New Approach Limits Damage After Heart Attack and Improves
By Jason Socrates Bardi
A team led by scientists at The Scripps Research Institute
has developed a potential new treatment for heart attacks.
The therapy inhibits fluid leakage from cardiac blood vessels
following a heart attack and thereby significantly prevents
long-term heart damage and improves survival.
"Immediately following a heart attack, blood vessels near
the site of injury become leaky, causing fluid accumulation
in the healthy area of the heart surrounding the injured site,"
says Immunology Professor David A. Cheresh, who led the research
with postdoctoral fellow Sara Weis at The Scripps Research
Institute. This permeability response is devastating to normal
"Until now," continues Cheresh, "nobody has realized the
extent to which this leak response damages heart tissue and
causes long-term tissue injury. We discovered a way to block
this process and thus save heart tissue from irreversible
Using laboratory models that are designed to mimic the pathology
of heart attacks in humans, Cheresh, Weis, and their colleagues
found that a single dose of a compound designed to block this
fluid leakage (which is called edema) can, even if given as
late as six hours after the event, drastically reduce tissue
injury and increase long-term survival following a heart attack.
A biopharmaceutical company, TargeGen Inc. in San Diego,
is finalizing preclinical studies to translate these initial
research findings into practical human therapies. Using extensive
preclinical models that mirror human heart attacks, TargeGen
scientists report that 40 to 60 percent reductions in infarct
(tissue injury) size with a small molecule drug that inhibits
vascular leak and edema. Based on the encouraging preclinical
efficacy and safety studies, TargeGen plans to initiate a
combined Phase I/II human clinical trial in the second half
of 2004 for patients undergoing an acute heart attack.
In addition to Cheresh and Weis, the team included scientists
from St. Elizabeth's Medical Center at Tufts University School
of Medicine in Boston, Massachusetts; the Department of Radiology
at Beth Israel Deaconess Medical Center in Boston; and the
private company TargeGen, Inc. of San Diego, California.
Public Health Enemy Number One
According to the National Heart, Lung, and Blood Institute,
about 12.6 million Americans suffer from coronary heart disease,
the most common form of heart disease. This disease often
leads to an acute myocardial infarction, the technical term
for a heart attack. Some 1.1 million Americans suffer heart
attacks each year, and approximately 515,000 of these attacks
are fatal, making coronary heart disease the number one cause
of death in the United States today.
Currently, the main treatments for heart attacks address
the initial thrombus or blockage to the artery in order to
restore blood flow to the heart. Doctors use thrombolytic
"clot busting" drugs to dissolve the blockage chemically,
or angioplastytiny balloon catheters often followed
by a wire mesh stentto mechanically prevent the artery
However, because the blockage starves the heart tissue of
oxygen, says Cheresh, the tissue damage that occurs following
a heart attack may continue to worsen in the hours following
the attack, even after the clot is gone. The damage occurs
because when the heart is starved of oxygena situation
called ischemiaa whole cascade of events occurs, including
edema (the leaking of blood vessels).
Edema causes fluid to accumulate in the heart tissue, which
leads to rapid cell death in the local area where the fluid
accumulates. It also leads to further loss of heart tissue
through inflammatory reactions in the several hours following
a heart attack. Over the long term, this edema-induced cell
death leads to fibrosis, the formation of scar tissue which
replaces dead heart tissue. Heart attack survivors often have
weakened hearts because this scar tissue cannot function properly.
These patients often require additional procedures, such as
the insertion of pacemakers or heart transplants.
For the first time, a possible treatment for this secondary
damage has been proposed by Cheresh, Weis, and their colleaguesthe
use of a class of compounds known as Src kinase inhibitors.
In the latest issue of the Journal of Clinical Investigation,
the team reports a dramatic effect of using Src kinase inhibitors
to stop the edema-induced damage following a heart attack,
thereby reducing heart tissue injury and increasing survival.
Cell Adhesion and the Sequence of Events Following the
This possible treatment strategy stems from several years
of basic research conducted by Cheresh and his collaborators
into an area of biology known as cell adhesion.
Cell adhesion is a topic of major importance because it
is the basis for how groups of cells form and define functionally
distinct tissues and organs in the body. Blood vessels are
lined by what are known as endothelial cells, which adhere
to one another and line the body's blood vessels like bricks
lining a subterranean tunnel.
Through the work of Cheresh and other basic science researchers
over the past decades, a number of the adhesion molecules
that hold these endothelial cells together and the signaling
molecules that induce them to let go of one another during
events like edema have been identified.
A heart attack occurs when a blood vessel in the heart becomes
blocked. This leads to oxygen deprivation, and that rapidly
induces the production of vascular endothelial cell growth
factor (VEGF), which is known to promote new blood vessel
growth. However, VEGF also produces the unwanted side effect
of causing vascular permeability, and Cheresh and his colleagues
wanted to develop a strategy to block blood vessel leak without
blocking the beneficial vascular growth-promoting effects
of VEGF. This was accomplished with a Src kinase inhibitor.
Cheresh, Weis, and colleagues found that VEGF stimulates
Src kinase to cause junctional adhesion proteins (cadherins)
to disengage from each other, thereby causing endothelial
cells lining the blood vessels to permit fluid leak into the
Normally cadherins form mortar-like junctions between the
endothelial cell bricks and maintain the integrity of blood
vessel walls. But cadherins come apart rapidly when they are
given the right stimulussuch as VEGF.
Just as removing mortar between bricks in a subterranean
tunnel might cause the tunnel to become permeable to groundwater,
blood vessels become leaky when the mortar that holds these
endothelial cells together crumbles.
A few years ago, Cheresh and his colleagues discovered that
mice born without the ability to make certain proteins belonging
to the Src family have a deficiency in vascular permeability.
These animals showed a high degree of resistance to the damaging
effects of a heart attack. Src, it turns out, is necessary
for breaking the cadherin junctions in response to VEGF. In
fact, these mice lacking Src were protected against the edema
that followed a heart attack.
This led Cheresh and his colleagues to speculate that treating
normal mice with Src inhibitors might do the same thing. In
their latest study, they demonstrate exactly that result.
The cadherin junctions between cells lining the blood vessels
in animals treated with Src inhibitors following a heart attack
do not break down.
"Src inhibitors prevent the endothelial barrier breakdown,
thereby preventing the edema in the heart. This early protection
reduces the loss of cardiac tissue and thus the necessity
for replacement by a functionally inadequate scar," Cheresh
The article "Src blockade stabilizes a Flk/cadherin complex,
reducing edema and tissue injury following myocardial infarction"
is authored by Sara Weis, Satoshi Shintani, Alberto Weber,
Rudolf Kirchmair, Malcolm Wood, Adrianna Cravens, Heather
McSharry, Atsushi Iwakura, Young-sup Yoon, Nathan Himes, Deborah
Burstein, John Doukas, Richard Soll, Douglas Losordo, and
David Cheresh and appears in the March 15, 2004 issue of The
Journal of Clinical Investigation (113, 885-894). See:
The research was supported by grants and fellowships funded
by the National Institutes of Health, and by a Banyu Fellowship
Award in Cardiovascular Medicine.
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