Leading the Way in Cardiovascular Regenerative Medicine

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Leading the Way in Cardiovascular Regenerative
Medicine
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CV disease US prevalence
Myocardial ischemia 37 million
Acute MI 865,000/year
Heart failure 5 million
Chest Pain 4.2 million emergency visits/year6.4
million outpatient visits/year
Peripheral vascular disease8 million
Stroke5.7 million
American Heart Association. Heart Disease and
Stroke Statistics2007 Update.
Symptomatic coronary artery disease (CAD) or
angina pectoris.
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New paradigm for CV disease

• Human heart can regenerate
• Bone marrow derived stem cells (BMCs)
• Circulating progenitor cells (CEPCs)
• Circulating hematopoietic stem cells
• Resident stem cells
• With certain risk conditions (eg, hypertension,
  diabetes, hypercholesterolemia, aging) and
  diseases (eg, ischemic heart disease) stem cells
  are inadequate (number/quality/time)
• Can stem cell therapy correct/regenerate blood
  vessels and/or myocardium?

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Cell therapy

• Embryonic stem cells
• Cord blood stem cells
• Adult stem cells
• Circulating
• Bone marrow (BM)
• Hematopoietic
• Mesenchymal
• Tissue specific
• Fat, muscle, etc

Gulati R, Simari RD et al. Med Clin N Am.
200791769-85.
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CV disease targets for cell therapy clinical
trials

• CAD
• Refractory angina (no other options)
• Acute myocardial infarction with left ventricular
  dysfunction (early vs late)
• Heart failure (reversible ischemia vs scar)
• Peripheral arterial disease
• Claudication and critical limb ischemia
• Abdominal aortic aneurysm
• Ischemic stroke
• Nonischemic cardiomyopathy

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Some examples of CV disease targets in cell
therapy trials in the US

• Refractory angina
• Baxter CD 34 cells post G-CSF (Phase 1 2)
• Acute myocardial infarction
• Osiris IV mesenchymal cells (Phase 1)
• Neuronyx IM mesenchymal cells
• NHLBI-CCTRN IC BM mononuclear cells (TIME and
  late TIME)
• Heart failure
• Bioheart skeletal myoblasts (MARVEL)
• NHLBI-CCTRN BM mononuclear cells (FOCUS)
• Peripheral arterial disease
• Baxter CD34 cells post G-CSF for claudication
  and CLI

Courtesy of Timothy Henry, MD.
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Cell transplantation for cardiac repair and/or
inadequate blood supply Rationale
Chronic heart diseases are characterized
byirreversible loss of myocytes
Although some mitotic activity can be
identified, proliferative capacity is inadequate
Permanent deficits in number of viable,
functioning myocytes promotes development and
progression of HF
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Damaged myocardium repair New paradigm
Traditional view no new heart muscle cell formed
Usual Outcome Replacement of heart muscle with
SCAR TISSUE
New view replacement of damaged heart cells by
new cardiomyocytes
Strategy (1) Replicationof endogenous
cardiomyocytes
Strategy (2) Conversionof stem cells into new
cardiomyocytes
Grounds MD et al. J Histochem Cytochem.
200250589-610.
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Why use adult stem cells?

• Readily available
• Easy to isolate
• Autologous
• May be altered to increase gene expression
• No ethical concerns

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Role of the cell in cardiac regeneration therapy
As a cell
As a factory
As a courier
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Cell-mediated CV repair
Angiogenesis and re-endothelialization
Apoptotic bodies, cell-cell contact
(?),adhesion (?)
Exercise, VEGF,Estrogen, G-CSFEpo,
Statins,SDF-1
SDF-1, VEGF
Mobilization
Differentiation
Homing
CV risk factors
Re-endothelialization
Angiogenesis
Werner N, Nickenig G. Arterioscler Thromb Vasc
Biol. 200626(2)257-66.
VEGF vascular endothelial growth factor.
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Stem-cell homing Chemoattractive hypothesis
Adult stemcells
Chemokinereceptors
Circulating stem cellsattracted to injury
Heart withmyocardialinfarction
Area of injurysecretes chemokines
Rosenthal N. N Engl J Med. 2003349267-74.
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Possible routes for cell therapy to the heart
RCA
CFX
Balloon catheter
Intracoronary
LAD
Intravenous
Intramyocardial
Transendocardial
Strauer BE, Kornowski R. Circulation
2003107929-34.