Novel Approach May Protect Against Heart Attack Injury

Manipulating the cell activity that occurs during an ischemic interruption of blood flow could potentially become a protective emergency treatment option for heart attack patients.

Researchers at The Children's Hospital of Philadelphia (CHOP, PA, USA) and the University of Pennsylvania School of Medicine (UPENN, Philadelphia, USA) examined a family of drugs called histone deactylase (HDAC) inhibitors (which alter the way DNA is packaged within cells, as well as modifying the function of other proteins) in mice with induced heart damage. The researchers found that HDAC inhibitors prevented ischemia-induced activation of gene programs that include hypoxia inducible factor-1alpha, cell death, and vascular permeability in vivo and in vitro. The researchers found that the HDAC inhibitors reduced the area of the myocardial infarction (MI, the area of dead tissue caused by obstructed blood flow) by more than half.

In investigating how the HDAC inhibitors worked, the researchers discovered that the HDAC's blocked gene pathways that led to cell death and ischemia-induced vascular permeability. They also identified a specific molecule, HDAC4, as the likely HDAC enzyme with the most critical role in affecting how cells respond to ischemia. Since the protective effect of HDAC inhibitors may occur even after the initial blockage of blood flow, potential therapies based on the study may lead to an emergency treatment following a heart attack. In addition, because open-heart surgery for both children and adults requires a period in which the heart is stopped, such treatment might also protect tissues from the adverse effects of interrupting blood flow during surgery. The findings may also help extend the time window for cardiac transplantation, which at four to six hours after blood flow stops is much shorter than that required in transplanting other organs, such as kidneys or livers. The study was published online on July 7, 2008, in the journal of the Federation of American Societies for Experimental Biology (FASEB).

"Reduced blood flow, or ischemia, is a major problem in many organs, where it can lead to cell death and tissue damage,” said lead author Peter J. Gruber, M.D., Ph.D., a cardiothoracic surgeon at CHOP and UPENN. "These results demonstrate that HDAC inhibitors alter the response to ischemic injury in the heart and reduce infarct size, suggesting novel therapeutic approaches for acute coronary syndromes.”


Related Links:
The Children's Hospital of Philadelphia
University of Pennsylvania School of Medicine