DREAM CAMPAIGN SUPPORTS 11 RESEARCH FUNDING PRIORITIES
Duke Dream Campaign Podcast
Brain Injury in the Animal Model of Cardiac Surgery
Burkhard Mackensen, MD
Hello I’m Elizabeth Perez and welcome to the Duke Dream Campaign Podcast.
We are here today with anesthesiologist and researcher, Dr. Burkhard Mackenson. Dr. Mackensen is currently an associate professor of anesthesiology and director of the cardiopulmonary bypass research laboratory here at Duke University Medical Center. His major research focus is finding potential strategies for therapy related to brain injury after heart surgery. We will be discussing Dr. Mackensen’s current research endeavor, Brain Injury in the Animal Model of Cardiac Surgery, which is part of the 11 funding priorities of the Duke DREAM Campaign.
The name of this study indicates that you are going to be using an animal model to study brain injury after heart surgery in human beings. How do you plan to do this?
This study utilizes an established rodent model of heart surgery and modern genetic analysis techniques to identify genes and gene-associated mechanism that may help to understand how to better protect the brain tissue from damage during heart surgery. Major surgeries to the heart or to the large arteries arising from the heart utilizing the heart-lung-machine and deep hypothermic circulatory arrest (DHCA) are among the most common surgical procedures in the world, with over 500,000 performed in the U.S. alone. Patients undergoing these procedures are prone to a spectrum of neurological complications ranging from neurologic injury such as stroke to cognitive dysfunction resulting in prolonged hospitalization, increased morbidity and mortality as well as increased overall health care costs.
Why use a rodent model?
There are several reasons for using a rodent model. First of all, it would be difficult to obtain any human brain tissue to study after heart surgery. Secondly, in the past, people have used larger animals that were quite expensive and cumbersome to use. This is why we have developed some rodent models that undergo principally the same procedure you would see in an operating room with human patients. Therefore these models allow us to not only mimic what is happening in the operating room but we also can study their behavior, meaning these animals are actually quite intelligent animals that can learn and be trained as well. We then study how their brain functions after surgery and then eventually we can get access to tissue and then use that tissue to use on our genetic analysis.
The study says you are going to study neurological and cognitive injuries. Can you explain to us the difference between neurological injury and cognitive injury?
Neurological injury may simply be described as major damage to the brain such as a stroke or a coma. Patients experiencing a neurologic injury might be unable to move one half of their body, will have difficulty to walk and possibly have problems with speech. Cognitive injury might be described as a more subtle damage to the brain which affects the way a patient thinks or processes information. Patients who experience a cognitive decline suffer from memory loss, slurring or loss of speech.
Specifically, what kinds of cognitive and neurological injuries are common in heart surgery patients?
Brain injury after heart surgery describes a wide spectrum of disorders, from frank stroke or coma to confusion and memory loss and varies considerably depending upon the type of injury as well as the risk status of the patient. The overall stroke rate in the analysis of large cohorts is approximately 1-3%. Far more common than neurologic injury, is cognitive decline after heart surgery. As can be appreciated from a longitudinal study done by our group, the early incidence at discharge ranges as high as 53%, decreases to around 40% at 6 weeks and drops further to 24% at one year. However long-term studies such as our study have demonstrated that this cognitive loss is not temporary but indeed may persist up to five years after heart surgery where the incidence has been reported to be over 40%.
How do these injuries affect the daily lives of these patients?
Neurological injuries may restrict the patients in their ability to function independently or to return to work. Although cognitive decline may appear not as dramatic and devastating as neurologic injury, it too has been associated with a decreased quality of life, inability to return to work and depression. In elderly patients, cognitive decline has been linked to loss of independence and even death. In summary, little is more devastating to a patient, the patient's family or those caring for a patient than to have a successful operation that prolongs life, but diminishes the quality of that life.
If a patient makes the decision to undergo heart surgery, why would they be at risk for brain injury?
One has to differentiate between the patients’ own risk factors coming into the operation and risk factors that relate to the operation itself. Main risk factors on the patients’ side include age and preexisting diseases such as high blood pressure, diabetes, a previous neurologic injury or atherosclerosis. Surgical risk factors include the type and length of the operation and the number of bypass grafts placed by the surgeon.
Besides these risk factors, are there any other causes of brain injury after heart surgery?
Current thinking is that a combination of very small particles that circulate into the brain and insufficient blood flow to the brain during surgery are contributing factors. Others include exposure to the foreign surface of the heart-lung machine, the inflammatory response, swelling of the tissue and the so-called ischemia-reperfusion injury caused by lack of oxygen associated with heart surgery. There also are strong indicators that certain genetic factors place patients at higher risk for suffering injury.
Can you explain to us what ischemia is?
Ischemia basically means that there is no blood flow and therefore there is no oxygen delivered to the tissue in this case the brain. It is thought that there are periods of time during surgery when the brain suffers from ischemia, or lack of oxygen.
In going back to the animal model, you said that this study will use different breeds of rats. Why not just use one breed?
These different strains of rats were chosen to better represent the variability in gene expression patterns in humans. For example, we have selected stroke-prone rats with high blood pressure and the other rats that are prone to the development of plaque of their blood vessels. These rat strains resemble those of the heart surgery population in 2007 - namely; high blood pressure, cerebro-vascular disease, high cholesterol, diabetes, kidney disease and obesity. We believe it is important to provide host animals that reproduce the human condition as closely as possible when modeling a disease process, and both of these strains represent a much closer resemblance to patients undergoing heart surgery.
How will a genetic analysis help you to understand these kinds of injuries in heart surgery patients? Aren’t genetics and surgery two completely separate fields of medicine?
Despite the fact that surgery and genetics are complete separate fields of medicine, they definitely have a lot of overlap as well. As mentioned before, the genetic composition of a given patient may predispose this patient to a higher or lower risk of suffering a brain injury during surgery. Our genetic analysis should allow us to identify key genes and networks of genes that are associated with the brain injury that then could be genetically or pharmacologically modulated.
Now in this study, you are going to be silencing genes to better understand the function of the genes and how to use them in therapy. Can you explain to us what selective gene silencing is?
Gene silencing is a general term describing a processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification. That is, a gene which would be expressed (turned on) under normal circumstances is switched off by machinery in the cell. Once our genetic analysis has identified target genes that appear to be highly important and turned on, we would then utilize gene silencing in the animal to affect specifically that particular gene to confirm its importance and ideally improve brain function after surgery.
After completing this research project, say you determine that genetic factors do influence brain injury in rats, how can you translate this discovery to help in the treatment of human patients?
This is a very important question. The animal models we are utilizing in these studies are clinically relevant in that they are mimicking the conditions in the operating room as closely as possible. Still, translating our findings to the human will likely require confirmation of our findings in a larger animals such as pigs or dogs or will lead to development of certain drugs that first need to be tested in animals before they can make their way to the human.
The DREAM Campaign has a goal of raising $180,000 for this research project. Is $180,000 enough to complete this project?
It will most likely not be sufficient to complete the project. It will certainly help us to get started with the project until a later stage when we could use some of the preliminary data obtained with these studies to obtain additional funding. This money would also help us to bridge during times when it is difficult to obtain funding from federal agencies such as the National Institute of Health.
Thank you for listening to the Duke Dream Campaign podcast. Special thanks Tom Freeland and to our producer, Cindy Cho. For more information about this research project or how you help this featured research project come through fruition, please visit us at http://dreamcampaign.duhs.duke.edu or call (919) 681-2849.
Disclosure: This recording and other materials in this Podcast are not statements of advice, opinion or information of Duke University Health System or Duke University. If you feel you might be offended by the content, you should not continue listening. If you have any questions about the services or programs offered at the Duke University Medical Center or you would like to schedule an appointment with one of our physicians, please call 1-888 ASK DUKE or visit healthview.dukehealth.org.
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If you are interested in becoming a donor to the Duke Dream Campaign, please contact Elizabeth Perez at 919-681-2849.