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Johns Hopkins team uses gene-Expression Test to Distinguish Heart Failure Cases

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A survey of the expression of 90 genes can accurately distinguish ischemic heart failure and non-ischemic heart failure, findings that may lead to diagnostic tests to guide treatment options and deliver a prognosis, possibly using only blood samples, according to a Johns Hopkins cardiac researcher.

“Studies have shown that these two major subtypes of patients with heart failure respond differently to therapy and also have different prognoses,” said Michelle Kittleson, a cardiology fellow at the Johns Hopkins Heart Institute and lead author of the study. Kittleson presented the research at the American Heart Association’s Scientific Sessions 2004, and it will be published in the December or January issue of Cardiology.

The study is most important as proof of concept, because it is the first time that gene expression profiling has been used to distinguish two subtypes of cardiovascular disease, said Kittleson. There are other ways to distinguish ischemic and non-ischemic heart failure, but “this profile could still be relevant in the subgroup of patients who have heart failure that appears to be out of proportion to their coronary artery disease,” she said. When a patient’s heart failure subtypes overlap, a doctor may need the tests for additional guidance in the decision of whether to send the patient for an angioplasty or a cardiovascular bypass .

A patient’s subtype can also affect drug response. For example, “ACE-inhibitor intolerance […] is much more common in patients with ischemic disease; there are certain intravenous inotropes that we give patients with heart failure” that are tolerated less well by ischemic patients, said Kittleson.

The researchers collected 16 biopsy samples from “end-stage” heart tissue following removal prior to transplantation, six from ischemic and 10 from non-ischemic cases, and measured gene expression using the Affymetrix U133A DNA chip. Later prediction analysis identified 90 genes that best differentiated the two types of heart failure cases. The profile was validated through comparison with 38 samples collected during every stage of heart failure, including newly diagnosed patients, according to a Johns Hopkins statement describing the study.

Biopsy samples are collected using an “intensive procedure,” but one that is “safe and well tolerated,” said Kittleson. Of more than 1,200 biopsies performed in 16 years, only one or two deaths resulted, she said.

However, cancer literature suggests that profiles obtained from serum can be “correlated with things you can obtain from solid tumor,” so Kittleson and her colleagues have begun a project to determine whether they can get similar results from blood samples, she said. Results will not be available for “about another year,” she added.

The profile needs validation in a greater number of patients before it can be transformed into an etiology-specific chip for cardiomyopathy that could “absolutely have clinical relevance,” said Kittleson. “To make our technique more clinically feasible, we performed [RNA extractions] on whole tissue only, meaning it would be a much easier technique if it is ever extrapolated to a clinical setting.”

Based on the study’s results, the group demonstrated that it is feasible to produce a chip that can guide prognosis following heart failure, said Kittleson. “That is one of the other, next steps we’re doing in our research [working] to develop a profile that can distinguish patients, not just by the etiology of disease, but by their ultimate prognosis,” she said.

The group has not been contacted by any pharmaceutical or molecular diagnostic companies regarding a commercial product.

Ischemic heart failure is a condition in which blood flow is reduced by weakened heart muscle or through heart disease. Non-ischemic heart failure is caused by a variety of conditions, including enlargement due to physical deformity or alcohol abuse.

— CW

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