Jan. 16, 2001 ANN ARBOR --- The same protein that helped Maurice Greene become the "world's fastest man" at this summer's Olympic Games in Australia could one day help millions of Americans who suffer from a common type of progressive heart failure, according to a new animal study by scientists at the University of Michigan Medical School.
This protein, called parvalbumin, helps skeletal muscle fibers in the arms and legs contract and relax rapidly and efficiently. Olympic sprinters have high levels of parvalbumin in their skeletal muscle, which helps explain why they can run faster than the rest of us, according to Joseph M. Metzger, Ph.D., associate professor of physiology and of internal medicine in the U-M Medical School. Parvalbumin works like a sponge helping skeletal muscle cells relax faster by soaking up calcium ions.
In a study published in the Jan. 15 issue of the Journal of Clinical Investigation, Metzger and a team of U-M researchers show for the first time that parvalbumin also can improve heart function in laboratory rats---restoring normal relaxation rates in hearts with a condition that mimics the abnormally slow cardiac relaxation common in human heart failure.
"Although important and challenging scientific obstacles remain, our findings raise the intriguing possibility of one day using parvalbumin therapy to treat progressive heart failure in humans," Metzger says.
Exacerbated by high-fat diets and not enough exercise, heart failure is a growing medical problem affecting approximately five million Americans, with more than 700,000 new cases reported each year. About 40 percent of the time, heart failure is associated with a condition called diastolic dysfunction where the heart contracts normally, but doesn't relax fast enough to allow the cardiac chambers to fill with blood before the next contraction. "In a healthy, living heart all cells work together like an orchestra with one conductor," Metzger says. "In a heart with diastolic dysfunction, the cells relax too slowly, so the heart pumps inefficiently and body tissues are starved for oxygen."
The gene for parvalbumin is found in every cell in the body, but it is not naturally activated or expressed in heart muscle cells. To test the protein's ability to relax cardiac muscle, U-M researchers used a common adenovirus to deliver human parvalbumin genetic material into heart cells of laboratory rats used in the study.
In three separate experiments, all reported in the Journal of Clinical Investigation article, U-M researchers found that:
* When human parvalbumin was injected into the left ventricle of the heart, cardiac relaxation speed was significantly faster than in control animals that did not receive the gene.
* Pressure measurements inside the left ventricle confirmed that rats receiving parvalbumin injections had a much faster relaxation time than control rats.
* Echocardiograms showed that the time interval from aortic valve closure to mitral valve opening in rats receiving parvalbumin was shorter than in control rats.
* Parvalbumin restored normal cardiac relaxation rates in an experimental animal model with the same type of slow relaxation found in human heart failure.
"This was a proof-of-principle, short-term study," Metzger says. "Since adenoviral vectors elicit an immune response after about six days in animals, they aren't suitable for this application in humans where parvalbumin must be expressed for long periods of time. There are many new adenoviral-related vectors in development, however, which could be just as effective without provoking an immune response."
The U-M study was funded with grants from the American Heart Association, the National Institutes of Health, the Culpepper Foundation and the U-M Center for Integrative Genomics. The U-M has applied for a patent on the technology.
Michael Szatkowski, M.D., a senior research fellow in the U-M Medical School and a neonatology fellow at Thomas Jefferson University in Philadelphia, is first author on the paper. Other U-M collaborators include Margaret V. Westfall, assistant professor of physiology and surgery; Carly A. Gomez, M.D., clinical assistant professor of pediatrics and communicable diseases; Philip A. Wahr, Ph.D., assistant research scientist; graduate students Daniel E. Michele and Christiana DelloRusso; and research associates Immanuel I. Turner, Katie E. Hong and Faris P. Albayya.
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