Researchers at Johns Hopkins have shown that genetic
testing can be effectively used to distinguish between
heart failure patients who suffer from ischemic or
nonischemic forms of the disease. Using groupings or
clusters of a patient's gene expression to compare to a
diseased "test" set that identifies the cause of heart
failure, the Johns Hopkins team assembled a 90-gene profile
to determine which type of heart failure had most likely
developed. Results showed the test profile to be highly
accurate, with 90 percent specificity.
The findings, if affirmed and adapted to a
standardized and affordable test format, could someday aid
physicians in the diagnosis of heart failure and help
determine which kind of therapy is best to use for the
condition.
In ischemic heart disease, the patient's arteries have
narrowed, and the heart cannot pump normally because blood
flow (and thus oxygen) is often restricted to the heart
muscle. In nonischemic forms of the disease, the heart
cannot pump normally because the heart muscle has often
enlarged for other reasons, such as physical deformity or
alcohol abuse. Both conditions can lead to cardiac arrest
or more gradual heart failure as the muscle weakens over
time.
"The gene expression differences between various forms
of cardiovascular disease are poorly understood, despite
the fact that we know there are major differences in what
is happening at the cellular level," said Michelle
Kittleson,
cardiology fellow at the Johns Hopkins Heart Institute
and lead author, who was scheduled to present the study
Nov. 6 at the American Heart Association's Scientific
Sessions 2004 as a finalist for the Samuel A. Levine Young
Clinical Investigator Award.
"Our study shows that gene expression profiling for
heart failure patients is not only possible but accurate as
well. Based on these initial findings, we hope to close the
gaps in our understanding of the gene expression patterns
underlying heart failure and treatments for the illness.
Ultimately, we hope to be able to use genetic profiling to
classify patients according to their risk of developing all
kinds of heart disease."
To create a gene expression profile, or test, the
Johns Hopkins team collected 16 biopsy tissue samples, six
from patients with the ischemic form of the disease and 10
from nonischemic cases, all with end-stage heart failure.
Most of the test samples came from heart transplant
patients at Johns Hopkins in the last 20 years.
Using a biostatistical technique called prediction
analysis, the researchers identified the 90 genes that best
distinguished the two kinds of heart failure. The large
number of genes used also improved accuracy of the test.
This gene profile was later validated by testing it
against 38 other tissue samples, including 14 provided from
the University of Minnesota. These test samples involved
tissue from all stages of heart failure, including
end-stage, post-LVAD (a type of heart surgery) and biopsy
samples from newly diagnosed patients.
"Now that we know we can genetically profile heart
patients according to ischemic and nonischemic heart
disease, our next step is to develop a test that can be
used in a clinical setting," said senior study author and
cardiologist Joshua Hare, a professor of medicine at the
Heart Institute. "Ischemic patients need to be monitored
more closely in case they develop drug resistance and
require surgery to unblock clogged arteries. Knowing which
patients to treat and how closely to monitor them could
significantly improve how well physicians manage the
disease and, consequently, improve health outcomes."
This one-year study was funded by the National
Institutes of Health. Further assistance with statistical
analysis was provided by the Johns Hopkins Bloomberg School
of Public Health. Other investigators in this research,
conducted solely at Johns Hopkins, were Shui Ye, Rafael
Irizarry, Khalid Minhas, Gina Edness, John Conte, Giovanni
Parmigiani, Leslie Miller, Yingjie Chen, Jennifer Hall and
Joe Garcia.
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