Researcher's study of heart proteins targets disease of the young
During a routine football scrimmage to start the season, a seemingly healthy 14-year-old player collapses. He dies less than two hours later. The local medical examiner later rules that the boy died from "natural causes" because he had an enlarged heart.
The death of this football player, which occurred in Houston in 2001, and similar deaths of young athletes can often be attributed to hypertrophic cardiomyopathy (HCM), the most common cause of heart-related sudden death in people under 30. Ongoing research at the University of North Texas is targeting HCM and its underlying causes.
"We're trying to understand the processes by which the disease works," says Douglas Root, UNT associate professor of biological sciences. "This understanding will provide a theoretical basis for developing therapies and diagnostics for this illness."
Root's research is supported by grants from the National Institutes of Health and by funding from the American Heart Association. With the assistance of a group of graduate and undergraduate students, he is studying the interaction of proteins responsible for heart muscle contraction. Mutations in the genes of these proteins are responsible for HCM.
"When we understand the mechanism of muscle contraction and its regulation at the atomic level, it will be possible to have a model that includes the molecular changes known to give rise to this disease," Root explains.
Such a goal would have two benefits, he says.
"We would be able to see how the hundreds of mutations are related, thereby clarifying routes to therapies, and genetic profiles could be analyzed as a diagnostic tool to determine if a patient carries mutations that could cause the disease," he says.
Focusing on proteins
What, then, is this disease that can end a young life seemingly without warning?
A person with hypertrophic (enlarged) cardiomyopathy (disease of the heart muscle) experiences a thickening of the septum, or wall, of the heart over time. This thickening -- caused by an increase in the size, not number, of cardiac muscle cells and most frequently occurring in the left ventricle, or lower chamber -- stiffens the heart wall, decreasing the efficiency with which the heart pumps.
In some cases, Root says, the heart can go into sudden cardiac arrest. The process that causes this arrest is not well understood. Some researchers point to a chaotic heart rhythm known as ventricular fibrillation as a cause of death. By most estimates, about 0.2 percent of the population has HCM, and heredity is a factor in a large majority of the cases. The disease occurs equally in both sexes and across races.
In his research laboratory, Root and his assistants are focusing on myosin and actin, two proteins that bind to one another and affect the contraction of the heart.
"The disease can result from any of more than 150 mutations that can affect these proteins and several other proteins responsible for regulating contraction," he says.
He says his work is not made any easier by the fact that more mutations are constantly being discovered.
"Understanding the function of proteins at the molecular level would enable us to say that this change or that change is likely to give rise to the disease," Root says.
Using sophisticated microscopic, spectroscopic and biochemical techniques, Root's team is able to observe single molecules of proteins.
"We can dilute myosin down to a low concentration and add it to a surface coated with actin," he explains. "When the two proteins bind, we can tag the myosin fluorescently and watch the physical or structural characteristics of that myosin. We can narrow down which part of the molecule is giving rise to the response we're seeing. If that's a hot spot for mutations that give rise to HCM, then we can say mutations in that region are likely to affect the myosin molecule important to the mechanism that contracts the heart."
HCM is often undiagnosed until it's too late. Those who die from the condition usually don't know they have it. Symptoms -- including shortness of breath or fatigue upon physical exertion, rapid heartbeats, dizziness and fainting, and occasionally chest pain and cardiac arrhythmias (abnormal heart rhythms) -- are often ignored. Even the characteristic thickening of the heart is not always due to HCM; ironically, the ventricle wall can become harmlessly enlarged due to physical conditioning.
Doctors may use echocardiography, which employs ultrasonic waves to visualize structural and functional abnormalities of the heart, to examine patients with such symptoms. The procedure can easily detect thickening in the wall of the ventricle. If the condition is found to be a result of HCM, family members can be genetically screened and those with mutations advised to make appropriate lifestyle changes, such as avoiding strenuous exercise or rigorous athletic competition, to minimize their risk.
"Most people," Root says, "can live a normal life with HCM."
Treatment varies with the severity of the condition. For some, medications such as beta blockers and calcium channel blockers, which help relax the heart and reduce the degree of obstruction, are effective in maintaining proper cardiac function; anti-arrhythmic drugs may also be used.
A recently developed technique for treating the disease is alcohol ablation, which involves injecting alcohol directly into an artery that supplies blood to the extra muscle, resulting in the destruction of the muscle. It's still considered experimental. Some cases require more drastic intervention -- myectomy, or surgical removal of the extra muscle. Pacemakers, implantable defibrillators and even heart transplants are also possibilities.
Root says one of the goals of his research is to provide a basis for developing new therapies for HCM.
"If we find a common molecular mechanism affected by the variety of mutations that give rise to this disease, then it will become clear which aspects of muscle biochemistry should be targeted with drugs to ameliorate the condition," he says.
Help for other diseases
Happily, Root's research will have applications for other muscle diseases such as other cardiomyopathies, nemaline myopathy (characterized by extreme muscle weakness) and muscular dystrophies.
"These are all diseases that require understanding of muscle protein mechanisms at the atomic level," says Root.
Protein research, he believes, can unlock the mysteries of any number of diseases.
"A detailed understanding of proteomics (the cataloging of the identities, quantities, structures and function of proteins) can be critical to the handling of genetic diseases," he says. "While we have the sequence of the human genome, the 33,000 genes encode a large variety of protein structures. Until we understand how those structures function, it will not be possible to harvest all of the potential benefits from that DNA code."