An increasing number of patients survive acute myocardial infarction. Surgical and interventional revascularisation of the ischaemic myocardium can treat angina, reduce risk of myocardial infarction and improve the function of the viable myocardium. However, the therapeutic possibilities in end-stage heart failure patients are limited. This article investigates alternative treatment options such as combined therapies using bone marrow-derived stem cells (BMSCs).
Despite the success of current medical and surgical management of ischaemic heart disease, a growing number of patients have diffuse obstructive coronary artery disease that is not suitable for coronary artery bypass grafting or catheter-based interventions. Furthermore, complete revascularisation procedures are not suitable for many patients due to total arterial occlusion, poor distal vessels or unacceptable procedural risks caused by concomitant medical conditions. Regardless of maximal pharmacotherapy and conventional revascularisation, up to 15% of patients with end-stage coronary artery disease suffer from disabling symptoms.1 In addition, there is a lack of donors for heart transplants, which increases the need to offer viable alternatives for patients in the future. Recently, cell therapy has evolved as an option for the treatment of ischaemic heart disease. Several cell types including skeletal myoblasts, bone marrow stem cells, endothelial progenitors, mesenchymal stem cells, resident cardiac stem cells and embryonic stem cells are under pre-clinical and clinical investigation.2
Intra-myocardial Injection of Bone Marrow-derived Stem Cells
Within those different cell types, autologous BMSCs have raised the interest of many research and clinical investigators. So far, clinical data suggest that autologous BMSCs seem to have the potential to improve myocardial perfusion and contractile performance in patients suffering from myocardial infarction, severe ischaemic heart disease and chronic heart failure.3–10 Unselected autologous BMSCs have been injected into the myocardium during open-chest surgical procedures3–5 or via percutaneous intervention using injection catheters.6–10 Most of the patients undergoing surgery together with the cell injection had received a coronary artery bypass graft (CABG).
Clinical Experiences with Selected Bone Marrow Stem Cells
It is still unclear which cell types within the bone marrow cells are responsible for the positive trends observed in clinical studies so far. There is clear evidence from in vitro and in vivo pre-clinical work that haemopoietic/endothelial progenitor cells should have positive effects on neoangionesis in damaged myocardium. Endothelial stem cells have been identified in the adult and have been shown to participate in new blood vessel formation in normal and pathological states.11–14 Therefore, several groups are investigating the potential of selected progenitor cell fractions from bone marrow for cellular therapy in cardiac diseases. Defined surface markers such as CD3415 and CD13316-18 are used for immunomagnetic selection of progenitor cells under good manufacturing practice (GMP) conditions. While the majority of patients within these studies have received the selected stem cells in addition to revascularisation by CABG,15,17 substantial improvement of cardiac function was also found in patients who received CD133-selected cells as sole therapy.16,18
Selected Stem Cells and Laser Surgery
Many patients who are referred to heart surgery departments have already undergone a series of interventional procedures for revascularisation and have developed congestive heart failure (CHF). Prognosis is poor for patients after development of CHF with either medical or surgical treatment.19 Patients with an ejection fraction (EF) ≤35%, treated with CABG alone once left ventricular (LV) dilatation has occurred, have a five-year survival of 50–65%.20 In order to improve the efficacy of CABG and stem cell therapy, our own group has been using transmyocardial laser revascularisation (TMLR) for many years. Clinical trials have shown that symptomatic improvement after TMLR in patients with refractory angina is probably related to neoangiogenesis.21 The intention is to restore tissue viability by taking advantage of the synergistic angiogenic effects of TMLR and stem cell injection. The local inflammatory reaction induced by TMLR should serve as an informational platform for stem cells and may trigger their angiogenic differentiation.22 TMLR has recently been approved by the US Food and Drug Administration (FDA) for patients with disabling angina whose coronary arteries are not suitable for angioplasty or coronary artery bypass grafting alone and for patients with microvascular disease.1,23
Since 2002 we have treated more than 50 patients with a combination of TMLR and CD133+ cell injection, many of them in conjunction with CABG (see Figure 1). Bone marrow aspiration and stem cell selection using the CliniMACS® System have been established in a novel procedure within the operating room.24 For 12 patients treated with CABG, TMLR and stem cells, follow-up data of >12 months are available. The mean left ventricular ejection fraction (LVEF) increased from 26.7±2.7% preoperatively to 40.1±3.3% at 12 months post-operatively (see Figure 2). In addition, the mean end-systolic LV wall thickness improved from 5.6±0.7mm to 11.8±1.4mm (see Figure 3). One-year follow-up data are also available for five patients with late-stage cardiomyopathy who were not eligible for bypass grafting. These patients received CD133+ stem cell injections in conjunction with TMLR. Starting from a low mean EF of 14.6%±2.4% pre-operatively, the treatment regimen resulted in a marked increase to 30.6% at one-year post-operatively (see Figure 2).
Injection of Selected Stem Cells Alone
Most clinical studies of intramyocardial cell transplantation were performed in combination with CABG or other technologies (see above), yet the contribution of implanted cells could not be clearly distinguished from the effect of the standard methods used. Our group investigated the outcome of a current phase I study focusing on the safety and feasibility of the injection of CD133+ stem cells alone without CABG and TMLR in patients suffering from end-stage chronic ischaemic cardiomyopathy (EF <22%). Ten patients received CD133+ BMSCs with purities of up to 99% (see Table 1). Cells were injected into predefined regions and the cardiac function prior to this and at three, six and nine months was assessed by cardiac magnetic resonance imaging (MRI). Stem cell transplantation typically improved the heart function stage from New York Heart Association/Canadian Cardiovascular Society class III–IV to I–II. The mean pre-operative and post-operative ventricular EF were 15.8±5% and 24.8±5%, respectively.18 In addition, substantial increases in wall thickness were observed. These results provide the first clinical evidence that the application of CD133+ BMSCs contribute to the improvement of cardiac function in patients with chronic ischaemic heart failure.
These promising results have encouraged more investigators to explore the optimum conditions for stem cell therapy in combination with TMLR and surgical procedures. A number of multicentre and randomised controlled trials are now being initiated and should help to further improve this promising field for treatment of cardiac disease. One of the most prevalent questions is the choice of the cell type contained in bone marrow, which forces us to acknowledge the heterogenity of our cardiac surgery patient population. The choice of the bone marrow-derived cell type and even the cell isolation procedure will ultimately depend greatly on the cardiac injury to be treated. Highly selected haematopoietic progenitor cells might have angiogenic potential only, whereas mesenchymal stem cells were shown to represent subsets with cardiomyogenic and angiogenic potential. Also critical is the stem cell dose that can be obtained from bone marrow using various techniques. Recent investigations suggest that there may be a dose–response relationship, which it has not been possible to test in clinical trials so far because of the limited number of stem cells isolated from autologous bone marrow using current available technology. Increasing evidence from cardiac surgery studies suggests that therapy with certain bone marrow-derived stem and progenitor cells improves myocardial perfusion and LVEF. According to our and other groups’ experience, the BMSC therapy concept should be extended to patients with end-stage heart failure, myocardial non-viability and non-ischaemic cardiomyopathy, who might no longer be candidates for cardiac transplantation. In these indications, cardiac surgery techniques are the only choice or are superior to other treatments, corroborating the role of cardiac surgery in future stem cell therapies by delivering both cells with reparative capacities and surgeons with reparative capabilities.