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Unlocking the mystery of cardiovascular disease is the focus of intense research across the globe. Despite amazing advances, heart disease remains the number-one cause of death in the United States.
In his busy research laboratory at Indiana Center for Vascular Biology and Medicine (ICVBM), cardiac surgeon Daniel Meldrum and his team are trying to uncover the underlying mechanisms at work in heart disease, zeroing in on the action of one particular protein called tumor necrosis factor (TNF). An inflammatory protein, TNF is elevated after acute episodes--heart attack, stent placement, heart transplant--and during chronic heart diseases, such as congestive heart failure. Researchers believe that TNF may be a major culprit in the progression of heart failure.
By determining the role of TNF, Dr. Meldrum eventually hopes to develop novel drugs to block the production of the protein during ischemic conditions such as heart attacks and heart surgery, thereby helping to treat heart failure. To learn more about TNF and his promising research into organs for transplant, NHW spoke with Dr. Meldrum, an assistant professor in the departments of surgery and physiology at Indiana University School of Medicine and an ICVBM investigator.
NHW: What is the focus of your research at ICVBM?
DM: Basically, we are looking at ways to protect the heart during what is referred to as ischemia reperfusion injury, or reduced blood flow to the heart. Conditions that cause no or low blood flow to the heart include heart attacks, heart surgery, heart transplantation, and trauma--such as from an automobile accident that causes severe hemorrhage. Since heart disease is the leading cause of death among both men and women, this is an important area of research.
My research specifically focuses on how TNF is produced by the heart, and on developing ways to inhibit its production. TNF is a key component that injures the heart during heart attacks and heart surgery.
To better identify the mechanisms at work, we are investigating human tissue during heart surgery. With internal review board (IRB) approval, we are studying the function of portions of the heart discarded during surgery. If successful at identifying the mechanisms at work, we may be able to produce a drug more specific for human TNF production in acute low-blood states.
Low blood flow occurs and causes damage in other organs as well, and we are comparing the pathways of TNF-mediated injury in the kidney, heart, brain, and lungs. A big problem in patients with heart disease, for example, is poor kidney function and increased risk of stroke. The conditions go hand in hand.
NHW: Is TNF production a natural response?
DM: It's a natural response. The heart produces substances during low blood flow that results in injury to the organ itself. The heart produces the protein TNF, even though it may be bad for it. Why the heart produces a substance that hurts it during a heart attack is unknown.
NHW: How can you block the production of TNF?
DM: First, we are looking at the mechanisms of how the heart produces TNF. Many signaling proteins are turned on in the TNF production process, and we are looking at these pathways to identify potential targets of inhibition. We want to find the best way to inhibit the production of TNF during ischemia to prevent ischemia reperfusion injury.
NHW: Could you discuss your research into the development of an immunologically neutral heart for transplant?
DM: TNF plays a role in this research as well because the inflammatory protein is part of the body's immune response. When an organ is rejected, the body produces a lot of TNF. There is a heightened immune response to non-self organs because of certain receptors on the donor organ that identify the donor organ as "non-self.' We are working on producing cells that do not have these receptors that the body would recognize as non-self. If we can get rid of those receptors and produce organs minus the genetic code for those receptors, we will have an immunologically neutral organ that can be universally transplanted. That is the long-term goal of my research.
In the infant stages, there is small, but exciting, progress each year. It is a very slow process to create a whole organ that is immunologically neutral. But if we are able to develop a neutral organ for transplant, a person with severe heart disease may just get a whole new heart. The supply of donor organs would be unlimited. Learning the complete genetic code certainly represents a great advance because we can now identify each genetic component of each individual. With a perfectly matched, immunologically neutral organ, someone could immediately acquire a heart. There would no longer be a wait list.
Research is the key to discovering better ways to care for patients and improve their quality of life. For information about making a tax-deductible gift, contact me at 317-2780130, or e-mail: kmarch@iupui.edu.
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