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Leading the Way in Cardiovascular Regenerative Medicine 2 CV disease: US prevalence Myocardial ischemia 37 million* Heart failure 5 million Acute MI 865,000/year Chest Pain 4.2 million emergency visits/year 6.4 million outpatient visits/year Peripheral vascular disease 8 million *Symptomatic coronary artery disease (CAD) or angina pectoris. Stroke 5.7 million American Heart Association. Heart Disease and Stroke Statistics—2007 Update. 3 New paradigm for CV disease • Human heart can regenerate – – – – Bone marrow derived stem cells (BMCs) Circulating progenitor cells (CEPCs) Circulating hematopoietic stem cells Resident stem cells • With certain risk conditions (eg, hypertension, diabetes, hypercholesterolemia, aging) and diseases (eg, ischemic heart disease) stem cells are inadequate (number/quality/time) • Can stem cell therapy correct/regenerate blood vessels and/or myocardium? 4 Cell therapy • Embryonic stem cells • Cord blood stem cells • Adult stem cells – Circulating – Bone marrow (BM) • Hematopoietic • Mesenchymal – Tissue specific • Fat, muscle, etc Gulati R, Simari RD et al. Med Clin N Am. 2007;91:769-85. 5 CV disease targets for cell therapy clinical trials • CAD – Refractory angina (“no other options”) – Acute myocardial infarction with left ventricular dysfunction (early vs late) – Heart failure (reversible ischemia vs scar) • Peripheral arterial disease – Claudication and critical limb ischemia – Abdominal aortic aneurysm • Ischemic stroke • Nonischemic cardiomyopathy 6 Some examples of CV disease targets in cell therapy trials in the US • Refractory angina – Baxter: CD 34+ cells post G-CSF: (Phase 1 & 2) • Acute myocardial infarction – Osiris IV mesenchymal cells (Phase 1) – Neuronyx: IM mesenchymal cells – NHLBI-CCTRN: IC BM mononuclear cells (TIME and late TIME) • Heart failure – Bioheart: skeletal myoblasts (MARVEL) – NHLBI-CCTRN: BM mononuclear cells (FOCUS) • Peripheral arterial disease – Baxter: CD34+ cells post G-CSF for claudication and CLI Courtesy of Timothy Henry, MD. 7 Cell transplantation for cardiac repair and/or inadequate blood supply: Rationale Chronic heart diseases are characterized by irreversible loss of myocytes Although some mitotic activity can be identified, proliferative capacity is inadequate Permanent deficits in number of viable, functioning myocytes promotes development and progression of HF 8 Damaged myocardium repair: New paradigm Traditional view – no new heart muscle cell formed Usual Outcome: Replacement of heart muscle with SCAR TISSUE New view – replacement of damaged heart cells by new cardiomyocytes Strategy (1): Replication of endogenous cardiomyocytes Strategy (2): Conversion of stem cells into new cardiomyocytes Grounds MD et al. J Histochem Cytochem. 2002;50:589-610. 9 Why use adult stem cells? • Readily available • Easy to isolate • Autologous • May be altered to increase gene expression • No ethical concerns 10 Role of the cell in cardiac regeneration therapy As a cell As a factory As a courier 11 Cell-mediated CV repair Angiogenesis and re-endothelialization Exercise, VEGF, Estrogen, G-CSF Epo, Statins, SDF-1 Apoptotic bodies, cellcell contact (?), adhesion (?) SDF-1, VEGF Mobilization Differentiation Homing CV risk factors Angiogenesis VEGF = vascular endothelial growth factor. Re-endothelialization Werner N, Nickenig G. Arterioscler Thromb Vasc Biol. 2006;26(2):257-66. 12 Stem-cell homing: Chemoattractive hypothesis Adult stem cells Chemokine receptors Circulating stem cells attracted to injury Heart with myocardial infarction Area of injury secretes chemokines Rosenthal N. N Engl J Med. 2003;349:267-74. 13 Possible routes for cell therapy to the heart RCA CFX Balloon catheter Intracoronary LAD Intravenous Intramyocardial Transendocardial Strauer BE, Kornowski R. Circulation 2003;107:929-34.