From support to recovery: the evolving role of LVAD in reversing heart failure

Abstract

In recent years, the use of Left Ventricular Assist Devices (LVAD) in the treatment of heart failure has been increasingly widespread. Not only do they provide circulatory support for patients, but the reverse biological changes in myocardial tissue induced by LVAD have led to the recovery of heart function in some patients, allowing for the removal of the device—which termed bridge to recovery (BTR). Despite promising prospective studies reporting LVAD explantation rates exceeding 48–60% in BTR-focused cohorts, real-world registries (e.g., INTERMACS) demonstrate explantation rates below 5%, underscoring critical gaps in patient selection, standardized assessment protocols, and integration of optimized pharmacological and mechanical unloading strategies. This review synthesizes contemporary clinical and molecular insights into LVAD-mediated myocardial recovery. Clinically, key determinants of successful BTR include stringent hemodynamic and echocardiographic criteria for explantation (e.g., LVEF > 45%, PCWP ≤ 15 mmHg), and aggressive guideline-directed medical therapy (GDMT), particularly neurohormonal blockade. Mechanistically, LVAD unloading promotes reverse remodeling through metabolic reprogramming (e.g., enhanced pyruvate-lactate axis activity), restoration of calcium homeostasis, extracellular matrix modulation, and immune-mediated pathways. However, challenges persist, including the lack of predictive biomarkers, suboptimal GDMT adherence, and unresolved debates regarding concomitant cardiac procedures. Emerging evidence highlights the potential of novel pharmacotherapies (e.g., SGLT2 inhibitors, vericiguat) and individualized pump-speed algorithms to augment recovery. Pediatric populations exhibit unique recovery dynamics, with myocarditis and smaller body surface area correlating with higher explantation success. Partial cardiac recovery, observed in over 30% of LVAD recipients, warrants tailored therapeutic strategies to transition to full recovery. Future directions demand multicenter registries integrating molecular profiling with clinical outcomes, standardized BTR protocols, and exploration of adjuvant therapies. By redefining BTR as an achievable goal rather than a rare exception, this paradigm shift could transform advanced heart failure management, offering patients liberation from lifelong device dependency.

Introduction

Heart failure has long been considered an irreversible process, and even with optimized pharmacological treatment, the prognosis for patients with heart failure remains poor [1]. Heart transplantation is an effective treatment for end-stage heart failure, but its widespread adoption as a routine therapy is limited by a shortage of donor organs [2]. The application of long-term mechanical circulatory support devices (DMCS), such as the Left Ventricular Assist Device (LVAD), has gradually overcome these challenges. During the application of DMCS, a noteworthy phenomenon is that LVAD not only provides circulatory support, but its volume and pressure unloading effects can also induce reverse changes at the cellular and molecular levels of the myocardium, thereby improving myocardial structure and function. As a result, the cardiac function of some patients is restored to varying degrees, making it possible to wean from the LVAD [3,4,5]. This process is termed Bridge to Recovery (BTR). BTR has been included as one of the treatment goals for LVAD alongside Bridge to Transplantation (BTT), Bridge to Candidacy (BTC), and Destination Therapy (DT) in the latest domestic and international guidelines and expert consensus statements [6]. Although the annual INTERMACS reports indicate that the device explantation rate remains below 5%7,8, multiple prospective studies targeting BTR have demonstrated device removal rates exceeding 48–60% [9, 10] To address these discrepancies, it is essential to elucidate the mechanisms by which LVAD support either promotes or impedes myocardial recovery. This review provides a comprehensive summary of recent advances in the field of LVAD-induced myocardial recovery, focusing on both clinical and molecular perspectives. Furthermore, it discusses the current controversies surrounding myocardial recovery and explores future strategies to enhance the efficacy of LVAD therapy in facilitating durable myocardial recovery.

Clinical research advances

Recovery rate and prognosis

Multiple studies have demonstrated the potential for cardiac function recovery and subsequent weaning from mechanical assistance following the implantation of a Left Ventricular Assist Device (LVAD), with this recovery being potentially durable and of high quality [11,12,13,14,15,16]. THE RESTAGE-HF research [13] is the recently multicenter prospective study to date examining myocardial recovery using a Left Ventricular Assist Device (LVAD). In this study, the rate of device removal among patients implanted with an LVAD reached a high about 50%. The proportion of patients achieving myocardial recovery leading to device explantation has consistently remained low in the INTERMACS registry, with rates below 5% over a five-year period [7, 8, 16]. In contrast, prospective studies investigating LVAD explantation due to recovery have involved fewer than 200 patients, highlighting a significant discrepancy relative to the overall number of LVAD implantations. The limited number of explantations and the absence of large-scale cohort studies represent key points of ongoing controversy. Nevertheless, sustained myocardial function following device explantation has been demonstrated. In the RESTAGE-HF trial, post-explant survival rates at 1, 2, and 3 years were reported to be 90%, 77%, and 77%, respectively [13]. In similar studies, it has been reported that approximately 80% of patients who undergo cardiac functional recovery and have their LVADs removed experience no recurrence of heart failure within 2 to 3 years [17,18,19]. In an INTERMACS registry study, over 70% of patients remained free from heart failure recurrence four years after LVAD explantation [16].

Criteria for evaluation prior to LVAD removal

Standards for the removal of devices in patients with cardiac function recovery after LVAD implantation are still being refined. Typically, they include echocardiography, cardiac catheterization, and exercise capacity tests, among others [7, 13, 20,21,22]. A critical aspect of assessing cardiac function recovery is the reduction of pump speed to zero net flow, with careful monitoring for thrombosis. If the patient tolerates the decreased flow and echocardiography indicates signs of recovery, they are further evaluated with exercise testing and cardiac catheterization. Currently, the most fundamental criteria for device removal, as depicted in the figure, include LVEDD < 60 mm, LVESD < 50 mm, LVEF > 45%, LVEDP or PCWP ≤ 15 mm Hg, and a resting cardiac index (CI) > 2.4 L/min/m² [6, 13]. After a reduction in pump speed for at least 15 min, the absence of an increase in pulmonary capillary wedge pressure (PCWP) and no significant decrease in resting cardiac output index (CI) indicate significant and sustained myocardial recovery [13, 23, 24]. This comparison is crucial in the evaluation. Studies have indicated that if the evaluation results continue to improve, the removal should be postponed to achieve maximum cardiac recovery [13]. However, prolonged device support time can also increase the risks of bleeding, thrombosis, infection, and other complications. Therefore, it is necessary to conduct further research to determine the optimal timing for LVAD removal.

Surgical strategies for LVAD explantation and post- explantation management

LVAD explantation can be performed through various surgical approaches, all of which have been reported as feasible; however, outcome data remain heterogeneous across techniques. A meta-analysis demonstrated comparable early and late survival rates and clinical outcomes among different surgical methods [25]whereas a separate systematic review suggested that retaining device components in situ may be associated with a higher rate of heart failure recurrence [26].The principal surgical strategies include:

1. a.

Median Sternotomy with Cardiopulmonary Bypass (CPB): Considered the gold standard for complete device explantation. This approach enables direct ligation of the outflow graft near the aorta, patch closure of the left ventricular apex, and concomitant intracardiac procedures if necessary.

2. b.

Left Thoracotomy (± CPB): A less invasive option that allows for transthoracic closure or patching of the apical site. Off-pump explantation using an apical plug is technically feasible but poses greater surgical challenges [27, 28].

3. c.

Device Decommissioning (Graft Occlusion): In patients at high surgical risk, some centers adopt a conservative strategy involving occlusion of the outflow graft and driveline while leaving the pump in place. This approach has demonstrated short-term safety, although long-term infection risk remains a concern [19].

A full median sternotomy is typically preferred in cases of significant device-related infection, as it facilitates complete hardware removal and thorough debridement [19, 27].

Despite generally favorable outcomes, a subset of patients remains at risk for recurrent heart failure following device explantation. Key risk factors include prolonged duration of heart failure prior to LVAD implantation, low left ventricular ejection fraction (LVEF) at the time of weaning, and LVEF instability prior to explantation [4, 29]. After reestablishment of full native cardiac output, patients should remain on comprehensive guideline-directed medical therapy (GDMT) and undergo regular clinical follow-up to monitor for recurrent dysfunction [30, 31].

Multifactorial strategies affecting cardiac recovery

A greater degree of LVAD unloading can more effectively promote the recovery of cardiac function [32]. But unloading is not the more the better; excessive unloading may lead to left ventricular suction, potentially damaging the myocardium and structures such as valves, and it may also potentially cause right heart damage. There are no reports on studies regarding the appropriate pump speed for promoting myocardial recovery. The general approach to adjusting pump speed is through a ramp test. The speed adjustment aims to maintain the patient’s mean arterial pressure, with the interventricular septum in the midline position and intermittent opening of the aortic valve, while keeping mitral regurgitation below mild [13, 33,34,35]. Research indicates that there are widespread variations in hemodynamic and echocardiographic indices among patients after discharge [36]which may impact the recovery of cardiac function in patients, therefore, regular postoperative monitoring and adjustment of pump speed are necessary, and the pump speed adjustment protocol will be a focus of further research. In the process of promoting cardiac recovery, pharmacological therapy plays a crucial role. Multicenter studies have shown that the combination of LVAD and individualized pharmacological therapy can achieve Bridge to Recovery (BTR) in 40–77% of patients [13, 20, 37]. In studies where pharmacological therapy had not been previously combined or was not administered according to standard protocols, the incidence of myocardial recovery was lower, approximately 4.5–10% [3, 18, 38]. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as neurohormonal blockers have significant benefits in promoting cardiac functional recovery [39, 40]. A study involving 12,144 patients from 170 centers [41]using the INTERMACS data, indicated that the triple therapy group consisting of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), β-blockers, and mineralocorticoid receptor antagonists had the lowest mortality rate and the highest rate of device removal following LVAD implantation.

The emergence of novel pharmacological agents for heart failure (HF) and the expanded scope of guideline-directed medical therapy (GDMT), including angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), have demonstrated potential to facilitate cardiac recovery. Accumulating evidence suggests that SGLT2is exert multifaceted effects, including modulation of myocardial energy metabolism, reduction of cardiac preload and afterload, and attenuation of adverse ventricular remodeling [42,43,44]. A systematic review and meta-analysis evaluating SGLT2i use in left ventricular assist device (LVAD) recipients reported significant improvement in ejection fraction (EF), though no significant changes were observed in left ventricular dimensions, B-type natriuretic peptide (BNP) levels, or glomerular filtration rate (GFR) [45]. A small retrospective study documented that over 50% of patients receiving ARNI therapy post-LVAD implantation achieved NYHA class I functional status [46]. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, has been shown to be safe in LVAD patients, with reported reductions in pulmonary capillary wedge pressure and increases in cardiac index [47]. While phosphodiesterase-5 inhibitor use following LVAD implantation correlates with improved clinical outcomes, current evidence does not establish a direct association with myocardial recovery [48]. The safety profile and potential role of these pharmacotherapies in promoting post-LVAD cardiac recovery warrant further investigation. Helou et al. recently analyzed GDMT prescription patterns among 270 HeartMate 3 recipients at Cleveland Clinic (January 2022–December 2023), revealing suboptimal adherence: 50% for beta-blockers, 38.5% for ACE inhibitors/ARBs, 14.8% for SGLT2is, 36.3% for ARNIs, 47% for mineralocorticoid receptor antagonists, 19.6% for isosorbide dinitrate/hydralazine, and 81.1% for loop diuretics [49]. These findings underscore the current underutilization of GDMT, which may contribute to the limited observed rates of cardiac recovery. Notably, a multicenter registry study (NCT05278962) assessing SGLT2i therapy in LVAD patients is nearing completion.

The performance of concomitant cardiac procedures (e.g., valvular surgery or CABG) during LVAD implantation represents another debated factor influencing potential myocardial recovery. INTERMACS registry data from 8,245 patients receiving LVADs as destination therapy revealed that 41.5% underwent concurrent cardiac surgery during implantation, while 37.9% had prior cardiac surgical history [50]. Although correcting specific valvular pathologies is critical for optimal LVAD function—which may secondarily facilitate reverse remodeling and myocardial recovery [7]—current evidence does not conclusively demonstrate that concomitant procedures directly enhance the likelihood of cardiac recovery or eventual device explantation. Conversely, prior or concurrent cardiac surgery has been identified as a risk factor for early adverse outcomes (mortality or poor quality of life) post-LVAD, though this risk attenuates over time [50].The management of tricuspid regurgitation (TR) remains particularly contentious. Following isolated LVAD implantation, approximately 65% of patients exhibit immediate reduction from moderate-severe TR to none/mild TR, with further improvement observed during follow-up, suggesting LVAD-induced right ventricular and tricuspid annular remodeling [51]. A randomized study found no significant difference in moderate-severe right heart failure rates at 6 months between patients with preoperative moderate-severe TR undergoing LVAD implantation with versus without concomitant tricuspid valve procedures (50% vs. 46.9%) [52]. Notably, an INTERMACS analysis reported that tricuspid valve procedures in moderate-severe TR were associated with increased complication rates and mortality [53]. Concomitant surgeries inherently increase procedural complexity and duration, while their long-term benefits—including effects on myocardial recovery—remain unproven. Thus, although these adjunctive procedures aim to optimize cardiac function or address existing pathology, their necessity and therapeutic value require individualized assessment and further investigation.

Recovery prediction and patient selection

Evaluating and predicting patients with potential for recovery will be beneficial for better promoting and guiding Bridge to Recovery (BTR) treatments [18]. Young patients, those with non-ischemic etiologies, and those with a short history of illness typically exhibit greater plasticity and repair capabilities [18, 54]. Wever-Pinzon et al. [7] utilized the INTERMACS database and developed the I-CARS predictive score based on six factors: age < 50 years, non-ischemic cardiomyopathy, duration of heart failure diagnosis < 2 years, absence of an ICD, serum creatinine ≤ 1.2 mg/dl, and left ventricular end-diastolic diameter < 6.5 cm. They further validated the I-CARS in an external cohort, underscoring the importance of selecting appropriate patients. However, the RESTAGE-HF study [13] reported opposite results. Multivariate regression analysis showed that factors such as age, sex, duration of heart failure, use of cardiac resynchronization therapy (CRT), ventricular arrhythmias, hypertension, familial cardiomyopathy, myocardial disease induced by postpartum or chemotherapy, indications for Bridge to Transplant (BTT) versus Destination Therapy (DT), pre-LVAD ejection fraction (EF), creatinine levels, and pulmonary artery diastolic pressure were not predictive of whether a patient would recover. A recent study employed non-invasive continuous cardiac function monitoring and demonstrated that patients with ischemic etiology, low pump speed, and high pulsatility index were more likely to experience improvement in left ventricular function [55]. The controversy remains as to whether inter-patient variability is a key factor affecting the success rate of Bridge to Recovery (BTR). Future efforts are needed to develop predictive models based on larger datasets and reduced bias to achieve individualized treatment.

Recent studies suggest that a history of type 2 diabetes and preoperative blood glucose levels may have potential predictive value for the improvement of postoperative cardiac ejection fraction [56]. Echocardiography is not only an important tool for assessment during weaning, but it also plays a significant role in identifying potential BTR patients during post-implantation follow-up [4]. Speckle tracking echocardiography can also be used to predict cardiac recovery after LVAD implantation [57]. Some biomarkers, such as TNFα, have been found to possess predictive potential [58].

Partial cardiac recovery: a continuous remission process

It is important to recognize that cardiac recovery is not an all-or-none phenomenon, and a subset of patients achieve only partial recovery. In existing literature, recovery typically refers to the restoration of cardiac function sufficient for LVAD explantation, whereas reversal describes the process of reverse remodeling without necessarily achieving full functional restoration [19, 20, 59]. Shah et al. introduced the concept of partial responders, defined as patients with a > 5% increase in LVEF from baseline (but remaining ≤ 40%), irrespective of changes in LVEDD, and proposed the Utah-Inova staging system for recovery assessment [60]. In their study, 31% of LVAD patients were classified as partial responders, 10% as full responders, and 59% as non-responders, with a median LVEF improvement of 9%60. Data from the ELEVATE registry demonstrated that over 80% of patients achieved NYHA class I or II functional status at 2 years post-implantation, though this proportion declined to < 70% by 5 years, still indicating substantial functional improvement [61].Just as pre-implant prediction of full recovery remains challenging, identifying which patients will progress from partial to complete recovery is equally uncertain. Optimizing therapeutic strategies to promote further recovery in partial responders warrants dedicated investigation.

Cardiac recovery in pediatric patients undergoing LVAD

Given the long-term implications of destination therapy (either LVAD or heart transplantation) in children with heart failure, the potential for myocardial recovery warrants special consideration. A systematic review encompassing 18 studies (n = 928 pediatric patients) reported an explantation rate of 8.7% [62]. Underlying etiology significantly influences the likelihood of recovery. One study demonstrated that children with myocarditis had a substantially higher recovery rate (57%) compared to those with dilated cardiomyopathy (DCM) or congenital heart disease [63]. Notably, an analysis of the Berlin Heart EXCOR cohort revealed that patients with a body surface area (BSA) < 0.53 m² exhibited the highest recovery rate, with approximately 1 in 9 children achieving device explantation [64]. Delmo et al. evaluated 193 pediatric LVAD recipients (1990–2015) and found that 84.0% of explanted patients (n = 21) remained free of adverse events during long-term follow-up (1.3–19.1 years) [65]. These findings highlight the importance of careful patient selection and ongoing assessment of recovery potential in pediatric mechanical circulatory support.

Advances in the Study of the mechanisms of myocardial recovery

As the phenomenon of cardiac function recovery has gained more attention, the positive changes at the cellular and molecular levels in cardiac tissue have been increasingly revealed. These changes involve a multi-faceted regulation including energy metabolism, calcium homeostasis, and intracellular signaling pathways [66, 67]but the cellular and molecular mechanisms of these beneficial effects are still not entirely clear [66].

In the aspect of myocardial cell energy metabolism, Drakos and his team have conducted a series of studies. After grouping the patients that recovered versus those that did not recover following LVAD implantation, they found that in the recovery group, the flux of glucose entering the tricarboxylic acid cycle (TCA cycle) was reduced, while the flux into ancillary pathways such as the pentose phosphate pathway and one-carbon metabolism was increased. This resulted in the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and other biomacromolecules necessary for cardiac recovery​ [68]. Further research has introduced the concept of the pyruvate-lactate axis, indicating that the upregulation of the mitochondrial pyruvate carrier (MPC) along this axis promotes the oxidation of pyruvate in the mitochondria, which is associated with the reversal of myocardial hypertrophy following LVAD implantation and is consistent with changes in cardiac functional recovery​ [69]​. Natali Froese et al. [70] discovered that LVAD-induced cardiac recovery overlaps with hypoxia-induced cardiac recovery in terms of mechanism pathways suggests that there are common biological processes or signaling pathways involved in the heart’s response to both mechanical unloading (as provided by LVAD) and hypoxic stress. In this common pathway, the transcriptional activation of Tbx5 and the transcriptional inhibition of Hsd11b1 play a cardioprotective role. These studies suggest that LVAD may be one of the important mechanisms for promoting heart recovery by altering the energy metabolism of cardiomyocytes.

The cytoskeleton may play a significant role in the recovery of myocardial function. Following LVAD unloading in patients who recover, there are changes in the related gene lineage, with an increase in the expression of sarcomeric proteins (such as β-actin, α-tropomyosin, α1-actin) and non-sarcomeric proteins (such as laminin A/C), which is associated with the reversal of cytoskeletal remodeling [71,72,73].

Improvements in the Ca2+ handling pathways within cardiomyocytes appear to be associated with myocardial recovery. LVAD can influence the expression of genes related to calcium homeostasis, altering the sarcoplasmic reticulum (SR) calcium content and thereby improving myocardial contractile function [74, 75]. Studies have shown that in patients who successfully recover ventricular function (sufficient for explantation) after LVAD support, there are significant changes in the cardiomyocyte action potential and sodium-calcium exchanger (NCX) RNA expression when compared to the time of LVAD implantation. AND L-type Ca2+ current inactivation and faster Ca2+ extrusion are characteristics of patients who recover after LVAD surgery [76, 77].

The changes in the extracellular matrix (ECM) during the process of cardiac recovery are significant [78]. In the study by Müller, J et al. [79] and Brian A Bruckner et al. [80]it was found that the extracellular matrix (ECM) in hearts from which the device was removed due to recovery was significantly reduced compared to before the device was implanted. The initiating factors for the reversal of myocardial fibrosis and the extent to which it affects cardiac functional recovery are still to be further investigated.

The immune system also plays a role in the reverse remodeling process in the recovering heart. β1-adrenergic receptor autoantibodies (β1AR-Aab) are immunoglobulin G (IgG) associated with idiopathic cardiomyopathy. In one study, it was observed that β1AR-Aab disappeared in 97.1% of patients who had LVAD removed [81]. A single-nucleus RNA sequencing study found that the most significant transcriptional changes occurred in macrophages and fibroblasts, and identified RUNX1, associated with inflammatory-type symptoms, as a potential therapeutic target to promote heart recovery [82].

In terms of the cell cycle, studies have compared the differences in proteins and phosphorylation patterns between patients who did not recover and those who did recover after LVAD, suggesting the possibility of cardiomyocytes re-entering the regenerative cycle [78].

Conclusion and future research focus

Antonides and colleagues [18] have pointed out that the lack of data entries related to cardiac recovery in real-world data registries is a constraint on in-depth research of past cases. In centers aimed at evaluating, promoting, and optimizing myocardial recovery programs, the success rate of LVAD removal is significantly higher. There is a need to shift the mindset that bridge-to-transplant (BTT) and destination therapy (DT) are the ultimate treatment modalities for advanced heart failure. Instead, all the DMCS patients should be considered potential candidates for bridge-to-recovery (BTR) and efforts should be made towards cardiac recovery [18, 83]. The use of high-dose neurohormonal blockers has played a significant role in the reversal of cardiac function. Further optimization of regular post-LVAD cardiac function monitoring and assessment, exploration of recovery-oriented pump speed adjustment strategies, and improvement of postoperative anti-heart failure medication regimens are the focal points of the next phase of clinical research. This will help more patients achieve weaning off LVAD support and move towards recovery. Partial functional recovery, observed in over 30% of recipients, constitutes a distinct therapeutic window requiring targeted interventions rather than a failed endpoint.

The biological mechanisms of cardiac recovery have been partially reported, but they are often not associated with clinical outcomes. Integrating the biological study of tissue samples taken during surgery with clinical outcomes in a matched research approach is an important method for establishing causal relationships and providing insights into the mechanisms involved [54]. With the advancements in gene editing techniques and other novel technologies, how these new approaches can potentially be integrated with LVAD treatment to promote better cardiac recovery is an important topic that urgently needs to be explored.

Current explantation criteria lack sensitivity to detect subclinical myocardial vulnerability, while long-term (> 10-year) outcomes post-explantation remain poorly characterized. Furthermore, the ethical implications of device removal in marginally recovered patients demand rigorous risk-benefit frameworks. BTR offers a treatment option beyond lifelong device dependency and heart transplantation for patients with end-stage heart failure. At the same time, it provides a new perspective for studying the mechanisms of heart failure recovery.

Data availability

No datasets were generated or analysed during the current study.

References

Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC)Developed with the special contribution of the heart failure association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200. https://doi.org/10.1093/eurheartj/ehw128.

Lund LH, Khush KK, Cherikh WS, et al. The registry of the international society for heart and lung transplantation: Thirty-fourth adult heart transplantation Report-2017; focus theme: allograft ischemic time. J Heart Lung Transpl. 2017;36(10):1037–46. https://doi.org/10.1016/j.healun.2017.07.019.

Maybaum S, Mancini D, Xydas S, et al. Cardiac improvement during mechanical circulatory support: a prospective multicenter study of the LVAD working group. Circulation. 2007;115(19):2497–505. https://doi.org/10.1161/CIRCULATIONAHA.106.633180.

Dandel M, Weng Y, Siniawski H, et al. Heart failure reversal by ventricular unloading in patients with chronic cardiomyopathy: criteria for weaning from ventricular assist devices. Eur Heart J. 2011;32(9):1148–60. https://doi.org/10.1093/eurheartj/ehq353.

Taleb I, Tseliou E, Fang J, Drakos S. A mechanical Bridge to recovery as a Bridge to discovery: learning from few and applying to many. Circulation. 2022;145 8:562–4. https://doi.org/10.1161/CIRCULATIONAHA.120.052141.

Saeed D, Feldman D, Banayosy AE, et al. The 2023 international society for heart and lung transplantation guidelines for mechanical circulatory support: A 10- year update. J Heart Lung Transplantation. 2023;42(7):e1–222. https://doi.org/10.1016/j.healun.2022.12.004.

Wever-Pinzon O, Drakos S, McKellar S, et al. Cardiac recovery during Long-Term left ventricular assist device support. J Am Coll Cardiol. 2016;68 14:1540–53. https://doi.org/10.1016/j.jacc.2016.07.743.

Shah P, Yuzefpolskaya M, Hickey GW, et al. Twelfth interagency registry for mechanically assisted circulatory support report: readmissions after left ventricular assist device. Ann Thorac Surg. 2022;113(3):722–37. https://doi.org/10.1016/j.athoracsur.2021.12.011.

George RS, Yacoub MH, Tasca G, et al. Hemodynamic and echocardiographic responses to acute interruption of left ventricular assist device support: relevance to assessment of myocardial recovery. J Heart Lung Transplantation. 2007;26(10):967–73. https://doi.org/10.1016/j.healun.2007.07.021.

Segura AM, Frazier OH, Demirozu Z, Buja LM. Histopathologic correlates of myocardial improvement in patients supported by a left ventricular assist device. Cardiovasc Pathol. 2011;20(3):139–45. https://doi.org/10.1016/j.carpath.2010.01.011.

Birks EJ, George RS, Firouzi A, et al. Long-term outcomes of patients bridged to recovery versus patients bridged to transplantation. J Thorac Cardiovasc Surg. 2012;144(1):190–6. https://doi.org/10.1016/j.jtcvs.2012.03.021.

Jakovljevic DG, Yacoub MH, Schueler S, et al. Left ventricular assist device as a Bridge to recovery for patients with advanced heart failure. J Am Coll Cardiol. 2017;69(15):1924–33. https://doi.org/10.1016/j.jacc.2017.02.018.

Birks EJ, Drakos SG, Patel SR, et al. Prospective multicenter study of myocardial recovery using left ventricular assist devices (RESTAGE-HF [Remission from Stage D Heart Failure]): Medium-Term and Primary End Point Results. Circulation. 2020;142(21):2016–28. https://doi.org/10.1161/CIRCULATIONAHA.120.046415.

Monteagudo Vela M, Rial Bastón V, Panoulas V, Riesgo Gil F, Simon A. A detailed explantation assessment protocol for patients with left ventricular assist devices with myocardial recovery. Interact Cardiovasc Thorac Surg. 2020;32(2):298–305. https://doi.org/10.1093/icvts/ivaa259.

Tran P, Lau C, Joshi M, Kuehl M, Maddock H, Banerjee P. Exploring changes in myocyte structure, contractility, and energetics from mechanical unloading in patients with heart failure undergoing ventricular assist device implantation: A systematic review and Meta-Analysis. Heart Lung Circulation. 2024;33(8):1097–116. https://doi.org/10.1016/j.hlc.2024.01.039.

Itagaki S, Moss N, Toyoda N, et al. Incidence, outcomes, and opportunity for left ventricular assist device weaning for myocardial recovery. JACC: Heart Fail. 2024;12(5):893–901. https://doi.org/10.1016/j.jchf.2023.12.006.

Birks EJ, George RS, Hedger M, et al. Reversal of severe heart failure with a continuous-flow left ventricular assist device and Pharmacological therapy: a prospective study. Circulation. 2011;123(4):381–90. https://doi.org/10.1161/CIRCULATIONAHA.109.933960.

Antonides CFJ, Schoenrath F, de By TMMH, et al. Outcomes of patients after successful left ventricular assist device explantation: a EUROMACS study. ESC Heart Fail. 2020;7(3):1085–94. https://doi.org/10.1002/ehf2.12629.

Gerhard EF, Wang L, Singh R, et al. LVAD decommissioning for myocardial recovery: Long-term ventricular remodeling and adverse events. J Heart Lung Transpl. 2021;40(12):1560–70. https://doi.org/10.1016/j.healun.2021.08.001.

Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med. 2006;355(18):1873–84. https://doi.org/10.1056/NEJMoa053063.

Dandel M, Hetzer R. Evaluation of cardiac recovery in ventricular assist device recipients: particularities, reliability, and practical challenges. Can J Cardiol. 2019;35(4):523–34. https://doi.org/10.1016/j.cjca.2018.11.015.

Holzhauser L, Lang R, Raikhelkar J, Sayer G, Uriel N. Reverse ramp testing in left ventricular assist device support and myocardial recovery. ASAIO J. 2020;66:e1–4. https://doi.org/10.1097/MAT.0000000000001010.

Saito S, Toda K, Miyagawa S, et al. Hemodynamic changes during left ventricular assist device-off test correlate with the degree of cardiac fibrosis and predict the outcome after device explantation. J Artif Organs. 2015;18(1):27–34. https://doi.org/10.1007/s10047-014-0802-0.

Gyoten T, Amiya E, Kinoshita O, et al. Myocardial recovery evaluation from ventricular assist device in patients with dilated cardiomyopathy. ESC Heart Fail. 2022;9(4):2491–9. https://doi.org/10.1002/ehf2.13951.

Baldwin ACW, Sandoval E, Letsou GV, Mallidi HR, Cohn WE, Frazier OH. Surgical approach to continuous-flow left ventricular assist device explantation: A comparison of outcomes. J Thorac Cardiovasc Surg. 2016;151(1):192–8. https://doi.org/10.1016/j.jtcvs.2015.08.024.

Jh C, Mp W, Dp H, et al. Left ventricular assist device decommissioning compared with explantation for ventricular recovery: A systematic review. ASAIO J. 2020;66(1). https://doi.org/10.1097/MAT.0000000000000926.

Bhadra OD, Pausch J, Aubin H, et al. Left ventricular assist device explantation using a new double-patch technique†. Interdiscip Cardiovasc Thorac Surg. 2023;37(1):ivad110. https://doi.org/10.1093/icvts/ivad110.

Geoffrion TR, Lawrence KM, O’Connor MJ, Chen JM. Off-Pump explant of a left ventricular assist device using a recovery plug in a pediatric patient. Ann Thorac Surg. 2021;111(4):e291–3. https://doi.org/10.1016/j.athoracsur.2020.06.126.

Dandel M, Weng Y, Siniawski H, et al. Pre-explant stability of unloading-promoted cardiac improvement predicts outcome after weaning from ventricular assist devices. Circulation. 2012;126(11 Suppl 1):S9–19. https://doi.org/10.1161/CIRCULATIONAHA.111.084640.

Halliday BP, Wassall R, Lota AS, et al. Withdrawal of Pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019;393(10166):61–73. https://doi.org/10.1016/S0140-6736(18)32484-X.

Krishnamoorthi MK, Sideris K, Bhimaraj A, Drakos SG. Learnings from the 2024 Utah Cardiac Recovery Symposium: A Roadmap for the Field of Myocardial Recovery. Methodist Debakey Cardiovasc J. 20(4):88–97. https://doi.org/10.14797/mdcvj.1443

Jacobs S, Geens J, Rega F, Burkhoff D, Meyns B. Continuous-flow left ventricular assist devices induce left ventricular reverse remodeling. J Heart Lung Transpl. 2013;32(4):466–8. https://doi.org/10.1016/j.healun.2013.01.1045.

Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia ramp study. J Am Coll Cardiol. 2012;60(18):1764–75. https://doi.org/10.1016/j.jacc.2012.07.052.

Imamura T, Jeevanandam V, Kim G, et al. Optimal hemodynamics during left ventricular assist device support are associated with reduced readmission rates. Circ Heart Fail. 2019;12(2):e005094. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005094.

Uriel N, Levin AP, Sayer GT, et al. Left ventricular decompression during speed optimization ramps in patients supported by Continuous-Flow left ventricular assist devices: Device-Specific performance characteristics and impact on diagnostic algorithms. J Card Fail. 2015;21(10):785–91. https://doi.org/10.1016/j.cardfail.2015.06.010.

Uriel N, Sayer G, Addetia K, et al. Hemodynamic ramp tests in patients with left ventricular assist devices. JACC Heart Fail. 2016;4(3):208–17. https://doi.org/10.1016/j.jchf.2015.10.001.

Drakos SG, Wever-Pinzon O, Selzman CH, et al. Magnitude and time course of changes induced by continuous-flow left ventricular assist device unloading in chronic heart failure: insights into cardiac recovery. J Am Coll Cardiol. 2013;61(19):1985–94. https://doi.org/10.1016/j.jacc.2013.01.072.

Mancini DM, Beniaminovitz A, Levin H, et al. Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation. 1998;98(22):2383–9. https://doi.org/10.1161/01.cir.98.22.2383.

Yousefzai R, Brambatti M, Tran HA, et al. Benefits of neurohormonal therapy in patients with Continuous-Flow left ventricular assist devices. ASAIO J. 2020;66(4):409–14. https://doi.org/10.1097/MAT.0000000000001022.

Brinkley DM, Wang L, Yu C, Grandin EW, Kiernan MS. Impact of renin-angiotensin-aldosterone system Inhibition on morbidity and mortality during long-term continuous-flow left ventricular assist device support: an IMACS report. J Heart Lung Transpl. 2021;40(12):1605–13. https://doi.org/10.1016/j.healun.2021.08.015.

McCullough M, Caraballo C, Ravindra NG, et al. Neurohormonal Blockade and clinical outcomes in patients with heart failure supported by left ventricular assist devices. JAMA Cardiol. 2020;5(2):175–82. https://doi.org/10.1001/jamacardio.2019.4965.

Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73(15):1931–44. https://doi.org/10.1016/j.jacc.2019.01.056.

Pabel S, Wagner S, Bollenberg H, et al. Empagliflozin directly improves diastolic function in human heart failure. Eur J Heart Fail. 2018;20(12):1690–700. https://doi.org/10.1002/ejhf.1328.

Kario K, Okada K, Kato M, et al. Twenty-Four-Hour blood Pressure-Lowering effect of a Sodium-Glucose cotransporter 2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, Placebo-Controlled SACRA study. Circulation. 2019;139(18):2089–97. https://doi.org/10.1161/CIRCULATIONAHA.118.037076.

Hasabo EA, Isik B, Elgadi A, et al. A systematic review and Meta-Analysis of the efficacy and safety of Sodium-Glucose Cotransporter-2 inhibitor in patients using left ventricular assist devices. J Clin Med. 2024;13(23):7418. https://doi.org/10.3390/jcm13237418.

Goldberg RL, Freed KE, Klemans N, et al. Angiotensin Receptor-Neprilysin Inhibition improves blood pressure and heart failure control in left ventricular assist device patients. ASAIO J. 2021;67(12):e207. https://doi.org/10.1097/MAT.0000000000001435.

Elad B, Lee C, Baranowska J, et al. Vericiguat experience in durable left ventricular assist device patients. Artif Organs. 2025;49(5):907–10. https://doi.org/10.1111/aor.14971.

Xanthopoulos A, Wolski K, Wang Q, et al. Postimplant Phosphodiesterase-5 inhibitor use in centrifugal flow left ventricular assist devices. JACC: Heart Fail. 2022;10(2):89–100. https://doi.org/10.1016/j.jchf.2021.09.008.

Chedid El Helou M, Nandar PP, Tereshchenko LG, et al. Factors associated with the use of guideline-directed medical therapy in patients with left ventricular assist device. Eur J Heart Fail Published Online March. 2025;17. https://doi.org/10.1002/ejhf.3591.

Michelis KC, Zhong L, Peltz M, et al. Dynamic forecasts of survival for patients living with destination left ventricular assist devices: insights from INTERMACS. J Am Heart Assoc. 2020;9(14):e016203. https://doi.org/10.1161/JAHA.119.016203.

Veen KM, Mokhles MM, Soliman O, et al. Clinical impact and natural course of uncorrected tricuspid regurgitation after implantation of a left ventricular assist device: an analysis of the European registry for patients with mechanical circulatory support (EUROMACS). Eur J Cardiothorac Surg. 2021;59(1):207–16. https://doi.org/10.1093/ejcts/ezaa294.

Mendiola Pla M, Chiang Y, Nicoara A, et al. Surgical treatment of tricuspid valve regurgitation in patients undergoing left ventricular assist device implantation: interim analysis of the TVVAD trial. J Thorac Cardiovasc Surg. 2024;167(5):1810–e18202. https://doi.org/10.1016/j.jtcvs.2022.10.054.

Mullan C, Caraballo C, Ravindra NG, et al. Clinical impact of concomitant tricuspid valve procedures during left ventricular assist device implantation. J Heart Lung Transpl. 2020;39(9):926–33. https://doi.org/10.1016/j.healun.2020.05.007.

Sg D, Ag K. Bridge to recovery: Understanding the disconnect between clinical and biological outcomes. Circulation. 2012;126(2). https://doi.org/10.1161/CIRCULATIONAHA.111.040261.

Gunawan A, Robson D, Krishnaswamy RJ, et al. Longitudinal analysis left ventricular chamber responses under durable LVAD support. J Heart Lung Transplantation. 2024;43(3):420–31. https://doi.org/10.1016/j.healun.2023.10.004.

Kyriakopoulos CP, Taleb I, Tseliou E, et al. Impact of diabetes and glycemia on cardiac improvement and adverse events following mechanical circulatory support. Journal Am Heart Association Published Online July. 2024;16. https://doi.org/10.1161/JAHA.123.032936.

Bonios MJ, Koliopoulou A, Wever-Pinzon O, et al. Cardiac rotational mechanics as a predictor of myocardial recovery in heart failure patients undergoing chronic mechanical circulatory support: A pilot study. Circ Cardiovasc Imaging. 2018;11(4):e007117. https://doi.org/10.1161/CIRCIMAGING.117.007117.

Diakos NA, Taleb I, Kyriakopoulos CP, et al. Circulating and myocardial cytokines predict cardiac structural and functional improvement in patients with heart failure undergoing mechanical circulatory support. J Am Heart Assoc. 2021;10(20):e020238. https://doi.org/10.1161/JAHA.120.020238.

Boulet J, Mehra MR. Left ventricular reverse remodeling in heart failure: remission to recovery. Struct Heart. 2021;5(5):466–81. https://doi.org/10.1080/24748706.2021.1954275.

Shah P, Psotka M, Taleb I, et al. Framework to classify reverse cardiac remodeling with mechanical circulatory support. Circ-heart Fail. 2021;14:e007991. https://doi.org/10.1161/CIRCHEARTFAILURE.120.007991.

Schmitto JD, Shaw S, Garbade J, et al. Fully magnetically centrifugal left ventricular assist device and long-term outcomes: the ELEVATE registry. Eur Heart J. 2023;45(8):613–25. https://doi.org/10.1093/eurheartj/ehad658.

Rohde S, de By TMMH, Bogers AJJC, Schweiger M. Myocardial recovery in children supported with a durable ventricular assist device-a systematic review. Eur J Cardiothorac Surg. 2023;64(2):ezad263. https://doi.org/10.1093/ejcts/ezad263.

Miera O, Germann M, Cho MY, et al. Bridge to recovery in children on ventricular assist devices—protocol, predictors of recovery, and long-term follow-up. J Heart Lung Transplantation. 2018;37(12):1459–66. https://doi.org/10.1016/j.healun.2018.08.005.

Rohde S, Sandica E, Veen K, et al. Outcomes in small children on Berlin heart EXCOR support: age and body surface area as clinical predictive factors. Eur J Cardiothorac Surg. 2022;63(1):ezac516. https://doi.org/10.1093/ejcts/ezac516.

Javier Delmo EM, Javier MFDM, Böthig D, et al. Heart failure in the young: insights into myocardial recovery with ventricular assist device support. Cardiovasc Diagn Ther. 2021;11(1):148–63. https://doi.org/10.21037/cdt-20-278.

Birks EJ. Molecular changes after left ventricular assist device support for heart failure. Circ Res. 2013;113(6):777–91. https://doi.org/10.1161/CIRCRESAHA.113.301413.

Diakos NA, Navankasattusas S, Abel ED, et al. Evidence of Glycolysis Up-Regulation and pyruvate mitochondrial oxidation mismatch during mechanical unloading of the failing human heart: implications for cardiac reloading and conditioning. JACC Basic Transl Sci. 2016;1(6):432–44. https://doi.org/10.1016/j.jacbts.2016.06.009.

Badolia R, Ramadurai DKA, Abel ED, et al. The role of nonglycolytic glucose metabolism in myocardial recovery upon mechanical unloading and circulatory support in chronic heart failure. Circulation. 2020;142(3):259–74. https://doi.org/10.1161/CIRCULATIONAHA.119.044452.

Cluntun AA, Badolia R, Lettlova S, et al. The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab. 2021;33(3):629–e64810. https://doi.org/10.1016/j.cmet.2020.12.003.

Froese N, Szaroszyk M, Galuppo P, et al. Hypoxia attenuates pressure Overload-Induced heart failure. J Am Heart Assoc. 2024;13(3):e033553. https://doi.org/10.1161/JAHA.123.033553.

Birks EJ, Hall JL, Barton PJR, et al. Gene profiling changes in cytoskeletal proteins during clinical recovery after left ventricular-assist device support. Circulation. 2005;112(9 Suppl):I57–64. https://doi.org/10.1161/CIRCULATIONAHA.104.526137.

Gene Profiling Changes. In cytoskeletal proteins during clinical recovery after left Ventricular–Assist device support. https://doi.org/10.1161/CIRCULATIONAHA.104.526137

Latif N, Yacoub MH, George R, Barton PJR, Birks EJ. Changes in sarcomeric and Non-sarcomeric cytoskeletal proteins and focal adhesion molecules during clinical myocardial recovery after left ventricular assist device support. J Heart Lung Transplantation. 2007;26(3):230–5. https://doi.org/10.1016/j.healun.2006.08.011.

Heerdt PM, Holmes JW, Cai B, et al. Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation. 2000;102(22):2713–9. https://doi.org/10.1161/01.cir.102.22.2713.

Hall JL, Birks EJ, Grindle S, et al. Molecular signature of recovery following combination left ventricular assist device (LVAD) support and Pharmacologic therapy. Eur Heart J. 2007;28(5):613–27. https://doi.org/10.1093/eurheartj/ehl365.

Hall JL, Birks EJ, Grindle S, et al. Molecular signature of recovery following combination left ventricular assist device (LVAD) support and Pharmacologic therapy. Eur Heart J. 2006;28(5):613–27. https://doi.org/10.1093/eurheartj/ehl365.

Terracciano CMN, Koban MU, Soppa GK, et al. The role of the cardiac Na+/Ca2 + Exchanger in reverse remodeling. Ann N Y Acad Sci. 2007;1099(1):349–60. https://doi.org/10.1196/annals.1387.061.

Drakos SG, Badolia R, Makaju A, et al. Distinct transcriptomic and proteomic profile specifies heart failure patients with potential of myocardial recovery upon mechanical unloading and circulatory support. Circulation. 2023;147(5):409–24. https://doi.org/10.1161/CIRCULATIONAHA.121.056600.

Müller J, Wallukat G, Weng YG, et al. Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy. Circulation. 1997;96(2):542–9. https://doi.org/10.1161/01.CIR.96.2.542.

Bruckner BA, Stetson SJ, Perez-Verdia A, et al. Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support. J Heart Lung Transplantation. 2001;20(4):457–64. https://doi.org/10.1016/S1053-2498(00)00321-1.

Dandel M, Weng Y, Siniawski H, et al. Prediction of cardiac stability after weaning from left ventricular assist devices in patients with idiopathic dilated cardiomyopathy. Circulation. 2008;118(14 Suppl):S94–105. https://doi.org/10.1161/CIRCULATIONAHA.107.755983.

Amrute JM, Lai L, Ma P, et al. Defining cardiac functional recovery in end-stage heart failure at single-cell resolution. Nat Cardiovasc Res. 2023;2(4):399–416. https://doi.org/10.1038/s44161-023-00260-8.

Selzman CH, Madden JL, Healy AH, et al. Bridge to removal: A paradigm shift for left ventricular assist device therapy. Ann Thorac Surg. 2015;99(1):360–7. https://doi.org/10.1016/j.athoracsur.2014.07.061.