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Stem Cells in cardiovascular diseases

Arshed A. Quyyumi MD; FRCPArshed A. Quyyumi MD; FRCP

Professor of MedicineProfessor of Medicine

Division of CardiologyDivision of CardiologyEmory University School of Emory University School of

MedicineMedicineAtlanta, Georgia, USAAtlanta, Georgia, USA

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

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)

Adult Bone Marrow Stem Cell PlasticityAdult Bone Marrow Stem Cell Plasticity

EndodermalProgenitor Cells

Bone MarrowStem Cells

EctodermalProgenitor Cells

MesodermalProgenitor Cells

Neural cellsEpidermal cells

Hepatocytes

Hematopoeitic cells

Endothelial Progenitor Cells

Myocytes (Skeletal) (Cardiac)

Osteocytes, Chondrocytes

Stromal orMesenchymal MAPC

Blood cells

Resident stem cells:Heart, skeletal muscle,Adipose tissue, brain,Lung etc.

Rafii S & Lyden D Nature Medicine 9, 702 - 712 (2003)Cerdani DJ Nat Med 2004

Hypoxia

HIF-1

SDF-1CXCR4

Endothelial cells

Smooth muscle cells

VEGF

PDGF

Human studies with cell therapy in Human studies with cell therapy in cardiovascular diseasescardiovascular diseases

Cell types:Cell types: Endothelial progenitor cellsEndothelial progenitor cells::

Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etcBone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion) Cord bloodCord blood

Skeletal myoblastsSkeletal myoblasts Mesenchymal stem cellsMesenchymal stem cells Resident cardiac stem cellsResident cardiac stem cells Adipose tissue progenitorsAdipose 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 Chronic ischemia not amenable to conventional

revascularization revascularization

Delivery options for stem cellsDelivery options for stem cells

Intracoronary Intracoronary Coronary sinusCoronary sinus

Direct myocardial Direct myocardial injection injection epicardial, epicardial, endocardial),endocardial),

Intravenous Intravenous Bone marrow Bone marrow

mobilizationmobilizationDelivery devices

Human studies with cell therapy in Human studies with cell therapy in cardiovascular diseasescardiovascular diseases

Cell types:Cell types: Endothelial progenitor cellsEndothelial progenitor cells::

Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ Bone marrow endothelial progenitors eg. CD34+, CD133+

etcetc Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion) Cord bloodCord blood

Skeletal myoblastsSkeletal myoblasts Mesenchymal stem cellsMesenchymal stem cells Resident cardiac stem cellsResident 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 Chronic ischemia not amenable to conventional

revascularization revascularization

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;

Human studies with cell therapy in Human studies with cell therapy in cardiovascular diseasescardiovascular diseases

Cell types:Cell types: Endothelial progenitor cellsEndothelial progenitor cells::

Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etcBone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion) Cord bloodCord blood

Skeletal myoblastsSkeletal myoblasts Mesenchymal stem cellsMesenchymal stem cells Resident cardiac stem cellsResident cardiac stem cells Adipose tissue progenitorsAdipose 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 Chronic ischemia not amenable to conventional

revascularization revascularization

Allogeneic Mesenchymal Stem Cells forAllogeneic Mesenchymal Stem Cells forAcute Myocardial InfarctionAcute Myocardial Infarction

60 patients enrolled60 patients enrolled Baseline EF~50%Baseline EF~50% Intravenous adult human Intravenous adult human

MSCs (Provacel™, Osiris MSCs (Provacel™, Osiris Therapeutics) given 1-10 Therapeutics) given 1-10 days after infarct (vs. days after infarct (vs. placebo)placebo)

No increase in adverse eventsNo increase in adverse events No difference in baseline EFNo difference in baseline EF LAD infarcts:LAD infarcts:

MSC therapy: increase in EF MSC therapy: increase in EF at 3 (48.8 ± 11.9 vs 57.1 ± at 3 (48.8 ± 11.9 vs 57.1 ± 8.2; P 0.02) and and 6 8.2; P 0.02) and and 6 months (56.3 ± 8.7; P=0.05).months (56.3 ± 8.7; P=0.05).

Changes in EF in the placebo Changes in EF in the placebo patients and the non-LAD patients and the non-LAD groups were not significantgroups were not significant

Hare JM, et al., ACC Scientific Sessions 2007 (abstract) Zambrano, T, et al., Circulation. 2007;116:II_202. (abstract)

Human studies with cell therapy in Human studies with cell therapy in cardiovascular diseasescardiovascular diseases

Cell types:Cell types: Endothelial progenitor cellsEndothelial progenitor cells::

Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ Bone marrow endothelial progenitors eg. CD34+, CD133+

etcetc Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion) Cord bloodCord blood

Skeletal myoblastsSkeletal myoblasts Mesenchymal stem cellsMesenchymal stem cells Resident cardiac stem cellsResident 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 Chronic ischemia not amenable to conventional

revascularization revascularization

Human studies with cell therapy in Human studies with cell therapy in cardiovascular diseasescardiovascular diseases

Cell types:Cell types: Endothelial progenitor cellsEndothelial progenitor cells::

Bone marrow mononuclear cells, Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ Bone marrow endothelial progenitors eg. CD34+, CD133+

etcetc Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion) Cord bloodCord blood

Skeletal myoblastsSkeletal myoblasts Mesenchymal stem cellsMesenchymal stem cells Resident cardiac stem cellsResident 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 Chronic ischemia not amenable to conventional

revascularization revascularization

Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe,

Chronic Ischemic Heart Failure •

Perrin E Circulation 2003

Biosense Webster Myostar/ NOGA catheter

Losordo D et al ACC 2009

Losordo D et al ACC 2009

Disease states:– Acute MI, – Heart failure with hibernating myocardium– Myocardial ischemia and unrevascularizable

disease– Peripheral arterial disease

Clinical trials with endothelial progenitor cells

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Potential mechanisms of benefit of bone Potential mechanisms of benefit of bone marrow derived cells after myocardial marrow derived cells after myocardial

infarctioninfarction

Copyright ©2009 BMJ Publishing Group Ltd.

Mollmann, H. et al. Heart 2009;95:508-514

Figure 1 Potential mechanisms of stem cells in cardiac repair.

Transdifferentiation to cardiomyocytes

Attenuation ofRemodelling

Arteriogenesis or Angiogenesis

Copyright ©2009 BMJ Publishing Group Ltd.

Mollmann, H. et al. Heart 2009;95:508-514

Figure 1 Potential mechanisms of stem cells in cardiac repair.

Paracrine effects

Cell fusionReduction of apoptosis

Promoting endogenousCardiac stem cell function

Improvement in left ventricular ejection fraction (LVEF) in patients Improvement in left ventricular ejection fraction (LVEF) in patients treated with bone marrow-derived cells (BMCs) 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;167:989-997.Lipinski et al J Am Coll Cardiol; 2007;50:1761

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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 Bone marrow CD34+ cell injection after STEMI (AMRS 1)STEMI (AMRS 1)

Chest pain + STEMI

Stenting +Usual medical Rx

Day 1-9Bone marrow

harvest

Assessments:SafetyFunctional ClassHolter monitoringTreadmillCardiac function:MRI, EchoPerfusion:SPECT, MRIIntracoronary cell

product infusion

Days 1-10

cell product

Screening Echo

EF <50%

SPECTMRI

Intracoronary bone marrow mononuclear Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI cell injection after acute ST elevation MI

Cell

product

concentration

Copyright ©2009 BMJ Publishing Group Ltd.

Mollmann, H. et al. Heart 2009;95:508-514

Figure 2 Application of stem cells into infarcted tissue by intracoronary transplantation. Cells are delivered over the lumen of an inflated over-the-wire balloon catheter placed in the reopened infarct

artery. MI, infarcted myocardium.

ISOLEX is a trademark of Baxter International Inc.

Progenitor cellTherapeutics, NJ

SterilityPyrogenicityEx vivo viability

Paramagnetic CD34 Positive Cell Selection

S

SS

SSS S

S

S

SSS

S

MagnetSS

S

S

S

S

Anti-CD34 mAb Paramagnetic bead

SAM Ig antibodyMNC Fraction Containing CD34+ Stem Cells

Purified CD34+

Cells

PR34+ Release Agent

S

S

Volume reduction of CD34+ selected cells

CD34+ cells are infused via the infarct related artery6 to 9 days following successful coronary artery stenting.

Intracoronary cell therapy trial : bone marrow CD34+ cell injection post acute ST elevation MI

(AMR 1)

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Chest pain + STEMI

Stenting +Usual medical Rx

Day 1-9Bone marrow

harvest

Assessments:SafetyFunctional ClassHolter monitoringTreadmillCardiac function:MRI, EchoPerfusion:SPECT, MRIIntracoronary cell

product infusion

Days 1-10

cell product

Screening Echo

EF <50%

SPECTMRI

Intracoronary bone marrow mononuclear Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI cell injection after acute ST elevation MI

Cell

product

concentration

Copyright ©2009 BMJ Publishing Group Ltd.

Mollmann, H. et al. Heart 2009;95:508-514

Figure 2 Application of stem cells into infarcted tissue by intracoronary transplantation. Cells are delivered over the lumen of an inflated over-the-wire balloon catheter placed in the reopened infarct

artery. MI, infarcted myocardium.

Bone marrow CD34+ cell injection after STEMI Bone marrow CD34+ cell injection after STEMI (AMRS 1)(AMRS 1)

-5.7 mL vs. -0.1 mL +4% vs. +1%

-10% vs. -3%

Resting perfusion: SPECT total severity score

Resting total severity scoreControl, 5 million cells = +1310, 15 million cells = -256 (p=0.01)

Bone marrow CD34+ cell injection after Bone marrow CD34+ cell injection after STEMI (AMRS 1)STEMI (AMRS 1)

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 Bone marrow CD34+ cell injection after STEMI (AMRS 1)STEMI (AMRS 1)

Bone marrow-derived cell Bone marrow-derived cell therapy for AMItherapy for AMI

• Ongoing studies: www.clinicaltrials.org – 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)

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 MDA. Konstantinos M.D.Salman Sher Yusuf Ahmed Irina UphoffIbhar Al-MheidNino KavtaratzeHamid Syed Shawn Arshad

Progenitor Cell LaboratoryW. Robert Taylor M.D., PhDDiane Sutcliffe

Hematology/ Stem Cell ProcessingE. Waller M.D., PhDSagar Lonial M.D.

Kreton Mavromatis M.D.Ziyad Ghazzal M.D.Habib Samady M.D.Tanveer rab MD.Chandan Devireddy MDHenry Liberman MDDouglas Morris MDEmory Intereventional faculty

AMRS1Sponsor: Amorcyte Inc.PI: Arshed Quyyumi MDClinical sites:Emory University, Atlanta, GA Vanderbilt University, TNDouglas Vaughan MDLindner Center, OhioDean Keriakis MDTexas Heart InstituteJim Willerson MDCore labs:Fabio Esteves MDJames Galt PhDStam Lerakis MDJohn Oshinski PhD