2006 Vol. 3, No. 3
Dear Friends and Colleagues, In this letter, 1 would like to celebrate the second anniversary of the Journal of Geriatric Cardiology (JGC). With the help of all of you, friends and colleagues, readers, editorials consultants, authors and editorial staff, the JGC was able to grow and publish many quality papers from the world.
Human Myoblast Genome Therapy (HMGT) is a platform technology of cell transplantation, nuclear transfer, and tissue engineering. Unlike stem cells, myoblasts are differentiated, immature cells destined to become muscles. Myoblasts cultured from satellite cells of adult muscle biopsies survive, develop, and function to revitalize degenerative muscles upon transplantation. Injection injury activates regeneration of host myofibers that fuse with the engrafted myoblasts, sharing their nuclei in a common gene pool of the syncytium. Thus, through nuclear transfer and complementation, the normal human genome can be transferred into muscles of patients with genetic disorders to achieve phenotype repair or disease prevention. Myoblasts are safe and efficient gene transfer vehicles endogenous to muscles that constitute 50% of body weight. Results of over 280 HMGT procedures on Duchenne Muscular Dystrophy (DMD) subjects in the past 15 years demonstrated absolute safety. Myoblast-injected DMD muscles showed improved histology. Strength increase at 18 months post-operatively averaged 123%. In another application of HMGT on ischemic cardiomyopathy, the first human myoblast transfer into porcine myocardium revealed that it was safe and effective. Clinical trials on approximately 220 severe cardiomyopathy patients in 15 countries showed a <10% mortality. Most subjects received autologous cells implanted on the epicardial surface during coronory artery bypass graft, or injected on the endomyocardial surface percutaneously through guiding catheters. Significant increases in left ventricular ejection fraction, wall thickness, and wall motion have been reported, with reduction in perfusion defective areas, angina, and shortness of breath. As a new modality of treatment for disease in the skeletal muscle or myocardium, HMGT emerged as safe and effective. Large randomized multi-center trials are under way to confirm these preliminary results. The future of HMGT is bright and exciting.
Objectives This study investigated the efficacy of human skeletal myoblasts (SkJVI) mediated either human vascular endothelial growth factor-! 65 (hVEGF1(5) or angiopoietin-1 (Ang-1) on vascular development and myocardial regional perfusion. Methods A porcine heart model of chronic infarction was created in 28 female swine by coronary artery ligation. The animals were randomized into: (1) group- 1, DMEM injected (n=6), (2) group-2, Ad-null transduced SkM transplanted (n=6), (3) group-3, Ad-hVEGF]65 transduced SkM transplanted (n=8), and (4) group-4, Ad-Ang-1 transduced SkM (n=8). Three weeks later, 5 ml DMEM containing 3X 10s SkM carrying exogenous genes were intramyocardially injected into 20 sites in left ventricle in groups-2, -3 and -4. Animals in group- 1 were injected 5 ml DMEM without cells. Animals were kept on 5 mg/kg cyclosporine per day for 6 weeks. Regional blood flow was measured using fluorescent microspheres. The heart was explanted at 2, 6 and 1 2 weeks after transplantation for histological studies. Results Histological examination showed survival of lac-z expressing myoblasts in host tissue. Capillary density based on Von Willebrand factor-VHI (vWF-VIH) at low power field (x 100) was 57.1 3±1 1.85 in group-3 at 6 weeks and declined to 32. 1±5.21 at 12 weeks, while it was 39.9±10.26 at 6 weeks and increased to 45. 14±6.54 at 12 weeks in group-4. The mature blood vessel index was highest in group-4 at 6 and 1 2 weeks after transplantation. The regional blood flow in the center and peri-infarct area was significantly increased in animals of groups-3 and -4. Conclusions SkM carrying either hVEGF|65 or Ang-1 induced neovascularization with increased blood flow. Ang-1 overexpression resulted in mature and stable blood vessel formation and may be a more potent arteriogenic inducer for neovascularization.
Molecular and cellular processes gleaned from the most fundamental of biomedical studies are now harnessed for their potential healing properties. In the US and through-out the world, millions of patients suffer from myocardial infarction and many succumb to the morbidity and mortal-ity of the ensuing cardiac failure, a protracted condition in need of healing. While pharmacological agents have been the mainstay intervention that ameliorates cardiac failure through increased contractility or reduction of cardiac workload, these agents do not inherently heal the wounds inflicted by poor perfusion of the affected cardiac tissue. Cell therapy, however, holds the promise of repleting the damage heart with new contractile cells that can be engi-neered to secrete concoctions that promote healing by recruiting new blood vessel development or angiogenesis. Such cell therapeutic promise has already been fulfilled for many decades for hematological diseases through trans-plantation of bone marrow stem cells, which are now more broadly implicated for their healing potential of other tissues.
Heart failure (HF) affects a rapidly growing popula-tion of patients. Despite improvements in the understand-ing and therapy of many stages of cardiovascular disease, there has been little progress in treating HF. In late-stage disease, current options are cardiac transplantation and mechanical support-options that are limited to a small pa-tient collective. The ischemically injured failing heart lacks contractile myocardium, functional vasculature, and electri-cal integrity, which has made treatment of the underlying injury untenable in the past. Restoring all of these compo-nents at once seems to be an overwhelming challenge.
Over 200 humans have been treated with myoblast transplantation for heart muscle repair since June 2000. Bioheart sponsored percutaneous delivery studies began in May 2001 in Europe. Approximately one third of the patients have exhibited substantial improvement in left ventricular ejection traction (LVEF) of over 30% and two heart failure class improvements. Over 80% of the patients have exhibited one heart failure class improvement with moderate improvement of LVEF. Clinical trials seem to demonstrate a marked reduction in emergency hospitalizations in myoblast treated patients. Many years of careful studies have lead to randomized controlled studies that are enrolling patients now at numerous centers worldwide. A firm conclusion on the safety and efficacy of myoblast transplantation cannot be determined until these randomized studies are completed. Final results from randomized controlled studies should be available soon.
Myocardial regeneration is an exciting new frontier for the treatment of heart disease. Many approaches are currently being tested. The use of autologous skeletal myoblasts has been the earliest, with over 10 years of research having been conducted. Current progress in the area of skeletal myoblasts for cardiac regeneration is presented. Reviewed is work from both pre-clinical and clinical studies. Work in this area continues to progress and definitive studies to assess efficacy of myoblasts for heart failure either have been initiated or will be initiated shortly. One result that is clear is that myoblasts can survive and form myotubes and myofibers in the area of myocardial infarction. In the early clinical trials, arrhythmia was a concern. However, further studies have shown that the risk was assumed prematurely based on limited human studies. Myoblasts, therefore, provide a highly promising treatment for heart disease.
Advances in stem cell science and potential clinical applications have brought clinical medicine closer to the actualization of Regenerative Medicine—an extension of transplantation of organs and cells and implantation of bioprosthetics and biodevices. The goal of such therapeutics will be intervention prior to onset of severe individual disability, enhance organ function and enhance patient performance status without incurring the economic impacts of standard organ transplantation. Regenerative Medicine is already demonstrating proof of principle or efficacy in restora-tion of myocardial contractility, joint mobility and function, immune competence, pulmonary function, immunologic self-tolerance, motor function and normal hemoglobin production with the next targets—diabetes mellitus (type I and type II), neurologic injury, hepatic dysfunction preparing to enter trials.
Objectives To assess the clinical efficacy, safety, and feasibility of autologous transplantation of mobilized peripheral blood mononuclear cells (PBMNCs) for patients with peripheral arterial occlusive disease (PAOD) of the lower extremity. Methods A total of 152 patients with PAOD of the lower extremity were enrolled into this non-controlled observational study from November 2003 to March 2006. All patients received subcutaneous injections of recombinant human granulocyte colony-stimulating factor (G-CSF, 450-600 ug/day) for 5 days in order to mobilize stem/progenitor cells; their PBMNCs were collected and transplanted by multiple intramuscular injections into ischemic limbs. Patients were followed up for at least 12 weeks. Results At 12 weeks, primary manifestations, including lower limb pain and coldness, were significantly improved in 137 (90.1 %) of the patients; limb ulcers improved or healed in 46 (86.8%) of the 53 patients, while 25 of the 48 (47.9%) patients with limb gangrene remained steady or improved. Ankle-brachial index (AB1) improved in 33 (22%) of the cases, and TcPO, increased in 45 (30%) of the cases. Angiography before treatment, and at 12 weeks after treatment, was performed in 10 of the patients and showed formation of new collateral vessels. No severe adverse effects or complications specifically related to cell transplantation were observed. Conclusion Autologous transplantation of G-CSF-mobilized PBMNCs might be a safe and effective treatment for lower limb ischemic disorder.
For more than two decades, the morbidity and mortality of coronary artery disease (CAD) has been increasing rapidly in China. Despite tremendous advances in treatment strate-gies of CAD, heart failure after acute myocardial infarction (AMI) continues to be one of the greatest medical chal-lenges throughout the world. In 1994, Soonpaa and col-leagues first reported the possibility of cardiomyocytes implantation and suggested that intracardiac cell grafting might provide a useful approach for myocardial repair.1 Cell implantation has become a novel therapeutic option for is-chemic cardiac injury and heart failure.
The World Congress of Cardiology (WCC) 2006 was a joint meeting of the European Society of Cardiology (ESC) and the World Heart Federation (WHF) held in Barcelona Spain on September 2-5, 2006. The highlight scientific theme of this year's congress is cardiovascular diseases and aging. With the increase of aging population, the prevalence of many cardiovascular diseases increases exponentially, and the spectrum of our patients has changed to the elderly. It is a fact that management of older patients differs from that of younger patients and does not follow international recommendations. The WCC 2006 is the perfect opportu-nity to review in depth the grounds for this situation and examine solutions to improve it.