Main topic/CME Herz 2011 · 36:121–134 DOI 10.1007/s00059-010-3419-y Published online: 9 March 2011 © Urban & Vogel 2011
C. Nesselmann · A. Kaminski · G. Steinhoff Department of Cardiac Surgery, University of Rostock, Rostock
Cardiac stem cell therapy Registered trials and a pilot study in patients with dilated cardiomyopathy
Cardiac stem cell therapy has been a promising albeit controversial approach in the treatment of cardiovascular disorders ever since Orlic et al. [1, 2] reported in 2001 about adult bone marrow cell transplantation directly into infarcted mice myocardium. Nowadays, a wide range of research strategies and clinical treatment strategies exist in the field of cardiac stem cell therapy. Beginning with the nominal issue, the attempts and strategies may be subsumed under restorative or reparative medicine rather than regenerative medicine as suggested by Krause et al. [3]. These strategies need to be orchestrated at the different stages in order to gain comparable and genuine data. Clinical attempts of stem cell application to the heart were soon performed after the first preclinical reports in rodent models. Current surgical treatment of cardiomyopathy includes mitral valve repair. Stem cell transplantation in addition to coronary artery bypass grafting (CABG) in patients with chronic ischemia can enhance ventricular function and perfusion [4]. We hypothesized that additional administration of cardiac stem cells may lead to a better recovery of cardiac function and could enhance positive remodeling.
search terms “heart” and “stem cells” in December 2010. A total of 385 registered trials were found, of which 71 ongoing and 13 (including one follow-up) completed clinical trials could be identified as meeting the criteria of stem cell applications for heart diseases (. Fig. 1). Indirect stem cell approaches, e.g., the use of statins, stem cell mobilization alone, and endothelial progenitor cell capture techniques in stent technologies, were not included in the search as it would go beyond the scope of this article. The results are listed in . Tab. 1 and . Tab. 2, respectively.
Results Autologous versus allogeneic
In the majority of all registered studies, autologous cell preparations come to use. However, allogeneic cell transplantation for MSCs (mesenchymal stem cells) is re-
www.clinicaltrials.gov Search: heart AND stem cell – 385 studies
ported to be investigated in four of the ongoing studies (Nos. 22, 27, 39, and 66) with one comparing autologous and allogeneic MSCs (No. 22). No completed registered trials involved allogeneic approaches.
Cell types and sources
Frequently used single cell types in ongoing investigations are bone marrow mononuclear cells (BM-MNCs) (Nos. 4, 10, 18, 20, 21, 29, 36, 37, 42, 49, 53, 58, 59, 65, and 67) and in a number of study registrations unspecific terms are being used, e.g. stem cells and/or progenitor cells from bone marrow, bone marrowderived progenitor cells, bone marrow cells, bone marrow aspirate, for which these had in common that the cell origin was bone marrow (Nos. 5–7, 13–15, 17, 24, 25, 32, 38, 40, 41, 43, 50, 62, and 64). Other currently investigated cell types were subpopulations, such as CD 133+ cells (or AC
84 (71 ongoing and 13 completed) registered clinical trials meeting criteria of cardiac stem cell application
Registered clinical studies Methods For an orientating analysis of registered studies, the webpage clinicaltrials. gov was scanned systematically using the
Autologous (80)
Allogeneic (3)
Autologous vs. allogeneic (1)
Fig. 1 8 Overview of registered clinical trials Herz 2 · 2011
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Main topic/CME 60 rel. ∆EF=1.9+22 % (Median 0.2%) 50
LVEF %
40 30 20 10
MRI Echo
0 preoperative
discharge
6 months
ΔLVEDD=1.4+5.0
80
L V E D D in mm
75 70 65 60 55 50 45 40
preop.
postop.
6 months
Fig. 3 8 Left ventricular enddiastolic diameter (LVEDD) in mitral surgery + stem cell injection compared to coronary artery bypass surgery alone + stem cell injection
133) from bone marrow (Nos. 7, 11, 16, 42, 48, 53, 54, 60, and 63), CD 34+ endothelial progenitor cells (EPCs) from peripheral blood and bone marrow (Nos. 19, 26, 28, 30, 31, 33, and 57), angiogenetic precursor cells from peripheral blood (Nos. 52, 55, and 56), aldehyde dehydrogenase bright stem cells from bone marrow (No. 12), mesenchymal stem cells (MSCs) from bone barrow (Nos. 2, 21, 22, 34, 49, 45, 47, 51, and 66) and umbilical cord blood (No. 69), mesenchymal precursor cells (Nos. 23, 27, and 39), cardiosphere-derived/cardiac stem cells (CSCs) (Nos. 1, 3, and 8), adipose-derived stem and regenerative cells (ADRCs) (Nos. 35 and 44), endothelial-like, culture-modified mononuclear cells (E-CMMs) from peripheral blood (No. 61), and skeletal myoblasts (No. 46). In the registered completed clinical trials, the cell preparations used were BM-MNCs (9/13), autologous CD 34+ cells from peripheral blood (2/13), bone marrow-derived progenitor cells (1/13),
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Herz 2 · 2011
p= not significant
Fig. 2 9 Changes in left ventricular ejection fraction (LVEF) measured by magnetic resonance imaging (MRI) and echocardiography (Echo)
and mesenchymal stem cells from bone marrow (1/13). Cell combinations introduced were BM-MNCs plus AC 133+ (Nos. 42 and 53), as well as BM-MNCs plus MSCs (No. 21). One group is investigating a combination of autologous stem cells, termed “final cell mixture”, from bone marrow (No. 24). Comparison of different cell types is approached in one ongoing study using MSCs versus BMMNCs (No. 34). The cell source is compared in one ongoing study using CD34+ cells from peripheral blood versus bone marrow (No. 31).
Cell modification
Modification strategies are tested in two registered ongoing studies. One group uses hypoxia-stress to precondition BMMNCs (No. 67). Another group uses mononuclear cells genetically modified with endothelial nitric oxide synthase (eNOS) (No. 61).
Dose escalation
Dose escalation approaches were found in 12 of the 71 ongoing studies (Nos. 1, 9, 19, 21–23, 27, 28, 34, 39, 46, and 68), and in two completed trial (Nos. IX and X). In one study, stem cell application was performed twice at an interval of 6 month (No. 33).
Application method
Intracoronary route was used in 36 of the ongoing studies (1, 6, 8, 11, 13, 15, 17, 18, 20, 21, 24, 26, 28, 29, 33, 37–41, 43, 48–50, 52, 53, 55, 57, 59, 60, 61, 65, 67, 68, 70, and 71) and in five of the completed studies (Nos. II, V, VI, VII, X, and XI). No application route could be identified from registration information in three ongoing studies (Nos. 35, 44, and 64) and two completed studies (Nos. III and XIII). The intramyo-
cardial route was selected in 31 of the ongoing studies (2–7, 9, 10, 12, 14–16, 19, 22, 23, 25, 27, 30–32, 34, 36, 42, 45–47, 54, 56, 58, 62, and 63); 14 of these were transendocardial (Nos. 5, 10, 12, 19, 22, 25, 27, 31, 34, 45–47, 54, and 58). In six of the completed studies, the application route was intramyocardial (Nos. I, IV, VII, VIII, IX, and X) of which two were epicardial application via mini-thoracotomy (Nos. IV and VIII). Three ongoing studies involve comparison of application methods, intracoronary versus intramyocardial route (Nos. 6, 15, and 21). An intravenous route is studied in two ongoing studies (Nos. 51 and 66). One study uses limb muscle injection (No. 69). Another option that has not reached clinical study status in stem cell therapy, yet, is the intrapericardial administration of stem cells or activators, allowing for minimal invasive access to the heart [5].
Primary outcome measures
Primary outcomes of phase I and I/II studies were mainly safety and/or efficacy measures. Interestingly, the parameters that determine safety range widely from infectious and immunogenic parameters to severe adverse events (SAE). Efficacy measures were predominantly LV function after 6 months and this represents a mid- to short-term outcome. Global LV function may not be the ideal measure for regional application strategies. Alternative investigations include strain rate in echocardiography and regional magnetic resonance imaging (MRI) analysis. Follow-up studies provide more profound data regarding temporary effects of stem cell therapy. A classification of safety and also efficacy measures would result in more comparable data on clinical studies. In our opinion, this would include arrhythmia events, malformation and unwanted tissue, and changes like calcification.
Indications
Chronic myocardial ischemia was the treated condition in 39 of the ongoing studies (Nos. 1–12, 14, 16, 19, 21–25, 30– 34, 37, 40, 44–48, 52, 54, 55, 56, 62, and 63) and in five of the completed studies (Nos. I, III, V, IX, and X). In four of these studies, angina is the focus of the studies (Nos.
Abstract · Zusammenfassung
Fig. 4 7 Thallium SPECT perfusion scan of the study population preoperatively, at discharge, and at the 6-month follow-up
Activity in area of interest (ratio to preop)
1.2
P=0.02
1.15 1.1 1.05
C. Nesselmann · A. Kaminski · G. Steinhoff
Cardiac stem cell therapy. Registered trials and a pilot study in patients with dilated cardiomyopathy
1 0.95 0.9 0.85 preoperative
5, 52, 54, 55). Acute myocardial infarction was introduced as the condition to treat in 28 of the ongoing studies (Nos. 13, 15, 17, 18, 20, 28, 29, 35, 37, 38, 39, 41–43, 49– 51, 53, 57–61, 65–68, and 70) and in four of the completed studies (Nos. VI, VII, XI, XII and XIII). Ischemic or dilated cardiomyopathy was found as the treated condition in six of the ongoing studies (Nos. 3, 10, 26, 27, 64, and 69) and one of the completed studies (No. IV). One ongoing and two completed studies address nonischemic cardiomyopathy (Nos. 71 and Nos. II and VIII). In one ongoing study, idiopathic cardiomyopathy in children is being test-treated with skeletal muscle cells applied in the limb muscle (No. 69).
Timing
Herz 2011 · 36:121–134 DOI 10.1007/s00059-010-3419-y © Urban & Vogel 2011
P=0.05
Stem cell application for acute myocardial ischemia is often performed during the first week after acute PCI (Nos. 20, 29, 43, 51, 57, 59, and 65; Nos. VII and XIII) in addition to best medical treatment. Other groups chose a slightly wider time range, such as 6–9 days (No. 28), 2–3 weeks (No. 18, same group as No. 20), 3–14 days (No. 37), 2–10 days (No. 39), less than 3 weeks (No. 53), 5–10 days (No. 60), 7–10 days (No. XI), and 4–8 days (No. XIII). In one study, stem cell application is carried out not before 3 weeks to 3 months after myocardial infarction (No. 42). One study is investigating stem cell therapy at the time of PCI for reperfusion (No. 58). Three studies were designed to compare different time points, which are 4–24 hours versus <12 months (Nos. 15), 5–7 days versus 21–28 days (No. 41) and 21–42 days versus three months (No. VIII). It was not possible to determine the timing from the registration information for all studies. Timing itself is an increasingly noted issue and is being discussed as a cru-
discharge
6 months
cial factor for successful stem cell application. In acute myocardial ischemia, stem cell application is likely to be most efficient during the first month after myocardial ischemic injury [6]. According to ter Horst [6], the optimal time to administer stem cells in humans may be when the acute inflammatory response diminishes within the first week and vascularized granulation tissue is formed.
Stand alone and concomitant procedures
In the majority of clinical studies and other stem cell transplantation settings, stem cells are being given as an additional treatment. Stand alone, placebo controlled procedures can most likely uncover isolated stem cell effects. In some cases, the study registration information does not provide details about treatments and all concomitant procedures. Intramyocardial stem cell application in addition to coronary artery bypass surgery was reported for 10 of the ongoing studies (Nos. 7, 9, 14, 15, 30, 32, 42, 56, 62, and 63) and none of the completed registered studies. Our institution is currently running a phase III clinical study (PERFECT study) in order to investigate intramyocardial application of bone marrow mononuclear stem cells in addition to coronary artery bypass grafting (No. 16). One group studies stem cell application in left ventricular assist device (LVAD) bridge to transplant patients (No. 23). Another group addresses stem cell application together with cardiac resynchronization therapy (No. 4). To our knowledge, none of the mentioned as well as nonregistered studies is being carried out for dilated cardiomyopathy within the setting of a surgical procedure. The pilot study shown below will focus on this issue for the first time.
Abstract In cardiac stem cell therapy, the past decade has been interesting with respect to preclinical and clinical research. The high diversity of applied stem cell populations and evaluation methods represent a challenge to fully understand the impact of stem cell administration, leaving uncertain answers to the questions that have been dealt with thus far. In the present work, registered studies in cardiac stem cell therapy are summarized and the study aims are highlighted. Furthermore, preliminary data on the additional intramyocardial administration of CD133+ stem cells in patients undergoing mitral valve surgery are presented. Keywords Cardiac stem cell therapy · Registered studies · Stem cells · Dilated cardiomyopathy · Intramyocardial
Kardiale Stammzelltherapie. Eingetragene Studien und Pilotuntersuchung an Patienten mit dilatativer Kardiomyopathie Zusammenfassung In der Stammzelltherapie von kardialen Erkrankungen blicken wir auf ein interessantes Jahrzehnt präklinischer und klinischer Forschung zurück. Die große Vielfalt von angewendeten Stammzellpopulationen und Untersuchungsmethoden fordern unser Verständnis für den erzielten Effekt von admi nistrierten Stammzellen heraus und lassen einige behandelte Fragen offen. In dieser Arbeit wollen wir die wesentlichen aktuellen registrierten Studien zusammenfassen und einzelne Untersuchungsziele herausarbeiten. Desweiteren stellen wir vorläufige Daten zur zusätzlichen intramyokardialen Anwendung von CD133+ Stammzellen bei Patienten, die einer Mitralklappenoperation unterzogen werden, vor. Schlüsselwörter Kardiale Stammzelltherapie · Eingetragene Studien · Stammzellen · Dilatative Kardiomyopathie · Intramyokardial
Herz 2 · 2011
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124 |
Study type
R
RPCDB
NR
SB
RCSB
RPCDB
RPCDB
R
No
1
Herz 2 · 2011
2
3
4
5
6
7
8
Treatment (study arms)
CAD, CHF
MI, heart failure
Chronic ischemic heart failure
Autologous cardiac stem cells
(1–4) Granulocyte-colony stimulating factor (GCSF) or placebo + percutaneous intracoronary stem/progenitor cells or placebo, (5–8) GCSF or placebo + percutaneous intramyocardial stem/progenitor cells or placebo (1) CABG + saline solution with autologous plasma, (2) CABG + CD133+ stem cells
(1) Observation (control group), (2) autologous cardiosphere-derived stem cells, (3) autologous cardiosphere-derived stem cells – dose escalated Heart failure, MI, (1) CABG + autologous mesenCAD chymal stem cell (MSC) treatment, (2) CABG + autologous serum CHF, ICM, venCABG + autologous human cartricular dysfunction diac derived stem cells + gelatin (LVEF 15–35%) hydrogel sheet incorporating human recombinant basic fibroblast growth factor (bFGF) Heart failure Mononuclear cells + implantation of cardiac resynchronization therapy Angina, CAD (1) Transmyocardial laser revascularization (TMR), (2) TMR + stem cells (n.s.)
MI, ventricular dysfunction, CHF, heart failure
Condition(s)
Heart (right atrial appendage)
BM
BM
BM
BM
Heart
BM
Heart
Intramyocardial
0.5×106
n.g.
n.g.
n.g.
n.g.
30
6
60
30
Intracoronary
Intramyocardial
40
20
02/09–12/10
12/09–07/12
08/05–08/11
10/10–10/12
11/08–12/09 (recruiting)
09/09–03/13
10/06–12/10
05/09–07/11
I
II
II, III
II
I
I
II
I
Estimated Start date–study Phase enrollment completion date
Trans20 myocardial (PHOENIX™) Intracoro- 165 nary vs. intramyocardial
Intramyocardial
Intramyocardial
5–1000×106
n.g.
Intracoronary
Delivery route
25×106 and 50×106
Cell Source Dose
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov)
Freedom from major adverse cardiac events and major arrhythmia Safety
LVEF
NYHA
EF, NYHA
Safety
EF (MRI)
Primary outcome measure/ secondary outcome Safety/ efficacy
NCT00981006
NCT00418418
NCT00893360
Reference (short name if specified)
University of Louisville
Centre hospitalier de l’Université de Montréal
Barts & The London NHS Trust
NCT00474461 (SCIPIO)
NCT01033617 (IMPACTCABG)
NCT00747708
Instituto de NCT00800657 Molestias Cardiovasculares Hospital Uni- NCT01214499 versitario de la Princesa
Kyoto Prefectural University of Medicine
Helsinki University
Cedars-Sinai Medical Center
Sponsor
Main topic/CME
Herz 2 · 2011
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RPCDB
RPCDB
NR
RPCDB
RPCDB
RSB (pilot trial) R
RPCDB
RPCDB
9
10
11
12
13
14
16
17
15
Study type
No
(1) CABG + lower dose autologous MSC, (2) CABG + higher dose autologous MSC, (3) CABG + placebo (PBS + 1% HSA)
Treatment (study arms)
BM
Acute MI
Myocardial ischemia, CAD
CAD, acute MI
Ischemic heart disease
CAD, acute MI
CAD
BM
BM
(1) Combination of autologous BM stem/ progenitor cells – intracoronary, AMI 4–24 hours, (2) combination of autologous stem/ progenitor cells – intracardiac, MI <12 months + CABG (1) Autologous CD 133+ stem BM cells + CABG, (2) placebo (physiological saline + 10% autologous serum) (1) Autologous stem/progenitor BM cells, (2) placebo infusion
(1) CABG, (2) CABG + autologous BM bone marrow- derived stem cells
(1) Bone marrow-derived progenitor cells, (2) placebo medium
(1) Autologous aldehyde dehydrogenase bright stem cells, (2) placebo (5% albumin)
Intramyocardial
Delivery route
45
Intracoronary
Intramyocardial
1–10×106
n.g.
Intracoronary vs. intramyocardial
Intramyocardial
102
142
20
30
Percutane- 20 ous intramyocardial (NOGA mapping) Intracoro- 100 nary
n.g.
n.g.
n.g.
n.g.
II
I, II
I
I
II
I, II
03/08–03/11
07/09–01/12
II, III
III
10/07–04/09 I (ongoing but not recruiting)
05/08–06/11
09/08–04/11
04/06–04/11
01/06–09/07*
03/09–12/11
11/07–06/11
Estimated Start date–study Phase enrollment completion date
apPercutane- 87 prox.100×106 ous intramyocardial (NOGA mapping) n.g. Intracoro- 10 nary
2×107 and 2×108
Cell Source Dose
Chronic ischemic (1) Placebo (HSA), (2) autologous BM heart failure, left BM- mononucleated cells ventricular dysfunction, angina, ICM Coronary occlusion Autologous AC 133+ BM
Left ventricular dysfunction
Condition(s)
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov) (Continued)
Left ventricular EF (MRI)
Left ventricular EF (MRI)
Improvement of coronary flow reserve in the infarct vessel Left ventricular volume and contractility Safety and feasibility
Safety
Safety and feasibility
MVO2, LVESV, reversible defect size
Primary outcome measure/ secondary outcome Severe adverse events
Barts & The London NHS Trust
Miltenyi Biotec GmbH
Johann Wolfgang Goethe University Hospitals University Hospital, Clermont-Ferrand TCA Cellular Therapy
National Heart, Lung, and Blood Institute (NHLBI) National Heart, Lung, and Blood Institute (NHLBI) Case Western Reserve University Texas Heart Institute
Sponsor
NCT00765453 (REGEN-AMI)
NCT00950274 (PERFECT)
NCT00548613 (MESENDO)
NCT00690209
NCT00711542 (REPAIR-ACS)
NCT00314366
NCT00365326
NCT00824005 (The FOCUS Study)
NCT00587990 (PROMETHEUS)
Reference (short name if specified)
126 |
Study type
RPCDB
NR
RPCDB
RPC
R (pilot study)
RPCDB
R
RPCSB
RPCSB
No
18
Herz 2 · 2011
19
20
21
22
23
24
25
26
n.g. (presumably BM)
(1–2) Total nucleated cells 3 or 7 BM days after PCI, (3–4) placebo (5% HSA/saline solution) 3 or 7 days after PCI
(1) Low dose of CD34+ cells, (2) high dose of CD34+ cells
Dilated cardiomyopathy
ICM
Severe coronary ischemia
(1) Prior filgrastim stimulation + technetium-labeled autologous CD34+ stem cells, (2) prior filgrastim stimulation + placebo (saline)
(1) Autologous bone marrow cells, (2) sham treatment
Peripheral blood (apheresis)
BM
Combination of autologous stem BM cells termed “final cell mixture”
n.g.
n.g.
n.g.
25×106, 75×106
20×106, 100×106, 200×106
n.g.
150×106
n.g.
150×106
Cell Source Dose
(1) Autologous total nucleated BM stem cells (=BM mononucleated cells), (2) placebo (5% HSA)
Treatment (study arms)
(1) Combination of BM-MNC and BM MSC – low dose, (2) combination of BM-MNC and MSC – high dose, (3) placebo (5% HSA/PBS) Chronic ischemic (1–3) Three different doses of au- BM left ventricular dys- tologous human mesenchymal function secondary stem cells (auto-hMSC), (4–6) to myocardial three different doses of allogeinfarction neic auto-hMSC Heart failure (LVAD (1–2) Low dose or high dose au- BM bridge to transtologous mesenchymal precurplant) sor cell (3) placebo (cryoprotective medium)
Severe coronary ischemia
Left ventricular dysfunction, acute MI
Myocardial ischemia, CHF, CVD
LV dysfunction
Condition(s)
120
10
87
Intramyocardial (NOGA mapping) Intracoronary
Intracoronary
Intramyocardial
50
30
10
80
05/06–05/10
02/08–02/09 (ongoing, not recruiting) 04/04–11/09
08/09–09/10
03/10–04/11
11/08–03/11
07/08–12/11
03/08–09/11
07/08–12/11
II
I
I
II
I, II
II
II
I
II
Estimated Start date–study Phase enrollment completion date
Intracoro- 60 nary vs. transendocardial Transendo- 30 cardial
Catheterbased intramyocardial Intracoronary
Intracoronary
Delivery route
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov) (Continued)
Heart failure mortality (safety)
Safety
Safety
Safety
Safety
Safety
LVEF
Safety
Primary outcome measure/ secondary outcome LVEF
University Medical Centre Ljubljana
Texas Heart Institute
National Heart, Lung, and Blood Institute (NHLBI) National Heart, Lung, and Blood Institute (NHLBI) TCA Cellular Therapy
National Heart, Lung, and Blood Institute (NHLBI) TCA Cellular Therapy
National Heart, Lung, and Blood Institute (NHLBI) Losordo, Douglas, M.D
Sponsor
NCT00629018
NCT00203203
NCT00643981
NCT00927784
NCT01087996 (The POSEIDON-Pilot Study)
NCT00790764
NCT00684021 (The TIME Study)
NCT00620048
NCT00684060 (The Late TIME Study)
Reference (short name if specified)
Main topic/CME
Herz 2 · 2011
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Study type
RSB
R
RPCDB
NR
RSB
RPCDB
NR
RPCDB
No
27
28
29
30
31
32
33
34
Left ventricular dysfunction
Chronic myocardial ischemia, nooption patients
Coronary disease, MI
Ischemic heart failure
CHF with ischemic etiology
Acute MI
Ischemic and idiopathic cardiomyopathy, heart failure Acute MI
Condition(s)
(1–2) Two different doses of autologous human mesenchymal stem cells, (3–4) two different doses of autologous human BM cells, (5) placebo (1%HSA/PBS)
Autologous peripheral blood endothelial progenitor cells (CD34+)
Autologous BM cells + CABG (randomization n.g.)
(1) Autologous CD34+ BMMNCs, (2) autologous peripheral blood stem cells, (3) medication alone
(1) Autologous CD34+ progenitor cells + off-pump CABG surgery, (2) ad hoc procedure (mini-thoracotomy)
(1–4) Four different doses of autologous BM-derived CD34+ stem cell, (5) no cell treatment Autologous, unfractioned BM mononuclear cells
(1–3) Three different doses of allogeneic mesenchymal precursor cells, (4) sham treatment
Treatment (study arms)
BM
Peripheral blood (apheresis)
BM
BM, peripheral Blood
centrally grafted or mobilized in peripheral blood
BM
BM
n.g. (presumably BM)
Intracoronary
Transendocardial
n.g.
100×106, 200×106
Intramyocardial
Endocardial
250×106
n.g.
Intramyocardial
Intracoronary
100×106
n.g.
Intracoronary
Transendocardial
Delivery route
5, 10, 20, and 30×106
25×106, 75×106, 150×106
Cell Source Dose
60
10
50
250
n.g.
41
40
60
08/08–08/10 (recruiting)
09/05–09/09 (recruiting)
01/07–06/09 (ongoing, not recruiting)
02/07–03/11
05/07; not determined (recruiting)
12/05–01/12
03/06–03/12
08/08–07/11
I, II
I, II
I, II
III
II
I
I
II
Estimated Start date–study Phase enrollment completion date
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov) (Continued)
TE-SAE
Safety (SAE) and efficacy (SPECT stress myocardial scintigraphy)
No survival benefit (null hypothesis), survival benefit (alternative hypothesis) LVEF
Safety
Safety
Cardiac function
Primary outcome measure/ secondary outcome Safety and feasibility
China National Center for Cardiovascular Diseases Foundation for Biomedical Research and Innovation University of Miami
Minneapolis Heart Institute Foundation The Mediterranean Institute for Transplantation and Advanced Specialized Therapies Meshalkin Research Institute of Pathology of Circulation
Emory University
Angioblast Systems
Sponsor
NCT00768066 (TAC-HFT)
NCT00221182
NCT00395811
NCT00841958 (ESCAPE)
NCT00480961
NCT00268307
NCT00313339 (AMR-1)
NCT00721045
Reference (short name if specified)
128 |
Study type
RPCDB
RPCDB
R
RPCDB
RSB
RPCDB
R
RSB
RPCDB
RPCDB
No
35
Herz 2 · 2011
36
37
38
39
40
41
42
43
44
IHD, non-revascurable ischemic myocardium
Acute MI
Acute MI
Acute MI
Congestive heart failure
Recent acute myocardial infarction
Acute MI
Myocardial infarction
Severe left ventricular dysfunction and left ventricular assist device support
STEMI, CAD
Condition(s)
Bone marrow cells at day 5–7 or 21–28 after successful PCI vs. state of the art medicine only (1) CABG + BM-MNCs, (2) CABG + BM derived AC 133, (3) CABG + placebo (cell carrier (1) AMI + prior reperfusion therapy + enriched BM derived progenitor cells, (2) AMI + prior reperfusion therapy + placebo medium (1) Adipose derived stem and regenerative cells (ADRCs), (2) placebo
(1) Autologous stem cells, (2) placebo (integrated are autologous erythrocytes) (1–3) Three different dosages of allogeneic mesenchymal precursor cells, (4) standard-of-care treatment with NOGA® mapping and staged injection Prior extracorporeal shock wave therapy + BM progenitor cells (randomization n.g.)
Autologous BM-MNC (randomization n.g.)
(1) BM MNC, (2) placebo (5% albumin)
(1) Adipose derived stem and regenerative cells (ADRCs), (2) placebo
Treatment (study arms)
Lipoaspirate
BM
BM
BM
BM
n.g. (presumably BM)
BM
BM
BM
Lipoaspirate
n.g.
n.g.
n.g.
n.g.
n.g.
Intracoronary
Intramyocardial
Intracoronary
Intracoronary
Intracoronary
25×106, 75×106, 150×106
n.g.
Intracoronary
n.g.
Intracoronary
Intramyocardial
20×106
n.g.
n.g. (presumably intracoronary)
Delivery route
n.g.
Cell Source Dose
36
200
105
150
100
25
40
30
24
48
01/07–01/11
04/04–n.g.
Jan 2008
08/06–12/10
05/06–11/10
03/08–12/13
10/05–01/09
06/05–12/17
12/10–06/12
11/07–11/11
I
III
III
II
I, II
I, II
II
I
I
I
Estimated Start date–study Phase enrollment completion date
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov) (Continued)
Safety (MACE)
Global EF (LVangiography)
EF (stress-echocardiography)
EF (MRI)
Global EF (LVangiography)
Safety and feasibility
Cytori Therapeutics
Johann Wolfgang Goethe University Hospitals
Royan Institute
Johann Wolfgang Goethe University Hospitals University of Zurich
Angioblast Systems
NCT00426868 (The PRECISE Trial)
NCT00279175 (REPAIR-AMI)
NCT01167751
NCT00355186 (SWISS-AMI)
NCT00326989
NCT00555828
Primary outSponsor Reference come measure/ (short name if secondary outspecified) come Safety (major Cytori Thera- NCT00442806 adverse cardiac peutics (The APOLLO and cerebral Trial) events = MACCE) Safety, myoUniversity of NCT00869024 cardial viabilMinnesota – ity (PET scan), Clinical and death + reTranslational hospitalization Science Insti(combined end tute point) Safety and feasi- Cedars-Sinai NCT00874354 bility, LVEF (MRI Medical Cen- (REVITALIZE) and echocarter diography) LVEF (MRI) University of NCT00669227 Ulm (SCAMI)
Main topic/CME
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Study type
NR
RPCDB
RPCDB
NR
RCT
NR
RPCDB
NR
RSB
RPCDB
NR
NR
No
45
46
47
48
49
50
51
52
53
54
55
56
Ischemic heart disease, congestive heart failure
CAD, severe anginal syndrome
CAD, refractory angina
AMI
Angina pectoris
AMI
AMI
AMI
Coronary artery disease
Congestive heart failure
Chronic myocardial ischemia, left ventricular dysfunction Congestive heart failure
Condition(s)
CABG + angiogenetic cell precursors
Autologous EPCs/angiogenetic cell precursors
(1) BM-derived AC 133+, (2) mononuclear cells, (3) placebo (autologous serum) (1) Autologous progenitor cell CD 133, (2) placebo
(1) Ex vivo cultured adult human mesenchymal stem cells (PROCHYMAL®), (2) placebo Autologous angiogenic cell precursors (APCs)
Autologous bone marrowderived stem cells
Autologous mononuclear bone marrow cells
CD 133+ cells
(1–2) Two different doses of skeletal myoblasts, (3) placebo (transport medium alone) (1) Mesenchymal stromal cells, (2) placebo (saline)
Mesenchymal stem cells
Treatment (study arms)
Peripheral blood
Peripheral blood
n.g.
BM
Peripheral blood
n.g.
BM
BM
BM
BM
Skeletal muscle
BM
Transendocardial (NOGA) Intracoronary
20–30×106
Transendocardial Intracoronary Intramyocardial
n.g.
≥1.5×106
≥1.5×106
Intracoronary
Intracoronary
≥1.5×106
n.g.
Intravenous
Intracoronary
n.g.
n.g.
n.g.
Intracoronary
Transendocardial
400×106, 800×106
≥1×106
Transendocardial (NOGA)
Delivery route
60×106
Cell Source Dose
5
24
30
100
10
220
10
50
10
60
170
10
07/04–09/06 (ongoing, not recruiting) 01/06–09/07 (recruiting)
05/08–05/09 (recruiting)
08/07–8/07 (not yet open for recruitment) 05/09–12/11
03/09–12/12
02/06–03/07 (recruiting)
07/05–02/07
12/09–06/11
09/08–09/12
09/07–02/12
10/09–10711
I
II
I, II
II, III
I, II
II
I
I, II
I, II
I, II
II, III
I, II
Estimated Start date–study Phase enrollment completion date
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov) (Continued)
Safety, efficacy, NYHA, 6-minute walk test, quality of life questionnaire
Safety and efficacy
MAE
EF
Safety
ESV
Safety
Myocardial contractility and perfusion Mortality, mortality + morbidity, LV function
6-minute walk test, quality of life questionnaire EF, clinical improvement
Primary outcome measure/ secondary outcome Safety and feasibility
TheraVitae Ltd.
Hospital San Carlos, Madrid TheraVitae Ltd.
Royan Institute
TheraVitae Ltd.
Rigshospitalet, Denmark Hospital y Clinica OCA, S.A. de C.V. Azienda Unità Sanitaria Locale di Piacenza Odense University Hospital Osiris Therapeutics
Bioheart, Inc.
University Hospital, Toulouse
Sponsor
NCT00523224
NCT00384514
NCT00694642
NCT01187654
NCT00416663
NCT00877903
NCT00275977
NCT00437710 (CARDIAC)
NCT01049867
NCT00644410
NCT00526253 (MARVEL)
NCT01076920
Reference (short name if specified)
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Study type
RSB
NR
RPCDB
RPCDB
RPCDB
NR
RPCDB
RPCDB
RCT
RPCDB
RCT
RPCDB
No
57
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58
59
60
61
62
63
64
65
66
67
68
STEMI, CAD
MI, AMI
STEMI, CAD
Dilated cardiomyopathy STEMI, CAD
Congestive heart failure CAD with CABG
AMI
AMI
AMI, early left ventricular dysfunction AMI
AMI
Condition(s)
(1–2) Two different doses of ADRCs, (3) placebo
(1) Ex vivo cultured adult allogeneic mesenchymal stem cells, (2) placebo (Plasma-Lyte A) (1) Hypoxia-stressed BM-MNC, (2) placebo (sham)
(1) BM-MNCs, (2) placebo (saline containing autologous serum) (1) Prior PCI + CD 133+ autologous progenitor cells, (2) prior PCI + placebo (buffered normal saline) (1) Autologous endothelial-like, culture modified mononuclear cells (E-CMMs), (2) autologous E-CMMs transfected with human endothelial nitric oxide synthase (eNOS), (3) placebo (Plasma-Lyte A) CABG + bone marrow aspirate concentrate (1) CABG + CD 133+ cell, (2) CABG + placebo Autologous bone marrow stem cells (1) Prior PCI + BM-MNCs, (2) prior PCI + placebo (saline)
(1) PCI + mononuclear cells, (2) PCI
(1) Prior PTCA + CD 34+ cells, (2) PTCA only
Treatment (study arms)
n.g.
BM
n.g.
BM
BM
BM
BM
Peripheral blood (apheresis)
BM
BM
BM
Bone marrow
Intracoronary
Intracoronary
1×107
n.g.
Intravenous
Intracoronary
Intramyocardial Intramyocardial n.g.
Intracoronary
Intramyocardial (NOGA) Intracoronary Intracoronary
Intracoronary
Delivery route
n.g.
n.g.
n.g.
10, 15, or 20×106 n.g.
20×106
n.g.
100×106
n.g.
1–2 x 106
Cell Source Dose
360
100
20
37
300
60
20
100
60
300
40
80
01/11–06/12
11/10–12/12
04/07–08/08 (recruiting) 01/06–02/09 (recruiting) 03/08–03/08 (active not recruiting) 04/09–12/11
05/10–12/11
11/10–12/13
06/06–06/08 (recruiting) 09/07–12/13
01/09–01/12
05/08–12/09
II, III
n.g.
I, II
I, II
III
I, II
I, II
II
n.g.
III
II
II, III
Estimated Start date–study Phase enrollment completion date
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov) (Continued)
Reduction in infarct size (MRI)
Heart function
AE, ECG parameters
LV function
LV function (MRI) LV function
LV function
Global EF, regional wall motion, wall thickening and infarct volume (MRI)
Safety and efficacy
Global EF
LVEF
Primary outcome measure/ secondary outcome LVEF (MRI)
Stempeutics Research Pvt Ltd Second Affiliated Hospital, School of Medicine, Zhejiang University Cytori Therapeutics
Harvest Technologies German Heart Institute Ministry of Health, Brazil Xijing Hospital
Ottawa Hospital Research Institute
Ministry of Health, Brazil Onze Lieve Vrouw Hospital
National Heart Institute, Mexico Asklepios proresearch
Sponsor
NCT01216995 (The ADVANCE Study)
NCT01234181
NCT00883727
NCT00626145
NCT00333827
NCT00462774
NCT01061580
NCT00936819 (ENACT-AMI)
NCT00529932 (SELECT-AMI)
NCT00350766
NCT00939042
NCT00725738
Reference (short name if specified)
Main topic/CME
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NR
R
NR
69
70
71
Nonischemic dilated cardiomyopathy
Large myocardial infarction
Idiopathic dilated cardiomyopathy in children
Condition(s)
Autologous BMCs
Autologous BM-MNCs
Umbilical cord mesenchymal stem cells
Treatment (study arms)
BM
Human umbilical cord blood BM
n.g.
n.g.
n.g.
Cell Source Dose
Intracoronary
Intracoronary
Intramuscular (limb muscle)
Delivery route
30
n.g.
30
02/08–08/10 (recruiting)
n.g. (ongoing, not recruiting)
10/10–12/12
II
II
I, II
Estimated Start date–study Phase enrollment completion date
LV function
Not specified
Primary outcome measure/ secondary outcome Echocardiography
Charles University, Czech Republic Hospital Universitario Reina Sofia
Qingdao University
Sponsor
NCT00629096
NCT00389545
NCT01219452
Reference (short name if specified)
Study type
NR
R
RPCDB
RCT
NR
No
I
II
III
IV
V
Severe ischemic heart failure and no other option for standard therapies
Dilated cardiomyopathy
Severe chronic myocardial ischemia Nonischemic dilatative cardiomyopathy Chest pain, myocardial ischemia, CAD
Condition(s)
Autologous bone marrow mesenchymal stem cells (1) BM-derived progenitor cells, (2) standard medical therapy alone (1) Prior stem cell mobilization + autologous CD34+ cells, (2) Prior stem cell mobilization + placebo (saline) (1) Autologous BMMNCs, (2) control (monitoring) BM transplantation
Treatment or arms (if specified)
BM
BM
Peripheral blood (apheresis)
BM
BM
Cell source
Intramyocardial (left mini-thoracotomy) Intracoronary
9×107
n.g.
n.g.
Intracoronary
Intramyocardial
Delivery route
n.g.
n.g.
n.g.
Dose
35
30
24
30
Estimated enrollment 40
Completed
Completed
Completed
Completed
Start date – study completion date Completed
II
II, III
I
I, II
LVEF
Safety and Efficacy
n.g. (presumably symptom relief)
LV (Simpson)
Phase Primary outcome measure / secondary outcome I, II Myocardial perfusion (SPECT)
Instituto de Cardiologia do Rio Grande do Sul Odense University Hospital
Johann Wolfgang Goethe University Hospitals Losordo, Douglas, M.D.
Rigshospitalet, Denmark
Sponsor
NCT00235417
NCT00743639 (SDILCM)
NCT00284713 (TOPCARE DCM-trial) NCT00081913
NCT00260338
Reference (short name if specified)
Tab. 2 Completed registered trials in December 2010 (http://www.clinicaltrials.gov). Acute myocardial infarction (AMI), ST-elevation myocardial infarction (STEMI), intravascular ultrasound (IVUS)
MSCs mesenchymal stem cells, MI myocardial infarction, ICM ischemic cardiomyopathy, CABG coronary artery bypass grafting, CHF chronic heart failure, CAD coronary artery disease, BM bone marrow, LVEF left ventricular ejection fraction, LVESV left ventricular end-systolic volume, LVAD left ventricular assist device, MNCs mononuclear stem cells, MVO2 myocardial oxygen consumption, RPCDB randomized, placebo controlled, double blind, RCT randomized clinical trial, SB single blind, R randomized, NR nonrandomized, n.g. information not given, PBS phosphate buffered saline, HAS human serum albumin, CVD cardiovascular disease.
Study type
No
Tab. 1 Ongoing registered clinical trials in cardiac stem cell therapies in 12/2010 (http://www.clinicaltrials.gov) (Continued)
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Herz 2 · 2011
RPCDB
RCT
NR
RPCDB
RPCDB
RCT
RCT
RPCDB
VI
VII
VIII
IX
X
XI
XII
XIII
AMI (STEMI)
Acute anterior wall MI
Acute and severe MI
Refractory chronic myocardial ischemia
Nonischemic dilated cardiomyopathy Refractory chronic myocardial ischemia
AMI
STEMI
Condition(s)
(1–2) Two different doses of G-CSF mobilized auto-CD34+ cells, (3) placebo (saline plus 5% autologous plasma) (1–2) Two different doses of G-CSF mobilized auto-CD34+ cells, (3) placebo (saline plus 5% autologous plasma) (1) Prior (7–10 days) PCI + autologous BMMNCs, (2) PCI + optimal care (1) Prior PCI (4–8 days) and autologous bone marrow stem cells, (2) control (1) Prior thrombolysis and PCI plus BMderived stem cells after 2–6 days, (2) placebo (sham infusion)
BM MNCs
Autologous BM-derived stem cells (randomization n.g.) (1–4) Early or late, percutaneous intracoronary or combined (intramyocardial and intracoronary) BM-MNCS
Treatment or arms (if specified)
BM
BM
BM
n.g. (presumably peripheral blood)
n.g. (presumably peripheral blood)
BM
BM
BM
Cell source
n.g.
68×106 (median)
Intracoronary
Intracoronary
Intracoronary
Intramyocardial
Intramyocardial (left mini-thoracotomy) Intramyocardial
9.6×107
1×105 (±10%) cells/kg of body weight, 5×105 (±10%) cells/kg of body weight 1×105 (±10%) cells/kg of body weight, 5×105 ±10%) cells/kg of body weight n.g.
Intracoronary or/ and intramyocardia
Intracoronary
Delivery route
n.g.
n.g.
Dose
100
100
100
150
150
6
116
Estimated enrollment 68
Completed
Completed
Completed
Completed
Completed
Completed
Completed
Start date – study completion date Completed
II, III
II
II
II
II
I, II
II
Arrhythmia risk variables, left ventricular function, restenosis assessed by IVUS
LVEF (SPECT)
Myocardial viability (thallium scintigraphy)
Frequency of angina episodes
Frequency of angina episodes
Resting myocardial perfusion and global left ventricular ejection fraction (SPECT) Safety (morbidity/ mortality)
Phase Primary outcome measure / secondary outcome II Global EF (MRI)
University of Oulu
Oslo University Hospital
Nantes University Hospital
Baxter Healthcare Corporation. Baxter Healthcare Corporation
Instituto de Cardiologia do Rio Grande do Sul Baxter Healthcare Corporation. Baxter Healthcare Corporation
Medical University of Vienna.
University Hospital, Gasthuisberg
Sponsor
NCT00363324
NCT00199823 (ASTAMI study)
NCT00200707 (BONAMI)
NCT00545610– 12 month Follow up study
NCT00300053
NCT00615394
NCT00384982 (MYSTAR)
NCT00264316
Reference (short name if specified)
MSCs mesenchymal stem cells, MI myocardial infarction, ICM ischemic cardiomyopathy, CABG coronary artery bypass grafting, CHF chronic heart failure, CAD coronary artery disease, BM bone marrow, MNCs mononuclear stem cells, RPCDB randomized, placebo controlled, double blind, RCT randomized clinical trial, SB single blind, R randomized, NR nonrandomized, n.g. information not given, PBS phosphate buffered saline, HAS human serum albumin, CVD cardiovascular disease, IVUS intravascular ultrasound, AMI acute myocardial infarction, STEMI ST-elevation myocardial infarction.
Study type
No
Tab. 2 Completed registered trials in December 2010 (http://www.clinicaltrials.gov). Acute myocardial infarction (AMI), ST-elevation myocardial infarction (STEMI), intravascular ultrasound (IVUS) (Continued)
Main topic/CME
Clinical translation Management of the process from basic research to approval and application of stem cells as standardized and quality-checked therapies is the mission of reference and translation centers, which are linked to clinical and preclinical research centers as our institution provides (http://www.cardiac-stemcell-therapy. com). The translation process is meant to provide reference for further research projects. While one focus is good manufacturing practice (GMP) and good clinical practice (GCP), many other factors also need to be taken in to consideration, e.g., patient selection, concomitant procedures, cell delivery, timing, cell survival, cell tracking, dose, age, regulatory issues, and funding (reviewed in [7]).
Injection of stem cells during mitral valve surgery in patients with cardiomyopathy Cardiac stem cell transplantation in addition to coronary artery bypass surgery in patients with chronic myocardial ischemia has been the focus of research in our institution since our first clinical attempts started in 2001 [8]. Considerable experience has been gained in stem cell application since then. Long-term results from phase II trial in the above mentioned patients revealed significant gain in regional perfusion and left ventricular function [4]. Surgical treatment of dilated cardiomyopathy includes mitral valve surgery and coronary artery bypass grafting aiming to reduce intractable congestive heart failure [9]. For these cases, the inhospital mortality and mid-term cardiac-related mortality were 4.9% and 3.4%, respectively, and is accompanied by significantly improved left ventricular ejection fraction and reduction in NYHA class [10]. Therefore, we initiated a pilot study in which the surgical procedure and autologous stem cell transplantation were combined.
Methods Operation candidates were screened for mitral valve regurgitation and scheduled for surgery and intramyocardial stem
Tab. 3 Patients’ baseline data
Patient
Age
Gender
Mean
1 2 3 4 5 6 7 8 9 10
41 53 54 55 62 63 67 68 71 75 61±10
F M M M M M M M M M 9/10
Mitral regurgitation 3 4 3 3 3 3 3 3.5 4 3 3.2
Tricuspid regurgitation − − − − − − + + + − 3/10
Ischemic cardiomyopathy + − + + + + + + − + 8/10
LVEDD
NYHA score
76 80 75 63 72 53 66 56 74 55 67±10
2.5 3.5 2.5 2 2.5 2 2.5 2.5 .5 3.5 2.5
MI myocardial infarction, LVEDD left ventricle enddiastolic diameter, NYHA New York Heart Association.
Tab. 4 Surgical treatment: mitral surgery + stem cell injection Patient 1 2 3 4 5 6 7 8 9 10
Mitral repair − + + + + + + + − + 8
Mitral replacement + − − − − − − − + − 2
Tricuspid repair − − − − − − + + + − 3
CABG − − + + + + − − − − 4
Stem cells + + + + + + + + + + 10
CABG coronary artery bypass grafting.
cell transplantation, if indicated. Indication criteria for stem cell transplantation in patients scheduled for CABG surgery have been described elsewhere [11]. Preoperative work-up included Holter electrocardiogram (Holter ECG), magnetic resonance imaging (MRI) or SPECT perfusion scan, echocardiography (Echo), and NYHA classification at ≤10 days before surgery. On the morning of the operation, bone marrow was harvested from the iliac crest under local anesthesia and cluster of differentiation 133 (CD133+) stem cells were isolated using the CliniMACS® System. All operations were performed on cardiopulmonary bypass and cardioplegic arrest. The mitral valve was either repaired or replaced. Coronary arteries with relevant stenoses and sufficient diameter were grafted. The area was visualized, and CD133+ bone marrow stem cells were injected in the myocardium that corresponded to the charted lo-
calization, at the end of cardioplegia and before unclamping of the aorta. The operation was completed as usual. Standard postoperative care was performed. Before discharge, Holter ECG, MRI or SPECT perfusion scan, Echo, and NYHA classification was repeated. At the 6 month follow-up, these studies were repeated, and at the 12 month follow-up Echo and Holter ECG were performed.
Results A total of 10 patients were included in the study. The mean age was 61±10 years and 9 patients were male. Severe mitral regurgitation was present in all 10 patients with a mean degree of 3.2. Concomitant severe tricuspid regurgitation was detected in 3 patients. In 8 patients ischemic cardiomyopathy with previous myocardial infarction was diagnosed. All baseline data are shown in . Tab. 3. Eight patients Herz 2 · 2011
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Main topic/CME received mitral valve repair by ring annuloplasty and 2 patients received mitral valve replacement. Tricuspid valve repair was carried out in 3 patients with third degree tricuspid insufficiency. Concomitant CABG was performed in 4 cases. All patients received stem cell injection, with a mean cell number of 10.2±4.6×106 Treatment data are summarized in . Tab. 4. Perioperative complications were renal failure (n=3) of whom 1 patient needed temporary hemofiltration (n=1), pericardial effusion (n=1). No ventricular arrhythmias (ventricular tachycardia or fibrillation) were detected. No temporary or persistent mechanical assistance was necessary. No patient died in the hospital or after 6 months. After 12 months, 2 patients had died. Postoperative NYHA class was 2.6±0.5 on average at discharge and 2.0±SD on average after 6 months. Left ventricular ejection fraction (LVEF), measured by MRI and Echo improved nonsignificantly after 6 months ( . Fig. 2). Mean LVEF (Echo) was 28±8.5% after 6 months and 26.5±8.9% after 12 months. LVEDD did not change after the surgery (. Fig. 3). A significant perfusion gain was observed throughout the study time frame (. Fig. 4).
Conclusion Intramyocardial transplantation of autologous CD133+ stem cells in addition to surgical therapy of dilated cardiomyopathy is a safe procedure. While myocardial perfusion clearly increased, improvement of left ventricular function was modest compared to patients undergoing coronary artery bypass graft surgery and additional stem cell injection. Growing evidence suggests that with respect to the results of this pilot study, phase I and II trials are needed to further define the effects of cell treatment in these patients.
Summary Stem cell transplantation depicts a promising strategy in cardiac diseases. A large number of ongoing trials outweighs the number of completed trials in cardiac stem cell therapy applications and, therefore, suggests that we will soon experience a further increase
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in the understanding of stem cell effects on the human body. Pilot studies as well as safety and efficacy studies have been completed and are ongoing. At the same time, phase III trials have been conducted to further evaluate the variables of stem cell transplantation. Concomitant basic research and independent basic research are needed in order to discover the mechanisms in cardiac stem cell therapy, which are not clearly understood yet.
Corresponding address Dr. C. Nesselmann Department of Cardiac Surgery, University of Rostock Schillingallee 35, 18057 Rostock
[email protected] Conflict of interest. The corresponding author declares that there are no conflicts of interest.
References 1. Orlic D, Kajstura J, Chimenti S et al (2001) Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci 938:221–229; discussion 29–30 2. Orlic D, Kajstura J, Chimenti S et al (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410(6829):701–705 3. Krause K, Schneider C, Kuck KH, Jaquet K (2010) Stem cell therapy in cardiovascular disorders. Cardiovasc Ther 28(5):e101–e110 4. Stamm C, Kleine HD, Choi YH et al (2007) Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J Thorac Cardiovasc Surg 133(3):717–725 5. Rupp H, Rupp TP, Alter P et al (2010) Intrapericardial procedures for cardiac regeneration by stem cells: need for minimal invasive access (AttachLifter) to the normal pericardial cavity. Herz 35(7):458–465 6. Horst KW ter (2010) Stem cell therapy for myocardial infarction: are we missing time? Cardiology 117(1):1–10 7. Stamm C, Nasseri B, Choi YH, Hetzer R (2009) Cell therapy for heart disease: great expectations, as yet unmet. Heart Lung Circ 18(4):245–256 8. Stamm C, Westphal B, Kleine HD et al (2003) Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361(9351):45–46 9. Maisch B, Pankuweit S (2010) Treatment of progressive heart failure: pharmacotherapy, resynchronization (CRT), surgery. Herz 35(2):94–101 10. Nicolini F, Zoffoli G, Cagnoni G et al (2006) Mitral valve annuloplasty and myocardial revascularization in the treatment of ischemic dilated cardiomyopathy. Heart Vessels 21(1):28–32 11. Kaminski A, Donndorf P, Klopsch C, Steinhoff G (2010) Surgical intramyocardial stem cell therapy for chronic ischemic heart failure. Herz 35(5):324– 333
