05.08>> Preconditioned Hearts    
Exercise for the Heart  

Approximately 5 million Americans are living with heart failure and nearly 600,000 people die of heart failure every year in this country. Heart failure, or cardiac failure, means that the heart isn’t pumping as well as it should. As a result there is reduced blood flow to the heart. The heart needs to pump blood in order to deliver oxygen- and nutrient-rich blood to all cells in the body. When the cells are nourished properly, the body can function normally. When the cells do not have enough blood, such as with heart failure, a person will feel tired, get short of breath easily and everyday activities such as walking, climbing stairs or carrying groceries become hard to do.

Let’s discuss the heart in more detail. The heart cannot sustain itself for long with low blood flow, and will die when exposed to low blood flow for an extended period of time. The condition of reduced blood flow to the heart is called ischemia.

When the body senses low blood flow, the heart tries to compensate by increasing blood flow. It can be increased two ways: by having your heart beat more times a minute (increasing your heart rate), or by increasing the force of each beat or contraction. These mechanisms can work for a while, but usually they cause the heart to enlarge, or hypertrophy. An enlarged heart can result from numerous body conditions. Two of the leading ones are high blood pressure and obesity. The hearts of patients with high blood pressure or obesity will eventually hypertrophy because of the increased blood pressure needed to pump blood around the body.

In a hypertrophied heart, heart cells will die. When they die, they are replaced by scar tissue that cannot contract like normal heart cells. As a result, the heart muscle becomes stiffer and stiffer as scar tissue builds up over time. Eventually the heart will not be able to contract properly and the patient will experience cardiac failure, and even a heart attack.

Once a heart has hypertrophied it may be months, years, or decades before cardiac failure ensues, but no matter how long it takes, cardiac failure is the next step after hypertrophy.

What can we do to protect a hypertrophied heart?

Almost three decades ago, a technique called preconditioning was proposed to protect hypertrophied hearts from cardiac failure. In the same way that you build up strength as you exercise over time, the heart muscle builds up resistance to ischemia (reduced blood flow). Hearts that recover from ischemia appeared to be more resistant to further ischemia, so the idea was to condition the heart to adapt to ischemia and thus survive for longer periods of time. In the decades since the idea was first proposed, much research has gone into what makes preconditioned hearts able to withstand long periods of ischemia.

Dr. Karyn Butler, Associate Professor of Surgery in the Division of Trauma and Critical Care at the University of Cincinnati, has recently made a significant breakthrough in identifying a specific mechanism associated with preventing ischemia in hypertrophied hearts. In particular, she investigated the JAK-STAT pathway. JAK-STAT stands for Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT). The details of this intimidating-sounding pathway are beyond this What A Year! story: for now what we need to know is that the pathway has been identified in many different cardiac functions or diseases. In particular, studies have shown that parts of the JAK-STAT pathways are activated during ischemia.

Dr. Butler is both a surgeon and a researcher specializing in cardiac biology. She has been interested in the preconditioning of hypertrophied hearts for many years. She wanted to know what specific proteins were involved in the increased resistance to ischemia in hypertrophied hearts. One goal at some time in the future is to develop a drug that might assist the JAK-STAT pathway in protecting people’s hearts.

The lab setup that mimics the function of the cardiovascular system.To study ischemic preconditioning, Dr. Butler first needed an animal model of an enlarged heart. She began by feeding rats a high-salt diet for two weeks to induce high blood pressure, and eventually, cardiac hypertrophy developed in these animals. Once hypertrophied, the hearts were studied ex vivo, or outside of the body. In order to study the function of the heart, Dr. Butler uses a machine that mimics the cardiovascular system, pumping a solution through the heart to keep it functioning. Using this system (shown above), Dr. Butler can simulate ischemia by stopping the flow of solution to the heart.

Diagram of the preconditioning tests.
Courtesy of Garret Gross, PhD

To test the idea of preconditioning, Dr. Butler stopped the flow of solution briefly (5 minutes) prior to stopping it for a longer period (30 minutes). After this preconditioning, the flow to the heart was restored. Dr. Butler then examined the post-ischemia hypertrophied heart function and the heart tissue itself. She compared it to post-ischemia hypertrophied hearts that had not been preconditioned (control hearts). Dr. Butler found that rats whose hearts were preconditioned had less infarcted (= dead) tissue compared with control hearts, as shown in the figure above. [Note: reperfusion is the return of blood flow to the heart after ischemia.]

Next, Dr. Butler tried to find the protein that had been activated by the hypertrophied heart and that could therefore be responsible for reducing heart damage. These experiments helped Dr. Butler identify a protein in the intracellular signaling JAK-STAT pathway, shown in the figure below. She and her team identified the protein called STAT3, as being activated in hypertrophied hearts after preconditioning. In contrast, STAT3 was not activated in the hearts from control animals. She identified this as an important step in the mechanism that leads to preventing damage from ischemia, called ischemia resistance.

Stress Stimuli Diagram

The next step was for Dr. Butler to study animals without the STAT3 protein, called STAT3 “knock-out” animals. By observing how hypertrophied hearts of animals without the STAT3 protein fare during ischemia, Dr. Butler hoped to gain broader insight into the particular role of this protein in strengthening hypertrophied hearts.

“This is an important step along the way,” said Dr. Butler, “but there are many more steps left before we can fully identify this complicated pathway that is crucial to heart function.” Dr. Butler demonstrated that STAT3 was a key player in preconditioning by using knock-out animals as well as animals given a drug to inhibit the JAK-STAT pathway. Both of these animals responded just like controls – they could not deal with ischemia and had larger areas of infarcted tissue. In contrast, preconditioned animals responded to ischemia by increasing STAT3 protein, and decreasing the size of damaged cells. As a result, preconditioning was shown to improve heart function.

How Will This Help?

Dr. Butler’s research has identified a key component of the pathway. In addition, she has shown that preconditioning the heart is helpful in protecting hypertrophied hearts from further damage. This practice of preconditioning may be used in hospitals during heart operations such as cardiac bypass surgery. It is hoped that one day a drug such as an activator of the JAK-STAT pathway can be used to precondition hearts as a way of protecting them.

Dr. Karyn Butler is an Associate Professor of Surgery at the University of Cincinnati specializing in trauma and critical care. She splits her time between performing surgeries and doing research. She notes that her career took a different path than she imagined as a kid. In high school, Dr. Butler had planned on becoming a veterinarian, but sickness in her family changed her mind and she decided to go to medical school. After medical school, residency and specialized training in trauma and critical care, she was offered a job at the University of Colorado where she was exposed to cardiovascular research. “I absolutely loved research,” said Dr. Butler. “I knew this is what I wanted to do. I love combining research and clinical medicine as a career!”



Beating Heart
Medical Illustration Copyright © 2008 Nucleus Medical Art. All Rights Reserved. www.nucleusinc.com

Photo of Dr. Kayrn Butler
Dr. Karyn Butler

Photo of Dr. Butler's tem in the lab
Dr. Butler and her lab team. [enlarge]

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May 2008
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What A Year! is a project of the Massachusetts Society for Medical Research.

And it is funded by a grant from The William Townsend Porter Foundation.


To Learn More

  • Karyn Butler, Alice Huang, and Judith Gwathmey. "AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium." American Journal of Physiology. Heart and Circulatory Physiology (1999): 2482-2487.
  • Karyn Butler, Lynn Huffman, Sheryl Koch, Harvey Hahn, and Judith Gwathmey. "STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium." American Journal of Physiology. Heart and Circulatory Physiology 291(2006): 797-803
  • Lynn Huffman, Sheryl Koch, and Karyn Butler. "Coronary effluent from a preconditioned heart activates the JAK-STAT pathway and induces cardioprotection in a donor heart." American Journal of Physiology. Heart and Circulatory Physiology 294(2007): In press.
  • Bolli, Roberto, et al. "Myocardial Protection at a Crossroads: The Need for Translation Into Clinical Therapy." Circulation Research 95(2004): 125-134.
  • Roberto Bolli, Dawn Buddhadeb, and Yu-Ting Xuan. "Role of the JAK-STAT Pathway in Protection Against Myocardial Ischemia/Reperfusion Injury." Trends in Cardiovascular Medicine 13(2002): 72-79.
  • Meldrum, Daniel. "Mechanisms of Cardiac Preconditioning: Ten Years after the Discovery of Ischemic Preconditioning." Journal of Surgical Research 73(1997): 1-13.

For More Information About the Heart:

Rebecca Kranz with Andrea Gwosdow, Ph.D. Gwosdow Associates



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