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Stem Cells in cardiovascular diseases Arshed A. Quyyumi MD; FRCP Professor of Medicine Division of Cardiology Emory University School of Medicine Atlanta,

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Presentation on theme: "Stem Cells in cardiovascular diseases Arshed A. Quyyumi MD; FRCP Professor of Medicine Division of Cardiology Emory University School of Medicine Atlanta,"— Presentation transcript:

1 Stem Cells in cardiovascular diseases Arshed A. Quyyumi MD; FRCP Professor of Medicine Division of Cardiology Emory University School of Medicine Atlanta, Georgia, USA

2 Disclosure of Financial Relationships Grant/research support: National Institutes of Health, American Heart Association Eli Lilly, Novartis, Pfizer, Amorcyte, Biomarin, Forest Advisory Boards: Amorcyte, Endothelix, Novartis

3 Types of Stem Cells Embryonic stem cells – Pluripotent Fetal and adult stem cells (e.g. mesenchymal cells) – Multipotent; capable of producing a small range of differentiated cell lineages appropriate to their location Adult progenitor cells (e.g. skeletal myoblasts and endothelial progenitor cells) – Unipotent; has the least differentiation potential Induced pluripotent stem cells (IPS)

4 Adult Bone Marrow Stem Cell Plasticity Endodermal Progenitor Cells Bone Marrow Stem Cells Ectodermal Progenitor Cells Mesodermal Progenitor Cells Neural cells Epidermal cells Hepatocytes Hematopoeitic cells Endothelial Progenitor Cells Myocytes (Skeletal) (Cardiac) Osteocytes, Chondrocytes Stromal or Mesenchymal MAPC Blood cells Resident stem cells: Heart, skeletal muscle, Adipose tissue, brain, Lung etc.

5 Rafii S & Lyden D Nature Medicine 9, (2003) Cerdani DJ Nat Med 2004 Hypoxia HIF-1 SDF-1 CXCR4 Endothelial cells Smooth muscle cells VEGF PDGF

6 Human studies with cell therapy in cardiovascular diseases Cell types: Cell types: Endothelial progenitor cells: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Peripheral blood progenitors (ex vivo expansion) Cord blood Cord blood Skeletal myoblasts Skeletal myoblasts Mesenchymal stem cells Mesenchymal stem cells Resident cardiac stem cells Resident cardiac stem cells Adipose tissue progenitors Adipose tissue progenitors Disease states: Disease states: Acute MI, Acute MI, Heart failure with scar or hibernating myocardium, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization Chronic ischemia not amenable to conventional revascularization

7 Delivery options for stem cells Intracoronary Coronary sinus Intracoronary Coronary sinus Direct myocardial injection epicardial, endocardial), Direct myocardial injection epicardial, endocardial), Intravenous Intravenous Bone marrow mobilization Bone marrow mobilization Delivery devices

8 Human studies with cell therapy in cardiovascular diseases Cell types: Cell types: Endothelial progenitor cells: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Peripheral blood progenitors (ex vivo expansion) Cord blood Cord blood Skeletal myoblasts Skeletal myoblasts Mesenchymal stem cells Mesenchymal stem cells Resident cardiac stem cells Resident cardiac stem cells Disease states: Disease states: Acute MI, Acute MI, Heart failure with scar or hibernating myocardium, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization Chronic ischemia not amenable to conventional revascularization

9 Skeletal myoblasts Myoblasts derived from satellite cells in skeletal muscle With appropriate stimulus, satellite cells differentiate into muscle fibres Highly resistant to ischemia Do not contract spontaneously Do not differentiate into cardiomyocytes Orient towards cardiac stress reducing thinning and dilation Improve diastolic and systolic function Potential risk of fatal arrhythmia;

10 Human studies with cell therapy in cardiovascular diseases Cell types: Cell types: Endothelial progenitor cells: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Peripheral blood progenitors (ex vivo expansion) Cord blood Cord blood Skeletal myoblasts Skeletal myoblasts Mesenchymal stem cells Mesenchymal stem cells Resident cardiac stem cells Resident cardiac stem cells Adipose tissue progenitors Adipose tissue progenitors Disease states: Disease states: Acute MI, Acute MI, Heart failure with scar or hibernating myocardium, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization Chronic ischemia not amenable to conventional revascularization

11 Allogeneic Mesenchymal Stem Cells for Acute Myocardial Infarction 60 patients enrolled 60 patients enrolled Baseline EF~50% Baseline EF~50% Intravenous adult human MSCs (Provacel™, Osiris Therapeutics) given 1-10 days after infarct (vs. placebo) Intravenous adult human MSCs (Provacel™, Osiris Therapeutics) given 1-10 days after infarct (vs. placebo) No increase in adverse events No increase in adverse events No difference in baseline EF No difference in baseline EF LAD infarcts: LAD infarcts: MSC therapy: increase in EF at 3 (48.8 ± 11.9 vs 57.1 ± 8.2; P 0.02) and and 6 months (56.3 ± 8.7; P=0.05). MSC therapy: increase in EF at 3 (48.8 ± 11.9 vs 57.1 ± 8.2; P 0.02) and and 6 months (56.3 ± 8.7; P=0.05). Changes in EF in the placebo patients and the non-LAD groups were not significant Changes in EF in the placebo patients and the non-LAD groups were not significant Hare JM, et al., ACC Scientific Sessions 2007 (abstract) Zambrano, T, et al., Circulation. 2007;116:II_202. (abstract)

12 Human studies with cell therapy in cardiovascular diseases Cell types: Cell types: Endothelial progenitor cells: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Peripheral blood progenitors (ex vivo expansion) Cord blood Cord blood Skeletal myoblasts Skeletal myoblasts Mesenchymal stem cells Mesenchymal stem cells Resident cardiac stem cells Resident cardiac stem cells Disease states: Disease states: Acute MI, Acute MI, Heart failure with scar or hibernating myocardium, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization Chronic ischemia not amenable to conventional revascularization

13 Human studies with cell therapy in cardiovascular diseases Cell types: Cell types: Endothelial progenitor cells: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Peripheral blood progenitors (ex vivo expansion) Cord blood Cord blood Skeletal myoblasts Skeletal myoblasts Mesenchymal stem cells Mesenchymal stem cells Resident cardiac stem cells Resident cardiac stem cells Disease states: Disease states: Acute MI, Acute MI, Heart failure with scar or hibernating myocardium, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization Chronic ischemia not amenable to conventional revascularization

14 Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure Perrin E Circulation 2003 Biosense Webster Myostar/ NOGA catheter

15 Losordo D et al ACC 2009

16

17 Disease states: –Acute MI, –Heart failure with hibernating myocardium –Myocardial ischemia and unrevascularizable disease – Peripheral arterial disease Clinical trials with endothelial progenitor cells

18 Potential mechanisms of benefit of bone marrow derived cells after myocardial infarction Transdifferentiation to cardiomyocytes Attenuation of Remodelling Arteriogenesis or Angiogenesis Paracrine effects Cell fusion Reduction of apoptosis Promoting endogenous Cardiac stem cell function

19 Improvement in left ventricular ejection fraction (LVEF) in patients treated with bone marrow-derived cells (BMCs) More than 1200 patients with STEMI randomized Modest improvement in ejection fraction (EF 3%) Reduction in infarct size Reduction in end-systolic volume Comparison with pharmacological therapy post MI: Capricorn study (Carvedilol vs. placebo after AMI EF<40%): EF increased by 3.9% and end-systolic volume by 9.2 mls. Mortality reduced by 25%. Enca Martin-Rendon Eur Heart J 2008; 29:1807 Abdel-Latif, A. et al. Arch Intern Med 2007;167: Lipinski et al J Am Coll Cardiol; 2007;50:1761

20 Emory University, Atlanta, GA ; Vanderbilt University, Nashville, TN; Lindner Center, Cincinnatti, Ohio; Texas Heart Institute Primary Objective Feasibility and safety of intra-coronary infusion of autologous CD34 + cells at three dose levels (5, 10, 15 million). Secondary Objective To assess the effect on cardiac function (MRI, echo) and infarct region perfusion (SPECT). Assess mobility/homing (CXCR-4), viability and in vitro hematopoietic and precursor cell growth (CFU-G). Only study to investigate cell dose-response Largest dose of i.c. CD34+ cells given to date Bone marrow CD34+ cell injection after STEMI (AMRS 1)

21 Chest pain + STEMI Stenting + Usual medical Rx Day 1-9 Bone marrow harvest Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRI Intracoronary cell product infusion Days 1-10 cell product Screening Echo EF <50% SPECT MRI Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI Cell product concentration

22 ISOLEX is a trademark of Baxter International Inc. Progenitor cell Therapeutics, NJ Sterility Pyrogenicity Ex vivo viability

23 Paramagnetic CD34 Positive Cell Selection S S S S S S S S S S S S S Magnet S S S S S S Anti-CD34 mAb Paramagnetic bead SAM Ig antibody MNC Fraction Containing CD34+ Stem Cells Purified CD34+ Cells PR34+ Release Agent S S

24 Volume reduction of CD34+ selected cells

25 CD34+ cells are infused via the infarct related artery 6 to 9 days following successful coronary artery stenting. Intracoronary cell therapy trial : bone marrow CD34+ cell injection post acute ST elevation MI (AMR 1)

26 Chest pain + STEMI Stenting + Usual medical Rx Day 1-9 Bone marrow harvest Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRI Intracoronary cell product infusion Days 1-10 cell product Screening Echo EF <50% SPECT MRI Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI Cell product concentration

27 Bone marrow CD34+ cell injection after STEMI (AMRS 1) -5.7 mL vs mL +4% vs. +1% -10% vs. -3%

28 Resting perfusion: SPECT total severity score Resting total severity score Control, 5 million cells = , 15 million cells = -256 (p=0.01) Bone marrow CD34+ cell injection after STEMI (AMRS 1)

29 Intracoronary infusion of autologous bone marrow CD34+ cells during the repair phase after STEMI at higher doses than previously administered is safe, and may be associated with improved functional recovery from enhanced perfusion to the peri-infarct zone. Bone marrow CD34+ cell injection after STEMI (AMRS 1)

30 Bone marrow-derived cell therapy for AMI Ongoing studies: –Worldwide: Ten studies – US: Bone marrow: Intracoronary administration TIME (n=120), (NHLBI), Late –TIME (n=87) (NHLBI), Minneapolis (n=60) CD34+ cells: AMRS (Amorcyte) -Allogeneic Mesenchymal Precursor Cells n=25 Direct myocardial injection (Angioblast Systems) - Mesenchymal Stem Cells (Provacel) Intravenous injection (Osiris)

31 Cell therapy trials in acute MI Quyyumi Lab: Jonathan Murrow M.D. Mick Ozkor MD. Saurabh Dhawan M.D. Riyaz Patel M.D. Ayaz Rehman MD A. Konstantinos M.D. Salman Sher Yusuf Ahmed Irina Uphoff Ibhar Al-Mheid Nino Kavtaratze Hamid Syed Shawn Arshad Progenitor Cell Laboratory W. Robert Taylor M.D., PhD Diane Sutcliffe Hematology/ Stem Cell Processing E. Waller M.D., PhD Sagar Lonial M.D. Kreton Mavromatis M.D. Ziyad Ghazzal M.D. Habib Samady M.D. Tanveer rab MD. Chandan Devireddy MD Henry Liberman MD Douglas Morris MD Emory Intereventional faculty AMRS1 Sponsor: Amorcyte Inc. PI: Arshed Quyyumi MD Clinical sites: Emory University, Atlanta, GA Vanderbilt University, TN Douglas Vaughan MD Lindner Center, Ohio Dean Keriakis MD Texas Heart Institute Jim Willerson MD Core labs: Fabio Esteves MD James Galt PhD Stam Lerakis MD John Oshinski PhD


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