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Mechanical Support Induces Genetic Changes in Failing Hearts

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Duke Health News 919-660-1306

DURHAM, N.C. -- Using new DNA microarray technology, Duke
University Medical Center researchers have found significant
changes in the expression pattern of hundreds of genes in heart
muscle cells after mechanical pumps are used to take over from
failing hearts.

This finding represents a first step, they say, in a line of
research that could help predict how heart failure patients
will respond when supported by a left ventricular assist device
(LVAD). These devices are employed when the heart's left
ventricle -- the chamber of the heart that pumps blood
throughout the body -- is too weak to pump enough blood to
nourish the body's tissues. They have been used as successful
short-term "bridges to heart transplant" and are increasingly
being considered as long-term heart failure destination
therapy, also known as "bridge to recovery."

Additionally, the researchers report, the new gene screening
technology appears to genetically differentiate between the two
main forms of heart failure.

Physicians have noticed that over time, a heart that is
allowed to recover while the LVAD pumps the blood appears to
undergo a "remodeling" process of both its structure and
function. Some patients have even been "weaned" off the LVAD
without needing a transplant. However, the mechanism for these
beneficial effects is not well understood, the researchers
said.

"We have identified differential expression of numerous
genes significantly associated of these functional
improvements," said Burns Blaxall, Ph.D., first author of a
paper published today (April 2, 2003) in the Journal of the
American College of Cardiology. "The data and the microarray
technology provide substantial insights into the potential
mechanisms of remodeling, and with further study, may lead to
ways of predicting how individual patients will respond to the
LVAD."

DNA microarrays, also known as gene chips, are basically
large numbers of known genes deposited as a regular array of
tiny dots on a small chip. Researchers can detect which genes
are increased or decreased in expression by extracting from
target cells messenger RNA -- the levels of which reflect the
expression of each gene. They then apply this RNA mixture to
the chips, and the expression level of individual genes is
revealed by the amount of fluorescence of an indicator molecule
attached to the RNA molecules.

The researchers were able to perform genetic analysis on
left ventricle muscle tissue from six heart failure patients
both before and after implantation of the LVAD. As part of the
normal procedure, surgeons cut a quarter-sized piece of tissue
from the chamber to insert the LVAD; and later they had access
to the tissue of the same hearts at the time of organ
transplantation. Patients were maintained from two to four
months on an LVAD before their heart transplants.

"Our analysis showed significantly distinct genomic profiles
or 'footprints' for the pre- vs. the post-LVAD hearts," said
Blaxall. "It appears that the remodeling we see in these hearts
is associated with a specific pattern of gene expression."

After extracting the genetic material from the tissue
samples, the researchers employed the DNA microarray technology
to screen the individual samples against a known bank of
approximately 6,800 genes. They found 295 genes with increased
levels of expression and 235 with decreased levels of
expression.

The researchers are quick to point out that, although the
altered expression of these 530 genes provides a global view of
the extent of genetic changes following LVAD use, further
studies will be needed to understand which of these genes --
whether acting alone or in combinations -- are associated with
the actual remodeling of the heart.

"Although the expression of some genes already known to be
altered by LVADs were found to be similarly changed in this
analysis, the majority of the differential gene expression we
found consisted of genes not previously known to be effected by
LVAD support," said Walter Koch, Ph.D., senior member of the
research team.

"Of particular interest are some genes not previously
associated with heart failure, so further investigation of
these genes will be needed to better understand their specific
roles in the underlying disease process and subsequent
remodeling after LVAD support," Koch continued. "Importantly,
these genes may provide a host of novel targets for future
diagnostic or therapeutic indications."

Particularly significant, said the researchers, was that of
the six genetic footprints that emerged from the analysis, two
groups of three patients had distinct footprints.
Serendipitously, they said, three of the patients had the
ischemic form of cardiomyopathy, while the other three had the
non-ischemic form. Ischemia is a condition where a lack of
blood flow causes cell death -- in this case, heart cell
death.

"When considering the vast human heterogeneity, it is
striking that a small sample size could clearly distinguish the
difference between ischemic and non-ischemic based on gene
expression," Blaxall explained. "Importantly, we found
significant differences in gene expression after LVAD support
when starting with either a failing ischemic or non-ischemic
heart."

Since hearts that have suffered from ischemia will have
areas of dead, or scar, tissue along with functional heart
muscle, the researchers said that these patients may be less
likely to see significant remodeling of the remaining viable
cardiac tissue compared to those patients with the non-ischemic
form of heart failure.

The researchers also believe that the results of this and
subsequent studies could help physicians determine which
patients can eventually be weaned from an LVAD without needing
a transplant and those who could benefit from long-term, or
even permanent, LVAD support.

The study was supported by grants from the National
Institutes of Health and the American Heart Association. In
addition to Blaxall and Koch, other members of the Duke team
were Bryn Tschannen-Moran and Carmelo Milano, M.D.

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