Stem Cells Int. 2013;2013:582527.

Intracoronary Infusion of Autologous CD133(+) Cells in Myocardial Infarction and Tracing by Tc99m MIBI Scintigraphy of the Heart Areas Involved in Cell Homing.

Ubaidullo  Kurbonov1, Abdusamad Dustov1, Alisher  Barotov2,Murtazokul Khidirov1, Zikrie Rahimov2, Navjuvon Navjuvonov2, Jamila Irgasheva3, Azadeh Didary1, Suhayli Muminjonov3, , Giesidin  Mirojov1 , Toshpulod Gulmuradov2, Massoud Mirshahi1, 4*.

1AvicennaTajik State Medical University 2, Institute of Gastroenterology, 3Tajikistan Ministry of Health Dushanbe, Tajikistan,  4 UMRS 872, CRC-INSERM, Marie Curie University and University of Paris Descartes, Paris, France.

*Corresponding Author:

M. Mirshahi, M. D., Ph. D.  INSERM UMRS 872, Université Pierre et Marie Curie, Paris-VI,

Université Paris Descartes, Paris-V, 15 Rue de l’Ecole de Médecine, 75006 Paris, France.

TEL (33)  1 44 27 81 58, FAX (33) 1 44 27 81 61 E-mail: massoud.mirshahi@upmc.fr

 

Abstract: 

Autologous transplantation of bone marrow derived CD133+ was undertaken with the high degree of success for a cohort of patients with heart disease.   Single Intracoronary infusion of autologous CD133+/CD34+ BMMNCs are effective and reduce infarct size in patients as analyzed by Tc-99m MIBI myocardial scintigraphy. Majority of patients were treated via left coronary artery. 9 months after cell therapy, 5 out of 8 patients showed a net positive response to therapy in different regions of the heart. Uptake of Tc99 isotope and revitalization of the heart area in Inferoseptal region is more pronounced (p=0.016) as compared to apex and anterosptal regions after intracoronary injection of the stem cells. The cell therapy proposed here is safe and should be practiced, as we found, in conjunction with scintigraphic observation of areas of heart which respond optimally to the infusion of autologous CD133+/CD34+BMMNCs.

PMID: 23983717

 

Supplements:

Introduction: Heart failure is the leading cause of death worldwide, and current therapies only delay progression of the disease. Cardiomyocytes are a stable cell population with only limited potential for renewal after injury [1, 2]. Tissue regeneration may be due to infiltration of stem cells, which differentiate into cardiomyocytes [3]. Laboratory experiments and recent clinical trials suggest that cell-based therapies can improve cardiac function [4, 5], and the implications of this for cardiac regeneration are causing great excitement. These new findings have stimulated optimism that the progression of heart failure can be prevented or even reversed with cell-based therapy [6]. Source of stem cell therapy for heart disease may come from progenitors from Hematopoietic (BM, peripheral blood, umbilical cord blood), mesenchymal (BM, adipose tissues), skeletal (muscle), endothelial (BM, peripheral blood) and cardiac (infarct border, epicardium) cells [5].  These cells are characterized by a high potential of pluripotent activity and can participate in tissues remodeling by secretion of growth factors in an autocrine or paracrine manner.   In an   animal model (rat), two cell types, namely skeletal myoblasts  and CD133+ progenitors led to improvement of cardiac function [7, 8 ].  Here we show that when bone marrow CD133+ cells are infused immediately in patients with coronary heart disease and post infarction cardiosclerosis, they are able to modify revitalization of infarct scar as explored by scintigraphy.

Material and Methods: Bone marrow mononuclear cells (BMMNCs) were isolated andCD133+ cells were separated from BMMNCs by a magneticbead separation method following the manufacturer’s instructions (MACS; Miltenyi Biotec, France). BMMNC derived CD133+ /CD34+ were employed in the treatment regimen described in this work. 15 patients with a diagnosis of ischemic heart diseases and myocardial infarction (deferred Q-myocardial infarction without significant complications barred from 3 to 6 months) were selected. Arteriography performed on left coronary artery at 4-6 projections and the right coronary artery at 3-4 projections. In some of the subjects coronary angiography revealed severe coronary artery pathology: left coronary artery trunk (4 cases) and 3 vascular lesions (7 cases).  5 ml of CD133+ cell suspension (0,8-1,5 million cells in 0·9% NaCl ) perfused in the coronary artery taking into account the angiographic findings and areas of myocardial ischemia. In 12 cases of the stem cells introduced directly into the left coronary artery, and in 3 cases – into both the coronary arteries. All the patients, in addition of their classic treatments, treated by estradiol (Estreva 0.75 mg/day for two months).

Clinical examination and currently used tests such as ECG, EFLV, LVESV and LVEDV were performed in order to evaluate the dynamics of myocardial perfusion in all patients with coronary heart disease and post-infarction cardiosclerosis before and after cell therapy. For 11 out of 15 of the treated patients, we carried out myocardial scintigraphy using Tc99m with the ligand methoxyisobutylisonitrile (MIBI) after an interval of 1 and 3 months. 8 out of 11 of these patients were further investigated by scintigraphy again after 9 months.

Results and discussion:  CD133+ cells were isolated from BMMNCs and their purity was found to be more than 89±4% as assessed by flow cytometry.  For cell therapy, these cells were injected into the coronary arteries via the femoral artery.  Patients were examined after 3, 6 and 9 months.  The results of clinical examinations showed a net improvement beginning three months and also six and nine months post infusion. Examination indicated that the general physical state of patients improved, such as effort tolerance, physical endurance and overall autonomy. In addition, the treated patients had a better psychic state “the effect of a perfect action” as compared to the control. One of patients in the treated group died as also two others in the control group (one of them by accident). Myocardial Tc99m MIBI scintigraphy in 11 patients was performed to evaluate the dynamics of myocardial perfusion.  As presented in table-1, the treated patients were divided into two categories:  (A) responders and (B) non responders.  High inclusion of Tc99, after cell therapy, changed significantly only in inferoseptal region (p = 0.016) in responder patients (n=5). In non responders, inclusion of Tc99 in different regions of the heart was not significantly different between preoperative and postoperative perfusion under stress conditions (n=3). These results suggest that the inferoseptal zone is a good target for stem cell therapy. In 7 patients out of 8, uptakes of isotope in all parts of the heart were seen increased.  The areas that benefit from a myocardial revitalization, 9 months after cell therapy in case of two patients is presented in Figure-1. These results clearly demonstrate a positive effect of cell therapy as ascertained by scintigraphic diagnostics with Tс-99m in patients with CHD and post-infarction cardiosclerosis during 9 months monitoring periods following cell therapy. These patients continue to make progress as of present.

9 months after cell therapy, 5 out of 8 patients showed a net positive response to therapy in different regions of the heart evaluated by scintigraphy.  Uptake of Tc99 isotope and revitalization of the heart area in Inferoseptal region is more pronounced as compared to apex and anterosptal regions after intracoronary injection of the stem cells(Figure-2).

In conclusion, in this non randomized study, we showed that intracoronary infusion of autologous CD133+/CD34+ BMMNCs reduces infarct size in patient with coronary heart disease and post infarction cardiosclerosis.  The cell therapy approach proposed here should be practiced in conjunction with scinthigraphy observation of areas of heart which respond optimally to the infusion of autologous CD133+/CD34+ BMMNCs.

 

References:

1- Wagers AJ, Conboy IM. Cellular and molecular signatures of muscle regeneration: current concepts and controversies in adult myogenesis. Cell. 2005 Sep 9;122(5):659-67. Review.

2- Shi X, Garry DJ. Muscle stem cells in development, regeneration, and disease. Genes Dev. 2006 Jul 1;20(13):1692-708. Review.

3- Leri A, Kajstura J, Anversa P. Role of cardiac stem cells in cardiac pathophysiology: a paradigm shift in human myocardial biology. Circ Res. 2011 Sep 30;109(8):941-61. doi: 10.1161/CIRCRESAHA.111.243154. Review.

4- Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, Zuba-Surma EK, Al-Mallah M, Dawn B. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007 May 28;167(10):989-97. Review.

5- Hoover-Plow J, Gong Y. Challenges for heart disease stem cell therapy. Vasc Health Risk Manag. 2012;8:99-113. doi: 10.2147/VHRM.S25665. Epub 2012 Feb 17. Review.

6- Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008 Feb 21;451(7181):937-42. doi: 10.1038/nature06800. Review.

7- Agbulut O, Vandervelde S, Al Attar N, Larghero J, Ghostine S, Léobon B, Robidel E, Borsani P, Le Lorc’h M, Bissery A, Chomienne C, Bruneval P, Marolleau JP, Vilquin JT, Hagège A, Samuel JL, Menasché P. Comparison of human skeletal myoblasts and bone marrow-derived CD133+ progenitors for the repair of infarcted myocardium. J Am Coll Cardiol. 2004 Jul 21;44(2):458-63.

8- Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy MC, Hutcheson KA, Glower DD, Kraus WE. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med. 1998 Aug;4(8):929-33. Erratum in: Nat Med 1998 Oct;4(10):1200.

Massoud Mirshahi-tab1Table-1:  Scintigraphy investigations of heart in 5 out of 8 patients (A) as a responders and 3 out of 8 patients (B) as a non responders before treatment and after a period of 9 months. Inclusion of Tc99 (%) in the regions of anteroseptal, inferoseptal and apex before and after cell therapy (stress condition) significantly increased only in inferoseptal region (p = 0.016) in responders patients. In non responders, inclusion of Tc99 (%) in different regions of the heart is not significantly different between preoperative and postoperative perfusion in stress condition.

 

Massoud Mirshahi-1

Figure-1: The areas that benefit from myocardial revascularization after single cell therapy in two patients, carried out by myocardial scintigraphy (post stress condition) before treatments and after 9 months. (Black, no perfusion; blue–green–yellow–red, increasing perfusion).

 

Massoud Mirshahi-2Figure-2: Tc99 isotope uptake in different areas of the heart in post stress condition, quantitative measurements of activity in the area at risk (anteroseptal, inferoseptal and apex) expressed as the difference between postoperative perfusion and preoperative perfusion.

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann