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DOI: 10.1055/s-2007-989351
© Georg Thieme Verlag KG Stuttgart · New York
Direct Minimally Invasive Intramyocardial Injection of Bone Marrow-Derived AC133+ Stem Cells in Patients with Refractory Ischemia: Preliminary Results
Publication History
received May 28, 2007
Publication Date:
18 February 2008 (online)
![](https://www.thieme-connect.de/media/thoracic/200802/lookinside/thumbnails/10.1055-s-2007-989351-1.jpg)
Abstract
Background: Bone marrow-derived stem cells (BMSC) may represent a viable option for patients with myocardial ischemia refractory to conventional treatments. Material and Methods: In 5 patients (4 males and 1 female, mean age 64 ± 8 years) with untreatable angina pectoris (Canadian Cardiovascular Society Class III/IV), myocardial segments with stress-induced ischemia as assessed by gated single-photon emission computed tomography were injected with 4 to 12 million CD133+ BMSC. Cells were injected into the myocardium (2 anterior, 2 lateral, 1 inferior wall) through minimally invasive approaches (left minithoracotomy [n = 4] and subdiaphragmatic approach [n = 1]). At baseline, at 6 months and at 1 year of follow-up, an exercise test, gated single-photon emission computed tomography (SPECT), 2-D echocardiography and coronary angiography were performed to assess exercise capacity, myocardial perfusion, LV function and coronary anatomy. Results: Intramyocardial injection of autologous CD133+ BMSC cells was safe. No early or long-term complications were observed. After an average of 3.8 weeks from cell inoculation, all patients experienced a significant improvement of CCS class (from 3.8 to 1.8 at 6 months) and serial SPECT documented improvements of rest and stress perfusion in the injected territories at 6 months from operation. In 3 cases, coronary angiography showed an increase in the collateral score of the target areas. Clinical improvements still persist unchanged in 4 out of 5 cases at a mean of 36.5 months postoperatively. Conclusions: After stand-alone BMSC transplantation for refractory myocardial ischemia, we observed long-term clinical and perfusion improvements in the absence of adverse events.
Key words
coronary artery disease - refractory ischemia - stem cells
References
- 1 Fuchs S, Satler L F, Kornowski R. et al . Catheter-based autologous bone marrow myocardial injection in no option patients with advanced coronary artery disease. J Am Coll Cardiol. 2003; 41 1721-1724
- 2 Tse H F, Kwong Y L, Chan J KF, Lo G, Ho C L, Lau C P. Angiogenesis in ischemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet. 2003; 361 47-49
- 3 Beeres S LMA, Bax J J, Kaandorp T AM. et al . Usefulness of intramyocardial injection of autologous bone marrow-derived mononuclear cells in patients with severe angina pectoris and stress-induced myocardial ischemia. Am J Cardiol. 2006; 97 1326-1331
- 4 Perin E C, Dohmann H FR, 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 (Suppl II) II‐213-II‐218
- 5 Asahara T, Masuda H, Takahashi T. et al . Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999; 85 221-228
- 6 Fuchs S, Baffour R, Zhou Y F. et al . Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol. 2001; 37 1726-1732
- 7 Kinnaird T, Stabile E, Burnett M S, Epstein S E. Bone-marrow-derived cells for enhancing collateral development: mechanisms, animal data, and initial clinical experiences. Circ Res. 2004; 95 354-363
- 8 Pompilio G, Capogrossi M C, Cannata A. et al . Endothelial progenitor cells: a potential versatile tool for the treatment of ischemic cardiomyopathies - a clinician's point of view. Int J Cardiol. 2004; 95 (Suppl 1) S34-S37
- 9 Takahashi T, Kalka C, Masuda H. et al . Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999; 5 434-438
- 10 Asahara T, Masuda H, Takahashi T. et al . Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999; 85 221-228
- 11 Kinnaird T, Stabile E, Burnett M S. et al . Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004; 109 1543-1549
- 12 Reyes M, Dudek A, Jahagirdar B. et al . Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest. 2002; 109 337-346
- 13 Pompilio G, Cannata A, Peccatori F. et al . Autologous peripheral blood stem cells transplantation for myocardial regeneration: a novel strategy for cell collection and surgical injection. Ann Thorac Surg. 2004; 78 1808-1813
- 14 Pompilio G, Cannata A, Pesce M, Capogrossi M C, Biglioli P. Long-lasting improvement of myocardial perfusion and chronic refractory angina after autologous intramyocardial PBSC transplantation. Cytotherapy. 2005; 7 494-496
- 15 Stamm C, Westphal B, Kleine H D. et al . Autologous bone marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003; 361 45-46
- 16 Cerqueira M D, Weissman N J, Dilsizian V. et al . Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002; 105 539-542
- 17 van't Hof A WJ, Liem A, Suryapranta H. Angiographic assessment of myocardial reperfusion in patients treated with primary coronary angioplasty for acute myocardial infarction. Myocardial blush grade. Circulation. 1998; 97 2302-2306
- 18 Berman D S, Abidov A, Kang X. et al . Prognostic validation of a 17-segment score derived from a 20-segment score for myocardial perfusion SPECT interpretation. J Nucl Cardiol. 2004; 11 414-423
- 19 Klein H M, Ghodsizad A, Marktanner R. et al . Intramyocardial implantation of CD133+ stem cells improved cardiac function without bypass surgery. Heart Surg Forum. 2007; 10 E66-E69
- 20 Archundia A, Aceves J L, Lopez-Hernandez M. et al . Direct cardiac injection of G‐CSF mobilized bone-marrow stem-cells improves ventricular function in old myocardial infarction. Life Sci. 2005; 78 279-283
- 21 Briguori C, Reimers B, Sarais C. et al . Direct intramyocardial percutaneous delivery of autologous bone marrow in patients with refractory myocardial angina. Am Heart J. 2006; 151 674-680
- 22 Beeres S L, Bax J J, Dibbets P. et al . Effect of intramyocardial injection of autologous bone marrow-derived mononuclear cells on perfusion, function, and viability in patients with drug-refractory chronic ischemia. J Nucl Med. 2006; 47 574-580
- 23 Perin E C, Dohmann H FR, Borojevic R. et al . Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003; 107 2294-2302
- 24 Losordo D W, Shatz R A, White C J. et al . Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/II, double-blind randomized controlled trial. Circulation. 2007; 115 3165-3172
- 25 Dongming Hou. Eyas Al-Shaykh Youssef . Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery implications for current clinical trials. Circulation. 2005; 112 (Suppl 1) I‐150-I‐156
- 26 DeJongste M JL, Tio R A, Foreman R D. Chronic therapeutically refractory angina pectoris. Heart. 2004; 90 225-230
- 27 Kornowski R, Fuchs S, Zafrir N. Refractory myocardial ischemic syndromes: patients' characterization and treatment goals. Future Cardiol. 2005; 1 629-635
- 28 Goldberg R F, Fass A E, Frishman W H. Transmyocardial revascularization: defining its role. Cardiol Rev. 2005; 13 52-55
- 29 Werner N, Nickenig G. Influence of cardiovascular risk factors on endothelial progenitor cells. Limitation for therapy?. Arterioscl Thromb Vasc Biol. 2006; 26 257-266
- 30 Iwaguro H, Yamaguchi J, Kalka C. et al . Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation. 2002; 105 732-738
Dr. MD, PhD Giulio Pompilio
Cardiovascular Surgery
Centro Cardiologico Monzino IRCCS
Via Parea 4
20138 Milan
Italy
Phone: + 39 2 58 00 25 62
Fax: + 39 2 58 01 11 94
Email: giulio.pompilio@ccfm.it