Transcript Cell transplantation for cardiac repair and/or inadequate

Leading the Way in
Cardiovascular
Regenerative Medicine
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CV disease: US prevalence
Myocardial
ischemia
37 million*
Heart
failure
5 million
Acute MI
865,000/year
Chest Pain
4.2 million emergency visits/year
6.4 million outpatient visits/year
Peripheral
vascular
disease
8 million
*Symptomatic coronary artery disease (CAD)
or angina pectoris.
Stroke
5.7 million
American Heart Association.
Heart Disease and Stroke Statistics—2007 Update.
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New paradigm for CV disease
• Human heart can regenerate
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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. 2007;91:769-85.
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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 by
irreversible 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): Replication
of endogenous cardiomyocytes
Strategy (2): Conversion
of stem cells into new cardiomyocytes
Grounds MD et al. J Histochem Cytochem. 2002;50:589-610.
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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
Exercise, VEGF,
Estrogen, G-CSF
Epo, Statins,
SDF-1
Apoptotic bodies, cellcell contact (?),
adhesion (?)
SDF-1, VEGF
Mobilization
Differentiation
Homing
CV risk factors
Angiogenesis
VEGF = vascular endothelial growth factor.
Re-endothelialization
Werner N, Nickenig G.
Arterioscler Thromb Vasc Biol. 2006;26(2):257-66.
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Stem-cell homing: Chemoattractive hypothesis
Adult stem
cells
Chemokine
receptors
Circulating stem cells
attracted to injury
Heart with
myocardial
infarction
Area of injury
secretes chemokines
Rosenthal N. N Engl J Med. 2003;349:267-74.
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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 2003;107:929-34.