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Heart failure with recovered ejection fraction: Current understanding and future prospects

Published:September 06, 2022DOI:https://doi.org/10.1016/j.amjms.2022.07.018

      Abstract

      Heart failure with reduced ejection fraction (HFrEF) is a prevalent kind of heart failure in which a significant amount of the ejection fraction can be repaired, and left ventricular remodeling and dysfunction can be reversed or even restored completely. However, a considerable number of patients still present clinical signs and biochemical features of incomplete recovery from the pathophysiology of heart failure and are at risk for adverse outcomes such as re-deterioration of systolic function and recurrence of HFrEF. Furthermore, it is revealed from a microscopic perspective that even if partial or complete reverse remodeling occurs, the morphological changes of cardiomyocytes, extracellular matrix deposition, and abnormal transcription and expression of pathological genes still exist. Patients with “recovered ejection fraction” have milder clinical symptoms and better outcomes than those with continued reduction of ejection fraction. Based on the unique characteristics of this subgroup and the existence of many unknowns, the academic community defines it as a new category-heart failure with recovered ejection fraction (HFrecEF). Because there is a shortage of natural history data for this population as well as high-quality clinical and basic research data, it is difficult to accurately evaluate clinical risk and manage this population. This review will present the current understanding of HFrecEF from the limited literature.

      Keywords

      Introduction

      Heart failure (HF) is a type of clinical syndrome characterized by dyspnea and limited activity tolerance, which is attributed to impairment of ejection dysfunction or ventricular filling, or a combination of both.
      • Murphy S.P.
      • Ibrahim N.E.
      • Januzzi J.L.
      Heart failure with reduced ejection fraction: a review.
      In clinical practice, left ventricular ejection fraction (LVEF) is an important indicator to measure left ventricular systolic function.
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      Dynamic trajectories of left ventricular ejection fraction in heart failure.
      With the development of new drugs and device-based therapies, researchers have repeatedly identified that LVEF can be significantly improved in some patients with HF with reduced ejection fraction (HFrEF), whether treated or not.
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      ,
      • Yancy C.W.
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      • et al.
      2013ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      Previous literature has reported the clinical features, pathophysiology, and prognosis of these patients with HF are different from those with HFrEF or preserved ejection fraction (HFpEF), suggesting that this type of HF may be a unique phenotype, defined as HF with recovered ejection fraction (HFrecEF).
      • Nijst P.
      • Martens P.
      • Mullens W.
      Heart failure with myocardial recovery - the patient whose heart failure has improved: what Next?.
      ,
      • Wilcox J.E.
      • Fang J.C.
      • Margulies K.B.
      • et al.
      Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
      Contemporary management of HF is mainly based on LVEF. However, due to insufficient attention to the recovery of LVEF in the past and a lack of understanding of its internal pathophysiological mechanism, an accurate and unified definition of HFrecEF has not yet been formed. More importantly, there may be large measurement variability in LVEF
      • Pellikka P.A.
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      • et al.
      Variability in Ejection fraction measured by echocardiography, gated single-photon emission computed tomography, and cardiac magnetic resonance in patients with coronary artery disease and left ventricular dysfunction.
      and LVEF alone may not reflect hemodynamic changes well,
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      • Butler J.
      • Abboud F.M.
      • et al.
      The continuous heart failure spectrum: moving beyond an ejection fraction classification.
      further weakening the understanding of the HFrecEF subgroup from previous literature. All of these have made it difficult to recognize, evaluate, and treat these patients effectively.
      This review will present the definition, epidemiological data, clinical characteristics, predictors of HFrEF recurrence, and prognosis of HFrecEF. Based on the limited data, the pathophysiological mechanism and the management strategy of drugs and devices are discussed, and the deficiencies and controversies of current research and further investigation are put forward.

      Definition of HFrecEF

      In 2013, the ACCF/AHA guidelines introduced a new phenotype of HFpEF, defined as “HFpEF, improved”, which refers to those with previous HFrEF and LVEF recovered to more than 40%. It has unique clinical characteristics that need to be distinguished from HFrEF and HFpEF.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2013ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      The 2016 ESC guidelines propose a new classification approach as follows: HFrEF (LVEF<40%), HF with middle-range ejection fraction (HFmrEF, LVEF41%−49%), HFpEF (LVEF≥50%). However, for HFmrEF, the origin of the intermediate range of LVEF is not strictly distinguished.
      ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for thediagnosis 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.
      Indeed, previous studies have revealed that HFmrEF is heterogeneous and represents a mixture of HFrEF with improvement in LVEF and HFpEF with the reduction in LVEF.
      • Dunlay S.M.
      • Roger V.L.
      • Weston S.A.
      • et al.
      Longitudinal changes in ejection fraction in heart failure patients with preserved and reduced ejection fraction.
      ,
      • Nauta J.F.
      • Hummel Y.M.
      • van Melle J.P.
      • et al.
      What have we learned about heart failure with mid-range ejection fraction one year after its introduction?.
      The data showed that in HF with LVEF 41%−49%, the proportion of HFmrEF after HFrEF improvement is significantly higher than that of HFmrEF that remains stable.
      • Nauta J.F.
      • Hummel Y.M.
      • van Melle J.P.
      • et al.
      What have we learned about heart failure with mid-range ejection fraction one year after its introduction?.
      HFmrEF contains a considerable part of HFrecEF (Fig. 1). As a result, the kind of HF cannot be reliably recognized only on a single LVEF record, and it is even stated that HFmrEF cannot be physiologically or clinically regarded as HFrEF with LVEF recovery when the LVEF trajectory is unclear.
      • Wilcox J.E.
      • Fang J.C.
      • Margulies K.B.
      • et al.
      Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
      Owing to the scarcity of in-depth understanding of HFrecEF, there is still no unified definition for the cut-off value of LVEF recovery (≥40% or ≥50%), so the LVEF improvement criteria used in previous studies vary greatly (ranging from 5% to 15%).
      • Givertz M.M.
      • Mann D.L.
      Epidemiology and natural history of recovery of left ventricular function in recent onset dilated cardiomyopathies.
      Until 2020, a JACC Scientific Expert Panel, based on most of the previous studies, came up with a working definition of HFrecEF: 1) Baseline LVEF<40%; 2) Absolute improvement of LVEF≥10%; 3) LVEF >40% at the second measurement.
      • Wilcox J.E.
      • Fang J.C.
      • Margulies K.B.
      • et al.
      Heart failure with recovered left ventricular ejection fraction: JACC scientific expert panel.
      Fig 1
      FIG. 1Classification according to LVEF. HFrecEF=heart failure with recovered ejection fraction. HFpEF=heart failure with preserved ejection fraction. HFmrEF=heart failure with middle-range ejection fraction. HFrEF=heart failure with reduced ejection fraction.

      Pathophysiological mechanism of HFrecEF

      As we know, HFrecEF is defined according to LVEF, and the formula for calculating LVEF takes left ventricular end-diastolic volume as the denominator. Thus, the improvement of LVEF is directly related to the reversal of left ventricular remodeling. In recent years, with the deepening of the pathophysiological research on HF, it has been proposed that HFrecEF recovery should be considered at two levels: reversal remodeling and myocardial recovery.
      • Nijst P.
      • Martens P.
      • Mullens W.
      Heart failure with myocardial recovery - the patient whose heart failure has improved: what Next?.
      ,
      • Mann D.L.
      • Barger P.M.
      • Burkhoff D.
      Myocardial recovery and the failing heart: myth, magic, or molecular targe?.
      ,
      • Levin H.R.
      • Oz M.C.
      • Chen J.M.
      • et al.
      Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading.
      The term “reverse remodeling” refers to the spontaneous or post-drug/instrumentation therapy return of ventricular size and function. The recovery of myocardial cell structure and metabolisms, extracellular matrix, gene, and transcriptome, among other things, at the cellular and molecular levels in the process of reverse remodeling, such as the shrinkage of hypertrophy of cardiac muscle cells, recovery of gene expression related to excitation-contraction coupling, reduction of total collagen content in the extracellular matrix, an increase of myocardial micro-vessel density, and reversal of abnormal embryonic genetic proclivities.
      • Kim G.H.
      • Uriel N.
      • Burkhoff D
      Reverse remodeling and myocardial recovery in heart failure.
      Another concept, myocardial recovery, refers to a failing heart that regains both normal function and molecular composition, with long-term HF morbidity and mortality, HF biomarkers, and exercises tolerance similar to those of non-HF.
      • Kim G.H.
      • Uriel N.
      • Burkhoff D
      Reverse remodeling and myocardial recovery in heart failure.
      Many of the multi-molecules that were dysregulated during advancing ventricular remodeling are still dysregulated in the reverse remodeled heart, despite improvements in shape and function.
      • Mann D.L.
      • Barger P.M.
      • Burkhoff D.
      Myocardial recovery and the failing heart: myth, magic, or molecular targe?.
      Transcriptome analysis showed that the gene expression profile of reverse remodeling myocardium was different from that of normal myocardium, a new subset of “reverse remodeling genes” was dysregulated and only about 5% of HF-related genes returned to normal expression levels.
      • Margulies K.B.
      • Matiwala S.
      • Cornejo C.
      • et al.
      Mixed messages: transcription patterns in failing and recovering human myocardium.
      Furthermore, the reverse remodeling process of the left ventricle is usually accompanied by a series of new gene expressions associated with the extracellular matrix, sarcomere, cytoskeleton, and excitation-contraction coupling.
      • Topkara V.K.
      • Chambers K.T.
      • Yang K.C.
      • et al.
      Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodeling.
      As more of the HF inherent genetic procedures returned to normal, the heart is more able to withstand second hemodynamic stress.
      • Topkara V.K.
      • Chambers K.T.
      • Yang K.C.
      • et al.
      Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodeling.
      These results partially explain the reasons for the recurrence of left ventricular dysfunction in patients with HFrecEF at the microscopic level. Indeed, it is not clear why reverse remodeling sometimes accompanies myocardial recovery and why HFrEF still recurs in many cases. Most of the time, the normalization of certain ventricular geometry and function is only the return of HF to a relatively stable clinical state, rather than a true myocardial recovery.
      • Mann D.L.
      • Barger P.M.
      • Burkhoff D.
      Myocardial recovery and the failing heart: myth, magic, or molecular targe?.
      ,
      • Kim G.H.
      • Uriel N.
      • Burkhoff D
      Reverse remodeling and myocardial recovery in heart failure.
      ,
      • Uriel N.
      • Kim G.
      • Burkhoff D.
      Myocardial recovery after LVAD implantation: a vision or simply an illusion?.

      Epidemiology of HFrecEF

      Prevalence of HFrecEF

      Non-ischemic etiologies such as acute myocarditis, alcoholic cardiomyopathy, perinatal cardiomyopathy, tachycardiomyopathy, drug-induced cardiomyopathy, and hyperthyroidism-associated cardiomyopathies cause HF; once the underlying causes are removed, up to 40% to 50% of left ventricular structure and function can be restored spontaneously in these patients.
      • D'Ambrosio A.
      • Patti G.
      • Manzoli A.
      • et al.
      The fate of acute myocarditis between spontaneous improvement and evolution to dilated cardiomyopathy: a review.
      ,
      • Kramer D.G.
      • Trikalinos T.A.
      • Kent D.M.
      • et al.
      Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach.
      ,
      • McNamara D.M.
      • Elkayam U.
      • Alharethi R.
      • et al.
      Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC Study (investigations of pregnancy-associated cardiomyopathy).
      For the majority of patients with HF, drug therapy may account for partially or wholly of the improvement in LVEF.
      • Nijst P.
      • Martens P.
      • Mullens W.
      Heart failure with myocardial recovery - the patient whose heart failure has improved: what Next?.
      In a comprehensive review, when cardiomyopathy was caused by tachycardia, Takotsubo, and hyperthyroidism, the rate of LVEF improvement (to LVEF >50%) in these patients was as high as 60%−100%.
      • Givertz M.M.
      • Mann D.L.
      Epidemiology and natural history of recovery of left ventricular function in recent onset dilated cardiomyopathies.
      A total of 358 patients with chronic HF were enrolled in Brigham and Women's Hospital and followed up for more than 9 months. Statistically, HFrEF, HFrecEF (to LVEF>40%), and HFpEF accounted for 50.6%, 33.8%, and 15.6%, respectively; notably, 70% of HFpEF patients had a prior record of HFrEF.
      • Punnoose L.R.
      • Givertz M.M.
      • Lewis E.F.
      • et al.
      Heart failure with recovered ejection fraction: a distinct clinical entity.
      Another survey conducted at the Emory Medical Institution showed that HFrEF, HFrecEF (to LVEF>40%), and HFpEF accounted for 62.3%, 16.2%, and 21.5% of 2166 outpatients after a 3-year follow-up; If the LVEF recovery cut-off value increased to 50%, the prevalence of HFrecEF decreased to 7.1%.
      • Kalogeropoulos A.P.
      • Fonarow G.C.
      • Georgiopoulou V.
      • et al.
      Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.
      The Penn Heart Study found that only 10% of 1821 HF patients enrolled were classified as HFrecEF (to LVEF>50%), with a median improvement of 28% in LVEF at 29 months.
      • Basuray A.
      • French B.
      • Ky B.
      • et al.
      Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.
      Similarly, an analysis of 3519 patients with baseline LVEF <35% showed that only 9% of patients had an increase in LVEF above 40% during the 12-month follow-up.
      • Florea V.G.
      • Rector T.S.
      • Anand I.S.
      • et al.
      Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the Valsartan Heart Failure Trial.
      Besides, a very noteworthy group was those with HFrEF who receive cardiac resynchronization therapy (CRT). In the MADIT-CRT study, 752 patients who survived at 12 months of follow-up were analyzed. The data showed that 79% of patients had partial recovery of LVEF (from <30% to 36%−50%), while only 7.3% of patients had a complete recovery of LVEF (>50%).
      • Ruwald M.H.
      • Solomon S.D.
      • Foster E.
      • et al.
      Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial.
      Several other studies have reported that in HFrEF patients treated with CRT, the incidence of super-responders (baseline LVEF<35%, to LVEF≥50%) was between 10–26%.
      • Gasparini M.
      • Regoli F.
      • Ceriotti C.
      • et al.
      Remission of left ventricular systolic dysfunction and of heart failure symptoms after cardiac resynchronization therapy: temporal pattern and clinical predictors.
      ,
      • Reant P.
      • Zaroui A.
      • Donal E.
      • et al.
      Identification and characterization of super-responders after cardiac resynchronization therapy.
      ,
      • Tian Y.
      • Zhang P.
      • Li X.B.
      • et al.
      True complete left bundle branch block morphology strongly predicts good response to cardiac resynchronization therapy.
      To summarize the preceding literature, the key factors underlying the various percentage of HFrecEF reported were disparities in fundamental clinical features, treatment, follow-up period, and the lack of universal standards for LVEF recovery among patients.

      Characteristics associated with LVEF improvement

      Several studies have revealed some demographic and clinical characteristics linked to a higher likelihood of LVEF improvement. These variables include generally younger, females, non-ischemic etiology, fewer complications, shorter HF duration, and non-left bundle branch block (Non-LBBB) (Table 1).
      • Punnoose L.R.
      • Givertz M.M.
      • Lewis E.F.
      • et al.
      Heart failure with recovered ejection fraction: a distinct clinical entity.
      • Kalogeropoulos A.P.
      • Fonarow G.C.
      • Georgiopoulou V.
      • et al.
      Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.
      • Basuray A.
      • French B.
      • Ky B.
      • et al.
      Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.
      • Florea V.G.
      • Rector T.S.
      • Anand I.S.
      • et al.
      Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the Valsartan Heart Failure Trial.
      • Ruwald M.H.
      • Solomon S.D.
      • Foster E.
      • et al.
      Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial.
      • Gasparini M.
      • Regoli F.
      • Ceriotti C.
      • et al.
      Remission of left ventricular systolic dysfunction and of heart failure symptoms after cardiac resynchronization therapy: temporal pattern and clinical predictors.
      ,
      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      ,
      • Wilcox J.E.
      • Fonarow G.C.
      • Yancy C.W.
      • et al.
      Factors associated with improvement in ejection fraction in clinical practice among patients with heart failure: findings from improve HF.
      ,
      • Aimo A.
      • Vergaro G.
      • Castiglione V.
      • et al.
      Effect of sex on reverse remodeling in chronic systolic heart failure.
      The aforementioned factors are also related to the super-response of CRT except for non-LBBB.
      • Proclemer A.
      • Muser D.
      • Facchin D.
      What we can learn from “super-responders”.
      Interestingly, however, LBBB is a powerful predictor of LVEF improvement after CRT implantation in HFrEF patients,
      • Ruwald M.H.
      • Solomon S.D.
      • Foster E.
      • et al.
      Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial.
      ,
      • Hsu J.C.
      • Solomon S.D.
      • Bourgoun M.
      • et al.
      Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study.
      indicating that left ventricular dys-synchrony is the main cause of CRT “super responders”,
      • Proclemer A.
      • Muser D.
      • Facchin D.
      What we can learn from “super-responders”.
      while LBBB is related to the adverse improvement of LVEF in drug therapy alone.
      • Sze E.
      • Samad Z.
      • Dunning A.
      • et al.
      Impaired recovery of left ventricular function in patients with cardiomyopathy and left bundle branch block.
      Table 1Predictors of LVEF improvement among HFrEF patients.
      Predictor CategoryPredictorsReferences
      Clinical indicatorsYounger

      Non-ischemic etiology

      Female

      Shorter duration of HF

      Non-LBBB

      LBBB in CRT
      • Punnoose L.R.
      • Givertz M.M.
      • Lewis E.F.
      • et al.
      Heart failure with recovered ejection fraction: a distinct clinical entity.
      ,
      • Kalogeropoulos A.P.
      • Fonarow G.C.
      • Georgiopoulou V.
      • et al.
      Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.
      ,
      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.


      • Punnoose L.R.
      • Givertz M.M.
      • Lewis E.F.
      • et al.
      Heart failure with recovered ejection fraction: a distinct clinical entity.
      ,
      • Kalogeropoulos A.P.
      • Fonarow G.C.
      • Georgiopoulou V.
      • et al.
      Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.
      ,
      • Basuray A.
      • French B.
      • Ky B.
      • et al.
      Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.
      ,
      • Florea V.G.
      • Rector T.S.
      • Anand I.S.
      • et al.
      Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the Valsartan Heart Failure Trial.
      ,
      • Gasparini M.
      • Regoli F.
      • Ceriotti C.
      • et al.
      Remission of left ventricular systolic dysfunction and of heart failure symptoms after cardiac resynchronization therapy: temporal pattern and clinical predictors.
      ,
      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      • Wilcox J.E.
      • Fonarow G.C.
      • Yancy C.W.
      • et al.
      Factors associated with improvement in ejection fraction in clinical practice among patients with heart failure: findings from improve HF.
      • Aimo A.
      • Vergaro G.
      • Castiglione V.
      • et al.
      Effect of sex on reverse remodeling in chronic systolic heart failure.
      ,
      • Hsu J.C.
      • Solomon S.D.
      • Bourgoun M.
      • et al.
      Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study.
      ,
      • Lupón J.
      • Gaggin H.K.
      • de Antonio M.
      • et al.
      Biomarker-assist score for reverse remodeling prediction in heart failure: the ST2-R2 score.


      • Ruwald M.H.
      • Solomon S.D.
      • Foster E.
      • et al.
      Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial.
      ,
      • Gasparini M.
      • Regoli F.
      • Ceriotti C.
      • et al.
      Remission of left ventricular systolic dysfunction and of heart failure symptoms after cardiac resynchronization therapy: temporal pattern and clinical predictors.
      ,
      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      • Wilcox J.E.
      • Fonarow G.C.
      • Yancy C.W.
      • et al.
      Factors associated with improvement in ejection fraction in clinical practice among patients with heart failure: findings from improve HF.
      • Aimo A.
      • Vergaro G.
      • Castiglione V.
      • et al.
      Effect of sex on reverse remodeling in chronic systolic heart failure.
      ,
      • Hsu J.C.
      • Solomon S.D.
      • Bourgoun M.
      • et al.
      Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study.


      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      ,
      • Aimo A.
      • Vergaro G.
      • Castiglione V.
      • et al.
      Effect of sex on reverse remodeling in chronic systolic heart failure.
      ,
      • Lupón J.
      • Gaggin H.K.
      • de Antonio M.
      • et al.
      Biomarker-assist score for reverse remodeling prediction in heart failure: the ST2-R2 score.


      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      ,
      • Lupón J.
      • Gaggin H.K.
      • de Antonio M.
      • et al.
      Biomarker-assist score for reverse remodeling prediction in heart failure: the ST2-R2 score.


      • Ruwald M.H.
      • Solomon S.D.
      • Foster E.
      • et al.
      Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial.
      ,
      • Hsu J.C.
      • Solomon S.D.
      • Bourgoun M.
      • et al.
      Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy) study.
      Genetic factorsPathogenetic gene variants does not involve ACE, β1- adrenergic receptor, sarcomere proteins or cytoskeletal proteins / Z-disk proteins
      • Rigolli M.
      • Cicoira M.
      • Bergamini C.
      • et al.
      Progression of left ventricular dysfunction and remodelling under optimal medical therapy in CHF Patients: role of individual genetic background.


      • Jansweijer J.A.
      • Nieuwhof K.
      • Russo F.
      • et al.
      Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy.


      • Dal-Ferro M.
      • Stolfo D.
      • Altinier A.
      • et al.
      Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy.
      Echocardiography/CMRLower LVEF

      Greater contractility in strain imaging

      Absence of LGE
      • Punnoose L.R.
      • Givertz M.M.
      • Lewis E.F.
      • et al.
      Heart failure with recovered ejection fraction: a distinct clinical entity.
      ,
      • Lupón J.
      • Gaggin H.K.
      • de Antonio M.
      • et al.
      Biomarker-assist score for reverse remodeling prediction in heart failure: the ST2-R2 score.
      ,
      • Masci P.G.
      • Schuurman R.
      • Andrea B.
      • et al.
      Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study.


      • Reant P.
      • Zaroui A.
      • Donal E.
      • et al.
      Identification and characterization of super-responders after cardiac resynchronization therapy.
      ,
      • Park S.M.
      • Kim Y.H.
      • Ahn C.
      • et al.
      Relationship between ultrasonic tissue characterization and myocardial deformation for prediction of left ventricular reverse remodelling in non-ischaemic dilated cardiomyopathy.


      • Barison A.
      • Grigoratos C.
      • Todiere G.
      • et al.
      Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance.
      • Ishii S.
      • Inomata T.
      • Fujita T.
      • et al.
      Clinical significance of endomyocardial biopsy in conjunction with cardiac magnetic resonance imaging to predict left ventricular reverse remodeling in idiopathic dilated cardiomyopathy.
      • Chimura M.
      • Onishi T.
      • Tsukishiro Y.
      • et al.
      Longitudinal strain combined with delayed-enhancement magnetic resonance improves risk stratification in patients with dilated cardiomyopathy.
      • Barison A.
      • Aimo A.
      • Ortalda A.
      • et al.
      Late gadolinium enhancement as a predictor of functional recovery, need for defibrillator implantation and prognosis in non-ischemic dilated cardiomyopathy.
      • Masci P.G.
      • Schuurman R.
      • Andrea B.
      • et al.
      Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study.
      • Kida K.
      • Yoneyama K.
      • Kobayashi Y.
      • et al.
      Late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol.
      BiomarkersLower NT-proBNP

      Lower troponin

      Lower sST2

      Lower Galectin-3

      Mimecan

      MicroRNAs

      Orexin A
      • Basuray A.
      • French B.
      • Ky B.
      • et al.
      Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.
      ,
      • Florea V.G.
      • Rector T.S.
      • Anand I.S.
      • et al.
      Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the Valsartan Heart Failure Trial.
      ,
      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      ,
      • Daubert M.A.
      • Adams K.
      • Yow E.
      • et al.
      NT-proBNP Goal achievement is associated with significant reverse remodeling and improved clinical outcomes in HFrEF.
      • Bhardwaj A.
      • Rehman S.U.
      • Mohammed A.
      • et al.
      Design and methods of the Pro-B type natriuretic peptide outpatient tailored chronic heart failure therapy (PROTECT) study.
      • Fruhwald F.M.
      • Fahrleitner-Pammer A.
      • Berger R.
      • et al.
      Early and sustained effects of cardiac resynchronization therapy on N-terminal pro-B-type natriuretic peptide in patients with moderate to severe heart failure and cardiac dyssynchrony.


      • Basuray A.
      • French B.
      • Ky B.
      • et al.
      Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.
      ,
      • Florea V.G.
      • Rector T.S.
      • Anand I.S.
      • et al.
      Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the Valsartan Heart Failure Trial.
      ,
      • Motiwala S.R.
      • Gaggin H.K.
      • Gandhi P.U.
      • et al.
      Concentrations of highly sensitive cardiactroponin-I predict poor cardiovascular outcomes and adverse remodeling in chronic heart failure.
      ,
      • Gaggin H.K.
      • Szymonifka J.
      • Bhardwaj A.
      • et al.
      Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.


      • Florea V.G.
      • Rector T.S.
      • Anand I.S.
      • et al.
      Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the Valsartan Heart Failure Trial.
      ,
      • Lupón J.
      • Sanders-van W.S.
      • Januzzi J.L.
      • et al.
      Prediction of survival and magnitude of reverse remodeling using the ST2-R2 score in heart failure: a multicenter study.
      ,
      • Lupón J.
      • Gaggin H.K.
      • de Antonio M.
      • et al.
      Biomarker-assist score for reverse remodeling prediction in heart failure: the ST2-R2 score.
      ,
      • Gaggin H.K.
      • Szymonifka J.
      • Bhardwaj A.
      • et al.
      Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.


      • Karatolios K.
      • Chatzis G.
      • Holzendorf V.
      • et al.
      Galectin-3 as a predictor of left ventricular reverse remodeling in recent-onset dilated cardiomyopathy.
      ,
      • Florea V.G.
      • Rector T.S.
      • Anand I.S.
      • et al.
      Heart failure with improved ejection fraction: clinical characteristics, correlates of recovery, and survival: results from the Valsartan Heart Failure Trial.


      • Shah R.
      • Ziegler O.
      • Yeri A.
      • et al.
      MicroRNAs associated with reverse left ventricular remodeling in humans identify pathways of heart failure progression.


      • Motiwala S.R.
      • Szymonifka J.
      • Belcher A.
      • et al.
      Measurement of novel biomarkers to predict chronic heart failure outcomes and left ventricular remodeling.


      • Ibrahim N.E.
      • Rabideau D.J.
      • Gaggin H.K.
      • et al.
      Circulating concentrations of orexin A predict left ventricular myocardial remodeling.
      Abbreviations: LVEF =left ventricular ejection fraction; HFrEF = heart failure with reduced ejection fraction;HF = heart failure; LBBB= left bundle branch block; CRT =cardiac resynchronization therapy; LGE = late gadolinium enhancement; ACE=angiotensin-converting enzyme; CMR =cardiac magnetic resonance; NT-proBNP= N-terminal pro-B-type natriuretic peptide; sST2 =soluble suppression of tumorigenicity- 2.
      In recent years, circulating biomarkers have also played an important role in predicting LVEF recovery or ventricular remodeling reversal. N-terminal pre-B-type natriuretic peptide (NT-proBNP), as a classic biomarker in the field of HF, was confirmed in a recent study that the decrease in its concentration is proportional to the decrease in left ventricular volume and the improvement in LVEF.
      • Daubert M.A.
      • Adams K.
      • Yow E.
      • et al.
      NT-proBNP Goal achievement is associated with significant reverse remodeling and improved clinical outcomes in HFrEF.
      Other previous studies had also demonstrated that lower levels of NT-proBNP were parallel to left ventricular reverse remodeling and LVEF improvement, including in individuals with drug or CRT intervention.
      • Bhardwaj A.
      • Rehman S.U.
      • Mohammed A.
      • et al.
      Design and methods of the Pro-B type natriuretic peptide outpatient tailored chronic heart failure therapy (PROTECT) study.
      ,
      • Fruhwald F.M.
      • Fahrleitner-Pammer A.
      • Berger R.
      • et al.
      Early and sustained effects of cardiac resynchronization therapy on N-terminal pro-B-type natriuretic peptide in patients with moderate to severe heart failure and cardiac dyssynchrony.
      Soluble suppression of tumorigenesis-2 (sST2), another promising biomarker for HF, has been confirmed that its concentration is related to reverse remodeling.
      • Lupón J.
      • Sanders-van W.S.
      • Januzzi J.L.
      • et al.
      Prediction of survival and magnitude of reverse remodeling using the ST2-R2 score in heart failure: a multicenter study.
      ,
      • Lupón J.
      • Gaggin H.K.
      • de Antonio M.
      • et al.
      Biomarker-assist score for reverse remodeling prediction in heart failure: the ST2-R2 score.
      Alongside sST2, a lower concentration of high-sensitivity troponin T or I is also an effective tool for predicting cardiac reverse remodeling.
      • Motiwala S.R.
      • Gaggin H.K.
      • Gandhi P.U.
      • et al.
      Concentrations of highly sensitive cardiactroponin-I predict poor cardiovascular outcomes and adverse remodeling in chronic heart failure.
      ,
      • Gaggin H.K.
      • Szymonifka J.
      • Bhardwaj A.
      • et al.
      Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.
      Other biomarkers that may be linked to reverse remodeling include Galectin-3,
      • Karatolios K.
      • Chatzis G.
      • Holzendorf V.
      • et al.
      Galectin-3 as a predictor of left ventricular reverse remodeling in recent-onset dilated cardiomyopathy.
      several MicroRNAs,
      • Shah R.
      • Ziegler O.
      • Yeri A.
      • et al.
      MicroRNAs associated with reverse left ventricular remodeling in humans identify pathways of heart failure progression.
      mimecan,
      • Motiwala S.R.
      • Szymonifka J.
      • Belcher A.
      • et al.
      Measurement of novel biomarkers to predict chronic heart failure outcomes and left ventricular remodeling.
      Orexin A (ligand of hypocretin receptor),
      • Ibrahim N.E.
      • Rabideau D.J.
      • Gaggin H.K.
      • et al.
      Circulating concentrations of orexin A predict left ventricular myocardial remodeling.
      which require further research in the future. Furthermore, as we learn more about the genes and genetic variables linked to cardiomyopathy, we're learning that left ventricular reverse remodeling is less common in dilated cardiomyopathy caused by genetic or familial factors than in those caused by non-genetic or non-familial reasons.  (25% vs. 40%, p = 0.04).
      • Hazebroek M.R.
      • Moors S.
      • Dennert R.
      • et al.
      Prognostic relevance of gene-environment interactions in patients with dilated cardiomyopathy: applying the MOGE(S) classification.
      ,
      • Verdonschot J.A.J.
      • Hazebroek M.R.
      • Wang P.
      • et al.
      Clinical phenotype and genotype associations with improvement in left ventricular function in dilated cardiomyopathy.
      Angiotensin-converting enzyme, β1-adrenergic receptor,
      • Rigolli M.
      • Cicoira M.
      • Bergamini C.
      • et al.
      Progression of left ventricular dysfunction and remodelling under optimal medical therapy in CHF Patients: role of individual genetic background.
      and sarcomere or structural cytoskeleton Z-disk gene mutation are associated with poor LVEF recovery response to drug therapy.
      • Jansweijer J.A.
      • Nieuwhof K.
      • Russo F.
      • et al.
      Truncating titin mutations are associated with a mild and treatable form of dilated cardiomyopathy.
      ,
      • Dal-Ferro M.
      • Stolfo D.
      • Altinier A.
      • et al.
      Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy.
      In addition, with the development of medical imaging technology, ultrasound and magnetic resonance imaging (MRI) have played a pivotal role in evaluating cardiac structure and function. Because strain imaging is essentially unaffected by left ventricular volume and morphology, it is more sensitive than LVEF in detecting systolic insufficiency and detects fewer abnormalities in assessing contraction deformation, making it a better predictor of remodeling reversal.
      • Park S.M.
      • Kim Y.H.
      • Ahn C.
      • et al.
      Relationship between ultrasonic tissue characterization and myocardial deformation for prediction of left ventricular reverse remodelling in non-ischaemic dilated cardiomyopathy.
      Cardiac MRI is progressively becoming more widely used in clinical practice, thanks to improvements in contrast resolution and reliability. It can provide information that echocardiography cannot, such as the extent of cardiac fibrosis with late gadolinium enhancement (LGE).
      • Barison A.
      • Grigoratos C.
      • Todiere G.
      • et al.
      Myocardial interstitial remodelling in non-ischaemic dilated cardiomyopathy: insights from cardiovascular magnetic resonance.
      Several studies had revealed that absence of LGE was an effective indicator for predicting left ventricular reverse remodeling, confirming that the degree of myocardial fibrosis was inversely proportional to reverse remodeling.
      • Ishii S.
      • Inomata T.
      • Fujita T.
      • et al.
      Clinical significance of endomyocardial biopsy in conjunction with cardiac magnetic resonance imaging to predict left ventricular reverse remodeling in idiopathic dilated cardiomyopathy.
      ,
      • Chimura M.
      • Onishi T.
      • Tsukishiro Y.
      • et al.
      Longitudinal strain combined with delayed-enhancement magnetic resonance improves risk stratification in patients with dilated cardiomyopathy.
      ,
      • Barison A.
      • Aimo A.
      • Ortalda A.
      • et al.
      Late gadolinium enhancement as a predictor of functional recovery, need for defibrillator implantation and prognosis in non-ischemic dilated cardiomyopathy.
      Regardless of the degree of left ventricular remodeling or LVEF level, the absence of LGE has high specificity and positive predictive value for predicting reverse remodeling and LVEF recovery.
      • Masci P.G.
      • Schuurman R.
      • Andrea B.
      • et al.
      Myocardial fibrosis as a key determinant of left ventricular remodeling in idiopathic dilated cardiomyopathy: a contrast-enhanced cardiovascular magnetic study.
      ,
      • Kida K.
      • Yoneyama K.
      • Kobayashi Y.
      • et al.
      Late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol.

      Prognosis of HFrecEF

      The improvement of LVEF is significantly associated with reductions in mortality and hospitalization rates.
      • Kalogeropoulos A.P.
      • Fonarow G.C.
      • Georgiopoulou V.
      • et al.
      Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.
      ,
      • Konstam M.A.
      Reliability of ventricular remodeling as a surrogate for use in conjunction with clinical outcomes in heart failure.
      It has even been reported that LVEF was the strongest predictor of survival regardless of recovery level and remained significant after adjustment for treatment or other confounding factors,
      • Cintron G.
      • Johnson G.
      • Francis G.
      • et al.
      Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. The V-HeFT VA Cooperative Studies Group.
      indicating that any substantial improvement in LVEF is associated with survival benefits. Some cohort studies had shown the 5-year survival rate was as high as 80%−90% for HFrecEF patients, compared with 65%−75% for HFrEF patients.
      • Lupón J.
      • Díez-López C.
      • de Antonio M.
      • et al.
      Recovered heart failure with reduced ejection fraction and outcomes: a prospective study.
      ,
      • de Groote P.
      • Fertin M.
      • Duva Pentiah A.
      • et al.
      Long-term functional and clinical follow-up of patients with heart failure with recovered left ventricular ejection fraction after β-blocker therapy.
      According to the median 3-year follow-up data of Emory Medical in the United States, the age-and gender-adjusted mortality of HFrecEF patients was 4.8%, which was lower than HFrEF (16.3%) and HFpEF (13.2%); Further analysis showed that the composite endpoint was also significantly lower than HFrEF and HFpEF.
      • Kalogeropoulos A.P.
      • Fonarow G.C.
      • Georgiopoulou V.
      • et al.
      Characteristics and outcomes of adult outpatients with heart failure and improved or recovered ejection fraction.
      What's more, a study on the prognosis of HF patients based on different LVEF trajectories and levels as classified phenotypes revealed HFrEF recovered to middle-range LVEF (HFm-recEF, LVEF:40%−55% and previous LVEF <40%) had a lower risk of composite events than those of HFrEF (HR 0.25; 95%, CI 0.13–0.47) and HFmrEF without recovered ejection fraction (LVEF: consistent between 40% and 55%. HR 0.31; 95% CI 0.15–0.67), and similar to the prognosis of HFpEF.
      • Nadruz W.
      • West E.
      • Santos M.
      • et al.
      Heart failure and midrange ejection fraction: implications of recovered ejection fraction for exercise tolerance and outcomes.
      Despite the relatively good survival rate of HFrecEF, however, the overall survival rate is still worse than that of health controls,
      • de Groote P.
      • Fertin M.
      • Duva Pentiah A.
      • et al.
      Long-term functional and clinical follow-up of patients with heart failure with recovered left ventricular ejection fraction after β-blocker therapy.
      and a considerable proportion of HFrecEF patients will relapse left ventricular dysfunction or progress to HFrEF again.
      • de Groote P.
      • Fertin M.
      • Duva Pentiah A.
      • et al.
      Long-term functional and clinical follow-up of patients with heart failure with recovered left ventricular ejection fraction after β-blocker therapy.
      • Nadruz W.
      • West E.
      • Santos M.
      • et al.
      Heart failure and midrange ejection fraction: implications of recovered ejection fraction for exercise tolerance and outcomes.
      • Park J.S.
      • Kim J.W.
      • Seo K.W.
      • et al.
      Recurrence of left ventricular dysfunction in patients with restored idiopathic dilated cardiomyopathy.
      • Gupta A.
      • Goyal P.
      • Bahl A.
      Frequency of recovery and relapse in patients with nonischemic dilated cardiomyopathy on guideline-directed medical therapy.
      • Zhang J.
      • Zou C.H.
      • Huang Y.
      • et al.
      Recovery and relapse of left ventricular systolic dysfunction in hospitalized patients with dilated cardiomyopathy: frequency and related factors.
      • Nishimura S.
      • Izumi C.
      • Himura Y.
      • et al.
      Very long-term follow-up data of non-ischemic idiopathic dilated cardiomyopathy after beta-blocker therapy: recurrence of left ventricular dysfunction and predictive value of I-metaiodobenzylguanidine scintigraphy.
      It is unclear why HFrecEF patients with similar left ventricular structure and functional recovery have various clinical presentations during follow-up, and some patients still have recurrent HFrEF, from a biological standpoint.
      • Nijst P.
      • Martens P.
      • Mullens W.
      Heart failure with myocardial recovery - the patient whose heart failure has improved: what Next?.
      One probable explanation is that this adaptation lacks biological and contractile reserves, making it more prone to trigger left ventricular dysfunction when hemodynamics, neurohumoral hormones, or environmental stress alter.
      • Lupón J.
      • Gavidia-Bovadilla G.
      • Ferrer E.
      • et al.
      Dynamic trajectories of left ventricular ejection fraction in heart failure.
      ,
      • Amorim S.
      • Rodrigues J.
      • Campelo M.
      • et al.
      Left ventricular reverse remodeling in dilated cardiomyopathy- maintained subclinical myocardial systolic and diastolic dysfunction.
      In conclusion, it is still difficult to accurately predict which HFrecEF is at high risk, and some existing risk factors are of limited use in predicting the likelihood of HFrEF recurrence (Table 2).
      Table 2HFrEF recurrence among HFrecEF patients.
      Author (References)Publication YearSample Size (n)Average Follow-up (Months)HFrEF Recurrence (%)Predictors of HFrEF Recurrence
      Moon et al.
      • Moon J.
      • Ko Y.G.
      • Chung N.
      • et al.
      Recovery and recurrence of left ventricular systolic dysfunction in patients with idiopathic dilated cardiomyopathy.
      2009424819Cessation of therapy
      Park et al.
      • Park J.S.
      • Kim J.W.
      • Seo K.W.
      • et al.
      Recurrence of left ventricular dysfunction in patients with restored idiopathic dilated cardiomyopathy.
      2014855039Older, larger LVEDD,diabetes longer duration before LVEF improved
      DeGroote et al.
      • de Groote P.
      • Fertin M.
      • Duva Pentiah A.
      • et al.
      Long-term functional and clinical follow-up of patients with heart failure with recovered left ventricular ejection fraction after β-blocker therapy.
      20141749226Lower LVEF, larger LVEDD, LBBB,lower heart rate
      Ankur et al.
      • Gupta A.
      • Goyal P.
      • Bahl A.
      Frequency of recovery and relapse in patients with nonischemic dilated cardiomyopathy on guideline-directed medical therapy.
      2014783636Long QRS duration
      Jian et al.
      • Zhang J.
      • Zou C.H.
      • Huang Y.
      • et al.
      Recovery and relapse of left ventricular systolic dysfunction in hospitalized patients with dilated cardiomyopathy: frequency and related factors.
      2015882419Less decrease in LVEDD at initial recovery
      Nadruz et al.
      • Nadruz W.
      • West E.
      • Santos M.
      • et al.
      Heart failure and midrange ejection fraction: implications of recovered ejection fraction for exercise tolerance and outcomes.
      20161233216Older, hypertension, lower GFR
      Nishimura et al.
      • Nishimura S.
      • Izumi C.
      • Himura Y.
      • et al.
      Very long-term follow-up data of non-ischemic idiopathic dilated cardiomyopathy after beta-blocker therapy: recurrence of left ventricular dysfunction and predictive value of I-metaiodobenzylguanidine scintigraphy.
      20194713823Longer time to initial LVEF recovery, higher mean pulmonary arterial pressure at baseline, higher mean papillary wedge pressure at baseline
      Abbreviations: HFrecEF=heart failure with recovered ejection fraction; LVEDD= Left ventricular end diastolic diameter; GFR= glomerular filtration rate; other abbreviations as in Table 1.

      Management of HFrecEF

      Medical treatment

      There are currently no authorized guidelines to guide treatment strategy for HFrecEF due to the scarcity of evidence-based medicine data. As discussed earlier, even if effective in reversing remodeling and restoring LVEF, these improvements usually represent cardiac “remission” rather than a complete cure of HF. It is currently believed that patients with HFrecEF may have sustained neurohormonal activation and still be at risk of HFrEF recurrence and adverse cardiovascular events,
      • Basuray A.
      • French B.
      • Ky B.
      • et al.
      Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes.
      ,
      • Hopper I.
      • Samuel R.
      • Hayward C.
      • et al.
      Can medications be safely withdrawn in patients with stable chronic heart failure? systematic review and meta-analysis.
      suggesting that sustained neurohormonal blockade is generally beneficial in patients with HFrecEF. Korean scholars analyzed 42 patients with idiopathic dilated cardiomyopathy with LVEF recovery (to LVEF ≥40%, absolute value increase ≥10%), and found that 19% of patients LVEF dropped below 40% again, and more patients in the recurrence group discontinued anti-HF medication (62.5% vs 5.9%).
      • Moon J.
      • Ko Y.G.
      • Chung N.
      • et al.
      Recovery and recurrence of left ventricular systolic dysfunction in patients with idiopathic dilated cardiomyopathy.
      The result of asymptomatic HFrecEF patients with gradual withdrawal of HF medication was studied in an open-label, randomized pilot trial.
      • Halliday B.P.
      • Wassall R.
      • Lota A.S.
      • et al.
      Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.
      51 enrolled patients were randomly divided into the therapy withdrawal group (n = 25) and therapy continue group (n = 26). During the first 6 months, HFrEF recurred in 11 patients (44%) in the withdrawal group and none in the continuing group. In the next 6 months, the original therapy continue group also discontinued HF medications, and 9 patients (36%) had HFrEF recurrence; No deaths were reported in either group. Notably, in the above literature, recurrence of HF occurred in a few months rather than a few days or weeks after discontinuation of guideline-directed medical therapy. That is, if patients stop taking neurohormone antagonists for disease or other clinical reasons, they are less likely to experience a recurrence of HFrEF in the short term. Besides neuro-antagonists, diuretics are the most commonly used drugs for HF. It has been reported that the incidence of recurrent HFrEF was low in HFrecEF patients who can tolerate discontinuation of diuretics.
      • Wilcox J.
      • Yancy C.W.
      Stopping medication for heart failure with improved ejection fraction.
      Therefore, the latest consensus on HFrecEF management encourages the withdrawal of diuretics.
      • Lupón J.
      • Gavidia-Bovadilla G.
      • Ferrer E.
      • et al.
      Dynamic trajectories of left ventricular ejection fraction in heart failure.

      Device therapy

      Discontinuation of CRT in individuals with LVEF improvement or even normalization is contraindicated. In an observational study on the effect of biventricular pacing on left ventricular reverse remodeling, 25 individuals with NYHA class III-IV were included in this study. After 3 months of implantation, the mean LVEF increased from 27.9 ± 10.2 at baseline to 40.0 ± 14.7% (P < 0.05). LVEF, on the other hand, declined with time following CRT termination (33.1 ± 13.9% after 1 week, 29.8 ± 11.6 after 4 weeks, P < 0.05), and the size of the left ventricle increased.
      • Yu C.M.
      • Chau E.
      • Sanderson J.E.
      • et al.
      Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure.
      As a consensus, CRT should generally be maintained since left and right ventricular systolic incoordination is a major factor in LVEF decline.
      Additionally, limited data are available to guide the significance of the ongoing use of implantable cardioverter-defibrillator (ICD) in HFrecEF. One study showed the appropriate ICD shock incidence was the same between patients with LVEF improvement or not.
      • Naksuk N.
      • Saab A.
      • Li J.M.
      • et al.
      Incidence of appropriate shock in implantable cardioverter-defibrillator patients with improved ejection fraction.
      In a subsequent study, researchers found a similar mortality benefit from ICD in individuals whose LVEF improved by more than 35% compared with individuals whose LVEF remained below 35%.
      • Adabag S.
      • Patton K.K.
      • Buxton A.E.
      • 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.
      Recently, the PROSE-ICD research prospectively observed 538 subjects who received ICD placement for primary prevention. During a 4.9-year follow-up, LVEF improved by more than 35% in 126 subjects, of which only 4 received appropriate ICD shocks.
      • Zhang Y.Y.
      • Guallar E.
      • Blasco-Colmenares E.
      • et al.
      Changes in Follow-up left ventricular ejection fraction associated with outcomes in primary prevention implantable cardioverter-defibrillator and cardiac resynchronization therapy device recipients.
      Other studies, focusing on patients who no longer met ICD indications during generator exchange, found that patients without ongoing ICD implantation indications received less appropriate ICD shocks than patients with indications, but again, patients with myocardial recovery from HF were still observed receiving appropriate ICD shocks.
      • Zhang Y.Y.
      • Guallar E.
      • Blasco-Colmenares E.
      • et al.
      Changes in Follow-up left ventricular ejection fraction associated with outcomes in primary prevention implantable cardioverter-defibrillator and cardiac resynchronization therapy device recipients.
      ,
      • Kini V.
      • Soufi M.K.
      • Deo R.
      • et al.
      Appropriateness of primary prevention implantable cardioverter-defibrillators at the time of generator replacement: are indications still met?.
      There seems to be a correlation between fluctuations in LVEF and changes in risk. The MADIT-CRT trial revealed that among HF patients with ICD implantation, those with LVEF >50% had the lowest rate of appropriate ICD therapies, followed by those with LVEF 36%−50%.
      • Ruwald M.H.
      • Solomon S.D.
      • Foster E.
      • et al.
      Left ventricular ejection fraction normalization in cardiac resynchronization therapy and risk of ventricular arrhythmias and clinical outcomes: results from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial.
      Only one ventricular arrhythmia incident occurred among the 55 individuals whose LVEF improved >50%. Therefore, the researchers of MADIT-CRT suggested that if ventricular arrhythmias are not detected during the device's lifetime, these patients may consider being downgraded from CRT-D to CRT pacemaker when the battery runs out. However, although the incidence of life-threatening ventricular arrhythmia in patients with improved LVEF is lower than in patients who continue to meet the ICD indications, this risk is unavoidable. Current academic opinions support the replacement of ICD generators in most HFrecEF patients, especially if there is evidence of deleterious genes associated with a high risk of arrhythmia mutations, a history of appropriate electrical shocks, or abnormalities maintained in electrocardiograms.
      • Thomas I.C.
      • Wang Y.
      • See V.Y.
      • et al.
      Outcomes following implantable cardioverter-defibrillator generator replacement in patients with recovered left ventricular systolic function: the National Cardiovascular Data Registry.
      ,
      • Hershberger R.E.
      • Givertz M.M.
      • Ho C.Y.
      • et al.
      Genetic evaluation of cardiomyopathy-a heart failure Society of America Practice Guideline.

      Conclusions

      HFrecEF, as a newly recognized and focused group of unique HF phenotypes, still has many unresolved problems. Although a significant proportion of systolic dysfunction is improved and LVEF is close to normal or completely normal after treatment with existing medications and devices, the underlying biological abnormalities of the myocardium are not completely recovered. Such patients usually retain signs of neurohormonal activation and the possibility of detectable cardiac function and biomarker abnormalities. Importantly, they are still at risk of cardiac function deteriorating again.
      In the past 2 decades, research on HFrecEF was mainly derived from retrospective data analysis and used different LVEF cut points, resulting in limited data credibility. Before the emergence of high-quality evidence, continued use of neuroendocrine antagonists and implantable devices appears to be a prudent approach for HFrecEF patients, except for the aforementioned special causes that may not require long-term intervention.
      Classification of HF based solely on LVEF has some limitations, such as cardiac valve condition, preload and afterload, blood pressure, heart rate, etc., which may affect the value of LVEF. Moreover, the prognosis of HF varies with different disease spectrums, and the underlying pathological factors cannot be included in the classification of HF based on ejection fraction alone. Future research may need to establish an initial cohort of subjects with various etiologies in order to better understand the natural properties of HFrecEF, investigate the pathophysiological characteristics of the myocardium during recovery using molecular biology techniques, and investigate the mechanism of abnormal transcription or expression of HF-related genes using genomics and proteomics methods. Eventually, a reliable understanding of HFrecEF can be achieved from the macro and micro levels, to formulate reasonable clinical management guidelines, develop new drugs for effective targets, and apply genetic intervention methods to achieve precision treatment.

      Declaration of Competing Interest

      The authors have declared that no competing interests exist.

      Funding

      The authors received no specific funding for this work.

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