Review Article

Reverse Remodelling, Myocardial Recovery and Remission in Heart Failure with Reduced Ejection Fraction: Clinical Implications and Management Strategies

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Abstract

Cardiac reverse remodelling (RR) is a complex process involving structural and functional recovery of the myocardium, with significant implications for the prognosis of patients with heart failure (HF). This review summarises current concepts, underlying mechanisms, therapeutic strategies, and clinical implications of RR, while distinguishing it from myocardial recovery and remission. Both pharmacological therapies and non-pharmacological interventions have shown potential to induce RR in selected populations. Clinical features, echocardiographic parameters, advanced imaging findings, and biomarkers help stratify patients according to the likelihood of recovery and risk of relapse. The management of HF with improved ejection fraction remains debated. High recurrence rates are seen after therapy discontinuation; however, evidence suggests that partial withdrawal may be safe in specific patient profiles. RR should be considered a central therapeutic goal in HF care, although its extent and stability vary widely. Differentiating between transient improvement, remission under therapy, and true myocardial recovery is critical for guiding long-term treatment decisions, highlighting the importance of individualised follow-up.

Keywords

Reverse remodelling, myocardial recovery, heart failure, improved ejection fraction, pharmacological therapy, prognosis.,

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Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.41

Disclosure: SRF has received travel support from Pfizer. MTSSL has received speaker honoraria from AstraZeneca. EAB has received consulting fees from Servier, AstraZeneca and Boehringer Ingelheim; subsidised travel/registration fees/hotel fees from Servier; membership in steering committees from Servier, Novartis and Boehringer Ingelheim; research grant support through Heart Institute from Jansen, Bayer/Merck, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Cardiol Therapeutics and Eurofarma; and honoraria form Servier, Novartis, Astra-Zeneca and Boehringer Ingelheim. SMAF has received honoraria from Abbott, Novartis and CSL Vifor. All other authors have no conflicts of interest to declare.

Correspondence: Silas Ramos Furquim, Heart Failure Department, Instituto do Coração, R. Dr Eneas de Carvalho Aguiar 44, São Paulo 05403-900, Brazil. E: silas.furquim@hc.fm.usp.br

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Over the past three decades, heart failure (HF) management has advanced significantly, transforming the prognosis of a condition once regarded as inevitably progressive. This therapeutic evolution has led to substantial improvements in both quality of life and patient survival, often evidenced by structural recovery assessed via objective parameters such as left ventricular ejection fraction (LVEF); this structural recovery is known as reverse remodelling (RR).1

RR has become an increasingly recognised and desirable outcome in clinical practice. Patients with left ventricular (LV) RR have 5-year survival rates between 80% and 90%, compared with the 65–75% in those with persisting reduced LVEF.2–5 Moreover, RR is independently associated with lower rates of mortality, HF-related hospitalisations and heart transplantation, even after adjustment for baseline LVEF, duration of HF, functional class and β-blocker therapy.6–8

Recognising the clinical and prognostic relevance of this subgroup, recent guidelines have introduced the classification ‘HF with improved ejection fraction’ (HFimpEF) to describe individuals who, following an initial diagnosis of HF with reduced ejection fraction (HFrEF), demonstrate significant improvement in LVEF.9,10 However, the clinical management of the HFimpEF phenotype remains surrounded by uncertainty: some patients remain at risk of recurrent deterioration, while others appear to achieve sustained recovery.11

For this reason, the literature has proposed terms such as ‘myocardial remission’, to describe functional improvement that may be transient and dependent on continued therapy, and ‘myocardial recovery’ to denote cases in which functional normalisation is more complete and potentially independent of ongoing treatment, particularly when the primary causal factor has been eliminated.6,12,13 Scientific literature addressing the long-term evolution and optimal therapeutic strategies for these patients remains relatively scarce, although it is steadily expanding.

The aim of this review is to comprehensively present and discuss the concepts of RR, HFimpEF, myocardial recovery and myocardial remission. It will address the underlying pathophysiological mechanisms, clinical and prognostic implications, predictors of RR occurrence and sustainability, associated therapies, current knowledge gaps, and the current recommended clinical management approach.

Methods

We conducted a comprehensive narrative review of the literature on cardiac reverse remodelling in HFrEF. A systematic search was performed in the PubMed, Embase and Cochrane databases from January 2010 to July 2025, using the following search terms: ‘reverse remodelling’, ‘heart failure’, ‘improved ejection fraction’, ‘myocardial recovery’ and ‘remission’. We included original research articles, systematic reviews, meta-analyses, clinical trials and consensus statements published in English. Priority was given to recent publications (2020–2025), landmark studies, and guidelines from major cardiovascular societies. Additional references were identified through manual review of bibliographies from selected articles. We excluded case reports, editorials and studies focusing exclusively on paediatric populations. This review synthesises the current evidence on definitions, epidemiology, pathophysiology, therapeutic strategies and clinical management of RR, with an emphasis on practical clinical applications and recent therapeutic advances.

Definition and Classification

RR refers to the process by which a previously dilated and dysfunctional left ventricle undergoes normalisation, or substantial improvement, in its geometry and contractile function. This recovery may occur spontaneously in certain aetiologies, but more commonly results from effective therapeutic interventions, often leading to improvement in HF symptoms.14

Despite the growing clinical relevance of this phenomenon, major international guidelines have yet to reach consensus on its definition and classification criteria.15–17 An attempt at standardisation was proposed in 2021 through a consensus statement developed by the American, European and Japanese Heart Failure Societies.18 That document recommended the classification of HFimpEF for patients with documented baseline LVEF ≤40%, who subsequently demonstrate an absolute increase in LVEF of at least 10%, resulting in a follow-up LVEF >40%.19 Similarly, an expert panel from the Journal of the American College of Cardiology proposed a comparable definition: baseline LVEF <40%, an absolute increase of ≥10%, and a subsequent LVEF >40%. Furthermore, that document differentiated between complete LVEF normalisation, defined as LVEF >50%, and partial normalisation when LVEF is between 40% and 50%.6

In contrast, neither the 2022 American College of Cardiology/American Heart Association (ACC/AHA) guidelines nor the 2021 European Society of Cardiology (ESC) guidelines adopted these prior definitions. The ACC/AHA guidelines define improved LVEF simply as a baseline value ≤40% and a follow-up value >40%, whereas the ESC considers HFimpEF when baseline LVEF ≤40% subsequently improves to ≥50%.15 Neither guideline specifies a minimum time interval required before reassessing LVEF.15,16 Supplementary Table 1 summarises the main definitions proposed.

It is crucial to recognise that even after RR and apparent normalisation of ventricular structure, biomarkers and symptom resolution, a significant proportion of patients remain at risk for HF recurrence.11 This has led some authors to consider the condition as myocardial remission rather than a true cure.20,21 In contrast, the term ‘myocardial recovery’ would be more appropriate in scenarios in which complete removal of the primary stressor leads to restoration of cardiac function with low likelihood of HF recurrence.22

Epidemiology

The prevalence of RR in patients with HFrEF is influenced by multiple factors, including the specific definition used, population characteristics, and critically, the aetiology of ventricular dysfunction. General estimates indicate that RR can be observed in approximately 26–46% of HFrEF patients, reflecting the inherent heterogeneity of this phenomenon.13

In a cohort of patients with sustained RR (Figure 1), the distribution of aetiologies reflects the complexity and heterogeneity of HF populations in clinical practice, with important implications for prognosis and therapeutic decision-making.23

Figure 1: Reverse Remodelling Outcomes by Cardiomyopathy Aetiology

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Reversible Aetiologies

Conditions associated with acute and potentially transient insults demonstrate the greatest potential for functional recovery. In tachycardia-induced cardiomyopathy, takotsubo syndrome and thyrotoxicosis-related cardiomyopathy, complete improvement in LVEF may occur in 60–100% of cases after resolution of the triggering factor.9 Acute lymphocytic myocarditis and peripartum cardiomyopathy also have high rates of functional recovery. There is substantial evidence of RR following withdrawal of cardiotoxic agents.

Anthracycline-induced cardiomyopathy shows recovery potential in 30–50% of cases when detected early and cardiotoxic therapy is discontinued. Similar patterns are observed with tyrosine kinase inhibitors and monoclonal antibodies, emphasising the importance of early detection and intervention.24

Chronic Aetiologies

In contrast, chronic aetiologies with higher likelihood of irreversible myocardial injury tend to have lower degrees of RR. Ischaemic cardiomyopathy consistently shows the lowest rates of functional recovery, with RR occurring in approximately 15–25% of patients. Studies evaluating response to cardiac resynchronisation therapy (CRT) have demonstrated that patients with non-ischaemic cardiomyopathy experience greater mean improvements in LVEF than those with ischaemic aetiology.

Idiopathic dilated cardiomyopathy presents more favourable outcomes, with average increases in LVEF of up to 22.4% and significant reductions in major cardiovascular events.25 This difference is likely to reflect the absence of irreversible ischaemic injury and the potential for more complete myocardial recovery.

Surgical Interventions

Following surgical correction of aortic valvular disease, regression of hypertrophy and functional normalisation occurs in more than half of patients. Importantly, postoperative echocardiographic parameters are more predictive of LVEF improvement than preoperative values, suggesting that the degree of irreversible myocardial damage is a key determinant of recovery potential.26

Special Populations

Chagas cardiomyopathy, often associated with poor prognosis, may also present with RR. Data from a Brazilian cohort showed that improvement in LVEF to above 40% or an absolute increase of ≥10% from baseline was associated with a 55% reduction in mortality and need for heart transplantation over 15 years of follow-up.27

In patients with coronary artery disease and reduced LVEF undergoing high-risk percutaneous coronary intervention, approximately 51% had RR, with an average LVEF increase of 13.2% and improved composite clinical outcomes.28

Clinical Profile

Beyond aetiology, clinical variables influence recovery likelihood. Female sex and white race have been associated with greater likelihood of functional recovery and event-free survival, as demonstrated in multicentre studies involving patients with recent-onset cardiomyopathy.29 These findings underscore that both aetiology and clinical profile are key determinants in the course of RR in patients with HFrEF, with direct implications for risk stratification and individualised therapeutic decision-making.

Pathophysiological Mechanisms

LV RR is a dynamic and multifactorial process involving the interplay of structural, molecular, haemodynamic and neurohormonal mechanisms that lead to partial or complete restoration of cardiac structure and function. This phenomenon reflects the activation of intrinsic repair pathways and response to therapeutic interventions that promote myocardial recovery.

Cellular and Molecular Mechanisms

At the cellular level, RR is characterised by reduction in cardiomyocyte size, cytoskeletal reorganisation, restoration of mitochondrial function and attenuation of oxidative stress.30 The regression of pathological myocardial hypertrophy is closely linked to modulation of regulatory pathways, including changes in microRNA expression, imbalances in protein synthesis and degradation pathways, and alterations in cellular metabolism.31

Mitochondrial dysfunction, a hallmark of HF, improves markedly during RR, with restored oxidative phosphorylation, reduced reactive oxygen species and normalised mitochondrial calcium handling.32 This recovery of intracellular calcium dynamics re-establishes excitation–contraction coupling, essential for contractile function.33

Extracellular Matrix Remodelling

The dynamics of the extracellular matrix in RR is associated with reduced collagen deposition and, in some cases, regression of established fibrosis. This process includes a favourable balance between collagen synthesis and degradation. The regression of fibrosis is particularly important for the restoration of ventricular compliance and improvement in diastolic function.34

Neurohormonal Modulation

Therapies targeting the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system are central to improving ventricular function. Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), aldosterone antagonists, β-blockers and angiotensin receptor–neprilysin inhibitors (ARNIs) attenuate hypertrophy, limit fibrosis and enhance performance.35,36 RAAS blockade reduces angiotensin II-mediated vasoconstriction, aldosterone-driven sodium retention, and direct profibrotic effects, while β-blockade mitigates sympathetic overstimulation, lowering heart rate, prolonging diastolic filling and decreasing oxygen demand.35,36 Natriuretic peptides (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP]) provide complementary antifibrotic and vasodilatory actions, alleviating volume and pressure overload and contributing to haemodynamic decompression.37

Haemodynamic Mechanisms

The occurrence of RR is closely linked to haemodynamic decompression, with reductions in ventricular pressure and volume overload. Left ventricular assist device (LVAD) implantation promotes RR by unloading the ventricle, decreasing wall stress and improving coronary perfusion, which favour normalisation of cell size and calcium handling.38 Myocardial revascularisation in ischaemic cardiomyopathy restores regional contractility and synchrony when viability is preserved, highlighting the concept of hibernating myocardium.39

In non-ischaemic cardiomyopathy, CRT enhances RR by improving contraction synchrony, reducing mitral regurgitation and relieving wall stress. In valvular disease, valve replacement leads to regression of hypertrophy and functional improvement, although irreversible fibrosis may limit complete reversibility.40

Metabolic Reprogramming

HF is associated with significant metabolic alterations, including a shift from fatty acid to glucose usage and impaired mitochondrial function. During RR there is often a restoration of normal metabolic flexibility, with improved fatty acid oxidation and enhanced mitochondrial biogenesis. This metabolic reprogramming is essential for sustained functional improvement.41

Inflammatory Resolution

Chronic inflammation plays a significant role in HF progression. RR is associated with resolution of inflammatory processes, including reduction in pro-inflammatory cytokines and increase in anti-inflammatory mediators. This shift in the inflammatory balance contributes to reduced myocardial injury and enhanced repair processes.42

Integration of Mechanisms

RR results from a spectrum of adaptive processes, ranging from immediate haemodynamic relief to sustained molecular reprogramming. The relative contribution of each mechanism varies depending on the underlying aetiology, duration of dysfunction, and therapeutic interventions used. Understanding these pathways not only helps identify patients likely to benefit from ventricular function recovery but also guides personalised therapies aimed at maximising functional improvement and minimising adverse outcomes (Figure 2).

Figure 2: Integrated Mechanisms of Cardiac Reverse Remodelling in Heart Failure

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Therapies Involved in Reverse Remodelling

β-Blockers, ACEIs, ARBs, ARNIs, mineralocorticoid receptor antagonists (MRAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2Is) exert synergistic effects in reducing LV size and improving LVEF, in addition to their well-established benefits in reducing mortality and hospitalisations.43 However, each therapy contributes differently to the RR process.14

While the clinical benefit of neurohormonal therapies is indisputable, the isolated impact of ACEIs, ARBs, MRAs, ARNIs and SGLT2Is on RR remains controversial.44 In contrast, β-blockers consistently demonstrate favourable effects on LV geometry, including reductions in LV diameter and volume and improvements in LVEF. Subanalyses from CAPRICORN, MERIT-HF and CIBIS trials reported LVEF improvements ranging from 3.9% to 6% and consistent reductions in LV volumes.45–48 Mechanistic studies further suggest a more prominent remodelling effect with β-blockers than with ACEIs, with synergistic benefit when both are combined.49,50 A meta-analysis showed that carvedilol, bisoprolol and metoprolol succinate were superior to ACEIs, ARBs, ARNIs and MRAs in improving LVEF and reducing LV dimensions.44

Therapeutic response is amplified when these agents are used in combination and titrated to target doses. A prospective study of 598 patients with new-onset HFrEF (LVEF <35%) reported that 68% of patients achieved LVEF >35% after 6 months of optimal therapy and 77%, within 1 year. Notably, 89% of patients receiving all drugs at target doses improved to LVEF >35% at 6 months.51

Beyond pharmacological therapy, select patients benefit from device-based interventions. CRT improves contractility and reduces mitral regurgitation by correcting electrical dyssynchrony, leading to decreased LV end-diastolic volume (LVEDV), lower myocardial mass and increased LVEF. These effects are most pronounced in patients with left bundle branch block (LBBB), QRS >150 ms and non-ischaemic aetiology. In some, CRT normalises ventricular function (so-called ‘super responders’)particularly when LBBB is a causal factor in systolic dysfunction.52 Additionally, patients with significant right ventricular (RV) pacing (>20%) using single- or dual-chamber pacemakers benefit from CRT upgrade, which has been associated with reduced hospitalisation rates, significant reductions in LVEDV and improved LVEF.53

In advanced HF, long-term LVADs contribute to RR in select patients. Although registry data show recovery in only 1–2%, protocols combining LVAD support with intensive pharmacologic therapy have reported RR rates up to 40%.54,55 LVADs enhance cardiac output and blood pressure, facilitating optimisation of neurohormonal blockade.56 Furthermore, LV unloading leads to reduced LVEDV and left atrial volume, a more tubular ventricular shape, improved contractile efficiency, reduced hypertrophy and cytoskeletal injury and favourable changes in calcium-handling gene expression.56,57 However, these benefits are not observed in the right ventricle.

Clinical Implications

Patients with RR demonstrate more favourable outcomes compared with individuals with persistent HFrEF, particularly regarding mortality rates. However, HF-related events may still occur, and symptoms can persist.5 Patients who achieve RR with LVEF >50% present the lowest risk for HF-related death, all-cause mortality and HF rehospitalisation (Supplementary Figure 1).8

Predictors of RR

Several factors have been consistently associated with greater likelihood of LVEF improvement, including non-ischaemic aetiology, shorter HF duration, absence of late gadolinium enhancement on cardiac MRI, less severe initial remodelling and reduction in BNP levels following pharmacological treatment (Table 1).10,13

Table 1: Predictors of Reverse Remodelling: Occurrence, Maintenance and Risk of Relapse

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RR does not equate to definitive cure. Patients remain at risk for recurrent LVEF decline and HF relapse.58 Approximately 37% of patients who initially experience LVEF improvement later show deterioration.59 Factors associated with increased likelihood of relapse include advanced age, lower baseline LVEF and longer HF duration.21

Evidence suggests that isolated assessment of LVEF and symptoms is insufficient for comprehensive evaluation. In the TRED-HF study, patients who discontinued therapy had increases in blood pressure and heart rate, indicating enhanced neurohormonal activation. In patients who relapsed, LVEF decline preceded the rise in N-terminal proBNP (NT-proBNP), suggesting that NT-proBNP may not be sensitive for early relapse detection.58

Recent studies identified clinical predictors of long-term RR maintenance, including fewer symptoms, higher systolic blood pressure, absence of loop diuretics, greater LVEF improvement, larger septum and greater LV end-systolic diameter reduction.23

Management of Patients with Reverse Remodelling

In the setting of clinical, echocardiographic and biomarker improvement, the need to maintain indefinitely optimised HF therapy remains uncertain. Small human studies involving heterogeneous populations have yielded conflicting results.60,61 To address this question, the TRED-HF trial (2019) randomised 51 patients: 25 to a protocol of sequential withdrawal of spironolactone, β-blocker and ACEI or ARB, and 26 to continued guideline-directed medical therapy. The primary outcome was recurrence of LV dysfunction.11 In the withdrawal group, 11 patients (44%) had recurrence of ventricular dysfunction in the first 6 months, although there were no associated hospitalisations or death. In contrast, none of the 26 patients who maintained their therapy had recurrence. In a second phase of the trial, 25 of the 26 control group patients subsequently underwent treatment withdrawal; of these, nine (36%) had recurrent dysfunction within 6 months.11

These findings reinforce the concept that many patients are not cured of the underlying cardiomyopathy, but rather go into remission. At a 6-year follow-up, 65% of patients had had at least one recurrence of ventricular dysfunction.62 Higher baseline NT-proBNP level was associated with increased risk of relapse, and patients with recurrence had higher heart rates during follow-up, even when compared with patients off β-blockers who did not relapse. This suggests that heart rate may be a contributing mechanism to ventricular deterioration.63

Given that patients with RR often retain underlying molecular and biochemical alterations, it is plausible that ongoing pharmacological therapy is necessary to prevent recurrence. New studies are exploring partial medication withdrawal strategies. For instance, the CATHEDRAL-HF trial evaluated medication tapering while maintaining optimised carvedilol therapy in patients with HF with mildly reduced ejection fraction (HFmrEF). At 1-year follow-up the recurrence rates of ventricular dysfunction were similar between groups (14.8% in the withdrawal group versus 15.4% in controls; p=0.95), with no hospitalisation or death due to HF.64 That was a small, open-label pilot study, and larger trials with adequate non-inferiority power are needed to validate the findings.

Considering the central role of β-blockers in RR (through antiarrhythmic effects, heart rate control and neurohormonal blockade) maintenance of this class appears to be associated with improved outcomes in patients with HFmrEF.65 Other ongoing trials are assessing partial withdrawal of HF medications in HFrEF (Supplementary Table 2).

Few studies have investigated the withdrawal of HF medications in specific patient subgroups. The STOP-CRT trial evaluated different pharmacological strategies in 80 patients with HFmrEF after CRT implantation.66 In contrast to TRED-HF, this study found a similar 2-year increase in LVEDV of 7.5% across four groups: those who maintained full medical therapy; those who discontinued RAAS inhibitors; those who discontinued β-blockers; and those who discontinued both RAAS inhibitors and β-blockers. However, 21% of patients needed to restart the withdrawn medications due to comorbidities.

Another trial, WITHDRAW-HF, randomised 60 patients with tachycardia-induced cardiomyopathy who had undergone AF ablation and demonstrated RR. Patients were assigned to either medication withdrawal or continued guideline-directed therapy.67 At 6 months, 91.7% of patients in the withdrawal group maintained preserved ventricular function, and this percentage was 81.8% at 12 months, with no hospitalisations or adverse HF events reported (Table 2).

Table 2: Randomised Studies of Discontinuation or Reduction of Pharmacological Therapy in Patients with HFimpEF

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Other potentially ‘reversible’ aetiologies of HF, such as alcoholic cardiomyopathy, peripartum cardiomyopathy, prior myocarditis and chemotherapy-induced cardiotoxicity, still lack specific studies addressing pharmacologic management following recovery of ventricular function. These conditions may have a higher likelihood of sustained RR compared with genetic aetiologies. Ongoing randomised trials are exploring this topic (Supplementary Table 2). Given the distinct injurious and perpetuating mechanisms of myocardial damage, a deeper understanding of each underlying aetiology and the related markers associated with post-recovery remodelling deterioration is necessary.

Box 1: Independent Predictors of Sustained Reverse Remodelling in HFrEF

  • 2nd LVEF (%): OR 1.06 (per 1%)
  • 2nd LVESD (mm): OR 0.93 (per 1 mm)
  • 2nd IV septum (mm): OR 1.12 (per 1 mm)
  • Systolic BP (mmHg): OR 1.01 (per 1 mmHg)
  • NYHA class I–II: OR 1.86
  • No furosemide use: OR 1.87

BP = blood pressure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; LVESD = left ventricular end-systolic diameter; NYHA = New York Heart Association.

Despite variations in study design and patient populations, one consistent finding across all trials is the proportion of patients who have recurrence of ventricular dysfunction, regardless of treatment arm. Observational studies suggest that up to one-fourth of patients with recovered ejection fraction may redevelop systolic dysfunction over time, independent of ongoing pharmacological therapy.4,60,68 Identifying this high-risk subgroup is essential for closer follow-up and caution when considering medication withdrawal (Box 1).23

In the light of current evidence, Brazilian, American and European guidelines recommend maintaining guideline-directed medical therapy for HFrEF even in patients with improved ventricular function, unless there is a compelling reason for discontinuation. If de-escalation is pursued, close clinical follow-up is imperative, including serial NT-proBNP measurements and echocardiographic assessments. Immediate reinstatement of therapy is advised at the first sign of functional decline (Supplementary Figure 2).15,17,43

Conclusion

RR should be considered a key therapeutic goal in HFrEF management, requiring systematic and individualised strategies. Early therapy optimisation with guideline-directed medical therapy is crucial for maximising RR. Patients with RR require ongoing clinical, echocardiographic and biomarker assessment. Full withdrawal of therapy should generally be avoided, particularly in idiopathic or ischaemic cardiomyopathies. For many patients, recovery represents therapy-dependent remission rather than cure, requiring vigilance and long-term individualised treatment strategies. The pursuit of RR should guide therapeutic decision-making at all stages of HF management.

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