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From mid-range to mildly reduced ejection fraction heart failure: A call to treat

  • Davide Stolfo
    Affiliations
    Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Univeristy Hospital of Trieste, Trieste, Italy

    Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
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  • Enrico Fabris
    Affiliations
    Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Univeristy Hospital of Trieste, Trieste, Italy
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  • Lars H. Lund
    Affiliations
    Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

    Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
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  • Gianluigi Savarese
    Affiliations
    Division of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

    Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden
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  • Gianfranco Sinagra
    Correspondence
    Corresponding author at: Cardiothoracovascular Department, Division of Cardiology, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and University of Trieste, Via Valdoni 7, 34149, Trieste, Italy.
    Affiliations
    Cardiothoracovascular Department, Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI) and Univeristy Hospital of Trieste, Trieste, Italy
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      Abstract

      The historical classification of heart failure (HF) has considered two distinct subgroups, HF with reduced ejection fraction (HFrEF), generally classified as EF below 40%, and HF with preserved ejection fraction (HFpEF) variably classified as EF above 40%, 45% or 50%. One of the principal reasons behind this distinction was related to presence of effective therapy in HFrEF, but not in HFpEF.
      Recently the expanding knowledge in the specific subgroup of patient with a LVEF between 41% and 49% and the potential benefit of new therapies and of those used in patients with LVEF below 40%, has led to rename this group as HF with mildly reduced EF (HFmrEF).
      In this review we discuss the reasons behind this modification, we summarize the main characteristics of HFmrEF the similarities and differences with the two other EF categories, and finally we provide a comprehensive overview of the current available evidence supporting the treatment of patients with HFmrEF.

      Graphical Abstract

      Keywords

      Heart failure (HF) is a global pandemic that affects more than 64 million people worldwide and its prevalence is steadily growing [
      • Groenewegen A
      • Rutten FH
      • Mosterd A
      • Hoes AW.
      Epidemiology of heart failure.
      ,
      • Conrad N
      • Judge A
      • Tran J
      • et al.
      Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals.
      ,
      • van-Riet EE
      • Hoes AW
      • Wagenaar KP
      • Limburg A
      • Landman MA
      • Rutten FH.
      Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review.
      ,
      • Taylor CJ
      • Ordonez-Mena JM
      • Roalfe AK
      • et al.
      Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study.
      ]. The overall aging of the worldwide population leads to increasing burden of HF-related hospital admissions and higher demand of HF specific therapies with increasing impact on health-care costs [
      • Malek M.
      Health economics of heart failure.
      ,
      • Farre N
      • Vela E
      • Cleries M
      • et al.
      Medical resource use and expenditure in patients with chronic heart failure: a population-based analysis of 88 195 patients.
      ]. In the United States the health expenditures for the yearly 1.1 million hospital stays for chronic HF corresponds to 10% of the total health expenditures [
      • Roger VL
      • Go AS
      • Lloyd-Jones DM
      • et al.
      Heart disease and stroke statistics–2011 update: a report from the American Heart Association.
      ]. Health care-related costs associated with an increasing HF prevalence are projected to increase three-fold between 2010 and 2030 [
      • Heidenreich PA
      • Albert NM
      • Allen LA
      • et al.
      Forecasting the impact of heart failure in the United States: a policy statement from the.
      ].
      Despite therapeutic advances with impact on morbidity and survival, the prognosis of HF remains poor. HF is one of the most common causes of hospitalization and the mortality rate is paradoxically growing [
      • Sidney S
      • Go AS
      • Jaffe MG
      • Solomon MD
      • Ambrosy AP
      • Rana JS.
      Association Between Aging of the US Population and Heart Disease Mortality From 2011 to 2017.
      ].
      Despite the high complexity of HF, one single parameter endures as the primary classification tool in clinic and in research. Left ventricular ejection fraction (EF), indeed, remains the milestone of HF management as it is essential for diagnosis, prognostic stratification, eligibility for therapies and it is the first criteria for inclusion in randomized clinical trials (RCTs) [
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ].
      The historical classification of HF has considered two distinct subgroups, HF with reduced ejection fraction (HFrEF - formerly “systolic” HF, generally classified as EF below 40%) and HF with preserved ejection fraction (HFpEF - formerly “diastolic” HF, generally classified as EF above 50%) [
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ], and the principal reason behind this distinction was related to the fact that there was effective therapy in HFrEF but not in HFpEF. The remaining gap between the two categories created the premise for a novel HF category which was introduced by the European Society of Cardiology (ESC) guidelines in 2016 and denominated HF with mid(dle) range EF. The main aim was to explore the “underlying characteristics, pathophysiology and treatment of this group of patients” [
      • Ponikowski P
      • Voors AA
      • Anker SD
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ]. After 5 years, the expanding knowledge in this specific subgroup led the writing committee of the last HF ESC guidelines, published in 2021, to rename it as HF with mildly reduced EF (HFmrEF) [
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ]. In this review we discuss the reasons behind this modification, we summarize the main characteristics of HFmrEF, the similarities and differences with the two other EF categories, and finally we provide a comprehensive overview of the current available evidence supporting the treatment of patients with HFmrEF.

      1. The genesis of mildly reduced ejection fraction heart failure

      Since the 1980s, EF is the main tool for diagnosis, classification and risk stratification of HF [
      • Dougherty AH
      • Naccarelli GV
      • Gray EL
      • Hicks CH
      • Goldstein RA.
      Congestive heart failure with normal systolic function.
      ,
      • Soufer R
      • Wohlgelernter D
      • Vita NA
      • et al.
      Intact systolic left ventricular function in clinical congestive heart failure.
      ]. For a long period, the classification of HF based on EF differentiated two distinct subgroups, HF with reduced ejection fraction (HFrEF - formerly “systolic” HF) and HF with preserved ejection fraction (HFpEF - formerly “diastolic” HF) [
      • Hunt SA
      • Abraham WT
      • Chin MH
      • et al.
      ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society.
      ]. The rational of this dichotomization was the proof of evidence from large randomized clinical trials (RCT) that antineurohormonal drugs, and later HF devices, were able to improve survival in patients with reduced EF, and 40% was the “critical” threshold identifying patients with proven benefit from therapies.
      On the other side, before the publication of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial, there were no therapeutic strategies that demonstrated to reduce morbidity and mortality in patients with HFpEF [
      • McHugh K
      • DeVore AD
      • Wu J
      • et al.
      Heart Failure With Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review.
      ,
      • Anker SD
      • Butler J
      • Filippatos G
      • et al.
      Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
      ]. The initial definition of HFpEF derived from the The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program that encompassed patients with HF regardless of EF [
      • Swedberg K
      • Pfeffer M
      • Granger C
      • et al.
      Candesartan in heart failure–assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators.
      ]. The CHARM-Preserved enrolled patients with EF >40% that were defined as with HFpEF [
      • Yusuf S
      • Pfeffer MA
      • Swedberg K
      • et al.
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      ]. This strategy aimed to include patients excluded from RCT on HFrEF, acknowledging that “subclinical” LV dysfunction was amenable to be compared with the “true normal” EF. In the following years various thresholds were adopted to enroll patients in HFpEF RCT; the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study, the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) and more recently the Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) included patients with EF≥45% [
      • Pitt B
      • Pfeffer MA
      • Assmann SF
      • et al.
      Spironolactone for heart failure with preserved ejection fraction.
      ,
      • Massie BM
      • Carson PE
      • McMurray JJ
      • et al.
      Irbesartan in patients with heart failure and preserved ejection fraction.
      ,
      • Solomon SD
      • McMurray JJV
      • Anand IS
      • et al.
      Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.
      ]. The absence of univocal agreement in the definition of preserved EF created the first premise to the introduction of an alternative entity. Moreover, in guidelines the accepted lower range of normal EF is 52% in males and 54% in females [
      • Lang RM
      • Badano LP
      • Mor-Avi V
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      ]. Thus, in a rigorous interpretation, values of EF below 50% cannot be considered as normal. This originates a gap between the two entities that corresponds to the classification of mildly reduced EF in the guidelines for echocardiographic quantification of LV function [
      • Lang RM
      • Badano LP
      • Mor-Avi V
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      ]. The first attempt to fill this gap was made by the last ACCF/AHA (American College of Cardiology Foundation/American Heart Association) guidelines on HF in 2013 that classified patients with EF within 40 and 49% as having borderline HFpEF in order to differentiate them from patients with HFrEF [
      • Yancy CW
      • Jessup M
      • Bozkurt B
      • et al.
      2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      ]. In 2016 the European Society of Cardiology (ESC) guidelines first introduced the term “middle range” by creating a category of HF in between the two classical entities that was named HF with mid-range EF (HFmrEF) [
      • Ponikowski P
      • Voors AA
      • Anker SD
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ]. The aim of the guidelines committee was not to suddenly introduce a new clinical entity with a distinct pathophysiological background and specific therapy, but rather to stimulate dedicated research into the “underlying characteristics, pathophysiology and treatment of this group of patients” [
      • Ponikowski P
      • Voors AA
      • Anker SD
      • et al.
      2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      ]. Although a certain confusion was generated among clinicians, in the years following its origin greater attention has been dedicated to HFmrEF and several studies have explored different aspects of this subgroup. Data collected during the first years following the publication of 2016 ESC guidelines allowed to better define the characteristics of HFmrEF and, in addition to the data from retrospective analyses of RCTs suggesting that HFmrEF may potentially benefit from the treatments for HFrEF, led to rename this entity from ‘heart failure with mid-range ejection fraction’ to ‘heart failure with mildly reduced ejection fraction’ [
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ]. The revised category has also changed for two additional aspects: following the criteria, and the demonstration of treatment benefit, from RCTs in HFrEF that included patients with EF ≤40%, patients with EF=40% are now included in the HFrEF group, and HFmrEF, thus, includes now the EF in the range 41-49%; the presence of symptoms and/or signs of HF (i.e. elevated BNP or NT-proBNP and other evidence of structural heart disease) are not considered mandatory anymore for the diagnosis of HFmrEF if the measurement of EF is considered reliable(10).

      2. Epidemiology

      The proportion of HFmrEF within the overall HF population ranges between 10 and 25% [
      • Kapoor JR
      • Kapoor R
      • Ju C
      • et al.
      Precipitating Clinical Factors, Heart Failure Characterization, and Outcomes in Patients Hospitalized With Heart Failure With Reduced, Borderline, and Preserved Ejection Fraction.
      ,
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ,
      • Bhambhani V
      • Kizer JR
      • Lima JAC
      • et al.
      Predictors and outcomes of heart failure with mid-range ejection fraction.
      ,
      • Lam CSP
      • Gamble GD
      • Ling LH
      • et al.
      Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.
      ,
      • Rickenbacher P
      • Kaufmann BA
      • Maeder MT
      • et al.
      Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).
      ]. In a large community-based longitudinal cohort free from HF and followed for > 10 years, the incidence rate of HFmrEF was 6.7 cases per 10,000 person- years, vs 26.9 and 34.9 in HFpEF and HFrEF, respectively [
      • Bhambhani V
      • Kizer JR
      • Lima JAC
      • et al.
      Predictors and outcomes of heart failure with mid-range ejection fraction.
      ]. With few exceptions, predictors of incident HF were similar across the spectrum of EF [
      • Bhambhani V
      • Kizer JR
      • Lima JAC
      • et al.
      Predictors and outcomes of heart failure with mid-range ejection fraction.
      ]. In European registries the rate of prevalent HFmrEF was >20% of the entire HF cohort, and precisely 24% in the European Society of Cardiology Heart Failure Long-Term (ESC‐HF‐LT) Registry and 21% in the Swedish HF (SwedeHF) Registry [
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ]. Slightly lower rates were reported in Asian, Australian and American registries [
      • Kapoor JR
      • Kapoor R
      • Ju C
      • et al.
      Precipitating Clinical Factors, Heart Failure Characterization, and Outcomes in Patients Hospitalized With Heart Failure With Reduced, Borderline, and Preserved Ejection Fraction.
      ,
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Lam CSP
      • Gamble GD
      • Ling LH
      • et al.
      Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.
      ]. Finally, in the world of RCTs, and specifically in the CHARM population, 17% had HFmrEF [
      • Lund LH
      • Claggett B
      • Liu J
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      ].

      3. Clinical characteristics of HFmrEF – one reason behind the ‘mildly reduced ejection fraction’

      After the introduction of HFmrEF within the spectrum of HF phenotypes, the debate about which was the most appropriate matching for the newborn category became essential. The obvious approach might be defining HFmrEF as the intermediate phenotype, but this is not supported by available evidences that rather highlight the difficulty to set HFmrEF in a precise scenario [
      • Lund LH.
      Heart Failure with Mid-range Ejection Fraction: Lessons from CHARM.
      ]. Earlier studies suggested that HFmrEF was closer to HFpEF in terms of clinical characteristics [
      • Fonarow GC
      • Stough WG
      • Abraham WT
      • et al.
      Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry.
      ,
      • Sweitzer NK
      • Lopatin M
      • Yancy CW
      • Mills RM
      • Stevenson LW.
      Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (>or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions.
      ]. In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) study, patients with borderline EF presented features similar to the HFpEF population in particular in terms of age, systemic hypertension and atrial arrhythmias, and intermediate in terms of sex and ischemic etiology [
      • Fonarow GC
      • Stough WG
      • Abraham WT
      • et al.
      Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry.
      ]. Similarly, in the Acute Decompensated Heart Failure Registry (ADHERE), that extended the limit of “borderline” EF to 55%, age, arterial blood pressure, atrial fibrillation, diabetes and chronic obstructive pulmonary disease (COPD) were comparable to HFpEF, while again gender and ischemic etiology were intermediate [
      • Sweitzer NK
      • Lopatin M
      • Yancy CW
      • Mills RM
      • Stevenson LW.
      Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (>or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions.
      ]. Although the Get With The Guidelines–Heart Failure (GWTG-HF) Registry recently reported characteristics of borderline EF that were more similar to HFpEF [
      • Shah KS
      • Xu H
      • Matsouaka RA
      • et al.
      Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes.
      ], the trend changed in later studies and HFmrEF appeared to be more close to HFrEF [
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ]. The ESC‐HF‐LT provided an extensive assessment of characteristics of the HF population in Europe. HFmrEF shared with HFrEF several aspects, including younger age, male sex, ischemic etiology, lower prevalence of atrial fibrillation. Of note, patients with HFmrEF were less symptomatic, less likely to receive diuretics and with less comorbidities compared to the other phenotypes. The proposed explanation was that HFmrEF represented early-stage or rather recovered, and therefore milder, HFrEF [
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Kalogeropoulos AP
      • Fonarow GC
      • Georgiopoulou V
      • et al.
      Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered Ejection Fraction.
      ]. In the CHARM programme 1,322 patients with HFmrEF were recruited and most of their characteristics, including age, systolic blood pressure, prevalence of females, history of myocardial infarction and atrial fibrillation were similar to HFrEF [
      • Lund LH
      • Claggett B
      • Liu J
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      ]. In the SwedeHF Registry, the > 9,000 of patients with HFmrEF were more similar to HFpEF for the prevalence of atrial fibrillation and for the values of systemic blood pressure, but more similar to HFrEF for many other characteristics including age, chronic kidney disease, diabetes mellitus and ischemic etiology [
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ]. Regarding the gender distribution, the proportion of females in HFmrEF was intermediate between HFrEF and HFpEF, but more similar to HFrEF [
      • Stolfo D
      • Uijl A
      • Vedin O
      • et al.
      Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum: Phenotyping, and Prognostic and Therapeutic Implications.
      ].

      3.1 Ischemic etiology

      Ischemic etiology is important in the interpretation of HFmrEF as a mild form of HFrEF. Prevalence of ischemic heart disease has been systematically reported as similar in HFrEF and HFmrEF [
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Rickenbacher P
      • Kaufmann BA
      • Maeder MT
      • et al.
      Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).
      ,
      • Ibrahim NE
      • Song Y
      • Cannon CP
      • et al.
      Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry(R).
      ]. Not only the crude, but also the adjusted prevalence of ischemic heart disease appears comparable between the two phenotypes and HFmrEF patients were exposed to a risk of new ischemic events that was similar to HFrEF and higher compared to HFpEF [
      • Vedin O
      • Lam CSP
      • Koh AS
      • et al.
      Significance of Ischemic Heart Disease in Patients With Heart Failure and Preserved, Midrange, and Reduced Ejection Fraction: A Nationwide Cohort Study.
      ]. Additional insights into comorbidities within the spectrum of EF provided interesting observations related to the HFmrEF subgroup.

      3.2 Atrial fibrillation and Comorbidities

      Although the prevalence of atrial fibrillation decreases with declining EF, characteristics of patients with and the prognostic implications of atrial fibrillation are consistent across EF categories [
      • Sartipy U
      • Dahlstrom U
      • Fu M
      • Lund LH.
      Atrial Fibrillation in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction.
      ]. Other non-cardiovascular comorbidities are typically more prevalent in HFpEF than in HFmrEF and HFrEF, but their impact on prognosis may be different. Both chronic kidney disease and anemia similarly demonstrated higher prevalence in HFpEF vs HFrEF and HFmrEF, but a stronger association with, respectively, mortality and mortality/HF hospitalizations in HFrEF and HFmrEF than in HFpEF [
      • Lofman I
      • Szummer K
      • Dahlstrom U
      • Jernberg T
      • Lund LH.
      Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction.
      ,
      • Savarese G
      • Jonsson A
      • Hallberg AC
      • Dahlstrom U
      • Edner M
      • Lund LH.
      Prevalence of, associations with, and prognostic role of anemia in heart failure across the ejection fraction spectrum.
      ]. Obesity showed different profiles according to type of study report (i.e. observational studies vs RCTs). European registries described intermediate values of BMI in HFmrEF [
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ,
      • Rickenbacher P
      • Kaufmann BA
      • Maeder MT
      • et al.
      Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).
      ], whereas at least two important RCTs on HFpEF, the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study and the Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) study, reported high BMI in HFmrEF, more similar to the HFpEF cohort [
      • Solomon SD
      • Claggett B
      • Lewis EF
      • et al.
      Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
      ,
      • Solomon SD
      • Vaduganathan M
      • B LC
      • et al.
      Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.
      ].

      3.3 Biomarkers profiles

      The biomarkers´ profiles also demonstrated peculiarities in HFmrEF. Data from the SwedeHF reported lower values of NT-proBNP in HFmrEF compared to HFrEF, that were more similar to HFpEF [
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ]. Interestingly, in HFmrEF NT-proBNP suffered more of the confounding effect of other variables such as atrial fibrillation and showed higher prognostic and discriminatory power compared to HFpEF [
      • Savarese G
      • Orsini N
      • Hage C
      • et al.
      Associations With and Prognostic and Discriminatory Role of N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Versus Mid-range Versus Reduced Ejection Fraction.
      ]. Finally, a dedicated analysis on patients with acute HF explored the patterns of distribution of different biomarkers across the EF spectrum and demonstrated an intermediate profile in the HFmrEF category, with enhanced expression of both markers of cardiac stretch and of inflammation, and this suggested potential pathophysiological implications in the classification of HFmrEF [
      • Tromp J
      • Khan MAF
      • Mentz RJ
      • et al.
      Biomarker Profiles of Acute Heart Failure Patients With a Mid-Range Ejection Fraction.
      ].

      4. Prognosis

      Larger observational studies that have explored the prognosis of HFmrEF reported in large part more benign outcomes in HFmrEF compared to HFpEF and HFrEF [
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ,
      • Lam CSP
      • Gamble GD
      • Ling LH
      • et al.
      Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.
      ].
      In a prospective international multi-ethnic cohort study, two-year all-cause mortality in HFmrEF was 12%, with adjusted hazard of mortality comparable to HFpEF and lower than HFrEF [
      • Lam CSP
      • Gamble GD
      • Ling LH
      • et al.
      Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.
      ]. Similarly, one-year mortality was also observed to be closer to HFpEF and better than HFrEF in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study and in the SwedeHF Registry [
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ]. In the ESC-LT-HF Registry, observed one-year all-cause mortality was 7.6%, vs 6.3% in HFpEF and 8.8% in HFrEF [
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ]. Interestingly, the proportion of non-cardiovascular mortality was numerically higher, while the incidence of hospitalization for HF was lower (8.7% and 9.7% vs 14.6%), in HFmrEF and HFpEF vs HFrEF [
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ].
      On the other hand, the retrospective analysis of 39,982 patients enrolled in the GWTG-HF have reported similar 5-years mortality across the spectrum of EF, whereas cardiovascular and HF readmission rates were higher in HFrEF and HFmrEF compared with HFpEF [
      • Shah KS
      • Xu H
      • Matsouaka RA
      • et al.
      Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes.
      ], and in the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) both mortality and rate of hospitalizations did not differ across the range of EF [
      • Rickenbacher P
      • Kaufmann BA
      • Maeder MT
      • et al.
      Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).
      ].
      Differences in outcome between real-world studies and RCTs are also evident for HFmrEF patients. In RCTs the divergence in risk across the EF spectrum is larger than in observational studies, with HFpEF and HFmrEF at lower risk of events compared to HFrEF. In the CHARM-Programme, the incidence of all-cause mortality at ∼3 years was 12.6% in HFmrEF, remarkably lower compared to the data from registries, and HFmrEF and HFpEF were at lower risk compared to HFrEF for all the study outcomes [
      • Lund LH
      • Claggett B
      • Liu J
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      ]. When EF was assessed as a continuous variable, the adjusted relationship between EF and outcomes was characterized by a steep decrease in incidence rate with increasing EF up to 50% for all-cause and cardiovascular mortality, and up to 40% for the risk of HF hospitalization, than flattened attesting the similarity between HFmrEF and HFrEF [
      • Lund LH
      • Claggett B
      • Liu J
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      ].
      In incident HF the relationship between HF phenotype and outcome appears to have different features. Data collected from a prospective, observational community-based cohorts free from HF reported an all-cause mortality rate after the onset of HF that was 497 events per 10,000 person years in HFmrEF, 394 events per 10,000 person years in HFpEF and 459 per 10,000 person years in HFrEF. The survival in HFmrEF was lower than HFpEF (p=0.02) and similar to HFrEF (p=0.78). The inclusion of patients limited to incident HF and the exclusion of patients with a documented transition of EF from HFrEF to HFmrEF, provided a reliable picture of the prognosis of HFmrEF, supporting the same treatment approach for HFmrEF and HFrEF [
      • Bhambhani V
      • Kizer JR
      • Lima JAC
      • et al.
      Predictors and outcomes of heart failure with mid-range ejection fraction.
      ].
      The risk of sudden cardiac death (SCD) in HFmrEF has not been explored in depth and remains an unsolved issue. EF is key in the risk estimation of SCD in HF [
      • Priori SG
      • Blomstrom-Lundqvist C
      • Mazzanti A
      • et al.
      2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
      ], and among HFpEF and HFmrEF SCD is not considered one of the leading causes of death. However, possible underestimation in observational studies and in RCTs should be accounted due to imprecise reporting or events adjudication, especially considering the potential confounding effect of non-cardiovascular causes of deaths. In a previous report specifically focusing on the modalities of death in HFpEF, SCD accounted for the 30-40% of the cardiovascular causes of death and, thus, deserves future dedicated attention [
      • Vaduganathan M
      • Patel RB
      • Michel A
      • et al.
      Mode of Death in Heart Failure With Preserved Ejection Fraction.
      ].

      4.1 Treatment of HFmrEF (Summary Figure)

      Neurohormonal antagonists have been the cornerstone of pharmacological therapy for HF for the last decades [
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ]. However, these agents have demonstrated to be effective in HFrEF, whereas until the recent release of studies on SGLT2i [
      • Anker SD
      • Butler J
      • Filippatos G
      • et al.
      Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
      ], no therapies demonstrated proven benefit in the two other categories of HF. Specifically, no dedicated studies have been designed to address the specific question of whether there is any pharmacological strategy active in improving outcomes in HFmrEF. Observational data from registries are relatively scarce and suffers of obvious limitations due to confounding. The rate of GDMT use in registries is high among the HFmrEF population, suggesting that in clinical practice these patients are frequently assimilated to the HFrEF, have alternative indications to these treatments (i.e. systemic hypertension, atrial fibrillation) or alternatively, are “in transition” from HFrEF [
      • Tsuji K
      • Sakata Y
      • Nochioka K
      • et al.
      Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
      ,
      • Chioncel O
      • Lainscak M
      • Seferovic PM
      • et al.
      Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
      ,
      • Koh AS
      • Tay WT
      • Teng THK
      • et al.
      A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
      ,
      • Rickenbacher P
      • Kaufmann BA
      • Maeder MT
      • et al.
      Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).
      ,
      • Shah KS
      • Xu H
      • Matsouaka RA
      • et al.
      Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes.
      ,
      • Ibrahim NE
      • Song Y
      • Cannon CP
      • et al.
      Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry(R).
      ]. These data may apparently support the use of GDMT in HFmrEF, although in a former study there was a lacking association between GDMT and outcomes in HFmrEF [
      • Fonarow GC
      • Stough WG
      • Abraham WT
      • et al.
      Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry.
      ].
      In previous RCTs on HFpEF, the heterogeneity in the inclusion criteria permits deriving partial considerations on the potential of GDMT in HFmrEF. In most of this RCTs the lower threshold of EF was set to include completely, or partially, the HFmrEF spectrum [
      • Yusuf S
      • Pfeffer MA
      • Swedberg K
      • et al.
      Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
      ,
      • Pitt B
      • Pfeffer MA
      • Assmann SF
      • et al.
      Spironolactone for heart failure with preserved ejection fraction.
      ,
      • Massie BM
      • Carson PE
      • McMurray JJ
      • et al.
      Irbesartan in patients with heart failure and preserved ejection fraction.
      ,
      • Solomon SD
      • McMurray JJV
      • Anand IS
      • et al.
      Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.
      ]. Pooled data and post-hoc analysis of these studies can be helpful to formulate some recommendations on the most appropriate approach (Table 1) . In CHARM, candesartan reduced the primary outcome and the risk of recurrent HF hospitalizations in HFmrEF [
      • Lund LH
      • Claggett B
      • Liu J
      • et al.
      Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
      ]. In the TOPCAT study, a significant interaction between EF and outcome was observed both for the primary composite endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest and for the secondary endpoint of HF hospitalizations, with potential efficacy in the lower EF range in the trial [
      • Solomon SD
      • Claggett B
      • Lewis EF
      • et al.
      Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
      ]. Noteworthily, the interaction between EF and outcome was more evident in males than in females [
      • Solomon SD
      • Claggett B
      • Lewis EF
      • et al.
      Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
      ]. An individual patient data meta-analysis of 11 RCT on betablockers demonstrated a treatment benefit for patients in sinus rhythm across the entire spectrum of EF. The hazard ratio for cardiovascular mortality in HFmrEF patients was 0.48 (95% CI 0.24–0.97) [
      • Cleland JGF
      • Bunting KV
      • Flather MD
      • et al.
      Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
      ]. More recently, the PARAGON-HF assessed the effect of sacubitril/valsartan in the largest cohort of HFpEF to date. EF threshold for inclusion was ≥45%. Although the overall study was inconclusive, subgroup analysis demonstrated a benefit in patients with EF below the median (i.e. <57%) [
      • Solomon SD
      • McMurray JJV
      • Anand IS
      • et al.
      Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.
      ]. In a pre-specified analysis of the pooled data from this study and from the Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting– Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) [
      • McMurray JJ
      • Packer M
      • Desai AS
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      ], the effect of sacubitril/valsartan varied by EF and was greatest in patients with EF below normal [
      • Solomon SD
      • Vaduganathan M
      • B LC
      • et al.
      Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.
      ]. Due to the post-hoc design of the analysis and the gap in EF with values >40% and <45% excluded from both the RCTs, these observations should be considered as hypotheses generating and claim for specifically designed studies. When pooled together on a continuous scale, data from these studies suggest treatments might provide benefit in the mildly reduced range of EF, as also contemplated by the recently published European guidelines on HF (Figure 1) [
      • McDonagh TA
      • Metra M
      • Adamo M
      • et al.
      2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      ,
      • Bohm M
      • Bewarder Y
      • Kindermann I.
      Ejection fraction in heart failure revisited- where does the evidence start?.
      ].
      Table 1Summary of randomized controlled trials with subgroups/post-hoc analyses providing evidence on treatment effect in HFmrEF.
      StudyYearSizeDrugClassRange EFPrimary OutcomeFollow-up (months)
      CHARM-Preserved20033023CandesartanARB>40%CV death/first HF hospitalization37
      DIG (ancillary)2006988Digoxin->45%HF mortality/HF hospitalization37
      TOPCAT20143445SpironolactoneMRA≥45%CV death/aborted cardiac arrest/first HF hospitalization40
      BB-metanalysis201717312-BBOverallAll cause mortality and CV death16
      PARAGON-HF20194822Sacubitril/ValsartanARNI≥45%CV death/total HF hospitalizations35
      SOLOIST-WHF20211222SotagliflozinSGLT2i<50%CV death/total HF hospitalizations/urgent HF visits9
      EMPEROR-PRESERVED20215988EmpagliflozinSGLT2i>40%CV death/first HF hospitalization26
      EMPULSE2022530EmpagliflozinSGLT2iOverallClinical benefit90 days
      Figure 1
      Figure 1Treatment effects over a broad range of EF from major RCTs including the overall EF spectrum. The EF threshold for treatment effect appears to be around 55%. Dark red areas depict ejection fractions which are not covered by dedicated RCTs, but where evidence exists from exploratory analyses. Reproduced from Böhm et al. Eur Heart J 2020 Jul 1;41(25):2363-2365.
      The astonishing results from the two major RCTs on SGLT2 inhibitors for the treatment of HFrEF have generated great expectations for the potential of this class of drugs for the treatment of HFmrEF and HFpEF [
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • et al.
      Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
      ,
      • Packer M
      • Anker SD
      • Butler J
      • et al.
      Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.
      ]. In the SOLOIST-WHF trial, patients with HF and type 2 diabetes who were stabilized after hospitalization for worsening HF or recently discharged from hospital were randomly assigned, regardless of EF, to the SGLT2–SGLT1 inhibitor sotagliflozin or placebo [
      • Bhatt DL
      • Szarek M
      • Steg PG
      • et al.
      Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure.
      ]. The benefits of sotagliflozin for risk reduction of cardiovascular death or hospitalizations or urgent visits for HF was consistent in patients with EF <50% or ≥50%. However, the premature conclusion of the study due to the loss of funding, the larger predominance of HFrEF in the study cohort and the exclusive inclusion of diabetic patients limit the applicability of results to the overall population of HFmrEF/HFpEF. In 2021, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) study has become the first RCT that provided solid evidence of benefit in the treatment of HFpEF [
      • Anker SD
      • Butler J
      • Filippatos G
      • et al.
      Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
      ], with a 21% reduction in cardiovascular mortality/HF hospitalization in the treatment arm compared to the placebo group, although with not significant effect on mortality. With an EF threshold for inclusion of >40%, one-third of the trial population had HFmrEF. The results were consistent across the entire EF spectrum.
      More recently, the EMPULSE trial enrolled 530 patients hospitalized for HF within the overall spectrum of EF and demonstrated a significant clinical benefit in the treated arm, defined by a hierarchical composite of all-cause death, number of HF events and time to first HF event, or change in symptoms at 90 days. No interaction with EF was observed [
      • Voors AA
      • Angermann CE
      • Teerlink JR
      • et al.
      The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.
      ]. If the upcoming results of the second mortality trial in HFpEF/HFmrEF with a SGLT2 inhibitor, the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) [
      • Solomon SD
      • de-Boer RA
      • DeMets D
      • et al.
      Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial.
      ], will be confirmatory, SGLT2 inhibitors will be the first class of drugs with proven positive effect on the prognosis of patients with HFpEF/HFmrEF.

      4.2 Additional strategies for phenotype characterization and longitudinal assessment of ejection fraction – implications for treatment

      EF is a largely adopted and universally accepted parameter in clinical practice. It is widely available, easy to calculate and applicable to different imaging techniques [
      • Mele D
      • Nardozza M
      • Ferrari R.
      Left ventricular ejection fraction and heart failure: an indissoluble marriage?.
      ]. It can rapidly be estimated visually in urgent settings and can be assessed by high as well low-quality equipment. There are also limitations, inter and intraobserver variability have been reported to be wide enough to generate potential misclassifications [
      • McGowan JH
      • Cleland JG.
      Reliability of reporting left ventricular systolic function by echocardiography: a systematic review of 3 methods.
      ]. The thresholds of EF, as proposed by current recommendations, vary according to age and gender and a range of normality, rather than a single value, is defined [
      • Lang RM
      • Badano LP
      • Mor-Avi V
      • et al.
      Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      ]. This is in partial contrast with the arbitrary and fixed cut-off proposed by guidelines and adopted for inclusion in RCTs. In the rational approach to the single specific cases, further steps are required and alternative techniques are emerging to aid the clinicians. Myocardial tissue characterization by cardiac magnetic resonance imaging is part of the routine diagnostic work-up of patients with HF and can support the etiological characterization. Emerging studies suggest its importance in patients with EF>40% [
      • Celutkiene J
      • Plymen CM
      • Flachskampf FA
      • et al.
      Innovative imaging methods in heart failure: a shifting paradigm in cardiac assessment. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology.
      ,
      • Quarta G
      • Gori M
      • Iorio A
      • et al.
      Cardiac magnetic resonance in heart failure with preserved ejection fraction: myocyte, interstitium, microvascular, and metabolic abnormalities.
      ]. Late gadolinium enhancement (LGE) demonstrated to correctly classify the risk of mortality and SCD in patients with EF>40%, identifying patients that could be considered for primary prevention strategies regardless of their EF [
      • Halliday BP
      • Gulati A
      • Ali A
      • et al.
      Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction.
      ].
      The assessment of global longitudinal strain (GLS) from speckle-tracking analysis of 2-dimensional echocardiography is an emerging technique complementary to EF for the quantification of myocardial function and with incremental prognostic performance [
      • Potter E
      • Marwick TH.
      Assessment of Left Ventricular Function by Echocardiography: The Case for Routinely Adding Global Longitudinal Strain to Ejection Fraction.
      ,
      • Kalam K
      • Otahal P
      • Marwick TH.
      Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction.
      ,
      • Stanton T
      • Leano R
      • Marwick TH.
      Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring.
      ].
      In the era of precision medicine, deep etiological characterization of HF may maximize the understanding of the underlying disease, to predict its natural progression and to individualize the strategies of treatment. Specific aetiologies such as sarcoidosis may portend increased risks of poor outcome irrespective of the severity of LV dysfunction [
      • Trivieri MG
      • Spagnolo P
      • Birnie D
      • et al.
      Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review.
      ]. The genetic background of non-severe reduced EF in some cases can lead to alternative strategies in order to protect individuals with irremediably high risk of dying suddenly regardless of EF. Specific genotypes of dilated cardiomyopathy, including Lamin A/C, Filamin C and desmosomal genes, demonstrated lower survival free-from potentially fatal ventricular arrhythmias despite EF values above the 35% “critical” threshold for ICD implantation [
      • Gigli M
      • Merlo M
      • Graw SL
      • et al.
      Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy.
      ,
      • Wahbi K
      • Ben-Yaou R
      • Gandjbakhch E
      • et al.
      Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.
      ].

      4.3 Ejection fraction, a “dynamic“ parameter

      It should be considered that EF is a dynamic parameter inevitably subject to variation with time. In observational registries collecting patients with prevalent HF, the value of EF provides a static snapshot of something that is shifting over time as the results of treatment or merely due to the natural progression of the underlying disease. In the Olmsted County, Minnesota, cohort, over a 5-years observation period ≈ 40% crossed from HFpEF to HFrEF and viceversa [
      • Dunlay SM
      • Roger VL
      • Weston SA
      • Jiang R
      • Redfield MM.
      Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction.
      ]. In the SwedeHF Registry trends in EF across the spectrum of baseline EF were specifically explored in patients with available longitudinal data. Among individuals with HFmrEF, 37% and 25% switched respectively to HFrEF and HFpEF, while among HFrEF and HFpEF 16% and 21%, respectively, switched to HFmrEF [
      • Savarese G
      • Vedin O
      • D'Amario D
      • et al.
      Prevalence and Prognostic Implications of Longitudinal Ejection Fraction Change in Heart Failure.
      ]. The temporal trends of EF have also important implications on outcomes [
      • Kalogeropoulos AP
      • Fonarow GC
      • Georgiopoulou V
      • et al.
      Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered Ejection Fraction.
      ,
      • Savarese G
      • Vedin O
      • D'Amario D
      • et al.
      Prevalence and Prognostic Implications of Longitudinal Ejection Fraction Change in Heart Failure.
      ,
      • Lupon J
      • Diez-Lopez C
      • de-Antonio M
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      ]. A recent retrospective cohort study focused specifically on patients with EF within the mid-range interval. The investigators collected all the patients examined in 2015 with EF between 40% and 50% and at least one previous echocardiographic examination. Of note only 15% of patients had stable HFmrEF. The risk of all-cause mortality, cardiovascular mortality and HF hospitalization was higher for those with EF decreasing from >50% compared to those improving EF from <40%, even after adjustment for confounding factors. Interestingly, the outcome of patients improving EF was similar to patients with stable mid-range EF, suggesting that stable HFmrEF might configure a relatively low risk entity [
      • Brann A
      • Janvanishstaporn S
      • Greenberg B.
      Association of Prior Left Ventricular Ejection Fraction With Clinical Outcomes in Patients With Heart Failure With Midrange Ejection Fraction.
      ].
      The transition from the HFrEF to the HFmrEF category is in general the results of therapy. In this case the indefinite maintenance of GDMT is advocated and the withdrawal of neurohormonal antagonists after the improvement (or recovery) of EF should be strongly discouraged [
      • Wilcox JE
      • Fang JC
      • Margulies KB
      • Mann DL.
      Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel.
      ]. In the Withdrawal of Pharmacological Treatment for Heart Failure in Patients With Recovered Dilated Cardiomyopathy (TRED-HF) trial, therapy was withdrawn in a small group of patients with dilated cardiomyopathy and recovered EF. After weaning about 40% of patients experienced a recurrence of HF within 6 months, defined by a fall in EF >10% to <50%, an increase in left ventricular end-diastolic volume >10% to greater than the normal range, a doubling of the NT-proBNP to >400 ng/l, or clinical evidence of HF, but no deaths were observed [
      • Halliday BP
      • Wassall R
      • Lota AS
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.
      ].
      Further considerations in patients switching from HFrEF to HFmrEF concern the devices. With the progression of medical treatments for HFrEF, the number of patients with primary prevention implantable-cardioverter defibrillator (ICD) that at the time of generator replacement have improved the EF not fulfilling anymore the criteria for ICD implantation, is growing(11). There is not univocal consensus on the most appropriate strategy to follow in this specific situation. In a previous retrospective study, patients with no longer guidelines indications to ICD at the time of replacement experienced a 3% annual rate of appropriate interventions, that was lower compared to patients with persisting indications [
      • Kini V
      • Soufi MK
      • Deo R
      • et al.
      Appropriateness of primary prevention implantable cardioverter-defibrillators at the time of generator replacement: are indications still met?.
      ]. A retrospective analysis of the Sudden Cardiac Death in Heart Failure Trial (SCD HeFT) showed that the mortality benefit gained by ICD was similar between patients who improved EF>35% vs those with persisting EF≦35% [
      • Adabag S
      • Patton KK
      • Buxton AE
      • et al.
      Association of Implantable Cardioverter Defibrillators With Survival in Patients With and Without Improved Ejection Fraction: Secondary Analysis of the Sudden Cardiac Death in Heart Failure Trial.
      ]. Therefore, available evidences suggest that the arrhythmic risk persists despite the improvement in EF.

      4.4 Remaining gaps and future perspectives

      After the introduction of this new “intermediate” category in 2016(11), a large amount of literature has been published that shed some light on this gray area and contribute to our understanding of the epidemiology, clinical characteristics and prognosis of HFmrEF. The overall picture supports the notion that this category should be probably paired to the reduced rather than the preserved EF area and in this sense, it was reclassified as “mildly reduced” EF in the recent ESC guidelines. However, the broad heterogeneity in etiology, clinical presentation and natural progression requires a focused approach that overcomes the simple categorization by EF. In this era of precision medicine, the efforts should be directed to a more individualized work-up that involves alternative tools that can aid the diagnosis, characterization and risk stratification of patients. Emerging imaging techniques beyond the mere assessment of EF are destined to integrate the clinical management and perhaps to provide further elements to improve the selection criteria for inclusion in RCT. Novel biomarkers and -omics studies might help to provide further insights into the pathophysiological knowledge of HFmrEF.
      The absence of medical treatments with proven benefit has remained for long the most concerning aspect in the management of this category, but evidences from recent RCTs that included also patients in the HFmrEF category have probably determined the turning point in the treatment of HFpEF and HFmrEF. Low recruitment rate and limited number of events might interfere with the conduction of specific randomized studies on HFmrEF that will continue to be included in RCTs on HFpEF or, more appropriately, on HFrEF. Designing RCT that cover the whole spectrum of EF might represent a potential solution, although it might lead to underestimate the effect of interventions on the lower range of EF. Finally, novel strategies of intervention and novel emerging drugs acting through different targets might further implement in the future the options of treatment.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      References

        • Groenewegen A
        • Rutten FH
        • Mosterd A
        • Hoes AW.
        Epidemiology of heart failure.
        Eur J Heart Fail. 2020; 22: 1342-1356
        • Conrad N
        • Judge A
        • Tran J
        • et al.
        Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals.
        Lancet. 2018; 391: 572-580
        • van-Riet EE
        • Hoes AW
        • Wagenaar KP
        • Limburg A
        • Landman MA
        • Rutten FH.
        Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review.
        Eur J Heart Fail. 2016; 18: 242-252
        • Taylor CJ
        • Ordonez-Mena JM
        • Roalfe AK
        • et al.
        Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study.
        BMJ. 2019; 364: l223
        • Malek M.
        Health economics of heart failure.
        Heart. 1999; 82 (Suppl): IV11-IV13
        • Farre N
        • Vela E
        • Cleries M
        • et al.
        Medical resource use and expenditure in patients with chronic heart failure: a population-based analysis of 88 195 patients.
        Eur J Heart Fail. 2016; 18: 1132-1140
        • Roger VL
        • Go AS
        • Lloyd-Jones DM
        • et al.
        Heart disease and stroke statistics–2011 update: a report from the American Heart Association.
        Circulation. 2011; 123: e18-e209
        • Heidenreich PA
        • Albert NM
        • Allen LA
        • et al.
        Forecasting the impact of heart failure in the United States: a policy statement from the.
        American Heart Association. Circ Heart Fail. 2013; 6: 606-619
        • Sidney S
        • Go AS
        • Jaffe MG
        • Solomon MD
        • Ambrosy AP
        • Rana JS.
        Association Between Aging of the US Population and Heart Disease Mortality From 2011 to 2017.
        JAMA Cardiol. 2019; 4: 1280-1286
        • McDonagh TA
        • Metra M
        • Adamo M
        • et al.
        2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
        Eur Heart J. 2021; 42: 3599-3726
        • Ponikowski P
        • Voors AA
        • Anker SD
        • et al.
        2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
        Eur Heart J. 2016; 37: 2129-2200
        • Dougherty AH
        • Naccarelli GV
        • Gray EL
        • Hicks CH
        • Goldstein RA.
        Congestive heart failure with normal systolic function.
        Am J Cardiol. 1984; 54: 778-782
        • Soufer R
        • Wohlgelernter D
        • Vita NA
        • et al.
        Intact systolic left ventricular function in clinical congestive heart failure.
        Am J Cardiol. 1985; 55: 1032-1036
        • Hunt SA
        • Abraham WT
        • Chin MH
        • et al.
        ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society.
        Circulation. 2005; 112: e154-e235
        • McHugh K
        • DeVore AD
        • Wu J
        • et al.
        Heart Failure With Preserved Ejection Fraction and Diabetes: JACC State-of-the-Art Review.
        J Am Coll Cardiol. 2019; 73: 602-611
        • Anker SD
        • Butler J
        • Filippatos G
        • et al.
        Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
        N Engl J Med. 2021; 385: 1451-1461
        • Swedberg K
        • Pfeffer M
        • Granger C
        • et al.
        Candesartan in heart failure–assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators.
        J Card Fail. 1999; 5: 276-282
        • Yusuf S
        • Pfeffer MA
        • Swedberg K
        • et al.
        Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
        Lancet. 2003; 362: 777-781
        • Pitt B
        • Pfeffer MA
        • Assmann SF
        • et al.
        Spironolactone for heart failure with preserved ejection fraction.
        N Engl J Med. 2014; 370: 1383-1392
        • Massie BM
        • Carson PE
        • McMurray JJ
        • et al.
        Irbesartan in patients with heart failure and preserved ejection fraction.
        N Engl J Med. 2008; 359: 2456-2467
        • Solomon SD
        • McMurray JJV
        • Anand IS
        • et al.
        Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.
        N Engl J Med. 2019; 381: 1609-1620
        • Lang RM
        • Badano LP
        • Mor-Avi V
        • et al.
        Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
        Eur Heart J Cardiovasc Imaging. 2015; 16: 233-270
        • Yancy CW
        • Jessup M
        • Bozkurt B
        • et al.
        2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
        Circulation. 2013; 128: 1810-1852
        • Kapoor JR
        • Kapoor R
        • Ju C
        • et al.
        Precipitating Clinical Factors, Heart Failure Characterization, and Outcomes in Patients Hospitalized With Heart Failure With Reduced, Borderline, and Preserved Ejection Fraction.
        JACC Heart Fail. 2016; 4: 464-472
        • Tsuji K
        • Sakata Y
        • Nochioka K
        • et al.
        Characterization of heart failure patients with mid-range left ventricular ejection fraction-a report from the CHART-2 Study.
        Eur J Heart Fail. 2017; 19: 1258-1269
        • Chioncel O
        • Lainscak M
        • Seferovic PM
        • et al.
        Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.
        Eur J Heart Fail. 2017; 19: 1574-1585
        • Koh AS
        • Tay WT
        • Teng THK
        • et al.
        A comprehensive population-based characterization of heart failure with mid-range ejection fraction.
        Eur J Heart Fail. 2017; 19: 1624-1634
        • Bhambhani V
        • Kizer JR
        • Lima JAC
        • et al.
        Predictors and outcomes of heart failure with mid-range ejection fraction.
        Eur J Heart Fail. 2018; 20: 651-659
        • Lam CSP
        • Gamble GD
        • Ling LH
        • et al.
        Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study.
        Eur Heart J. 2018; 39: 1770-1780
        • Rickenbacher P
        • Kaufmann BA
        • Maeder MT
        • et al.
        Heart failure with mid-range ejection fraction: a distinct clinical entity? Insights from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF).
        Eur J Heart Fail. 2017; 19: 1586-1596
        • Lund LH
        • Claggett B
        • Liu J
        • et al.
        Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
        Eur J Heart Fail. 2018; 20: 1230-1239
        • Lund LH.
        Heart Failure with Mid-range Ejection Fraction: Lessons from CHARM.
        Card Fail Rev. 2018; 4: 70-72
        • Fonarow GC
        • Stough WG
        • Abraham WT
        • et al.
        Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry.
        J Am Coll Cardiol. 2007; 50: 768-777
        • Sweitzer NK
        • Lopatin M
        • Yancy CW
        • Mills RM
        • Stevenson LW.
        Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (>or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions.
        Am J Cardiol. 2008; 101: 1151-1156
        • Shah KS
        • Xu H
        • Matsouaka RA
        • et al.
        Heart Failure With Preserved, Borderline, and Reduced Ejection Fraction: 5-Year Outcomes.
        J Am Coll Cardiol. 2017; 70: 2476-2486
        • Kalogeropoulos AP
        • Fonarow GC
        • Georgiopoulou V
        • et al.
        Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered Ejection Fraction.
        JAMA Cardiol. 2016; 1: 510-518
        • Stolfo D
        • Uijl A
        • Vedin O
        • et al.
        Sex-Based Differences in Heart Failure Across the Ejection Fraction Spectrum: Phenotyping, and Prognostic and Therapeutic Implications.
        JACC Heart Fail. 2019; 7: 505-515
        • Ibrahim NE
        • Song Y
        • Cannon CP
        • et al.
        Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry(R).
        ESC Heart Fail. 2019; 6: 784-792
        • Vedin O
        • Lam CSP
        • Koh AS
        • et al.
        Significance of Ischemic Heart Disease in Patients With Heart Failure and Preserved, Midrange, and Reduced Ejection Fraction: A Nationwide Cohort Study.
        Circ Heart Fail. 2017; 10
        • Sartipy U
        • Dahlstrom U
        • Fu M
        • Lund LH.
        Atrial Fibrillation in Heart Failure With Preserved, Mid-Range, and Reduced Ejection Fraction.
        JACC Heart Fail. 2017; 5: 565-574
        • Lofman I
        • Szummer K
        • Dahlstrom U
        • Jernberg T
        • Lund LH.
        Associations with and prognostic impact of chronic kidney disease in heart failure with preserved, mid-range, and reduced ejection fraction.
        Eur J Heart Fail. 2017; 19: 1606-1614
        • Savarese G
        • Jonsson A
        • Hallberg AC
        • Dahlstrom U
        • Edner M
        • Lund LH.
        Prevalence of, associations with, and prognostic role of anemia in heart failure across the ejection fraction spectrum.
        Int J Cardiol. 2020; 298: 59-65
        • Solomon SD
        • Claggett B
        • Lewis EF
        • et al.
        Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction.
        Eur Heart J. 2016; 37: 455-462
        • Solomon SD
        • Vaduganathan M
        • B LC
        • et al.
        Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.
        Circulation. 2020; 141: 352-361
        • Savarese G
        • Orsini N
        • Hage C
        • et al.
        Associations With and Prognostic and Discriminatory Role of N-Terminal Pro-B-Type Natriuretic Peptide in Heart Failure With Preserved Versus Mid-range Versus Reduced Ejection Fraction.
        J Card Fail. 2018; 24: 365-374
        • Tromp J
        • Khan MAF
        • Mentz RJ
        • et al.
        Biomarker Profiles of Acute Heart Failure Patients With a Mid-Range Ejection Fraction.
        JACC Heart Fail. 2017; 5: 507-517
        • Priori SG
        • Blomstrom-Lundqvist C
        • Mazzanti A
        • et al.
        2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).
        Eur Heart J. 2015; 36: 2793-2867
        • Vaduganathan M
        • Patel RB
        • Michel A
        • et al.
        Mode of Death in Heart Failure With Preserved Ejection Fraction.
        J Am Coll Cardiol. 2017; 69: 556-569
        • Cleland JGF
        • Bunting KV
        • Flather MD
        • et al.
        Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.
        Eur Heart J. 2018; 39: 26-35
        • McMurray JJ
        • Packer M
        • Desai AS
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • Bohm M
        • Bewarder Y
        • Kindermann I.
        Ejection fraction in heart failure revisited- where does the evidence start?.
        Eur Heart J. 2020; 41: 2363-2365
        • McMurray JJV
        • Solomon SD
        • Inzucchi SE
        • et al.
        Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Packer M
        • Anker SD
        • Butler J
        • et al.
        Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.
        N Engl J Med. 2020; 383: 1413-1424
        • Bhatt DL
        • Szarek M
        • Steg PG
        • et al.
        Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure.
        N Engl J Med. 2021; 384: 117-128
        • Voors AA
        • Angermann CE
        • Teerlink JR
        • et al.
        The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.
        Nat Med. 2022; 28: 568-574
        • Solomon SD
        • de-Boer RA
        • DeMets D
        • et al.
        Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial.
        Eur J Heart Fail. 2021; 23: 1217-1225
        • Mele D
        • Nardozza M
        • Ferrari R.
        Left ventricular ejection fraction and heart failure: an indissoluble marriage?.
        Eur J Heart Fail. 2018; 20: 427-430
        • McGowan JH
        • Cleland JG.
        Reliability of reporting left ventricular systolic function by echocardiography: a systematic review of 3 methods.
        Am Heart J. 2003; 146: 388-397
        • Celutkiene J
        • Plymen CM
        • Flachskampf FA
        • et al.
        Innovative imaging methods in heart failure: a shifting paradigm in cardiac assessment. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology.
        Eur J Heart Fail. 2018; 20: 1615-1633
        • Quarta G
        • Gori M
        • Iorio A
        • et al.
        Cardiac magnetic resonance in heart failure with preserved ejection fraction: myocyte, interstitium, microvascular, and metabolic abnormalities.
        Eur J Heart Fail. 2020; 22: 1065-1075
        • Halliday BP
        • Gulati A
        • Ali A
        • et al.
        Association Between Midwall Late Gadolinium Enhancement and Sudden Cardiac Death in Patients With Dilated Cardiomyopathy and Mild and Moderate Left Ventricular Systolic Dysfunction.
        Circulation. 2017; 135: 2106-2115
        • Potter E
        • Marwick TH.
        Assessment of Left Ventricular Function by Echocardiography: The Case for Routinely Adding Global Longitudinal Strain to Ejection Fraction.
        JACC Cardiovasc Imaging. 2018; 11: 260-274
        • Kalam K
        • Otahal P
        • Marwick TH.
        Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction.
        Heart. 2014; 100: 1673-1680
        • Stanton T
        • Leano R
        • Marwick TH.
        Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring.
        Circ Cardiovasc Imaging. 2009; 2: 356-364
        • Trivieri MG
        • Spagnolo P
        • Birnie D
        • et al.
        Challenges in Cardiac and Pulmonary Sarcoidosis: JACC State-of-the-Art Review.
        J Am Coll Cardiol. 2020; 76: 1878-1901
        • Gigli M
        • Merlo M
        • Graw SL
        • et al.
        Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy.
        J Am Coll Cardiol. 2019; 74: 1480-1490
        • Wahbi K
        • Ben-Yaou R
        • Gandjbakhch E
        • et al.
        Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.
        Circulation. 2019; 140: 293-302
        • Dunlay SM
        • Roger VL
        • Weston SA
        • Jiang R
        • Redfield MM.
        Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction.
        Circ Heart Fail. 2012; 5: 720-726
        • Savarese G
        • Vedin O
        • D'Amario D
        • et al.
        Prevalence and Prognostic Implications of Longitudinal Ejection Fraction Change in Heart Failure.
        JACC Heart Fail. 2019; 7: 306-317
        • Lupon J
        • Diez-Lopez C
        • de-Antonio M
        • et al.
        Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
        Eur J Heart Fail. 2017; 19: 1615-1623
        • Brann A
        • Janvanishstaporn S
        • Greenberg B.
        Association of Prior Left Ventricular Ejection Fraction With Clinical Outcomes in Patients With Heart Failure With Midrange Ejection Fraction.
        JAMA Cardiol. 2020; 5: 1027-1035
        • Wilcox JE
        • Fang JC
        • Margulies KB
        • Mann DL.
        Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel.
        J Am Coll Cardiol. 2020; 76: 719-734
        • Halliday BP
        • Wassall R
        • Lota AS
        • et al.
        Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.
        Lancet. 2019; 393: 61-73
        • Kini V
        • Soufi MK
        • Deo R
        • et al.
        Appropriateness of primary prevention implantable cardioverter-defibrillators at the time of generator replacement: are indications still met?.
        J Am Coll Cardiol. 2014; 63: 2388-2394
        • Adabag S
        • Patton KK
        • Buxton AE
        • et al.
        Association of Implantable Cardioverter Defibrillators With Survival in Patients With and Without Improved Ejection Fraction: Secondary Analysis of the Sudden Cardiac Death in Heart Failure Trial.
        JAMA Cardiol. 2017; 2: 767-774