Cardiac Stem Cell Therapy Clinical Experiences

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Cardiac Stem Cell TherapyClinical Experiences

• David Zhao, MD, FACC, FSCAI
• Harry and Shelley Page Professor of Medicine
• in Interventional Cardiology
• Director, Cardiac Catheterization Laboratory
• Interventional Cardiology
• Vanderbilt University Medical Center
• Nashville, TN USA

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Mending a Brocken HeartA Real Challenge in
Medicine

• Acute MI 7,200,000
• New cases 865,000/y
• Mortality 221,000/y
• CHF 5,000,000
• New cases 550,000/y
• Mortality 57,218/y
• Transplant 2,016/y

Regenerate a new heart dream comes true!?
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Cell Based Cardiac Regeneration

• Intracoronary infusion
• Coronary artery
• Coronary vein
• Direct intramyocardial injection
• Epicardial (Surgery)
• Endocardial (Percutaneous)
• Intravenous infusion
• Systemic growth factors
• Tissue-engineered constructs

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Cell Based Cardiac RegenerationIntracoronary
Injection

• Advantages
• Allow homogeneous homing of cells into target
  zone
• Easy delivery
• Disadvantages
• Risk of induce myonecrosis
• Low cell homing due to rapid coronary transit and
  barriers.

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Cell Based Cardiac RegenerationIntracoronary
Injection
CCTRN TIME Late TIME Trials PI David Zhao
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6 and 18 mon Results from BOOST
N60
Stem Cell
Controls
?EF
6.7 5.9
6 Mon 18 Mon
0.7 3.1
plt0.05 p0.27
Meyer et al, Cir 20061131272
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TOPCARE-AMI
N28
Continuous improvement in EF at 4 and 12 Mon
JACC 2004441690
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REPAIR-AMI Change in LVEF Endsystolic Volume
EF
ESV
Schachinger et al NEJM 20063551210
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Post MI EF and Benefit
Schachinger et al NEJM 20063551210
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BMC Modifies LV RemodelingInteraction Between EF
and ES Volume
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REPAIR-AMI 2Year Follow Up
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Problems and Potential Solutions

• Problems
• Rapid coronary transit
• Endothelial barrier
• Increase coronary permeability
• VEGF, bradykinin, adenosine, serotonin
• Sonicated microbubbles
• Prolong intracoronary dwell time
• Coronary vein occlusion
• Selected coronary artery occlusion
• Increase intracapillary pressure
• Aortic and pulmonary artery occlusion
• Pressured perfusion
• Retrograde perfusion

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Cell Based Regeneration Endomyocardial Injection

• Advantages
• Small number of cells required
• Localized delivery
• Disadvantages
• Leads to islands of cells
• Complex delivery system
• High cell death due to tissue hypoxia and
  physical stress

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Cell Based Cardiac RegenerationEndomyocardial
Injection
NOGA System
CCTRN FOCUS Trial PI Zhao
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Chronic Ischemia Cardiomyopathy6 months Results
from PROTECT-CAD
N28
Stem Cell
Controls
ETT EF Ischemia
?20.9 ?7.6 ?31
p0.026 plt0.01 p0.04
?18 ?4.6 ?26
ACC 2006
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Cell Based Cardiac RegenerationEpicardial
Intramyocardial Injection
LIMA
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Cell Based Cardiac Regeneration Intravenous Cell
Infusion

• Advantages
• Simple and least invasive
• Disadvantages
• Limited cell number to home target area
• Homing to non-cardiac organs

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IV Infusion PROVACEL Trial
Joshua Hare NY Cell Synposium 2008
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Cell Based Cardiac Regeneration Systemic Growth
Factors

• Advantages
• Simple and least invasive (GCSF)
• Disadvantages
• Limited cell number to home target area
• Cell homing to non-cardiac organs
• Potential negative effects on restenosis and
  malignancy

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Systemic GCSF Infusion after Acute Myocardial
Infarction
Zohlnhofer, JACC in press
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Cell Based Cardiac RegenerationTissue
Engineering Constructs

• Advantages
• Plasticity of implanted cells
• Permanent release of effective substrates
• Selective cell types and functions
• Disadvantages
• Complex delivery system
• Potential oncogenic effects

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Cardiac Cell Therapy Savior for the Dying
Heart!?

• Mechanisms underlining cardiac regeneration are
  largely unknown
• Clinical outcomes are modest at the best
• Ethics in embryogenic cell research are
  controversial

One small step for man, one giant leap for
mankind Neil Armstrong, Apollo 11, 7/1969, lunar
landing