023 Elsevier Inc and European Society of Cardiology. Published by Elsevier Inc and Wiley. All rights reserved.<br /><br /><small>Eur J Heart Fail: 26 Apr 2023; epub ahead of print</small></div>

<div><h4>Sex Differences in the Generalizability of Randomized Clinical Trials in Heart Failure with Reduced Ejection Fraction.</h4><i>Schroeder M, Lim YMF, Savarese G, Suzart-Woischnik K, ... Cronin M, Koudstaal S</i><br /><b>Aims</b><br />To understand how sex differences impact the generalizability of randomized controlled trials (RCTs) in patients with heart failure and reduced ejection fraction (HFrEF, we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex.<br /><b>Methods and results</b><br />Data from 2 HF registries and 5 HFrEF RCTs were used to create three subpopulations: one RCT population (n=16,917; 21.7% females), registry patients eligible for RCT inclusion (n=26,104; 31.8% females), and registry patients ineligible for RCT inclusion (n=20,910; 30.2% females). Clinical endpoints included all-cause mortality, CV mortality, and first HF hospitalization at one-year. Males and females were equally eligible for trial enrollment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (Standardized mortality ratio (SMR) 0.72; 95% CI 0.62 - 0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95%CI 0.76-1.03 for females, SMR 1.43; 95%CI 1.33-1.53 for males).<br /><b>Conclusion</b><br />Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and females trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 26 Apr 2023; epub ahead of print</small></div>

<div><h4>Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the Heart Failure Association of the European Society of Cardiology.</h4><i>Metra M, Tomasoni D, Adamo M, Bayes-Genis A, ... Coats AJS, Rosano G</i><br /><AbstractText>Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline-recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice.</AbstractText><br /><br />© 2023 European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 26 Apr 2023; epub ahead of print</small></div>

<div><h4>Safety, usability, and performance of a wireless left atrial pressure monitoring system in patients with heart failure: the VECTOR-HF trial.</h4><i>D\'Amario D, Meerkin D, Restivo A, Ince H, ... Perl L, VECTOR-HF Trial Investigators</i><br /><b>Aims</b><br />In heart failure (HF), implantable hemodynamic monitoring devices have been shown to optimize therapy, anticipating clinical decompensation and preventing hospitalization. Direct left-sided hemodynamic sensors offer theoretical benefits beyond pulmonary artery pressure (PAP) monitoring systems. We evaluated the safety, usability, and performance of a novel left atrial pressure (LAP) monitoring system in HF patients.<br /><b>Methods and results</b><br />The VECTOR-HF study(NCT03775161) was a first-in-human, prospective, multicenter, single-arm, clinical trial enrolling 30 patients with HF. The device consisted of an interatrial positioned leadless sensor, able to transmit LAP data wirelessly. After three months, a right heart catheterization (RHC) was performed to correlate mean pulmonary capillary wedge pressure (PCWP) with simultaneous mean LAP obtained from the device. Remote LAP measurements were then used to guide patient management. The miniaturized device was successfully implanted in all 30 patients, without acute Major Adverse Cardiac and Neurological Events (MACNE). At 3 months, freedom from short-term MACNE was 97%. Agreement between sensor-calculated LAP and PCWP was consistent, with a mean difference of -0.22±4.92mmHg, the correlation coefficient and the Lin\'s Concordance Correlation Coefficient values were equal to 0.79 (P<0.0001) and 0.776 (95%CI=0.582-0.886), respectively. Preliminary experience with VLAP-based HF management was associated with significant improvements in NYHA functional class (32% of patients reached NYHA II class at 6 months, P<0.005; 60% of patients at 12 months, P<0.005) and 6-minute walk-test distance (from 244.59±119.59m at baseline to 311.78±129.88m after 6 months, P<0.05, and 343.95±146.15m after 12 months, P<0.05).<br /><b>Conclusion</b><br />The V-LAP™ monitoring system proved to be generally safe and provided a good correlation with invasive PCWP. Initial evidence also suggests possible improvement in HF clinical symptoms. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 24 Apr 2023; epub ahead of print</small></div>

<div><h4>Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.</h4><i>Böhm M, Abdin A, Slawik J, Mahfoud F, ... Batailler C, Komajda M</i><br /><b>Aims</b><br />In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with heart failure and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of heart rate reduction and the significant treatment effect on outcomes among patients with HFrEF.<br /><b>Methods and results</b><br />The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days.<br /><b>Conclusion</b><br />Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta blockers at maximally tolerated doses.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 24 Apr 2023; epub ahead of print</small></div>

<div><h4>Biventricular Cardiac Power Reserve in Heart Failure and Preserved Ejection Fraction.</h4><i>Alogna A, Omar M, Popovic D, Sorimachi H, ... Pieske B, Borlaug BA</i><br /><b>Background</b><br />Cardiac and extracardiac abnormalities play important roles in heart failure with preserved ejection fraction (HFpEF). Biventricular cardiac power output (BCPO) quantifies the total rate of hydraulic work performed by both ventricles, suggesting that it may help to identify patients with HFpEF and more severe cardiac impairments to better individualize treatment.<br /><b>Methods and results</b><br />Patients with HFpEF (n = 398) underwent comprehensive echocardiography and invasive cardiopulmonary exercise testing. Patients were categorized as low BCPO reserve (n = 199, <median of 1.57 W) or preserved BCPO reserve (n = 199). As compared to those with preserved BCPO reserve, those with low reserve were older and leaner, with more atrial fibrillation, higher NT-proBNP levels, worse renal function, more impaired left ventricular (LV) global longitudinal strain, worse LV diastolic function and RV longitudinal function. Cardiac filling pressures and pulmonary artery pressures at rest were higher in low BCPO reserve, but central pressures were similar during exercise to those with preserved BCPO reserve. Exertional systemic and pulmonary vascular resistances were higher and exercise capacity was more impaired in those with low BCPO reserve. Reduced BCPO reserve was associated with increased risk for the composite endpoint of HF hospitalization or death over 2.9 (IQR 0.9-4.5) years of follow up (HR 2.77 [95%CI: 1.73-4.42], p < 0.0001).<br /><b>Conclusions</b><br />Inability to enhance biventricular CPO during exercise is associated with more advanced HFpEF, increased systemic and pulmonary vascular resistance, reduced exercise capacity and increased adverse events in patients with HFpEF. Novel therapies that enhance biventricular reserve merit further investigation for patients with this phenotype. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights from the EMPEROR-Preserved Trial.</h4><i>Sharma A, Ferreira JP, Zannad F, Pocock SJ, ... Butler J, Anker SD</i><br /><b>Background</b><br />In the EMPEROR-Preserved trial, empagliflozin improved clinical outcomes of patients with heart failure with preserved ejection fraction. In this pre-specified analysis, we aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function.<br /><b>Methods</b><br />Patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (CKD defined by an estimated glomerular filtration rate [eGFR] <60ml/min/1.73m<sup>2</sup> or urine albumin to creatinine ratio [UACR]>300mg/g). The primary and key secondary outcomes were (1) a composite of cardiovascular death or first HF hospitalization (primary outcome); (2) total number of HF hospitalization, (3) eGFR slope; and a prespecified exploratory composite kidney outcome including a sustained ≥ 40% decline in eGFR, chronic dialysis or renal transplant. The median follow-up was 26.2 months.<br /><b>Results</b><br />5,988 patients were randomized to empagliflozin or placebo, of whom 3,198 (53.5%) had CKD. Irrespective of CKD status, empagliflozin reduced the primary outcome (with CKD HR 0.80 [95% CI 0.69, 0.94], and without CKD HR 0.75 [95% CI 0.60 0.95], interaction P=0.67) and total (first and recurrent) hospitalizations for HF (with CKD 0.68, [95% CI 0.54, 0.86], and without CKD 0.89 [95% CI 0.66, 1.21], interaction P=0.17). Empagliflozin slowed the slope of eGFR decline by 1.43 (1.01, 1.85) ml/min/1.73m<sup>2</sup> /year in patients with CKD and 1.31 (0.88, 1.74) ml/min/1.73m<sup>2</sup> /year without CKD (interaction P=0.70). Empagliflozin did not reduce the pre-specified kidney outcome in patients with or without CKD (with CKD HR 0.97 [95% CI 0.71,1.34]; without CKD HR 0.92 [0.58, 1.48], interaction P=0.86) but slowed progression to macroalbuminuria and reduced the risk of acute kidney injury. The effect of empagliflozin on the primary composite outcome and the key secondary outcomes was consistent across 5 baseline eGFR categories (all interaction p-value > 0.05). Empagliflozin was well tolerated independent of CKD status.<br /><b>Conclusions</b><br />In EMPEROR-Preserved, empagliflozin had a beneficial effect on the key efficacy outcomes in patients with and without CKD. Overall, the benefit and safety of empagliflozin was consistent across a wide range of kidney function spectrum, down to a baseline eGFR of 20 ml/min/1.73m<sup>2</sup> .<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Contemporary insights into the epidemiology, impact and treatment of secondary tricuspid regurgitation across the heart failure spectrum.</h4><i>Heitzinger G, Pavo N, Koschatko S, Jantsch C, ... Bartko PE, Goliasch G</i><br /><b>Background</b><br />Tricuspid regurgitation secondary to heart failure (sTR) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of sTR across the entire heart failure (HF) spectrum are lacking yet are necessary for health care decision-making.<br /><b>Methods</b><br />This population-based study included data from 13469 patients with HF and sTR from the Viennese community over a 10-year period. Primary outcome was long-term mortality.<br /><b>Results</b><br />Overall, HF with preserved ejection fraction (HFpEF) was the most frequent (57%, n=7733) HF subtype and the burden of comorbidities was high. Severe sTR was present in 1514 patients (11%), most common among patients with reduced EF (HFrEF) (20%, n=496). Mortality of patients with sTR was higher than expected survival of sex- and age-matched community and independent of HF subtype (moderate sTR: Hazard ratio [HR] 6.32; 95% Confidence Interval [CI] 5.88-6.80, P<0.001, severe sTR: HR 9.04; 95% CI 8.27-9.87, P<0.001). In comparison to HF and no/mild sTR patients, mortality increased for moderate sTR (HR 1.58, 95%CI 1.48-1.69, P<0.001) and for severe sTR (HR 2.19, 95%CI 2.01-2.38, P<0.001). This effect prevailed after multivariate adjustment and was similar across all HF subtypes. In subgroup analysis severe sTR mortality-risk was more pronounced in younger patients (<70a). Moderate and severe sTR were rarely treated (3%, n = 147), despite availability of state-of-the-art facilities and universal health care.<br /><b>Conclusion</b><br />sTR is frequent, increasing with age and associated with excess mortality independent of HF subtype. Nevertheless, sTR is rarely treated surgically or percutaneously. With the projected increase in HF prevalence and population ageing the data suggest a major burden for health-care systems, that needs to be adequately addressed. Low-risk transcatheter treatment options may provide a suitable alternative. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Potential Global Impact of Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure.</h4><i>Talha KM, Butler J, Greene SJ, Aggarwal R, ... Vaduganathan M, Fonarow GC</i><br /><b>Aims</b><br />Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are effective across the spectrum of the left ventricular ejection fraction (LVEF) in heart failure (HF); however, population-wide medication use in eligible patients remains suboptimal. We evaluated the potential implications of optimal global implementation of SGLT-2 inhibitors in HF.<br /><b>Methods and results</b><br />A decision analytical study was performed using the global prevalence of HF from the Global Burden of Disease 2017 report. Exclusion criteria were applied using the NHANES to ascertain an SGLT-2 inhibitor-eligible population, which was mapped onto global LVEF distributions from the REPORT-HF registry. The number needed to treat for 3 years for the composite of worsening HF events and cardiovascular deaths was calculated from estimated event rates in the EMPEROR-Reduced, EMPEROR-Preserved, DAPA-HF, and DELIVER trials and projected onto the eligible population. An estimated 49,329,000 (95%CI, 43,882,000-54,929,000) HF patients would be eligible for SGLT-2 inhibitors across all LVEFs, including 25,651,000 (95%CI, 22,818,000-28,563,000) with LVEF of <40% and 23,678,000 (95%CI, 21,063,000-26,366,000) with LVEF >40%. Optimal implementation of SGLT-2 inhibitors would be projected to prevent/postpone 4,512,011 (95%CI, 4,013,686-5,024,232) to 5,986,943 (95%CI, 5,325,721-6,666,604) total worsening HF events and cardiovascular deaths over 3 years in patients with LVEF <40%. An additional 2,102,606 (95%CI, 1,870,394-2,341,301) to 2,557,224 (95%CI, 2,274,804-2,847,528) events would be prevented/postponed in patients with LVEF >40%. Among all eligible HF patients, irrespective of LVEF, 7,069,235 (95%CI, 6,288,490-7,871,760) to 8,089,549 (95%CI, 7,196,115-9,007,905) total worsening HF events and cardiovascular deaths would be prevented/postponed over this period.<br /><b>Conclusions</b><br />Optimal implementation of SGLT-2 inhibitors globally in HF is projected to prevent approximately 7-8 million worsening HF events and cardiovascular deaths over 3 years. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation.</h4><i>Filippatos G, Farmakis D, Butler J, Zannad F, ... Anker SD, EMPEROR-Preserved Trial Committees and Investigators</i><br /><b>Aims</b><br />Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF.<br /><b>Methods and results</b><br />In this predefined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any ECG before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p<0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF [HR=0.78(0.66,0.93) versus 0.78(0.64,0.95)], interaction p=0.96]. Empagliflozin also reduced total HF hospitalizations [HR=0.73(0.57,0.94) versus 0.72(0.54,0.95), interaction p=0.94] and annual eGFR decline (difference=1.368 versus 1.372 mL/min/1.73m<sup>2</sup> /year, interaction p=0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF.<br /><b>Conclusions</b><br />In patients with HF and ejection fraction above 40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Effect of Intravenous Iron Replacement on Recurrent Heart Failure Hospitalizations and Cardiovascular Mortality in Patients with Heart Failure and Iron Deficiency: A Bayesian Meta-Analysis.</h4><i>Anker SD, Shahzeb Khan M, Butler J, von Haehling S, ... Ponikowski P, Friede T</i><br /><b>Aims</b><br />Iron deficiency is common in patients with heart failure and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron-deficient HFrEF patients using consistent subgroup definitions across trials.<br /><b>Methods</b><br />Individual participant data was used from the FAIR-HF (n=459), CONFIRM-HF (n=304) and AFFIRM-AHF (n=1,108) trials. This data was re-analyzed following as closely as possible the approach taken in the analyses of IRONMAN (n=1,137), for which study level data was used. Definitions of outcomes and subgroups from the FAIR-HF, CONFIRM-HF and AFFIRM-AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin-Wei-Yang-Ying model, and the data were pooled using Bayesian random effect meta-analysis.<br /><b>Results</b><br />Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR: 0.73, 95% credible interval (CI) [0.48-0.99]; between-trial heterogeneity tau=0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR]: 1.49 , 95% CI [0.95-2.37], age < vs ≥69.4 years (RRR= 0.68 [0.40-1.15]), ischemic vs non-ischemic etiology of HF (RRR=0.73 [0.42-1.33]), transferrin saturation < vs ≥20% (RRR=0.75 [0.40-1.34]), estimated glomerular filtration rate (≤ vs >60 mL/min/1.73m<sup>2</sup> (RRR=0.97 [0.56-1.68]), haemoglobin < vs ≥ 11.8 (RRR=0.95 [0.53-1.60]), ferritin < vs ≥35 μg/L (RRR=1.26 [0.72-2.48]) and New York Heart Association Class II vs III/IV (RRR=0.91 [0.54-1.56]).<br /><b>Conclusions</b><br />Treatment of iron-deficient HFrEF patients with intravenous iron - namely with ferric carboxymaltose or ferric derisomaltose - results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Impact of multimorbidity on mortality in HFrEF: Which comorbidities matter most? - An analysis of PARADIGM-HF and ATMOSPHERE.</h4><i>Dewan P, Ferreira JP, Butt JH, Petrie MC, ... Jhund PS, McMurray JJ</i><br /><b>Aims</b><br />Multimorbidity, the coexistence of two or more chronic conditions, is synonymous with heart failure(HF). How risk related to comorbidities compare at individual and population levels is unknown. The aim of this study is to examine the risk related to comorbidities, alone and in combination, both at individual and population levels.<br /><b>Methods</b><br />Using two clinical trials in HF- the Prospective comparison of ARNI(Angiotensin Receptor Neprilysin Inhibitor) with ACEI(Angiotensin Converting Enzyme Inhibitor) to Determine Impact on Global Mortality and morbidity in HF trial(PARADIGM-HF) and the Aliskiren trial to Minimize OutcomeS in Patients with HF trial(ATMOSPHERE), we identified the ten most common comorbidities and examined 45 possible pairs. We calculated population attributable fractions(PAF) for all-cause death and relative excess risk due to interaction with Cox proportional hazard models.<br /><b>Results</b><br />Of 15 066 patients in the study, 14 133(93.7%) had at least one and 11 867(78.8%) had at least two of the ten most prevalent comorbidities. The greatest individual risk among pairs was associated with peripheral artery disease(PAD) in combinations with stroke(HR 1.73;95% CI 1.28-2.33) and anaemia(1.71;1.39-2.11). The combination of CKD and hypertension had the highest PAF(5.65%;95% CI 3.66 to 7.61). Two pairs demonstrated significant synergistic interaction(atrial fibrillation with CKD and coronary artery disease respectively) and one an antagonistic interaction(anaemia & obesity).<br /><b>Conclusions</b><br />In HF, the impact of multimorbidity differed at the individual-patient and population level, depending on the prevalence of and the risk related to each comorbidity, and the interaction between individual comorbidities. Patients with co-existent PAD and stroke were at greatest individual risk whereas, from a population perspective, co-existent CKD and hypertension mattered most This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Sodium and Potassium Changes During Decongestion with Acetazolamide - a prespecified analysis from the ADVOR trial.</h4><i>Dhont S, Martens P, Meekers E, Dauw J, ... Dupont M, Mullens W</i><br /><b>Aims</b><br />Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide.<br /><b>Methods and results</b><br />This is a prespecified sub-analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1-ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2±0.6 and 139±4 mmol/L in the acetazolamide arm versus 4.2±0.6 and 140±4 mmol/L in the placebo arm. Hypokalaemia (<3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatremia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatremia (p=0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non-significant over time (p=0.053) and had no significant impact on hypokalaemia incidence (p=0.061). Severe hypokalaemia (<3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p=0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels.<br /><b>Conclusions</b><br />Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatremia and improves decongestion over the entire range of baseline serum potassium and sodium levels. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Diagnostic Value of Reduced Left Atrial Compliance during Ergometry Exercise in Heart Failure with Preserved Ejection Fraction.</h4><i>Harada T, Kagami K, Shina T, Sorimachi H, ... Ishii H, Obokata M</i><br /><b>Aims</b><br />Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging in patients presenting with chronic dyspnea. We sought to determine the diagnostic value of reduced left atrial (LA) compliance during exercise to diagnose HFpEF.<br /><b>Methods and results</b><br />Ergometry exercise stress echocardiography was performed in 225 patients with HFpEF and 262 non-HF controls (non-cardiac dyspnea: NCD) in Protocol 1, where the diagnosis of HFpEF was defined by the HFA-PEFF algorithm. In Protocol 2, the diagnosis of HFpEF was ascertained by exercise right heart catheterization in 67 participants (49 HFpEF and 18 NCD). Speckle-tracking echocardiography was performed at rest and during exercise to determine LA compliance (ratio of LA reservoir strain to E/e\'). As compared with NCD, patients with HFpEF demonstrated decreased LA reservoir strain and compliance at rest, and these differences further increased during exercise in Protocol 1. Exercise LA compliance discriminated HFpEF from NCD (AUC 0.87, p<0.0001), with a superior diagnostic ability to exercise E/e\' ratio (DeLong p=0.005). Exercise LA compliance demonstrated incremental diagnostic value over clinical factors (age, systemic hypertension, and atrial fibrillation) and resting LA compliance (χ<sup>2</sup> 212.4 vs 166.2, p<0.0001). These findings were confirmed in Protocol 2.<br /><b>Conclusion</b><br />LA compliance during exercise demonstrated superior diagnostic ability to exercise E/e\' ratio, with incremental diagnostic value over the resting LA compliance. Exercise LA compliance may enhance the diagnosis of HFpEF among patients with dyspnea. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>A machine learning derived echocardiographic algorithm identifies people at risk of heart failure with distinct cardiac structure, function, and response to spironolactone: findings from the HOMAGE trial.</h4><i>Kobayashi M, Huttin O, Ferreira JP, Duarte K, ... Girerd N, HOMAGE Trial Committees and Investigators</i><br /><b>Background</b><br />An echocardiographic algorithm derived by machine learning (e\'VM) characterizes preclinical individuals with different cardiac structure and function, biomarkers, and long-term risk of heart failure (HF). Our aim was the external validation of the e\'VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone.<br /><b>Methods</b><br />The HOMAGE (Heart OMics in Aging) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e\'VM algorithm was applied to 416 participants (mean age 74±7years, 25% women) with available echocardiographic variables (i.e., e\' mean, left ventricular [LV] end-diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e\'VM phenotypes.<br /><b>Results</b><br />A majority (>80%) had either \"diastolic changes (D)\", or \"diastolic changes with structural remodeling (D/S)\" phenotype. D/S phenotype had the highest LVMi, left atrial volume, E/e\', natriuretic peptide and troponin levels (all p<0.05). Spironolactone significantly reduced E/e\' and b-type natriuretic peptide (BNP) levels in D/S phenotype (p<0.01), but not in other phenotypes (p>0.10; P<sub>interaction</sub> <0.05 for both). These interactions were not observed when considering guideline-recommended echocardiographic structural and functional abnormalities. The magnitude of effects of spironolactone on LVMi, left atrial volume and a type I collagen marker was numerically higher in D/S phenotype than D phenotype but the interaction test did not reach significance.<br /><b>Conclusions</b><br />In the HOMAGE trial, the e\'VM algorithm identified echocardiographic phenotypes with distinct responses to spironolactone as assessed by changes in E/e\' and BNP. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Apr 2023; epub ahead of print</small></div>

<div><h4>Geographic Differences in Patients With Acute Myocardial Infarction in The PARADISE-MI Trial.</h4><i>Butt JH, Claggett BL, Miao ZM, Jering KS, ... McMurray JJ, Pfeffer MA</i><br /><b>Introduction</b><br />The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments, and outcomes. We examined these differences in PARADISE-MI.<br /><b>Methods and results</b><br />23.0% were randomized in Eastern Europe/Russia, 17.5% in Western Europe, 12.2% in Southern Europe, 10.1% in Northern Europe, 12.0% in Latin America (LA), 9.3% in North America (NA), 10.0% in East/South-East Asia and 5.8% in South Asia (SA). Those from Asia, particularly SA, were different from patients enrolled in the other regions, being younger and thinner. They also differed in terms of comorbidities (high prevalence of diabetes and low prevalence of AF), type of MI (more often STEMI), and treatment (low rate of primary PCI). By contrast, patients from LA did not differ meaningfully from those randomized in Europe or NA. Use of ACE-inhibitor/ARB (34.8%) and beta-blockers (65.5%) was low in SA, whereas MRA use was lowest in NA (22%) and highest in Eastern Europe/Russia (53%). Rates of the primary composite outcome of cardiovascular death or incident HF varied two-fold among regions, with the lowest rate in SA (4.6/100person-years) and the highest in LA (9.2/100person-years). Rates of incident HF varied almost six-fold among regions, with the lowest rate in SA (1.0/100person-years) and the highest in Northern Europe (5.9/100person-years). The effect of sacubitril/valsartan was not modified by region.<br /><b>Conclusion</b><br />In PARADISE-MI, there were substantial regional differences in patient characteristics, treatments and outcomes. Although the generalizability of these findings to a \"real-world\" unselected population may be limited, these findings underscore the importance of considering both regional and within-region differences when designing global clinical trials.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 11 Apr 2023; epub ahead of print</small></div>

<div><h4>The blunted loop diuretic response in acute heart failure is driven by reduced tubular responsiveness rather than insufficient tubular delivery.</h4><i>Biegus J, Zymliński R, Testani J, Fudim M, ... Ponikowska B, Ponikowski P</i><br /><b>Aims</b><br />Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness.<br /><b>Methods and results</b><br />We conducted a prospective, observational study of fifty patients with acute heart failure patients divided into two groups based on previous furosemide use: furosemide naïve n=28 (56%) and chronic furosemide users n=22 (44%). Each patient received a protocol-derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints, all p<0.05. Urine furosemide delivery was similar in furosemide naïve vs. chronic users after accounting for differences in eGFR: 28.02 [21.03-35.89] vs 29.70 [18.19-34.71] mg, respectively, p=0.87. However, the tubular response to delivered diuretic was dramatically higher in naïve vs. chronic users, i.e.: the urine volume per 1μg/ml of urine furosemide at 2h was: 148.6±136.1 vs 50.6±56.1 ml, p=0.005.<br /><b>Conclusions</b><br />Patients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 11 Apr 2023; epub ahead of print</small></div>

<div><h4>The Win Ratio Method in Heart Failure Trials: Lessons Learnt From Empulse.</h4><i>Pocock SJ, Ferreira JP, Collier TJ, Angermann CE, ... Zeller C, Voors AA</i><br /><b>Aims</b><br />The EMPULSE trial evaluated the clinical benefit of empagliflozin versus placebo using the stratified win ratio approach in 530 patients with acute heart failure (HF) after initial stabilization. We aim to elucidate how this method works and what it means, thereby giving guidance for use of the win ratio in future trials.<br /><b>Methods and results</b><br />The primary trial outcome is a hierarchical composite of death, number of heart failure (HF) events, time-to-first HF event, or a 5-point + difference in KCCQ-TSS change at 90 days. In an overall (unstratified) analysis we show how comparison of all 265 x 265 patients pairs contribute to \"wins\" for empagliflozin and placebo at all four levels of the hierarchy, leading to an unstratified win ratio of 1.38 (95% CI 1.11, 1.71) P = 0.0036. How such a win ratio should (and should not) be interpreted is then described. The more complex primary analysis using a stratified win ratio is then presented in detail leading to a very similar overall result. Win ratios for de novo acute HF and decompensated chronic HF patients were 1.29 and 1.39 respectively, their weighted combination yielding an overall stratified win ratio of 1.36 (95% CI 1.09, 1.68) P = 0.0054. Alternative ways of including HF events and KCCQ scores in the clinical hierarchy are presented, leading to recommendations for their use in future trials. Specifically, inclusion of both number of HF events and time-to-first HF event appears an unnecessary complication. Also, the use of a 5-point margin for KCCQ score paired comparisons is not statistically necessary.<br /><b>Conclusions</b><br />The EMPULSE trial findings illustrate how deaths, clinical events and patient-reported outcomes can be integrated into a win ratio analysis strategy that yields clinically meaningful findings of patient benefit. This has implications for future trial designs that recognize the clinical priorities of patient evaluation and the need for efficient progress towards approval of new treatments. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 10 Apr 2023; epub ahead of print</small></div>

<div><h4>The small molecule ACM-001 improves cardiac function in a rat model of severe cancer cachexia.</h4><i>Poetsch MS, Palus S, Van Linthout S, von Haehling S, ... Anker SD, Springer J</i><br /><b>Aims</b><br />Cachexia, a common manifestation of malignant cancer, is not only associated with weight loss, but also with severe cardiac atrophy and impaired cardiac function. Here, we investigated the effects of ACM-001 (0.3 or 3mg/kg/d) in comparison to carvedilol (3 or 30mg/kg/d), metropolol (50 or 100mg/kg/d), nebivolol (1 or 10mg/kg/d) and tertatolol (0.5 or 5 mg/kg/d) on cardiac mass and function in a rat cancer cachexia model.<br /><b>Methods</b><br />Young male Wistar Han rats were inoculated with 10<sup>8</sup> Yoshida hepatoma AH-130 cells ip and treated once daily with verum or placebo by gavage. Cardiac function (echocardiography), body weight and body composition (NMR-Scans) were assessed. The hearts of animals were euthanized on day 11 (placebo and 3 mg/kg/d ACM-001) were used for signaling studies.<br /><b>Results</b><br />Beta-blockers had no effect on tumour burden. ACM-001 reduced body weight loss (placebo: -34±2.4g vs 3mg/kg/d ACM-001: -14.8±8.4g, p=0.033). Lean mass wasting was attenuated (placebo: -16.5±2.34g vs 3mg/kg/d ACM-001: -2.4±6.7g, p=0.037), while fat loss was similar (p=0.4) on day 11. Placebo animals lost LVmass (-101±14mg), which was prevented only by 3mg/kg/d ACM-001 (7±25mg, 0<0.01 vs placebo). ACM-001 improved the EF (ΔEF: placebo: -24.3±2.6, 3mg/kg/d ACM-001: 0.1±2.9, p<0.001). Cardiac output was 50% lower in the placebo group (-41±4mL/min) compared to baseline, while 3mg/kg/d ACM-001 preserved cardiac output (-5±8, p<0.01). The molecular mechanisms involve inhibition of protein degradation and activation of protein synthesis pathways.<br /><b>Conclusion</b><br />This study shows that 3mg/kg/d ACM-001 restores the anabolic/catabolic balance in cardiac muscle leading to improved function. Moreover, not all beta-blockers have similar effects. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 31 Mar 2023; epub ahead of print</small></div>

<div><h4>Effect of Vericiguat on Left Ventricular Structure and Function in Patients with Heart Failure with Reduced Ejection Fraction: The VICTORIA Echocardiographic Substudy.</h4><i>Pieske B, Pieske-Kraigher E, Lam CSP, Melenovský V, ... Armstrong PW, VICTORIA Study Group</i><br /><b>Background</b><br />Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodeling with vericiguat in patients with HF with reduced ejection fraction (HFrEF).<br /><b>Aim</b><br />To compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF.<br /><b>Methods</b><br />Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co-primary endpoints were changes in LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading was performed by an echocardiographic core laboratory blinded to treatment assignment.<br /><b>Results</b><br />A total of 419 patients (208 vericiguat, 211 placebo) with high-quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7±26.8 to 56.8±30.4 mL/m<sup>2</sup> ; p<0.01) and LVEF significantly increased (33.0±9.4% to 36.1±10.2%; p<0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI -3.8±15.4 vs. -7.1±20.5 mL/m<sup>2</sup> ; p=0.07 and LVEF +3.2±8.0% vs. +2.4±7.6%; p=0.31). The absolute rate per 100 pt-years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8%) than the placebo group (29.6%) (p=0.07).<br /><b>Conclusions</b><br />In this pre-specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high-risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat\'s benefit in HFrEF.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 30 Mar 2023; epub ahead of print</small></div>

<div><h4>Ventricular Stiffening and Chamber Contracture in Heart Failure with Higher Ejection Fraction.</h4><i>Popovic D, Alogna A, Omar M, Sorimachi H, ... Burkhoff D, Borlaug BA</i><br /><b>Background</b><br />Ancillary analyses from clinical trials have suggested reduced efficacy for neurohormonal antagonists among patients with heart failure and preserved ejection fraction (HFpEF) and higher range EF.<br /><b>Methods</b><br />621 patients with HFpEF were grouped into those with low-normal LVEF (HFpEF<sub><65%</sub> , n=319, 50%≤LVEF<65%) or HFpEF<sub>≥65%</sub> (n=302, LVEF≥65%), and compared with 149 age-matched controls undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing. A sensitivity analysis was performed in a second noninvasive community-based cohort of patients with HFpEF (n=244) and healthy controls without cardiovascular disease (n=617).<br /><b>Results</b><br />Patients with HFpEF<sub>≥65%</sub> had smaller LV end diastolic volume (LVEDV) than HFpEF<sub><65%</sub> , but LV systolic function assessed by preload recruitable stroke work and stroke work/EDV was similarly impaired. Patients with HFpEF<sub>≥65%</sub> displayed an end diastolic pressure volume relationship (EDPVR) that was shifted leftward, with increased LV diastolic stiffness constant β in both invasive and community-based cohorts. Cardiac filling pressures and pulmonary artery pressures at rest and during exercise were similarly abnormal in all EF subgroups. While patients HFpEF<sub>≥57%</sub> displayed leftward shifted EDPVR, those with HFpEF<sub><57%</sub> had a rightward shifted EDPVR more typical of HFrEF.<br /><b>Conclusion</b><br />Most pathophysiologic differences in patients with HFpEF and higher EF are related to smaller heart size, increased LV diastolic stiffness, and leftward shift in the EDPVR. These findings may help to explain the absence of efficacy for neurohormonal antagonists in this group and raise a new hypothesis, that interventions to stimulate eccentric LV remodeling and enhance diastolic capacitance may be beneficial for patients with HFpEF and EF in the higher range.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 30 Mar 2023; epub ahead of print</small></div>

<div><h4>Cardio-hepatic syndrome in patients undergoing transcatheter mitral valve edge-to-edge repair.</h4><i>Stolz L, Orban M, Karam N, Lubos E, ... Massberg S, Hausleiter J</i><br /><b>Aims</b><br />The impact of the cardio-hepatic syndrome (CHS) on outcomes in patients undergoing transcatheter edge-to-edge repair (M-TEER) for relevant mitral regurgitation (MR) is unknown. The objectives of this study were three-fold: (I) to characterize the pattern of hepatic impairment, (II) to investigate the prognostic value of CHS, and (III) to evaluate the changes in hepatic function after M-TEER.<br /><b>Methods and results</b><br />Hepatic impairment was quantified by laboratory parameters of liver function. In accordance with existing literature, two types of CHS were distinguished: Ischemic type I CHS (elevation of both transaminases) and cholestatic type II CHS (elevation of two out of three parameters of hepatic cholestasis). The impact of CHS on two-year mortality was evaluated using a Cox model. The change in hepatic function after M-TEER was assessed by laboratory testing at follow-up. We analyzed 1083 patients who underwent M-TEER for relevant primary or secondary MR at four European centers between 2008 and 2019. Ischemic type I and cholestatic type II CHS were observed in 11.1% and 23.0% of patients, respectively. Predictors for two-year all-cause mortality differed by MR etiology. While in primary MR cholestatic type II CHS was independently associated with two-year mortality, ischemic CHS type I was an independent mortality predictor in SMR patients. At follow-up, patients with MR reduction ≤2+ (obtained in 90.7% of patients) presented with improved parameters of hepatic function (median reduction of 0.2mg/dl, 0.2U/l and 21U/l for bilirubin, ALT and GGT, respectively, p<0.01).<br /><b>Conclusions</b><br />CHS is frequently observed in patients undergoing M-TEER and significantly impairs two-year survival. Successful M-TEER may have beneficial effects on CHS.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 30 Mar 2023; epub ahead of print</small></div>

<div><h4>Current and future trial design in refractory cardiogenic shock.</h4><i>Arrigo M, Blet A, Morley-Smith A, Aissaoui Balanant N, ... Zeymer U, Mebazaa A</i><br /><AbstractText>Cardiogenic shock is a life-threatening syndrome of peripheral hypoperfusion and organ dysfunction due to primary cardiac disease. Few adequately designed randomized clinical trials provide guidance on the optimal management strategies, which frequently includes vasoactive drugs, circulatory and ventilatory support, and reversal of any underlying cause, including coronary revascularization in case of acute myocardial infarction. Management is largely based on experience rather than evidence-based recommendations and patient outcomes remain poor. Particular attention is currently given to refractory patients (i.e., not responding to medical treatment) with a growing number of studies investigating various modalities of mechanical circulatory support. This consensus document summarizes the output from the third Critical Care Clinical Trialists Workshop, where a group of experts convened to discuss, debate, and reflect on approaches related to trials in refractory cardiogenic shock, to provide recommendations for the design of future trials. Invited participants included clinical trialists, clinicians (including cardiologists, intensive care specialists, anaesthesiologists, and cardiac surgeons), epidemiologists, patient representatives, regulators from the United States and Europe, United States federal grant managers, and industry representatives. Special attention is given to current and future definitions of cardiogenic shock including refractory states, recent and ongoing clinical trials in refractory cardiogenic shock and future directions in light of the most recent literature.</AbstractText><br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 29 Mar 2023; epub ahead of print</small></div>

<div><h4>Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation.</h4><i>Oyama K, Giugliano RP, Ruff CT, Berg DD, ... Braunwald E, Morrow DA</i><br /><b>Aims</b><br />Cardiac functional and structural remodeling in patients with atrial fibrillation (AF) contributes to development of heart failure (HF) as their major cardiovascular comorbidity. Circulating biomarkers may reflect these cardiac alterations.<br /><b>Methods and results</b><br />ENGAGE AF-TIMI 48 was a randomized trial of edoxaban vs warfarin in 21,105 patients with AF. We performed a nested biomarker study in 8,765 patients, analyzing high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) at baseline and 12 months. Of 8765 patients, 5207 had a history of HF, among whom 3996 had known ejection fraction (EF): 926 with reduced EF (HFrEF; ≤40%), 1043 with mildly-reduced EF (HFmrEF; 40-49%), and 2027 with preserved EF (HFpEF; ≥50%). Elevated baseline hsTnT, NT-proBNP, and GDF-15 were associated with higher risk of hospitalization for HF (HHF)/HF death overall and in subpopulations defined by HF history and EF (P<0.001 for each). These associations of outcome with each biomarker were consistent regardless of a history of HF or EF (P-interaction>0.05 for each). Patients who had an increase in or had persistently elevated values in any of the three biomarkers over 12 months were at higher risk for HHF/HF death in overall population (P<0.001 for each biomarker and category).<br /><b>Conclusion</b><br />Serial measurement of hsTnT, NT-proBNP, and GDF-15 revealed that higher baseline values, and increasing or persistently elevated values over 1 year are associated with higher risk of HF outcomes in patients with AF regardless of HF history or HF phenotype based on EF.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 29 Mar 2023; epub ahead of print</small></div>

<div><h4>Deep phenotype characterization of hypertensive response to exercise: implications on functional capacity and prognosis across the heart failure spectrum.</h4><i>Pugliese NR, De Biase N, Del Punta L, Balletti A, ... Williams B, Masi S</i><br /><b>Aims</b><br />Limited evidence is available regarding the role of hypertensive response to exercise (HRE) in heart failure (HF). We evaluated the systolic blood pressure (SBP) to workload slope during exercise across the HF spectrum, investigating haemodynamic and prognostic correlates of HRE.<br /><b>Methods and results</b><br />We prospectively enrolled 369 patients with HF Stage C (143 had preserved [HFpEF], and 226 reduced [HFrEF] ejection fraction), 201 subjects at risk of developing HF (HF Stages A-B), and 58 healthy controls. We performed a combined cardiopulmonary exercise stress echocardiography testing. We defined HRE as the highest sex-specific SBP/workload slope tertile in each HF stage. Median SBP/workload slope was 0.53 mmHg/W (interquartile range 0.36-0.72); the slope was 39% steeper in women than men (p < 0.0001). After adjusting for age and sex, SBP/workload slope in HFrEF (0.47, 0.30-0.63) was similar to controls (0.43, 0.35-0.57) but significantly lower than Stages A-B (0.61, 0.47-0.75) and HFpEF (0.63, 0.42-0.86). Patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (all-cause mortality and hospitalization for cardiovascular reasons: hazard ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p = 0.005) and HFpEF (p < 0.001), but not HFrEF.<br /><b>Conclusion</b><br />A steeper SBP/workload slope is associated with impaired functional capacity across the HF spectrum and could be a more sensitive predictor of adverse events than absolute SBP values, mainly in patients in Stages A-B and HFpEF.<br /><br />© 2023 European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 29 Mar 2023; epub ahead of print</small></div>

<div><h4>Health Status Across Major Subgroup of Patients with Heart Failure and Preserved Ejection Fraction.</h4><i>Siddiqi TJ, Anker SD, Filippatos G, Ferreira JP, ... Packer M, Butler J</i><br /><b>Aims</b><br />There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anemia, and atrial fibrillation/flutter.<br /><b>Methods and results</b><br />In the EMPEROR-Preserved trial, Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12-, 32- and 52-weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5- and 10-point increase and 5-point decrease in KCCQ score from baseline to week-12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ-CSS score improved during follow-up; patients with atrial fibrillation/flutter at enrollment (P trend=0.014) and CKD (P trend<0.001) had less improvement. A 5-point increase in KCCQ-CSS at week-12 was associated with lower risk of cardiovascular death or HF hospitalization (5%), cardiovascular death (8%), and first HF hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ-CSS, -TSS and -OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (P-trend 0.153, 0.08 and 0.078, respectively).<br /><b>Conclusion</b><br />Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 28 Mar 2023; epub ahead of print</small></div>

<div><h4>Impact of left ventricular ejection fraction phenotypes on healthcare-resource utilization in hospitalized heart failure: A secondary analysis of REPORT-HF.</h4><i>Farmakis D, Tromp J, Marinaki S, Ouwerkerk W, ... Lam CS, FIlippatos G</i><br /><b>Background</b><br />Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly-reduced (HFmrEF) and preserved (HFpEF) left ventricular ejection fraction (LVEF) is limited.<br /><b>Methods</b><br />We analysed HCRU in relation to LVEF phenotypes, clinical features and in-hospital and 12-month outcomes in 16,943 patients hospitalized for HF in a worldwide registry.<br /><b>Results</b><br />HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; 2 or more in- and out-hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and ICU by 41%, 41% and 37%, respectively.Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively for beta-blockers). Compared to HFrEF, 12-month all-cause and cardiovascular mortality were lower for HFmrEF [adjusted hazard ratios, 0.76 (0.68-0.84) and 0.77 (0.68-0.88)] and HFpEF [0.62 (0.56-0.68) and 0.60 (0.53-0.68)]; 12-month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% versus 25% for HFrEF). In-hospital mortality, 12-month non-cardiovascular mortality and 12-month all-cause hospitalization were similar among groups.<br /><b>Conclusions</b><br />In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors were suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long-term cardiovascular outcomes than HFrEF, but similar risk for non-cardiovascular events. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 28 Mar 2023; epub ahead of print</small></div>

<div><h4>European Society of Cardiology Quality Indicators for the care and outcomes of adults with pulmonary arterial hypertension.</h4><i>Aktaa S, Gale CP, Brida M, Giannakoulas G, ... Rosenkranz S, Delcroix M</i><br /><b>Aims</b><br />To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH).<br /><b>Methods and results</b><br />We followed the ESC methodology for the development of QIs. This included the 1) identification of key domains of care for the management of PAH, 2) proposal of candidate QIs following systematic review of the literature, and 3) selection of a set of QIs using a modified-Delphi method. The process was undertaken in parallel with the writing of the 2022 European Society of Cardiology (ESC) / European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH; structural framework, diagnosis and risk stratification, initial treatment, follow up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected.<br /><b>Conclusion</b><br />This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>PATIENT REPORTED OUTCOME MEASURES AND PATIENT ENGAGEMENT IN HEART FAILURE CLINICAL TRIALS: MULTI-STAKEHOLDER PERSPECTIVES.</h4><i>Zannad F, Alikhaani J, Alikhaani S, Butler J, ... Yancy C, Spertus JA</i><br /><AbstractText>There are many consequences of heart failure (HF), including symptoms, impaired health-related quality of life (HRQoL), and physical and social limitations (functional status). These have a substantial impact on patients\' lives, yet are not routinely captured in clinical trials. Patient-reported outcomes (PROs) can quantify patients\' experiences of their disease and its treatment. Steps can be taken to improve the use of PROs in HF trials, in regulatory and payer decisions, and in patient care. Importantly, PRO measures (PROMs) must be developed with involvement of patients, family members, and caregivers from diverse demographic groups and communities. PRO data collection should become more routine not only in clinical trials but also in clinical practice. This may be facilitated by the use of digital tools and interdisciplinary patient advocacy efforts. There is a need for standardisation, not only of the PROM instruments, but also in procedures for analysis, interpretation and reporting PRO data. More work needs to be done to determine the degree of change that is important to patients and that which is associated with increased risks of clinical events. This \"minimal clinically important difference (MCID)\" requires further research to determine thresholds for different PROMs, to assess consistency across trial populations, and to define standards for improvement that warrant regulatory and reimbursement approvals. PROs are a vital part of patient care and drug development, and more work should be done to ensure that these measures are both reflective of the patient experience and that they are more widely employed.</AbstractText><br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 16 Mar 2023; epub ahead of print</small></div>

<div><h4>Characteristics and outcomes of patients with a history of cancer recruited to heart failure trials.</h4><i>Dobbin SJH, Shen L, Petrie MC, Packer M, ... Lang NN, Jhund PS</i><br /><b>Aims</b><br />Heart failure (HF) therapy trials usually exclude cancer patients. We examined the association between cancer history and outcomes in trial participants with HF and reduced (HFrEF) or preserved ejection fraction (HFpEF).<br /><b>Methods and results</b><br />We combined PARADIGM-HF and ATMOSPHERE, which enrolled HFrEF patients (n = 15 415) and we pooled HFpEF patients (ejection fraction ≥45%) enrolled in PARAGON-HF and CHARM-Preserved (n = 7363). The associations between cancer history, cardiovascular (CV) death, HF hospitalization, non-CV and all-cause death in these trials were examined. Incident cancer diagnoses during these trials were also measured. There were 658 (4.3%) and 624 (8.5%) patients with a cancer history in the HFrEF and HFpEF trials, respectively. HFrEF patients with a cancer history had a higher risk of HF hospitalization (adjusted hazard ratio [HR] 1.28; 95% confidence interval [CI] 1.07-1.52, p = 0.007) and non-CV death (adjusted HR 1.57; 95% CI 1.16-2.12, p = 0.003) than those without. The risks of other outcomes were similar. There were no differences in the risk of any outcome in HFpEF patients with and without a cancer history. Adjusting for age and sex, the incidence of new cancer in the HFrEF and HFpEF trials was 1.09 (95% CI 0.83-1.36) and 1.07 (95% CI 0.81-1.32) per 100 person-years, respectively.<br /><b>Conclusions</b><br />Although participants in HFrEF trials with a cancer history had higher risks of HF hospitalization and non-CV death than those without, the risks of CV and all-cause death were similar. Outcomes in HFpEF patients with and without a cancer history were similar. Incident cancer diagnoses were similar in HFrEF and HFpEF trials.<br /><br />© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 15 Mar 2023; epub ahead of print</small></div>

<div><h4>Left ventricular wall thickness and severity of cardiac disease in women and men with transthyretin amyloidosis.</h4><i>Aimo A, Tomasoni D, Porcari A, Vergaro G, ... Emdin M, Rapezzi C</i><br /><b>Aims</b><br />Cardiac amyloidosis (CA) is due to a deposition of amyloid fibrils in the heart causing an increase in wall thickness. A left ventricular (LV) wall thickness ≥12 mm plus at least one red flag should raise the suspicion of CA. As normal values of LV wall thickness are lower in women, the adoption or the same cut-off values for men and women could lead to underdiagnosis or delayed diagnosis in women. We investigated the relationship between LV wall thickness and the severity of cardiac involvement in women and men with transthyretin (ATTR) CA.<br /><b>Methods and results</b><br />We evaluated 330 consecutive patients diagnosed with ATTR-CA at three centres (Pisa, n = 232; Brescia, n = 69; Trieste, n = 29). Interventricular septum (IVS) and posterior wall (PW) thickness values were lower in women (n = 53, 16%) than men, but most differences were abolished when indexing by body surface area (BSA), height, or height<sup>2.7</sup> , suggesting similar disease severity when accounting for the smaller body size of women. PW thickness indexed for height<sup>2.7</sup> was even higher in women. We also searched for correlations between IVS and PW thickness and other indicators of the severity of cardiac disease. IVS values indexed by height<sup>2.7</sup> displayed tighter associations with N-terminal pro-B-type natriuretic peptide values than non-indexed IVS values. Similarly, indexed values displayed closer relationships with relative wall thickness, E/e\' ratio, and tricuspid annular plane systolic excursion.<br /><b>Conclusions</b><br />Indexed LV wall thickness values, particularly by height<sup>2.7</sup> , reflect more accurately the severity of cardiac involvement than non-indexed values.<br /><br />© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 15 Mar 2023; epub ahead of print</small></div>

<div><h4>Impact of mitral regurgitation in patients with acute heart failure: insights from the RELAX-AHF-2 trial.</h4><i>Pagnesi M, Adamo M, Ter Maaten JM, Beldhuis IE, ... Teerlink JR, Metra M</i><br /><b>Aims</b><br />The impact of mitral regurgitation (MR) in patients hospitalized for acute heart failure (AHF) is not well established. We assessed the role of MR in patients enrolled in the Relaxin in Acute Heart Failure 2 (RELAX-AHF-2) trial.<br /><b>Methods and results</b><br />Patients enrolled in RELAX-AHF-2 with available data regarding MR status were included in this analysis. Baseline characteristics, in-hospital data, and clinical outcomes through 180-day follow-up were evaluated. The impact of moderate/severe MR was assessed. Among 6420 AHF patients with known MR status, 1810 patients (28.2%) had moderate/severe MR. Compared to patients with no/mild MR, those with moderate/severe MR were more likely to have history of heart failure (HF), prior HF hospitalization, more comorbidities, symptoms/signs of HF, lower left ventricular ejection fraction and higher N-terminal pro-B-type natriuretic peptide levels. Moderate/severe MR was associated with longer length of hospital stay, higher rates of residual dyspnoea, increased jugular venous pressure through the index hospitalization and a higher unadjusted risk of the composite of cardiovascular (CV) death or rehospitalization for HF/renal failure (RF) through 180 days (crude hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.03-1.27, p = 0.01). The association between moderate/severe MR and poorer outcomes was not maintained in a multivariable model including several covariates of interest (adjusted HR 1.03, 95% CI 0.91-1.17, p = 0.65). Similar findings were observed for HF/RF rehospitalization alone.<br /><b>Conclusions</b><br />In patients with AHF, moderate/severe MR was associated with a worse clinical profile but did not have an independent prognostic impact on clinical outcomes.<br /><br />© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 13 Mar 2023; epub ahead of print</small></div>

<div><h4>Disproportionate exercise-induced pulmonary hypertension in relation to cardiac output in heart failure with preserved ejection fraction: a non-invasive echocardiographic study.</h4><i>Saito Y, Obokata M, Harada T, Kagami K, ... Okumura Y, Ishii H</i><br /><b>Aims</b><br />Pulmonary hypertension (PH) and pulmonary vascular remodelling are common in patients with heart failure with preserved ejection fraction (HFpEF). Many patients with HFpEF demonstrate an abnormal pulmonary haemodynamic response to exercise that is not identifiable at rest. This can be estimated non-invasively by the mean pulmonary artery pressure-cardiac output relationship (mPAP/CO slope). We sought to characterize the pathophysiology of disproportionate exercise-induced PH in relation to CO (DEi-PH) and its prognostic impact in patients with HFpEF.<br /><b>Methods and results</b><br />A total of 345 patients (166 HFpEF and 179 controls) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. DEi-PH was defined as the mPAP/CO slope >5.2 mmHg/L/min (median value). At rest, there were no differences in right ventricular (RV) function and severity of PH between HFpEF patients with and without DEi-PH. Compared with controls (n = 179) and HFpEF without DEi-PH (n = 83), HFpEF with DEi-PH (n = 83) demonstrated worse exercise capacity (lower peak oxygen consumption), depressed RV systolic function, impaired RV-pulmonary artery coupling, limitation in CO augmentation, more right-sided congestion, and worse ventilatory efficiency (higher minute ventilation vs. carbon dioxide volume) during peak exercise. Kaplan-Meier analyses showed that HFpEF patients with DEi-PH had higher rates of composite outcomes of all-cause mortality or heart failure events than those without (log-rank p = 0.0002).<br /><b>Conclusion</b><br />Patients with HFpEF and DEi-PH demonstrated distinct pathophysiologic features that become apparent only during exercise. These data suggest that DEi-PH is a pathophysiologic phenotype of HFpEF and reinforce the importance of exercise stress echocardiography for detailed characterization of HFpEF.<br /><br />© 2023 European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 13 Mar 2023; epub ahead of print</small></div>

<div><h4>Autonomic and respiratory consequences of altered chemoreflex function: clinical and therapeutic implications in cardiovascular diseases.</h4><i>Giannoni A, Borrelli C, Gentile F, Sciarrone P, ... Emdin M, Passino C</i><br /><AbstractText>The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases.</AbstractText><br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 12 Mar 2023; epub ahead of print</small></div>

<div><h4>Diagnostic Pathways to Wild-Type Transthyretin Amyloid Cardiomyopathy: a Multicenter Network Study.</h4><i>Tini G, Milani P, Zampieri M, Caponetti AG, ... Palladini G, Canepa M</i><br /><b>Background</b><br />Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis.<br /><b>Objectives</b><br />To describe characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival.<br /><b>Methods</b><br />This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different \'pathways\' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint.<br /><b>Results</b><br />1281 ATTRwt-CA patients were included in the study. Diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of NYHA III-IV and chronic kidney disease. Survival was significantly worse in the HF vs. other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA III-IV and some comorbidities but not the HF pathway were independently associated with worse survival.<br /><b>Conclusions</b><br />Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself. This article is protected by copyright. All rights reserved.<br /><br />This article is protected by copyright. All rights reserved.<br /><br /><small>Eur J Heart Fail: 12 Mar 2023; epub ahead of print</small></div>

<div><h4>Safety and performance of a novel implantable sensor in the inferior vena cava under acute and chronic intravascular volume modulation.</h4><i>Sheridan SW, Wetterling F, Testani JM, Borlaug BA, ... Sweeney F, Burkhoff D</i><br /><b>Aims</b><br />The management of congestion is one of the key treatment targets in heart failure. Assessing congestion is, however, difficult. The purpose of this study was to investigate the safety and dynamic response of a novel, passive, inferior vena cava (IVC) sensor in a chronic ovine model.<br /><b>Methods and results</b><br />A total of 20 sheep divided into three groups were studied in acute and chronic in vivo settings. Group I and Group II included 14 sheep in total with 12 sheep receiving the sensor and two sheep receiving a control device (IVC filter). Group III included an additional six animals for studying responses to volume challenges via infusion of blood and saline solutions. Deployment was 100% successful with all devices implanted; performing as expected with no device-related complications and signals were received at all observations. At similar volume states no significant differences in IVC area normalized to absolute area range were measured (55 ± 17% on day 0 and 62 ± 12% on day 120, p = 0.51). Chronically, the sensors were completely integrated with a thin, reendothelialized neointima with no loss of sensitivity to infused volume. Normalized IVC area changed significantly from 25 ± 17% to 43 ± 11% (p = 0.007) with 300 ml infused. In contrast, right atrial pressure required 1200 ml of infused volume prior to a statistically significant change from 3.1 ± 2.6 mmHg to 7.5 ± 2.0 mmHg (p = 0.02).<br /><b>Conclusion</b><br />In conclusion, IVC area can be measured remotely in real-time using a safe, accurate, wireless, and chronic implantable sensor promising to detect congestion with higher sensitivity than filling pressures.<br /><br />© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 09 Mar 2023; epub ahead of print</small></div>

<div><h4>Transcatheter mitral valve replacement or repair for secondary mitral regurgitation: a propensity score-matched analysis.</h4><i>Ludwig S, Kalbacher D, Ali WB, Weimann J, ... Conradi L,  on behalf of the CHOICE-MI and the EuroSMR Investigators (see online Appendix S1)</i><br /><b>Aims</b><br />This study aimed to compare outcomes after transcatheter mitral valve replacement (TMVR) and mitral valve transcatheter edge-to-edge repair (M-TEER) for the treatment of secondary mitral regurgitation (SMR).<br /><b>Methods and results</b><br />The CHOICE-MI registry included 262 patients with SMR treated with TMVR between 2014 and 2022. The EuroSMR registry included 1065 patients with SMR treated with M-TEER between 2014 and 2019. Propensity score (PS) matching was performed for 12 demographic, clinical and echocardiographic parameters. Echocardiographic, functional and clinical outcomes out to 1 year were compared in the matched cohorts. After PS matching, 235 TMVR patients (75.5 years [70.0, 80.0], 60.2% male, EuroSCORE II 6.3% [interquartile range 3.8, 12.4]) were compared to 411 M-TEER patients (76.7 years [70.1, 80.5], 59.0% male, EuroSCORE II 6.7% [3.9, 12.4]). All-cause mortality was 6.8% after TMVR and 3.8% after M-TEER at 30 days (p = 0.11), and 25.8% after TMVR and 18.9% after M-TEER at 1 year (p = 0.056). No differences in mortality after 1 year were found between both groups in a 30-day landmark analysis (TMVR: 20.4%, M-TEER: 15.8%, p = 0.21). Compared to M-TEER, TMVR resulted in more effective mitral regurgitation (MR) reduction (residual MR ≤1+ at discharge for TMVR vs. M-TEER: 95.8% vs. 68.8%, p < 0.001), and superior symptomatic improvement (New York Heart Association class ≤II at 1 year: 77.8% vs. 64.3%, p = 0.015).<br /><b>Conclusion</b><br />In this PS-matched comparison between TMVR and M-TEER in patients with severe SMR, TMVR was associated with superior reduction of MR and superior symptomatic improvement. While post-procedural mortality tended to be higher after TMVR, no significant differences in mortality were found beyond 30 days.<br /><br />© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.<br /><br /><small>Eur J Heart Fail: 08 Mar 2023; epub ahead of print</small></div>