Cardiovascular diseases (CVD) refer to diseases of heart and blood vessels. Most of CVD are caused by reduced blood flow to the heart (Coronary Heart Disease, CHD). Coronary Heart Disease is considered to be the main cause of morbidity and mortality in both men and women worldwide. Coronary Heart Disease (CHD) is an ischemic heart disease that develops progressively into chronic condition when coronary arteries become narrow and diminish blood supply to the heart. The major outcome of ischemic damage is aggravation of the heart muscle function, known as cardiomyopathy. Eventually, acute myocardial infarction occurs when blood supply to the heart or part of it is fully blocked or when the blood supply becomes completely insufficient to support energetic needs for normal heart function. Both conditions lead to a congestive heart failure. All components of the myocardium (myocytes, extracellular matrix, and capillary microcirculation) undergo complex, dynamic, and time-dependent changes resulting in significant necrosis of heart muscle tissue. These structural changes occur in two steps: in the early phase (within 72 hours of acute ischemia), serine proteases and activated matrix metallo-proteases act to degrade the extracellular matrix resulting in expansion of the infarcted area. Myocyte hypertrophy develops during the late phase (after 72 hours) as a compensatory response for the changes in heart muscle architecture. Despite its initial positive impact on the heart function, adaptive hypertrophy usually causes ventricular dilatation and leads to congestive heart failure. Although medical and surgical treatments available today for the ischemic heart disease patients diminish the risk of acute myocardial infarction and reduce to some extent the incidence of recurrent heart attack, one of the unsolved challenges is to affect myocardium remodeling occurring during ischemic heart failure.
Given their ability to self-renew and differentiate, stem cells have been proposed to be excellent candidates to repopulate and regenerate the infarcted myocardium. As soon as nor pharmaceutical not surgical therapy could prevent or treat the ventricular remodeling, up to date stem cells therapy seems to be promising new approach to post-infarction myocardial regeneration.
Cells isolation and delivery methods are of the highest importance in developing stem cells applications for clinical use. Cells isolation procedures have to be performed at GMP conditions and viability and purity of the cells has to be determined.
Currently, intracoronary, intra-myocardial and endocardial cells injections are used for cells delivery to the heart.
Intracoronary cell injection allows direct supply of the cells to the entire infarcted myocardial region. The delivery is performed employing the conventional clinical percutaneous transluminal coronary angioplasty (PTCA) method. The balloon catheter is placed and fixed in the target coronary artery and cell suspension is transfused via the catheter. The balloon prevents leakage of the cells to the other areas and promotes their contact with the endothelium facilitating trans-endothelial migration to the infarcted region.
Intra-myocardial injection of the cells with a thin needle is performed manually at defined target areas of myocardium. Up to date, this type of injection has been performed immediately at the end of the coronary artery bypass grafting (CABG) surgery and is considered to be standard technique for surgical stem cell therapy.
Endocardial injection is relatively new method less invasive than surgical approach. Here, the cells are injected via the NOGATM catheter that is placed via the aortic valve into the ventricle where the cells infusion can be performed. Detailed electoro-mechanical mapping of the left ventricle is necessary prior to the cells delivery to define the infarcted areas.
At least three types of stem cells were tested for their ability to improve cardiac function: bone marrow derived stem cells (BMSCs), skeletal myoblasts and mesenchymal stem cells (MSCs).
The best characterized and potentially clinically accepted are BMSCs, as their isolation procedures, delivery to the patient methods, safety and therapeutic efficiency has been evaluated and established in the treatment of hematologic diseases. Based on accumulated pre-clinical and clinical data, it is considered today that the best results are achieved when BMSCs are intra-myocardially injected. In addition to the total BMSCs, there are several fractions of bone marrow-derived stem cells that are tested in clinics related to cardiac diseases, among them bone marrow-derived mononuclear cells (BM-MNCs) used mostly for autologous transplantation, CD133+ stem cells and CD34+ hematopoietic progenitors. These types of BMSCs, proved their safety and feasibility and many of them reached advanced 2nd and 3rd phases in a number of clinical trials.
Originally, the positive impact of BMSCs on myocardial remodeling was thought to be due to their contribution to de novo myocardiogenesis. The majority of clinical trials conducted during the last decade proved that BMSCs are able to improve significantly the left ventricular function deteriorated due to ischemic damage. Various studies demonstrated that stem cells treatment reduced scar burden, affected fibroblast proliferation, reduced Type I and Type III Collagen synthesis, improved ventricular function and affected left ventricular geometry. At present it is recognized that positive influence of BMSCs on cardiac function is closely related to myocardial regeneration. Stem cells affect the infarcted myocardium via neovascularization, reduction of apoptosis and paracrine effect, they are able to increase myocardial perfusion, inhibit synthesis of pro-inflammatory cytokines (IL6 and TNFα) and promote expression of anti-inflammatory cytokines (IL10) minimizing the necrosis damage caused by local inflammatory reaction.
The first licensed treatment using bone marrow–derived stem cells to treat diseases outside of the blood and immune systems was Hearticellgram®-AMI and it was approved was by the Korean FDA. Hearticellgram®-AMI are BMSCs used to treat acute myocardial infarction and are delivered by intracorononary injection. The study assessed safety and efficacy of intracoronary autologous transplantation of bone marrow-derived human MSCs in patients with acute myocardial infarction. There was an improvement in left ventricular ejection fraction and in myocardial function.
Mesenchymal stem cells (MSCs) are multipotent stem cells with a strong potential to differentiate into diverse types of mesenchymally-derived cells. MSCs can be obtained from various sources in the body, such as bone marrow, adipose tissue, umbilical cord etc., although the number of derived cells varies significantly from one source to another. Yet, following appropriate stimulation they are able to differentiate towards cardiomyocytic lineage as well. It has been demonstrated that MSCs injected into the infarcted myocardium significantly improve the left ventricular function and reduce the infarcted area size. Despite the threat of spontaneous differentiation, adipose-derived MSCs were tested in a number of clinical trials and succeeded to reach advanced 2nd phase. Moreover, bone marrow-derived mesenchymal stem cells differentiaied into cardiomyocytes before re-injection into the heart (C-Cure® cells) have reached the 3rd phase of clinical trials and demonstrated their ability to improve significantly left ventricular function.
Skeletal myoblasts have been considered as possible candidates for treatment of myocardial ischemia as well. These cells are able to differentiate and are resistant to ischemic conditions – the characteristics that might be beneficial at the infarcted area. There are several cellular products that are currently tested in clinics. MyoCell®, skeletal myoblasts obtained from quadriceps muscle and injected into the scar tissue of the ischemic heart, proved their safety and ability to improve cardiac function and are currently in phase 2-3 of clinical trials. Another example is AMDC – autologous adult skeletal muscle primary cells that are expanded in culture prior to injection and are tested for the treatment of ischemic heart failure.
Embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) possess unlimited proliferative capacity and represent the infinite supply of pluripotent cells. Their cardiogenic potential was successfully demonstrated in vitro and in animal models. One such a study was performed Rambam Medical Center, Israel, and used undifferentiated hESCs and hESCs-derived cardiomyocytes (hESC-CMs) to treat chronic ischemic heart failure in rats. Only hESC-CMs formed stable cardiomyocyte grafts and improved the typical infarct remodeling process of left ventricle (LV) expansion. An additional animal model study was conducted at Stanford University, USA, and proved significant improvement of the ischemic myocardium function when hESCs-derived cardiomyocytes were injected into the ischemic heart area of SCID mice.
Cardiosphere-derived stem cells (CDCs) are cells grown from small biopsy samples taken from the heart and are delivered back to the patient's heart by intracoronary infusion. This is another interesting example of cell therapy used for ischemic heart disease, when the autologous cardiac cells are used to repair the heart damage. This therapy is currently tested in clinical trial, Phase 1/2
In summary, a number of promising stem cell products are currently tested in clinics in attempt to repopulate the infarcted myocardium and bring a solution to the patients suffering from the damage to the cardiac tissue.