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An Essential Guide to Cardiac Cell Therapy

2006 Edition, September 15, 2006

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Active, Most Current

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ISBN: 978-0-203-64092-0
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Product Details:

  • Revision: 2006 Edition, September 15, 2006
  • Published Date: September 15, 2006
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 210
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:


All humans are products of stem cell biology. Each human develops from two cells, following the union of a father's sperm and mother's egg, which subsequently develop into all of the organs in the human body under the influence of programs that direct their differentiation, organization, and structural development. Thus, our general appearance, our intellect, and all of our organs are products of stem cell differentiation. From a fundamental understanding of the programs that direct the differentiation of stem cells will ultimately come the ability to regenerate each of the organs of the body from a person's own stem cells or from a universal stem cell created in vitro. Based on this perspective of human development, it is clear that stem cell biology will be a vital part of regenerative cardiovascular medicine.

Humans have rescue systems of stem cells that are activated following injury to organs – including a system to repair the heart and arteries. While the genius of such a system deserves recognition and respect, it is also apparent that it is relatively inadequate as far as recovery from experimental myocardial infarction is concerned. The recruited circulating and activated resident stem cells arrive too late and are present in too few numbers in the early evolution of the injury process to be completely protective. In the last several years, numerous experimental studies have attemtpted to amplify the intrinsic system of stem cell presence in animal models with experimentally created myocardial infarcts.1–7 Fetal cells, adult circulating stem cells (often with CD34+ and/or CD133+ markers), stem cells derived from adipose tissue, and stem cells obtained from bone marrow have been administered into a coronary artery or by direct injection into the heart or into the venous circulation to monitor homing to experimentally created myocardial infarctions. In almost every case, these stem cells appear to assist in the recovery of heart function and to improve blood flow in and around the area of myocardial infarction. However, controversy persists concerning the ability of such stem cells to differentiate into new myocytes.3–9

Several previous studies have attempted to delineate the fate of injected stem cells following experimental myocardial infarction. In the last few years, we have performed studies with CD34+ circulating human stem cells injected into the tail veins or the left ventricular cavities of severe combined immune-deficient (SCID) mice with experimentally created myocardial infarcts.3,4 In these studies, the mice were euthanized 2 days after injection to determine whether the injected human stem cells homed to the area of infarction, and, if so, whether they developed into cells of interest. Our studies showed that the injected human circulating stem cells homed to the area of infarction in the murine heart; there, they developed into endothelial cells and smooth muscle cells, and fused to reversibly injured murine myocytes.3,4 A smaller number differentiated into new myocytes.3,4 Other groups have not always been able to demonstrate either the fusion process or the differentiation of stem cells into myocytes in experimentally injured animal hearts.9

However, we believe that this process does occur and can be observed when models are used that preclude rejection of the injected stem cells and allow a distinction to be made between injected stem cells and native myocytes in organs that have been experimentally injured. We and others have begun clinical studies using adult stem cells derived from a patient's own bone marrow.10–13 In 2000, our group petitioned the Brazilian government to allow us to begin clinical studies with autologous bone marrow-derived mononuclear cells (BMMNCs) in patients with severe heart failure. 10 These patients had coronary heart disease and prior myocardial infarctions. They had undergone coronary artery bypass surgery and/or percutaneous coronary intervention procedures; nevertheless, they had developed large, dilated hearts and severe heart failure. All patients were receiving appropriate medical therapy.

Based on our earlier animal studies, we decided to take bone marrow aspirates from the iliac crests of these patients, separate the mononuclear cells, and reinject them into the patient's hearts by using a NOGA "electromechanical" catheter placed retrograde across the aortic valve. The NOGA catheter was used to identify sites of reversible injury as locations for injection of the BMMNCs.10,14 We used single photon emission computed tomography (SPECT) studies to identify areas of reversible blood flow reduction. These studies were initiated at the Heart Hospital in Rio de Janeiro, Brazil, with Hans Dohmann and his colleagues.

We injected 2 × 106 BMMNCs transendocardially at 15 different sites where the NOGA catheter and SPECT studies suggested reversible injury.10 We have not found evidence of harm in these patients at 3 years of follow-up.15 Imaging and clinical studies have demonstrated improvement in clinical symptoms and in regional blood flow and contractile function.10 This was the first study in patients with severe heart failure that used the NOGA catheter to map appropriate areas for injection of patients' own BMMNCs.10 Subsequently, we obtained Food and Drug Administration (FDA) approval to proceed with similar studies in the USA at the Texas Heart Institute/St Luke's Episcopal Hospital in Houston, Texas. To date, we have randomized 24 patients in a treatment protocol similar to that used in Brazil. Patients are usually discharged from the hospital the day after the procedure. Regular follow-up visits include imaging procedures that evaluate changes in regional blood flow and function and in heart rhythm and clinical status. When we began these studies in Brazil, two different German groups, unknown to us at that time, were pursuing similar studies in patients with acute myocardial infarction, also using BMMNCs. These groups, however, were treating patients within several days of their infarcts by opening the infarct-related artery by angioplasty and injecting the patients' mononuclear cells directly into the artery.11,12 Patients in the German studies, which were led respectively by Strauer11 and by Dimmeler and Zeiher,12,16,17 did not have heart failure. More recently, Wollert et al13 have performed a randomized, controlled study in 60 patients with acute myocardial infarction using the German model of opening the infarct-related artery by angioplasty and injecting the BMMNCs directly into the infarct-related coronary arteries. The German-led studies demonstrated improvement in regional blood flow and function in the treated patients.11–13 Similar to our own studies, the German studies did not identify untoward clinical effects.

Careful reflection upon the ability of humans to develop from two cells and the acceptance of experimental results in multiple animal models has led to these early stem cell studies in patients. Emerging clinical data appear to show at least modest benefits in patients with new myocardial infarcts, chronic coronary heart disease, and/or severe heart failure treated with BMMNCs. With these considerations in mind, the potential usefulness of stem cells in regenerative cardiovascular medicine appears promising.

An Essential Guide to Cardiac Cell Therapy has been written for physicians wishing to acquaint themselves with stem cell therapy for cardiac disease. The Guide includes chapters written to provide an understanding of stem cells and stem cell therapy. These chapters cover basic stem cell biology, treatment of "no-option" patients, the use of large animal models, and the basics of embryonic stem cells and cloning. The book also addresses the applications of stem cell therapy, covering areas such as the use of mesenchymal lineage progenitor cells, methods of stem cell delivery, and concerns from a clinical perspective. The immediate needs now are to identify the best stem cell type(s), the optimal ways to deliver stem cells, and the patients most likely to benefit from this form of therapy. The more distant but achievable goals are the regeneration of the heart (and other organs) and repair of injured blood vessels with stem cells. These studies bring us closer to the promise and future of stem cell biology.