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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, Georgia, USA. Disclosure of Financial Relationships.

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Stem Cells in cardiovascular diseases

Arshed A. Quyyumi MD; FRCP

Professor of Medicine

Division of CardiologyEmory University School of Medicine

Atlanta, Georgia, USA


Disclosure of financial relationships
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
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 plasticity

Endothelial Progenitor Cells

Blood cells

Hematopoeitic cells

Stromal or

Mesenchymal

MAPC

Osteocytes,

Chondrocytes

Myocytes (Skeletal)

(Cardiac)

Adult Bone Marrow Stem Cell Plasticity

Neural cells

Epidermal cells

Ectodermal

Progenitor Cells

Mesodermal

Progenitor Cells

Bone Marrow

Stem Cells

Endodermal

Progenitor Cells

Hepatocytes

Resident stem cells:

Heart, skeletal muscle,

Adipose tissue, brain,

Lung etc.


Endothelial cells

VEGF

Hypoxia

HIF-1

SDF-1

PDGF

Smooth muscle cells

CXCR4

Rafii S & Lyden D Nature Medicine 9, 702 - 712 (2003)

Cerdani DJ Nat Med 2004


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

  • Cell types:

    • Endothelial progenitor cells:

      • Bone marrow mononuclear cells,

      • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc

      • Peripheral blood progenitors (ex vivo expansion)

      • Cord blood

    • Skeletal myoblasts

    • Mesenchymal stem cells

    • Resident cardiac stem cells

    • Adipose tissue progenitors

  • Disease states:

    • Acute MI,

    • Heart failure with scar or hibernating myocardium,

    • Chronic ischemia not amenable to conventional revascularization


Delivery options for stem cells
Delivery options for stem cells

  • Intracoronary Coronary sinus

  • Direct myocardial injection epicardial, endocardial),

  • Intravenous

  • Bone marrow mobilization

Delivery devices


Human studies with cell therapy in cardiovascular diseases1
Human studies with cell therapy in cardiovascular diseases

  • Cell types:

    • Endothelial progenitor cells:

      • Bone marrow mononuclear cells,

      • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc

      • Peripheral blood progenitors (ex vivo expansion)

      • Cord blood

    • Skeletal myoblasts

    • Mesenchymal stem cells

    • Resident cardiac stem cells

  • Disease states:

    • Acute MI,

    • Heart failure with scar or hibernating myocardium,

    • Chronic ischemia not amenable to conventional revascularization


Skeletal myoblasts
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 cardiovascular diseases2
Human studies with cell therapy in cardiovascular diseases

  • Cell types:

    • Endothelial progenitor cells:

      • Bone marrow mononuclear cells,

      • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc

      • Peripheral blood progenitors (ex vivo expansion)

      • Cord blood

    • Skeletal myoblasts

    • Mesenchymal stem cells

    • Resident cardiac stem cells

    • Adipose tissue progenitors

  • Disease states:

    • Acute MI,

    • Heart failure with scar or hibernating myocardium,

    • Chronic ischemia not amenable to conventional revascularization


Allogeneic mesenchymal stem cells for acute myocardial infarction
Allogeneic Mesenchymal Stem Cells forAcute Myocardial Infarction

  • 60 patients enrolled

  • Baseline EF~50%

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

  • No increase in adverse events

  • No difference in baseline EF

  • 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).

  • 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)


Human studies with cell therapy in cardiovascular diseases3
Human studies with cell therapy in cardiovascular diseases

  • Cell types:

    • Endothelial progenitor cells:

      • Bone marrow mononuclear cells,

      • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc

      • Peripheral blood progenitors (ex vivo expansion)

      • Cord blood

    • Skeletal myoblasts

    • Mesenchymal stem cells

    • Resident cardiac stem cells

  • Disease states:

    • Acute MI,

    • Heart failure with scar or hibernating myocardium,

    • Chronic ischemia not amenable to conventional revascularization


Human studies with cell therapy in cardiovascular diseases4
Human studies with cell therapy in cardiovascular diseases

  • Cell types:

    • Endothelial progenitor cells:

      • Bone marrow mononuclear cells,

      • Bone marrow endothelial progenitors eg. CD34+, CD133+ etc

      • Peripheral blood progenitors (ex vivo expansion)

      • Cord blood

    • Skeletal myoblasts

    • Mesenchymal stem cells

    • Resident cardiac stem cells

  • Disease states:

    • Acute MI,

    • Heart failure with scar or hibernating myocardium,

    • Chronic ischemia not amenable to conventional revascularization


Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure

Biosense Webster Myostar/ NOGA catheter

Perrin E Circulation 2003


Losordo D et al ACC 2009 Transplantation for Severe, Chronic Ischemic Heart Failure


Losordo D et al ACC 2009 Transplantation for Severe, Chronic Ischemic Heart Failure


Clinical trials with endothelial progenitor cells Transplantation for Severe, Chronic Ischemic Heart Failure

Disease states:

  • Acute MI,

  • Heart failure with hibernating myocardium

  • Myocardial ischemia and unrevascularizable disease

  • Peripheral arterial disease


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

Transdifferentiation Transplantation for Severe, Chronic Ischemic Heart Failure

to cardiomyocytes

Attenuation of

Remodelling

Arteriogenesis or

Angiogenesis

Paracrine effects

Cell fusion

Reduction of apoptosis

Promoting endogenous

Cardiac stem cell

function

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


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;167:989-997

.

Lipinski et al J Am Coll Cardiol; 2007;50:1761


Bone marrow cd34 cell injection after stemi amrs 1
Bone marrow CD34+ cell injection after STEMI (AMRS 1) patients treated with bone marrow-derived cells (BMCs)

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


Intracoronary bone marrow mononuclear cell injection after acute st elevation mi

Day 1-9 patients treated with bone marrow-derived cells (BMCs)

Bone marrow

harvest

SPECT

MRI

Screening Echo

Stenting +

Usual medical Rx

EF <50%

Intracoronary cell product infusion

Days 1-10

Chest pain + STEMI

cell

product

Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI

Assessments:

Safety

Functional Class

Holter monitoring

Treadmill

Cardiac function:

MRI, Echo

Perfusion:

SPECT, MRI

Cell

product

concentration


Progenitor cell patients treated with bone marrow-derived cells (BMCs)

Therapeutics, NJ

Sterility

Pyrogenicity

Ex vivo viability

ISOLEX is a trademark of Baxter International Inc.


Paramagnetic bead patients treated with bone marrow-derived cells (BMCs)

Anti-CD34 mAb

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

S

Magnet

MNC Fraction Containing

CD34+ Stem Cells

SAM Ig antibody

PR34+ Release Agent

Purified CD34+

Cells

Paramagnetic CD34 Positive Cell Selection


Volume reduction of cd34 selected cells
Volume reduction of CD34+ selected cells patients treated with bone marrow-derived cells (BMCs)


Intracoronary cell therapy trial bone marrow cd34 cell injection post acute st elevation mi amr 1
Intracoronary cell therapy trial : patients treated with bone marrow-derived cells (BMCs) bone marrow CD34+ cell injection post acute ST elevation MI (AMR 1)

CD34+ cells are infused

via the infarct related artery

6 to 9 days following

successful coronary

artery stenting.


Intracoronary bone marrow mononuclear cell injection after acute st elevation mi1

Day 1-9 patients treated with bone marrow-derived cells (BMCs)

Bone marrow

harvest

SPECT

MRI

Screening Echo

Stenting +

Usual medical Rx

EF <50%

Intracoronary cell product infusion

Days 1-10

Chest pain + STEMI

cell

product

Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI

Assessments:

Safety

Functional Class

Holter monitoring

Treadmill

Cardiac function:

MRI, Echo

Perfusion:

SPECT, MRI

Cell

product

concentration


Bone marrow cd34 cell injection after stemi amrs 11
Bone marrow CD34+ cell injection after STEMI (AMRS 1) patients treated with bone marrow-derived cells (BMCs)

-5.7 mL vs. -0.1 mL

+4%vs.+1%

-10% vs. -3%


Bone marrow cd34 cell injection after stemi amrs 12
Bone marrow CD34+ cell injection after STEMI (AMRS 1) patients treated with bone marrow-derived cells (BMCs)

Resting perfusion: SPECT total severity score

Resting total severity score

Control, 5 million cells = +13

10, 15 million cells = -256 (p=0.01)


Bone marrow cd34 cell injection after stemi amrs 13
Bone marrow CD34+ cell injection after STEMI (AMRS 1) patients treated with bone marrow-derived cells (BMCs)

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 derived cell therapy for ami
Bone marrow-derived cell therapy for AMI patients treated with bone marrow-derived cells (BMCs)

  • 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 patients treated with bone marrow-derived cells (BMCs)

Progenitor Cell Laboratory

W. Robert Taylor M.D., PhD

Diane Sutcliffe

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

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

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


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