Autologous Adult Stem Cell Transplantation for heart Failure Program       Regenerative medicine and cell therapy are emerging clinical disciplines in the field of stem cell biology. Stem cells are undifferentiated or partially differentiated cells; therefore they are capable of dividing and renewing themselves and also give rise to specialized cell types, a phenomenon known as plasticity or transdifferentiation. The most important sources for cell transplantation are human embryonic and adult stem cells. Embryonic stem cells normally exist only in preimplantation embryos (4–8 cell stage to blastocyst) and have the ability to form all the cells of the body however there are technical and ethical concerns.
The use of adult stem cells to regenerate damaged tissue circumvents the moral and technical issues associated with the use of those from an embryonic source. The adult stem cells are the stem cells found in the mature tissue. Some scientists use the term “somatic stem cell” instead of adult stem cell. Adult stem cells are considered to be multipotent and therefore capable of producing a small range of differentiated cell lineages appropriate to their location. Some adult stem cells or progenitor cells with the least differentiation potential such as skeletal myoblasts, circulating endothelial progenitor cells or epidermal stem cells in the basal layer of the skin are designated as unipotent.      Adult stem cells are set aside during development in order to provide a source for replenishment of tissue over time in response to damage or simply wear and tear. The literature suggests that stem cells can be found in most major organ systems in adult mammals e.g. skin, intestine, brain, bone marrow and endosteal line of the end of bone. Heart failure is a complex clinical syndrome that can result from any structural or functional heart disorder that impairs the ability of the heart's ventricle to fill with or eject blood. Cardiomyopathy is a type of heart disease in which the heart muscle is abnormally enlarged, thickened and/or stiffened. As a result, the heart muscle's ability to pump blood is usually impaired. The causes of heart failure are coronary artery disease (ischemic cardiomyopathy) and non-ischemic cardiomyopathy. The cause of non-ischemic cardiomyopathy may be known (e.g. due to hypertension, valvular disease, or heart infection) or unknown (e.g. idiopathic dilated cardiomyopathy).

Heart failure and Cardiomyopathy are one of the detrimental diseases in which incidence increased progressively. Even though survival has been improved, five-year age-adjusted survival was only 52% in 1996-2000. Stem Cell Therapy for Heart is a relatively new procedure for severe heart failure caused by Ischemic or Dilated Cardiomyopathy that could not be managed well by conventional medications. This is usually done on patients with Ejection Fraction (a measure of heart function test) 35% or lower who have marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain.
     
     The aim of cell transplantation is to repopulate the failing myocardium with cells that could restore contractility and blood supply. A number of stem cells have been investigated, mainly skeletal myoblast, bone marrow and peripheral blood stem cell. Most of reports show the improvement of the left ventricular ejection fraction.
      
     At Bangkok Heart Hospital, we initiated this program in May 2005. So far we have done over hundred cases. The procedure is relatively safe and carries small risk. However, it all depends on patient’s condition before the procedure is done as well as initial cause of heart problem. Bangkok Heart Hospital has used the autologous “Angiogenic Cell Precursors (ACPs)” derived from patient’s own peripheral blood since May 2005. It is not an embryonic stem cell. There are no immunological concerns as it is autologous. These cells stimulate growth of new vessel and perhaps muscle to improve the heart functions (Figure1.).


Figure 2. Peripheral Blood Stem Cell: Angiogenic Cell Precursors
   
     The multipotent progenitor cells are isolated from the peripheral blood, rich in CD45, CD31Bright, CD34+CD45-/Dim and CD34Bright cells. The cells at a concentration of 1.5-3.0 x 106 cells/ml are then cultured with vascular endothelial growth factor (VEGF, R&D Systems, Minneapolis, MN, USA) and 5 IU/ml heparin (Kamada, Beit-Kama, Israel). The final product “Angiogenic Cell Precursors” expressed CD34, CD133, KDR, Tie-2, CD144, von Willebrand factor, CD31Bright, concomitant binding of Ulex-Lectin and uptake of acetylated low density lipoprotein (Ac-LDL), secreted interleukin-8, vascular endothelial growth factor and angiogenin and formed tube-like structures in vitro.

     The candidates for the cell therapy are patients with cardiomyopathy either ischemic (ICM) or dilated cardiomyopathy (DCM). NYHA class, six-minute walk test, brain natridiuretic peptide level, echocardiogram/ cardiac MRI are obtained prior to surgery. These tests are repeated at 1, 3, 6 months and 1 year. In case of ICM, the cardiac MRI with gadolinium contrast or myocardial perfusion scan is used for locating the areas of myocardial infarction. The ACPs are directly injected into the myocardium via thoracoscopic approach, microthoracotomy or median sternotomy together with coronary artery bypass grafting. For the DCM, cells were injected into all areas of left ventricle. The following is a summary of our clinical experiences.

     Between May 2005 and January 2008, 122 consecutive patients underwent ACPs injection. Fifty two were dilated cardiomyopathy (DCM) and 69 were ischemic cardiomyopathy (ICM). Mean age was 59.5 ? 13.4 years. The number of cells prior to injection was 41.6 ? 34.7 million cells. In DCM group, ACPs were injected into all areas of the left ventricle. In ICM group, 41 had ACPs injection alone, 23 had combined coronary artery surgery and ACPs injection and 5 had transcoronary ACPs injection.

     For this report, we will focus only the results in patients who underwent surgical intramyocardial ACPs injection and who had left ventricular ejection fraction (LVEF) less than 40%. There were 104 patients in this group. Forty seven were DCM and 57 were ICM. There was no new ventricular arrhythmia after the surgical intramyocardial ACPs injection. The 30-day mortality was 4.3% and 3.5 % in the DCM and ICM groups, respectively. NYHA class improved significantly 314.3?197.2 days postoperatively in both DCM and ICM group (P < 0.001, McNemar test). LVEF improved significantly over a period of 3 and 6 months follow up (P = 0.04, Repeated measured ANOVA) in the ICM group. The overall LVEF was significantly improved in both DCM (4.5 points percent, from 23.4 ? 6.4 to 27.9 ? 10.1 %, P = 0.024) and ICM (7.4 points percent, from 23.5 ? 7.8 to 30.9 ? 10.5 %, P < 0.001). The six-minute walk test and Quality of life postoperatively evaluated by SF-36 were also improved. Myocardial infarction area was also reduced (Figure 2).


Figure 2. Cardiac Magnetic Resonance Imaging with Gadolinium Contrast. Myocardial infarction demonstrated as bright signal at the anterior and lateral walls of the left ventricle (LV), extended from the base to apex on the first row, preoperative. The left ventricular ejection fraction was 13.2%. The second row was the contrast enchancement MRI study obtained at 3 months after the ACPs injection alone. There was no myocardial scar and the left ventricular ejection fraction was 20%. The heart size was also reduced.

     In conclusions, intramyocardial ACPs injection is feasible and safe in both DCM and ICM. The NYHA, quality of life and ejection fraction were significantly improved in both DCM and ICM.

     The safety and efficacy results have been reported and published in many international meeting as followings

1. Arom K., Ruengsakulrach P., Jotisakulratana V.  
   Intramyocardial angiogenic Cell Precursors Injection for Cardiomyopathy.  Asian Cardiovasc Thorac Ann 2008; Download.
2. Arom K., Ruengsakulrach P., Jotisakulratana V.
   Efficacy of Intramyocardial Injection of Angiogenic Cell Precursors for Ischemic Cardiomyopathy:
   A Case Match Study. Innovations 2008; Download.
3. Ruengsakulrach P., Arom K., Jotisakulratana v.
   Direct Intramyocardial Injection of Autologous Angiogenic Cell Precursors for Cardiomyopathy (abstract) Chest 2007; 132(4) October: 439s – 440s
   
4. Arom K., Ruengsakulrach P., Jotisakulrata V.
   Efficacy of Intramyocardial Autologous Angiogenic Cell Precursors Injection for Ischemic Cardiomyopathy (abstract) Circ. Res. 2007; 101; e57

Abstracts and Communications at International Scientific Meetings

• A Case Match Study of Efficacy of Direct Intramyocardial Injection of Autologous Angiogenic Cell Precursors for Ischemic Cardiomyopathy
  The 11th ISMICS Annual Scientific Meeting, Boston, Massachusetts, USA June 2008
• Quality of Life after Direct Intramyocardial Injection of Autologous Angiogenic Cell Precursors for Cardiomyopathy
  The 11th ISMICS Annual Scientific Meeting, Boston, Massachusetts, USA June 2008
• Efficacy of Intramyocardial Injection of Angiogenic Cell Precursors for Dilated Cardiomyopathy: A Case Match Study The 88th AATS Annual Meeting, San Diego, California USA May 2008
• Efficacy of Intramyocardial Autologous Angiogenic Cell Precursors Injection for Ischemic Dardiomyopathy 4th Annual Symposium of the American Heart Association Council of Basic Cardiovascular Sciences: Cardiovascular Repair and Regeneration: Structural and Molecular Approaches in the Cellular Era, Keystone, CO, USA 2007
• Thoracoscopic Intramyocardial Autologous Angiogenic Progenitor Cell Transplantation For Cardiomyopathy
  The 9th ISMICS Annual Scientific Meeting, San Francisco, California, USA 2007
• Autologous Angiogenic Cell Precursors Intramyocardial Injection for Ischemic and Dilated Cardiomyopathy
  The 13th Annual Meeting of the International Society for Cellular Therapy (ISCT), Sydney, Australia 2007
• Efficacy of Intramyocardial Injection of Angiogenic Cell Precursors for Ischemic Cardiomyopathe: A Case Match Study
  The 10th ISMICS Annual Scientific Meeting, Rome, Italy 2007
• Safety And Efficacy of Intramyocardial Injection of Angiogenic Progenitor Cells for Ischemic Cardiomyopathy Combined Winter ISMICS/ASCTS Conference, Cairns, Australia 2006
• Improved Left Ventricular Function after Direct Intramyocardial Jnjection of Angiogenic Progenitor Cells for Cardiomyopathy
  The 4th Annual Meeting Inter national Society for Stem Cell Research (ISSCR), Toronto, ON, Canada 2007
• Direct Intramyocardial Injection of Autologous Angiogenic Cell Precursors for Cardiomyopathy, Chest, Chicago, Illinois. USA 2007

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