December 26, 2017

Heart & Artery

Cell Therapy in Cardiovascular Diseases

Cardiovascular disease (CVD) is one of the leading cause of mortality in the world. According to the world health organization (WHO), 17/3 million people died from this disorder in 2008 and estimated that the number of deaths will reach 23.3 million by 2030. Meanwhile, one of the most important heart disorder is heart failure. Heart failure often recognized as congestive heart failure (CHF) which defined as the inability of the heart to provide sufficient blood flow to meet the needs of the body. This disorder is a common, disabling, costly and mortality disorder. The disease is one of the increasing health problems, especially in developing countries which has infected 23 million people in worldwide. The incidence of this disease is 2% in adults and 6-10% in the elderly over 65 years. The annual hospitalization incidence of this disease is 2% and annual mortality reported nearly 30%. The cardiovascular failure is the most common cause of hospitalization in the world and devoted 5% of post-discharge diagnosis.

Recent research has shown that the heart consists of 5 million cells which daily replaced with 3 million news cells. Therefore, each 4-5 years, all of the heart cells are renewed and this helps to natural human life. The repair and regeneration is done by special cells called stem cells. On the other hand, the regeneration ability of heart cells is less than cell damaged and also the number of local stem cell has been reduced in this area.  The sample of such damage can be seen in heart infractions. Myocardial infraction is a permanent and irreversible cell death of a myocardial cells parts. As noted, despite the potential repair of heart, there is no effective recovery during myocardial infraction. Over time, the scar tissue replaces the functional tissue of the heart and will cause the heart failure.

Regarding to receive astonishing results from stem cell transplantation in cardiovascular patients, cardiovascular subgroup of Cell therapy section in Royan Institute was established in 2007. The researcher studied on using autologous bone marrow derived mononuclear stem cells in heart failure patients by conducting phases II, III of clinical trials.

Prevalence of cardiovascular and corner disorder is 19/4% (between ranges of 35-79 years) in Iran. This means, one out of five Iranian people has been suffering from a coronary heart disease. The common therapeutic methods such as drugs, surgical and rehabilitation treatments only reduced symptoms and improve the general conditions of the patients which never have the ability to repair and rebuild of heart tissue. These treatments are including blood pressure control, lipid disorder control, salt restriction and drug treatments such as ACEi, beta blocker, diuretic and digital. Surgical intervention include CRT, rehabilitation of blood transfusion, VAD insertion and eventually cardiac transplantation. Unfortunately, the last stage of the current treatment, heart transplantation, also has own problems such as high cost, suitable donor, underlying illness in the recipient, using immunosuppressive drugs and the possibility of transplant rejection. Therefore, current treatments are using to reduce the symptoms and prolong the lifetime. But all of these methods can not relieve symptoms of diseases and cannot regenerate the damaged cells in heart tissue. In this case, new strategies will introduce to scientific world which one of them is cell-based therapy.

Stem cells can restore and create new heart tissue by reducing the inflammation and ability to differentiation and proliferation to other tissue cells such as heart cells. In this case, cell therapy can compensate damaged tissue functions and improve the quality of life patients.

 

Therapeutic steps:

In the first stage patient should examine by specialist and after confirmed the cardiovascular symptoms, subsequent examination are done on the patient. In cell therapy process, the sample of stem cells is derived from bone marrow, separated and cultured in laboratory, finally they will injected to heart muscles. The cell injection is so simple and no side effects were observed till now. The most efficacy of cells obtained from the first injection and there is no need to re-injection.

Several studies on stem cell transplantation in cardiovascular patients have shown the great effects of these cells in quality of life and this procedure has more safety and efficacy rather than other methods.

Cell therapy by using mesenchymal stem cells (MSCs):

The studies have been shown three major groups of embryonic stem cell, somatic stem cells and induced pluripotent stem cells used in repair of cardiovascular lesion but several somatic stem cells just authorized to use for human treatment. In general, the 6 main types of stem cells are used in heart regeneration.

First type: The skeletal myoblast which is derived from skeletal muscles. Research on the therapeutic effects of these cells begun in 2000, but was limited because of several mild erythema.

Second type: Mononuclear cells derived from bone marrow has the most side effects because of easy processing and no need to cultivate.

Third type: This type is mesenchymal stem cells which derived from bone marrow and considered due to the high proliferation and differentiation capabilities.

Fourth type: the CD34+ and CD 133+ which derived from bone marrow have proliferation and angiogenesis capabilities.

Fifth type: This cells are derived from adipose tissue which is considered to be the great resource because of easy access and abundance.

Sixth type: The stem cell reside in the human heart and is the newest cells in the treatment of cardiovascular disease.

Study 1

In this study, ischemic patients with myocardial infraction for transplantation of CD133 derived bone marrow were admitted to Royan institute in 1385. The safety and efficacy of stem cell transplantation was studied and there is no side effects till now.

Patient selection:

In this study, Ischemic patients with cardiovascular problems who have been admitted to the Baqiyatallah hospital, Shahid rajaee heart center hospital. Based on inclusion and exclusion criteria, 18 patients who have under coronary artery bypass grafting were selected and informed consent was obtained from them. They randomly divided into two groups, 9 patients were in patients group and 9 patients were in placebo group.

Inclusion criteria:

1-Ranging in age of 18-65 years

2- Myocardial thickness at least 3 mm or more

3- The first MI Acute

4- At least 4 or more segments from Hypo or Akinetic segments

5- Candidate for CABG at the same time

6- Less than 45% but more than 20%

 

Exclusion criteria:

1- Patients with cardiogenic shock

2- Patients with End-Origin Damage

3- Failure to inject the cell for any reason

4- CABG emergency or urgency

5- Patients with severe coronary artery disease or sustained vital signs

6- History of leukopenia, anemia, thrombocytopenia or liver or kidney dysfunction, evidence of malignancy

Cell Preparation:

Patients under the operating room and in sterile conditions were subjected to bone marrow aspiration and 100 cc blood were taken from bone marrow and separated by mononuclear cells method.

Cell injection:

Prepared cells were injected intra myocardial of heart by a surgeon.

Study Description:

This study included two groups of 9 patients with acute myocardial infarction, which were subjected to cell and placebo injection according to the above criteria. The main goal of this study, which was to evaluate the performance of this method after 6 months and then 5 years. To stem cell aspiration, after anesthetic injection, the sampled were extracted from bone marrow by special syringes. After isolation of CD133+ cells from the population of mononuclear stem cell, these cells were injected at 10 points of muscle during in the operation of the heart.

Results:

The obtained data showed that using cell therapy in acute myocardial infraction does not have any complications. The amount of blood flow has been increased after 6 months of follow up (Image 1).  There was no significant difference in mutational fraction in both cell and control groups due to the small sample size. However, data analysis demonstrated that quality of life in patients who received stem cell is higher than the control group after 5 years. The result of these 6 months and 5 years follow up was published in Current Neurovascular Research journals and Archives of Iranian Medicine, respectively, in 2007 and 2012.

سلول درمانی-سکته قلبیFig 1: Image of hemorrhage improvement in the SPECT scan before injection (A) and 6 months after injection (B). The image B showed that the improvement of blood flow through the possible mechanism of neovascularization.

 

 

Study 2

In this study, ischemic patients with myocardial infraction for transplantation of CD133 derived bone marrow were admitted to Royan institute in 1385.

Patient selection:

In this study, acute myocardial infraction patients who were candidates for CABG surgery, 77 patients were selected by 45> EF >20 angiography and CABG candidates.

Inclusion criteria:

1-Ranging in age of 18-65 years

2- Myocardial thickness at least 3 mm or more

3- The first MI Acute

4- At least 4 or more segments from Hypo or Akinetic segments

5- Candidate for CABG at the same time

6- Less than 45% but more than 20%

 

Exclusion criteria:

1- Patients with cardiogenic shock

2- Patients with End-Origin Damage

3- Failure to inject the cell for any reason

4- CABG emergency or urgency

5- Patients with severe coronary artery disease or sustained vital signs

6- History of leukopenia, anemia, thrombocytopenia or liver or kidney dysfunction, evidence of malignancy

Cell Preparation:

Patients under the operating room and in sterile conditions were subjected to bone marrow aspiration and 100 cc blood were taken from bone marrow and separated by mononuclear cells method.

Cell injection:

Prepared cells were injected intra myocardial of heart by a surgeon.

Study description:

In this study, the effect of intra-muscle stem cell injection on the acute myocardial infraction patients was evaluated in comparison with the control group. The population was randomly assigned into 3 groups and cells were injected at 10 points of infract areas during the operation of the heart simultaneously CABG surgery. 1) Bone marrow derived mononuclear cells 2) CD133 cells derived from bone marrow 3) Placebo

Results:

The results of intra-myocardial infusion of mononuclear cell (MNCs) and CD133 were notable after 18 months follow-up. The result shows significantly improves the leakage fraction value and cardiac wall thickness in patients with ischemic heart disease. Both cell therapy groups had a significant difference with the control group in this parameter. However, there were no significant difference between two cell therapy groups. The results of the heart scan showed significant improvement in other evaluated parameters including improvement of blood flow and cardiac wall movement and reduction of non-vital segments in the cell therapy group, but their difference was not significant with the control group.

Improvement of cardiac performance in all parameters measured by scan, except for the mutation fraction, was significantly better in patients who were treated less than twenty days of myocardial infraction rather than rest of patients. These results included a reduction of four more units in the abnormal score (p = 0.02), a decrease in one unit in the number of non-obstructed segments (p = 0.01), a decrease of two more units in the wall scoring score index (p = 0.003) 0) and increased by two and a half units more in muscle thickness (p = 0.07). The results of this study in image 3 are presented by evaluation of cardiac performance improvement indicators such as ejection fraction (EF), wall motion score (WMS), non-viable segments (NV), wall decrease thickening (Dec. thick), perfusion defect score (P.D.S) and end systolic diameter (ESD).

The circles and white triangles respectively represent the groups receiving the CD133 and MNC cells, and the black squares represent the control group symbol. As indicated, in cell therapy groups, there is an increased in ejection fraction and decreased other parameters such as wall motion score (WMS), number of non-viable segments (NV), wall decrease thickness, perfusion defect score and end systolic diameter which showed effectiveness of cell therapy method in compare of control group.

 

سلول درمانی-بیماری قلبی و عروقی

 

Image 3- Evaluation of changes in cardiac function criteria in three groups of heart failure patients under intra-muscular injection of CD133, MNC and placebo during CABG surgery. The cell transplanted patients observed improving SPECT criteria, especially in EF, increasing wall decrease thickening (Dec. thick), decreasing non-viable segments.

 

Study 3

In this study, CD133+ and bone marrow derived mononuclear cells (MNC) were transplanted in acute myocardial infraction patients by intravascular injection. This group compared with placebo injection in the control group. This study conducted in Royan Institute in collaboration with several heart centers.

Patient selection:

In this study, 23 patients who suffered from anterior acute myocardial infraction which observed less than one week of their clinical symptoms, have been admitted to the research after doing coronary angiographies and begin appropriate for PCI. Based on inclusion and exclusion criteria that will be discussed in following and informed consent was obtained from them.

 

Inclusion criteria:

1-Ranging in age of 18-65 years

2- Myocardial thickness at least 3 mm or more

3- The first MI Acute

4- At least 4 or more segments from Hypo or Akinetic segments

5- Candidate for CABG at the same time

6- Less than 45% but more than 20%

 

Exclusion criteria:

1- Patients with cardiogenic shock

2- Patients with End-Origin Damage

3- Failure to inject the cell for any reason

4- CABG emergency or urgency

5- Patients with severe coronary artery disease or sustained vital signs

6- History of leukopenia, anemia, thrombocytopenia or liver or kidney dysfunction, evidence of malignancy

 

Cell Preparation:

Patients under the operating room and in sterile conditions were subjected to bone marrow aspiration and 100 cc blood were taken from bone marrow and separated by CD 133+ and mononuclear cells method.

Cell infusion:

Prepared cells were injected intra myocardial of heart by a surgeon.

 

Study description:

In this study, 3 groups of cardiovascular patients were evaluated to research which included 5 cases in the control group, 14 cases in the MNC group and 4 cases in the CD133 group. All cell transplanted (CD133 and MNC) patients were undergo bone marrow aspiration, and were under intracranial injection based on their type of group (CD133, MNC, Placebo) during PCI. Then, patients were followed up by cardiography and scan at specified intervals.

Results

The mean age of 23 patients was 53.3 in the control group (5 patients), 55.5 in the MNC group (14 patients) and 51.4 in the CD133 group (4 patients). In this population 89.6% of the patients were male. Symptomatic patients (NYHA Class II-III) with a percentage of their left ventricular ejection fraction were 20-45 divided into three groups: CD133 (red chart), MNC (blue chart) and control (yellow chart). Left ventricular leakage fraction changes in cell therapy groups were increased compared to base time (30%) during 18 months follow up. (Control 40%, CD133 48%, MNC 47% and P <0.02). Non-viable segments also decreased in cell therapy groups especially in CD133+. No significant changes were observed in the Diameter of the systolic echocardiography at different group of patients after 18 months.

سلول درمانی-نارسایی قلبی

Image 4- Evaluation of changes in cardiac function criteria in three groups of heart failure patients under intra- articular injection of CD133, MNC and placebo during PCI. In cell transplanted patients especially who received CD133+ cells, some changes were observed such as improving in SPECT criteria, improving in ejection fraction (EF), increasing wall decrease thickening (Dec. thick), decreasing non-viable segments, and improving perfusion defect score (PDS).