Pump it Up
Researchers study how the heart pumps to help kids avoid heart failure
Dr. James is a cardiologist and researcher in the Division of Cardiovascular Molecular Biology at Cincinnati Children’s and associate professor in the Department of Pediatrics at the University of Cincinnati College of Medicine.
Learn more about Dr. James’ research.
Although more children with congenital heart defects survive heart surgery, some can be left with circulation problems that keep them from enjoying active lives and may even lead to heart failure.
Pediatric cardiologist and researcher Jeanne James, MD, wants to get to the bottom of why this happens. Her team’s research on how heart muscles contract is helping scientists understand heart failure and the role proteins play in heart function.
Dr. James and her team in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s are defining the critical events on the road to heart failure. They want to determine where and how physicians can intervene to slow or stop the debilitating process. One key is heart proteins.
What Does a Pumping Heart Need?
Contractile proteins are the catalysts that make heart muscle squeeze. “The workhorse of the contraction process is called myosin heavy chain, which occurs in two isoforms, alpha and beta,” Dr. James explains. “Scientists believed that beta-myosin was the more essential and energy-efficient of the two, so when the heart’s motor was stressed, the heart would jettison the alpha-myosin to keep pumping.”
She wanted to learn how important alpha-myosin really is to the heart’s function. What would happen when the alpha- and beta-myosin heavy chain isoforms were switched in a relevant animal model?
To find out, the team used transgenic rabbits designed to hold on to alpha-myosin when their hearts were failing. They induced cardiomyopathy in the three most common ways it occurs in children and adults: tachycardia, myocardial infarction and left ventricular pressure overload.
“Using transgenic techniques, we determined that there is no detrimental consequence to keeping the alphamyosin around,” Dr. James says. “It doesn’t cause pathology, even looking out three to four years.”
Different Causes, Different Failures
Interestingly, different causes of heart failure produced varying results. “Our hypothesis was that the rabbits with tachycardia would do worse, but in fact they did significantly better than we anticipated. This debunks the theory that the heart gets rid of alphamyosin to preserve function. We found that the heart can produce what it needs to run its motor even under heart failure,” Dr. James explains. These results were published in the journal Circulation in 2005.
In the rabbits with infarction, researchers discovered that heart function remained the same, whether the alpha- or beta-myosin was switched on. “There was no difference in either the heart’s structure or its function, nor did persistence of the alpha isoform hurt the heart. This is significant because there’s some commercial interest in developing myosin activators to make the beta isoform act more like alpha,” Dr. James reports.
Banding the aorta to induce pressure overload of the left ventricle also did not produce any noticeable differences in heart function, Dr. James says. “We’re working now to tease out why that’s so.”
One of the most significant findings of her studies is that not all heart failures are created equal. “It’s likely the molecular mechanisms of failure are different based on the stressors that caused it,” she says. “This means new drugs and treatments may need to consider both the age of the patient and the underlying cause.”
Up Next: The Role of Misfolded Proteins
Years of research by Dr. James and her team have helped to put to rest the theory that heart failure could be rescued by shifting myosin heavy chains. Now they’re beginning to study the role that misfolded proteins, called preamyloid oligomers, play in heart failure.
“Misfolded proteins clump up inside the cell and may interfere with its function,” Dr. James explains. She notes that they’re present in many types of tissue throughout the body and are associated with Alzheimer’s and other diseases. Scientists first discovered them in adults with heart failure and speculated that they took years to develop.
To understand how misfolded proteins might affect children, Dr. James and her team are examining failed hearts removed from children who had a heart transplant. “We’ve found misfolded proteins in these diseased hearts, some from very young patients,” Dr. James says.
“So now we know that misfolded proteins can develop very quickly. Eventually, we want to determine if we can prevent them from forming in the heart — or if we can dissolve them — to rescue a failing heart.”
