Genetic 'Missing Link' Sheds Light On Sudden Cardiac Death

Findings are reported in the Nov. 21 print edition of the journal Circulation, a publication of the American Heart Association. The journal has posted the findings online.

Electrical impulses originate in the top of the heart's right atrium and travel through the muscle fibers, causing the heart to contract. The genetic and molecular basis of sudden cardiac arrest, which occurs when these impulses are disrupted, is not well understood.

Study investigators began to close this gap of understanding by becoming the first to isolate a gene called Caveolin-3, which influences the electrical-muscular impulses that drive the heart's rhythm. A mutation of the gene can trigger arrhythmia associated with long QT syndrome, a hereditary disorder that can occur in otherwise-healthy people of all ages, and increases the risk of sudden cardiac death.

"This is part of a totally new concept in which the structural part of the heart is intertwined and connected with the electrical part," said first author Dr. Matteo Vatta, assistant professor of pediatrics at BCM and pediatric cardiac researcher at Texas Children's Hospital. "This is the missing link between the heart's electrical and muscular activities."

Vatta says that conventional treatments for long QT syndrome have targeted ion channels, or proteins that govern membrane structure, rather than proteins that regulate the heart's electrical impulses through these channels.

"Many people that have arrhythmia abnormalities take medications that do not work," said Vatta. "Perhaps they should target the other proteins that are modulating the ion channels rather than the ion channel itself."

The effect of the mutation may also be enhanced by medications for unrelated conditions, such as asthma, increasing the risk of cardiac arrhythmia.

Caveolin-3 regulates the cardiac sodium channel, an important protein that can cause rapid structural changes in the heart in response to fluctuations in the electrical field. Heart muscle disease can also disrupt caveolin-3.

Muscle diseases called cardiomyopathies are the leading cause of sudden cardiac death, of which there are more than 300,000 cases every year in the United States. Electrical abnormality in the heart is the leading cause of sudden cardiac death in the absence of muscle disease.

The study, funded by the National Institutes of Health, reviewed 905 cases of patients of all ages with long QT syndrome. Dr. Jeffery Towbin, professor of pediatrics at BCM and chief of pediatric cardiology at Texas Children's Hospital, served as senior author.

The study was also conducted at the Mayo Clinic in Rochester, Maryland and at the University of Wisconsin.