Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure

doi:10.1161/01.CIR.0000070596.30552.8B

Home
/
Papers
/
Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure

Journal Article•DOI•

Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure

Emerson C. Perin¹, Hans F. Dohmann, Radovan Borojevic², Suzana A. Silva, Andre L.S. Sousa, Claudio Tinoco Mesquita, Maria Isabel D. Rossi², Antonio Carlos Carvalho², Hélio S. Dutra², Hans J.F. Dohmann, Guilherme V. Silva¹, Luciano Belem, Ricardo Vivacqua, Fernando Oswaldo Dias Rangel, Roberto Esporcatte, Yong-Jian Geng, William K. Vaughn¹, Joao A.R. Assad, Evandro Tinoco Mesquita, James T. Willerson¹ - Show less +16 more•Institutions (2)

St Lukes Episcopal Hospital¹, Federal University of Rio de Janeiro²

13 May 2003-Circulation (Lippincott Williams & Wilkins)-Vol. 107, Iss: 18, pp 2294-2302

TL;DR: The present study demonstrates the relative safety of intramyocardial injections of bone marrow–derived stem cells in humans with severe heart failure and the potential for improving myocardial blood flow with associated enhancement of regional and global left ventricular function.

read less

Abstract: Background— This study evaluated the hypothesis that transendocardial injections of autologous mononuclear bone marrow cells in patients with end-stage ischemic heart disease could safely promote neovascularization and improve perfusion and myocardial contractility. Methods and Results— Twenty-one patients were enrolled in this prospective, nonrandomized, open-label study (first 14 patients, treatment; last 7 patients, control). Baseline evaluations included complete clinical and laboratory evaluations, exercise stress (ramp treadmill), 2D Doppler echocardiogram, single-photon emission computed tomography perfusion scan, and 24-hour Holter monitoring. Bone marrow mononuclear cells were harvested, isolated, washed, and resuspended in saline for injection by NOGA catheter (15 injections of 0.2 cc). Electromechanical mapping was used to identify viable myocardium (unipolar voltage ≥6.9 mV) for treatment. Treated and control patients underwent 2-month noninvasive follow-up, and treated patients alone underwen...

...read moreread less

Citations

PDF

Open Access

More filters

Journal Article•DOI•

Human mesenchymal stem cells modulate allogeneic immune cell responses

[...]

Sudeepta Aggarwal, Mark F. Pittenger

15 Feb 2005-Blood

TL;DR: Insight is offered into the interactions between allogeneic MSCs and immune cells and mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that could be therapeutic for reduction of GVHD, rejection, and modulation of inflammation.

...read moreread less

4,264 citations

Journal Article•DOI•

Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration

[...]

Antonio Paolo Beltrami¹, Laura Barlucchi¹, Daniele Torella¹, Mathue Baker¹, Federica Limana¹, Stefano Chimenti¹, Hideko Kasahara², Marcello Rota¹, Ezio Musso¹, Konrad Urbanek¹, Annarosa Leri¹, Jan Kajstura¹, Bernardo Nadal-Ginard¹, Piero Anversa¹ - Show less +10 more•Institutions (2)

New York Medical College¹, University of Florida²

19 Sep 2003-Cell

TL;DR: The existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells, which are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells are reported.

...read moreread less

3,651 citations

Cites result from "Transendocardial, Autologous Bone M..."

...Alternatively, it et al., 2002; Tse et al., 2003; Perin et al., 2003) based,is possible that cardiogenesis and cardiac regeneration in part, on our early results with myocardial regenerationmight result from distinct differentiation programs, as is with bone marrow derived cells (Orlic et al.,…...
[...]

Journal Article•DOI•

Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells

[...]

Jalees Rehman, Dmitry O. Traktuev¹, Jingling Li¹, Stephanie Merfeld-Clauss¹, Constance J. Temm-Grove¹, Jason E. Bovenkerk¹, Carrie L. Pell¹, Brian H. Johnstone¹, Robert V. Considine¹, Keith L. March¹ - Show less +6 more•Institutions (1)

Indiana University¹

16 Mar 2004-Circulation

TL;DR: The findings suggest that autologous delivery of either native or transduced subcutaneous ASCs, which are regulated by hypoxia, may be a novel therapeutic option to enhance angiogenesis or achieve cardiovascular protection.

...read moreread less

Abstract: Background— The delivery of autologous cells to increase angiogenesis is emerging as a treatment option for patients with cardiovascular disease but may be limited by the accessibility of sufficient cell numbers. The beneficial effects of delivered cells appear to be related to their pluripotency and ability to secrete growth factors. We examined nonadipocyte stromal cells from human subcutaneous fat as a novel source of therapeutic cells. Methods and Results— Adipose stromal cells (ASCs) were isolated from human subcutaneous adipose tissue and characterized by flow cytometry. ASCs secreted 1203±254 pg of vascular endothelial growth factor (VEGF) per 106 cells, 12 280±2944 pg of hepatocyte growth factor per 106 cells, and 1247±346 pg of transforming growth factor-β per 106 cells. When ASCs were cultured in hypoxic conditions, VEGF secretion increased 5-fold to 5980±1066 pg/106 cells (P=0.0016). The secretion of VEGF could also be augmented 200-fold by transfection of ASCs with a plasmid encoding VEGF (P<0...

...read moreread less

2,174 citations

Journal Article•DOI•

Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration.

[...]

Shahin Rafii¹, David Lyden¹•Institutions (1)

Cornell University¹

01 Jun 2003-Nature Medicine

TL;DR: Identification of factors that promote differentiation of the progenitor cells will permit functional incorporation into neo-vessels of specific tissues while diminishing potential toxicity to other organs.

...read moreread less

Abstract: Emerging evidence suggests that bone marrow-derived endothelial, hematopoietic stem and progenitor cells contribute to tissue vascularization during both embryonic and postnatal physiological processes. Recent preclinical and pioneering clinical studies have shown that introduction of bone marrow-derived endothelial and hematopoietic progenitors can restore tissue vascularization after ischemic events in limbs, retina and myocardium. Corecruitment of angiocompetent hematopoietic cells delivering specific angiogenic factors facilitates incorporation of endothelial progenitor cells (EPCs) into newly sprouting blood vessels. Identification of cellular mediators and tissue-specific chemokines, which facilitate selective recruitment of bone marrow-derived stem and progenitor cells to specific organs, will open up new avenues of research to accelerate organ vascularization and regeneration. In addition, identification of factors that promote differentiation of the progenitor cells will permit functional incorporation into neo-vessels of specific tissues while diminishing potential toxicity to other organs. In this review, we discuss the clinical potential of vascular progenitor and stem cells to restore long-lasting organ vascularization and function.

...read moreread less

1,623 citations

Journal Article•DOI•

Mesenchymal Stem Cells and Their Potential as Cardiac Therapeutics

[...]

Mark F. Pittenger¹, Bradley J. Martin¹•Institutions (1)

Osiris Therapeutics, Inc.¹

09 Jul 2004-Circulation Research

TL;DR: HMSCs isolated from adult bone marrow provide an excellent model for development of stem cell therapeutics, and their potential use in the cardiovascular system is currently under investigation in the laboratory and clinical settings.

...read moreread less

Abstract: Mesenchymal stem cells (MSCs) represent a stem cell population present in adult tissues that can be isolated, expanded in culture, and characterized in vitro and in vivo. MSCs differentiate readily...

...read moreread less

1,461 citations

Cites background from "Transendocardial, Autologous Bone M..."

...The hMSCs, with their attributes of (1) ease of isolation, (2) high expansion potential, (3) genetic stability, (4) reproducible attributes from isolate to isolate, (5) reproducible characteristics in widely dispersed laboratories, (6) compatibility with tissue engineering principles, and (7) potential to enhance repair in many vital tissues, may be the current preferred stem cell model for cellular therapeutic development....
[...]

1
2
3
4
…
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200

Collapse

References

PDF

Open Access

More filters

Journal Article•DOI•

Isolation of putative progenitor endothelial cells for angiogenesis.

[...]

Takayuki Asahara¹, Toyoaki Murohara¹, Alison Sullivan¹, Marcy Silver¹, Rien van der Zee¹, Tong Li¹, Bernhard Witzenbichler¹, Gina C. Schatteman¹, Jeffrey M. Isner¹ - Show less +5 more•Institutions (1)

Tufts University¹

14 Feb 1997-Science

TL;DR: It is suggested that EC progenitors may be useful for augmenting collateral vessel growth to ischemic tissues (therapeutic angiogenesis) and for delivering anti- or pro-angiogenic agents, respectively, to sites of pathologic or utilitarianAngiogenesis.

...read moreread less

Abstract: Putative endothelial cell (EC) progenitors or angioblasts were isolated from human peripheral blood by magnetic bead selection on the basis of cell surface antigen expression In vitro, these cells differentiated into ECs In animal models of ischemia, heterologous, homologous, and autologous EC progenitors incorporated into sites of active angiogenesis These findings suggest that EC progenitors may be useful for augmenting collateral vessel growth to ischemic tissues (therapeutic angiogenesis) and for delivering anti- or pro-angiogenic agents, respectively, to sites of pathologic or utilitarian angiogenesis

...read moreread less

8,598 citations

Journal Article•DOI•

Bone marrow cells regenerate infarcted myocardium

[...]

Donald Orlic, Jan Kajstura¹, Stefano Chimenti¹, Igor Jakoniuk¹, Stacie M. Anderson, Baosheng Li¹, James Pickel², Ronald D.G. McKay², Bernardo Nadal-Ginard¹, David M. Bodine, Annarosa Leri¹, Piero Anversa¹ - Show less +8 more•Institutions (2)

New York Medical College¹, Laboratory of Molecular Biology²

05 Apr 2001-Nature

TL;DR: It is indicated that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.

...read moreread less

Abstract: Myocardial infarction leads to loss of tissue and impairment of cardiac performance The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time1 Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation2,3,4,5; these events promote structural and functional repair6,7,8 This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein9 by fluorescence-activated cell sorting on the basis of c-kit expression10 Shortly after coronary ligation, Lin- c-kitPOS cells were injected in the contracting wall bordering the infarct Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9 days after transplanting the bone marrow cells The developing tissue comprised proliferating myocytes and vascular structures Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease

...read moreread less

5,331 citations

"Transendocardial, Autologous Bone M..." refers background or methods in this paper

...The following inclusion criteria were required for patient enrollment: (1) chronic coronary artery disease with reversible perfusion defect detectable by singlephoton emission computed tomography (SPECT); (2) left ventricular (LV) ejection fraction (EF) 40%; (3) ineligibility for percutaneous or surgical revascularization, as assessed by coronary arteriography; and (4) signed, informed consent....
[...]
...Before every injection of cells into the LV wall, the following criteria had to be met: (1) perpendicular position of the catheter to the LV wall; (2) excellent loop stability ( 4 mm); (3) underlying voltage 6....
[...]
...Patients were not enrolled in the study if any 1 of the following exclusion criteria was met: (1) difficulty in obtaining vascular access for percutaneous procedures; (2) previous or current history of neoplasia or other comorbidity that could impact the patient’s short-term survival; (3) significant ventricular dysrhythmias (sustained ventricular tachycardia); (4) LV aneurysm; (5) unexplained abnormal baseline laboratory abnormalities; (6) bone tissue with abnormal radiological aspect; (7) primary hematologic disease; (8) acute myocardial infarction within 3 months of enrollment in the study; (9) presence of intraventricular thrombus by 2D Doppler echocardiogram; (10) hemodynamic instability at the time of the procedure; (11) atrial fibrillation; or (12) any condition that, in the judgment of the investigator, would place the patient at undue risk....
[...]

Journal Article•DOI•

Neovascularization of ischemic myocardium by human bone-marrow–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function

[...]

Alfred Kocher¹, Michael D. Schuster¹, Matthias Szabolcs¹, Shin Takuma¹, Daniel Burkhoff¹, Jennifer Wang¹, Shunichi Homma¹, Niloo M. Edwards¹, Silviu Itescu¹ - Show less +5 more•Institutions (1)

Columbia University¹

01 Apr 2001-Nature Medicine

TL;DR: It is shown that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed and proliferation of preexisting vasculature after experimental myocardial infarction.

...read moreread less

Abstract: Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.

...read moreread less

2,688 citations

"Transendocardial, Autologous Bone M..." refers background or methods in this paper

...Before every injection of cells into the LV wall, the following criteria had to be met: (1) perpendicular position of the catheter to the LV wall; (2) excellent loop stability ( ,4 mm); (3) underlying voltage ....
[...]
...The following inclusion criteria were required for patient enrollment: (1) chronic coronary artery disease with reversible perfusion defect detectable by singlephoton emission computed tomography (SPECT); (2) left ventricular (LV) ejection fraction (EF),40%; (3) ineligibility for percutaneous or surgical revascularization, as assessed by coronary arteriography; and (4) signed, informed consent....
[...]
...Patients were not enrolled in the study if any 1 of the following exclusion criteria was met: (1) difficulty in obtaining vascular access for percutaneous procedures; (2) previous or current history of neoplasia or other comorbidity that could impact the patient’s short-term survival; (3) significant ventricular dysrhythmias (sustained ventricular tachycardia); (4) LV aneurysm; (5) unexplained abnormal baseline laboratory abnormalities; (6) bone tissue with abnormal radiological aspect; (7) primary hematologic disease; (8) acute myocardial infarction within 3 months of enrollment in the study; (9) presence of intraventricular thrombus by 2D Doppler echocardiogram; (10) hemodynamic instability at the time of the procedure; (11) atrial fibrillation; or (12) any condition that, in the judgment of the investigator, would place the patient at undue risk....
[...]

Journal Article•DOI•

ACC/AHA 2002 Guideline Update for Exercise Testing: Summary Article A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines)

[...]

Raymond J. Gibbons, Gary J. Balady, J. Timothy Bricker, Bernard R. Chaitman, Gerald F. Fletcher, Victor F. Froelicher, Daniel B. Mark, Ben D. McCallister, Aryan N. Mooss, Michael G. O’Reilly, William L. Winters, Elliott M. Antman, Joseph S. Alpert, David P. Faxon, Valentin Fuster, Gabriel Gregoratos, Loren F. Hiratzka, Alice K. Jacobs, Richard O. Russell, Sidney C. Smith - Show less +16 more

01 Oct 2002-Circulation

TL;DR: The American College of Cardiology (ACC)/AHA Task Force on Practice Guidelines regularly reviews existing guidelines to determine when an update or full revision is needed.

...read moreread less

Abstract: The American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines regularly reviews existing guidelines to determine when an update or full revision is needed. This process gives priority to areas where major changes in text, and particularly recommendations

...read moreread less

2,537 citations

"Transendocardial, Autologous Bone M..." refers background in this paper

...Patients were not enrolled in the study if any 1 of the following exclusion criteria was met: (1) difficulty in obtaining vascular access for percutaneous procedures; (2) previous or current history of neoplasia or other comorbidity that could impact the patient’s short-term survival; (3) significant ventricular dysrhythmias (sustained ventricular tachycardia); (4) LV aneurysm; (5) unexplained abnormal baseline laboratory abnormalities; (6) bone tissue with abnormal radiological aspect; (7) primary hematologic disease; (8) acute myocardial infarction within 3 months of enrollment in the study; (9) presence of intraventricular thrombus by 2D Doppler echocardiogram; (10) hemodynamic instability at the time of the procedure; (11) atrial fibrillation; or (12) any condition that, in the judgment of the investigator, would place the patient at undue risk....
[...]

Journal Article•DOI•

Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart

[...]

Catalin Toma¹, Mark F. Pittenger, Kevin S. Cahill, Barry J. Byrne, Paul D. Kessler - Show less +1 more•Institutions (1)

Johns Hopkins University¹

01 Jan 2002-Circulation

TL;DR: The persistence of the engrafted hMSCs and their in situ differentiation in the heart may represent the basis for using these adult stem cells for cellular cardiomyoplasty.

...read moreread less

Abstract: Background— Cellular cardiomyoplasty has been proposed as an alternative strategy for augmenting the function of diseased myocardium. We investigated the potential of human mesenchymal stem cells (hMSCs) from adult bone marrow to undergo myogenic differentiation once transplanted into the adult murine myocardium. Methods and Results— A small bone marrow aspirate was taken from the iliac crest of healthy human volunteers, and hMSCs were isolated as previously described. The stem cells, labeled with lacZ, were injected into the left ventricle of CB17 SCID/beige adult mice. At 4 days after injection, none of the engrafted hMSCs expressed myogenic markers. A limited number of cells survived past 1 week and over time morphologically resembled the surrounding host cardiomyocytes. Immunohistochemistry revealed de novo expression of desmin, β-myosin heavy chain, α-actinin, cardiac troponin T, and phospholamban at levels comparable to those of the host cardiomyocytes; sarcomeric organization of the contractile pro...

...read moreread less

2,317 citations