Abstract Heart failure (HF) is characterized by complex systemic alterations that extend beyond the local environment in the myocardium, yet the molecular signatures present in peripheral, circulating immune cells remain incompletely defined. In mice, a shift toward pro-inflammatory macrophages has been linked to fibrosis and heart failure. Epigenetic modulators have also been associated with cardiac dysregulation and inflammation, including promotion of hypertrophy, fibroblast proliferation and arterial stiffness in rodents. For the current molecular study, we used biological material and an existing data set from a HF-cohort. To investigate HF-associated systemic changes in immune cells, we profiled the transcriptome and investigated the chromatin accessibility in peripheral white blood cells from patients with new onset HF (n=12) and compared with that of age- and gender-matched healthy controls (n=6). HF cases were stratified into heart failure with reduced ejection fraction (HFrEF; n=6) and heart failure with preserved ejection fraction (HFpEF; n=6) to explore phenotype-specific molecular patterns. In parallel, we evaluated data on 158 circulating plasma proteins to assess systemic inflammatory and metabolic signaling. Frozen EDTA whole blood samples were used for both bulk ATAC and bulk RNA sequencing. The plasma immune profile was retrieved from an existing data set from the HF-cohort where the plasma proteome has been investigated in detail by a multi-parameter approach. The transcriptomics data reveal that HFpEF cases have a more inflammatory-related systemic immune phenotype, while HFrEF cases have alterations in pathways correlated to metal- and potassium ion transport and regulation as well as neuron development and differentiation. The ATAC sequencing did not reveal major changes in the global chromatin landscape between the HF- phenotypes and/or controls. However, the integrative analysis combining the transcriptomic and ATAC sequencing data suggest 10 chromatin sites that are likely to impact transcription factor binding, and thereby also gene expression. Additionally, the integration of the data sets further emphasized differences, separating HFpEF, HFrEF and healthy controls into distinct groups. Finally, a primary analysis of the proteomics data showed a potential difference between the HF-phenotypes, highlighting proteins linked to inflammation, such as IL18BP, IL1RT2, SPON2 and SOD2. In conclusion, our findings suggest that there are fundamental mechanistic differences between HFpEF and HFrEF. This supports the hypothesis that HFpEF represents a hyper-inflammatory condition, which may have substantial clinical implications.Integrative analysis of RNA and ATAC seqFor image description, please refer to the figure legend and surrounding text.

Abstract Introduction Cardiac resynchronization therapy (CRT) is underutilized in women despite well-known clinical benefits. Several analyses have demonstrated sex differences in CRT response. In 2023, the Heart Rhythm Society upgraded CRT indications for women with left bundle branch block (LBBB) and QRS 120-149 ms from class 2a to class 1 but more studies are needed to understand sex differences in CRT response particularly in such patients. Purpose To compare 6-month post-implant left ventricular (LV) end-systolic volume (LVESV) changes in male and female patients with CRT devices in relation to QRS morphology and QRS width. Methods Individual patient level data were pooled from 5 randomized CRT trials (MIRACLE, MIRACLE ICD, REVERSE, Adaptive CRT, and ECG Belt). LVESV change was calculated as (LVESV at 6-month post implant - LVESV at baseline) / LVESV at baseline (%). LVESV change analysis using linear mixed models for 2 cohorts (Figure 1) were conducted to evaluate: (1) sex differences in LVESV change in CRT and No CRT patients from 3 studies; (2) sex differences in LVESV change among CRT patients from all 5 studies [a] by clear CRT indication class (per 2022 AHA/ACC/HFSA heart failure guidelines) based on QRS morphology, LV ejection fraction (LVEF), New York Heart Association (NYHA) class, and QRS width without adjustment, and [b] by QRS morphology, LVEF, NYHA class and QRS width adjusting for other covariates. Results Among the 2521 patients from 5 studies, 1840 were eligible (479 women) – met inclusion criteria (LBBB/non-LBBB, LVEF ≤50%, QRS ≥120 ms, NYHA I–IV), had CRT indication classified, and LVESV data. Of 1840 patients, 1230 (698 CRT, 532 No CRT) from 3 studies showed that female CRT patients had a greater reduction in LVESV compared to males (-22.9 % vs -9.1%, p<0.0001), while no significant sex difference in % LVESV change was seen in the No CRT group. Data from 1308 eligible CRT patients across all 5 studies showed that:[a] Female LBBB patients experienced greater reduction in LVESV than males for both QRS >150 ms (-25.6% vs -18.7%, p=0.0035) and QRS 120-149 ms (-13.7% vs -2.6%, p=0.0068), and the LVESV change in female LBBB patients with QRS 120-149 ms was comparable to that of male LBBB patients with QRS >150 ms; [b] Sex differences in LVESV change varied significantly by QRS morphology, NYHA class, and body mass index (BMI) - after adjusting for covariates, women showed a greater LVESV reduction than men in those with LBBB, NYHA I/II and lower BMI but this did not hold in non-LBBB, NYHA III/IV and higher BMI patients (Table 1). Conclusion Female CRT patients exhibit more reverse LV remodeling than males. Females with LBBB had greater LVESV reduction than men even with only moderately prolonged baseline QRS (120-149ms). Our findings reinforce the indications for CRT use, and improved outcomes in women, particularly those with symptomatic HF, LVEF ≤35%, LBBB and QRS 120-149ms highlighting the need for sex-specific QRS duration criteria.Figure 1For image description, please refer to the figure legend and surrounding text.Table 1 For image description, please refer to the figure legend and surrounding text.

Abstract Background The ARTESiA trial showed that apixaban reduces stroke and increases major bleeding compared to aspirin in patients with subclinical atrial fibrillation (SCAF). Purpose To assess the sex-specific efficacy and safety of apixaban versus aspirin in patients with SCAF. Methods We performed a pre-specified subgroup analysis of the ARTESiA trial according to sex. The primary endpoints were stroke/systemic embolism (SE) (efficacy) and major bleeding (safety). We adjusted for the individual components of the CHA2DS2-VA score. Results Female patients had a lower mean CHA2DS2-VA score than male patients (3.3±1.1 vs. 3.8±1.1; p<0.001). All of congestive heart failure, diabetes, prior stroke and coronary artery disease were less prevalent in female compared to male patients (all p<0.001). The proportion of patients with a CHA2DS2-VA score ≥4 was 35% in females and 52% in males (p<0.001). Among females, the crude rate of stroke/SE was 0.6%/year with apixaban and 0.9%/year with aspirin (adjusted hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.36-1.28); including 0.5%/year with apixaban and 0.7%/year with aspirin (HR=0.68; 95% CI 0.28-1.64) in those with a CHA2DS2-VA score <4 and 0.9%/year with apixaban and 1.4%/year with aspirin (HR=0.65, 95% CI 0.26-1.62) in those with a CHA2DS2-VA-score ≥4. Among males, the crude rate of stroke/SE was 0.9%/year on apixaban and 1.5%/year on aspirin (adjusted HR 0.61, 95% CI 0.41-0.91), including 0.9%/year with apixaban and 1.1%/year with aspirin (HR=0.82, 95% C I 0.45-1.49) in those with a CHA2DS2-VA score <4 and 0.9%/year with apixaban and 1.9%/year with aspirin (HR=0.48, 95% CI 0.28-0.83) in those with a CHA2DS2-VA score of ≥4. We did not find evidence for interaction of the reduction in stroke with apixaban vs. aspirin with sex (p for interaction=0.75). In female patients, the crude rate of major bleeding was 1.5%/year on apixaban and 1.1%/year on aspirin (adjusted HR 1.39, 95% CI 0.86-2.25), including 1.4%/year with apixaban and 0.8%/year with aspirin (HR=1.72, 95% CI 0.91-3.24) in those with a CHA2DS2-VA score <4 and 1.7%/year on apixaban and 1.6%/year on aspirin (HR=1.04, 95% CI 0.50-2.16) in those with CHA2DS2-VA score of ≥ 4. In male patients, the crude rate of major bleeding was 1.5%/year on apixaban and 1.2%/year on aspirin (adjusted HR 1.29, 95% CI 0.89-1.87), including 1.2%/year on apixaban and 1.3%/year on aspirin (HR=0.83, 95% CI 0.49-1.42) in those with a CHA2DS2-VA <4 and 1.9%/year on apixaban and 1.0%/year on aspirin (HR=1.92, 95% CI 1.13-3.26) in those with CHA2DS2-VA score ≥4. We did not find evidence for interaction of the increase in bleeding with apixaban vs. aspirin with sex (p for interaction=0.76). Conclusions The reduction in stroke/SE and the increase in major bleeding with apixaban compared to aspirin were consistent in female and male patients, including in high-risk patients with a CHA2DS2-VA score ≥4.Stroke or SE in female and male patientsMajor bleeding in female and male patien

Abstract Background Right ventricular pacing (RVP) is an established treatment in patients with atrioventricular block (AVB). However, a high burden of RVP may impair cardiac function, particularly in patients with pre-existing heart failure (HF). The aim of this study was to describe the characteristics and outcomes of patients with HF, irrespective of ejection fraction, by comparing those with high burden of RVP to those without. Methods Patients with a first recorded diagnosis of HF between January 2011 and December 2021 (index date) were identified from the Swedish National Patient Register and linked with several national registries, including the Swedish ICD and pacemaker registry. The exposed group included patients with assumed high burden of RVP at the HF diagnosis, defined as complete AVB as the main indication for pacemaker (PM) or implantable cardiac defibrillator (ICD) implantation). The unexposed group consisted of patients without device therapy at HF diagnosis or assumed low burden of RVP. Baseline characteristics and clinical outcomes were compared. Cox proportional hazard models were used to identify variables associated with subsequent upgrading to cardiac resynchronization therapy (CRT). In addition, a sensitivity analysis was performed comparing exposed patients with a subgroup of unexposed patients who had a PM or ICD at the time of HF diagnosis but without complete AVB. Results Among 220,752 patients with a first diagnosis of HF, 22,415 had a PM (88%) or an ICD (12%). Of these, 5,558 (25%) were classified as exposed to a high burden of RVP. The exposed group had a higher risk of cardiovascular death (HR 1.08 95% CI: 1.03-1.13) and first HF hospitalisation (HR 1.25 95% CI: 1.19-1.30) compared with the unexposed group, figure 1. During a median follow-up of 1.9 years, 637 exposed patients (11,5%) were upgraded to CRT, corresponding to an upgrading rate of 48 per 1000 person-year. Older age (HR 0.31 95% CI: 0.25-0.39) and hypertension (HR 0.83 95% CI: 0.69-0.99) were independently associated with a lower probability CRT upgrade, whereas male sex (HR 1.83 95% CI: 1.5-2.23) and higher educational level (HR 1.13 95% CI: 1.01-1.26) were associated with increased likelihood of upgrade. Conclusion A high burden of RVP in patients with HF is associated with increased risk of HF hospitalization and CV death. Despite this, few patients are upgraded to CRT, highlighting the need for improved identification and management of patients who may benefit from advanced pacing strategies.

Abstract Background Cardiac resynchronization therapy (CRT) is recommended for the treatment of heart failure (HF) patients with reduced ejection fraction and left bundle branch block (LBBB) but is still largely underused which may further deteriorate the HF condition. Studying the impact and factors related to delays in CRT with or without an Implantable cardioverter defibrillator (ICD) is fundamental to enhance CRT implementation in clinical practice. Methods We used a central ECG database together with National patient registries to identify LBBB patients with a QRS duration of more than 150 ms and estimated a class I indication for CRT based on a registered diagnosis of HF and ejection fraction < 35% (baseline date). We compared patient characteristics in those with CRT-D, CRT without defibrillator (CRT-P) and patients with an indication but without CRT. Factors associated with CRT-P or CRT-D were analyzed as well as factors related to delay in CRT utilization. Outcome parameters were HF hospitalization and combined total and CV mortality and the impact of the delay in CRT utilization on outcome was analysed. Results Of 5359 patients with LBBB and QRS > 150ms, 1268 (24%) developed a class I indication for CRT. Of these 31% received a CRT-P, 36% CRT-D and 33% were not implanted. Independent predictors for CRT-P were age > 75 years and for CRT-D ischemic heart failure aetiology, hypertension and male sex. Patients with CRT-D had similar HF hospitalization rate (hazard ratio (HR): 0.95, 95% (CI) 0.80-1.14) as patients with CRT-P. In contrast, patients indicated but not implanted with CRT had a significantly higher prevalence of HF hospitalization (HR: 1.65, CI 1.39-1.96). A delay in CRT use > 365 days (161 patients) from indication (baseline) was associated with increased risk of overall mortality and cardiovascular mortality compared to CRT implantation < 30 days from the indication (HR: 1.64, CI 1.05-2.55 and HR: 1.87, CI 1.10-3.18). Age > 75 years, male sex, paroxysmal atrial fibrillation, diabetes and ischemic heart disease were associated with significant delay in CRT use (>365 days). Conclusion In a large real-world setting, delay in CRT implantation was common and associated with increased mortality. The findings suggest a need for new methods to find and treat HF patients with an indication for CRT.

Abstract Background/Introduction Few contemporary studies are available for long term outcome in patients with new onset heart failure (HF) of the three 3 phenotypes; HF with preserved ejection fraction (HFpEF), mildly reduced (HFmrEF) and reduced EF (HFrEF). The Stockholm PREFERS study (Preserved and Reduced Ejection Fraction Epidemiological Regional Study) included new onset HF patients between 2014-18. Purpose To report and compare long term outcomes for patients with new onset HFpEF, vs HFmrEF and HFrEF. Methods Totally 547 patients, HFpEF n = 137 (25%), HFmrEF n = 61 (11%) and HFrEF n = 349 (64%) were included and followed to end of August 2021. Time to total and cardiovascular (CV) mortality and CV mortality and first HF hospitalizations were compared by log rank test and Cox regression models. All patients were followed at hospital-based HF clinics for guideline directed information and treatment. HFpEF patients were recommended optimal treatment for comorbidities including hypertension, diabetes, ischemic heart disease and atrial fibrillation, and RAAS-inhibition or diuretics. Primary endpoint: CV mortality and HF hospitalizations. Results Mean age was 76 (HFpEF), 71 (HFmrEF) and 67 (HFrEF) years (p<0.001). Female sex 49% (HFpEF), 30% (HFmrEF) and 30% (HFrEF) (p<0.001). Median follow up was 3.8 years (IQR 3.0;4.7). Median EF was 55%, 45% and 30% in HFpEF, HFmrEF, and HFrEF, respectively (p<0.001). All-cause mortality was 13% (n = 70), and CV mortality 7.3% (n = 40). The overall CV hospitalization rate was 13.9% (n = 76). The combined endpoint of CV mortality and HF hospitalizations was 21.2% (n = 116) and higher in HFpEF compared to HFrEF (Univariate Hazard ratio (HR) 2.3 (95% CI 2.0-2.5, p<0.001) and vs HFmrEF (HR 2.5; 2.1-2.6, p<0.001). In analysis adjusted for age, sex and diabetes, HFpEF had worse outcome vs HFrEF and HFmrEF (HR 1.5; 0.2-2.0, p<0.05). Conclusions New onset HFpEF patients have worse long term outcome vs new onset HFrEF and HFmrEF patients. There is a need for effective evidence based treatment in HFpEF.Figure 1

Background: Iron deficiency (ID) is associated with adverse prognosis in patients with heart failure. This study aims to investigate the relationship between ID and expression of genes involved in iron metabolism in human myocardium and skeletal muscle, focusing on Transferrin 1 receptor (TfR1), the main pathway of cellular iron uptake.Methods: Patients undergoing elective CABG were assessed prior to surgery with echocardiography and serum iron parameters. Core needle biopsies were collected from the left and right ventricle (LV, RV), the right atrium and intercostal skeletal muscle (SM). Gene expression analyses were done by mRNA sequencing.Results: Of 69 patients (median age 69 years, 91% men), 28% had ID. 26% had HFrEF, 25% had HFpEF phys-iology according to echocardiographic findings and NT-proBNP levels, and 49% had normal LV function. The expression of TfR1 was increased in patients with ID compared to patients without ID in ventricular tissue (p = 0.04) and in intercostal SM (p = 0.01). The increase in TfR1 expression in LV and RV was more pronounced when analysing patients with absolute ID (S-Ferritin<100 mu g/L). Analysing the correlation between various iron pa-rameters, S-Ferritin levels showed the strongest correlation with TfR1 expression. There was no correlation with NT-proBNP levels and no difference in TfR1 expression between different HF phenotypes.Conclusions: In patients undergoing elective CABG we found an association between ID and increased TfR1 expression in myocardium regardless of LV function, indicating physiologically upregulated TfR1 expression in the presence of ID to restore intracellular iron needs. Clinical Trial Registration: Clinicaltrials.gov NCT03671122

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Supported by Swedish Heart and Lung foundation and Stockholm County Council. Background/Introduction Cardiac resynchronization therapy (CRT) is a valuable treatment in selected patients with heart failure (HF) but is still underutilized. Aim We compared three informative data sources, which enrolled patients with HF at different organization setting and identified clinical, organizational, and level of care factors linked to CRT implantation in these cohorts. Methods Data from three large cohorts of patients with HF were compared. Patients with HF with reduced ejection fraction (HFrEF) in an ESC HF-Long Term Registry (ESC-HF-LT, n=25,621), a National HF Registry - Swede HF (n=156,621) and in the ESC-CRT Survey II (n=11088, all receiving CRT across 42 ESC countries), contributed data to the analysis. The ESC Survey II recruited patients at implanting centers, ESC-HF-LT at HF centers, whereas SwedeHF enrolled HF patients at different levels of care. Firstly, we compared patient characteristics, socio-economic and organizational factors between cohorts as well as between overlapping countries participating both in CRT Survey II and ESC HF LT. Secondly, we identified independent predictors of CRT use in the two registries using multivariable logistic regressions. Results Of the 1031 patients in ESC-HF-LT and the 5008 patients in Swede-HF, CRT was not used in 53-75 % of guideline- indicated patients. Women constituted 22% and median age ranged between 68-72 years. Guideline Directed Medical Therapy (GDMT), atrial fibrillation, previous myocardial infarction (SwedeHF) and HF hospitalization (ESC-HF-LT) was associated with more CRT use as was enrollment at university hospital and follow-up at HF center/Hospital. In Swede-HF above median income and higher education level were also independently associated with use of CRT. In the ESC-CRT Survey II (n=11.088) all patients received CRT with differences in the clinical indications between countries. Conclusion(s) CRT is an important treatment option for eligible patients with HF, which is still largely underused. The findings reported demonstrate that awareness of CRT indications as well as demographics, organizational and economic factors play an important role in CRT utilization.

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Medtronic. Background Left bundle branch block (LBBB) might be the first finding of cardiovascular diseases but it is also the target of cardiac resynchronization therapy (CRT) in heart failure (HF) with reduced ejection fraction (HFrEF). LBBB prognosis and the implication of CRT in an unselected real-world setting are of great potential clinical impact. Methods A central ECG database together with national registries has been screened to identify LBBB patients. Cox models were fitted to assess the hazard ratio (HR) of death, cardiovascular death (CVD) and HF hospitalization (HFH) according to gender and CRT use. A subdistribution of the hazard ratio (SHR) was used to account for non-cardiovascular death as a competing risk. Logistic regression was fitted to investigate characteristics associated with CRT use. Results Of 5359 patients with LBBB and QRS duration over 150ms, 36% were female. The median age was 76 years and males had a significantly higher risk of death after 5 years from the LBBB diagnosis. CRT, when indicated, has a large benefit on all-causes of death (HR: 0.53, 95% confidence intervals (CI): 0.42-0.67), CVD (HR: 0.53 CI: 0.39-0.71) and HFH (HR: 0.71 CI: 0.60-0.82), especially in the first 5 years after the indication. These results are consistent with the competing risk analysis. Conclusion In an unselected LBBB population, CRT is underused but extremely beneficial. Therefore it’s crucial to find ways of better implementing and understanding CRT utilization, focusing on characteristics that influence recommendations.

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Heart, Lung, and Blood Institute Background Many patients with heart failure who are considered for cardiac resynchronization therapy (CRT) have a history of (h/o) atrial fibrillation (AF) but there are doubts about the efficacy of CRT in patients with AF. Purpose To investigate the association of CRT on morbidity and mortality among patients with and without a h/o AF. Methods Original, patient-level data from five clinical trials of CRT that permitted enrolment of patients with a h/o AF were included: COMPANION, MADIT-CRT, BLOCK HF, REVERSE, and MIRACLE trial. Patients with permanent or persistent AF were excluded from these trials, and therefore from this analysis. The outcomes of interest were the composite endpoint of time to heart failure hospitalization (HFH) or all-cause mortality or all-cause mortality alone. The association of CRT (versus no CRT) with outcomes for patients with and without a h/o AF was assessed using a Bayesian-Weibull survival regression model with random terms for the trial-specific treatment effects and the trial-specific baseline hazard functions including an interaction between history of paroxysmal AF and CRT. All results are presented as hazard ratios (HRs) with 95% posterior credible intervals (CIs) and posterior probabilities of no association, adjusting for baseline characteristics. Results A total of 4062 patients were included, 661 (16.3%) of whom had a h/o AF. Patients with a h/o AF were older (mean [SD] age 68 [10] years versus 64 [11] years) and had a higher proportion of ischemic cardiomyopathy (67% versus 53%, p<0.001), a higher baseline serum creatinine (1.3 mg/dl versus 1.2 mg/dl, p<0.001), and a lower left ventricular ejection fraction (25% versus 26%, p<0.001). The HRs for all outcomes and the interaction term are shown in Table 1. For the overall population, CRT delayed the time to HFH or all-cause mortality (HR: 0.74, 95% CI: 0.62 – 0.87, p=0.005); for patients with a h/o AF, it did not (HR: 0.87, 95% CI: 0.64 to 1.19, p=0.37). In this patient-level meta-analysis, CRT was not associated with a reduction in mortality, overall or by h/o AF. Howevber, the interaction (estimate shown as a ratio of HRs) between those with or without a h/o AF and the effects of CRT was not significant for either outcome (Table 1). Conclusion In the largest post hoc analysis to date, we confirm the benefits of CRT in patients without a h/o AF in reducing HFH or mortality. There was no statistically significant interaction between CRT and h/o AF for any analysed outcome.

Background: Whether conduction system pacing (CSP) is an alternative option for cardiac resynchronization therapy (CRT) in patients with heart failure and reduced ejection fraction (HFrEF) remains to be learned. Objective: To assess the technical and echocardiographic outcomes of His Bundle pacing (HBP) and left bundle branch area pacing (LBBAP). Methods: This multi-center retrospective study included 121 patients who fulfilled CRT indications for HFrEF and received HBP or LBBAP. The implant and echocardiographic outcomes assessed. Conclusion: Both HBP and LBBAP resulted in significant ventricular resynchronization in patients with HFrEF. Large-scale randomized trials are needed to validate these outcomes and further investigate the different options available for CSP. Background: The societal guidelines recommend physiologic pacing for patients who are anticipated to require high burden ventricular pacing. This includes patients with a) AV block and LVEF between 35-50%, b) tachy-cardiomyopathy undergoing AV node ablation, c) chronic RV pacing induced cardiomyopathy, and d) failed CS lead implants as a rescue CRT strategy. There are limited data on the utility of left bundle branch area pacing (LBBAP) as an alternative to CRT in this patient sub-groups. Objective: To evaluate the feasibility and outcomes of LBBAP in patients eligible for CRT. Methods: Patients referred for pacemaker implantation at two academic centers between 02/2019-07/2021 were considered for LBBAP. LBBAP was performed by implanting the 3830 lumenless lead using the C315 fixed curve or C304 His deflectable sheath (Medtronic, MN). Implant success rates, complications, electrophysiological and echocardiographic parameters were assessed. Results: LBBAP was successful in 135/161 CRTeligible patients (84%). Mean age was 75 6 9 years and 34% were women. Failed cases were more likely to be men and had wider QRS duration at baseline (163 6 34 vs. 137 6 32, p , 0.001) compared with successful cases. Background: His-Purkinje conduction system pacing (HPCSP) has been proposed as an alternative to cardiac

Abstract Background The period after newly diagnosed heart failure (HF) presents challenges in HF management. Although recent HF guidelines recommend immediate initiation of HF therapies, little is known about real life HF therapy. Purpose We analyzed differences in treatment management in patients with new onset and chronic HF across the ejection fraction (EF) spectrum in the large nationwide Swedish HF registry. Methods In patients enrolled 2000–2018 in the Swedish HF registry, clinical characteristics, co-morbidities, laboratory values and use of therapy were analyzed in all HF patients with new onset HF (HF duration <3 months from diagnosis) and chronic HF (HF duration ≥3 months from diagnosis). Additionally, therapy use was studied separately for patients with HFrEF (defined as EF <40%). Results Of 90,383 patients, 40% had new onset and 60% had chronic HF. Patients with new onset HF were more likely females (42 vs. 37%) compared to chronic HF. They had lower NYHA class, with higher EF, less often had atrial fibrillation (46 vs. 60%) and left bundle branch block (14 vs. 21%). They more often had hypertension (31 vs. 24%), and less often ischemic heart disease (34 vs. 44%), dilated cardiomyopathy (4.1 vs. 8.1%) and known alcoholic cardiomyopathy (0.6 vs. 0.8) as cause of HF. Chronic HF was associated with worse renal function (eGFR 58 [41, 77] vs. 69 [51, 87] mL/min/1.73 m2) and higher co-morbidity burden. Overall, new onset HF were less often on beta-blockers (85 vs. 88%) and MRAs (26 vs. 40%), whereas patients with chronic HF more often received HF medication and HF related device therapy. Patients with new onset HFrEF and thus with an indication for guidelines directed medical therapies were more often treated with beta-blockers (93 vs. 92%), ACE/ARB (91 vs. 83%), but less often ARNi (2.5 vs. 16%) and device therapy. Conclusions In this large HF population, patients with new onset HF were more often females, with less severe HF symptoms, and with fewer co-morbidities; New onset HF was associated with less MRA use. Our findings implies that faster and concomitant HF therapy initiation as recommended in 2021 ESC HF/HFA guidelines should occur in new onset HF patients. Funding Acknowledgement Type of funding sources: None.