Heart Failure Research Articles

The development and long-term maintenance of heart failure with improved ejection fraction after a heart failure hospitalization: how are mortality rates affected?

Abstract Background According to the current ESC HF Guidelines (GLs), the implementation of the guideline-directed medical therapy (GDMT) is of strategic importance in heart failure (HF) with reduced ejection fraction (HFrEF). In the effect of the successful implementation of the modern GDMT, significant improvement in terms of the left ventricular ejection fraction (LVEF) might be expected in HFrEF. Hence, a new HF category, the improved ejection fraction (HFimpEF), was introduced in the current ESC HF GLs, which has come to the spotlight in the recent years. However, its course and long-term prognosis are still not clearly understood. Aim To assess the development and long-term maintenance of the HFimpEF category among a consecutive patient cohort requiring hospitalization due to HFrEF, evaluate its effect on prognosis, and examine the independent predictors of its development. Patients and methods A retrospective analysis was carried in a real-world cohort of 270 HFrEF patients (male: 77%, age: 61[49-68]years, coronary artery disease: 47%, diabetes: 30%, hypertension: 60%, atrial fibrillation: 35%, LVEF: 25[20-30]%, eGFR at admission: 59[45-73]mL/min/1.73m², NT-proBNP at admission: 4733[2368-9711]pg/mL, SBP: 120[107-135]mmHg) hospitalized for HF in 2019-2023 at two tertiary cardiac centers. At admission the complex modern GDMT of HFrEF had been already introduced (RASi[ACEi/ARB/ARNI]: 61%, βB: 63%, MRA: 47%, SGLT2i: 6%) in the minority of the cohort. The improvement to the HFimpEF category was examined after the therapy optimization (OMT). All-cause mortality (ACM) rates were evaluated with Kaplan-Meier method and the predictors of the development to HFimpEF category were assessed with logistic regression analysis. Results In the total cohort at discharge, a high proportion of patients received RASis (94%), βBs (90%), MRAs (97%), and SGLT2is (35%). 79 patients (29%) evolved to the HFimpEF category after OMT. During the median 810 [456-1161] days of follow-up (FU), HFimpEF patients had lower, but unquestionably still increased mortality rates (29% vs. 10%, p=0.001; non-HFimpEF vs. HFimpEF patients). At two years of the FU period, based on the available echocardiographies, 98 % of the patients remained in the HFimpEF category. After performing a multivariate logistic regression analysis, the severity of the LV systolic dysfunction (LVSD) and the „de novo" diagnosis of HFrEF proved to be independent predictors of the development of the HFimpEF category. Conclusions In the effect of the implementation of GDMT, a significant proportion (29%) of our multimorbid, hospitalized HFrEF patient cohort improved to the HFimpEF category. The predictors of its development were the severity of the LVSD and "de novo" HFrEF diagnosis. During the FU period, most of the HFimpEF patients remained in this category. However, their persistently elevated mortality rates raise the awareness of the importance of the conscious application and maintenance of GDMT.

Temporal trends in treatment patterns, morbidity, and mortality in patients with new-onset heart failure compared to heart failure survivors: a nationwide 23-year perspective

Abstract Background New therapy options have improved the prognosis of heart failure (HF) over recent decades. However, temporal trends in the prognosis and treatment disparities between patients with new-onset HF and HF survivors remain unexplored. Purpose To investigate temporal trends in HF treatment patterns, worsening HF and all-cause mortality, in new-onset HF patients compared to HF survivors. Methods We defined two separate cohorts of patients with HF, using the Danish nationwide registers. One cohort comprised all patients with new-onset HF each year from 1996 to 2018, included at the date of HF diagnosis (new-onset HF patients). The second cohort comprised patients with HF who have survived at least three years since being diagnosed with HF, included on January 1st of each year from 1996 to 2018 (HF survivors). Patients were allowed to contribute in both cohorts. The proportion of patients in guideline recommended therapy and the absolute five-year risk of worsening HF and all-cause mortality were assessed in the two cohorts separately, accounting for competing risks where relevant. Results From 1996 to 2018, the proportion of HF survivors tripled, while the number of yearly new-onset HF patients remained constant (figure 1). The proportion of new-onset HF patients who redeemed a prescription of BB increased from 17.1% in 1996 to 78.2% in 2018, while it increased from 15.9% to 69.4% in HF survivors during the same period. The proportion of patients in ACEi/ARB therapy increased from 49.1% to 81.5% in the new-onset HF patients, while it increased from 37.8% to 69.0% in HF survivors. The proportion of patients in MRA therapy increased from 14.4 to 33.0% in those with new-onset HF, and from 19.1% to 24.8% in HF survivors. The absolute risk (AR)[±95CI] for all-cause mortality decreased from 68.4% [67.9-68.9] in the first year group (1996-2000) to 45.7% [45.0-46.3] in the latest year group (2013-2018) for new-onset HF patients, while it decreased from 58.4% [58.2-58.9] to 39.7% [39.4-40.0] for the HF survivors. Additionally, the AR for worsening HF went from 27.4% [26.9-27.8] in the first year group to 27.8% [27.3-28.2] in the latest year group for the new-onset HF patients, whereas it for the HF survivors decreased from 19.6% [19.3-20.0] to 16.7% [16.4-19.9]. Conclusions Over a 23-year period, the annual number of patients with incident HF has remained constant while the number of HF survivors has increased by 304%. Although HF survivors show a lower prescription redemption prevalence for essential HF medications compared to incident HF patients, they exhibit significantly lower risk of all-cause mortality and worsening HF.Figure 1:OverviewFigure 2:Prescription redememption rates

Effect of exogenous ketone supplementation on cardiac energetics, function, and perfusion in type 2 diabetes, heart failure, and healthy participants- A single center, open labelled clinical study

Abstract Background Type 2 diabetes (T2D) confers loss of cardiac metabolic flexibility in fuel selection and impaired mitochondrial function. Enhanced ketone metabolism observed in T2D may represent a compensatory adaptive mechanism as ketones are a more energy efficient resource than carbohydrates or fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure (HF). Purpose To test whether exogenous oral ketone supplementation would reverse cardiac energetic deficit, as well as improve cardiac function and perfusion in patients with T2D, with HF with reduced ejection fraction (HFrEF), and healthy volunteers (HV). Methods Three groups of patients were recruited: patients with T2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs(n=25). Participants underwent cardiovascular magnetic resonance and spectroscopy to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio[PCr/ATP]). After the initial visit, participants had an identical second visit following 2 weeks of oral ketone supplementation (30g daily). Results Participants were matched in age and sex distribution. There were no significant differences in LV ejection fraction (LVEF) between T2D and HV groups with significantly lower LVEF in HFrEF group. Both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and stress GLS compared to the HV. The resting and dobutamine-stress myocardial blood flow (MBF) were only significantly reduced in patients with HFrEF compared to T2D and HV groups. Subgroup analyses of HFrEF group with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. Significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone supplementation (Visit-1:1.6[1.5,1.8] vs Visit-2:1.9[1.7,2.1]; P=0.01). This significant increment was not observed in HFrEF or HV groups. Two weeks of ketone supplementation was not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (Table-1). Conclusions Short-term ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D and preserved LVEF, without changes cardiac function or perfusion. In contrast to patients with T2D and preserved LVEF, short-term ketone supplementation does not lead to any significant improvements in energetics in patients with HFrEF suggesting loss of mitochondrial plasticity with transition to HFrEF. Moreover, healthy volunteers experience no further increments of myocardial energetics from the normal range values at baseline with ketone supplementation.

Elegibility for Sacubitril/Valsartan in italian clinical practice: insights from the OPTIMA-HF registry

Abstract Background/Introduction Guidelines strongly recommend patients with heart failure with reduced ejection fraction (HFrEF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. Among them, angiotensin receptor blocker/neprylisin inhibitor (ARNi) are the foundation of neuro-hormonal blockade in patients with HFrEF, however the degree to which gaps in this medication use and dosing persist in outpatient practice is unclear. Purpose To assess the proportion of patients with HFrEF who are eligible for ARNi based on the PARADIGM-HF trial criteria and the association between eligibility and baseline characteristics. Methods The OPTIMA-HF (Optimization of Therapy in the Italian Management of Heart Failure) registry included outpatients in Italy with chronic HFrEF receiving at least 1 oral medication for management of HF. Patients were characterized by baseline use and dose of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)/ARNI, beta-blocker, mineralocorticoid receptor antagonist (MRA) and sodium glucose co-transporter II inhibitor (SGLT2i). Patient-level factors associated with medication use were examined. Results Outpatients with HFrEF from 29 ambulatory cardiology practices and university hospitals in the OPTIMA-HF registry recruited between January 2022 and September 2023 were included. Of 1291 patients, 1018 (79%) met the PARADIGM-HF criteria and 949 of them (93%) were on ARNi. Of the enrolled patients, 342 (27%) were not on ARNi, however only 129 (38%) did not met the PARADIGM-HF inclusion criteria for ARNi prescription. Reasons for not meeting PARADIGM-HF criteria were no beta-blocker background therapy (22%), hyperkalemia (4%), hypotension (15%), chronic kidney disease (65%) and hyperkalemia (79%). In a logistic regression model not being on ARNi was associated with older age, chronic kidney disease, not being on cardiac resynchronization therapy, lower systolic blood pressure, lower BMI, and higher PAPs (Figure), representing the picture of a more fragile patient net of compliance with the PARADIGM-HF criteria. Conclusions Among outpatients with HFrEF in the OPTIMA-HF Registry, 79% met the PARADIGM-HF criteria. Strategies to improve guideline-directed use of HFrEF medications remain urgently needed, and these findings may inform targeted approaches to optimize outpatient medical therapy.

Presence of Atrial Fibrillation (AF) is a poor prognostic marker in patients with Heart Failure with reduced Ejection Fraction (HFrEF) and Left Bundle Branch Block (LBBB)

Abstract Background Observational data indicate that between 20-30% of patients with HFrEF have LBBB. While numerous independent variables are implicated in the overall prognosis of these patients, this group of patients respond poorly to medical therapy. Presence of AF further impairs the functioning of the left ventricle by several mechanisms e.g., left atrial dilatation, decreased left ventricular filling, irregular cycle length, functional mitral regurgitation etc. Literature is sparse on the cumulative effect of AF in this group of patients. Purpose To assess the effect of AF on left ventricular ejection fraction (LVEF) and mortality in patients presenting with HFrEF and LBBB Methods Single centre, retrospective, observational study over 33 months (Jan 2021 – Sept 2023). Patients with HFrEF and LBBB (as defined by the European Society of Cardiology, 2021) identified from the heart failure database. Results (Table) N=80 Whole cohort: age 74.8 +/- 13.6 years (median:79, range 39-96); 57/80 (67.5%) males. Hypertension [41/80 (51.3%)] was most common comorbidity. Majority were on 3 drugs (23/80, 28.8%) of guideline directed medical therapy (GDMT) with ~1 in 4 patients [19/80 (23.8%)] on all 4 drugs. 32/80 (40.0%) were in AF, remainder in sinus rhythm (SR). Mean baseline LVEF: 21.8 +/- 8.4. Mean LVEF continued to be ≤35% (paired echocardiograms available in 50.0% patients) inspite of GDMT. The QRS duration continued to prolong on follow-up. Patients in AF were statistically significantly older, were less often on all 4 GDMT drugs (particularly sodium glucose transporter 2 inhibitors - SGLT2i’s), and were less likely to survive than those in SR. No difference in comorbid conditions or QRS prolongation on follow-up were seen between patients with AF versus SR. There was trend towards a larger increase in mean LVEF in patients with SR than AF. Conclusions In our experience, patients with HFrEF and LBBB continue to have a high mortality (45.0% at ~ 3 years) inspite of GDMT. AF is seen in a high percentage of patients (40.0%) in this cohort, worsening the prognosis further, with mortality nearly 3 times higher than those in SR. Aggressive management of patients with HFrEF and LBBB with, where indicated, early cardiac resynchronisation therapy (CRT) and more so, of those with AF (with +/- atrioventricular node ablation or left atrial ablation) should be considered at an early stage after diagnosis.Table

The prognostic interplay of heart failure and chronic kidney disease in atrial fibrillation, focus on cardiorenal outcomes

Abstract Background Heart failure (HF) and chronic kidney disease (CKD) create a mutually reinforcing cycle, escalating disease development, and increasing morbidity and mortality rates. Both are common comorbidities promoting atrial fibrillation (AF) and contributing to heightened symptom burden and poorer outcomes in AF. Purpose To investigate the relationship of HF and CKD with cardiorenal outcomes in patients with AF. Methods For this analysis we included patients with known AF, treated at a tertiary centre between 01/2005 and 07/2019. The primary endpoint was a composite of cardiovascular (CV) death and hospitalization for HF (HHF). Secondary outcomes were renal death and dialysis. The multivariate model has been adjusted for age, sex, body mass index, HF, diabetes mellitus, CKD, coronary artery disease, previous myocardial infarction, and C-reactive protein. Results We included in total 7412 patients (median age 70 years, 39.7% female) with AF and followed them over a median of 4.5 years. A total of 1668 patients (22.5%) were diagnosed with HF, 806 (10.9%) with CKD and 372 (5.0%) were suffering from both conditions. Both CKD (adjusted HR 1.87, 95% CI 1.55-2.25) and HF (adjusted HR 2.57, 95% CI 2.22-2.98) were significantly associated with the composite of CV death/ HHF after multivariable adjustment. There was a significant stepwise increase in 5-year’s event rates of CV death/ HHF (no CKD & no HF: 23%, HF: 61%, CKD: 63%, CKD & HF: 82%; P-logrank <0.001). These results remained significant in the multivariate analysis, showing the highest increase in risk in patients with both HF and CKD with an adjusted HR of 3.96 (95% CI 3.34-4.68), followed by patients with only HF (adjusted HR 2.53, 95% CI 2.26 to 2.84) and only CKD (adjusted HR 2.22, 95% CI 1.87-2.63, p-value of <0.001, respectively). Regarding renal death/ dialysis we could observe a similar distribution of the 5-year’s event rates (no CKD & no HF: 1.5%, HF: 4.0%, CKD: 11.8%, CKD & HF: 17.7%; P-logrank <0.001). Both conditions, CKD and HF, remained independently associated with the combined endpoint of renal death/ dialysis after multivariable adjustment (only HF: adjusted HR of 2.80, 95% CI 1.84 to 4.25; only CKD: adjusted HR of 5.31, 95% CI 3.22 to 8.76; CKD & HF: adjusted HR of 7.47, 95% CI 4.70 to 11.87; Figure 1). Conclusions Both CKD and HF significantly increase the risk of CV death and HHF, as well as renal death and dialysis in patients with AF. Risk assessment should expand beyond stroke and bleeding to cardiorenal complications including HHF, CV and renal death, as well as kidney failure in an unselected AF patient population.

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

Determinants of changes in peak oxygen consumption in patients with new onset heart failure

Abstract Background Patients with heart failure (HF) with reduced ejection fraction (HFrEF) have a high risk of mortality. Cardio-Pulmonary Exercise Test (CPET) assesses peak oxygen consumption (pVO2) which is considered a key predictor of mortality and morbidity in patients with HFrEF. Factors responsible for the changes in pVO2 could consequently be of interest, as optimizing these factors may improve prognosis and overall quality of life in patients with HFrEF. Purpose To investigate factors contributing to changes in pVO2 within a contemporary cohort of new-onset patients with HFrEF. Methods From December 2022 to September 2023, patients with new-onset HFrEF (European Society of Cardiology (ESC) criteria) were included from a HF outpatient clinic, who after referral to the clinic underwent 12 weeks of HF management according to ESC guidelines. This included physical training and optimization of pharmacological management of HFrEF. Baseline characteristics, CPET, medication and echocardiography were collected at referral and after 12 weeks. Changes in pVO2 were investigated according to baseline characteristics, changes in medication, and changes in echocardiographic parameters in both uni- and multivariable linear regression models. Significant independent variables were identified using stepwise selection (p<0.1), adjusted for age and sex. A p-value of 0.05 was considered significant. Results We included 48 patients with new-onset HFrEF with a median age of 73 (interquartile range (IQR): 60-77) years, 10 (20.8%) women, a baseline median left ventricular ejection fraction (LVEF) of 30% (IQR: 25-35), and a baseline median pVO2 of 17.3 ml/min/kg (IQR: 14.1-21.9). After 12 weeks, pVO2 improved with a mean of +2.18 ml/min/kg (95% confidence interval (CI) 1.25 to 3.10, p<0.01) and LVEF improved with a mean of +11.7% (95% CI 7.9 to 15.6, p<0.01). In univariable analyses increasing age were negatively associated with pVO2 changes (p=0.04) and increasing minute ventilation (MV) and initiation of sodium-glucose cotransporter (SGLT2) inhibitors were all positively associated with pVO2 changes (p<0.01 and p=0.03, respectively). Other clinical variables included in the analysis were not significantly associated with a change in pVO2. In the multivariable analysis, body mass index emerged as an independent variable negatively associated with pVO2 changes, and MV and initiation of SGLT2 inhibitors remained significantly positively associated with pVO2 changes. Conclusion Optimal pharmacological management and physical training in patients with new-onset HFrEF, induce a significant recovery of cardiorespiratory performance and ejection fraction. Furthermore, our results suggest that the initiation of SGLT2 inhibitors in patients with new-onset HFrEF appears to improve their pVO2 already after 12 weeks of optimal HF management.Table 1:BaselineTable 2:Associations

Coronary microvascular dysfunction in patients with heart failure with reduced and mildly reduced ejection fraction: results from the PANACEA study

Abstract Aims Coronary microvascular dysfunction (CMD) is common and associated with impaired survival in patients with heart failure with preserved ejection fraction (HFpEF). In patients with heart failure with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF) the impact of CMD is not fully known. Purpose We aimed to investigate the prevalence of CMD and its association with phenotype, biomarkers, endothelial function and echocardiographic measurements in patients with HFrEF or HFmrEF. Method A prospective, exploratory bi-center study in patients with chronic stable heart failure, New York Heart Association (NYHA) Class II-IV, and ejection fraction (EF) <50% was performed. Study procedures included echocardiography, adenosine-based transthoracic Doppler echocardiography to assess coronary flow reserve (CFR), physical examination, fasting blood and urine sample, pulse wave velocity (PWV) and hemodynamic measurements. The cutoff of CFR<2.5 was used to diagnose CMD. A multivariable linear regression analysis with CFR as dependent variable, adjusted for age, sex, body mass index, smoking, atrial fibrillation and left ventricular mass, was performed to explore biomarkers, endothelial function, and echocardiographic measurements associated with CMD. Results Of 112 included patients, 87 (78%) were men, with a mean age of 73.3 (±7.5) years. Among patients with a successful CFR measurement (n=62), CMD was present in 40 (65%), mean age of 75.4 (±5.8) years (Table 1). Patients with CMD had higher N-terminal pro B-type natriuretic peptide (NTproBNP) and Troponin T (p<0.05), and more often HFrEF ( p=0.06). Patients with CMD had larger ventricles with greater left ventricular mass and larger end-diastolic volumes (p<0.05). In a linear regression analysis CMD was associated with higher NTproBNP, lower EF, PWV and global strain (table 2). Conclusion CMD was common and present in two thirds of patients with HFrEF or HFmrEF. Further CMD was associated with markers of more severe heart failure and systemic endothelial dysfunction indicating that CMD may be an important predictor of outcome in patients with HFrEF and HFmrEF.

Sinus rhythm restoration as an independent predictor of left ventricular ejection fraction improvement in patients with the first hospitalization for heart failure and reduced ejection fraction

Abstract Background and Purpose Tachycardiomyopathy (TCM) is prevalent in heart failure with reduced ejection fraction (HFrEF). Despite its significance, a comprehensive understanding of its evolutionary trajectory and prognosis remains limited. This study aims to investigate the prognosis and left ventricular ejection fraction (LVEF) trajectory in patients with TCM compared to other etiologies within a cohort initially admitted for "de novo" HFrEF (LVEF < 40%). Methods A prospective registry was conducted across two University Hospitals, incorporating patients hospitalized with a diagnosis of HFrEF. The study encompassed 370 patients admitted between March 2021 and October 2023, with a median follow-up of 15 months (IQR 7-22). Two distinct groups were delineated based on etiology (TCM vs other etiologies). Within the TCM cohort, subgroups were established concerning LVEF improvement, following the criteria outlined in the "Universal Definition and Classification of Heart Failure" report. Categorical variables were presented as absolute frequencies and percentages, analyzed using the chi-square test. Continuous variables were expressed as mean +/- SD and compared through Student's t-test or Mann-Whitney U test. Hazard functions were estimated using the Kaplan-Meier method. Data analysis was executed using SPSS Statistics. Results In our cohort, both TCM and other etiologies groups exhibited improved LVEF post-neurohumoral blockage titration. Nonetheless, the TCM cohort demonstrated notably higher LVEF (49.1% vs. 43.5%, p = 0.005) [Figure 1]. Moreover, overall mortality, cardiovascular mortality, and the composite of CV mortality and hospitalizations for CV causes were notably lower in the TCM group compared to other etiologies [Figure 2]. Among TCM patients, those with improved LVEF during follow-up were younger (66 vs. 72), with no differences in treatment at discharge or after neurohumoral blockage titration. While achieving sinus rhythm before discharge did not correlate with LVEF improvement, attaining sinus rhythm during follow-up (at titration completion) significantly correlated with LVEF improvement [Table 1]. Multivariate analysis revealed that sinus rhythm restoration after up-titration emerged as an independent predictor of LVEF improvement, irrespective of sinus rhythm restoration at discharge or the attainment of quadruple therapy during follow-up, among other variables (Table 2). Conclusions Among patients initially admitted for "de novo" HFrEF, TCM presents a potentially more favorable clinical trajectory compared to other HF causes, showcasing reduced total and cardiovascular mortality, as well as combined cardiovascular mortality and hospitalizations for cardiovascular causes. Notably, in this patient subset, sinus rhythm restoration during follow-up emerged as an independent predictor of improved LVEF, irrespective of pre-discharge sinus rhythm restoration or adherence to comprehensive four-pillar HF management.

Understanding the benefits of renin-angiotensin-aldosterone system inhibitors and influence of hyperkalaemia on their prescription: a UK survey of healthcare professionals' views and practice

Abstract Background Renin–angiotensin–aldosterone system inhibitors (RAASi) improve outcomes in heart failure with reduced ejection fraction (HFrEF) and they should be increased to the maximally tolerated dose. However, their use is often hindered by hyperkalaemia leading to discontinuation or down titration. Purpose Assess perceptions of primary and secondary healthcare professionals regarding benefits of RAASi according to indication and, in the context of developing hyperkalaemia, to identify barriers to optimal utilisation, and to explore options for improving management protocols, specifically in HFrEF. Methods An electronic survey was distributed in primary and secondary care setting in Hampshire, UK, to evaluate knowledge about benefits of RAASi, clinical response to varying level of potassium (K+), and decision-making using several clinical scenarios. Hyperkalaemia was graded into mild (serum K+ 5.5 – 5.9 mmol/L), moderate (serum K+ 6.0 – 6.4 mmol/L) or severe (serum K+ ≥ 6.5 mmol/L). Results Between November 2021 and January 2023, 300 questionnaires were completed by 274 (91%) physicians (varying grades of seniority), 22 (7%) non-medical prescribers, and 4 (1%) pharmacists. 80% were working in secondary care across different specialities (31 working in cardiology and 15 in nephrology). The majority were aware of prognostic benefit of angiotensin converting enzyme inhibitors (ACEi) in patients with HFrEF although this was lower for mineralocorticoid receptor antagonists (MRA) (Fig 1). Fewer than 2/3 of respondents were aware of impact of ACEi on symptoms. In the presence of mild hyperkalaemia, 75% and 88% of healthcare professionals would stop or reduce ACEi and MRA, respectively. In moderate or severe hyperkalaemia, this increased to 96% and 97%, respectively (Fig 2A-B). When considering the scenario of a patient with HFrEF who had ACEi stopped due to K+ 5.9 mmol/L, the potassium at which the responder would consider re-starting the ACEi ranged from 77% when potassium level < 5.5 mmol/L to 1% in moderate or severe hyperkalaemia (Fig 2C). 74% of healthcare professionals were familiar with local hyperkalaemia management protocol and 93% supported dedicated training on RAASi dose adjustment and hyperkalaemia management. Conclusion This survey, across a broad range of healthcare professionals, shows uncertainties around knowledge of benefits of RAASi in patients with HFrEF and there is sizeable variation in the prescribing response to degrees of hyperkalaemia. Given the voluntary nature of the survey, it is plausible that these data are biased towards individuals with greater understanding. Regardless, there is a need for continued education with a goal of improving patient-centred care.

Baroreflex activation therapy in heart failure patients with reduced ejection fraction: a long-term follow up

Abstract Introduction Heart failure with reduced ejection fraction (HFrEF) is a major public health concern with substantial morbidity and mortality. Overactivation of the sympathetic nervous system is a key pathophysiological process driving heart failure progression. Baroreceptor activation therapy (BAT) targets this autonomic imbalance and is a promising treatment strategy for patients with HFrEF. Current short-term studies indicate that BAT provides symptomatic relief, improvement in left ventricular function and cardiac biomarkers. However, data regarding the long-term effect of BAT on HFrEF are scarce. Purpose This study aims to assess long-term outcome in HFrEF patients who underwent BAT. Methods Patients with HFrEF who received BAT between 2014-2023 were followed until latest available follow-up. Symptom burden, echocardiography and laboratory testing were assessed before BAT implantation and in subsequent follow ups. Results 23 patients (mean age 66±10 years, 83% men) with HFrEF were included in the study. Etiology of heart failure was ischemic in 70%. The majority of patients (96%) suffered from NYHA III with a mean left ventricular ejection fraction (LVEF) of 23±8% and NTproBNP of 2463±2922pg/ml. Complication occurred in one patient during BAT implantation (4%). Mean follow-up was 3±2 (max. 7.5) years. BAT reduced NYHA classification in 12 patients (52%) after 1 year, of which 1 patient remained in ameliorated NYHA for 7.5 years. Evolution of NYHA functional class over time is shown in Figure 1. Echocardiographic evaluation revealed significant improvement in LVEF of 9±9% after 1 year (p<0.001) and by 11±9% after 2 years (p=0.005). In long-term a trend towards improved LVEF could be observed (Figure 2). In addition, BAT mildly reduced NTproBNP in the first 2 years (after 1 year non-significantly by -396±1006pg/ml and significantly after 2 years by -566±651pg/ml (p=0.039)). Seven patients reaching recommended replacement time underwent device exchange. Four patients deceased during observation time. Conclusion BAT resulted in a substantial reduction in NYHA classification, improvement in LVEF, and a delayed reduction in NTproBNP levels. These findings highlight the long-term efficacy and potential benefits of BAT as a therapeutic intervention for patients with HFrEF.Sankey plot of NYHA class over timeAlteration of LVEF over time

Impact of paroxysmal atrial fibrillation ablation on cardiac sympathetic nervous system: a prospective stratified randomized comparative study in patients with and without heart failure

Abstract Background Catheter ablation of atrial fibrillation (AF) might influence the cardiac sympathetic nervous system (CSNS). We sought to investigate the impact of AF ablation with 2nd generation cryoballoon catheter (CB) and contact force sensing radiofrequency ablation catheter (RF) on CSNS and the association of this effect with early AF recurrence in patients with and without heart failure (HF), using cardiac iodine-123-metaiodobenzylguanidine (MIBG) scintigraphy. Methods and Results One hundred sixty-five paroxysmal AF patients who were scheduled for ablation were enrolled. All patients were categorized into two groups: one with HF (n=31), defined as left ventricular ejection fraction ≤ 40% or previous history of hospitalization for worsening HF, and the other without HF (n=134). They were then randomly assigned to CB (17 patients with HF and 68 without HF) or RF (14 with HF and 66 without HF). MIBG scintigraphy was performed at baseline and 3 months post-ablation and the washout rate (WR) was measured. There were no significant changes in WR from baseline to 3 months after RF and CB ablation (28.7±18.6% to 27.9±16.7% in RF and 29.4±16.7% to 30.5±16.4% in CB). WR decreased more in patients with HF at 3 months after ablation than without HF, while WR significantly increased in patients without HF and there was a significant interaction in WR change between with or without HF (interaction p<0.001). WR change from the baseline to 3 months after ablation (dWR) was not significantly different between CB and RF, irrespectively of the HF presence. In the blanking period of 3 months after ablation, early AF recurrence (EAR) was observed in 37 (22%) patients with no antiarrhythmic drugs (17(21%) patients in RF and 20(24%) in CB). dWR was significantly greater in patients with than without EAR (4.0±14.1% vs -0.9±11.0%, p=0.027). Higher dWR (≥ 6.9% (AUC 0.644, 95%CI [0.535-0.753]) by ROC curve analysis) was independently associated with EAR (adjusted odds ratio = 4.15, 95%CI [1.87-9.22], p<0.001, adjusted for age, sex, and left atrial diameter). Conclusions Irrespectively of CB and RF, AF ablation might reduce adrenergic tone in patients with HF, while it might induce more adrenergic tone in patients without HF. Excessive adrenergic tone might be associated with early AF recurrence.WR changes before and after ablationdWR in patients with or without HF

A comparative analysis of conventional echocardiographic findings among different heart failure stages and phenotypes: insights from the national echocardiographic society registry

Abstract Background The contemporary conceptualization of heart failure (HF) encompasses four developmental stages (at risk for HF, pre-HF, symptomatic HF, and advanced HF) and three distinct HF phenotypes categorized by left ventricular ejection fraction (LVEF) (HFpEF, HFmrEF, HFrEF). However, there is a need for a more comprehensive understanding of echocardiographic similarities and differences among pre-HF stages and various HF phenotypes. Material and Methods Our national echocardiographic society conducted a multicenter HF screening initiative. General practitioners in 13 primary care centers utilized the original mobile phone app to determine referrals for transthoracic echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing in individuals without a prior HF diagnosis. The 2021 ESC guidelines' algorithms were used to diagnose HF phenotypes and 2016 EACVI/ASA recommendation² to assess diastolic function. This study defined "heart stress" (elevated NT-proBNP in asymptomatic individuals with risk factors, regardless of structural heart disease or cardiac dysfunction) and "patients at risk for HF" (normal NTproBNP and at least one HF risk factor). All patients were categorized into six groups: (I) no HF, no risk, (II) at risk for HF, (III) heart stress, (IV) HFpEF, (V) HFmrEF, and (VI) HFrEF. Echocardiographic findings were compared among groups (II) to (VI), using ANOVA, Kruskal-Wallis and Chi-squared test, when needed. Results In a cohort of 930 outpatients (mean age 66±11 years, 61% female), 34.2% were diagnosed with HF, 22.3% experienced heart stress, 37.8% were at risk for HF, and 12.8% had neither HF nor risk factors (Figure). While NT pro BNP showed progressive increase, LVEF showed a progressive decline across the groups, reaching its lowest in HFrEF patients (Table). Simultaneously, left ventricular mass index (LVMi), left atrial volume index (LAVi), and maximal velocity of tricuspid regurgitation (TR Vmax) significantly increased in a stepwise manner. Variations in predominant LV geometry were significant across groups (p<0.001): normal LV geometry in those without HF (60.8%), concentric LV remodeling in at-risk patients (38.6%), normal LV geometry in heart stress (49%), concentric LV hypertrophy (LVH) in HFpEF (27.7%), eccentric LVH in HFmrEF (42.3%), and both concentric and eccentric LVH in HFrEF (43.3% each). Diastolic dysfunction increased prevalence across the groups (12.9% vs 24.7% vs 37.6% vs 19.6% vs 51.1%, p<0.001). Remarkably, HFmrEF group had the highest proportion of undetermined diastolic function (14.7% vs 23.1% vs 27.9% vs 50% vs 26.7%, p<0.001). Conclusions The mobile phone app used in primary care setting allowed identification of significant number of individuals in the pre-HF stages, warranting further investigation. Distinct echocardiographic differences in pre-HF stages and HF phenotypes provide valuable insights for early detection and tailored treatments.

Multimorbidity patterns in adults admitted to hospital with heart failure: an analysis of 175 million hospitalisation episodes

Abstract Background The prevalence of heart failure (HF) is increasing as a result of population ageing, improved survival following myocardial infarction and the widespread uptake of evidence-based HF treatments. Greater understanding of multimorbidity patterns in patients with HF may enable the development of treatment strategies that target multiple, related long-term conditions (LTCs), producing synergistic benefits. Purpose To characterise multimorbidity patterns in patients with HF and compare these to a matched population without HF. Methods A retrospective matched cohort study was conducted using the United States National Readmission Database (NRD), 2010–2020. International Classification of Disease (ICD) codes were used to identify HF and 92 other common LTCs. The most frequent combinations of LTCs were identified for individuals with HF and a control cohort of individuals of the same age and sex, with a non-HF-related hospital admission in the same year (matched in a 1:5 ratio). Multivariable regression analysis (adjusted for age, sex, socioeconomic status, tobacco use, year of hospitalisation, and hospital characteristics) was used to evaluate the association between multimorbidity burden, length of stay (LOS; negative binomial regression) and 30-day readmission (logistic regression). Results From a total of 175,388,410 hospitalisation episodes, 3,913,924 individuals with an HF-related hospitalisation were identified and matched to 19,552,954 controls (Figure 1a). The median (interquartile range, IQR) age of a patient admitted with HF was 74 (63–85) years; 1,856,268 (47.5%) were female. The most common comorbidities in those with HF were hypertension (87.2 vs. 72.8% in matched controls), chronic kidney disease (CKD; 55.3 vs. 34.6%), coronary artery disease (CAD; 53.7 vs. 31.0%), dyslipidaemia (46.9 vs. 39.7%), diabetes (46.6 vs. 33.9%), atrial fibrillation (AF; 43.0 vs. 23.0%) and anaemia (33.2 vs. 30.1%; p all < 0.001). Patients with HF had a greater number of LTCs compared with matched controls (median [IQR] 7 [5–9] vs. 6 [4–8]; p < 0.001). From 2010–2020, the number of LTCs in those with an HF admission increased (from 6 [4–8] in 2020, to 8 [6–10] in 2020; Figure 1b). The most common multimorbidity patterns in those with HF are presented in Figure 2. In the HF cohort, a greater multimorbidity burden was associated with a longer LOS (+6% for each additional LTC; 95% confidence interval [CI] 5–7%; p<0.001) and greater risk of 30-day readmission (adjusted odds ratio [aOR] for 6 vs. 0 LTCs: 1.15, 95% CI 1.08–1.22; aOR for ≥12 vs. 0 LTCs: 1.54, 95% CI 1.45–1.64). Conclusions Patients admitted to hospital with HF have a significant burden of multimorbidity, which has increased over time and is associated with increased length of stay and unplanned hospital re-admission. The high prevalence of multiple LTCs warrants the development of novel treatment strategies that target common multimorbidity patterns observed in HF.

Heart failure and advanced chronic kidney disease: differences in characteristics, treatment and outcomes in patients with glomerular filtration rate greater or less than 30 ml/minute/m2

Abstract Introduction Heart failure (HF) is a serious health problem and continues to have a high mortality and incidence of decompensation, despite advances in its management. Chronic kidney disease (CKD) is very prevalent in patients with HF, hinders their treatment and worsens their prognosis, especially when it is advanced CKD (glomerular filtration rate-GFR <30 ml(min/m2). It is important to know the differential characteristics of these patients to improve their management. Purpose To analyze in a contemporary registry of HF patients followed in specialized HF units in Spain the differences in clinical characteristics and treatment between patients with HF and advanced CKD. Methods We analyzed data from the registry of the SEC-Excelente-IC quality accreditation program of the Spanish Society of Cardiology, with 1716 patients with HF included between 2019 and 2021 by 45 specialized HF units accredited by the SEC. Patients were included consecutively in two 1-month cutoffs (March and October) in that period. The clinical and demographic characteristics and comorbidities of the patients were compared according to GFR < or > 30ml/min/m2. Results Of the 1,716 patients, 11.1% had a GFR<30 and 88.9% >30 mL/min/m2. Figure 1 shows the main clinical characteristics and comorbidities of the 2 groups. Median LVEF was similar in both groups: 42 (30-58) vs 38% (29-54). The group with advanced CKD was older (77±9.6 vs 70.5±12.6 years; p<0.001), had greater HF severity (more admissions for HF in the last year, worse NYHA functional class and longer evolution time), and a higher prevalence of coronary heart disease, hypertension, diabetes mellitus, cognitive impairment, anemia, iron deficiency and hyponatremia. There were no differences in sex, BMI, serum potassium or other comorbidities (Figure 1). Figure 2 shows the treatment received in each group. Patients with GFR <30 received in a significantly lower proportion all drugs for HF (p<0.001), except diuretics and potassium binders (ACEI/ARA, sacubitril-valsartan, MRA, beta-blockers, digoxin and SLGT2 inhibitors), and less cardiac rehabilitation (5.2 vs 10.4%; p=0.029). Incidence of one-year mortality was significantly higher in patients with GFR<30 ml/min/m2 (37.2 vs 14.4 per 100 persons-year, p<0.001), as were HF hospitalizations (61.3 vs 33.0; p<0.001) and HF decompensations without hospitalization (24.1 vs 11; p<0.001). Conclusions In our contemporary cohort of real-life HF patients, the prevalence of advanced CKD was 11.1%. These patients had a higher severity of HF, despite which, the utilization of HF drugs, including SGLT2 inhibitors was much lower than in those with GFR >30 ml/min/m2. One-year mortality, HF hospitalization and HF decompensations were almost 3-times higher. This treatment trend needs to be modified to improve the prognosis of these patients.

Defining patterns of comorbidity accrual before and after the diagnosis of heart failure

Abstract Introduction People with heart failure (HF) usually have multiple comorbidities and these confer adverse prognosis. The chronology of comorbidity development in relation to HF has not been investigated, which hinders development of preventative strategies. Purpose We aimed to define the chronology of comorbidity diagnoses in relation to HF diagnosis and hypothesised that HF is preceded by most of its comorbidities. Methods We used UK Biobank data to identify 21,127 people with HF diagnosis at any stage before or after recruitment. Comorbidities were defined using primary care records, and were not included if self-reported or their date of diagnosis unknown. Comorbidities were selected based on methods of Conrad et al. (Lancet 2018; 391(10120): 572-580), and defined using CALIBER or UK Biobank criteria. We investigated the time between first diagnosis of HF and first diagnosis of 15 common comorbidities, including after stratification by sex and age at HF diagnosis. Analysis was conducted using RStudio. Results For all studied comorbidities, except dementia, at least half of diagnoses predated or developed synchronously with HF. For myocardial infarction, obesity, cancer, atrial fibrillation, hypertension, diabetes and depression, at least three quarters of diagnoses predated or developed synchronously with HF. The median time between comorbidity and HF diagnoses varied substantially between comorbidities, ranging from depression preceding HF by 10.7 years to dementia proceeding HF by 0.7 years. The interquartile range of time between comorbidity and HF diagnoses varied substantially, ranging from 2.4 years for myocardial infarction to 15.2 years for depression, indicating most cases of the former develop in a narrow window (usually prior to HF diagnosis). All comorbidities presented earlier in women, with this being most marked for cancer (median time between cancer and HF -2.6 years for men and -7.1 years for women). As the age of HF diagnosis increased, the time spent with all studied comorbidities also increased. Indeed, in HF diagnosed before the age of 60, a majority of comorbidity diagnoses (except for depression) occurred after HF. Conclusion HF most often develops late in the process of comorbidity accrual, although this pattern is reversed in people developing HF at younger ages. Sex differences are also notable, with women developing comorbidities earlier in relation to their HF diagnosis. Understanding the chronology of comorbidity development may help to guide strategies to prevent multimorbidity, which are likely to require a personalised approach. For people with established HF, our data also emphasise the importance of holistic care that accounts for complex multimorbidity.Figure 1

Serum expression of mirnas in obese and lean patients with heart failure

Abstract Background Heart Failure (HF) is a progressive disease that results in increased morbidity and mortality, and clinical studies have demonstrated that body mass index (BMI) is an independent risk factor for the development of HF. Evidence has suggested that human obesity is associated with reduced mortality among patients with HF, a clinical phenomenon known as the "Obesity Paradox." MicroRNAs (miRNAs) have been underscored for their pivotal regulatory roles in numerous diseases, particularly in the context of HF. Nevertheless, our understanding of the impact of these miRNAs on obesity in conjunction with HF remains limited. Purpose The objective of this study was to evaluate the serum expression of miRNAs in obese and lean patients with HF and establish the relationship between these miRNAs and BMI. Additionally, we explored this association within two distinct phenotypes: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Methods Sixty-five patients with symptomatic HF (all NYHA >/=II, mean-LVFE 44.4 %), 29 lean (BMI= 25.87 ± 2.52 Kg/m2) and 36 obese (BMI= 34.52 ± 4.15 Kg/m2), were prospectively evaluated by clinical, laboratory and echocardiographic analyses. Serum expression of miRNAs was assessed by the TaqMan OpenArray Human MicroRNA system, a polymerase chain reaction-based quantitative platform that contains 754 microRNAs in a microfluidic platform. Results Among the studied miRNAs, seventeen were upregulated and one downregulated in obese HF patients compared to lean HF patients (Figure 1A). Ten miRNAs were differentially expressed in the serum of obese HFpEF patients compared to lean HFrEF patients (Figure 1B) and five were differentially expressed in the serum of obese HFpEF patients when compared to lean HFpEF patients (Figure 1C). miR-132 was upregulated in obese patients with HFrEF and HFpEF compared to lean patients, whereas miR-1291 was downregulated only in obese patients with HFpEF. Correlation analysis demonstrated a positive association between BMI and miR-132 (r=0.502; p=0.001), miR-148b (r=0.510; p<0.001), miR-103a-3p (r=0.373; p =0.011) and miR-374b-5p (r=0.325; p=0.034) in HF patients and gene set enrichment analysis identified seventy-nine potential target genes common to at least three of these four miRNAs, with the EIF4E3 and TRA2B genes common to the four miRNAs. Conclusions Our study reveals a profile of miRNAs that are differentially expressed in obese patients with HF when compared to lean patients with HF. Furthermore, four of these miRNAs showed a positive correlation with BMI in patients with HF. Although the literature indicates that miR-132 presents reduced expression in obesity models, our study identified increased serum expression of this miRNA, suggesting that it might be a potential "missing link" in the obesity paradox in patients with HF. Further studies with a larger sample are needed to confirm and explore the mechanisms linking these miRNAs to the obesity paradox.

Modern heart failure treatment is superior to conventional treatment across the left ventricular ejection spectrum: Real-life data from the Swedish Heart Failure Registry 2013-2020

Abstract Background Heart failure (HF) is a clinical syndrome characterized by high mortality and morbidity. In 2016, Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was recommended as a new treatment option for HF in patients with HFrEF. In the 2021 European Society of Cardiology guidelines for treatment of HFrEF patients Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were introduced because they demonstrated significantly reduced HF events or cardiovascular (CV) mortality. Since ARNI and SGLT2i were introduced to treat HF, its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). Purpose This study is aimed to compare effectiveness of modern therapy including ARNI and SGLT2i with conventional heart failure treatment. Conventional HF treatment includes (BB, ACEi/ARB, with or without MRA) and modern heart failure treatment (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i) in real-world. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n=20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n=709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality compared to conventional HF treatment (adjusted HR [aHR]: 0.72 (95% CI 0.54 - 0.96), p=0.024), and had 33% reduced all-cause mortality (aHR: 0.67 (95% CI 0.48 - 0.94), p=0.019) within 2 years of index registration. Similarly, modern HF therapy was associated with a significant 62% reduction in CV mortality compared to conventional HF treatment (aHR: 0.38 (95% CI 0.21 - 0.68), p=0.0013). In addition, we found a 58% reduced CV mortality (aHR 0.42 (95% CI 0.22 - 0.79), p=0.0067) within 2 years of index registration. In the propensity score 1:1 matched cohort in which ARNI was included in the matching procedure, i.e., no ARNI was used in any of the two treatment groups and the effect of SGLT2i was the target assessment. The results were associated with a statistically significant risk reduction of 42% in all-cause mortality in the modern HF treatment group compared to the conventional treatment group (aHR: 0.58 (95% CI 0.36 - 0.94), p=0.028), and a 49% (aHR: 0.51 (95% CI 0.29 - 0.89), p=0.018) risk reduction within 2 years of index registration. Conclusion This study demonstrates that modern HF therapy in a real-world Swedish HF population is associated with a statistically significant risk reduction in all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF compared to conventional HF therapy.Central Illustration

Machine learning for prediction of incident heart failure and heart failure hospitalisation: multi-cohort development, validation and association with clinical phenotypes

Abstract Background Delayed heart failure (HF) diagnosis is associated with adverse outcomes and costs of hospitalisation.(1,2) Whilst previous tools have been developed to predict incident HF,(3) risk of HF incidence may correlate poorly with risk of HF hospitalisation, which may be more important in targeting diagnostics. Purpose To develop and validate a novel decision support tool for prediction of incident HF and HF hospitalisation, and investigate association of score with HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Methods We developed the models (FIND-HF) in UK primary care health record data from individuals aged ≥40 years without known HF (Jan 2, 1998 to Feb 28, 2022), randomly divided into training (80%) and testing (20%) datasets. We evaluated logistic regression and supervised machine learning models for prediction of 1- and 5- year HF and HF hospitalisation risk in the testing dataset with internal bootstrap validation. Models were externally validated for HF hospitalisation in data from a Taiwanese university hospital. Association of FIND-HF score with HF phenotypes of HFpEF and HFrEF was assessed in two prospective cohorts, the MATCH registry of patients diagnosed with HFrEF and the FIND-AF cohort of individuals at higher predicted risk of atrial fibrillation who underwent echocardiography. Results Of 565 284 UK individuals (mean age 68.9 (SD 12.2) years, 49.2% women), incidence of HF and HF hospitalisation was 1.1% and 0.5% at 1-year, and 6.6% and 3.4% at 5-years, respectively. Prediction performance was superior for machine learning algorithms compared with logistic regression, with best performance for XGBoost (area under receiver operating characteristic curve (AUROC) at 1 and 5-years: 0.755 and 0.723 for incident HF, and 0.738 and 0.711 for incident HF hospitalization). On external validation in 106,026 individuals in Taiwan (mean age 64.7 (SD 10.6) years, 52.8 % women), HF hospitalisation incidence was 0.71%, and 2.46% at 1- and 5- years, respectively, and discrimination performance was excellent (AUROC at 1- and 5-years: 0.834 and 0.843). When the FIND-HF score was applied to individuals in the MATCH cohort (n = 133, mean age 69.0 (SD 11.7) years, 38.3% women) and FIND-AF cohort (n = 82, mean age 71.6 (SD 7.5) years, 50.0% women), the distribution of score to clinical phenotypes demonstrated a binomial distribution (Figure 1), and likelihood of HFpEF diagnosis correlated with the numeric score (Figure 2). Conclusions The machine learning FIND-HF decision support tool can accurately identify individuals at risk of incident HF and HF hospitalisation, to enable new approaches for early detection and prevention. The variation of score amongst high risk individuals with different HF clinical phenotypes emphasizes the distinct pathophysiological pathways but shared adverse outcome profile across the HF syndrome.Figure 1Figure 2