Autologous Bone Marrow Mononuclear Cell Transplantation In Patients With Heart Disfunction Due To Previous Myocardial Infarction.

Background and Objective: In Western countries, ischemic heart disease and myocardial ischernia-induced heart failure are major health concerns because of their high morbidities and high mortalities. In China, along with improved medical care and advanced therapeutic treatments, ageing of the population and increasing of post-infarction survival rates, the incidence of heart failure is also expected to be increased in the forthcoming years. Sudden occlusion of a major coronary artery and acute myocardial ischemia lead to rapid death of myocytes (M) and vascular structures in the supplied region of the ventricle. Because of cardiac myocyte, generally believes, terminally differentiated cell and lacks capability to be regenerated after ischemic incidents or myocardial infarction, myocardial ischemia results in the necrosis and the apoptosis of cardiac myocyte. Instead, the injured or infracted myocardium will be replaced by fibrosis and becomes a noncontracting fibrous scar. Although cardiomyocytes of infarcted or failing human hearts have been shown to undergo mitosis, this regenerative capacity is by far too limited to compensate for the loss of cardiac cells resulting from a large infarct. To date, no therapeutic procedure like angioplasty and/or thrombolytic agents could reverse the irreversible myocardial injury completely. As the disease progresses, heart failure will be developed, infarct-related heart failure remains a major cause of morbidity and mortality. Thus, the key approaches of treatments for heart failure are how to rescue myocytes from ischemic infarct or promote the regeneration of cardiac myocytes, and to prevent, even reverse left ventriclar. remodeling. In animal experiments, attempts to replace the necrotic zone by transplanting other cells (eg, fetal cardiomyocytes or skeletal myoblasts) haveinvariably succeeded in reconstituting heart muscle structures, ie, myocardium and coronary vessels. However, these cells fail to integrate structurally and do not display characteristic physiological functions. Another approach to reverse myocardial remodeling is to repair myocardial tissue by using bone marrow-derived cells. Bone marrow contains multipotent adult stem cells that have a high capacity for differentiation. Animal studies have shown that bone marrow cells (BMCs) are capable of regenerating infarcted myocardium and inducing myogenesis and angiogenesis. Several initial clinical trails demonstrated that transplantation of BMCs in patients with AMI resulting in improvement in myocardial perfusion and segmental contractility. Consequently, the purpose of this study is to assess the safety and effects of autologous bone marrow stem cell transplantation in patients with congestive heart failure due to previous myocardial infarction.Method: Eighteen patients with congestive heart failure due to OMI at least three months ago were taken as the target population. The eligibility criteria was as follows: New York Heart Association class II~IV; an ejection fraction of lower than 45%; with a range of 35—75 years old; without malignant disease; chronic renal failure; chronic hepatic failure or other comorbidity that could impact the patient's short-term survival; without primary hematological disease and significant ventricular dysrhythmias (sustained ventricular tachycardia). The ethics committee of the first Affiliated Hospital of Zhengzhou University approved the study protocol, and all patients provided written informed consent and were willing to comply with planned follow-up. Baseline evaluations included a complete clinical evaluation (history and physical), laboratory evaluation (complete blood cells count, blood chemistry, C-reactive protein [CRP], brain natriuretic peptide [BNP], creatine kinase [CK]-MB and troponin serum levels, 6-minute walking tests, 2-D echocardiography, technetium -99m -methoxyieo -butylieonitrile (99mTc-MIBI). All patients underwent standard medication consisting of acetylsalicylic acid, an ACE inhibitor, a 6-blocker, and a statin. They were scheduled on the optional period which patient's heart condition was relatively stable and tolerable for PTCA or PCI and received additional cell transplantation. Bone marrow (about 100ml) was aspirated under local anesthesia from ilium 2 hours beforethe transplantation. Mononuclear BMCs were isolated by Ficoll density separation on Lymphocyte Separation Medium (BioWhittaker). BMCs were harvested and washed 3 times with heparinized saline before final resuspension in heparinized saline. Cell viability was determined by trypan-blue-dye exclusion test viable in each sample. After percutaneous transluminal coronary angioplasty (PTCA) was performed, Stem cells were transplanted into areas of injury by catheter, or with open-heart surgery once all bypass-to-coronary-artery anastomoses had been completed as usual injected cell suspension using a 22-gauge hypodermic needle along the circumference of the infarct border. As an internal reference group reflecting the standard care, we respectively selected each patient which matched for study population in ejection fraction, infarct localization, and infarct size, in whom reperfusion therapy was performed by stent implantation or by CABG All patients were followed-up for 3-6months according to standard protocols and with the same procedures used as at baseline. Results: Between March 2004 and December 2004, eighteen patients were enrolled in the study. 18 patients were as control groups. Patient population demographics and clinical date did not differ significantly between the implantation group and the control groups. 80-160ml of marrow blood were aspirated from the ilium of cell therapeutic patients under local anaesthesia. An average of (2. 62 + 1. 47) X108 cells were obtained. The cell suspension contained (3.2+2.4) % CD34+ cells, Cell viability was greater than 95%, all microbiological cultures were negative. After coronary angiography, the infarct-related arteries of 6 patients were recanalized by balloon angioplasty and subsequent stent implantation. Then autologous mononuclear BMCs were transplanted via a balloon catheter placed into the infracted relation artery; 6 patients coronary angiography show unsuitable for PTCA were offered to CABG Once all bypass-to-coronary-artery anastomoses had been completed, the infarction area was visualised. We injected 25 samples of 0.5 ml cell suspension using a 22-gauge hypodermic needle along the circumference of the infarct border. The heart was then reperfused, and the operation completed as usual. 2 patients coronary angiography show the infracted relation artery was open were treated by autologous mononuclear transplantation alone via a balloon catheter placed into the infracted relation artery; 2patients were failed to reopen the infracted relation artery were treated by autologous mononuclear transplantation alone via a microcatheter placed into another collateral coronary artery. 2 patients shown a poor distal coronary bed unsuitable for the traditional treatment of PTCA or CABG were treated by autologous mononuclear transplantation alone though normal catheter which placed at the portal of the coronary artery. All patients had no arrhythmia and myocardial inflammation early. At an average of 4.9 month follow-up, all patients were surviving except for one patient died of pneumonia at the third month postoperatively. The mean NYHA functional class was improved from 2. 89 ±0. 58 to 2. 28 + 0. 57 (p=0.004), 6-minute walking tests increased from (292.47±77.76)m to (374. 13 + 46.45)m (p=0.005), LVEF was increased from (36. 89 + 3. 60)% to (39. 22 + 5. 00)% (p=0.041) and WMSI decreased from 1.61 ±0.28 to 1.36±0.33 (P=0.032); SPECT showed that the infarction area decreased from 43.80±8.08% to 35.47±10.57%. In contrast, in a nonrandomized matched reference group, left ventricular ejection fraction only slightly increased from (37.44 + 4.66) % to (38.00 + 5.37) %, and left ventricle end-diastolic volume, end-systolic volumes remained unchanged.Conclusion: The present study demonstrates that it is the relative safety and feasibility of autologous bone marrow stem cell transplantation in patients with congestive heart failure due to previous myocardial infarction. The marked therapeutic effect may be attributed to MBMC-associated myocardium regeneration and neovasculafization as well as the action of cytokines and growth factors. This approach opens a new window in the treatment of 'no hope' patients with congestive heart failure.