Transcript Do Bolus Thrombolytics Carry a Higher Risk of Intracranial

Cardiac regeneration
Cardiac regeneration:
mending the broken heart
Marc Pfeffer MD PhD
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Piero Anversa MD
Director, Cardiovascular Research Institute
New York Medical College
Valhalla, New York
Victor Dzau MD
Physician-in-Chief
Brigham and Women’s Hospital
Boston, Massachusetts
Heartbeat – Sep 2002
Cardiac regeneration
Quantum leaps forward
Major advances come in quantum leaps,
and then we fine-tune them. We think
we are at the crux of a new
breakthrough.
• what are the new discoveries based
on?
• how sound is this foundation?
• where are we going from here?
Heartbeat – Sep 2002
Cardiac regeneration
Regenerative hearts
Until recently, we were
told the heart is
terminally differentiated:
“What you have is what
you will die with.”
Pfeffer
Heartbeat – Sep 2002
Cardiac regeneration
Primitive cells
Considering the heart an organ that
cannot repair itself is wrong.
Anversa
The question is: do we have a primitive,
undifferentiated cardiac cell that can
generate all the cells in the heart?
If they do exist, where do they originate?
Heartbeat – Sep 2002
Cardiac regeneration
Isolated regeneration
Why do the myocytes not
move into the infarcted
area and repair it?
So far, the regeneration has
been seen only in the
surviving myocardium in
the area next to the
infarct
Heartbeat – Sep 2002
Cardiac regeneration
Death vs regeneration
We think so many patients develop heart
failure after infarct because the balance
between the cell-death processes (both
apoptosis and necrosis) and
regeneration favors cell death in endstage failure
We don't know the timing: how long does
it take a cell to die by necrosis, to die by
apoptosis, or to regenerate?
Anversa
Heartbeat – Sep 2002
Cardiac regeneration
Enhancing regeneration
"If we can agree that there is balance
here between death and regeneration, if
that concept can be developed further,
then what's so exciting about this is
that in the future we will […] have the
new tool of enhancing regeneration."
Pfeffer
Heartbeat – Sep 2002
Cardiac regeneration
Regenerative capacity
Regenerative capacity is like a bank
account
After an MI, do you have sufficient
capacity to repair a myocardium that is
injured?
If it is a small infarct, we can sometimes
repair it completely
If the infarct is too large, the mechanism
is insufficient
Heartbeat – Sep 2002
Cardiac regeneration
Pathological enlargement
"In heart failure, I think the horse is out
of the barn."
Dzau
Because you've already gotten to the
stage where there is pathological
enlargement, the repair mechanism
cannot turn the condition around
Heartbeat – Sep 2002
Cardiac regeneration
Stem cell source
Heartbeat – Sep 2002
Cardiac regeneration
Harvesting cells
Can harvest the primitive cells by
removing the blood elements (white
blood cells, red blood cells, and
platelets)
Cells can be injected directly into the
injured heart
Or they can be mobilized out of the
marrow with cytokines
Heartbeat – Sep 2002
Cardiac regeneration
Questions
Does this prevent further cardiac
dilatation after injury?
Is it mainly the formation of new blood
vessels that's important? Or does it just
provide more myocytes to work with?
What is the timing needed?
How do we best tap the therapeutic
potential?
Heartbeat – Sep 2002
Cardiac regeneration
Is the cell source important?
Do we care where the cells come from?
Yes. A primitive cell in the heart is already
programmed to produce everything in
the heart
A primitive heart cell should be naturally
more effective
Anversa
Heartbeat – Sep 2002
Cardiac regeneration
Two viewpoints
Biological viewpoint: primitive heart cells
from the myocardium will be
programmed to work the right way
without modification
Practical viewpoint: bone marrow cells
are easy to find, and the ischemic
environment seems to push them along
the right path to form myocytes
Dzau
Heartbeat – Sep 2002
Cardiac regeneration
The here and now
Autologous skeletal myoblasts are being
injected into infarcted myocardium
How do we put outside contractile tissue
into a hostile environment and get it to
work?
We need the whole myocardium
Heartbeat – Sep 2002
Cardiac regeneration
Limits of skeletal myoblasts
Skeletal myoblasts aren't able to generate
new tissue
There is no real electrical coupling
between the cells with skeletal
myoblasts, even though they contract
"I think there are some problems with the
skeletal myoblasts that I don't know
whether they will be resolved soon."
Anversa
Heartbeat – Sep 2002
Cardiac regeneration
Proof of concept
Let's look at skeletal myoblast as proof of
concept
If we put a skeletal myoblast into the
heart, we generate muscle
If we have some muscle in an area that is
dilating, it seems to help prevent
further dilation
Heartbeat – Sep 2002
Cardiac regeneration
More myoblast questions
Myoblast cells don't form syncytium and
so cannot coordinate electrical and
mechanical activity
Reports of people doing better may reflect
the heart not dilating as much, not an
improvement in contractility
Heartbeat – Sep 2002
Cardiac regeneration
Islands of arrhythmogenicity
These areas could develop into islands of
arrhythmogenicity, foci for ventricular
arrhythmia
• 4 out of 12 of the patients from France
are receiving ICDs
It is much better to go with a primitive
cell to create myocytes, or to create
more blood vessels with angioblasts
Heartbeat – Sep 2002
Cardiac regeneration
What next?
We are already harvesting marrow cells
by simple aspirate and trying to form
cardiomyocytes
• fortunately this is not technically hard
to do
• unfortunately we need a lot more
careful experimental data
Dzau
Heartbeat – Sep 2002
Cardiac regeneration
Patient safety
We want to do good, and do no harm, so
we need to know more:
• when is the best time to do this?
• what is the right environment?
• what's the best way to isolate these
cells?
Heartbeat – Sep 2002
Cardiac regeneration
The future
Injecting cells into systemic circulation
Using the right cocktail cytokine to free
cells from bone marrow
Activating the theoretical primitive stem
cell already in the myocardium
Heartbeat – Sep 2002
Cardiac regeneration
Controlled experiments
It is too early to go to humans yet
"If we can identify the mechanism of this
turnover and enhance this turnover, we
may be able to use the same process for
repairing the heart.“
Anversa
Heartbeat – Sep 2002
Cardiac regeneration
Stem cell controversy
We are talking here about using
autologous or primitive cells within the
adult tissue, not embryonic cells
These eliminate the need for
immunosuppression or other transplant
problems
However the overall potential of adult
cells is lower than embryonic cells
Dzau
Heartbeat – Sep 2002
Cardiac regeneration
Remodeling process
“The remodeling process is
the enemy. The infarct is
the beginning of an
opportunity to alter the
remodeling process.”
Pfeffer
Heartbeat – Sep 2002
Cardiac regeneration
Physician’s tools
For the practicing physician we have:
• preventive medicine
• infarct limitation therapies
• for certain patients there will be a
balance between hypertrophy, their
intrinsic capacity to restore function,
and reperfusion
Heartbeat – Sep 2002
Cardiac regeneration
Mending the broken heart
90 days after anterior MI, 1/3 of the
patients have no regional wall-motion
abnormality or enlargement on echo
We must learn to tweak this balance of
natural regeneration from 1/3 of patients
to 2/3 or even more in the future
Pfeffer
Heartbeat – Sep 2002