2025 HFA／HFSA／JHFS临床共识声明 ：左心室射血分数在心衰诊断和治疗中的应用

The use of left ventricular ejection fraction in the diagnosis and management of heart failure. A clinical consensus statement of the Heart Failure Association (HFA) of the ESC, the Heart Failure Society of America (HFSA), and the Japanese Heart Failure Society (JHFS)

Giuseppe M.C. Rosano 1 ,2 \* , John R. Teerlink 3 , Koichiro Kinugawa 4 , Antoni Bayes-Genis 5 , Ovidiu Chioncel 6 , James Fang 7 , Barry Greenberg 8 , Nasrien E. Ibrahim 9 , Teruhiko Imamura 4 , Takayuki Inomata 1 0 , Koichiro Kuwahara 11 , Brenda Moura 1 2 , Anekwe Onwuanyi 1 3 , Naoki Sato 1 4 , Gianluigi Savarese 1 5 , Yasuhiko Sakata 1 6 , Nancy Sweitzer 1 7 , Jane Wilcox 1 8 , Kazuhiro Yamamoto 1 9 , Marco Metra 20 , and Andrew J.S. Coats 2 1

1 San Raffaele Open University of Rome, Rome, Italy; 2 Cardiology, San Raffaele Cassino Hospital, Cassino, Italy; 3 University of California, San Francisco, San Francisco, CA, USA; 4 University of Toyama, Toyama, Japan; 5 Hospital Universitari Germans Trias i Pujol, Badalona, CIBERCV, Barcelona, Spain ; 6 Emergency Institute for Cardiovascular Diseases ‘Prof. C.C. Iliescu’, Bucharest, Romania; 7 University of Utah Hospital, Salt Lake City, UT, USA; 8 University of California, San Diego, San Diego, CA, USA; 9 Brigham and Women’s Hospital, Boston, MA, USA; 1 0 Kitasato University Kitasato Institute Hospital, Tokyo, Japan; 11 Shinshu University Hospital, Matsumoto, Japan; 1 2 Military Hospital, Porto, Portugal; 1 3 Grady Memorial Hospital, Atlanta, GA, USA; 1 4 Nippon Medical School, Tokyo, Japan; 1 5 Karolinska University Hospital, Stockholm, Sweden; 1 6 National Cerebral and Cardiovascular Center, Osaka, Japan; 1 7 Washington University School of Medicine, St. Louis, MO, USA; 1 8 Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 1 9 Tottori University, Yonago, Japan; 20 University of Brescia, Brescia, Italy; and 2 1 University of Warwick, Coventry, UK

Received 1 3 December 2024; revised 11 February 2025; accepted 1 0 March 2025

This clinical consensus statement revisits the role of left ventricular ejection fraction (LVEF) as a measurement of cardiac function, a prognostic marker and a major criterion to classify patients with heart failure, and gives new advice for clinical practice. Heart failure is traditionally classified on the basis of LVEF thresholds and this has major implications for treatment recommendations. However, the reproducibility of LVEF measurement is poor and its prognostic and diagnostic value lessens when it is above $45\%$ , with no relationship with the severity of either cardiac dysfunction or outcomes at higher values. These limitations dictate the need for a more comprehensive approach to classify and assess heart failure focusing more on the trajectory of LVEF rather than to its absolute value. Furthermore, the assessment of LVEF is not required for the initiation of treatments like sodium–glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists and diuretics in patients with suspected de novo heart failure and elevated N-terminal pro-B-type natriuretic peptide levels. Future research utilizing advanced imaging techniques and biomarkers which can better characterize myocardial structure, metabolism and performance may facilitate the identification of alternative therapeutic targets and better ways to monitor heart failure therapies across the entire spectrum ..........................................................................................................

Diagnosis •

Heart failure •

Left ventricular ejection fraction •

Management •

Phenotypes

255, Email: giuseppe.rosano@gmail.com

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The aim of this clinical consensus statement is to critically assess the role of left ventricular ejection fraction (LVEF) as a measurement of cardiac function, a prognostic marker and a major criterion to classify patients with heart failure (HF) and give advice for clinical practice ( Table 1 ). The limitations of this measurement will be shown and, specifically, a new classification based on LVEF trajectory, rather than its static measurement, will be introduced.

With these aims, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC), the Heart Failure Society of America (HFSA), and the Japanese Heart Failure Society (JHFS) selected the members of the writing committee. The writing committee consisted of 2 1 individuals with documented expertise in HF.

On 23 May 2023, the HFA of the ESC, the HFSA, the JHFS convened a face to face consensus conference to develop this clinical consensus statement.

The work of the writing committee was accomplished via a series of teleconference and web conference meetings, along with extensive email correspondence. The review work was distributed among subgroups of the writing committee based on individual interests and expertise. The proceedings of the workgroups were then assembled, and synthesized into a single final paper. All members reviewed and approved the final version.

## Left ventricular ejection fraction

## History of left ventricular ejection fraction as a measure

Left ventricular ejection fraction has been fundamental in understanding HF epidemiology, pathophysiology, and therapy. First quantitatively measured in 1 9 1 8 by James MacKenzie using heart rate and pulse pressure, 1 LVEF measurement evolved through several technological advances. Radiologic imaging in the 1 930s– 1 950s enabled cardiac chamber visualization, while cardiac catheterization in the 1 960s– 1 970s provided more accurate measurements. The 1 970s brought multiple developments: radioisotope imaging with multigated acquisition scanning and echocardiography, with the latter becoming the preferred method due to its safety and accessibility. Modern technological improvements include two-dimensional (2D), three-dimensional (3D), and Doppler imaging. While cardiac computed tomography can assess LVEF, radiation exposure limits its use. Cardiac magnetic resonance (CMR) imaging, though costly and less available, is now considered the gold standard for LVEF measurement.

Quantification of LVEF is now a cornerstone assessment of left ventricular (LV) function and the most commonly used guide for managing patients with HF. 2,3 However, the diagnosis and definition of HF historically did not require an assessment of LVEF. In fact, early HF studies did not require an assessment of LVEF for patient inclusion. Early randomized controlled clinical trials such as the Veterans Administration Cooperative Study (V-HeFT-I) and the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) included criteria such as radiologic parameters, cardiac size, increased LV diastolic diameter but not an assessment of LV function. 4,5 However, LVEF was included as an inclusion criterion by the SOLVD trial investigators. 1 ,6 Subsequent clinical trials in

HF used progressively lower LVEFs as an enrichment criterion based on the observation that lower LVEF values were associated with more of the clinical events that were part of the endpoints of these trials. 7 Subsequently, LVEF has been incorporated into all contemporary HF trial inclusion criteria. The upper limit of LVEF in clinical trials of HF with reduced ejection fraction (HFrEF) has progressively lowered over time. Concomitantly, the LVEF definition of HF with preserved ejection fraction (HFpEF) has changed and other LVEF categories have been introduced, for example, mildly reduced (HFmrEF) and improved ejection fraction (HFimpEF). 3 The scientific justification underlying this type of classification based on LV measurement cut-offs remains limited and complicated by the imprecision of the exact value. Furthermore, patients with HF may have different trajectories during the course of the disease that transition them from one category to another. 8 In addition, the considerable inherent intra- and inter-individual errors in measurement make it abundantly clear that many patients classified into one HF phenotype may in reality belong to another phenotype for much of their clinical course.

## Measurement considerations for left ventricular ejection fraction

The limitations in LVEF measurement are inherent to all imaging modalities. LVEF is an operator and load-dependent measure, affected by pre- and afterload, heart rate and rhythm. Additionally, LVEF has limited sensitivity to minor but clinically relevant changes in systolic function, particularly in patients with LVEF ${\tt>}45\%$ .

Cardiac magnetic resonance imaging has become the standard for the most precise and reproducible measurement of LVEF and LV volumes and serves as the contemporary comparator for other imaging modalities. 9 CMR can also provide location and quantification of focal myocardial fibrosis and scar with late gadolinium enhancement, myocardial tissue characterization though $\mathsf{T}_{1}$ (fibrosis), $\mathsf{T}_{2}$ (inflammation/oedema), ${\mathsf{T}}_{2}^{*}$ (iron) and extracellular volume, as well as pulsed fluid dynamic sequences that can assess intraventricular flow, assessments of myocardial energetics and fine structure and emerging molecular imaging techniques. CMR is, therefore, particularly useful in the diagnosis and phenotyping of patients with HF. 1 0 Despite these advantages, CMR has not yet become the clinical standard for LVEF assessment due to its high cost, limited availability of scanners and qualified technician/readers, long acquisition times, poor temporal resolution, contraindications or artefacts due to implantable devices or retained metallic fragments, and patient tolerance (claustrophobia, noise).

The most common and clinically useful measure of LVEF is derived from echocardiography. However, 2D echocardiography (2DE) has several significant disadvantages including poor image quality due to sonographer skill, poor acoustic windows, or other patient characteristics. The 2DE-LVEF is known to have large inter- and intra-observer variability and multiple factors have been shown to contribute. 11 , 1 2 While frequent in echo labs using visual estimation of LVEF, digit bias is another common challenge in 2DE-LVEF measurements which has been shown to potentially

## Introduction and methodology

Table 1 Reference Table and Table of advices

 result in clinically relevant reclassification of patients with HF. 1 3, 1 4 Significant age and gender differences in LV volumes and LVEF have also been identified and contribute to the large variability of 2DE-LVEF.

Multiple studies have compared 2DE-LVEF with CMR-LVEF although they are confounded by progressive improvements in imaging and measurement technologies over time. A study from the STICH trial of 204 patients enrolled from 2002 to 2007 with LVEF $\mathord{\llcorner}35\%$ who had core lab measured LVEF as assessed by 2DE (biplane) and CMR demonstrated that there was a $7.3\%$ mean absolute difference with a poor correlation $(r\!=\!0.493)$ between 2DE-LVEF and CMR-LVEF and only $43\%$ of the 2DE-LVEF values were within a specified acceptable absolute difference of ${\leq}5\%$ from CMR-LVEF. 1 5 These results suggest that as many as $20\%–25\%$ of patients in STICH would not have qualified as having a LVEF $\mathord{\llcorner}35\%$ .

The advent of 3D echocardiography (3DE) has provided a means to reduce the errors in measurement of LV volumes and LVEF by replacing the biplane images with 3D volumetric reconstructions of the LV chamber. However, while it is clear that 3DE can provide better estimates of LV volumes and more detail on cardiac structures, the superiority of 3DE over 2DE for measurement of LVEF is less clear. 1 6, 1 7

Contrast-enhancement improves endocardial definition allowing for better visualization, especially in suboptimal images. In a review of imaging methods for LVEF measurement, 1 8 all studies showed superiority of contrast 2DE over non-contrast 2DE for agreement with CMR and reproducibility, confirming the benefit of contrast enhancement of 2DE imaging. However, a prospective study comparing contrast-enhanced 2DE and 3DE to LVEF measurements from CMR similarly demonstrated that contrast enhancement with either modality did not significantly improve LVEF approximations, although contrast-enhanced 3DE most reliably correlated with volume measures from CMR. 1 9 Contrast enhancement can certainly improve acquisition in patients with suboptimal images, and it is in these patients where it holds the greatest promise for improving LVEF assessment.

Artificial intelligence (AI) based upon machine learning, deep learning and deep neural networks holds substantial promise in the assessment of LVEF in many imaging modalities. 20 Multiple studies with AI-guided imaging have demonstrated improvements in image view identification, image acquisition, myocardial border recognition, and measurements. While there will be tremendous contributions by AI to the evaluation of LVEF and cardiology as a whole in the future, it important to note that these AI programmes are limited by the datasets upon which they are trained, which are often derived from cardiologist interpretations.

While 2DE and 3DE will continue to be the predominant methods for assessing LVEF, multimodality imaging is advised and performed in many patients with HF for diagnosis and evaluation for therapeutic interventions.

Speckle tracking echocardiography can measure myocardial deformation using parameters such as global longitudinal (GLS), circumferential and radial strain. GLS has emerged as having high precision, better reproducibility and increased ability to detect subtle changes in LV systolic function than LVEF. 2 1 ,22 Both 2D and 3D

GLS are better predictors of cardiovascular mortality than either 2D or 3D LVEF. 1 7

Circulating biomarkers for the initial diagnosis of heart failure

Circulating biomarkers have played a significant role in our understanding of the pathogenesis, pathophysiology, treatment responses and prognosis in patients with HF. At present, natriuretic peptide testing is recommended for both diagnosis and prognosis. 3 These circulating biomarkers can provide important clinical information on myocardial stretch/congestion (natriuretic peptides), myocardial injury/necrosis/oxidative stress (e.g. troponin, heart-type fatty acid protein, myeloperoxidase), inflammation (e.g. high-sensitivity C-reactive protein, tumour necrosis factor-alpha, interleukins), extracellular matrix remodelling (e.g. soluble ST2, galectin-3, collagen pro-peptides, matrix metalloproteinases), apoptosis (e.g. growth differentiation factor- 1 5) and neurohormonal activation. While a recent proposed universal definition of HF included increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, all the clinical trials of current guideline-directed medical therapies have used LVEF to inform patient selection and no biomarker is currently poised to supplant this role of LVEF. 23 NT-proBNP testing in the emergency department can, when low, quickly rule out HF, while in outpatient settings elevated levels enable the early detection of HF, prompting further diagnostic tests, such as echocardiography, and the timely initiation of appropriate treatments that are proven to reduce morbidity and mortality regardless of LVEF values. 23

The importance of left ventricular ejection fraction trajectories

Left ventricular ejection fraction in the universal definition of heart failure and in the guidelines

Whilst LVEF is not an essential element for the diagnosis of HF, it is nonetheless useful for its categorization after a diagnosis has been made. Such categorization is now the mainstay to determine the therapeutic strategy, since evidence is built on the many clinical trials that have been conducted using LVEF for patient selection. 2 The universal definition of HF has updated the subgroup definitions of HF into separate LVEF classes when LVEF is measured at one time point. 24,25 In addition, the consensus statement about the universal definition of HF stressed the value of trajectories of LVEF change over time, with the addition of a fourth subset of HF – HFimpEF – which includes patients with HF (many of whom have responded to therapy) with a baseline LVEF ${\leq}40\%$ , followed by a ${\ge}10$ point increase from the initial LVEF, and a second measurement of LVEF ${>}40\%$ . These patients have different clinical characteristics and a different response to therapy, compared to those with HFpEF, despite superimposable LVEF values. Differently from patients with HFpEF, patients with improved

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LVEF have the indication for the persistent administration of neurohormonal antagonists, and furthermore deterioration in cardiac function and symptoms has been described upon their withdrawal.

The use of serial echocardiographic measurements during follow-up to track LVEF over time is preferred over the use of only a single echocardiographic measurement ( Table 1 ). This is due to the accumulating evidence that the trajectory of LVEF also has a significant prognostic impact, even in cases where the change in LVEF is modest. 26 The Japanese guidelines for the diagnosis and treatment of HF define the trajectory of LVEF in more detail, including HF with unchanged LVEF, HF with worsening LVEF, and HF with recovered LVEF ( Figure 1 ). 25 Previous studies have shown that patients with improved LVEF had a better prognosis than those with other LVEF phenotypes, while those with worsening LVEF had a poor prognosis. 27,28 It has been recently demonstrated that patients migrate between LVEF categories with those in the HFmrEF group being those with less persistence in the phenotype (only $25\%$ remained in the HFmrEF group at 1 year). 8 Therefore, the classification of HF according to LVEF trajectories and stages is to be preferred to the siloed definitions based on single measurement LVEF phenotypes.

Patient characteristics change across the LVEF spectrum with patients having higher LVEF being typically more likely to be of older

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age, female sex and with concomitant atrial fibrillation, chronic kidney disease, and non-cardiovascular comorbidities as compared to those with lower LVEF. In contrast, patients with LVEF between $40\%$ and $50\%$ are characterized by clinical backgrounds more similar to those of patients with lower LVEF and outcomes intermediate between the HFrEF and HFpEF phenotypes. 29,30 However, it is also noted that there is substantial overlap in the patient characteristics, prognostic factors, and outcomes amongst these LVEF categories, further showing the limitations of a classification merely based on a single LVEF measurement. In addition, comorbidities, such as ischaemic heart disease, valvular heart disease, diabetes or chronic kidney disease, are important prognostic factors across all HF categories. 30

Among HF patients in registries without pre-specified LVEF eligibility criteria, the distribution of ejection fraction is commonly bimodal, with a valley around LVEF $40{-}50\%$ between the two peaks for HFrEF and HFpEF ( Figure 2 ). 2,3,3 1 ,32 Thus, it was reasonable to set the intermediate category of LVEF values between $40\%$ and $50\%$ to separate classical HFrEF and HFpEF. This intermediate group was initially named HF with ‘mid-range’ ejection fraction but was later renamed as ‘mildly reduced’ ejection fraction. 1 4,33–36 However, apart from the valley of the LVEF distribution between HFrEF and HFpEF, the nadir of mortality risk was not necessarily located in this specific intermediate zone among HF patients. Several trial-based

 Figure 1 Guideline-defined trajectory in left ventricular ejection fraction (LVEF). 25 HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrecEF, heart failure with recovered ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFuncEF, heart failure with unchanged ejection fraction; HFworEF, heart failure with worsening ejection fraction.

 Figure 2 Bimodal distribution of ejection fraction in heart failure. Histogram of left ventricular ejection fraction (LVEF) in patients hospitalized with a primary discharge diagnosis of heart failure in the OPTIMIZE-HF registry ( $\cdot n\!=\!41\,267$ , left panel) 2 and consecutive patients admitted with heart failure to the Mayo Clinic ( $'n\!=\!4910$ , right panel). 3

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studies have shown that the adjusted all-cause and cardiovascular mortality amongst HF patients declined with increasing LVEF, but once LVEF is elevated to around $40{-}50\%$ , the outcomes appeared unrelated to LVEF. 1 4,33,34

Reconsidering the value of heart failure with mildly reduced ejection fraction, and the concept of normal and supra-normal left ventricular ejection fraction

An observed nadir of mortality risk related to LVEF has received renewed attention and a review of 403 977 echocardiograms from 203 1 35 patients using electronic health records ( 1 998–20 1 8) demonstrated a U-shaped relationship with a nadir of mortality risk at an LVEF of $60{-}65\%$ ( Figure 3 ). 8,37

The change from the negative to the positive correlation in the relationship between LVEF and mortality around LVEF $55{-}65\%$ may be explained by a directional change in LV stiffness at this LVEF zone. A retrospective analysis of 62 1 consecutive patients revealed that HF individuals with LVEF $50{-}57\%$ had a rightward shift in LV end-diastolic pressure–volume relationships, whereas those with LVEF ${>}58\%$ had a leftward shift, indicating more significant ventricular stiffening and more advanced diastolic dysfunction. 38 Interestingly, the change in LV volume and contracture toward the opposite direction of eccentric remodelling after LVEF $55{-}65\%$ may also explain the blunted benefits from neurohormonal antagonists in HF patients with LVEF above $55{-}65\%$ . 39 Recently, a study addressing the relationship between LVEF and survival in a large clinical cohort reported that LVEF ${>}65\%$ was associated with higher mortality ( Figure 4A ). 8 In this study the U-shaped relationship between LVEF and mortality was observed similarly regardless of gender and age, but the U-shape appears to be more prominent in women ( Figure 4B ). 8,37 The characteristics

 Figure 3 The relationship between left ventricular ejection fraction (LVEF) and mortality among patients with heart failure (number of echocardiograms = 40 6 1 6). 8 LVEF intervals are inclusive of the lower threshold. Error bars represent the $95\%$ confidence interval. The referent group was “’Outpatients with LVEF of $60–65\%'$ .

and outcomes of patients with HF and supra-normal ejection fraction (HFsnEF) were assessed among 6 1 28 patients with acute HF enrolled in RELAX-AHF-2. In this study, $2.5\%$ of patients were classified as HFsnEF. 35 These patients were mostly women with lower natriuretic peptides and a numerically higher mortality, especially with higher risk of non-cardiovascular death. The

 Figure 4 ( A ) Left ventricular ejection fraction (LVEF) hazard ratios for all-cause mortality in a large clinical cohort (number of echocardiograms = 403 977). 8 Error bars represent the $95\%$ confidence interval. ( B ) Analysis with interactions between age, sex, and LVEF. 8 The referent group was ‘female, under age 40 years, LVEF of ${\LARGE60\mathrm{-}65\%}'$ . LVEF intervals are inclusive of the lower threshold.

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prevalence, characteristics and outcomes in patients with HFsnEF compared to HF with normal ejection fraction (HFnEF) were also investigated among 11 573 patients enrolled in the nationwide registry of hospitalized patients with HF in Japan. 36 In this study, $17\%$ of patients were classified as HFsnEF and $28\%$ were classified as HFnEF. Patients with HFsnEF were older, more likely to be women, had lower natriuretic peptide values, and had smaller left ventricles than those with HFnEF. Though there was no significant difference in mortality between HFnEF and HFsnEF, HFsnEF was associated with a higher hazard ratio for the composite endpoint and all-cause death in women, and a higher hazard ratio for all-cause death in patients with renal dysfunction ( Figure 5 ). 8,36 In general, it is likely that patients with HFsnEF include patients with amyloid and, probably to a larger extent, hypertrophic cardiomyopathy. However, this has not been systematically assessed, to date.

The impact of genetic profiling in patients with HFsnEF was examined in two biobanks. 40 Sixteen genetic variants were associated with HFsnEF in a genome-wide association study and were incorporated into a genetic risk score. Both supra-normal LVEF genetic risk score and phenotype were associated with increased hazard ratio for mortality. Also, both supra-normal LVEF genetic risk score and phenotype were associated with reduced odds ratio for a HF diagnosis, but were associated with higher B-type natriuretic peptide levels and incremental odds ratio for HF symptoms and medications. The study demonstrates that individuals with a

genetic predisposition or phenotype of HFsnEF had worse survival and likely to be under-diagnosed for HF.

These lines of evidence suggest that HFsnEF is a relatively common and distinct phenotype from HFnEF but further studies are needed to define HFsnEF in clinical practice and provide guidance for its diagnosis and risk stratification.

If we redefined HFmrEF as LVEF from $40\%$ to $55\%$ or $60\%$ , the remaining HF patients with higher LVEF values would be termed as HFnEF but only up to an LVEF of $65\%$ , thereafter becoming HFsnEF patients. Therefore, in order to overcome the potential confusion of different terminologies, it is proposed to avoid to use the terms reduced, mildly reduced and preserved ejection fraction to define different subgroups of patients with HF. In keeping with the universal definition of HF, HF should, therefore, be classified upon symptoms, accompanied by signs and corroborated by elevated NT-proBNP levels. The assessment of LV function will be pivotal for the implementation of therapies that should take into account the individual trajectories rather than the absolute values of LV function. We therefore advise to define HF according to the LVEF trajectories as defined in the universal definition of HF. The use of LVEF trajectories, rather than a single measurement, can also effectively inform treatment as both patients with a persistently reduced LVEF as well as those with improved LVEF need to be treated also with neurohormonal modulators whereas these agents are not indicated in patients with persistently normal or supra-normal LVEF. Lastly, specific therapies

 Figure 5 Hazard ratios (HR) of heart failure (HF) with supra-normal ejection fraction (HFsnEF) for the composite of cardiovascular (CV) death or HF readmission and all-cause death in subgroup analysis among 11 573 patients enrolled in the nationwide registry of hospitalized patients with HF in Japan. 4 HRs of HFsnEF referenced to HF with normal ejection fraction are shown. CI, confidence interval; eGFR, estimated glomerular filtration rate.

may be indicated in patients with persistently supra-normal LVEF, such as novel myosin inhibitors. Treatment indications are further discussed in the following sections.

Heart failure therapy across the left ventricular ejection fraction range

The underlying pathophysiology and response to therapies differ across the range of LV function. Beta-blockers, angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), angiotensin receptor–neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) are the cornerstones of guideline-directed medical therapy for HF with HF with higher LVEF values, some being restricted to LVEF LVEF ${\tt<}{\tt40\%}$ . Apart from SGLT2i, these agents have less efficacy in ${\leq}40\%$ and some slightly higher (LVEF ‘below normal’) ( Figure 6 ). 3,24,4 1 –46

The evidence supporting the use of beta-blockers, ACEis/ARBs, ARNIs and MRAs for HFrEF largely stems from their impact on neurohormonal system activation—namely the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS)—all of which occur to a greater degree in HFrEF than in higher levels of LVEF. Certain devices are

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also restricted in their recommended use to certain ranges of LVEF.

A large meta-analysis of more than 30 000 HFrEF patients across multiple randomized controlled trials such as CIBIS-II, COPERNICUS and MERIT-HF demonstrated a $35\%$ reduction in mortality and $30\%$ reduction in HF hospitalizations from beta-blockers in HFrEF patients. However, the mortality benefits declined in those HF patients with higher LVEF values. For example, the relative risk reduction from beta-blocker use was only 4 1 –50% compared to $43\%$ for those with LVEF $17\%$ in those with LVEF ${\leq}30\%$ . 47

Moreover, in HFpEF where neurohormonal activation is substantially lower, beta-blockers have little proven survival advantage. While some meta-analyses suggest no effect on mortality and modest reductions in hospitalization rates with beta-blockers in HFpEF, effects on hard clinical outcomes have not been definitively established. The data on the benefit of beta-blockers in patients with LVEF ${>}40\%$ come mostly from the SENIORS study with nebivolol that demonstrated a benefit of nebivolol in patients with an LVEF up to $65\%$ . 44

Similarly, ACEis and ARBs reduce downstream RAAS signalling, thereby impeding maladaptive ventricular remodelling in HFrEF where this neurohormonal axis is considerably stimulated. Meta-analyses confirm ACEis reduce all-cause mortality by $13\%$ over about 4 years in HFrEF based on trials including CONSENSUS, SOLVD and SAVE which enrolled patients with

 Figure 6 Efficacy of treatments for heart failure (HF) across the left ventricular ejection fraction (LVEF) spectrum. ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; CKD, chronic kidney disease; CV, cardiovascular; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IPD, individual patient data; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium–glucose cotransporter 2 inhibitor; T2D, type 2 diabetes. a There are no specific trials of ACEis or ARBs ${\bf40–49\%})$ in patients with HFmrEF. A retrospective analysis of the CHARM programme showed that candesartan improved outcomes in HFmrEF (LVEF ) to a similar degree as in HFrEF (LVEF ${\leq}40\%)$ ). 4 1 To date, ACEis or ARBs have not been shown to convincingly reduce mortality nor morbidity in patients with HFpEF $(\mathsf{L V E F}>\!50\%)^{41-43}$ . b There are no specific trials of ARNIs in patients with HFmrEF. A subgroup analysis of the PARAGON-HF trial showed that, compared with valsartan alone, sacubitril/valsartan reduced the likelihood of the primary compos- ite outcome of CV death and total HF hospitalizations by $22\%$ in patients with an LVEF $\scriptstyle{\leq57\%}$ (median). 43 c There are no specific trials of beta-blockers in patients with HFmrEF. An IPD meta-analysis of (LVEF ${\bf40–49\%})$ ) as those in sinus rhythm with HFrEF (LVEF ${\leq}40\%$ 11 ). trials showed similar benefits for patients in sinus rhythm with HFmrEF 44 To date, beta-blockers have not been shown to reduce mortality nor morbidity in patients with HFpEF (LVEF ${>}50\%$ ). d There are no specific trials of MRAs in patients with HFmrEF. A retrospective analysis of the TOPCAT trial showed that the potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum (LVEF $45\mathrm{-}50\%)$ , with benefits for hospitalization for HF seen in those with LVEF $\scriptstyle{<55\%}$ . 45 e There is strong supporting evidence for use of dapagliflozin and empagliflozin in patients across the full spectrum of LVEF, with supporting evidence for use in patients with HFmrEF and HFpEF provided by the DELIVER and EMPEROR-Preserved trials and meta-analysis 46 . f In patients with HFrEF or HFmrEF and T2D. g Loop diuretics are recommended by guidelines for patients across the spectrum of LVEF to reduce the signs and symptoms of congestion, but their effects on morbidity and mortality in HF have not been studied in clinical trials. 3,24

LVEF ${\leq}35\%$ . 5,6 However, the effects of ACEis on mortality and hospitalization frequency in HFpEF patients are more modest if at all significant. The PEP-CHF trial stands alone in showing a reduction in hospitalizations but no mortality benefit from perindopril in HFpEF. 42 The ATTEND study observed no clinical improvements from atenolol or candesartan in HFpEF, 48 and the analysis of patients included in the CHARM programme demonstrated that candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF but had no effect in patients with an LVEF ${>}50\%$ . 4 1

The lack of efficacy of ACEis, ARBs and beta-blockers in HFpEF may again be related to the lower levels of neurohormonal activation in these patients relative to HFrEF patients.

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Sacubitril/valsartan augments beneficial natriuretic peptide pathway signalling while concurrently blocking the RAAS, thus more comprehensively improving the neurohormonal derangements in HFrEF. The PARADIGM-HF trial demonstrated a $20\%$ reduction in cardiovascular mortality from sacubitril/valsartan compared to ACEi therapy in patients with HFrEF. 43 However, the magnitude of benefit from sacubitril/valsartan diminished with higher LVEF values. The hazard ratio for the primary endpoint was 0.80 for LVEF ${\leq}30\%$ compared to 0.87 for LVEF $36{-}40\%$ . The PARAGON-HF study randomized 4822 HFpEF patients (LVEF ${\geq}45\%$ ) to treatment with sacubitril/valsartan versus valsartan. While sacubitril/valsartan did reduce hospitalizations compared to valsartan in HFpEF, it did not significantly impact mortality or the overall primary endpoint.

 Figure 7 Treatment of patients with de novo heart failure: it is advised to start sodium–glucose cotransporter 2 inhibitors (SGLT2i) together with diuretics, if congestion is present, in all heart failure patients without delay. It is appropriate to implement additional therapies according to the presence of comorbidities and left ventricular ejection fraction (LVEF) values. BNP, B-type natriuretic peptide; CCS, chronic coronary syndrome; HTN, hypertension; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; VA, ventricular arrhythmia; VHD, valvular heart disease.

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Importantly, PARAGON-HF also included pre-specified analyses of outcomes based on LVEF subgroups. 49 The investigators observed that as LVEF increased, there was a reduction in the efficacy of sacubitril/valsartan compared to valsartan. Thus, PARAGON-HF highlights that the advantages of ARNI attenuate with increasing LVEF, especially at higher LVEF ranges where neurohormonal pathways driving HFrEF may no longer be as important as therapeutic targets. 50

Vericiguat, a soluble guanylate cyclase stimulator, has been studied in patients with worsening chronic HF in the VICTORIA trial 5 1 which included patients with LVEF ${\tt<}{\tt45\%}$ . Importantly, the study population had a median LVEF of $29\%$ , lower than in many other HF trials, indicating a more severely ill cohort. When added to guideline-directed medical therapy, vericiguat reduced the composite endpoint of cardiovascular death or HF hospitalization compared to placebo. The benefit was consistent across the spectrum of LVEF studied $({\mathfrak{<}}45\%)$ . Subgroup analyses did not show significant differences in treatment effect based on LVEF categories ( $\cdot{<}30\%$ vs. ${\tt\ge}30\%$ ). However, the greatest absolute risk reduction was observed in patients with the most severe disease, including those with lower LVEF.

In summary, neurohormonal antagonism with beta-blockers, ACEis, ARBs and MRAs targets pathways integral to the disease progression in HFrEF. Robust clinical trials illustrate solid mortality and morbidity benefits from using these medications in HFrEF patients, especially those with LVEF ${\tt<}40\%$ . However, the effects

of these agents on hard clinical outcomes fade when values of LVEF are normal. Thus, the guideline-directed medical therapy for these two HF phenotypes may diverge dependent on the presence or absence of neurohormonal substrates to target therapeutically. Until more alternative effective treatment options are better elucidated in HFpEF, the historical HFrEF medication classes will remain restricted in terms of patient benefit to lower LVEF ranges. However, rather than considering treatments according to cut-offs of LVEF dictated by the current classifications of HF, drugs acting on the neurohormonal axis should be implemented according to their demonstrated efficacy across the range of LVEF values seen in their respective trials and treatments should be implemented based on the trajectories of LVEF rather than on rigid cut-offs values.

Drugs indicated across the spectrum of left ventricular ejection fraction

Sodium–glucose cotransporter 2 inhibitors are the only drug class for which there is incontrovertible evidence of efficacy across the full range of LVEF. The evidence is limited to dapagliflozin and empagliflozin for all patients with HF and extends to sotagliflozin for diabetic patients with HF. 46,52–58 DAPA-HF and EMPEROR-Reduced demonstrated the efficacy of dapagliflozin and empagliflozin, respectively, in patients with HF and LVEF

${\tt<}40\%$ while DELIVER and EMPEROR-Preserved demonstrated the efficacy of the two molecules in patients with HF and LVEF ${>}40\%$ . The combined analysis of the studies in patients with LVEF ${\tt<}40\%$ and ${>}40\%$ has demonstrated sustained efficacy without attenuation of efficacy of these two molecules across the full range of LVEF. Furthermore, the evidence that the beneficial effect of these molecules becomes manifest after just 2 weeks of treatment suggest that they could be started even without knowledge of the LVEF, if this would otherwise lead to a delay in treatment initiation. Therefore, given the high event rate in patients with de novo HF while waiting to receive an echocardiogram, it is advised that in settings where a long waiting time for an assessment of LVEF is expected, SGLT2i should be started together with diuretics, if congestion is present, in all HF patients without delay ( Table 1 , Figure 7 ).

Recent evidence has demonstrated the therapeutic value of MRAs across the spectrum of HF, challenging the traditional LVEF-centric approach to treatment selection with these agents. The FINEARTS-HF trial showed that the novel non-steroidal MRA finerenone significantly reduced the composite endpoint of total worsening HF events and cardiovascular death in patients with HF and mildly reduced or preserved LVEF, expanding our understanding of MRA benefits beyond reduced LVEF. 59 This finding was further substantiated by a comprehensive individual patient-level meta-analysis encompassing four major MRA trials, which revealed consistent beneficial effects across the entire LVEF spectrum. 60 While the magnitude of benefit showed some heterogeneity, with greater efficacy observed in reduced LVEF patients, the presence of positive effects regardless of LVEF supports a paradigm shift in HF treatment. This evidence suggests that MRA therapy should be considered based on the overall clinical profile of patients with HF and disease trajectory rather than arbitrary LVEF cut-offs. Such an approach acknowledges the dynamic nature of HF and the limitations of using LVEF as the sole determinant for therapeutic decisions. The consistent benefits of MRAs across LVEF values support a more nuanced, patient-centred approach to therapy that considers the complex interplay of factors beyond LVEF alone. This evolving understanding challenges clinicians to move treatment with MRAs beyond rigid LVEF-based treatment algorithms and adopt a more comprehensive approach for their use. Thus, also these agents may be useful across the whole spectrum of the patients with HF, independently of LVEF.

Devices restricted to certain left ventricular ejection fraction ranges

Various devices are employed in the management of HF based on LV function ranges. Despite many devices having been studied in patients with LVEF $\mathord{\llcorner}35\%$ , it is now clear that classification based solely on LVEF does not fully stratify prognosis. Outcomes are similarly poor across these categories, and the frequency of sudden cardiac death is not negligible even when LVEF is not $\mathord{\llcorner}35\%$ , suggesting that criteria for an implantable cardioverter-defibrillator (ICD) based solely on LVEF may not be entirely appropriate.

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scientific guidelines for patients with a LVEF Implantable cardioverter-defibrillators are recommended by ${\leq}35\%$ to prevent sudden cardiac death. (CRT) is another option for patients with LVEF 3,24,25 Cardiac resynchronization therapy ${\leq}35\%$ , a QRS duration $\geq\!150\,\mathsf{m s}$ , and left bundle branch block morphology. 24 For patients with moderate-to-severe mitral regurgitation and LVEF $20{-}50\%$ , the MitraClip, a percutaneous mitral valve repair system, may be considered. This device clips the mitral valve leaflets together, reducing regurgitation and improving symptoms. 24 The Barostim Neo, a baroreflex activation therapy device, is an option for patients with LVEF ${\leq}35\%$ who remain symptomatic despite optimal medical therapy. 6 1 ,62 This device stimulates the carotid baroreceptors, leading to vasodilatation and reduced cardiac workload. Cardiac contractility modulation is a treatment that delivers electrical impulses to the heart during the absolute refractory period, enhancing contractility without inducing additional action potentials and it is indicated for patients with LVEF 25–45% and narrow QRS complexes. 47,63 The choice of the device to use in patients with HF depends on the individual LVEF, symptoms, and other clinical factors. The implantation of devices should be performed only when the LVEF trajectory has been temporarily stabilized by guideline-directed medical therapy. Therefore, unless there is a clear urgent need, a period of at least 3 months of stability is required before the implantation of a cardiac device.

The use of left ventricular ejection fraction trajectories

Once a patient satisfies the universal definition of HF criteria to be diagnosed with HF, treatment can commence with an SGLT2i and diuretics as needed. An accurate measurement of LVEF will need to be documented and ideally this should be relatively soon after HF is suspected. Patients with proven HF will initially be treated based on initial LVEF criteria—for example, BB, ACEis, ARBs in HFrEF, ARNI and MRAs if LVEF below normal, and SGLT2i across the entire spectrum. Repeat measures of LVEF over time and/or in response to therapy are then useful and will then be taken into account in further treatment changes as described below:

1 . Persistent HFrEF with stable LVEF–optimize guidelinedirected medical therapy for HFrEF. 2. HF with worsening LVEF should be assessed for other interval cardiovascular and medical issues (e.g. coronary artery disease and valvular heart disease progression, thyroid disease, chronic kidney disease, obesity, drug abuse, etc.). Device-based therapies (e.g. ICD, CRT) and additional pharmacologic therapies (e.g. ivabradine, digoxin, vericiguat) may be indicated. Referral for advanced therapies (e.g. transplant, left ventricular assist device) should be entertained if patients do not respond to this escalation of therapies. 3. HFimpEF should remain on guideline-directed medical therapy–if not on SGLT2i and symptomatic, SGLT2i should be initiated. 45 4. All LVEF trajectory patterns–SGLT2is, diuretics as needed, disease management programmes including exercise and other lifestyle modifications.

Future areas of research

While LVEF remains a crucial parameter in the management of HF, further research is needed to refine its role and explore alternative approaches to patient stratification and treatment ( Table 1 ). Future studies should focus on better understanding the relationship between LVEF and clinical outcomes, particularly in the intermediate and higher LVEF ranges. The concept of HFnEF and HFsnEF warrants further investigation to elucidate the underlying pathophysiology, clinical characteristics, and optimal management strategies for these subgroups. Additionally, research into the trajectory of LVEF over time and its impact on prognosis and treatment response may provide valuable insights for personalized HF management. The development and validation of novel imaging techniques, such as AI-assisted echocardiography and advanced CMR imaging, could improve the accuracy and reproducibility of LVEF measurements and offer new ways to assess cardiac function and structure. Furthermore, the identification of alternative biomarkers or imaging parameters that can complement or even surpass LVEF in guiding HF management should be a priority. Finally, characterizing the cellular, molecular, and metabolic status of the myocardium itself regardless of LVEF should provide insights into more direct cardiac specific targets for therapy. In this manner, LVEF has more the characteristic of a ‘biomarker’ of the HF syndrome rather than as a mechanistic target of investigation and therapeutic development. By addressing these research gaps, we can move towards a more precise, personalized, and effective approach to managing HF, ultimately improving patient outcomes and quality of life.

Summary and conclusions

The assessment of LVEF has evolved significantly over the past century, with advancements in imaging techniques and technologies improving the accuracy and reproducibility of LVEF measurements. Despite its limitations, LVEF remains a cornerstone in the diagnosis, prognosis, and management of HF. However, the current classification of HF phenotypes based on LVEF ranges (HFrEF, HFmrEF, HFpEF) does not fully capture the complexity and heterogeneity of the disease.

The classification of HF should be based on a triad of clinical manifestations: symptomatology, physical signs, and biomarkers (i.e. NT-proBNP). Regular evaluation of LVEF is crucial in guiding therapeutic strategies, which should be tailored to individual trajectories of cardiac function rather than solely based on absolute values. Consequently, HF classification should align with the trajectories delineated in the universal definition of HF, avoiding a siloed definition based on LVEF cut-off values taken at a single timepoint and emphasizing the dynamic nature of the condition and facilitating more nuanced, patient-specific management approaches.

The efficacy of neurohormonal modulator therapies, such as beta-blockers, ACEis, ARBs, ARNis and MRAs, is largely dependent on the degree of neurohormonal activation, and these therapies have shown significant mortality and morbidity benefits especially in patients with LVEF ${\tt<}{\tt40\%}$ , but these effects fade with higher LVEF values due to lower levels of neurohormonal activation. In contrast, SGLT2is have shown efficacy across the LVEF spectrum,

representing a therapeutic option applicable regardless of LVEF status.

Similarly, the use of devices in the management of HF is guided by LVEF ranges, with ICDs, CRT, MitraClip, Barostim, and cardiac contractility modulation being recommended by the ESC and American College of Cardiology/American Heart Association/HFSA guidelines only for specific LVEF categories. 3,24

In conclusion, while LVEF remains a crucial parameter in the management of HF, the current classification of HF phenotypes based on LVEF ranges may not fully capture the complexities of the disease. LVEF is not required for the initiation of SGLT2is and diuretics in patients with suspected de novo HF and elevated NT-proBNP levels. Future research should focus on refining the definition of LVEF categories, exploring novel imaging techniques and biomarkers, and identifying alternative therapeutic targets for HF patients across the spectrum of LVEF. A more personalized approach to HF management, considering the individual patient LVEF trajectory, comorbidities, and response to therapies, may lead to improved outcomes and quality of life for patients with this complex and heterogeneous condition.

Acknowledgements

This article has been simultaneously co-published with the European Journal of Heart Failure and Journal of Cardiac Failure. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.

Funding

This study was supported by the Italian Ministry of Health (Ricerca Corrente 20/ 1 8 1 9).

Conflict of interest : none declared.

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