REVIEW URRENT C OPINION
Stem cell therapy for chronic heart failure Gregor Poglajen a and Bojan Vrtovec a,b
Purpose of review The aim of this review was to discuss recent advances in clinical aspects of stem cell therapy in heart failure with emphasis on patient selection, stem cell types and delivery methods. Recent findings Several stem cell types have been considered for the treatment of patients with heart failure. In nonischemic heart failure, transplantation of CD34þ cells improved myocardial performance, functional capacity and neurohumoral activation. In ischemic heart failure, cardiosphere-derived cells were shown to reduce myocardial scar burden with concomitant increase in viable tissue and regional systolic wall thickening. Both autologous and allogeneic mesenchymal stem cells were shown to be effective in improving heart function in patients with ischemic heart failure; this may represent an important step toward the development of a standardized stem cell product for widespread clinical use. Summary Although trials of stem cell therapy in heart failure have shown promising results, the findings are not consistent. Given the wide spectrum of heart failure, it may be difficult to define a uniform stem cell therapy for all subsets of patients; instead, future stem cell therapeutic strategies should aim for a more personalized approach by establishing optimal stem cell type, dose and delivery method for an individual patient and disease state. Keywords dilated cardiomyopathy, heart failure, ischemic cardiomyopathy, stem cells
INTRODUCTION Despite advances that have been achieved in medical and device therapy over the past few decades, heart failure represents an increasingly common, debilitating disorder that carries an adverse prognosis [1]. Although current heart failure treatment options have been shown to improve survival and reduce heart failure symptoms [2], no therapy to date has been shown to promote the regeneration of myocardial damage or replacement of lost myocardial tissue, which represent the main underlying pathophysiologic mechanisms of heart failure development and progression. Ever since the first successful use of bone marrow stem cells in an experimental model of acute myocardial infarction was published in 2001 [3], there has been a growing interest in the heart failure community in applying stem cell therapy for the treatment of chronic heart failure. Although the results of numerous preclinical and clinical studies conducted in the last decade support the potential of stem cells to improve myocardial function and affect adverse ventricular remodeling, there are a number of clinical questions that remain poorly defined. Thus, the aim of this
review was to discuss recent advances in clinical aspects of stem cell therapy in patients with heart failure, with emphasis on patient selection, stem cell types and delivery methods.
PATIENT SELECTION AND STEM CELL TYPES Stem cells represent a cell population with selfrenewal properties and the potential to generate daughter cells that are capable of differentiation along specific cell lineages [4]. To date, several stem cell types have been considered for the treatment of
a
Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Ljubljana, Slovenia and bStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA Correspondence to Bojan Vrtovec, MD, PhD, Advanced Heart Failure and Transplantation Center, Department of Cardiology, University Medical Center Ljubljana, Zaloska 7, MC SI-1000, Ljubljana, Slovenia. Tel: +3861 522 2844; fax: +3861 522 2828; e-mail: bvrtovec@ stanford.edu Curr Opin Cardiol 2015, 30:301–310 DOI:10.1097/HCO.0000000000000167
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Cardiac failure
KEY POINTS Several clinical trials using both autologous and allogeneic cell sources have proven beneficial effects of stem cell therapy in patients with ischemic and nonischemic heart failure. Transendocardial cell delivery may be more effective than the intracoronary route. Future studies of stem cell therapy in heart failure should aim at more personalized patient-specific and disease-specific approaches.
patients with ischemic and nonischemic chronic heart failure. An overview of clinical studies according to stem cell types and patient selection is presented in Table 1.
Skeletal myoblasts Skeletal myoblasts are derived from skeletal muscle satellite cells. Because of the easy access, quick in-vitro expansion and relative resistance to hypoxic environment, skeletal myoblasts were initially considered to represent an ideal cell population for myocardial regeneration. In animal models of heart failure, skeletal myoblasts have been shown to differentiate into myotubes and form viable skeletal muscle-like grafts. This was associated with improved myocardial performance, attenuated adverse ventricular remodeling and decreased myocardial fibrosis [26,27]. These encouraging preclinical data were the basis for three clinical trials [MAGIC [5], percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment (POZNAN) [28] and 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAUSMIC) [6]] which, however, failed to show a consistent benefit of this stem cell population. Also, a risk of life-threatening ventricular arrhythmias using skeletal myoblasts has raised significant concerns. With other stem cell types becoming more accessible, the interest in skeletal myoblasts has decreased in recent years and currently no large randomized controlled trial is exploring the role of skeletal myoblasts in patients with chronic heart failure.
Bone marrow-derived stem cells Bone marrow is the source of a mixed population of hematopoetic and nonhematopoetic stem cells. Both groups have been shown to possess the ability 302
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for transdifferentiation into different cell lineages. Because of the easy access and procurement, this group of stem cells has gained the most attention in preclinical and clinical settings in recent years. The results of studies using bone marrow mononuclear cells (BMMCs) for the treatment of chronic ischemic heart failure have been conflicting. The first study to evaluate BMMCs in patients with ischemic heart failure demonstrated a significant improvement in left ventricular ejection fraction and reduction in end-systolic volume in treated patients at 2 and 4 months after the procedure. In addition, an increase in myocardial perfusion and patients’ exercise capacity was demonstrated [11,29,30]. These results were corroborated by other studies that used intramyocardial injections of BMMCs in periscar area [31,32]. Interestingly, BMMC injections directly into the scar tissue failed to produce comparable results [9]. In the TOPCARE-CHD study, intracoronary infusion of BMMC versus endothelial progenitor cells in patients with ischemic heart failure was analyzed. Left ventricular ejection fraction improved significantly in the BMMC group but not in the endothelial progenitor cells group, the exact underlying mechanisms remaining undefined [33]. Registry data from TOPCARE-CHD further suggested that BMMC stem cell therapy significantly decreases neurohumoral activation as early as 3 months after therapy. In addition, it was shown that infusion of BMMCs with high functional capacity was associated with improved long-term survival in this patient cohort [8]. However, in contrast to these findings, the effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure (FOCUS-CCTRN) trial, one of the largest trials to evaluate the effects of BMMCs in patients with ischemic heart failure, failed to show any benefit of stem cell therapy on myocardial performance, volumes or perfusion [34]. Nevertheless, a post-hoc analysis showed that CD34þ stem cell count in BMMC samples correlated significantly with the improvement of myocardial performance, suggesting that specific bone marrow cell subpopulations may be responsible for the beneficial effects of BMMC therapy [34]. Unselected BMMCs were used also in patients with nonischemic heart failure. In the TOPCAREDCM study, intracoronary BMMC infusion into the left anterior descending coronary artery resulted in improved regional wall motion of the injected area and global left ventricular myocardial performance [25]. In the autologous bone marrow cells in dilated cardiomyopathy (ABCD) trial [23], the investigators enrolled patients with nonischemic heart failure, who received either intracoronary injection of Volume 30 Number 3 May 2015
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ISH
ISH
Ang et al. [12]
Patel et al. [13]
ISH
ISH
Focus-HF [11]
CADUCEUS [17]
ISH
Yao et al. [10]
ISH
ISH
Hendrikx et al. [9]
SCIPIO [16]
ISH
TOPCARE-CHD [8]
ISH
ISH
SEISMIC [7]
POSEIDON [15]
ISH
CAUSMIC [6]
ISH
ISH
MAGIC [5]
Perin et al. [14]
Cause of heart failure
Study name
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16/7
30/0
10/10
10/10
42 (21/21)/23
20/10
24/23
10/10
52/23
26/14
12/11
97/30
Number of patients (treatment/controls)
CDC
CSC
MSC
ALDH
br
BMMC
BMMC, CD34þ
BMMC
BMMC
BMMC
EPC [6]
BMMC [5]
SM
SM
SM
Cell type
Table 1. Randomized controlled trials in chronic patients with heart failure
Intracoronary
Intracoronary
Transendocardial
Transendocardial
Transepicardial
Transepicardial Intracoronary
Transendocardial
Intracoronary
Transepicardial
Intracoronary
Transendocardial
Transendocardial
Transepicardial
Method of cell delivery
1 year
1 year
1 year
1 106
12–25 106
6 months
22 106
20, 100, 200 106
1 year
IC: 115 106 BMMC and 245 103 CD34þ TE: 84 106 BMMC and 142 103 CD34þ
6 months
6 months
30 106
2.4 106
6 months
12 106
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Neutral for LV volumes
Neutral for LVEF
Reduced scar size
Reduced scar size
Reduced NYHA f.c.
Improved LVEF
Neutral for LVEF
Reduced LV volumes
(Continued )
Improved exercise capacity
Reduced LV volumes
Improved MVO2
Improved LVEF
Neutral for LVEF Neutral for LV volumes Neutral for scar reduction
Improved injection site myocardial perfusion
Neutral for LVEF
Neutral for scar reduction
Neutral for LV volumes
Neutral for LVEF
Reduced LV volumes
Reduced NYHA f.c.
Neutral for LVEF
Improved LVEF (BMMC)
Improved exercise capacity
4 months
3 months
BMMC: 205 106
Reduced NYHA f.c.
Neutral for LVEF
Reduced LV volumes
Reduced NYHA f.c.
Improved myocardial viability
60 106
6 months
150–800 106
Improved LVEF Improved regional wall motion abnormalities
Reduced NYHA f.c. (BMMC)
1 year
30, 100, 300 and 600 106
Reduced LV volumes
Neutral for LVEF
Main outcome
EPC: 22 106
6 months
Follow-up interval
Low dose 400 106 High dose 800 106
Cell dose
Stem cell therapy for chronic heart failure Poglajen and Vrtovec
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]
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ISH
NONISH
Poglajen et al. [22 ]
ABCD [23]
NONISH
TOPCARE-DCM [25]
33/0
55/55
24/20
33/33
21/6
6/0
30/30
38 (19/19)/21
Number of patients (treatment/controls)
BMMC
CD34þ
BMMC
CD34þ
ADRC
MSC
CD133þ
MSC and BMMC
Cell type
Intracoronary
Transendocardial
Intracoronary
Transendocardial
Transendocardial
Transepicardial
Transepicardial
Transendocardial
Method of cell delivery
1.5 years
1.5 years
6 months
6 months 5 years
1 year
0.4 106/kg 0.8 106/kg 1.20 106/kg 90 106
28 106 123 106
259 106
6 months
5.1 106
N/A
1 year
Follow-up interval
N/A
Cell dose
Neutral for LV volumes
Improved myocardial perfusion
Improved LVEF
Improved survival
Reduced NT-proBNP
Improved exercise capacity
Neutral for LV volumes
Improved LVEF
Reduced NYHA f.c.
Improved LVEF
Reduced NT-proBNP
Improved exercise capacity
Neutral for LV volumes
Improved LVEF
Neutral for perfusion
Neutral for LVEF Neutral for exercise capacity
Reduced scar size
Improved LVEF
Improved regional LV function
Neutral for perfusion improvement
Neutral for scar size
Neutral for LVEF
Neutral for LV volumes
Improved regional LV function
Reduced scar size
Improved exercise capacity
Main outcome
ABCD, autologous bone marrow cells in dilated cardiomyopathy trial; ADRC, adipose-derived stem cells; ALDHbr, aldehyde dehydrogenase bright cells; BMMC, bone marrow mononuclear cells; CADUCEUS, Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction: a prospective, randomized phase 1 trial; Cardio133þ, autologous CD133þ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial; CAUSMIC, one-year follow-up of feasibility and safety of the first u.S., randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAUSMIC study); CDC, cardiosphere-derived cells; CSC, cardiac stem cells; EPC, endothelial progenitor cells; Focus-HF, a randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure; LV, left ventricle; MSC, mesenchymal stem cells; MVO2, maximal oxygen consumption; NONISH, nonischemic heart failure; NT-proBNP, amino-terminal of the prohormone brain natriuretic peptide; NYHA f.c., New York Heart Association functional class; POSEIDON, comparison of allogeneic vs. autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial; PRECISE, adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE trial; PROMETHEUS, The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery trial; SCIPIO, Cardiac stem cells in patients with ischaemic cardiomyopathy: initial results of a randomized phase 1 trial; SEISMIC, final results of a phase IIa, randomized, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial; SM, smooth muscle cells; TAC-HFT, transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial; TOPCARE-CHD, transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD registry; TOPCARE-DCM, a pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy.
NONISH
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]
Vrtovec et al. [24
ISH
PRECISE [21]
&
ISH
PROMETHEUS [20 ]
&
ISH
ISH
Cause of heart failure
Cardio133þ [19]
TAC-HFT [18
&&
Study name
Table 1 (Continued)
Cardiac failure
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(Continued )
Completed, awaiting publication August 2010 IC NONISH 60 Prospective, randomized, placebo-controlled Bone marrow derived adult stem cells for dilated cardiomyopathy (REGEN-DCM)/NCT 01302171
III
I/II Prospective, randomized Percutaneous stem cell injection delivery effects on neomyogenesis in dilated cardiomyopathy (the POSEIDON-DCM study)/NCT 01392625
BMMC
Recruiting November 2013 TE NONISH 36
January 2014 TE NONISH 80 CD34þ II/III Prospective, randomized Repetitive intramyocardial CD34þ cell therapy in dilated cardiomyopathy (REMEDIUM)/NCT 02248532
AutoMSC/ AlloMSC
Recruiting
Recruiting January 2014 IC NONISH 51 BMMC Prospective, randomized, placebo-controlled Infusion intracoronary of mononuclear autologous adult no expanded stem cells of bone marrow on functional recovery in patients with dilated cardiomyopathy and heart failure/NCT 02033278
II/III
November 2014 IC NONISH 42 Prospective, randomized, placebo-controlled Dilated cardiomyopathy intervention with allogeneic myocardially-regenerative cells (DYNAMIC)/NCT 02293603
I
Trial design Trial name/NCT number
Trial phase
Table 2. Ongoing trials in patients with chronic heart failure
Hematopoietic stem cells (HSCs) represent a part of the hematopoetic cell compartment of the bone marrow and differentiate into mature cells along lymphoid and myeloid lineages. When HSCs are released in the peripheral circulation, they become EPCs. Both cell types are positive for the CD34þ surface marker and together they form a population of CD34þ stem cells, which have been shown to have a potential to differentiate into endothelial cells and promote neovascularization [36]. Initially, CD34þ cells were used in patients with ischemic heart failure undergoing cardiac surgery. In this population, it was shown that transepicardial CD34þ stem cell injections around the scar area at the time of surgical revascularization may significantly improve myocardial performance when compared with surgical revascularization alone [13]. However, a recent study evaluating the effects of HSC in patients with ischemic heart failure undergoing surgical revascularization failed to confirm these findings [19]. Therefore, it appears that when injected at the time of cardiac surgery, CD34þ cells may not exert consistent beneficial effects on myocardial performance and structure. Alternatively, when CD34þ cells were injected via percutaneous transendocardial approach in patients with chronic ischemic heart failure, such a therapy led to a significant improvement in left ventricular global function (mainly driven by improved contraction of injected segments), improvement of exercise capacity and reduced neurohumoral activation
Cell type
Hematopoietic stem cells
alloCDC
No. of patients
Cause of heart failure
Cell delivery method
Trial start date
Trial status
BMCMs or sham control. During the 3-year followup, the left ventricular ejection fraction (LVEF) improved in the treatment arm by 5.9%. Similarly, in a study of patients with refractory nonischemic heart failure, infusion of BMMCs into the left main coronary artery was associated with improved myocardial performance, maximal oxygen consumption and quality of life [35]. These data may suggest that BMMC therapy may be of more benefit in patients with nonischemic heart failure than in patients with heart failure because of coronary artery disease; however, the variations in BMMC populations, patient selection criteria and delivery methods make direct comparisons between the studies very difficult. Currently, five randomized controlled trials are exploring the effects of BMMCs in patients with chronic ischemic and nonischemic heart failure focusing on different stem cell delivery routes, feasibility and efficacy of repeated stem cell injections and the effects of stem cell therapy in patients with left ventricular assist devices (Table 2).
Recruiting
Stem cell therapy for chronic heart failure Poglajen and Vrtovec
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306
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Prospective, randomized, placebo-controlled Prospective, randomized, placebo-controlled
Prospective, randomized
Prospective, randomized
An efficacy, safety and tolerability study of ixmyelocel-T administered via transendocardial catheter-based injections to patients with heart failure because of ischemic dilated cardiomyopathy (IDCM) (ixCELL DCM)/NCT 01670981
Bone marrow-derived adult stem cells for chronic heart failure (REGEN-IHD)/NCT 00747708
Stem cell therapy in patients with severe heart failure and undergoing left ventricular assist device placement (ASSURANCE)/NCT 00869024
Intracoronary versus intramyocardial application of enriched CD133pos autologous bone marrowderived stem cells (AlsterMACS)/NCT 01337011
The transendocardial stem cell injection delivery effects on neomyogenesis study (the TRIDENT study)/NCT 02013674
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. II
II/III
II
II
III
II
I/II
CSC
BMMC
AlloMSC
CD133þ
BMMC
BMMC
BMMC
Cardiopoietic cells
MPC
MSC
AlloMPC
Cell type
50
676
30
64
24
148
108
240
60
59
1730
No. of patients
ISH
ISH
ISH
ISH
ISH
ISH
ISH
ISH
ISH/NONISH
ISH/NONISH
ISH/NONISH
Cause of heart failure
IC
IC
TE
IC/TE
TEPI
IV/IC/TE
TE
TE
TE
TE
TE
Cell delivery method
December 2013
November 2013
November 2013
July 2011
November 2011
August 2008
October 2012
November 2012
August 2008
September 2008
January 2014
Trial start date
Recruiting
Recruiting
Recruiting
Recruiting
Recruiting
Completed, awaiting publication
Active, not recruiting
Recruiting
Unknown
Active, not recruiting
Recruiting
Trial status
alloCDC, allogeneic cardiosphere-derived cells; auto/alloMSC, autologous/allogeneic MSC; auto/alloMPC, autologous/allogeneic MPC; BMMC, bone marrow mononuclear cells; IC, intracoronary; ISH, ischemic heart failure; IV, intravenous; MPC, mesenchymal progenitor cells; MSC, mesenchymal stem cells; NONISH, nonischemic heart failure; TE, transendocardial; TEPI, transepicardial.
Prospective, randomized, placebo-controlled
Prospective, randomized, sham-controlled
Safety and efficacy of autologous cardiopoietic cells for treatment of ischemic heart failure (CHART-1)/NCT 01768702
Transplantation of autologous cardiac stem cells in ischemic heart failure/NCT 01758406
I/II
Prospective, randomized
A phase-II dose-escalation study to assess the feasibility and safety of transendocardial delivery of three different doses of allogeneic mesenchymal precursor cells (MPCs) in patients with heart failure/NCT 00721045
Prospective, randomized
I/II
Prospective, randomized, placebo-controlled
Autologous mesenchymal stromal cell therapy in heart failure/NCT 00644410
Compare the effects of single versus repeated intracoronary application of autologous bone marrow-derived mononuclear cells on mortality in patients with chronic postinfarction heart failure (REPEAT)/NCT 01693042
II/III
Prospective, randomized, sham-controlled
The purpose of this study was to evaluate the efficacy and safety of an allogeneic mesenchymal precursor cell (CEP-41750) for the treatment of chronic heart failure/NCT 02032004
III
Trial design
Trial phase
Trial name/NCT number
Table 2 (Continued)
Cardiac failure
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Stem cell therapy for chronic heart failure Poglajen and Vrtovec &
[22 ]. Similar findings were found when using a novel population of CD34þ stem cells, ALDH-bright cells, which were shown to be well tolerated and to have a potential to reverse left ventricular remodeling [14]. In patients with nonischemic heart failure, transplantation of CD34þ stem cells obtained through peripheral blood apheresis and immunomagnetic selection significantly improved myocardial performance, patients’ functional capacity and neurohumoral activation [37]. Of note, these positive effects persisted through the 5-year followup period and translated into significantly improved survival of patients receiving CD34þ cell therapy [24 ] (Fig. 1). In the arena of HSCs currently only two larger randomized controlled trials are underway, exploring the effects of repeated CD34þ stem cell therapy, and the feasibility and efficacy of intracoronary versus transendocardial stem cell delivery in patients with nonischemic heart failure (Table 2). &&
Mesenchymal stem cells Mesenchymal stem cells (MSCs) represent a part of nonhematopoetic cell compartment and have been reported to differentiate into cardiomyocytes [38] and endothelial cells [39]. The potential advantage of these cells is that they are immunoprivileged and thus do not cause the activation of immune response, which enables them to be used in an allogeneic setting. The comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in
100 Stem cell group
Event free survival (%)
90 80 70 60
Controls
50 P = 0.015
40 30 20 10 0 0
12
24
36
48
60
Time (months)
FIGURE 1. Comparison of event-free survival in patients with nonischemic heart failure who received intracoronary CD34þ stem cell therapy (Stem cell group, dashed line) and patients treated with standard therapy (Controls, full line). Five-year survival as evaluated by the Kaplan–Meier analysis was 2.3 times higher in the Stem cell group [24 ]. &&
patients with ischemic cardiomyopathy (POSEIDON) study was the first to explore the dose–effect relation of MSCs and compared clinical effects of autologous and allogeneic MSCs in patients with ischemic heart failure [15]. The authors were able to show that both autologous and allogeneic MSCs exert favorable effects on patients’ quality of life, functional performance and ventricular remodeling. Furthermore, POSEIDON data showed that although scar size reduction was evident in all myocardial segments, scar size reduction and ventricular functional responses predominantly occurred in the segments that were injected with MSCs [40 ]. These results were confirmed by the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial, in which surgical application of MSCs was associated with a significant scar reduction, improvement in myocardial perfusion and regional function that occurred predominantly at the site of transepicardial MSC injection [20 ]. When compared with unselected BMMCs in the transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy (TAC-HFT) trial, MSCs were shown to outperform BMMCs with regard to scar reduction and improvements in myocardial function [18 ]. Thus, it appears that both autologous and allogeneic MSC therapy may be effective in improving heart function in patients with ischemic heart failure and can potentially also lead to beneficial clinical outcome in this patient population. This may represent an important step toward the development of a standardized stem cell product for widespread clinical use. To date, there have been no data on the effects of MSC in nonischemic heart failure, and the almost completed PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesis in Dilated CardioMyopathy (POSEIDON-DCM) study aims to evaluate this therapy in heart failure patients without coronary artery disease. In addition, there are several ongoing trials that also compare the efficacy of autologous and allogeneic MSC therapy in patients with ischemic and nonischemic heart failure. Furthermore, cardiopoietic stem cells, which were shown to be well tolerated and potentially effective in chronic heart failure patients, are being tested in a large-scale clinical trial (Table 2). &
&
&&
Cardiac stem cells Recently, it has been hypothesized that cardiac stem cells (CSCs) are responsible for continuous myocardial regeneration and that they have the capacity to differentiate into cardiomyocytes, endothelial
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Cardiac failure
cells and fibroblasts [41]. Several preclinical studies consistently demonstrated the positive effects of CSCs on left ventricular regeneration [42–45]. The first human study of CSCs, the cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO) trial, evaluated the effects of this stem cell type in patients with ischemic heart failure undergoing surgical revascularization. CSCs were isolated from the myocardial biopsy at the time of cardiac surgery and subsequently expanded in vitro. At 4 months after the surgery, these cells were injected via an intracoronary route. The results of the study were in accordance with the animal data and showed significant improvement of myocardial performance in the stem cell group but not in the control group. In addition, CSCs were shown to reduce the amount of scar in the myocardium as assessed by cardiac MRI. These positive effects persisted over the period of 12 months [16]. Currently, there is a small
(a)
15.00 m
Unipolar
Cardiosphere-derived cells Cardiosphere-derived cells (CDCs) represent a heterogeneous mix of cells derived from myocardial biopsy specimens and comprise cells that express hematopoietic and mesenchymal antigens [46]. CDCs were shown to differentiate in cardiomyocytes, and animal data suggested that intracoronary injections of CDCs may promote myocardial regeneration [47]. The Intracoronary cardiospherederived cells for heart regeneration after myocardial infarction (CADUCEUS) trial was the first to evaluate the effects of CDCs in patients with ischemic heart failure [17]. CDCs were implanted via the intracoronary route, and three different stem cell
(b)
12.00
LLS
1-Map >197 Tip
1-Map >197 Tip
(c)
randomized, placebo-controlled trial underway, exploring the effects of intracoronary infusion of CSCs in patients with ischemic heart failure (Table 2).
5.00 mV
6.00
1.00 c
1.00 c
15.00 m
Unipolar
1-Map >197 Tip
(d)
12.00
LLS
1-Map >197 Tip Anterior
Anterior Septal
Septal
5.00 mV
6.00
Lateral
Posterior
Lateral
Posterior
FIGURE 2. Exemplary three-dimensional (a and c) and corresponding two-dimensional (b and d) quantitative polar maps showing unipolar voltage and LLS. Segments with predominance of high unipolar voltage and high LLS (light grey areas) are defined as normal myocardium; segments with predominance of low unipolar voltage and low LLS (dark grey areas) are defined as scarred myocardium and segments with a predominance of high unipolar voltage (light grey areas on left panel) and low LLS (dark grey on right panel) are defined as electromechanical mismatch (hibernating myocardium) and represent the target areas for stem cell injections (black dots). LLS, local linear shortening. 308
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Stem cell therapy for chronic heart failure Poglajen and Vrtovec
doses were evaluated. In treated patients, CDCs were shown to significantly reduce myocardial scar burden with concomitant increase in viable tissue and regional systolic wall thickening. CDCs, however, failed to increase left ventricular ejection fraction, reduce left ventricular systolic and diastolic volumes or improve patients’ New York Heart Association (NYHA) functional class [17]. As a follow-up to these findings, an ongoing trial currently explores the effects of intracoronary injections of allogeneic CDCs in patients with nonischemic heart failure (Table 2).
when complemented with electroanatomical mapping, it provides the most direct and precise stem cell delivery to the target (viable, but not contracting) myocardium (Fig. 2). Although associated with higher costs and requiring additional training, it was demonstrated in several clinical trials to be well tolerated and efficient in delivering various doses of stem cells to the target myocardium. Furthermore, when compared with the intracoronary route, it has been associated with significantly higher myocardial cell retention rates [51].
CONCLUSION STEM CELL DELIVERY METHODS The ability of the injured myocardium to attract extracardiac stem cells could represent a very important mechanism for myocardial repair and regeneration. Indeed, there is increasing evidence that acutely injured myocardium generates signals for the mobilization of the extracardiac stem cell pool from bone marrow to peripheral circulation. After mobilization, these circulating bone marrowderived cells follow a cytokine gradient that enables them to home to the injured sites of the myocardium, in which they initiate reparative and regenerative processes [48]. However, in the setting of chronic heart failure, the recruitment and homing stimuli are significantly decreased and thus not sufficient to ameliorate the myocardial injury [49]. This limitation can be overcome by exogenous delivery of stem cells to the injured myocardium. To date, no consensus has been reached with regard to modes of stem cell delivery to the myocardium. Several routes have been used in preclinical and clinical settings: intramyocardial, intravenous and intracoronary. By far, the most widely clinically used approach is intracoronary stem cell delivery [50]. Although it has been demonstrated to be simple, cheap, well tolerated and efficient, it has two major limitations: stem cells cannot reach sites of poorly perfused myocardium, thereby limiting the feasibility of this approach in patients with chronic ischemic heart failure, who typically have diffuse and advanced coronary artery disease. The other significant limitation is that using larger cell types or higher stem cell doses may cause an obstruction of target coronary artery and thus cause ischemic damage to the myocardium. Intravenous stem cell delivery has been considered to be very inefficient, albeit well tolerated, simple and minimally invasive. However, no clinical study has used this approach recently and it is most likely going to be reserved for small animal preclinical experiments. The intramyocardial route is the most aggressive among the three approaches. However, especially
In summary, several types of stem cells for the treatment of ischemic and nonischemic heart failure have been evaluated in clinical settings. Although many small trials have shown promising results with regard to regional or global improvement of myocardial performance, myocardial scar reduction, improvement of patients’ functional capacity and quality of life, the findings have not been uniform. However, given the wide heterogeneity of patients with chronic heart failure it may be difficult to define a stem cell therapy that would fit all subsets of patients; instead, future stem cell therapeutic strategies should aim for a more personalized approach by establishing optimal stem cell type, dose and delivery method for an individual patient and stage of the disease. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics – 2012 update: a report from the American Heart Association. Circulation 2012; 125:e2–e220. 2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147–e239. 3. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410:701–705. 4. Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? Cell 2001; 105:829–841. 5. Menasche P, Alfieri O, Janssens S, et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008; 117:1189–1200. 6. Dib N, Dinsmore J, Lababidi Z, et al. One-year follow-up of feasibility and safety of the first U.S., randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAUSMIC study). JACC Cardiovasc Interv 2009; 2:9–16.
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Cardiac failure 7. Duckers HJ, Houtgraaf J, Hehrlein C, et al. Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: The SEISMIC trial. EuroIntervention 2011; 6:805–812. 8. Assmus B, Fischer-Rasokat U, Honold J, et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry. Circ Res 2007; 100:1234–1241. 9. Hendrikx M, Hensen K, Clijsters C, et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation 2006; 114:I101–107. 10. Yao K, Huang R, Qian J, et al. Administration of intracoronary bone marrow mononuclear cells on chronic myocardial infarction improves diastolic function. Heart 2008; 94:1147–1153. 11. Perin EC, Silva GV, Henry TD, et al. A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF). Am Heart J 2011; 161:1078–1087. 12. Ang KL, Chin D, Leyva F, et al. Randomized, controlled trial of intramuscular or intracoronary injection of autologous bone marrow cells into scarred myocardium during CABG versus CABG alone. Nat Clin Pract Cardiovasc Med 2008; 5:663–670. 13. Patel AN, Geffner L, Vina RF, et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg 2005; 130:1631–1638. 14. Perin EC, Silva GV, Zheng Y, et al. Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure. Am Heart J 2012; 163:415–421. 15. Hare JM, Fishman JE, Gerstenblith G, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 2012; 308:2369–2379. 16. Bolli R, Chugh AR, D’Amario D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 2011; 378:1847–1857. 17. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012; 379:895–904. 18. Heldman AW, DiFede DL, Fishman JE, et al. Transendocardial mesenchymal && stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 2014; 311:62–73. The first trial directly comparing mesenchymal and bone-marrow mononuclear cells in ischemic cardiomyopathy. Improvements in regional wall motion and exercise capacity were found in the mesenchymal, but not in the bone-marrow group. 19. Nasseri BA, Ebell W, Dandel M, et al. Autologous CD133þ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial. Eur Heart J 2014; 35:1263–1274. 20. Karantalis V, DiFede DL, Gerstenblith G, et al. Autologous mesenchymal stem & cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial. Circ Res 2014; 114:1302–1310. A positive trial of mesenchymal stem cell therapy in patients undergoing bypass grafting. 21. Perin EC, Sanz-Ruiz R, Sa´nchez PL, et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J 2014; 168:88–95. 22. Poglajen G, Sever M, Cukjati M, et al. Effects of transendocardial CD34þ cell & transplantation in patients with ischemic cardiomyopathy. Circ Cardiovasc Interv 2014; 7:552–559. A positive trial of transendocardial CD34þ cell transplantation in chronic ischemic heart failure. 23. Seth S, Narang R, Bhargava B, et al. Percutaneous intracoronary cellular cardiomyoplasty for nonischemic cardiomyopathy: clinical and histopathological results: the first-in-man ABCD (autologous bone marrow cells in dilated cardiomyopathy) trial. J Am Coll Cardiol 2006; 48:2350–2351. 24. Vrtovec B, Poglajen G, Lezaic L, et al. Effects of intracoronary CD34þ stem && cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res 2013; 112:165–173. The first trial of stem cell therapy in nonischemic dilated cardiomyopathy with a long-term follow-up. CD34þ cell therapy resulted in improved myocardial function, improved exercise capacity, a decrease in amino-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and improved 5-year outcome. 25. Fischer-Rasokat U, Assmus B, Seeger FH, et al. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail 2009; 2:417–423. 26. Farahmand P, Lai TY, Weisel RD, et al. Skeletal myoblasts preserve remote matrix architecture and global function when implanted early or late after coronary ligation into infarcted or remote myocardium. Circulation 2008; 118:S130–S137.
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27. Bonaros N, Rauf R, Wolf D, et al. Combined transplantation of skeletal myoblasts and angiopoietic progenitor cells reduces infarct size and apoptosis and improves cardiac function in chronic ischemic heart failure. J Thorac Cardiovasc Surg 2006; 132:1321–1328. 28. Siminiak T, Fiszer D, Jerzykowska O, et al. Percutaneous trans-coronaryvenous transplantation of autologous skeletal myoblasts in the treatment of postinfarction myocardial contractility impairment: the POZNAN trial. Eur Heart J 2005; 26:1188–1195. 29. Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003; 107:2294–2302. 30. Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation 2004; 110:II213–II218. 31. Galinanes M, Loubani M, Davies J, et al. Autotransplantation of unmanipulated bone marrow into scarred myocardium is safe and enhances cardiac function in humans. Cell Transplant 2004; 13:7–13. 32. Beeres SL, Bax JJ, Dibbets-Schneider P, et al. Intramyocardial injection of autologous bone marrow mononuclear cells in patients with chronic myocardial infarction and severe left ventricular dysfunction. Am J Cardiol 2007; 100:1094–1098. 33. Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006; 355:1222– 1232. 34. Perin EC, Willerson JT, Pepine CJ, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 2012; 307:1717–1726. 35. Bocchi EA, Bacal F, Guimara˜es G, et al. Granulocyte-colony stimulating factor or granulocyte-colony stimulating factor associated to stem cell intracoronary infusion effects in non ischemic refractory heart failure. Int J Cardiol 2010; 138:94–97. 36. Rehman J, Li J, Orschell CM, March KL. Peripheral blood ‘endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107:1164–1169. 37. Vrtovec B, Poglajen G, Sever M, et al. Effects of intracoronary stem cell transplantation in patients with dilated cardiomyopathy. J Card Fail 2011; 17:272–281. 38. Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002; 105:93–98. 39. Reyes M, Dudek A, Jahagirdar B, et al. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002; 109:337–346. 40. Suncion VY, Ghersin E, Fishman JE, et al. Does transendocardial injection of & mesenchymal stem cells improve myocardial function locally or globally?: an analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res 2014; 114:1292– 1301. An analysis of local and global effects of transendocardial injection of mesenchymal stem cells. 41. Leri A, Kajstura J, Anversa P. Role of cardiac stem cells in cardiac pathophysiology: a paradigm shift in human myocardial biology. Circ Res 2011; 109:941–961. 42. Linke A, Muller P, Nurzynska D, et al. Stem cells in the dogheart are selfrenewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A 2005; 102:8966– 8971. 43. Fischer KM, Cottage CT, Wu W, et al. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing pim-1 kinase. Circulation 2009; 120:2077–2087. 44. Angert D, Berretta RM, Kubo H, et al. Repair of the injured adult heart involves new myocytes potentially derived from resident cardiac stem cells. Circ Res 2011; 108:1226–1237. 45. Bolli R, Tang XL, Sanganalmath SK, et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 2013; 128:122–131. 46. Messina E, De Angelis L, Frati G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 2004; 95:911– 921. 47. Johnston PV, Sasano T, Mills K, et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 2009; 120:1075–1083. 48. Fazel S, Cimini M, Chen L, et al. Cardioprotective c-kitþ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest 2006; 116:1865–1877. 49. Theiss HD, David R, Engelmann MG, et al. Circulation of CD34þ progenitor cell populations in patients with idiopathic dilated and ischaemic cardiomyopathy (DCM and ICM). Eur Heart J 2007; 28:1258–1264. 50. Sheng CC, Zhou L, Hao J. Current stem cell delivery methods for myocardial repair. BioMed Res Int 2013; 2013:547902. 51. Vrtovec B, Poglajen G, Lezaic L, et al. Comparison of transendocardial and intracoronary CD34þ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation 2013; 128 (11 Suppl 1):S42–S49.
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Stem cell therapy for chronic heart failure Gregor Poglajen a and Bojan Vrtovec a,b
Purpose of review The aim of this review was to discuss recent advances in clinical aspects of stem cell therapy in heart failure with emphasis on patient selection, stem cell types and delivery methods. Recent findings Several stem cell types have been considered for the treatment of patients with heart failure. In nonischemic heart failure, transplantation of CD34þ cells improved myocardial performance, functional capacity and neurohumoral activation. In ischemic heart failure, cardiosphere-derived cells were shown to reduce myocardial scar burden with concomitant increase in viable tissue and regional systolic wall thickening. Both autologous and allogeneic mesenchymal stem cells were shown to be effective in improving heart function in patients with ischemic heart failure; this may represent an important step toward the development of a standardized stem cell product for widespread clinical use. Summary Although trials of stem cell therapy in heart failure have shown promising results, the findings are not consistent. Given the wide spectrum of heart failure, it may be difficult to define a uniform stem cell therapy for all subsets of patients; instead, future stem cell therapeutic strategies should aim for a more personalized approach by establishing optimal stem cell type, dose and delivery method for an individual patient and disease state. Keywords dilated cardiomyopathy, heart failure, ischemic cardiomyopathy, stem cells
INTRODUCTION Despite advances that have been achieved in medical and device therapy over the past few decades, heart failure represents an increasingly common, debilitating disorder that carries an adverse prognosis [1]. Although current heart failure treatment options have been shown to improve survival and reduce heart failure symptoms [2], no therapy to date has been shown to promote the regeneration of myocardial damage or replacement of lost myocardial tissue, which represent the main underlying pathophysiologic mechanisms of heart failure development and progression. Ever since the first successful use of bone marrow stem cells in an experimental model of acute myocardial infarction was published in 2001 [3], there has been a growing interest in the heart failure community in applying stem cell therapy for the treatment of chronic heart failure. Although the results of numerous preclinical and clinical studies conducted in the last decade support the potential of stem cells to improve myocardial function and affect adverse ventricular remodeling, there are a number of clinical questions that remain poorly defined. Thus, the aim of this
review was to discuss recent advances in clinical aspects of stem cell therapy in patients with heart failure, with emphasis on patient selection, stem cell types and delivery methods.
PATIENT SELECTION AND STEM CELL TYPES Stem cells represent a cell population with selfrenewal properties and the potential to generate daughter cells that are capable of differentiation along specific cell lineages [4]. To date, several stem cell types have been considered for the treatment of
a
Advanced Heart Failure and Transplantation Center, University Medical Center Ljubljana, Ljubljana, Slovenia and bStanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA Correspondence to Bojan Vrtovec, MD, PhD, Advanced Heart Failure and Transplantation Center, Department of Cardiology, University Medical Center Ljubljana, Zaloska 7, MC SI-1000, Ljubljana, Slovenia. Tel: +3861 522 2844; fax: +3861 522 2828; e-mail: bvrtovec@ stanford.edu Curr Opin Cardiol 2015, 30:301–310 DOI:10.1097/HCO.0000000000000167
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Cardiac failure
KEY POINTS Several clinical trials using both autologous and allogeneic cell sources have proven beneficial effects of stem cell therapy in patients with ischemic and nonischemic heart failure. Transendocardial cell delivery may be more effective than the intracoronary route. Future studies of stem cell therapy in heart failure should aim at more personalized patient-specific and disease-specific approaches.
patients with ischemic and nonischemic chronic heart failure. An overview of clinical studies according to stem cell types and patient selection is presented in Table 1.
Skeletal myoblasts Skeletal myoblasts are derived from skeletal muscle satellite cells. Because of the easy access, quick in-vitro expansion and relative resistance to hypoxic environment, skeletal myoblasts were initially considered to represent an ideal cell population for myocardial regeneration. In animal models of heart failure, skeletal myoblasts have been shown to differentiate into myotubes and form viable skeletal muscle-like grafts. This was associated with improved myocardial performance, attenuated adverse ventricular remodeling and decreased myocardial fibrosis [26,27]. These encouraging preclinical data were the basis for three clinical trials [MAGIC [5], percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment (POZNAN) [28] and 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAUSMIC) [6]] which, however, failed to show a consistent benefit of this stem cell population. Also, a risk of life-threatening ventricular arrhythmias using skeletal myoblasts has raised significant concerns. With other stem cell types becoming more accessible, the interest in skeletal myoblasts has decreased in recent years and currently no large randomized controlled trial is exploring the role of skeletal myoblasts in patients with chronic heart failure.
Bone marrow-derived stem cells Bone marrow is the source of a mixed population of hematopoetic and nonhematopoetic stem cells. Both groups have been shown to possess the ability 302
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for transdifferentiation into different cell lineages. Because of the easy access and procurement, this group of stem cells has gained the most attention in preclinical and clinical settings in recent years. The results of studies using bone marrow mononuclear cells (BMMCs) for the treatment of chronic ischemic heart failure have been conflicting. The first study to evaluate BMMCs in patients with ischemic heart failure demonstrated a significant improvement in left ventricular ejection fraction and reduction in end-systolic volume in treated patients at 2 and 4 months after the procedure. In addition, an increase in myocardial perfusion and patients’ exercise capacity was demonstrated [11,29,30]. These results were corroborated by other studies that used intramyocardial injections of BMMCs in periscar area [31,32]. Interestingly, BMMC injections directly into the scar tissue failed to produce comparable results [9]. In the TOPCARE-CHD study, intracoronary infusion of BMMC versus endothelial progenitor cells in patients with ischemic heart failure was analyzed. Left ventricular ejection fraction improved significantly in the BMMC group but not in the endothelial progenitor cells group, the exact underlying mechanisms remaining undefined [33]. Registry data from TOPCARE-CHD further suggested that BMMC stem cell therapy significantly decreases neurohumoral activation as early as 3 months after therapy. In addition, it was shown that infusion of BMMCs with high functional capacity was associated with improved long-term survival in this patient cohort [8]. However, in contrast to these findings, the effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure (FOCUS-CCTRN) trial, one of the largest trials to evaluate the effects of BMMCs in patients with ischemic heart failure, failed to show any benefit of stem cell therapy on myocardial performance, volumes or perfusion [34]. Nevertheless, a post-hoc analysis showed that CD34þ stem cell count in BMMC samples correlated significantly with the improvement of myocardial performance, suggesting that specific bone marrow cell subpopulations may be responsible for the beneficial effects of BMMC therapy [34]. Unselected BMMCs were used also in patients with nonischemic heart failure. In the TOPCAREDCM study, intracoronary BMMC infusion into the left anterior descending coronary artery resulted in improved regional wall motion of the injected area and global left ventricular myocardial performance [25]. In the autologous bone marrow cells in dilated cardiomyopathy (ABCD) trial [23], the investigators enrolled patients with nonischemic heart failure, who received either intracoronary injection of Volume 30 Number 3 May 2015
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ISH
ISH
Ang et al. [12]
Patel et al. [13]
ISH
ISH
Focus-HF [11]
CADUCEUS [17]
ISH
Yao et al. [10]
ISH
ISH
Hendrikx et al. [9]
SCIPIO [16]
ISH
TOPCARE-CHD [8]
ISH
ISH
SEISMIC [7]
POSEIDON [15]
ISH
CAUSMIC [6]
ISH
ISH
MAGIC [5]
Perin et al. [14]
Cause of heart failure
Study name
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. 17/8
16/7
30/0
10/10
10/10
42 (21/21)/23
20/10
24/23
10/10
52/23
26/14
12/11
97/30
Number of patients (treatment/controls)
CDC
CSC
MSC
ALDH
br
BMMC
BMMC, CD34þ
BMMC
BMMC
BMMC
EPC [6]
BMMC [5]
SM
SM
SM
Cell type
Table 1. Randomized controlled trials in chronic patients with heart failure
Intracoronary
Intracoronary
Transendocardial
Transendocardial
Transepicardial
Transepicardial Intracoronary
Transendocardial
Intracoronary
Transepicardial
Intracoronary
Transendocardial
Transendocardial
Transepicardial
Method of cell delivery
1 year
1 year
1 year
1 106
12–25 106
6 months
22 106
20, 100, 200 106
1 year
IC: 115 106 BMMC and 245 103 CD34þ TE: 84 106 BMMC and 142 103 CD34þ
6 months
6 months
30 106
2.4 106
6 months
12 106
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Neutral for LV volumes
Neutral for LVEF
Reduced scar size
Reduced scar size
Reduced NYHA f.c.
Improved LVEF
Neutral for LVEF
Reduced LV volumes
(Continued )
Improved exercise capacity
Reduced LV volumes
Improved MVO2
Improved LVEF
Neutral for LVEF Neutral for LV volumes Neutral for scar reduction
Improved injection site myocardial perfusion
Neutral for LVEF
Neutral for scar reduction
Neutral for LV volumes
Neutral for LVEF
Reduced LV volumes
Reduced NYHA f.c.
Neutral for LVEF
Improved LVEF (BMMC)
Improved exercise capacity
4 months
3 months
BMMC: 205 106
Reduced NYHA f.c.
Neutral for LVEF
Reduced LV volumes
Reduced NYHA f.c.
Improved myocardial viability
60 106
6 months
150–800 106
Improved LVEF Improved regional wall motion abnormalities
Reduced NYHA f.c. (BMMC)
1 year
30, 100, 300 and 600 106
Reduced LV volumes
Neutral for LVEF
Main outcome
EPC: 22 106
6 months
Follow-up interval
Low dose 400 106 High dose 800 106
Cell dose
Stem cell therapy for chronic heart failure Poglajen and Vrtovec
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304
]
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ISH
NONISH
Poglajen et al. [22 ]
ABCD [23]
NONISH
TOPCARE-DCM [25]
33/0
55/55
24/20
33/33
21/6
6/0
30/30
38 (19/19)/21
Number of patients (treatment/controls)
BMMC
CD34þ
BMMC
CD34þ
ADRC
MSC
CD133þ
MSC and BMMC
Cell type
Intracoronary
Transendocardial
Intracoronary
Transendocardial
Transendocardial
Transepicardial
Transepicardial
Transendocardial
Method of cell delivery
1.5 years
1.5 years
6 months
6 months 5 years
1 year
0.4 106/kg 0.8 106/kg 1.20 106/kg 90 106
28 106 123 106
259 106
6 months
5.1 106
N/A
1 year
Follow-up interval
N/A
Cell dose
Neutral for LV volumes
Improved myocardial perfusion
Improved LVEF
Improved survival
Reduced NT-proBNP
Improved exercise capacity
Neutral for LV volumes
Improved LVEF
Reduced NYHA f.c.
Improved LVEF
Reduced NT-proBNP
Improved exercise capacity
Neutral for LV volumes
Improved LVEF
Neutral for perfusion
Neutral for LVEF Neutral for exercise capacity
Reduced scar size
Improved LVEF
Improved regional LV function
Neutral for perfusion improvement
Neutral for scar size
Neutral for LVEF
Neutral for LV volumes
Improved regional LV function
Reduced scar size
Improved exercise capacity
Main outcome
ABCD, autologous bone marrow cells in dilated cardiomyopathy trial; ADRC, adipose-derived stem cells; ALDHbr, aldehyde dehydrogenase bright cells; BMMC, bone marrow mononuclear cells; CADUCEUS, Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction: a prospective, randomized phase 1 trial; Cardio133þ, autologous CD133þ bone marrow cells and bypass grafting for regeneration of ischaemic myocardium: the Cardio133 trial; CAUSMIC, one-year follow-up of feasibility and safety of the first u.S., randomized, controlled study using 3-dimensional guided catheter-based delivery of autologous skeletal myoblasts for ischemic cardiomyopathy (CAUSMIC study); CDC, cardiosphere-derived cells; CSC, cardiac stem cells; EPC, endothelial progenitor cells; Focus-HF, a randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure; LV, left ventricle; MSC, mesenchymal stem cells; MVO2, maximal oxygen consumption; NONISH, nonischemic heart failure; NT-proBNP, amino-terminal of the prohormone brain natriuretic peptide; NYHA f.c., New York Heart Association functional class; POSEIDON, comparison of allogeneic vs. autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial; PRECISE, adipose-derived regenerative cells in patients with ischemic cardiomyopathy: the PRECISE trial; PROMETHEUS, The Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery trial; SCIPIO, Cardiac stem cells in patients with ischaemic cardiomyopathy: initial results of a randomized phase 1 trial; SEISMIC, final results of a phase IIa, randomized, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial; SM, smooth muscle cells; TAC-HFT, transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial; TOPCARE-CHD, transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD registry; TOPCARE-DCM, a pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy.
NONISH
&&
]
Vrtovec et al. [24
ISH
PRECISE [21]
&
ISH
PROMETHEUS [20 ]
&
ISH
ISH
Cause of heart failure
Cardio133þ [19]
TAC-HFT [18
&&
Study name
Table 1 (Continued)
Cardiac failure
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(Continued )
Completed, awaiting publication August 2010 IC NONISH 60 Prospective, randomized, placebo-controlled Bone marrow derived adult stem cells for dilated cardiomyopathy (REGEN-DCM)/NCT 01302171
III
I/II Prospective, randomized Percutaneous stem cell injection delivery effects on neomyogenesis in dilated cardiomyopathy (the POSEIDON-DCM study)/NCT 01392625
BMMC
Recruiting November 2013 TE NONISH 36
January 2014 TE NONISH 80 CD34þ II/III Prospective, randomized Repetitive intramyocardial CD34þ cell therapy in dilated cardiomyopathy (REMEDIUM)/NCT 02248532
AutoMSC/ AlloMSC
Recruiting
Recruiting January 2014 IC NONISH 51 BMMC Prospective, randomized, placebo-controlled Infusion intracoronary of mononuclear autologous adult no expanded stem cells of bone marrow on functional recovery in patients with dilated cardiomyopathy and heart failure/NCT 02033278
II/III
November 2014 IC NONISH 42 Prospective, randomized, placebo-controlled Dilated cardiomyopathy intervention with allogeneic myocardially-regenerative cells (DYNAMIC)/NCT 02293603
I
Trial design Trial name/NCT number
Trial phase
Table 2. Ongoing trials in patients with chronic heart failure
Hematopoietic stem cells (HSCs) represent a part of the hematopoetic cell compartment of the bone marrow and differentiate into mature cells along lymphoid and myeloid lineages. When HSCs are released in the peripheral circulation, they become EPCs. Both cell types are positive for the CD34þ surface marker and together they form a population of CD34þ stem cells, which have been shown to have a potential to differentiate into endothelial cells and promote neovascularization [36]. Initially, CD34þ cells were used in patients with ischemic heart failure undergoing cardiac surgery. In this population, it was shown that transepicardial CD34þ stem cell injections around the scar area at the time of surgical revascularization may significantly improve myocardial performance when compared with surgical revascularization alone [13]. However, a recent study evaluating the effects of HSC in patients with ischemic heart failure undergoing surgical revascularization failed to confirm these findings [19]. Therefore, it appears that when injected at the time of cardiac surgery, CD34þ cells may not exert consistent beneficial effects on myocardial performance and structure. Alternatively, when CD34þ cells were injected via percutaneous transendocardial approach in patients with chronic ischemic heart failure, such a therapy led to a significant improvement in left ventricular global function (mainly driven by improved contraction of injected segments), improvement of exercise capacity and reduced neurohumoral activation
Cell type
Hematopoietic stem cells
alloCDC
No. of patients
Cause of heart failure
Cell delivery method
Trial start date
Trial status
BMCMs or sham control. During the 3-year followup, the left ventricular ejection fraction (LVEF) improved in the treatment arm by 5.9%. Similarly, in a study of patients with refractory nonischemic heart failure, infusion of BMMCs into the left main coronary artery was associated with improved myocardial performance, maximal oxygen consumption and quality of life [35]. These data may suggest that BMMC therapy may be of more benefit in patients with nonischemic heart failure than in patients with heart failure because of coronary artery disease; however, the variations in BMMC populations, patient selection criteria and delivery methods make direct comparisons between the studies very difficult. Currently, five randomized controlled trials are exploring the effects of BMMCs in patients with chronic ischemic and nonischemic heart failure focusing on different stem cell delivery routes, feasibility and efficacy of repeated stem cell injections and the effects of stem cell therapy in patients with left ventricular assist devices (Table 2).
Recruiting
Stem cell therapy for chronic heart failure Poglajen and Vrtovec
305
306
www.co-cardiology.com Prospective, randomized, sham-controlled
Prospective, randomized, placebo-controlled Prospective, randomized, placebo-controlled
Prospective, randomized
Prospective, randomized
An efficacy, safety and tolerability study of ixmyelocel-T administered via transendocardial catheter-based injections to patients with heart failure because of ischemic dilated cardiomyopathy (IDCM) (ixCELL DCM)/NCT 01670981
Bone marrow-derived adult stem cells for chronic heart failure (REGEN-IHD)/NCT 00747708
Stem cell therapy in patients with severe heart failure and undergoing left ventricular assist device placement (ASSURANCE)/NCT 00869024
Intracoronary versus intramyocardial application of enriched CD133pos autologous bone marrowderived stem cells (AlsterMACS)/NCT 01337011
The transendocardial stem cell injection delivery effects on neomyogenesis study (the TRIDENT study)/NCT 02013674
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. II
II/III
II
II
III
II
I/II
CSC
BMMC
AlloMSC
CD133þ
BMMC
BMMC
BMMC
Cardiopoietic cells
MPC
MSC
AlloMPC
Cell type
50
676
30
64
24
148
108
240
60
59
1730
No. of patients
ISH
ISH
ISH
ISH
ISH
ISH
ISH
ISH
ISH/NONISH
ISH/NONISH
ISH/NONISH
Cause of heart failure
IC
IC
TE
IC/TE
TEPI
IV/IC/TE
TE
TE
TE
TE
TE
Cell delivery method
December 2013
November 2013
November 2013
July 2011
November 2011
August 2008
October 2012
November 2012
August 2008
September 2008
January 2014
Trial start date
Recruiting
Recruiting
Recruiting
Recruiting
Recruiting
Completed, awaiting publication
Active, not recruiting
Recruiting
Unknown
Active, not recruiting
Recruiting
Trial status
alloCDC, allogeneic cardiosphere-derived cells; auto/alloMSC, autologous/allogeneic MSC; auto/alloMPC, autologous/allogeneic MPC; BMMC, bone marrow mononuclear cells; IC, intracoronary; ISH, ischemic heart failure; IV, intravenous; MPC, mesenchymal progenitor cells; MSC, mesenchymal stem cells; NONISH, nonischemic heart failure; TE, transendocardial; TEPI, transepicardial.
Prospective, randomized, placebo-controlled
Prospective, randomized, sham-controlled
Safety and efficacy of autologous cardiopoietic cells for treatment of ischemic heart failure (CHART-1)/NCT 01768702
Transplantation of autologous cardiac stem cells in ischemic heart failure/NCT 01758406
I/II
Prospective, randomized
A phase-II dose-escalation study to assess the feasibility and safety of transendocardial delivery of three different doses of allogeneic mesenchymal precursor cells (MPCs) in patients with heart failure/NCT 00721045
Prospective, randomized
I/II
Prospective, randomized, placebo-controlled
Autologous mesenchymal stromal cell therapy in heart failure/NCT 00644410
Compare the effects of single versus repeated intracoronary application of autologous bone marrow-derived mononuclear cells on mortality in patients with chronic postinfarction heart failure (REPEAT)/NCT 01693042
II/III
Prospective, randomized, sham-controlled
The purpose of this study was to evaluate the efficacy and safety of an allogeneic mesenchymal precursor cell (CEP-41750) for the treatment of chronic heart failure/NCT 02032004
III
Trial design
Trial phase
Trial name/NCT number
Table 2 (Continued)
Cardiac failure
Volume 30 Number 3 May 2015
Stem cell therapy for chronic heart failure Poglajen and Vrtovec &
[22 ]. Similar findings were found when using a novel population of CD34þ stem cells, ALDH-bright cells, which were shown to be well tolerated and to have a potential to reverse left ventricular remodeling [14]. In patients with nonischemic heart failure, transplantation of CD34þ stem cells obtained through peripheral blood apheresis and immunomagnetic selection significantly improved myocardial performance, patients’ functional capacity and neurohumoral activation [37]. Of note, these positive effects persisted through the 5-year followup period and translated into significantly improved survival of patients receiving CD34þ cell therapy [24 ] (Fig. 1). In the arena of HSCs currently only two larger randomized controlled trials are underway, exploring the effects of repeated CD34þ stem cell therapy, and the feasibility and efficacy of intracoronary versus transendocardial stem cell delivery in patients with nonischemic heart failure (Table 2). &&
Mesenchymal stem cells Mesenchymal stem cells (MSCs) represent a part of nonhematopoetic cell compartment and have been reported to differentiate into cardiomyocytes [38] and endothelial cells [39]. The potential advantage of these cells is that they are immunoprivileged and thus do not cause the activation of immune response, which enables them to be used in an allogeneic setting. The comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in
100 Stem cell group
Event free survival (%)
90 80 70 60
Controls
50 P = 0.015
40 30 20 10 0 0
12
24
36
48
60
Time (months)
FIGURE 1. Comparison of event-free survival in patients with nonischemic heart failure who received intracoronary CD34þ stem cell therapy (Stem cell group, dashed line) and patients treated with standard therapy (Controls, full line). Five-year survival as evaluated by the Kaplan–Meier analysis was 2.3 times higher in the Stem cell group [24 ]. &&
patients with ischemic cardiomyopathy (POSEIDON) study was the first to explore the dose–effect relation of MSCs and compared clinical effects of autologous and allogeneic MSCs in patients with ischemic heart failure [15]. The authors were able to show that both autologous and allogeneic MSCs exert favorable effects on patients’ quality of life, functional performance and ventricular remodeling. Furthermore, POSEIDON data showed that although scar size reduction was evident in all myocardial segments, scar size reduction and ventricular functional responses predominantly occurred in the segments that were injected with MSCs [40 ]. These results were confirmed by the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial, in which surgical application of MSCs was associated with a significant scar reduction, improvement in myocardial perfusion and regional function that occurred predominantly at the site of transepicardial MSC injection [20 ]. When compared with unselected BMMCs in the transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy (TAC-HFT) trial, MSCs were shown to outperform BMMCs with regard to scar reduction and improvements in myocardial function [18 ]. Thus, it appears that both autologous and allogeneic MSC therapy may be effective in improving heart function in patients with ischemic heart failure and can potentially also lead to beneficial clinical outcome in this patient population. This may represent an important step toward the development of a standardized stem cell product for widespread clinical use. To date, there have been no data on the effects of MSC in nonischemic heart failure, and the almost completed PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesis in Dilated CardioMyopathy (POSEIDON-DCM) study aims to evaluate this therapy in heart failure patients without coronary artery disease. In addition, there are several ongoing trials that also compare the efficacy of autologous and allogeneic MSC therapy in patients with ischemic and nonischemic heart failure. Furthermore, cardiopoietic stem cells, which were shown to be well tolerated and potentially effective in chronic heart failure patients, are being tested in a large-scale clinical trial (Table 2). &
&
&&
Cardiac stem cells Recently, it has been hypothesized that cardiac stem cells (CSCs) are responsible for continuous myocardial regeneration and that they have the capacity to differentiate into cardiomyocytes, endothelial
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Cardiac failure
cells and fibroblasts [41]. Several preclinical studies consistently demonstrated the positive effects of CSCs on left ventricular regeneration [42–45]. The first human study of CSCs, the cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO) trial, evaluated the effects of this stem cell type in patients with ischemic heart failure undergoing surgical revascularization. CSCs were isolated from the myocardial biopsy at the time of cardiac surgery and subsequently expanded in vitro. At 4 months after the surgery, these cells were injected via an intracoronary route. The results of the study were in accordance with the animal data and showed significant improvement of myocardial performance in the stem cell group but not in the control group. In addition, CSCs were shown to reduce the amount of scar in the myocardium as assessed by cardiac MRI. These positive effects persisted over the period of 12 months [16]. Currently, there is a small
(a)
15.00 m
Unipolar
Cardiosphere-derived cells Cardiosphere-derived cells (CDCs) represent a heterogeneous mix of cells derived from myocardial biopsy specimens and comprise cells that express hematopoietic and mesenchymal antigens [46]. CDCs were shown to differentiate in cardiomyocytes, and animal data suggested that intracoronary injections of CDCs may promote myocardial regeneration [47]. The Intracoronary cardiospherederived cells for heart regeneration after myocardial infarction (CADUCEUS) trial was the first to evaluate the effects of CDCs in patients with ischemic heart failure [17]. CDCs were implanted via the intracoronary route, and three different stem cell
(b)
12.00
LLS
1-Map >197 Tip
1-Map >197 Tip
(c)
randomized, placebo-controlled trial underway, exploring the effects of intracoronary infusion of CSCs in patients with ischemic heart failure (Table 2).
5.00 mV
6.00
1.00 c
1.00 c
15.00 m
Unipolar
1-Map >197 Tip
(d)
12.00
LLS
1-Map >197 Tip Anterior
Anterior Septal
Septal
5.00 mV
6.00
Lateral
Posterior
Lateral
Posterior
FIGURE 2. Exemplary three-dimensional (a and c) and corresponding two-dimensional (b and d) quantitative polar maps showing unipolar voltage and LLS. Segments with predominance of high unipolar voltage and high LLS (light grey areas) are defined as normal myocardium; segments with predominance of low unipolar voltage and low LLS (dark grey areas) are defined as scarred myocardium and segments with a predominance of high unipolar voltage (light grey areas on left panel) and low LLS (dark grey on right panel) are defined as electromechanical mismatch (hibernating myocardium) and represent the target areas for stem cell injections (black dots). LLS, local linear shortening. 308
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Stem cell therapy for chronic heart failure Poglajen and Vrtovec
doses were evaluated. In treated patients, CDCs were shown to significantly reduce myocardial scar burden with concomitant increase in viable tissue and regional systolic wall thickening. CDCs, however, failed to increase left ventricular ejection fraction, reduce left ventricular systolic and diastolic volumes or improve patients’ New York Heart Association (NYHA) functional class [17]. As a follow-up to these findings, an ongoing trial currently explores the effects of intracoronary injections of allogeneic CDCs in patients with nonischemic heart failure (Table 2).
when complemented with electroanatomical mapping, it provides the most direct and precise stem cell delivery to the target (viable, but not contracting) myocardium (Fig. 2). Although associated with higher costs and requiring additional training, it was demonstrated in several clinical trials to be well tolerated and efficient in delivering various doses of stem cells to the target myocardium. Furthermore, when compared with the intracoronary route, it has been associated with significantly higher myocardial cell retention rates [51].
CONCLUSION STEM CELL DELIVERY METHODS The ability of the injured myocardium to attract extracardiac stem cells could represent a very important mechanism for myocardial repair and regeneration. Indeed, there is increasing evidence that acutely injured myocardium generates signals for the mobilization of the extracardiac stem cell pool from bone marrow to peripheral circulation. After mobilization, these circulating bone marrowderived cells follow a cytokine gradient that enables them to home to the injured sites of the myocardium, in which they initiate reparative and regenerative processes [48]. However, in the setting of chronic heart failure, the recruitment and homing stimuli are significantly decreased and thus not sufficient to ameliorate the myocardial injury [49]. This limitation can be overcome by exogenous delivery of stem cells to the injured myocardium. To date, no consensus has been reached with regard to modes of stem cell delivery to the myocardium. Several routes have been used in preclinical and clinical settings: intramyocardial, intravenous and intracoronary. By far, the most widely clinically used approach is intracoronary stem cell delivery [50]. Although it has been demonstrated to be simple, cheap, well tolerated and efficient, it has two major limitations: stem cells cannot reach sites of poorly perfused myocardium, thereby limiting the feasibility of this approach in patients with chronic ischemic heart failure, who typically have diffuse and advanced coronary artery disease. The other significant limitation is that using larger cell types or higher stem cell doses may cause an obstruction of target coronary artery and thus cause ischemic damage to the myocardium. Intravenous stem cell delivery has been considered to be very inefficient, albeit well tolerated, simple and minimally invasive. However, no clinical study has used this approach recently and it is most likely going to be reserved for small animal preclinical experiments. The intramyocardial route is the most aggressive among the three approaches. However, especially
In summary, several types of stem cells for the treatment of ischemic and nonischemic heart failure have been evaluated in clinical settings. Although many small trials have shown promising results with regard to regional or global improvement of myocardial performance, myocardial scar reduction, improvement of patients’ functional capacity and quality of life, the findings have not been uniform. However, given the wide heterogeneity of patients with chronic heart failure it may be difficult to define a stem cell therapy that would fit all subsets of patients; instead, future stem cell therapeutic strategies should aim for a more personalized approach by establishing optimal stem cell type, dose and delivery method for an individual patient and stage of the disease. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
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Cardiac failure 7. Duckers HJ, Houtgraaf J, Hehrlein C, et al. Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: The SEISMIC trial. EuroIntervention 2011; 6:805–812. 8. Assmus B, Fischer-Rasokat U, Honold J, et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD Registry. Circ Res 2007; 100:1234–1241. 9. Hendrikx M, Hensen K, Clijsters C, et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation 2006; 114:I101–107. 10. Yao K, Huang R, Qian J, et al. Administration of intracoronary bone marrow mononuclear cells on chronic myocardial infarction improves diastolic function. Heart 2008; 94:1147–1153. 11. Perin EC, Silva GV, Henry TD, et al. A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF). Am Heart J 2011; 161:1078–1087. 12. Ang KL, Chin D, Leyva F, et al. Randomized, controlled trial of intramuscular or intracoronary injection of autologous bone marrow cells into scarred myocardium during CABG versus CABG alone. Nat Clin Pract Cardiovasc Med 2008; 5:663–670. 13. Patel AN, Geffner L, Vina RF, et al. Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg 2005; 130:1631–1638. 14. Perin EC, Silva GV, Zheng Y, et al. 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Effects of intracoronary CD34þ stem && cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ Res 2013; 112:165–173. The first trial of stem cell therapy in nonischemic dilated cardiomyopathy with a long-term follow-up. CD34þ cell therapy resulted in improved myocardial function, improved exercise capacity, a decrease in amino-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and improved 5-year outcome. 25. Fischer-Rasokat U, Assmus B, Seeger FH, et al. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail 2009; 2:417–423. 26. Farahmand P, Lai TY, Weisel RD, et al. 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Autotransplantation of unmanipulated bone marrow into scarred myocardium is safe and enhances cardiac function in humans. Cell Transplant 2004; 13:7–13. 32. Beeres SL, Bax JJ, Dibbets-Schneider P, et al. Intramyocardial injection of autologous bone marrow mononuclear cells in patients with chronic myocardial infarction and severe left ventricular dysfunction. Am J Cardiol 2007; 100:1094–1098. 33. Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006; 355:1222– 1232. 34. Perin EC, Willerson JT, Pepine CJ, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 2012; 307:1717–1726. 35. Bocchi EA, Bacal F, Guimara˜es G, et al. Granulocyte-colony stimulating factor or granulocyte-colony stimulating factor associated to stem cell intracoronary infusion effects in non ischemic refractory heart failure. Int J Cardiol 2010; 138:94–97. 36. Rehman J, Li J, Orschell CM, March KL. Peripheral blood ‘endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 2003; 107:1164–1169. 37. Vrtovec B, Poglajen G, Sever M, et al. Effects of intracoronary stem cell transplantation in patients with dilated cardiomyopathy. J Card Fail 2011; 17:272–281. 38. Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002; 105:93–98. 39. Reyes M, Dudek A, Jahagirdar B, et al. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002; 109:337–346. 40. Suncion VY, Ghersin E, Fishman JE, et al. Does transendocardial injection of & mesenchymal stem cells improve myocardial function locally or globally?: an analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res 2014; 114:1292– 1301. An analysis of local and global effects of transendocardial injection of mesenchymal stem cells. 41. Leri A, Kajstura J, Anversa P. Role of cardiac stem cells in cardiac pathophysiology: a paradigm shift in human myocardial biology. Circ Res 2011; 109:941–961. 42. Linke A, Muller P, Nurzynska D, et al. Stem cells in the dogheart are selfrenewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A 2005; 102:8966– 8971. 43. Fischer KM, Cottage CT, Wu W, et al. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing pim-1 kinase. Circulation 2009; 120:2077–2087. 44. Angert D, Berretta RM, Kubo H, et al. Repair of the injured adult heart involves new myocytes potentially derived from resident cardiac stem cells. Circ Res 2011; 108:1226–1237. 45. Bolli R, Tang XL, Sanganalmath SK, et al. Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 2013; 128:122–131. 46. Messina E, De Angelis L, Frati G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 2004; 95:911– 921. 47. Johnston PV, Sasano T, Mills K, et al. Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 2009; 120:1075–1083. 48. Fazel S, Cimini M, Chen L, et al. Cardioprotective c-kitþ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest 2006; 116:1865–1877. 49. Theiss HD, David R, Engelmann MG, et al. 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