Worsening Heart Failure Research Articles

Trajectory of health-related quality of life during and after hospitalisation due to worsening of heart failure.

This study aimed to examine the trajectory in health-related quality of life (HRQoL) during and after hospitalisation for worsening of heart failure (HF) in Malaysia. 200 patients with heart failure and reduced ejection fraction (HFrEF) admitted into two hospitals in Malaysia due to worsening of HF were surveyed using the EQ-5D-5L questionnaire. The primary outcomes were utility values at admission, discharge and 1-month post-discharge (1MPD). Secondary outcomes included the visual analogue scores (VAS) and the proportion of patients reporting each EQ-5D-5L dimension levels. Missing data were imputed using multiple imputation, and generalised linear mixed models were fitted. At admission, the unadjusted mean utility values and VAS scores for HFrEF patients in Malaysia were as low as 0.150 ± 0.393 and 38.2 ± 20.8, respectively. After a median hospital stay of 4 days, there was a significant improvement in utility values and VAS scores by 0.510 (95% CI: 0.455-0.564) and 28.8 (95% CI: 25.5-32.1), respectively. The utility value and VAS score at 1-month post-discharge were not significantly different from discharge. The proportion of HFrEF patients reporting problems and severe problems in mobility, self-care, usual activities, and anxiety/depression, pain/discomfort reduced at varying degree from admission to discharge and 1MPD. HF is a progressive condition with substantial variation in HRQoL during the disease trajectory. During hospitalisation due to worsening of HF, HFrEF population has unfavourable HRQoL. Rapid and significant HRQoL improvement was observed at discharge, which sustained over one month. The study findings can inform future cost-effectiveness analyses and policies.

Clinical and financial implications of inpatient and outpatient management strategies for worsening heart failure

Abstract Introduction Hospitalizations for worsening heart failure (HF) represent an enormous public health and financial burden. Accordingly, select centers have developed outpatient worsening HF (WHF) management strategies focused on care in emergency departments (ED), observation units, or intravenous (IV) diuretic clinics. However, broad use of these outpatient strategies and the associated outcomes and healthcare costs remain unclear. Methods Among US Medicare beneficiaries age ≥65 years hospitalized for HF in the Get With The Guidelines Heart Failure registry 2010-2018, we identified patients with a post-discharge non-fatal WHF event. Patients were divided into 4 mutually exclusive groups defined by type of first post-discharge WHF event (HF hospitalization, ED visit with ED discharge, observation unit stay, and outpatient clinic visit with IV diuretics). Following each type of WHF event, mortality, home-time (days alive and out of any healthcare institution), and healthcare costs were compared over the subsequent 12-months. Costs of the initial WHF management strategy were also assessed. Results Among 181,827 patients hospitalized for HF, during the 12-months post-discharge, 83,971 (46.2%) survived with no WHF event, 36,697 (20.2%) died prior to a WHF event, and 61,159 (33.6%) had a WHF event. Of patients with a WHF event, 48,612 were managed with HF hospitalization (79.5%), 8,139 (13.3%) with an ED visit, 1,767 (2.9%) with an observation unit stay, and 2,641 (4.3%) with an outpatient IV diuretic visit. Compared with HF hospitalization, patients with WHF managed in the ED, observation unit, or IV diuretic clinic experienced lower subsequent mortality (Figure 1). Mean 12-month home-time was lowest following HF hospitalization (207 ± 144 days), intermediate following ED (238 ±136 days) and outpatient IV diuretic visits (252 ±128 days), and highest following observation unit stays (277 ± 125 days). For the initial WHF event, median (25th, 75th) total per-patient costs were highest for HF hospitalization and lowest for outpatient IV diuretic visits (Figure 2). Over the 12-months following the WHF event, median total per-patient costs were highest following outpatient IV diuretic visits, intermediate following HF hospitalization and ED stays, and lowest following observation unit stays. Conclusions In a nationwide analysis of older US adults, 1 in 5 episodes of recurrent WHF were exclusively managed as an outpatient within the ED, observation unit, or IV diuretic clinic. High rates of death and substantial reductions in home-time occurred following WHF regardless of inpatient or outpatient management, but were worse following HF hospitalization. Outpatient IV diuretic administration was the least expensive initial management strategy, but was associated with the highest per-patient costs over the subsequent 12 months.

Right ventricular myocardial work predicts heart failure hospitalizations irrespective of ejection fraction

Abstract Hospitalization for heart failure worsening (HFW) associates with increased subsequent rehospitalization rate and mortality irrespective of left ventricular ejection fraction (EF). However there’s little evidence regarding predictors of HFW to timely apply preventive measurements. Since right ventricular (RV) dysfunction often associates with more advanced stages of HF we assumed that RV myocardial work (MW) assessment might be used in prediction of HFW. Methods 158 patients with HF (48% female) 58±7 years on guideline directed medical therapy in sinus rhythm and with at least one hospitalization in the last 6 months were enrolled in the study. Patients with HFrEF, HFmrEF and HFpEF were evenly represented. All patients were appropriately decongested prior to the study. The primary outcome was rehospitalization, HFW or cardiovascular death. RVMW was derived from RV global strain, including interventricular septum, and noninvasively estimated pulmonary arterial pressure (PAP). Systolic PAP (sPAP) was measured as the sum of maximum RV and right atrial (RA) pressure gradient (PGmax) from tricuspid regurgitation (TR) jet peak velocity and mean right atrial pressure (RAP) estimated from diameter and collapsing of inferior vena cava. Mean PAP (mPAP) was measured as the sum of PGmean RV-RA by tracing TR jet and RAP. Diastolic PAP was estimated as dPAP = 1.5 × [mPAP − (sPAP/3)]. Then RV global work index (RVGWI), constructive (RVGCW), and efficient work (RVGWE) were derived by the software dedicated for left ventricular MW. Left ventricular global longitudinal strain, left atrial (LA) reservoir strain (LAS), LA pump strain, LA volume index (LAVi), B lines, inferior vena cava, NT-pro-BNP, TAPSE/sPAP and RVMW were also measured. Patients followed up for 12 months. Results 53 events were registered at 12 months of which 42 rehospitalizations due to HFW and 11 CV deaths. Among all parameters in the multivariate analysis lower RVGCW was associated with HFW (HR 0.978, 95% CI 0.973–0.998, p = 0.014). RVGCW was the most powerful predictor of CV events (AUC 0.91) with cut off value of 148 mmHg% that had 96% sensitivity and 88% specificity. Number of patients who died with RVGCW < 148 mmHg% was 8 of 11 (73%) total deaths (HR 0.421, 95% CI 0.083–0.986, p = 0.028). Conclusion RVGCW was a predictor of HFW and 1 year mortality in patients with HF irrespective of EF.

The efficacy of IV iron in anemic heart failure patients: a systemic review and meta-analysis of randomised controlled trials

Abstract Introduction Iron deficiency in the context of heart failure is a multifaceted concern, where the intricate interplay between diminished iron stores, impaired absorption mechanisms, and reduced recycled iron in the reticuloendothelial system adds a layer of complexity to patient management. Initial attempts to address this issue with oral iron treatments have been questioned due to its poor absorption. Intravenous iron therapy is now preferred, as it has been shown to reduce heart failure hospitalisations and cardiovascular mortality. However, there is a lack of randomised studies specifically focused on heart failure patients, highlighting the need for more targeted investigations. Purpose The aim of this review is to provide reliable evidence from published randomised controlled trials (RCTs) regarding the beneficial effect of IV iron in heart failure patients. Methods We systematically searched PubMed, Web of Science, Scopus, and Cochrane Central, and EMBASE from inception until December 2023. We included randomised controlled trials (RCTs) comparing the effect of IV iron in heart failure patients versus placebo. The primary outcomes were 6MWT mean change, ferritin concentration mean change, transferrin saturation mean change and worsening heart failure. All data were pooled as either Mean difference in the random effect model with the corresponding SD or pooled as RR and 95% CI for dichotomous data. Results Twelve RCTs involving 6800 patients were included in the analysis. The overall effect on the measured primary outcomes was in favour of IV iron in terms of 6MWT mean change (MD= 34.45, 95% CI [ 29.58 to 39.31], P=<0.0001), ferritin concentration mean change (MD= 219.18, 95% CI [ 208.7 to 229.66], P=<0.0001), transferrin saturation mean change (MD= 9.77, 95% CI [ 8.14 to 1.39], P=<0.0001) and worsening heart failure (RR= 0.46, 95% CI [ 0.31 to 0.69], P=0.002). Conclusion The introduction of the IV iron therapy to heart failure patients showed a beneficial effect in terms of the measured haematological and cardiovascular metrics, which include 6MW test mean change, ferritin concentration mean change, and worsening heart failure.6MWT mean changeFerritin mean change

Remote management of worsening heart failure events and subsequent rate of emergency department admission

Abstract Background Worsening heart failure (WHF) is the leading cause of hospitalization among individuals aged ≥ 65 years and constitutes a substantial burden for both the patient and the healthcare systems. Moreover, heart failure contributes to exacerbate the pressure on emergency departments which are involved in 64% of heart failure hospital admission (1). Remote management of heart failure as been shown to reduce the number of days lost due to unplanned cardiovascular hospitalizations and all-cause mortality (2, 3), but little is known about the effect on the emergency healthcare use. We aimed to describe the effect of a telemonitoring program on the rate of emergency admissions for WHF in chronic heart failure patients. Methods All patients enrolled in the heart failure remote management program of two French centers between 13 April 2020 and 31 January 2023 were included in the study. Follow-up data were collected until 31 January 2023. Inclusion criteria were chronic heart failure (HF) with New York Heart Association ≥II and an elevated B-type natriuretic peptide (BNP > 100 pg/mL or N-terminal-pro-BNP > 1000 pg/mL). Remote evaluation included measurements of body weight, blood pressure, heart rate, symptoms, biochemical parameters, and data from cardiac implantable electronic devices when available. Results A total of 1,095 patients (72±11.8 years old, 69.7% male), were followed for a median [IQR] of 437 [182; 739] days with a mean adherence to the remote monitoring system of 67.6±30.3%. Over this period, 198 (18.1%) patients had 949 WHF events, the majority of whom were remotely detected: 830 (87.5%). Overall, 246 (26%) of the WHF episodes required hospitalisation and 109 (11%) prompted an emergency department visit. When the WHF event was remotely detected, hospitalization was only required in 127 (15%) cases and the rate of emergency department visit was reduced to 3%. Conclusion In HF patients engaged in a multiparametric remote management program, the rate of emergency department admission is very low. Adopting such a strategy for patients with chronic HF may be useful in reducing emergency department overcrowding.Baseline characteristics of patientsPatients course and use of resources

Metoprolol therapy in patients with Eisenmenger syndrome (MINES) study. A single-centre, double-blinded, randomised, placebo-controlled trial

Abstract Background Prevalence of Eisenmenger syndrome is still common in developing countries where early neonatal screening and referral for surgery is seldom possible. Limited number of drugs are available for treatment of this condition. Beta-blockers may improve functional status in these patients. Observational study has shown beta blockers to be safe and effective in improving effort intolerance in patients with Eisenmenger syndrome. Purpose To study the safety and efficacy of metoprolol succinate therapy in patients with Eisenmenger syndrome. Methods In this double-blind, placebo-controlled study, we randomly assigned 60 patients with Eisenmenger syndrome to receive placebo or to receive 25 mg of metoprolol succinate once daily for 2 weeks followed by 25 mg twice daily for 14 weeks (total of 16 weeks). The primary outcome was mean difference in 6-minute walk test (6MWT) distance. Secondary outcomes were clinical composite outcome (all-cause death, heart failure hospitalization, worsening of heart failure, change in WHO functional class, and new onset syncope), change in resting saturation, Tricuspid Annular Plane Systolic Excursion (TAPSE) and NT Pro BNP level at 16 weeks. Results At 16 weeks, the mean difference in 6MWT distance between treatment group and placebo group as per protocol analysis was 6 meters (95% confidence interval, - 7.43 to 19.49; P 0.37), and the mean difference in 6MWT distance as per intention to treat analysis was -1.1 meters (95% confidence interval, - 16.97 to 14.77; P 0.89). Clinical composite outcome occurred more in the treatment group 5(17%) as compared to the placebo group 1(3%) (P 0.197) though it did not reach statistical significance. This was primarily driven by worsening of heart failure in the treatment group. Compared to baseline metoprolol group had 37% increase in NT pro BNP level while placebo group had 13% (-313.69, 88.80) reduction in NT Pro BNP level. There was no difference in TAPSE 0.05 (95% confidence interval -0.62 to 0.72; P 0.88) or resting saturation -0.06 (95% confidence interval -0.88 to 0.75; P 0.87) between the two groups at 16 weeks Conclusion Metoprolol succinate therapy did not improve 6-minute walk distance at 16 weeks among patients with Eisenmenger syndrome compared to placebo. Metoprolol succinate therapy was associated with increased clinical composite outcomes, primarily driven by worsening of heart failure.Graphic Abstract of MINES study

Associations between biomarkers and P-wave indices in patients with heart failure

Abstract Background Atrial structural abnormalities linked to the risk of atrial fibrillation (AF), as indicated by P-wave indices on surface ECG, are associated with the fibrotic transformation of the atrial myocardium. To what extent incident AF can be predicted by ECG characteristics in patients with advanced atrial structural remodeling, such as patients with heart failure (HF), is less well studied. Purpose To evaluate the association between P-wave indices and biomarkers implicated in cardiac fibrosis, and incident AF in patients with HF. Methods Patients with new-onset or worsening of HF were prospectively recruited in a observational study (n=501) and followed-up for 5 years. Blood samples were collected for analysis using proximity extension assay that included a subset of biomarkers that were associated with fibrosis development (TIMP-2, MMP-2, MMP-3, MMP-9, ST-2, GDF-15, Gal-3). All ECGs ever recorded in the hospital catchment area were exported in digital format and processed using Glasgow algorithm for calculation of the P-wave indices (P-wave duration [PWD], P-wave terminal force in V1 [PTFV1] and P-wave axis [Paxis]) and rhythm identification. AF diagnosis was ascertained by manual ECG review. Only patients who did not have AF reported or ECG documented at enrolment were included in the analysis. Of those subjects, 121 patients also had biomarkers of fibrosis analyzed. Cox-regression analyses were used to assess biomarkers’ and p-wave indices’ associations with incident AF. Results After exclusion of patients with prevalent AF (n=317), 184 patients comprised the study group (mean age of 71 years, 33.2% women, 121 patients with biomarker data available). During follow-up, incident AF was observed in 39 patients. At enrolment, PWD>120 ms was observed in 38.7%, abnormal PTFV1>40 mm*ms in 24.5% and Paxis<0° in 5.4%. Among the seven biomarkers assessed, five demonstrated significant associations with incident AF in adjusted analyses: TIMP4 (HR 1.78; 95%CI 1.03-3.05; p=0.037); MMP2 (HR 1.97; 95%CI 1.03-3.80; p=0.042), MMP3 (HR 1.39; 95%CI 1.03-1.88; p=0.031); ST2 (HR 1.91; 95%CI 1.29-2.83; p=0.001) and GDF-15 (HR 2.56; 95%CI 1.50-4.35; p=0.001) (Figure 1). However, none of the tested P-wave variables (P-wave duration, P-wave terminal force, and P-wave axis) were associated to incident AF. Conclusions In this prospective long-term follow-up study of patients admitted for acute HF, biomarkers with proven associations to fibrosis were strongly associated with incident AF. P-wave indices used for prediction of AF in epidemiological cohorts appear to have limited value in patients with HF who have high prevalence of ECG atrial abnormalities at baseline.

Protein signatures associated with methylation patterns of heart failure phenotypes

Abstract Introduction The heart failure (HF) syndrome is highly susceptible to the exposome. The interplay between DNA methylation (DNAm), surrogate for exposomal influences, and the plasma proteome in the progression and development of phenotypes of heart failure is unclear. We investigated the relation between methylation patterns of HF phenotypes and proteins signatures. Methods Individuals with symptomatic HF (stage C/D with HFpEF, HFmrEF and HFrEF) of the MyoVasc cohort (N=3,289) were investigated. EDTA-Plasma and DNA were extracted from peripheral blood and stored in -80°C. DNAm was measured using the Infinium MethylationEPIC v2.0 methylation array. Concentrations for 538 proteins were measured using an immuno-qPCR assay in EDTA plasma. Multivariable regression models adjusted for age and sex were used to assess the relationship between DNAm signatures and individual proteins in each phenotype. Ridge-regularized linear regression was used to generate a phenotype-specific protein-signature in relation to each methylation signature, linear regression to estimate links between protein signatures and cardiovascular traits and Cox regression relate protein signatures to clinical outcome. Results Data from 1,317 individuals with symptomatic HF were analyzed. After FDR adjustment, 310 proteins were significantly related to HFpEF methylation signature, 314 to HFmrEF and 266 to HFrEF. Of associated proteins, 49.9% (198) were found in all phenotypes, 8.82% (35) only in HFpEF, 12.1% (48) in HFmrEF and 4.79% (19) in HFrEF. Tumor necrosis, arterial hypertension and T-cell regulation pathways were enriched in all three phenotypes. NT-proBNP had the strongest association with HFrEF (β=0.95 [0.82-1.08], p<0.0001) followed by presence of plaques in carotid artery and C-reactive protein, while left ventricular mass (LVM) had stronger association with HFpEF (β=0.22 [0.11-0.33], p=0.0001). All three signatures were associated with worsening of HF (HFpEF: HR=1.93 [1.61-2.30], p<0.0001; HFmrEF: HR=1.63 [1.29-2.04], p<0.0001; HFrEF: HR=1.64 [1.38-1.95], p<0.0001) and all-cause death in HF (HFpEF: HR=1.93 [1.65-2.26], p<0.0001; HFmrEF: HR=1.95 [1.58-2.42], p<0.0001; HFrEF: HR=2.24 [1.86-2.69], p<0.0001). Methylation-associated protein signatures had stronger associations with clinical outcome than the methylation signatures themselves (p < 0.01). Conclusion This study revealed protein signatures associated with methylation patterns of HF phenotypes that shared common and unique features for HF phenotypes. Important common pathways were enriched in tumour necrosis, arterial hypertension and regulation of T cells. However, important differences between phenotypes were also revealed, e.g. NT-proBNP was strongly associated with the HFrEF protein signature and LVM with the HFpEF signature. The methylation-associated protein signatures emphasise the possible exposomal influence on HF syndrome.

The condition of myocardium reserves score from a cloud-based analytics platform of Holter ECG data indicates better cardiometabolic function in heart failure

Abstract Introduction Cardiometabolic dysregulation, particularly type 2 diabetes mellitus (T2DM), is associated with subtle myocardial pathologies, even in individuals without known cardiovascular disease. These subclinical changes, often undetectable by standard electrocardiogram (ECG) analytics, can offer valuable insights into the relationship between metabolic health and cardiac function. Novel ECG markers, developed through machine learning and artificial intelligence (AI), may provide the sensitivity needed to detect such changes. Aim This study aims to evaluate novel composite cardiac parameters from an analytics platform in the context of heart failure (HF), seeking to understand their relationship to cardiometabolic dysregulation. Methods Data from the MyoVasc study, a prospective cohort on HF, were analysed. Participants underwent extensive clinical phenotyping, including a Holter ECG assessment. Holter ECG data was processed based on machine learning and AI models on a cloud-based analytics platform (Cardiolyse, Helsinki, Finland), generating both traditional and proprietary ECG, and heart rate variability cardiac health markers. LASSO-penalized logistic regression adjusted for sex and age was performed to select the marker most strongly associated with T2DM. The identified marker was then evaluated in relation to cardiac function and structure as well as HF-related outcome. Results A total of 953 subjects (mean±SD age 64.6±10.5 years; 35.7% women) were included in the analyses. Symptomatic HF stage C/D was present in 54.8% (n=522) of subjects and diabetes mellitus in 22.4% (n=213). The Condition of Myocardium Reserves Score (CMRS) was the novel composite cardiac parameter selected based on its relationship with T2DM. In a Poisson regression model with robust variance adjusted for sex and age, a lower score was associated with T2DM (Prevalence ratio per SD 1.24, 95% confidence interval [1.14;1.36], P=0.0002). In multivariable linear regressions adjusted for traditional cardiovascular risk factors, comorbidities, and medication, a higher CMRS was associated with better global longitudinal strain (β per SD –0.82 [–1.11;–0.53], P<0.0001), diastolic function (left ventricular E/e’; β per SD –0.04 [–0.06;–0.01], P=0.0059) and systolic function (LV ejection fraction; β per SD 2.06 [1.46;2.67], P<0.0001). A lower CMRS independently predicted all-cause death (Hazard ratio per SD 1.25 [1.09;1.45], P=0.0020) and worsening of HF (HR per SD 1.44 [1.21;1.72], P<0.0001) in Cox regression analysis adjusted for the same confounders. Conclusion The Condition of Myocardium Reserves Score exhibited a strong association with cardiometabolic dysregulation. A higher CMRS indicated preserved cardiac function, while a lower score independently predicted increased risk of all-cause death and worsening HF. This novel score offers potential as a non-invasive tool for assessing cardiometabolic health and stratifying risk in patients with HF.

Effects of body mass index on worsening of heart failure and all-cause death in patients with heart failure and reduced left ventricular ejection fraction: a 10-year follow-up study

Abstract Background/Introduction Obesity in patients with heart failure (HF) with reduced ejection fraction (HFrEF) is common, and with the emergence of effective anti-obesity drugs, a better understanding of the relation between BMI and clinical outcome in HFrEF is needed. Purpose This study aimed to analyse whether a body mass index (BMI) above 27 kg/m2 (cut-off used in trials) is associated with a greater rate of all-cause death and HF hospitalization in patients with HFrEF. Methods We included 1,017 medically optimized according to existing HF guidelines at the time and clinically stable HF patients with a left ventricular ejection fraction of <45% from the NorthStar study. Patients were included between 2005 and 2009 and followed for 10 years using Danish nationwide registries. The outcomes of interest were all-cause death and hospital discharge for HF (overnight stay). Descriptive statistics were grouped according to tertiles of BMI. The association between BMI as a continuous variable and the outcomes of interest was analysed using restricted cubic splines in Cox proportional-hazards models. Reported were hazard ratios (HR) with 95% confidence intervals (CI) adjusted for relevant prognostic covariates (reference: BMI = 27 kg/m2). Results At enrolment, the median age was 69 years, 75% were men, and the median BMI was 26.3 kg/m2 (Table 1). Patients in the upper 3rd BMI tertile were younger (median age 67), had a lower level of NT-proBNP level (median 737.5 pg/ml) and a higher proportion of diabetes (29.9%). During 10 years of follow-up, HF hospitalization occurred in 683 patients (61.7%), and 623 patients died (56.3%). A BMI above 27 kg/m2 was associated with a higher rate of HF hospitalization (significantly from BMI 35.2 kg/m2: HR 1.30 [CI 1.00-1.68]; Figure 1). Similar findings were observed for all-cause mortality (significantly from BMI 35.7 kg/m2: HR 1.27 [CI 1.00-1.62]) Conclusion In patients with HFrEF, a BMI above 27 kg/m2 was associated with a higher rate of HF hospitalization and all-cause death. Efforts to find effective and safe approaches to reducing weight in obese patients with HFrEF are warranted.Figure 1

OptiHeart: determinants and prognostic importance of optimal medical treatment in patients with heart failure discharged from the heart failure clinic

Abstract Background Heart failure (HF) is an increasing health problem globally. Current guidelines are based on studies with primarily male patients. Females are less likely to receive target dose of HF medication as recommended by the clinical guidelines. The reason for this is uncertain, but it has led to the question whether females might not need as high dosages as the males to achieve the beneficial effects of the HF medication. Aim To assess baseline predictors for achieving optimal medical treatment (OMT) and the prognostic importance of OMT for male and female patients who have attended a HF clinical program (HFCP). Methods OPTIHEART included 870 patients with left ventricular ejection fraction (LVEF) <45% leaving HFCP in 2018, 2019 or 2020 and followed in registers for a mean of 1083(SD 11.3) days. OMT was defined as receiving an angiotensin-converting-enzyme-inhibitor (ACEi), angiotensin-receptor blocker (ARB) or angiotensin-II-receptor blocker and nephrylisin-inhibitor (ARNI) AND a betablocker both in doses > 50% of target dose. Association between baseline data at referral and OMT at end of HFCP were calculated using logistic regression. The association between OMT and a 5-point Major Adverse Cardiovascular Event (a 5-Point MACE consisting of cardiovascular mortality, non-fatal acute myocardial infarction, non-fatal stroke, coronary revascularization, worsening of heart failure (both hospitalisation and re-referral to HFC)), were calculated and adjusted for other cardiovascular risk factors using multiple Cox-regression analyses. Results Achieving OMT was associated with male sex (OR: 2.05 95%CI 1.44-2.97; P<0.0001) independently of younger age, higher diastolic blood pressure (DBP), and lower creatinine at referral. A lower rate of 5-point MACE was associated achieved OMT (HR: 0.67 95%CI 0.50-0.89; P=0.006) independently of female sex (HR: 0.62 95%CI 0.47-0.82; P=0.002), younger age, never smoking and NYHA≤2. The beneficial effect of OMT was more pronounced in patients with BMI<26.5kg/m2 (HR=0.41[0.23-0.72] vs. HR=0.84[0.58-1.21], Pinteraction= 0.02), and insignificantly more pronounced in patients with male sex, older age, higher creatinine, and lower DBP. Conclusion OMT was more frequently achieved in patients with male sex independently of lower age, higher DBP, and lower creatinine. Achieving OMT was associated with less 5-point MACE independently of female sex, younger age, never smoking and NYHA≤2 and especially in patients with BMI<26.5kg/m2.Hazard RatioMedical treatment

Prevalence, characteristics, and long-term outcomes of patients with mitral annular disjunction undergoing surgery for degenerative mitral regurgitation

Abstract Background Mitral valve prolapse (MVP) is associated with progressive mitral regurgitation (MR) requiring surgical repair. A subset of patients with MVP may also suffer from malignant ventricular arrhythmias (VAs), especially in the presence of mitral annular disjunction (MAD). Purpose To assess the prevalence, associated characteristics, and long-term outcomes of patients with MVP with and without MAD undergoing mitral valve surgery for degenerative MR. Methods Patients with MVP and moderate-to-severe or severe degenerative MR undergoing mitral valve surgery between 2010-2022 at a university hospital in Sweden were included. MAD length was measured on echocardiograms at end-systole from the insertion of the posterior leaflet on the detached mitral annulus to the border of the bulging left ventricle. Patient demographics and clinical outcomes were collected from medical records. The primary endpoint consisted of VAs, defined as sustained- or non-sustained ventricular tachycardia or high burden of premature ventricular complexes causing hospitalizations or ablation or identified at Holter monitoring. Other endpoints included sudden cardiac death, all-cause mortality, new onset postoperative atrial fibrillation, stroke, mitral valve reoperation, endocarditis, new or worsened heart failure, myocardial infarction and implantation of permanent pacemaker or cardiac defibrillator. Results Of 599 patients undergoing mitral valve surgery, 96 (16%) had preoperative MAD, with a median (Q1, Q3) MAD length of 8.0 (5.0-10.0) mm. Compared with patients without MAD, patients with MAD were younger (55 vs 63 years), more likely to be female (31% vs 17%), to have diffuse myxomatous valve disease (66% vs 25%) and bileaflet prolapse (57% vs 17%). Most patients underwent mitral valve repair (84% vs 80%). No patient had residual MAD after surgical repair. At a mean follow up time of 5.8 ± 3.5 years after mitral valve repair, VAs were more common in patients with pre-operative MAD (10% vs 2% (adjusted HR 4.52, 95% CI 1.57-13.0)) (Figure 1). There were no significant differences in the risks of other clinical outcomes. Conclusions MAD was associated with almost a 5-fold increased long-term risk of VAs after mitral valve repair despite successful anatomical correction of MAD. These findings highlight the importance of increased awareness of VAs in patients with MAD also after mitral valve surgery.

Clinical characteristics and treatment patterns of new users of dapagliflozin for heart failure with reduced ejection fraction: an observational study programme across 12 countries (EVOLUTION HF)

Abstract Background Clinical trials have shown that dapagliflozin, a sodium–glucose cotransporter-2 inhibitor (SGLT-2i), reduces cardiovascular mortality and worsening heart failure (HF). Adoption of new therapies has historically been slow despite robust evidence. Furthermore, treatment profiles of patients in real-world settings are scarce. Purpose EVOLUTION HF is a multinational study programme that aims to describe clinical characteristics and treatment patterns among patients initiating dapagliflozin for HF with reduced ejection fraction (HFrEF) in routine clinical practice. Methods The EVOLUTION HF primary data study programme consists of prospective, observational, descriptive studies of new users of dapagliflozin for HFrEF in 12 countries (Italy, Portugal, UK and the Central and Eastern Europe and Baltic [CEEBA] region [Bulgaria, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovenia]). Patients with type 1 diabetes or prior SGLT-2i treatment were excluded. Clinical characteristics were obtained from electronic health records. A total of 2170/2555 (85%) patients were enrolled from November 2021 to November 2023; 1736 patient profiles were assessed using descriptive statistics in this interim analysis. Results In total, 256, 228, 125 and 1127 new dapagliflozin users were analysed from Italy, Portugal, the UK and the CEEBA region, respectively (Table 1). Across the 12 countries, mean patient age in the studies was 65–70 years. Patients were predominantly male (67–76%) and generally had HF with an ischaemic aetiology (35–56%) and New York Heart Association functional class II (52–85%). Mean left ventricular ejection fraction in the studies was 29–32% and estimated glomerular filtration rate was 61–77 mL/min/1.73m². Hypertension and atrial fibrillation were common comorbidities. Mean time between HF diagnosis and dapagliflozin initiation in the studies was 23–52 months. Background therapy included angiotensin receptor-neprilysin inhibitors (36–72%), angiotensin receptor blockers (4–12%) and angiotensin-converting enzyme inhibitors (9–33%). At 6 and 12 months after dapagliflozin initiation, respectively, treatment discontinuation rates across the CEEBA region were 5.22% (59/1131) and 4.66% (50/1072). Conclusions The EVOLUTION HF primary data study programme provides novel insights into clinical characteristics and treatment patterns in patients with HFrEF initiating dapagliflozin in real-world practice across a broad European population. At dapagliflozin initiation, a large proportion of patients were receiving other HF therapeutics, suggesting dapagliflozin is one of the later therapies to be initiated. Indeed, this study identified a substantial delay (23–52 months) in dapagliflozin initiation following HF diagnosis. Treatment discontinuation rates following dapagliflozin initiation were also low, reinforcing the findings of the EVOLUTION HF secondary data studies.

Right ventricular to pulmonary artery coupling credicts poor outcomes after interatrial shunting in heart failure

Abstract Background Left atrial decompression is under investigation for heart failure (HF) with the potential to improve symptoms and potentially clinical outcomes. However, heterogeneous outcomes have been observed in randomized controlled studies. Purpose This study aimed to explore whether right ventricular (RV) -pulmonary artery (PA) coupling, as assessed from the tricuspid annular plane systolic excursion (TAPSE) /systolic PA pressure ratio, can be useful in predicting outcomes after implantation of the interatrial shunting device. Methods A total of 106 HF patients, n=62 with reduced ejection fraction (HFrEF), n=44 with preserved ejection fraction (HFpEF), were prospectively enrolled in the PRELIEVE registry with the Atrial Flow Regulator (AFR) implantation. Serious adverse events included cardiovascular mortality and HF worsening (W). Results Serious adverse events (SAEs) occurred in a total of 19 (18%) patients. There were no differences in baseline comorbidities, KCCQ scores, the 6-minute walking distance between patients with and without SAEs (Table). Patients with SAEs showed higher systolic pulmonary arterial pressure, NT-proBNP, serum creatinine and lower TAPSE/PASP ratio. Incidence of SAEs was higher in patients within the first TAPSE/PASP vs the third tertile (59% vs 12%, p=0.026), respectively. A TAPSE/PASP of <0.55 was identified to bear the most optimal sensitivity to predict the event (AUC=0.683, CI95% (0.533-0.833). Conclusion The reduced TAPSE/PASP ratio was associated with higher rates of serious adverse events in patients with heart failure undergoing controlled inter-atrial shunting. The hypothesis generating finding that reduced RV-PA coupling may identify potential clinical non-responders to left atrial decompression should be further prospectively validated.

Prognostic significance of right ventricular dysfunction in patients with TTR amyloidosis

Abstract Background Transthyretin amyloidosis (ATTR) is increasingly recognized as a cause of heart failure (HF) that now benefits from effective treatment. While the role of right ventricular (RV) systolic dysfunction has been widely accepted as an independent predictor of poor prognosis in HF patients, its implications in ATTR remain poorly understood. Right ventricular free wall strain (FWS) over pulmonary arterial systolic pressure (PAsP) has been recently proposed as an accurate and sensitive tool to evaluate RV function and its coupling to the afterload. Purpose Our study sought to analyze whether indexing FWS to PASP should integrate the set of fundamental data we have to assess the prognosis of ATTR patients. Methods 191 consecutive patients diagnosed with ATTR were enrolled. A comprehensive echocardiographic examination was part of the systematic evaluation. The primary outcome was a composite of cardiovascular mortality and hospitalization caused by heart failure worsening. Results After a median follow-up of 24 months, among patients with ATTR [median age 82 (77, 85), 89.5% male], the primary composite outcome occured in 26%. Cardiovascular mortality rate was 7.3% and the hospital event rate was 18.8%. Tricuspid annular plane systolic excursion (TAPSE), FWS, TAPSE/PAsP and PAsP were univariately significant risk factors for adverse outcome. In multivariate Cox regression analysis, after adjustment of confounding factors, FWS/PASP emerged as an independent predictor of the composite endpoint of cardiac death and rehospitalization (HR 1.61, 95% CI 1.07-2.42, p=0.021). Based on receiver-operating characteristic analysis, the optimal FWS/PASP cut-off value for event prediction was 42.5% (area under the curve = 0.749, p = 0.001). Conclusion Right ventricular function assessed with speckle-tracking echocardiography is an independent prognostic marker for cardiac mortality and heart failure hospitalization in patients with ATTR. FWS/PAsP should be integrated into regular clinical practice for a better evaluation and follow-up of ATTR patients.

Long-term outcomes in hospitalized heart failure patients in China: results from the China National Heart Failure (CN-HF) registry study

Abstract Background There is a paucity of data on the long-term outcomes of heart failure (HF) patients in China. We aimed to investigate the incidence of cardiovascular (CV) death or rehospitalization due to worsening HF (WHF) and other outcomes among different subtypes of patients with chronic HF in China. Methods Data from the China National HF registry (CN-HF) during the period 1 February 2013–31 October 2015 were analyzed. Patients were categorized into three groups based on their left ventricular ejection fraction (LVEF): HF with reduced ejection fraction (HFrEF, LVEF≤40%), HF with mildly reduced ejection fraction (HFmrEF, LVEF 41%–49%), and HF with preserved ejection fraction (HFpEF, LVEF≥50%). Rates and risk of CV death or HF rehospitalization and other outcomes including all-cause mortality in each group were calculated and compared. Results In total 7171 patients (mean age 69.6 years, 59.5% male) with HF were enrolled across 45 centers in China. At discharge, ACEIs/ARBs, β-blockers and MRA were prescribed in 57.3%, 50.8% and 54.5% HF patients totally. The overall incidence of the primary outcome (CV death or HF rehospitalization) was 8.9%, 16.1%, and 23.5% at 6, 12, and 24 months post-discharge, respectively. Significantly higher rates of the primary outcome, all-cause mortality, and HF re-hospitalization were observed in patients with HFrEF and HFmrEF compared with those with HFpEF at 6, 12, and 24 months (P < 0.05). The incidence of CV death was similar across all LVEF subgroups. Conclusions Compared to patients with HFpEF, incidence of death or rehospitalization were higher among patients with HFrEF or HFmrEF in China. Optimal follow-up and management of HF both inside and outside of the hospital should be highlighted and put into practice.Primary outcome according to LVEFAll-cause death and rehospitalization

Prognostic value of circulating glypican-4 in patients with chronic heart failure with reduced ejection fraction

Abstract Background Chronic heart failure is one of the leading causes of hospitalization and mortality worldwide, with an ever-increasing prevalence. Glypican-4 (GPC4) is a cell surface protein part of the endothelial glycocalyx which is actively released into the circulation in the context of ischemia, inflammation, neurohumoral activity, and shear stress. The current literature on the association between circulating GPC4 and heart failure is limited and its prognostic value on top of established risk markers in chronic heart failure is unknown. Purpose In the present study, we aim to investigate the prognostic value of circulating GPC4 on clinical outcomes in a contemporary cohort of patients with stable chronic heart failure with reduced ejection fraction (HFrEF). Methods Symptomatic outpatients with stable chronic HFrEF were consecutively enrolled in a prospective cohort study. Circulating serum GPC4 levels were assessed using an enzyme-linked immunosorbent at baseline. Patient outcomes were retrieved from medical and health insurance records. Results We enrolled 205 patients with a median (interquartile range) age of 66 (59-74) years, with 22% females. Median left ventricular ejection fraction (LVEF) was 37 (30-43)%, median estimated glomerular filtration rate (eGFR) was 64 (48-80) ml/min/1,73 m2, median N-terminal pro-brain natriuretic peptide (NT-proBNP) was 964 (336-2173) pg/ml, median interleukin 6 (IL6) was 4.7 (3.2-7.9) pg/ml, and median GPC4 was 1553 (1034-1950) pg/ml. During a median follow-up of 4.7 (4.0-5.3) years, 46 patients (22%) were hospitalized due to worsening heart failure (WHF), 18 patients (9%) died of cardiovascular (CV) cause, and 58 patients (28%) died of any cause. In univariate Cox-regression, serum GPC4 levels predicted WHF (HR 1.57, 95%CI 1.29-1.92, p<0.001), CV death (HR 2.07, 95%CI 1.56-2.74, p<0.001), and all-cause mortality (HR 1.93, 95%CI 1.59-2.34, p<0.001). The association between serum GPC4 levels and both, CV death (HR 1.69, 95%CI 1.04-2.86, p=0.048) and all-cause mortality (HR 1.56, 95%CI 1.14-2.14, p=0.006) remained significant in a multivariable Cox-regression model adjusted for age, sex, eGFR, IL6, NT-proBNP, and LVEF. Conclusion In patients with stable chronic HFrEF, circulating GPC4 is significantly associated with cardiovascular outcome and is an independent predictor of all-cause mortality. The potential prognostic value in clinical routine of GPC4 should be addressed in prospective studies.

Prognostic value of peak heart rate on cardiopulmonary exercise testing in patients with chronic heart failure

Abstract Backgrounds Many factors are known to be related to impaired exercise capacity or worse clinical outcomes in patients with chronic heart failure (CHF). Peak heart rate achievement by cardiopulmonary exercise testing (CPET) can be easily obtained on CPET. However, less data is available regarding the impact of peak heart rate on exercise capacity or long-term clinical outcomes in patients with CHF. Purpose We sought to investigate whether lower heart rate during peak exercise displayed poorer exercise capacity and worse clinical outcomes in patients with CHF. Methods We examined consecutive 435 patients with CHF referred for CPET in our university hospital between 2013 and 2018. The primary outcome was a composite of all-cause death or hospitalization due to worsening heart failure. Patients were divided into two groups according to the optimal cut-off value of peak heart rate based on receiver operating characteristic curve analysis. Results Patients with lower peak heart rate (≤112/min, n=164) were older and, higher brain natriuretic peptide level compared to those with higher peak heart rate (>112/min, n=271). Heart rate during peak exercise was significantly correlated with peak oxygen consumption (peak V̇O2) (Figure 1A), peak workload achievement (Figure 1B), and ventilatory efficiency (V̇E/V̇CO2 slope) (Figure 1C). There were 80 patients with events over a median follow-up period of 3.4 (Interquartile range 0.7–5.6) years. Patients with lower peak heart rate had about 3.0-fold higher risk of events compared to those with high peak heart rate (hazard ratio [HR] 3.17; 95% confidence interval [CI], 2.01–4.98) (Figure 2). In a multivariable Cox regression, 10 bpm-decreased in peak heart rate was associated with 12% increased adverse events (HR 0.88; 95%CI, 0.78–0.98). Conclusions Peak heart rate achievement on CPET was associated with reduced exercise capacity and worse clinical outcomes, suggesting that peak heart rate is useful for risk stratification in patients with CHF. Further study is required to identify therapies targeting peak heart rate to improve the exercise capacity or clinical outcomes in patients with CHF.Figure1Figure2

Amiodarone-related thyroid dysfunction and associated outcomes in patients with heart failure - a matched case-control study

Abstract Aim The association between amiodarone-related thyroid dysfunction and the risk of worsening heart failure (HF) or death has been reported with conflicting results. Methods The study cohort was patients with HF and without a history of thyroid dysfunction (defined by medical treatment or diagnosis) who initiated treatment with amiodarone in the period 1996-2021. Within this cohort, those who developed thyroid dysfunction (cases) were identified and matched 1:3 on age, sex, calendar year, duration of HF, and time since initiation of amiodarone with patients (controls) from the same cohort and followed for the primary outcome of HF hospitalization or all-cause death at 1-year, assessed by Kaplan Meier curves and Cox regression models adjusted for ischemic heart disease, chronic kidney disease, malignancy, atrial fibrillation and ventricular tachycardia. Results The study cohort comprised 21,947 patients, of whom 4,137 (19%) developed thyroid dysfunction following initiation of amiodarone. After matching, the study population consisted of 4,063 cases (mean age 69 years, 68% men, 41.6% developed thyroid dysfunction within the first year after initiation of amiodarone) and 10,940 matched controls, (Figure 1). The index date was the date of thyroid dysfunction for cases, and for matched controls a date at a similar distance since amiodarone initiation. At 1-year follow-up, the primary outcome occurred in 1,543 (38.0%) cases and 3,681 (33.6%) matched controls (reference), adjusted hazard ratio (HR) 1.13 (95%, confidence interval CI 1.07-1.20), although this was solely driven by HF hospitalization (28.9% vs 21.8%; HR 1.32 (95% CI 1.23-1.41), whereas all-cause death was lower among cases (18.2% vs. 20.4%, HR 0.85 (95% CI 0.78-0.93), (Figure 2). Conclusions Among HF patients treated with amiodarone, the development of thyroid dysfunction was associated with an increased risk of HF hospitalization or all-cause death, but this was solely driven by the excess risk of HF hospitalization, whereas it was associated with a lower risk of all-cause death. The absence of excess mortality indicates that thyroid complications are manageable in this vulnerable population of patients with HF.Figure 1 Flowchart of the populationFigure 2 Cumulative risk

Multiple comorbidities are associated with poor prognosis in patients with ADHF-HFpEF and non-frailty or mild frailty but not moderate-severe frailty -PURSUIT-HFpEF Registry-

Abstract Background A variety of comorbidities are frequently observed and represent a major problem in the management of patients with heart failure. Frailty is a strong predictor of poor clinical outcome in patients with heart failure, which may be partially attributable to the presence of multiple comorbidities. However, it remains to be clarified whether frailty is prognostically useful in relation to multiple comorbidities in patients with acute decompensated heart failure and preserved ejection fraction (ADHF-HFpEF). Purpose The purpose of this study is to investigate the relationship between frailty, multiple comorbidities and prognosis in patients with ADHF-HFpEF. Methods We prospectively studied 1028 patients with ADHF-HFpEF. Frailty was assessed using Clinical Frailty Scale (CFS). Multiple comorbidities were defined as the presence of 4 or more factors from the following 11 groups: diabetes, obesity, lung disease, anemia, renal dysfunction, electrolyte disorder, dyslipidemia, depression, hypertension, stroke and cancer. The primary outcome of this study was the composite endpoint of all-cause mortality and rehospitalization for worsening heart failure. Results During a mean follow-up period of 1.6±1.3 years, 454 patients underwent primary outcome. CFS (p<0.001) and the number of comorbidities (p=0.006) were significantly independently associated with primary outcome after multivariate adjustment. Kaplan-Meier analysis revealed that patients with multiple comorbidities had significantly higher risk for primary outcome than those without multiple comorbidities in the group with non-frailty (defined as CFS of 1 or 2, p=0.019) and mild frailty (CFS of 3 or 4, p=0.036). However, there was no significant difference in the group with moderate or greater frailty (CFS of 5 or more) in patients with ADHF-HFpEF. Conclusion(s) Multiple comorbidities would be associated with poor prognosis in patients with ADHF-HFpEF and non-frailty or mild frailty but not in patients with moderate or greater frailty.Multiple comorbidities and MACE risk