The Effect of Left Ventricular Assist Device Therapy on Cardiac Biomarkers: Implications for the Identification of Myocardial Recovery
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Purpose of Review
Left ventricular assist device (LVAD) therapy serves as mainstay therapy for bridge to transplantation and destination therapy. Evidence is now mounting on the role of LVAD therapy as bridge to recovery. In the current review, we will summarize the data on biomarkers of myocardial recovery following LVAD implantation.
Myocardial recovery can occur spontaneously, following pharmacological intervention and in the setting of mechanical circulatory support such as LVAD. Several biomarkers such as B-type natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), ST2, etc. have been identified and are being used to guide medical therapy in heart failure (HF) patients. However, recent data raised concern that those biomarkers may not be helpful in managing heart failure patients in general, and as such questioned their use in the advanced heart failure population. At this point, the use of biomarker to identify patients with myocardial recovery during LVAD support has not been established, and LVAD explantation remains a decision driven by echocardiographic and hemodynamics improvement.
HF biomarkers in monitoring myocardial and neurohormonal activation response to mechanical unloading and medical therapy could be valuable. However, at this time, there is inadequate evidence to select a single or a set of HF biomarkers to reliably identify patients bridged to recovery for LVAD explantation.
KeywordsHeart failure Biomarkers Left ventricular assist device (LVAD) Myocardial recovery
Cardiac remodeling characterized by increase in chamber size, changes in shape, and reduction in function is largely driven by persistent volume and pressure overload and is the hallmark of cardiomyopathy and heart failure . Medical therapy with neurohormonal blockade and electrical synchronization (CRT) has been shown to induce reverse remodeling and regression of those anatomical changes [2, 3, 4, 5, 6]. Lately, left ventricular assist device (LVAD) therapy demonstrated robust reverse remodeling probably through significant unloading of the left ventricle and was associated with myocardial recovery and the ability to explant the pump. Research has been focused on comparing paired myocardial tissue at the time of LVAD implantation and later at the time of transplantation [7, 8, 9, 10, 11] analyzing the molecular changes accompanying the reverse remodeling process. However, the clinical dilemma still remains, which patients recover their myocardium to a level that will safely sustain LVAD explantation. Several investigators assessed the role of heart failure biomarkers to monitor and potentially identify patients with myocardial recovery. This review will summarize current knowledge on the role of biomarkers in diagnosing HF, monitoring and predicting outcome, and how or if to apply these findings on the advanced heart failure population supported with LVAD.
LVAD as Bridge to Recovery
To date, LVAD bridge to recovery (BTR) studies have revealed very large differences in the rate of defined recovery ranging from 4.5 to 73% depending on patient population with respect to etiology and duration of heart failure as well as patient age and gender .
In the overall LVAD population, myocardial recovery is a rare phenomenon. Topkara et al. reported that in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), the overall rate of myocardial recovery was only 1.4% . Similar to this finding, Wever-Pinzon reported that among 15,138 INTERMACS patients, cardiac recovery occurred in 192 (1.3%). However, the incidence of myocardial recovery was significantly higher among patients with a priori BTR strategy (11.2%) . Furthermore, those authors were able to identify parameters that were associated with higher recovery rate: age < 50 years, non-ischemic cardiomyopathy (NICM), time from cardiac diagnosis < 2 years, absence of ICD, creatinine < 1.2 mg/dl, and LVEDD < 6.5 cm (c-index 0.85; p < 0.0001) .
Other investigators reported higher rates of myocardial recovery in specific patient populations when designated myocardial recovery protocols were used. Birks et al. reported 73.3% recovery by using a protocol of aggressive neurohormonal blockade with the beta agonist clenbuterol in patients supported with pulsatile pump (HeartMate XVE). However, patients in this study were young and had a short HF duration prior to LVAD making these results less generalizable. Several years later, the same group reported a 63% explantation rate among patients supported with continuous-flow LVAD (HeartMate II) using a similar medical protocol [15, 16]. Though, when the same study was conducted in the USA as a multicenter study, the investigators were not able to replicate those results .
Multiple investigators continue to report varying success rates of myocardial recovery utilizing different medical protocols  and as such a systematic multicenter non-randomized longitudinal study to assess myocardial recovery was designed. The RESTAGE-HF (Remission From Stage D Heart Failure) (NCT01774656) has now completed recruitment and interim analysis had shown findings supportive of high rate of clinical myocardial recovery 36% with LVAD explantation in highly selected patients . The results of the study will be reported in the next few months.
Myocardial Changes After Mechanical Unloading
On the molecular level, mechanical unloading following LVAD therapy has been shown to promote changes in myocardial structural and gene expression. While the changes in the molecular and cellular substrate are beyond the scope of this review and have been extensively discussed in prior reviews , a consistent theme has been the persistent abnormalities in the molecular and cellular function in the setting of reverse remodeling. To this end, the concept of “myocardial remission” was introduced to distinguish improvement in ventricular function from the complete restoration of the pathogenic molecular changes of heart failure, including freedom from the clinical cardiovascular events seen in heart failure. This is highlighted by studies of patients with “recovery” of LV function and persistent abnormalities in biomarkers and increased risk for recurrent clinical cardiovascular events [21, 22, 23].
The clinical question remains how patients with LVAD and potential remission of heart failure could be better identified and thus selected for explantation. Biomarkers of heart failure would be attractive non-invasive tools since they might enable insight into molecular pathophysiology of HF with serial assessment to document improvement of molecular pathways following unloading with LVAD therapy . However, most available HF biomarkers have not been tested in patients with end-stage HF, and the direction and magnitude of expected changes in biomarker levels after LVAD reflecting hemodynamic improvement, mechanical unloading reflecting reduction in the degree of dysfunction in molecular pathways, is uncertain at this time .
Heart Failure Biomarkers
Peripheral blood heart failure biomarkers have been shown to predict HF and future events, assess severity, and guide therapy in acute and chronic stable HF .
A recent study enrolling 2516 patients with worsening heart failure from the BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) showed a reduction in hospitalization and death when using a biomarker-guided strategy of up-titrating HF medications compared to a hypothetical scenario in which all patients were successfully up-titrated [26•].
Myocardial overload/stretch and injury
Markers of co-morbidities such as creatinine and anemia markers
A full review on biomarkers in heart failure is beyond the scope of this review and has been discussed elsewhere .
Markers of Congestion Overload and Myocardial Stretch
Brain Natriuretic Peptides
B-type natriuretic peptide (BNP) gene transcription is induced following end-diastolic volume or pressure overload. BNP and its cleavage equivalent N-terminal pro B-type natriuretic peptide (NT-proBNP) are directly released into the circulation leading to diuresis and inhibition of the renin-angiotensin-aldosterone system (RAAS) [29, 30]. Both NT-proBNP and BNP reflect heart failure severity, and response to therapy, and are well-established predictors of de novo heart failure diagnosis and outcome [31, 32, 33]. Admission levels of BNP and NT-proBNP in acute decompensated heart failure as well as serial measurements in chronic heart failure have been shown to be associated with short- and long-term mortality [34, 35, 36]. Both markers decrease with heart failure therapy and rising levels have a poor prognosis . However, the recently published GUIDE-IT trial examining the role of a BNP and NT-proBNP-guided strategy to manage high-risk HFrEF (n 446) patients did not show a benefit over standard of care (n 448) to improve outcome including time to first hospitalization and cardiovascular mortality . These disappointing results differ from previous studies; among other considerations, this might have been related to the high-risk patient population with more severe heart failure, complicated by hypotension and azotemia limiting the ability to aggressively up-titrate medical therapy in response to NT-proBNP levels .
In a small study of 24 patients, serial measurements of both ANP and BNP demonstrated that the magnitude of BNP/ANP downregulation was dependent on LVAD type but was seen in all types of assist devices reaching normal levels in a small number of patients .
Circulating BNP levels (n = 17) as well as mRNA expression were measured in cardiac biopsy specimens of 27 patients before and after LVAD implantation. BNP plasma levels significantly decreased 3 months after LVAD implantation. This decrease in plasma levels was accompanied by a significant decrease of myocardial mRNA expression. Interestingly, BNP was found to be expressed not only by cardiomyocytes but also by endothelial cells, T cells, and macrophages . Among patients with proven myocardial recovery, lower BNP levels were measured; however, BNP has not been evaluated as a predictor of outcome in this study .
Recently, Ahmad et al. described changes in a broad panel of biomarkers following LVAD in 37 patients including NT-proBNP . Levels were measured prior to and a median of 136 days post-LVAD implantation. All biomarkers but neutrophil gelatinase-associated lipocalin (NGAL) decreased significantly post-LVAD but all levels remained significantly abnormal. Changes of HF biomarkers were also assessed based on prespecified changes in serial NT-proBNP levels, and, interestingly, when stratified for NT-proBNP levels, only the change of galectin-3 levels was significant post-LVAD .
Novel protein biomarkers in LVAD studies
Serial ST2 serum measurements at pre- and 1, 3 and 6 months post-LVAD (n = 38) [42•]
Serum levels pre and a median of 136 days (IQR 94 to 180) post-LVAD (n = 37) 
ST2 levels were significantly elevated in end-stage HF prior LVAD implantation and decreased post-LVAD to normal levels within 3 months 
ST2 levels decreased significantly post-LVAD 
ST2 may be useful as a biomarker to monitor therapy in end-stage heart failure patients
Galectin-3 levels pre and 1 month post-LVAD (n = 40) or TAH (n = 15) 
Galectin-3 level stratified for prespecified pro-BNP reduction (n = 37) pre and a median of 136 days (IQR 94 to 180) post-LVAD 
No significant change in expression pre- and post-LVAD. Patients who did not survive VAD due to MOF had significantly higher plasma concentrations of galectin-3 at the time of LVAD implant 
Greater significant reduction in galectin-3 was seen when stratified for pro-BNP with prespecified reduction post-LVAD 
No significant change with unloading as a single marker but potential additive information when assessed with other biomarkers
Serum and myocardial expression in NICM pre, 1, 3, and 6 months post-LVAD and at HT or VAD explant
(n = 30)
At 1 month post-LVAD, serum levels of GDF-15 were significantly decreased.
No difference in serum levels per LVAD strategies for BTT (n = 25) and BTR (n = 5) but observation limited by small sample size
Potential tool for monitoring post-LVAD but so far has not shown ability to discriminate between BTR and BTT
Serum levels in stable HF (n = 40), LVAD implantation (n = 40), HT (n = 40), and 24 controls 
Serum levels pre and a median of 136 days (IQR 94 to 180) post-LVAD (n = 37) 
NGAL levels increase with the severity of HF and decrease following LVAD. Higher in RV failure post-LVAD and higher in irreversible renal dysfunction 
NGAL did not decrease post-LVAD despite normalization of serum creatinine levels 
NGAL might be of value in prediction of RV failure post-LVAD and as a novel biomarker of renal dysfunction in patients with HF pending further clinical studies
Markers of Fibrosis
ST2 is a member of the interleukin 1 receptor family with soluble and membrane-bound isoforms . IL-33 is the functional ligand and the IL-33/ST2 signaling and is protective against myocardial hypertrophy and fibrosis in response to pressure overload . Soluble ST2 acts as a decoy receptor for IL-33 preventing this interaction and resulting in loss of cardioprotective effects of IL-33 in heart failure. The vascular endothelium is likely the predominant source of soluble ST2, rather than the human myocardium as initially described; however, results remain controversial . ST2 levels have been shown to be independent risk factors for mortality in chronic and acute decompensated heart failure and levels have been shown to decrease with treatment [49, 50, 51].
Data from the recently published TRIUMPH trial assessed the predictive value of frequently measured ST2 and NT-Pro-BNP levels in 496 patients with acute HF over 1 year follow-up for a primary composite endpoint of all-cause mortality and HF re-hospitalization. After adjustment for clinical factors and NT-proBNP, baseline ST2 was associated with an increased risk of the primary endpoint; additionally, ST2 levels appeared to be rising several weeks before the time of the primary endpoint . ST2 was identified as a strong predictor in acute decompensated HF independent of serial measured NT-proBNP. Thus, measuring ST2 could provide additional benefit to NT-proBNP assessment.
In an LVAD study, serial serum measurements of ST2 were performed at pre-implantation and 1, 3, and 6 months after LVAD implantation in 38 patients. As reported previously, ST2 levels were significantly elevated in end-stage HF prior to LVAD implantation (74.2 ng/ml (IQR 54.7–116.9; normal < 30 ng/ml)) and decreased substantially during LVAD support, to 29.5 ng/ml (IQR 24.7–46.6) (p < 0.001) to normal levels within 3 months in most patients. This suggests that even in patients with end-stage HF, ST2 may be used as a biomarker to monitor therapy [42•].
ST2 might be seen as the new gold standard biomarker for prognosis and monitoring in heart failure and has now been approved by the FDA and was included in the 2017 American College of Cardiology/American Heart Association update of HF guidelines [53, 54]. However, data on the value of ST2 in assessing for myocardial recovery in LVAD patients is sparse but promising at this point and the fact that ST2 levels do change with medical management could be a helpful asset [42•, 55, 56, 57]. The predictive value of ST2 now needs to be evaluated in large clinical trials .
Galectin-3 is secreted by activated cardiac macrophages and has pro-fibrotic properties implied in hypertrophy and adverse remodeling. Serum concentrations are increased in HF patients and have been shown to be associated with adverse outcomes in chronic heart failure [58, 59].
The PROTECT trial enrolling 151 patients with HF assessed serial galectin-3 levels. Time spent below serum levels of 20 ng/ml was an independent predictor of a lower cardiovascular event rate and increase of LV function even when adjusted for NT-proBNP, and renal function. Furthermore, galectin-3 levels at 6 months added prognostic value beyond the baseline level. Importantly, there were no significant effects of medications on galectin-3 levels .
Milting et al. described significantly elevated concentrations of galactin-3 at the time of LVAD implantation but no change by mechanical unloading or removal of the failing ventricles in the setting of total artificial heart. However, patients who did not survive LVAD due to multiple-organ failure (MOF) had significantly higher plasma concentrations of galectin-3 at the time of LVAD implantation as compared with those patients who were successfully bridged to transplantation .
Growth Differentiation Factor-15
Growth differentiation factor-15 (GDF-15) is a protein of the transforming growth factor beta superfamily and is emerging as a biomarker of heart failure, fibrosis, and potentially cardiac remodeling [62, 63, 64]. In a report of 30 patients with NICM, circulating levels and myocardial protein and mRNA expression of GDF-15 were analyzed before and 1, 3, and 6 months post-LVAD implantation as well as at the time of heart transplantation or LVAD explantation. One month post-LVAD implantation, serum levels of GDF-15 were significantly decreased compared with pre-implantation levels and remained stable thereafter. Furthermore, 96% of the end-stage HF patients were found to have elevated GDF-15 levels prior to LVAD, while only 25% had elevated level, 6 months following LVAD implantation.
Serum GDF-15 significantly correlated with kidney function and AST. Interestingly, serum GDF-15 levels also correlated with the severity of myocardial fibrosis but myocardial expression of GDF-15 was hardly detectable, suggesting that the myocardium is not a relevant source of GDF-15 production in these patients . Importantly, there was no difference in serum levels of GDF-15 between patients with LVAD strategies for bridge to transplantation (BTT) and BTR. Thus, the authors concluded that it is unlikely that GDF-15 can identify those patients that will demonstrate substantial recovery; however, this observation is limited by the small sample size of 25 BTT versus 5 BTR patients .
Changes of CRP concentrations post-LVAD have been infrequently studied. One report has shown persistently elevated CRP levels following LVAD and was shown to exacerbate end-organ dysfunction . Ahmad at et al. described decreasing CRP levels post-LVAD .
Grosman-Rimon et al. studied plasma levels of chemokines, cytokines, and inflammatory markers in 18 LVAD recipients, 14 heart failure patients waiting for LVAD placement, and 14 healthy control subjects. Levels of granulocyte-macrophage colony-stimulating factor, macrophage inflammatory proteins-1β, and macrophage-derived chemokine were significantly higher in the LVAD group compared with both the heart failure and the healthy control groups. CRP, interferon gamma-induced protein 10, monocyte chemotactic protein 1, and interleukin 8 levels were significantly higher in both the LVAD and heart failure groups compared to those in the control, but no significant differences were observed between the LVAD recipients and the heart failure patients. However, it is unknown if these elevated markers of inflammation have clinical implication . Our group recently showed elevated levels of TNF-α in LVAD patients contributing to vascular destabilization via induction of pericyte apoptosis and suppression of angiopoietin-1 expression as well as higher expression of tissue factor. Higher levels of TNF-α were associated with a higher risk of non-surgical bleeding. TNF-α might be a central regulator of LVAD-related angiodysplasia [67•].
Neutrophil Gelatinase-Associated Lipocalin
Neutrophil gelatinase-associated lipocalin (NGAL) is a small iron-binding protein and was originally characterized in extracts and secretions from human neutrophils . It is secreted at a baseline normal level from renal tubular cells with rapid increase during acute kidney injury and heart failure [69, 70]. In previous studies of post-myocardial infarction and HF as well as chronic HF, NGAL correlated with NYHA class and was associated with worsening renal function superior to BNP, creatinine, eGFR, and cystatin C to predict events and mortality [69, 71, 72, 73].
Pronschinske et al. assessed NGAL and cystatin C both in HF and after LVAD placement (n = 40). NGAL and cystatin C were elevated in patients with stable HF when compared to controls; NGAL increases with the severity of HF and decreased following LVAD implantation and hemodynamic improvement. NGAL was higher in patients developing irreversible renal dysfunction and correlated with eGFR. In this trial, NGAL outperformed established markers of renal function as well as cystatin C, but the underlying biologic mechanisms explaining this advantage are unclear. The authors introduce a cutoff of 200 ng/ml, representing the level at which it is 88.9% certain that a patient’s renal function will not improve following LVAD. Interestingly, NGAL was higher in those patients who developed right heart failure after LVAD implantation. NGAL level higher than 100 ng/ml was associated with right ventricular (RV) failure in 93.3% of the cases, while NGAL lower than 100 ng/ml was associated with only a 40.0% chance of developing RV failure . However, in a different study, NGAL remained abnormal post-LVAD despite normalization of serum creatinine levels. The authors raised the question if some aspects of renal function are not adequately captured by creatinine clearance alone .
It remains to be clarified if NGAL could be a direct marker of cardiac remodeling and HF severity or if it is mostly a marker or renal function affected by cardiac function? . Additionally, the value of NGAL in prediction of RV failure would need to be assessed in multicenter studies with confirmatory validation . The role of NGAL in myocardial recovery is unknown at this time.
MicroRNAs are short, non-coding RNAs that have been shown to be epigenetic regulators of stress responses in the heart via microRNA degradation or inhibition of protein translation. Despite being single-stranded RNA, microRNAs have demonstrated stability in both tissues and serum thus prompting investigation into the role of microRNAs as biomarkers.
Wang et al. assessed changes in plasma microRNA levels following LVAD implantation according to prespecified changes in the serially measured biomarkers galectin-3, NT-proBNP, and ST2. In one third of the cases, biomarkers improved, which was associated with an upregulation of a majority of microRNAs . In a study to investigate microRNA signatures in the setting of LVAD support, Akat et al. analyzed the cardiac-specific microRNA expression patterns in both myocardial tissue and serum in healthy individuals, in patients with stable heart failure, and in LVAD recipients (total n = 47). Healthy controls and stable heart failure patients demonstrated a low level of circulating levels of cardiac-specific miRNAs (< 0.1%) among all circulating mRNAs in serum. For the patients undergoing LVAD implant, serum levels of the cardiac-specific miR-208a, miR-208b, and miR-499 and the muscle-specific miR-1-1 and mir-133b increased by 140-fold (> 1%). Interestingly, serum levels of these cardiac-specific miRNAs declined to nearly normal during the period of LVAD support . Whether this signature is a reflection of mechanical unloading or more simply a marker of myocardial injury remains unanswered as these changes correlated with other cardiac biomarker of injury such as troponin I, yet did not correlate with BNP. Further studies of circulating miRNA expression patterns with rigorous assessments of reverse remodeling are warranted. LVAD therapy provides an opportunity to study changes in myocardial tissue and therefore a chance to understand the pathways that may promote recovery. These changes as reflected in serum may then provide powerful insight into the response to mechanical unloading and the potential to recover native ventricular function.
Can HF Biomarkers Reflect Myocardial Remission/Recovery? Potential Use of HF Biomarkers in LVAD
Several studies have shown that HF biomarkers change in response to neurohormonal blockade in chronic HF; however, it remains to be established if these findings are applicable to an end-stage heart failure population supported with LVAD [31, 32, 33, 49, 50, 51].
The field shows several promising developments, the most intriguing development possibly seen with the establishment of ST2 as a new biomarker. Nonetheless, not all studies assessing the response of HF biomarkers post-LVAD and/or initiation of neurohormonal blockade reported a measurable effect. At this time, no peripherally assessed biomarker reliably reflects myocardial recovery or remission. However, heart failure biomarkers might be helpful to assess response to medical management or adjustment in LVAD settings (such as LVAD speed) in these patients. Especially since centers with reported high rates of myocardial recovery post-LVAD report aggressive up-titration of neurohormonal blockade , the INTERMACS registry study revealed significantly higher likelihood of recovery with medical management . Thus, the ability of HF biomarkers to assess response to neurohormonal blockade could be a great asset.
A few HF biomarkers when studied in the LVAD population were associated with outcomes. Galectin-3 levels at the time of LVAD implantation were significantly higher in patients developing MOF compared to those successfully bridged to transplant .
NGAL levels were higher in patients with irreversible kidney failure and right ventricular failure post-LVAD . When compared between patients with LVAD for BTR or BTT, no difference in serum levels of GDF-15 was found; in this study, the authors concluded that it is unlikely that GDF-15 can identify those patients that will demonstrate substantial recovery . Novel biomarkers are summarized in the table.
The development and enhanced understanding of HF biomarkers in monitoring myocardial and neurohormonal activation response to mechanical unloading are promising and deserve further investigation in prospective studies with clearly defined endpoints, especially with the question of response to medical management and changes in LVAD settings. However, at this time, there is insufficient evidence to select a single or a set of heart failure biomarkers to reliably identify patients bridged to recovery for LVAD explantation.
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Conflict of Interest
The authors declare that they have no conflict of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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