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Childhood cardiomyopathy is relatively rare. However, infants are eight times more likely to contract the disease than children ages 1 to 18. Viral infections and genetic abnormalities of the heart are leading causes of the illness, although it also occurs as an unwanted side effect of chemotherapy in children being treated for cancer. While some symptoms can be controlled with drugs, many patients eventually require a pacemaker, or even a heart transplant, to survive.
Now, physicians, molecular biologists, geneticists, and other scientists at the Stanford Cardiovascular Institute are looking for new ways to treat pediatric cardiomyopathies. Their goal is to combat the disease at the cellular level with new drugs that block or stimulate key proteins that regulate every beat of a child's heart.
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| After collapsing while running, 14-year-old Joelle Earl had a heart transplant to treat his cardiomyopathy, caused by a previously undiagnosed heart defect. |
In cardiomyopathies, the heart muscle is either too weak or too rigid to work effectively, says Daniel Bernstein, MD, the Alfred Woodley Salter and Mabel G. Salter Endowed Professor of Pediatrics and codirector of the Packard Children's Heart Center.
To find the root cause of the disease, Bernstein's lab focuses on beta-adrenergic receptors -- proteins on the surface of heart muscle cells that are responsible for communicating signals from the stresshormone adrenalin.
Adrenalin controls events inside the heart muscle cell by interacting with beta receptors on the cell's surface, like a key fitting into a lock. If the lock and key match, then enzymes in the cell are immediately activated, causing the heart to pump harder and faster. "Working the heart for brief periods of time is healthy, as in routine exercise," Bernstein notes. "But prolonged stimulation actually can destroy heart tissue."
It turns out that many cardiomyopathy patients have extremely high levels of adrenalin in their bloodstream, which may exacerbate damage to the heart muscle. For years, doctors have been treating these patients with a class of drugs called beta blockers, so named because they block the adrenalin "key" from fitting into the beta receptor "lock."
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| A measure of heart muscle strain of healthy child (left); patient with caradiomyopathy (right). |
But Bernstein believes there is much more to the story. "There are two subtypes of beta receptors on the surface of the heart muscle cell called beta 1 and beta 2," he explains. "The beta blocker most commonly prescribed blocks both receptors, but no one has been able to separate out their different effects. There is some evidence that beta 1 receptors may be responsible for the deleterious effects of adrenalin, whereas beta 2 receptors may actually protect the heart. It may be that certain types of heart failure should be treated with beta 1 blockers in combination with drugs that stimulate beta 2 receptors to maximize the beneficial effects."
Bernstein and his colleagues are conducting laboratory experiments designed to tease out the different functions of beta 1 and beta 2 receptors, with the goal of finding drugs that will more effectively treat heart failure.
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| Cardiologist Dan Bernstein, MD, Packard patient Camila Gonzalez, and her mother. At 22 months, Camila was the youngest child in the U.S. to receive a donor's heart while also retaining her original one -- a procedure called a "piggyback" transplant. |
The research team also is interested in the role that genetics plays in diagnosing and treating children with heart failure. Our DNA contains six billion molecules called nucleotides, famously known as G, A, T, and C. In patients with cardiomyopathy, a seemingly minor change in the nucleotide sequence -- a G replaced with an A, for example -- could dramatically influence the course of the disease, alter the patient's response to beta blockers, and even affect the likelihood of survival.
Bernstein and his co-workers at the Cardiovascular Institute have begun collecting DNA samples from all Stanford cardiomyopathy patients -- adults and children -- to determine if there is a correlation between the patient's nucleotide sequence and his or her response to different treatments. "Perhaps one day soon we'll be able to prescribe specific drugs tailored to individual patients," he says.
"What's valuable about the Cardiovascular Institute is having the ability to do innovative research like this at a great medical school with a great university next door," he says. "My collaborators are adult cardiologists, physiologists, geneticists, pharmacologists, and biomedical engineers. It wouldn't be possible to do this work in isolation."
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