1 Stem Cells in cardiovascular diseases Arshed A. Quyyumi MD; FRCP Arshed A. Quyyumi MD; FRCP Professor of Medicine Professor of Medicine Division of Cardiology Division of Cardiology Emory University School of Emory University School of Medicine Medicine Atlanta, Georgia, USA Atlanta, Georgia, USA
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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
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
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
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
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
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
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,
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
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)
Intracoronary bone marrow mononuclear Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI cell injection after acute ST elevation MI
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
Intracoronary bone marrow mononuclear Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI cell injection after acute ST elevation MI
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
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)