Mechanical Support Induces Genetic Changes in Failing Hearts

Using new DNA microarray technology, 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.” From the Duke University Medical Center:Mechanical Support Induces Genetic Changes in Failing Hearts

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.

contact sources : Burns Blaxall , (919) 684-6361
Burns.Blaxall@duke.edu
Walter Koch Ph.D. , (919) 684-3007
koch0002@mc.duke.edu


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