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Combining Stem Cell Therapy for Advanced Heart Failure and Ventricular Assist Devices: A Review

Reich, Heidi J.*; Czer, Lawrence S. C.; Ramzy, Danny*; Arabia, Francisco*; Moriguchi, Jaime; Ascheim, Deborah D.; Henry, Timothy D.

doi: 10.1097/MAT.0000000000000782
Review Articles

The use of stem cell therapy in combination with a left ventricular assist device (LVAD) for patients with advanced heart failure (HF) is an attractive concept with the potential to alter the natural history of HF. Cell therapy trials for HF have demonstrated excellent safety and encouraging results, but current rates of myocardial recovery after LVAD implantation are limited. Early trials combining these 2 therapies to increase the likelihood of recovery and to potentially obviate the need for subsequent transplantation appear promising. Additionally, the application of cell therapy to patients undergoing LVAD implantation as a bridge to cardiac transplantation creates an opportunity to examine cardiac tissue before and after treatment and to study the mechanism of benefit. Despite the promise, there is a paucity of data for the combination of stem cell therapy with LVAD insertion in patients with HF. Of 11 case series or clinical trials, the largest enrolled 30 patients. We highlight clinical trials using stem cell therapy for end-stage HF most relevant to an LVAD patient population and comprehensively review the preclinical and clinical studies of combined stem cell therapy and long-term mechanical circulatory support. Based on the available clinical trials, the combination of stem cell therapy and LVAD support is a promising approach but requires further clinical refinement, with additional clinical data and larger numbers of patients required to support its clinical application.

From the Divisions of *Cardiothoracic Surgery and

Cardiology, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.

Submitted for consideration October 2017; accepted for publication in revised form February 2018.

Disclosure: T.D. Henry (scientific advisory board for Vericel, Mesoblast, Capricor, NHLBI CCTRN and Celyad), D.D. Ascheim (employee, Capricor Inc.). The other authors have no relevant potential conflicts of interest to disclose.

Correspondence: Lawrence S.C. Czer, M.D., 127 S San Vicente Boulevard A-3100, Los Angeles, CA 90048. Email: Lawrence.Czer@cshs.org.

An estimated 5.7 million American adults have heart failure (HF), which is the leading cause of morbidity and mortality in the United States.1 The prevalence of HF and related expenses are rising, with the costs attributable to HF in the United States expected to increase 127% to nearly $70 billion by 2030.2 Despite progress in medical and left ventricular (LV) assist device (LVAD) therapy, mortality within 5 years of diagnosis of HF remains as high as 50%.3 The combination of stem cell therapy and mechanical circulatory support is an attractive concept with the potential to alter the natural history of HF.

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Ventricular Assist Devices for Advanced Heart Failure and Rates of Recovery Following Insertion

HF with reduced ejection fraction (EF) is a progressive disease manifested by worsening cardiac dysfunction over time despite current standard medical therapy.3 , 4 For advanced HF patients, treatment options include heart transplantation, mechanical circulatory support, or supportive care.3 , 4 A considerable discrepancy exists between the large number HF patients in need of a heart transplant and the limited number of donor organs available. Left ventricular assist devices are increasingly used as a bridge to transplantation, destination therapy, or bridge to recovery for patients with refractory HF. Long-term mechanical circulatory support has been shown to improve survival; however, this comes at the cost of significant morbidity such as bleeding and stroke. Both continuous flow and pulsatile flow devices are available, but most bridge to transplantation and nearly all destination therapy patients today receive a continuous flow pump because of reduced device failure rate and superior stroke-free survival.5–8 Overall 1 and 2 year survival rates for HF patients receiving a continuous flow device are 80% and 70%, respectively.5 In addition to the survival benefit, LVAD placement is associated with improved functional capacity and quality of life.5

The failing heart undergoes maladaptive remodeling, characterized by eccentric ventricular dilation, reduced contractility, increased cardiac filling pressures and wall stress, accompanied by systemic neurohormonal changes.9 , 10 At the cellular and molecular level, corresponding changes include altered myocyte geometry and size, progressive interstitial fibrosis, upregulation of cytokines and inflammation, myosin isoform changes, aberrant myocardial energetics, and decreased beta receptor density and calcium handling proteins.9

Mechanical unloading of the heart provides symptomatic relief and may facilitate LV reverse remodeling and myocardial recovery. Reverse remodeling includes the structural and histologic changes observed with HF therapies that improve function or survival. Myocardial recovery occurs along a spectrum; here the term denotes improvement in cardiac function sufficient for device explantation without recurrence of refractory HF or the need for heart transplant.

Mechanical unloading of the heart using an LVAD may result in changes in myocardial structure,11 as well as biomarkers of stretch, inflammation, fibrosis, and metabolism.12 , 13 Reverse remodeling and myocardial recovery may occur to a greater extent with use of pulsatile-flow devices. Pulsatile devices lead to greater improvements in cardiac function by echocardiography, as well as greater improvement in natriuretic peptide levels and biomarkers of extracellular matrix turnover.14 Mechanical unloading of the heart with either device reduces myocyte hypertrophy and, less consistently, myocardial fibrosis, suggesting that myocardial work can be effectively reduced regardless of the type of pump flow.14 Despite concerns that there can be too much of a good thing—that excessive reverse remodeling may be pathologic—more recent data suggest that LVAD-associated regression of hypertrophy does not progress to the point of atrophy or degeneration.12 The extent to which ventricular remodeling represents detrimental pathology versus adaptive physiologic compensation remains controversial.15 The combination of LVAD and cell therapy is an attractive concept whereby the mechanical unloading of the heart may promote engraftment and both interventions may modulate the neurohormonal and inflammatory states to promote myocardial regeneration and recovery.16–18

Nevertheless, myocardial recovery remains the exception, not the rule, for HF patients who undergo LVAD placement. Excluding younger HF patients with select etiologies, such as infectious myocarditis, peripartum or alcoholic cardiomyopathy, recovery is infrequent. Although the reported incidence of recovery is variable, it appears to be less than 1% (Table 1) for patients with chronic ischemic cardiomyopathy. The rate of recovery is higher for patients with nonischemic cardiomyopathy, but it is unlikely to exceed 15% (average 3.7%, 272/8760; Table 1). Of 10,542 patients in the interagency registry for mechanically assisted circulatory support (INTERMACS) database who received implanted devices from June 2006 to December 2013, only 0.9% (93/10,542) were designated bridge to recovery.7

Table 1

Table 1

Variability in reported recovery rates may be explained, in part, by limitations in study design, with a bias toward underestimation of the myocardial recovery rate in retrospective studies plus considerable heterogeneity in the study populations.33 A predictive model for cardiac recovery with LVAD, INTERMACS Cardiac Recovery Score, estimates probability of recovery using patient age, HF etiology, time from cardiac diagnosis, presence of ICD, serum creatinine, and LV end diastolic diameter.32 Within the spectrum of myocardial recovery,34 a greater frequency of patients experience improvement of LV EF ≥40% with LVAD support (5% with ischemic and 21% with nonischemic cardiomyopathy).35 Treatment with neurohumoral blockade may promote myocardial recovery while on LVAD support.34 Development of a standard pharmacologic protocol for neurohumoral blockade is a challenging issue in LVAD recovery clinical trials, in which clinical problems such as right ventricular failure, arrhythmias, and renal failure may affect the utilization or titration of neurohumoral blockade. Additional factors that may potentially influence recovery rates include HF severity at the time of LVAD insertion (as measured by INTERMACS score), invasiveness of device procedure (sternotomy, thoracotomy, or percutaneous approach), and device strategy (temporary versus durable support). These and other factors potentially affecting recovery rates should be taken into account with future trials of cell therapy in LVAD patients. Choice of end-point for clinical trials of stem cell therapy in LVAD patients is likely to be important, given the modest effect of stem cells on LVEF, a commonly used end-point. Other end-points may include LV end diastolic diameter (or other measure of heart size), diastolic function, hemodynamic measures, imaging assessment of scar or fibrosis, functional assessment, survival, and freedom from stroke or other complications.

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Clinical Trials of Cell Therapy for Heart Failure: Cell Type, Method of Delivery, and HF Etiology

There is growing optimism that, unlike traditional medical or device therapies, cell therapy may result in myocardial regeneration, attenuate adverse ventricular remodeling, and improve cardiac function.36–38 Positive results in multiple preclinical models with a wide range of cells and methods of delivery provided the basis for clinical trials.36 , 37 Overall, early clinical trials have demonstrated excellent safety with encouraging results.37 , 38 In a meta-analysis of 31 independent clinical trials comparing administration of autologous cells to either no intervention or placebo, cell therapy significantly reduced both mortality (risk ratio (RR) 0.48 [95% confidence interval (CI), 0.34–0.69]) and HF rehospitalization (RR 0.39 [95% CI, 0.22–0.70]).38 Additionally, performance status, exercise capacity, LVEF (mean difference 4.66% [95% CI, 2.99–6.33]), and quality of life were significantly improved without an increase in arrhythmias (RR 1.45 [95% CI, 0.72–2.92]).38 The modest initial results may be explained, at least in part, by the variety of cell types, cell potency, dosage, method of delivery, patient selection and HF etiologies, and clinical end-points. The optimal strategy to achieve maximal clinical benefit likely depends on all of the above factors.

Although the best cell type for a given clinical situation has not been determined, selection of the cell type may need to be guided by the underlying etiology and pathophysiology: for example, ischemic cardiomyopathy with dead muscle and normal blood flow, ischemic cardiomyopathy with hibernating (or viable) muscle and impaired blood flow, or nonischemic cardiomyopathy. For the first group, the focus may need to be on myocardial regeneration. The second patient population may be better served by cells which improve myocardial blood flow. Finally, the approach to nonischemic cardiomyopathy might be geared toward cells with antifibrotic and anti-inflammatory regenerative properties. Key clinical trial results with specific cell types are worth reviewing.

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Skeletal Myoblasts

In the first clinical trial of cell therapy in HF patients with LVADs, Pagani et al. performed quadriceps muscle biopsies in five patients 2 to 4 weeks before LVAD insertion as a bridge to cardiac transplantation, then injected skeletal myoblasts intramyocardially (IM) during LVAD implantation.39 This landmark trial demonstrated successful engraftment by histologic assessment after the hearts were explanted for transplant with no adverse events related to the cell injections. Engraftment was determined by staining for skeletal muscle–specific myosin heavy chain (not present in the host cardiac myocytes). Total myoblast cell survival was calculated to be <1% based on the delivered dose of 300 million cells.39 No serious arrhythmias were observed; however, there was no information on gap junction formation or connexin-43 in the engrafted or cell delivery areas.

The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial was a randomized clinical study comparing low- or high-dose IM autologous skeletal myoblast therapy to placebo delivered at the time of coronary artery bypass grafting (CABG) for 97 patients with an LVEF ≤ 35% and myocardial ischemia.40 At 6 months, left ventricular volumes were reduced with cell therapy, although there was no difference in LVEF or regional wall motion recovery. A nonsignificant but twofold increase in the number of arrhythmias was observed in skeletal myoblast-treated patients. Following MAGIC, two small trials using percutaneous IM autologous skeletal myoblasts reported trends for improved HF symptoms but an increase in ventricular arrhythmias.41 The occurrence of arrhythmias was attributed to electrically isolated clusters of myoblasts and lack of gap junction formation, with resultant predisposition to re-entry.40 , 41

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Adipose-Derived Cells

Adipose tissue is an attractive potential source for regenerative cells because of the relative ease of tissue harvesting using liposuction. Two small trials, adipose-derived regenerative cells in patients with ischemic cardiomyopathy (PRECISE) (N = 27) and autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction (ATHENA) (N = 31) reported improvements in HF symptoms and quality of life without an improvement in LVEF in patients with reduced LVEF and evidence for ongoing ischemia.42 , 43

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Bone Marrow Mononuclear Cells

The most cell therapy clinical experience in HF is with bone marrow mononuclear cells (BMMC), and meta-analyses suggest a beneficial effect.37 , 38 , 44 , 45 The First Mononuclear Cells injected in the US (FOCUS) study was a Phase II randomized double-blind placebo controlled trial conducted by the Cardiovascular Cell Therapy Research Network (CCTRN) comparing IM injections of autologous BMMC to placebo in 92 HF patients not amenable to revascularization and LVEF ≤ 45% with evidence of ongoing ischemia.46 There was a significant improvement in LVEF by 2.7% with cell therapy, which correlated to the percentage of CD34+ cells administered, and was inversely correlated with age, suggesting the characteristics of the autologous cells matter, perhaps in relation to pluripotency versus specific lineage; CD34 is a surrogate marker for hematopoietic stem and progenitor cells.

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Mesenchymal Stem Cells

The Transendocardial Injection of Autologous Human Cells in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial was a randomized, double-blind, placebo-controlled comparison of autologous mesenchymal stem cells (MSC) and BMMC in 65 patients with ischemic cardiomyopathy and LVEF ≤ 50%.47 Each cell type had a placebo arm, with injection of placebo (instead of MSC or BMMC) into the target area. The primary end-point was the incidence of significant adverse events within 30 days of treatment, which was similar in both groups. Analysis of additional secondary end-points revealed encouraging within-group trends but none that were statistically significant between groups. Minnesota Living with Heart Failure (MLHF) scores improved with both types of cell therapy (−6.3, p = 0.02, and −8.2, p = 0.004) and not with placebo (p = 0.36). Six-minute walk distance increased (p = 0.03), scar size decreased (−18.9%, p = 0.004), and regional wall motion improved (−4.9, p = 0.03) with MSC treatment, but LVEF was similar.

The Mesenchymal Stromal Cells in chronic ischemic Heart Failure (MSC-HF) Trial randomized 60 patients with symptomatic HF (LVEF <45%, New York Heart Association [NYHA] Classes II-III) to IM injections of MSC or placebo.48 Using multislice cardiac magnetic resonance imaging or computed tomography images at end diastole and end systole, the endocardial and epicardial borders were manually traced, and the left ventricular volumes and EF were calculated. At 6-month follow-up, LV end systolic volume (ESV; −7.6, p = 0.001), LVEF (+6.2%, p < 0.0001), stroke volume (+18.4 mL, p < 0.0001), and myocardial mass (+5.7 g, p = 0.001) improved significantly with cell therapy, without corresponding improvements in NYHA class or 6-minute walk test.

The number and potency of autologous cells decline with age and cardiovascular risk factors.49 The clinical significance of this was demonstrated in the FOCUS trial46 and stimulated novel approaches to overcome this limitation, including the use of allogeneic cells. The Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) study randomized 30 patients to transendocardial injections of one of three doses (20, 100, or 200 million cells) of either autologous or allogeneic MSC for HF patients with LVEF ≤ 50% and found that in patients with ischemic cardiomyopathy, autologous MSC cells were associated with improvement in the 6-minute walk test and MLHF score, while allogeneic MSC cells reduced LV end-diastolic volume (EDV), with no effect of either cell type on EF but an improvement in sphericity index with both.50 In patients with nonischemic cardiomyopathy, allogeneic MSC cells were associated with an improvement in the 6-minute walk test and an increase in EF and a lower major adverse cardiac event rate.51 Importantly, there was a low rate of alloimmune reactions in patients receiving allogeneic MSCs (3.7%), suggesting an acceptable immunologic safety profile.51

A Phase II study of three increasing doses (25, 75, or 150 million) of allogeneic MSC or mock injections was conducted in 60 patients with ischemic or nonischemic cardiomyopathy with LVEF <40% and NYHA class II or III symptoms.52 An acceptable safety profile, with similar incidence of adverse events was reported in both groups. All-cause mortality was similar between groups, but importantly, HF-related major adverse cardiac events (MACE; HF hospitalization, successfully resuscitated cardiac death, or cardiac death) were reduced (100% vs. 67% HF-MACE-free; p = 0.025) by treatment with the high dose of allogeneic MSC (150 million cells) versus control.

Another approach to overcome the limitations of autologous cells is to enhance the autologous product. The Cardiopoietic stem Cell therapy in heart failure (C-CURE) trial randomized 48 patients with chronic ischemic cardiomyopathy (LVEF 15–40%) to receive endomyocardial delivery of enhanced autologous MSC compared with standard of care.53 The primary end-points were feasibility, with an acceptable dose of MSC achieved in 75% of patients, and safety, with a single episode of ventricular tachycardia during the cell delivery procedure that responded to cardioversion and no other delivery-related complications. In addition, they reported significantly greater improvement in LVEF (from 27.5 ± 1.0% to 34.5 ± 1.1% vs. from 27.8 ± 2.0% to 28.0 ± 1.8% with standard of care alone, p < 0.0001) and reduction in LVESV (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p < 0.001), 6-minute walk distance, and a composite score of NYHA functional class, quality of life, physical performance, hospitalization, and event-free survival for patients who received cell therapy. The results of the C-CURE trial provided the rationale for a Phase III trial, Chart-1, which recently reported the primary end-point at 39 weeks was negative in 271 patients but a subgroup of patients with elevated LVEDV of 200–370 ml (60% of patients) appeared to benefit (p = 0.015).54

Ixmyelocel-T is another enhanced autologous bone marrow–derived cell therapy, using autologous BMMCs with expansion of the CD90+ mesenchymal stem cells and the CD45+CD14+ autofluorescent M2-like macrophages through a special manufacturing process.55 The intramyocardial delivery of ixmyelocel-T via minithoracotomy in patients with end-stage HF because of ischemic and nonischemic dilated cardiomyopathy [DCM] (IMPACT-DCM) and intramyocardial delivery of ixmyelocel-T via Noga catheter in patients with end-stage HF because of ischemic and nonischemic dilated cardiomyopathy [DCM] (Catheter-DCM) trials randomized 61 patients with dilated cardiomyopathy to mini-thoracotomy and direct intramuscular injection or catheter-based IM injections of Ixmyelocel-T versus standard of care (on stable medical therapy according to accepted medical practice, with no new medications for the prior 3 months).55 Using the combined data from both trials, patients with ischemic dilated cardiomyopathy receiving Ixmyelocel-T had reduced rates of MACE, but similar benefit was not seen in patients with nonischemic dilated cardiomyopathy. Likewise, Ixmyelocel-T treatment improved NYHA class, 6-minute walk distance, and MLHF scores only in patients with ischemic dilated cardiomyopathy. A follow-up efficacy trial with Ixmyelocel-T using catheter-based transendocardial injection demonstrated the most positive cell therapy results to date. In a double-blind, placebo-controlled trial of 109 patients with LVEF <35% and NYHA class III-IV, the incidence of the primary end-point (a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated HF) was 38% with cell therapy versus 49% with placebo (RR 0.63 [95% CI, 0.42–0.97]), driven by reduction in death and HF hospitalization.56

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Heart-Derived Progenitor Cells

The Stem Cell Infusion in Patients with Ischemic CardiOmyopathy (SCIPIO) trial compared intracoronary autologous c-kit+ cardiac stem cells as a second procedure 4 months after CABG to no stem cell therapy for patients with previous myocardial infarction and LVEF ≤ 40% post-CABG.57 , 58 LVEF improved with stem cell therapy (from 27.5 ± 1.6% to 35.1 ± 2.4% [p = 0.004] at 4 months and to 41.2 ± 4.5% [p = 0.013] at 12 months) and regional wall motion in the cardiac stem cell–treated territories. Additionally, reduced infarct size (−6.9 ± 1.5 g [−22.7%] at 4 months [p = 0.002] and −9.8 ± 3.5 g [−30.2%] at 12 months [p = 0.039]), reduced nonviable mass (−11.9 ± 2.5 g [−49.7%] at 4 months [p = 0.001] and −14.7 ± 3.9 g [−58.6%] at 12 months [p = 0.013]), and increased LV viable mass (+11.6 ± 5.1 g at 4 months [p = 0.055] and +31.5 ± 11.0 g at 12 months [p = 0.035]) were seen in cell-treated patients by cardiac magnetic resonance imaging.57 , 58

After a positive trial of autologous cardiosphere-derived cells in a post-myocardial infarction model,59 , 60 the Dilated Cardiomyopathy Intervention with Allogeneic Myocardial-regenerative Cells (DYNAMIC; NCT02293603) Phase 2a dose-escalation trial in 14 Class III HF patients appears promising. At 6 months, there were statistically significant (p < 0.05) improvements in NYHA Class, left ventricular EF and end-systolic volume, and the MLHF score.61

Other stem cell sources such as induced pluripotent stem cells and embryonic stem cells hold promise for myocardial regeneration, but clinical trials are lacking,62 possibly because of concerns about use in humans with the genetic modifications in induced pluripotent stem cells and potential ectopic tissue or tumor formation with embryonic stem cells.

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Clinical Trials Combining Left Ventricular Assist Devices and Cell Therapy

There is little preclinical data combining LVAD and cell therapy likely because the trials are challenging given the expense and complexity. Mizuno et al. used a syngeneic rat heterotopic heart–lung transplant model as an unloaded and loaded heart to simulate an LVAD and studied whether the addition of cell therapy might mitigate HF recurrence after loading the heart (analogous to LVAD explantation). Using smooth muscle cells (SMCs) from the aorta of syngeneic (male Lewis) rats treated with trypsin and collagenase then cultured, one group of unloaded hearts received IM injection of SMCs and the other group did not. After 2 weeks of unloading (LVAD support), both groups were loaded (to simulate LVAD explantation). LV volumes were reduced more effectively during unloading (from 0.32 ± 0.02 at baseline to 0.11 ± 0.03 ml with cells vs. 0.16 ± 0.01 ml without cells, p = 0.03), the smaller LV volumes were maintained after the hearts were loaded (0.14 ± 0.06 with cells vs. 0.28 ± 0.05 ml without cells, p = 0.001), and there was less alteration of extracellular matrix proteins in hearts that received SMC injections than those that did not.63 A mouse isogenic heterotopic cardiac transplant model, mimicking the sustained ventricular unloading with LVAD, assessed cardiac function after IM injections of isogenic (C57BL/6) bone marrow–derived endothelial progenitor cells (Lin-/c-kit+/Sca1+ or KSL cells) in 14 mice compared with 13 mice injected with saline.64 In the mouse study, chronic LV-unloaded hearts treated with bone marrow–derived cells had less systolic dysfunction, increased coronary blood flow, increased capillary density, and increased myocardial mass relative to saline controls.64 A safety and feasibility study in six sheep combined LVAD implantation and transendocardial injections of allogeneic sheep mesenchymal precursor stem cells after induction of myocardial infarction (day 0), LVAD placement (day 30), and cell delivery (day 30 or 45) using NOGA mapping and transendomyocardial delivery.65 One of the sheep died during induction of the infarct, while five sheep tolerated the LVAD placement and delivery of cell therapy without apparent complication and provided the basis of assessment of the cell therapy with the LVAD.65

The advantages of studying investigational HF therapies in an LVAD patient population include ability to sample myocardial tissue before (at LVAD implantation) and after (at LVAD removal and heart transplantation) therapeutic intervention, hemodynamic support by the device should the therapy have adverse effects, and a rapidly growing volume of potential study subjects.66 Since the first clinical report of combined mechanical circulatory support and stem cell therapy in 2003,39 there have been eight additional case reports or case series, a single randomized trial, and one nonrandomized clinical trial describing clinical outcomes for HF patients treated with LVADs and stem cell therapy (Table 2). These studies included patients with ischemic (n = 37, 55%) and nonischemic (n = 30, 45%) cardiomyopathy, as well as pulsatile (n = 20, 30%) and continuous flow (n = 47, 70%) LVADs. Six studies involved concomitant cell therapy at the time of LVAD placement39 , 67 , 73–76 and five used a separate procedure for delivery.68–72

Table 2

Table 2

A total of 57 patients across 11 studies with LVADs received cell therapy (Table 2), and 10 patients were injected with medium as controls. Four of the patients (7%) experienced recovery of cardiac function adequate for explantation of the LVAD, and 11 (35.5%) of the patients died. For one patient, recovery was not sustained—this patient died from recurrent HF 351 days after device removal.75 Additional causes of death included sepsis at a mean of 179 (range, 24–466) days (n = 5),39 , 67 , 68 , 70 , 71 cancer at 211 and 379 days (n = 2),68 LVAD-related thrombus and stroke (n = 1),74 and not specified (n= 1).74 The patient for whom the cause of death was not specified died 33 months after cell therapy while awaiting heart transplant.

Ventricular arrhythmias are common after implantation of an LVAD, with an estimated incidence of 29.4% (347/1179) in a meta-analysis.77 Despite initial concerns about the potential arrhythmogenicity of cell therapy, four of the combined cell therapy-LVAD studies failed to report data on incidence of arrhythmias. Among the seven studies that included data on arrhythmias, five studies comprising 53 patients (with 43 patients receiving cells) detected arrhythmias after cell therapy in 34.9% (15/43; Table 2): seven (16.3%) with supraventricular arrhythmias, seven (16.3%) with sustained ventricular arrhythmias, and one (2.3%) with cardiac arrest. Transient, brief periods of ventricular premature beats were also detected.68 Although the numbers are small in the combined cell therapy–LVAD group, the rate of sustained ventricular arrhythmias (16.3%; 7/43) with combined cell therapy and LVAD was numerically lower than the rate (29.4%; 347/1179) with LVAD alone in the meta-analysis, with a trend toward statistical significance (p = 0.06, chi-square test), suggesting a possible target of clinical trials powered with larger numbers of cell therapy–LVAD patients.

In the largest trial to date, the NHLBI-funded Cardiothoracic Surgical Trials Network randomized 30 patients in a 2:1 allocation to receive IM injections of allogeneic MSC or medium at the time of LVAD implantation.75 At 90 days post implantation, no primary safety events (infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, or immune sensitization) occurred, and MSC treatment was associated with a higher rate of successful temporary reduction in LVAD support (50% vs. 20% for controls; p = 0.24). On the basis of the Bayesian design and these results, the posterior probability that MSC increased the likelihood of successful weaning was 93%. LVEF after successful LVAD weaning was 24.0% for MSC-treated vs. 22.5% for control patients (p = 0.56). Although this preliminary study was small, the safety data was encouraging and suggested that there may be a relevant benefit of cell therapy administered at the time of LVAD implantation, but that the treatment effect was attenuated by 12 months after administration. A follow-up randomized, double-blind, placebo-controlled trial with 159 patients is currently underway (Clinicaltrials.gov, NCT02362646).

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Challenges

Regenerative therapy in conjunction with LVAD implantation remains a compelling target for further clinical investigation for reasons previously discussed, as well as a variety of pragmatic reasons, including the opportunity to directly deliver cells into the myocardium at the time of device implantation and, for heart transplant candidates, the opportunity to obtain myocardial tissue for evaluation at the time of transplantation. Despite these opportunities, the discrepancy in rapid translation to clinical evaluation may be explained, at least in part, by unique challenges.78

The timing of cell therapy—before, during, or after LVAD implantation—presents complex tradeoffs (Figure 1). Administration during LVAD implantation can present challenges because patients are more ill and at increased risk for significant adverse events. Delivery post LVAD implantation requires an additional invasive procedure and has its own procedural challenges in light of the indwelling pump itself, as well as concomitant therapeutic considerations such as anticoagulation.

Figure 1

Figure 1

Additionally, measures of clinical efficacy after cell therapy remain ill-defined for patients on LVAD support. The efficacy end-point must be designed to assess the effect of the investigational cell therapy not the implant of the FDA-approved LVAD, and the optimal end-point remains unclear. The traditional primary clinical end-points in LVAD trials, stroke or LVAD replacement–free survival, do not meaningfully target the efficacy of the combination of the LVAD with the investigational adjunctive cell therapy. Identifying the optimal efficacy assessment for the combined therapies continues to be explored; however, to measure the impact of a regenerative therapy on cardiac function, the impact of LVAD support must be minimized. As such, it is likely that a meaningful efficacy assessment will continue to include some iteration of functional evaluation with temporary reduction of LVAD support. Other potential targets or end-points may include reduction in occurrence or frequency of sustained ventricular arrhythmias, reduction in unloaded heart size as measured by LVEDV or LVESV on LVAD support, histological evaluation of the myocardium for inflammatory changes, myocardial energetics, mitochondrial function,79 fibrosis, and scar, measurement of serological markers such as bin1,80 , 81 assessment of coronary blood flow and blood flow reserve, and myocardial perfusion.

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Conclusion

Stem cell therapy appears to be a safe and promising adjunct for patients with end-stage HF undergoing LVAD implantation. Cell therapy as synergistic therapy for advanced HF patients undergoing LVAD implantation remains an attractive hypothesis, with limited clinical experience. Further clinical data and larger numbers of patients are required to support this clinical application, and an ongoing clinical trial should provide important insight into the efficacy of the combination therapies.

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Acknowledgment

We extend our appreciation to Michele A. DeRobertis, R.N., who created Figure 1.

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                            Keywords:

                            heart failure; ventricular assist devices; stem cell therapy; cardiomyopathy; myocardial infarction; ischemic heart disease; clinical trials

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