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Bone Marrow Cell Therapy for Cardiovascular Diseases
US Hematology, 2007;1(1):46-8
Cardiologists battle our nation’s number one killer: heart disease. Bone marrow transplant and cancer have their own challenges and carry grave connotations, but cardiovascular (CV) disease causes most of the deaths and disabilities in the US, claiming nearly one million lives each year.1 The cost of cardiac care is estimated to approach $400 billion per year and, with an aging US population and epidemics in diabetes, metabolic syndrome, and obesity, the incidence of CV diseases will increase.2 Moreover, with improved survival rates after acute ischemic syndromes, the number of patients reaching the later stages of ischemic heart disease (e.g. left ventricular dysfunction, heart failure, arrhythmias, and premature death) will also increase.
Important strides have been made in optimizing medical management with antiplatelet agents, beta-blockers, statins, renin–angiotensin inhibitors, aldosterone inhibitors, blood-pressure reduction, and smoking cessation. However, additional pharmacotherapeutic manipulations are likely to bring only modest increases in benefit, as reflected by the pharmaceutical industry’s decreasing emphasis on this area. These considerations, plus the well-recognized limitations in mechanical hearts, heart transplantation, implantable defibrillators, restriction devices, and mitral valve repair, have spurred interest in novel approaches for left ventricular dysfunction.
Pre-clinical Evidence of Cell Therapy for Cardiovascular Disease
Numerous animal studies have demonstrated that transplantation of bone-marrow-derived cells improves cardiac function in settings of acute myocardial infarction (MI) and ischemic cardiomyopathy.3 Whole bone marrow (autologous and allogeneic), CD34+ cells, CD133+ cells, mesenchymal stem cells (MSC) (autologous and allogeneic), and endothelial progenitor cells represent several transplanted marrow elements. Moreover, various marrow-to-myocardium transplant techniques have been used, including intracoronary infusions, intraventricular myocardial injections, and extraventricular myocardial injections, via a surgical approach. Each technique has resulted in benefit to some degree.
Where the situation gets controversial is mechanism. How do marrowderived cells assist in myocardial regeneration? Initially, there was intense interest in direct transdifferentiation of hematopoietic cells into myocardium. Can adult marrow cells turn into heart muscle? Studies by Orlic et al.4 and Yoon et al.5 found evidence of bone marrow plasticity in rodent hearts, but further testing failed to show transdifferentiation of adult marrow cells into cardiomyocytes.6–8 A second possibility is paracrine regulation.
- Heart Disease and Stroke Statistics – 2005 Update, American Heart Association, 2005.
- Eyre H, Kahn R, Robertson RM, et al., Preventing cancer, cardiovascular disease, and diabetes: A common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association, Stroke, 2004;35:1999–2010.
- Quraishi A, Losordo DW, Ischemic tissue repair by autologous bone marrow-derived stem cells: scientific basis and preclinical data, Handb Exp Pharmacol, 2007;167–79.
- Orlic D, Kajstura J, Chimenti S, et al., Bone marrow cells regenerate infarcted myocardium, Nature, 2001;410:701–5.
- Yoon YS,Wecker A, Heyd L, et al., Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction, J Clin Invest, 2005;115: 326–38.
- Orlic D, Arai AE, Sheikh FH, et al., Cytokine mobilized CD34+ cells do not benefit rhesus monkeys following induced myocardial infarction, Blood, 2002;100:28a–29a.
- Murry CE, Soonpaa MH, Reinecke H, et al., Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts, Nature, 2004;428:664–8.
- Balsam LB,Wagers AJ, Christensen JL, et al., Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium, Nature, 2004;428:668–73.
- Haynesworth SE, Baber MA, Caplan AI, Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha, J Cell Physiol, 1996;166:585–92.
- Kinnaird T, Stabile E, Burnett MS, et al., Local delivery of marrowderived stromal cells augments collateral perfusion through paracrine mechanisms, Circulation, 2004;109:1543–9.
- Mirotsou M, Zhang Z, Deb A, et al., Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair, Proc Natl Acad Sci U S A, 2007;104:1643–8.
- Kocher AA, Schuster MD, Szabolcs MJ, et al., Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function, Nat Med, 2001;7:430–36.
- Jackson KA, Majka SM,Wang H, et al., Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells, J Clin Invest, 2001;107:1395–1402.
- Grant MB, May WS, Caballero S, et al., Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization, Nat Med, 2002;8:607–12.
- Cogle CR,Wainman DA, Jorgensen ML, et al., Adult human hematopoietic cells provide functional hemangioblast activity, Blood, 2004;103:133–5.
- Ince H, Nienaber CA, G-CSF and cardioprotection—deeper experimental insights, Cardiovasc Drugs Ther, 2006;20:155–6.
- Ince H, Petzsch M, Kleine HD, et al., Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI), Circulation, 2005;112:3097–3106.
- Zohlnhofer D, Ott I, Mehilli J, et al., Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial, JAMA, 2006;295:1003–10.
- Kang HJ, Kim HS, Zhang SY, et al., Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: The MAGIC cell randomised clinical trial, Lancet, 2004;363:751–6.
- Ince H, Valgimigli M, Petzsch M, et al., Cardiovascular events and restenosis following administration of G-CSF in acute myocardial infarction: Systematic Review of the literature and individual patient-data meta-analysis, Heart, 2007.
- Abdel-Latif A, Bolli R, Tleyjeh IM, et al., Adult bone marrow-derived cells for cardiac repair: A systematic review and meta-analysis, Arch Intern Med, 2007;167:989–97.
- Wollert KC, Meyer GP, Lotz J, et al., Intracoronary autologous bonemarrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial, Lancet, 2004;364:141–8.
- Lunde K, Solheim S, Aakhus S, et al., Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction, N Engl J Med, 2006;355:1199–1209.
- Schachinger V, Erbs S, Elsasser A, et al., Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: Final 1-year results of the REPAIR-AMI trial, Eur Heart J, 2006;27:2775–83.
- Janssens S, Dubois C, Bogaert J, et al., Autologous bone marrowderived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial, Lancet, 2006;367:113–21.
- Meyer GP,Wollert KC, Lotz J, et al., Intracoronary bone marrow cell transfer after myocardial infarction: Eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial, Circulation, 2006;113:1287–94.
- Perin EC, Dohmann HF, Borojevic R, et al., Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure, Circulation, 2003;107:2294–2302.
- Stamm C,Westphal B, Kleine HD, et al., Autologous bone-marrow stem-cell transplantation for myocardial regeneration, Lancet, 2003;361:45–6.
- Assmus B, Fischer-Rasokat U, Honold J, et al., Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: Results of the TOPCARE-CHD Registry, Circ Res, 2007;100:1234–41.
- Losordo DW, Schatz RA, White CJ, et al., Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: A phase I/IIa double-blind, randomized controlled trial, Circulation, 2007;115:3165–72.