Researchers at Penn Medicine have made a major advance in understanding the biology of a common, puzzling, and often fatal heart disorder, dilated cardiomyopathy (DCM), which features the enlargement of the heart and a progressive decrease in its function, for reasons other than cardiovascular disease. DCM is estimated to affect at least hundreds of thousands of people in the United States. The largest single known cause, accounting for an estimated 10-20% of cases, involves the mutation of the gene that encodes a key heart-muscle protein called titin.
Titin (pronounced “titan”) is a giant among proteins, and unfortunately its enormity has made it hard to study. How titin mutations lead to DCM has therefore been largely a mystery. But the Penn Medicine researchers, who report their findings in Science Translational Medicine, used an array of sophisticated methods to overcome the usual technical hurdles. They find that titin mutations in DCM patients lead to two key abnormalities in heart muscle cells: a shortage of normal-length titin, and the accumulation of mutant, truncated titin fragments—pointing to the possibility that both of these abnormalities drive heart dysfunction in DCM.
“These findings change how we look at this genetic form of DCM and give us new directions to pursue for possible future therapies,” says study co-senior author Zoltan Arany, Samuel Bellet Professor of Cardiology at the Perelman School of Medicine. Arany’s co-senior author is Benjamin L. Prosser, an associate professor of physiology.
There is a strong need for a disease-specific treatment for DCM, since the disorder is both common and lethal. It often leads, within a few years, to heart failure, and only about half of DCM patients live five years after their diagnosis. Many who survive do so by receiving heart transplants.
Read more at Penn Medicine News.
